Studies on the synthesis of valienamine and 1-epi-valienamine starting from d-glucose or l-sorbose

Available online at www.sciencedirect.com

Carbohydrate Research 343 (2008) 1675–1692

Studies on the synthesis of valienamine and 1-epi-valienamine

starting from ^D-glucose or L-sorbose

Ian Cumpstey,^*Sebastian Gehrke, Sayeh Erfan and Riccardo Cribiu

Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden

Received 5 February 2008; received in revised form 2 April 2008; accepted 5 April 2008

Available online 10 April 2008

Abstract—Two synthetic routes to a carbocyclic precursor to valienamine are reported, starting from either D-glucose or L-sorbose

and using ring-closing metathesis as a key step. A low-yielding synthesis of 1-epi-valienamine is reported. Results from an abortive

third possible route to valienamine based on an early introduction of nitrogen are discussed.

Keywords: Valienamine; Ring-closing metathesis; L-Sorbose

1. Introduction

5a

6

a

b _HO

NH₂

OH

1

NH₂

OH

HO

5

Valienamine 1 is a highly functionalised cyclohexene

that is found in nature as a substructure of acarbose

or the validamycin family of antibiotics,¹where it is cou-

pled to carbohydrates or other carbohydrate-like spe-

cies, and that can be considered to be a carbasugar

(Fig. 1).²Valienamine shares its stereochemistry at C-

1–C-4 with a-glucose, and has been shown to act as

an a-glucosidase inhibitor.¹Pseudooligosaccharides

containing a valienamine unit are linked by a bridging

amine rather than by an acetal, so they are hydrolyti-

cally stable and may bind to glycoprocessing enzymes

without the risk of hydrolysis, and natural and unnatu-

ral compounds containing a valienamine moiety have

been found to have interesting biological properties.³

We became interested in synthesising valienamine as

part of our ongoing interest in the synthesis of oligosac-

charide mimics.^4–6We needed a route to large quantities

2

4

HO

3

OH

2

OH

1

HO

O

c

HO

O

HO

N

H

OH

OH HO

OH

HO

OH

HO

OH

Figure 1. (a) Valienamine; (b) 1-epi-valienamine; (c) acarbose, a

naturally occurring valienamine-containing pseudotetrasaccharide.

of the unsaturated carbasugar or a suitable precursor. In

this article, we report our results on the synthesis of a

valienamine precursor 19 and also 1-epi-valienamine 2

(resembling b-glucose), starting from cheap carbohy-

drate starting materials, i.e. ^D-glucose or L-sorbose.

Various syntheses of valienamine have been reported,¹

including one by Vasella⁷where the carbocyclic ring was

closed using a metathesis reaction. In this case, the C@C

bond is not in the right position for valienamine, and an

isomerisation is necessary. Since many papers using ring-

closing metathesis of carbohydrate-derived substrates

have been published,⁸we decided to investigate a metath-

esis-based route to a cyclohexene derivative with the

*

Corresponding author. Tel.: +46 (0) 8 16 24 79; fax: +46 (0) 8 15 49

08; e-mail: cumpstey@organ.su.se

Throughout this paper, carbocyclic derivatives are numbered as

carbasugars formally derived from glucose (as shown in Fig. 1).

Cyclic glucose and sorbose derivatives are numbered as the parent

carbohydrates, while open-chain forms are numbered as shown in

Scheme 1 (i.e., with a change in numbering on ring-opening of

glucose, e.g., 3?4, but not of sorbose, e.g., 32?39).

doi:10.1016/j.carres.2008.04.010

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I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

C@C bond in the correct position for valienamine.⁹

Other groups have published similar metathesis ap-

proaches to C-5@C-5a unsaturated six-membered ring

carbasugars starting from the respective aldoses.^10–12

of 4 as the major product can be rationalised by using

a 1,2-chelate model;^15,16however, variation in stereose-

lectivity between many similar reported additions to car-

bohydrate aldehydes or hemiacetals, for example, a

dependence of stereoselectivity on protecting groups¹⁷

or on the stereochemistry of substituents remote from

the reaction centre,¹⁸suggests that a model to reliably

account for observed selectivities must be rather more

complex, as has been noted.¹⁷

2. Results and discussion

Our ﬁrst approach began from 2,3,4,6-tetra-O-benzyl

glucose 3, with the plan to introduce the two C@C

bonds necessary for metathesis by vinyl Grignard addi-

tion to an aldehyde and Wittig methylenation of a ke-

tone. Treatment of 3 with vinylmagnesium bromide

gave the alkene diols 4 (65%) and 5 (29%) (Scheme 1;

the stereochemistry of the products was assigned later,

after ring closure). It has been shown in related systems

that changing the solvent or counter-ion, or adding salts

(e.g., MgBr₂) can eﬀect signiﬁcant changes in the stere-

oselectivity of Grignard addition.^13,14However, for the

formation of 4 and 5 from 3, we were unable to ﬁnd con-

ditions to improve the stereoselectivity for the formation

of 4: using THF–Et₂O 1:1 as solvent gave virtually no

change in yield or selectivity; using vinylmagnesium

chloride in toluene–THF, 10:1 gave lower stereoselectiv-

ity and yield (4, 45%; 5, 33%); using a MgBr₂ꢀOEt₂

(3 equiv) additive (vinylmagnesium bromide (5 equiv)

in THF), resulted in slightly lower stereoselectivity and

lower reaction yield (4, 41%; 5, 21%). The formation

There is some precedent in the literature for the selec-

tive protection of allylic secondary alcohols over non-

allylic secondary alcohols,^19–21and also for the propar-

gylic case.^22,23However, when we attempted to selec-

tively protect the allylic alcohol of 4, we failed to get

good regioselectivity in favour of the allylic alcohol.

Our results are summarised in Table 1. In all cases,

the other major reaction components were either unre-

acted starting diol or diprotected compound. Rather

good selectivity was found in the alkylation reaction

with dimethoxybenzyl chloride,²⁴but this alkylation

was selective for the non-allylic secondary alcohol (Ta-

ble 1, entry 4); regioisomers 6a (R = DMB, R⁰= H)

and 6b (R = H, R⁰= DMB) were inseparable by column

chromatography. We decided nevertheless to proceed

with this mixture 6a/b and use a protection-deprotection

strategy to gain access to the required molecule with

OH-2 free. In contrast, for the epimer 5, treatment with

dimethoxybenzyl chloride and sodium hydride in DMF

RO OR'

HO OH

7

1

BnO

6

2

8

BnO

5

OBn

(ii)

3

BnO

4

OBn

6a R = DMB, R' = H

6b R = H, R' = DMB

or R, R' = Piv, Bz

O

OH

BnO

(i)

4

OBn

+

OBn

RO OR'

3

HO OH

BnO

(ii)

OBn

7a R = DMB, R' = H

7b R = H, R' = DMB

5

Scheme 1. Reagents and conditions: (i) Vinylmagnesium bromide, THF, 0 °C?rt; 4, 65%; 5, 29%; (ii) see Table 1.

Table 1. Attempted regioselective protection

Entry Starting material Conditions

X

Ratio (R = H, R⁰= X)/(R = X, R⁰= H) Yield

1

2

3

4

5

4

5

BzCl, py

Bz

75:25

25:75

50:50

9:91

29%

43%

27%

BzCl, Bu₄NI, NaOH, H₂O, CH₂Cl₂Bz

PivCl, py

DMBCl, NaH, DMF, 0 °C

Piv

DMB

DMB 65:35

55% (6a/b)^a

33% (7b) + 18% (7a)^b

DMB = 3,4-dimethoxybenzyl.

^aDisubstituted compound (R = R⁰= DMB), 26% was also isolated.

^bDisubstituted compound (R = R⁰= DMB), 9% was also isolated.

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

1677

resulted in the selective protection of the allylic alcohol

OH-6, albeit with a lower selectivity (Table 1, entry 5).

In this case, though the regioisomers 7a (R = DMB,

R⁰= H) and 7b (R = H, R⁰= DMB) could be partially

separated by column chromatography.

The inseparable mixture of selectively protected alco-

hols (6a:6b, 10:1) was treated with pivalyl chloride and

pyridine to form pivalate esters at the remaining free

OH groups, and the DMB ethers were then removed

(Scheme 2). The free alcohols 9a,b were oxidised under

Swern conditions to give the ketones 10 and 11, which

could be separated by column chromatography. Ketone

10 was methylenated by treatment with a phosphonium

ylid to give the diene 12.

Having selectively protected the epimeric diol 5 (the

minor diastereomer from Grignard addition), the free

alcohol 7b was subjected to the same Swern conditions,

however, this failed to give the ketone product and only

unreacted starting material could be recovered from the

reaction mixture. Oxidation with PCC was more suc-

cessful and gave ketone 13 in good yield (Scheme 3).

Wittig methylenation of this ketone gave diene 14.

Our attention then turned to the metathesis reaction.

Treatment of diene 12 with Grubbs’ second generation

catalyst (10%) gave the ring-closed carbocycle 15 after

a rather long reaction time in reasonable yield (Scheme

2). Starting material still remained and addition of fur-

ther catalyst did not induce further progress. Under

the same conditions, 14 gave the ring-closed product

16 in a rather lower yield. We deprotected 12 and 14

to give C-6-epimeric allylic alcohols 17 and 18, respec-

tively. Metathesis of these two dienes 17 and 18 now

proceeded quickly and with a lower catalyst loading to

give the respective carbocycles 19 and 20 in good yield.

Deprotected carbocycles 19 and 20 could also be ac-

cessed by deprotection after metathesis of 15 and 16,

respectively. The stereochemistry at C-1 could now be

assigned using coupling constants in the ¹H NMR

spectra.²⁵

To complete the synthesis of valienamine and 1-epi-

valienamine, it was necessary to introduce nitrogen at

C-1 and deprotect the resulting molecules.²⁶We ﬁrst

considered an alternative strategy based on Grignard

addition to a glycosylamine (a hemiaminal): the result-

ing amino alcohol would not have the same problems

of regioselective protection as diols 4 and 5, and further-

more, the extra steps to introduce nitrogen after ring

closure may be avoided.

Thus, the benzyl-protected glucose hemiacetal 3 was

treated with benzylamine to give the glycosylamine 21

(Scheme 4).^27–29This was treated with vinylmagnesium

bromide and the amino alcohols 22 were formed as a

mixture of diastereomers (ratio ca. 2:1). Boc protection

of the amine 22 was followed by oxidation of OH-2

and Wittig methylenation to give diene 25. How-

ever, treatment of this diene 25 with Grubbs’ second

RO OR'

BnO

PivO

O

OPiv

BnO

OBn

BnO

(iii)

OBn

+

OBn

10

6a R = DMB, R' = H

6b R = H, R' = DMB

11

(i)

8a R = DMB, R' = Piv

8b R = Piv, R' = DMB

(ii)

(iv)

9a R = H, R' = Piv

9b R = Piv, R' = H

OPiv

OBn

BnO

OPiv

(viii)

(vii)

(v)

OBn

OH

BnO

15

OBn

12

OBn

19

(vi)

OH

BnO

OBn

17

Scheme 2. Reagents and conditions: (i) PivCl (4 equiv), DMAP (0.5 equiv), pyridine, 96%; (ii) CAN (3 ꢁ 1 equiv), MeCN, H₂O, 88%; (iii) (COCl)₂

(2.2 equiv), Me₂SO (4.4 equiv), CH₂Cl₂; then Et₃N (5 equiv), 83%; (iv) PPh₃CH₃Br (5 equiv), t-BuOK (4.8 equiv), toluene, 80 °C; then 12, rt, 85%; (v)

Grubbs’ second generation catalyst (0.1 equiv), toluene, 60 °C, 24 h, 62%; (vi) NaOMe (3 equiv), MeOH, 45 °C, 48 h, 89%; (vii) Grubbs’ second

generation catalyst (0.015 equiv), toluene, 60 °C, 3 h, 89%; (viii) NaOMe, MeOH, 45 °C, 48 h, 88%.

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I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

HO ODMB

O

ODMB

BnO

(i)

OBn

7b

13

(ii)

ODMB

OBn

BnO

(iii)

(vi)

ODMB

OBn

OH

16

BnO

OBn

14

OBn

OH

(iv)

(v)

20

BnO

OBn

18

˚

Scheme 3. Reagents and conditions: (i) PCC (3.9 equiv), NaOAc (1.3 equiv), 4 A, CH₂Cl₂, 82%; (ii) PPh₃CH₃Br (5 equiv), t-BuOK (4.8 equiv),

toluene, 80 °C; then 13, rt, 88%; (iii) Grubbs’ second generation catalyst (0.08 equiv), DCE, 60 °C, 48 h, 54%; (iv) DDQ (1.2 equiv), CH₂Cl₂, H₂O,

0 °C, 1 h 20 min, 75%; (v) Grubbs’ second generation catalyst (0.01 equiv), toluene, 60 °C, 3 h, 90%; (vi) CAN (3 ꢁ 1.1 equiv), MeCN, H₂O, rt, 2 h

30 min, 74%.

HO NHBn

2

O

OH

O

NHBn

OBn

7

1

BnO

6

8

BnO

5

(i)

(ii)

3

OBn

4

OBn

3

21

22

(iii) or (iv)

NXBn

O

NXBn

HO NXBn

(vii) or (viii)

BnO

(v) or (vi)

BnO

OBn

25: X = Boc

28: X = Ts

24: X = Boc

27: X = Ts

23: X = Boc

26: X = Ts

˚

Scheme 4. Reagents and conditions: (i) BnNH₂, CH₂Cl₂, 4 A, CSA, 4 weeks, 69%; (ii) vinylmagnesium bromide (4 equiv), THF, 0 °C?rt, 42%; (iii)

Boc₂O (2.5 equiv), CH₂Cl₂, rt, 48 h, 23, 88%; (iv) TsCl (1 equiv), Et₃N (1.1 equiv), CH₂Cl₂, 0 °C?rt, 40 h, 26, 48%; (v) (COCl)₂, Me₂SO, CH₂Cl₂

˚

ꢂ60 °C, then Et₃N, rt, 24, 69%; (vi) PCC (4 ꢁ 1.3 equiv), NaOAc (1.3 equiv), 4 A, CH₂Cl₂, rt, 27, 83%; (vii) Ph₃PMeBr (2 equiv), NaN(SiMe₃)₂

(1.6 equiv), ꢂ78 °C, 25, 68%; (viii) PPh₃CH₃Br (1 equiv), t-BuOK (0.95 equiv), toluene, 90 °C then 27, rt, 28, 95%.

generation catalyst gave no reaction; only unreacted

starting material was seen in the NMR spectrum of

the crude reaction product. We tried also with the amine

protected as its sulfonamide.³⁰Thus, amino alcohol 22

was protected on nitrogen with tosyl chloride. Interest-

ingly, one diastereomer of the starting material was

much more reactive than the other, and it was possible

to obtain a single diastereomer of the sulfonamide prod-

uct 26 completely pure (according to NMR spectros-

copy). Oxidation of OH-2 and Wittig methylenation of

the resulting ketone gave the diene 28. However, once

again, Grubbs’ second generation catalyst completely

failed to give any product, and only starting material

could be seen. The results from all our attempted

metathesis reactions suggest that the nature of the sub-

stituent at the allylic position of one of the double bonds

can have a profound eﬀect on the outcome of the reac-

tion, and are consistent with a steric explanation, i.e.

that it is the increase in size of the allylic substituent

along the sequence: alcohol 17 or 18 < ester 12 or ether

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

1679

der Birch conditions to give 1-epi-valienamine

2

O

(Scheme 5).³⁵

OH

N

In a ﬁnal, alternative, and ultimately most successful

route to 19 and 20, we decided to abandon glucose as

starting material and instead use the unnatural ketose

L-sorbose. D-Glucose is related to L-sorbose by formal

reduction at C-1 and oxidation at C-5 (glucose number-

ing). As it was necessary to oxidise glucose at C-5 during

our synthetic sequences described above, starting with

this already oxidised ketose with a lack of stereochemi-

cal information at C-5 does not detract from the work.

Moreover, ^L-sorbose is a very cheap starting material

due to its being an intermediate in the industrial synthe-

sis of vitamin C from glucose.³⁶It has been used before

both as a starting material for the synthesis of modiﬁed

carbohydrates³⁷and in the synthesis of eﬀective

organocatalysts.³⁸

Hemiketal 32 is readily produced in three steps from

L-sorbose 31 in excellent yield according to a slightly

modiﬁed literature procedure (see Supplementary

data).³⁹Wittig reaction on hemiketal 32 would install

the methylene group at C-2, and free OH-6 for oxidation

to the aldehyde which could then undergo Grignard at-

tack to give the same diene metathesis precursor (17 or

18) as we synthesised earlier. Unfortunately, when hem-

iketal 32 was treated with the ylid generated from t-

BuOK and Ph₃PMeBr, elimination dominated and none

of the desired product 37 could be detected.

One solution to this was as follows: reduction of hem-

iketal 32 gave a mixture of diols 33 (Scheme 6). The pri-

mary alcohols could be selectively protected as their

trityl ethers, and the secondary alcohols could be reoxi-

dised to restore the ketone as described.³⁹This ketone 35

underwent clean Wittig methylenation, and detritylation

of the primary alcohol gave the desired compound 37.

However, despite high yielding reactions and a lack of

selectivity problems, this route was rather long-winded,

adding an extra four steps to the ideal, if unattainable,

reaction sequence.

BnO

(i)

O

OBn

20

OBn

29

(ii)

NH₂

OH

NH₂

OBn

HO

BnO

(iii)

OH

2

OBn

30

Scheme 5. Reagents and conditions: (i) Phthalimide (2 equiv), DIAD

(8 equiv), PPh₃(8 equiv), THF, 81%; (ii) Ethylene diamine, EtOH;

1:10, 89%; (iii) Na, NH₃, THF, ꢂ78 °C, 78%.

14 < doubly protected nitrogen 25 or 28 that is respon-

sible for a decrease in reaction rate. However, they do

not rule out alternative explanations based on the diﬀer-

ent reactivities of hydroxyl groups, esters, ethers, sulfon-

amides and carbamates towards the ruthenium catalyst.

The eﬀect of the stereochemistry and protecting group

of an allylic substituent on the outcome of a metathesis

reaction has been noted before. In some cases, having a

free allylic hydroxyl was necessary for successful metath-

esis,³¹while for other examples, the yield of metathesis

product is higher with a protected allylic hydroxyl (often

with a smaller protecting group such as acetate) than

with a free allylic alcohol.^32,33It may be so that for

our compounds 17 and 18, potential side-reactions aris-

ing from the free hydroxyl groups are minimal, and that

any beneﬁt of running the metathesis reaction with pro-

tected hydroxyl groups is lost due to the steric crowding

arising from the larger protecting groups in 12 or 14. A

related strategy towards the synthesis of Calystegine B₂

should be mentioned: a synthetic route based on ring-

closing metathesis with a doubly protected nitrogen

(NBnCbz) at the allylic position failed to give useful

yields of the 7-ring carbocycle,³³a failure ascribed to

the steric bulk of the nitrogen group, whereas a metath-

esis reaction with a doubly protected nitrogen (NBnCbz)

at the homoallylic position gave the 7-ring carbocycle in

excellent yield.^33,34

As the Wittig reaction worked so well on the C-6-pro-

tected ketone 35, we wondered whether it would be pos-

sible to access such

a compound directly from

hemiacetal 32, rather than going through the tedious

reduction–oxidation procedure. We found that acyla-

tion of the hemiacetal with either pivalyl chloride or

benzoyl chloride resulted in the exclusive high yielding

formation of the OH-6 protected ketones 38 or 39,

respectively (Scheme 7). These ketones 38 and 39 under-

went Wittig reaction to give the respective alkenes 40

and 41 with no elimination seen. In the case of the ben-

zoate-protected compound 41, however, some cleavage

of the ester was seen (presumably occurring after meth-

ylenation), resulting in the formation of the free C-6

alcohol 37.

In any case, we abandoned this approach and re-

turned to our original strategy. Key intermediate 19

could be converted to valienamine 1 following Fukase’s

procedure.²⁶The route to 1-epi-valienamine 2 from 20

followed an analogous route: nitrogen was introduced

at C-1 of 20 with inversion of conﬁguration by Mitsun-

obu reaction of the allylic alcohol with phthalimide.

Deprotection of phthalimide 29 using ethylene diamine

gave the free amine 30, which was then deprotected un-

We decided to pursue the benzoate route, due to the

ease of deprotection, which was the next reaction step.

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I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

HO

OH OH

OH OTr

OBn

34

O

BnO

(i)

(ii)

OBn

33

BnO

OBn

32

(iii)

OH

OTr

O

OTr

BnO

(iv)

(v)

OBn

BnO

OBn

37

36

35

Scheme 6. Reagents and conditions: (i) NaBH₄(3 equiv), MeOH, 0 °C?rt, 3 h, 85%; (ii) TrCl (1.5 equiv), DMAP (0.03 equiv), pyridine, 80 °C, 69%;

˚

(iii) PDC (7 equiv), 4 A, CH₂Cl₂, rt, 22 h, 92%; (iv) PPh₃CH₃Br (6 equiv), t-BuOK (5.8 equiv), toluene, 80 °C then 37, rt, >99%; HCOOH, Et₂O, rt,

2 h, 66%.

OR

HO

BnO

O

OR

O

BnO

(i) or (ii)

(iii) or (iv)

BnO

OBn

BnO

OBn

BnO

OBn

32

40: R = Piv

41: R = Bz

37: R = H

38: R = Piv

39: R = Bz

(v)

OH

BnO

OBn

19

O

OBn

OH

BnO

(vii)

(vi)

BnO

OBn

OH

BnO

OBn

42

OBn

17+18

OBn

20

Scheme 7. Reagents and conditions: (i) PivCl (5 equiv), pyridine, 60 °C, 17 h, 38, 83%; (ii) BzCl (3 equiv), pyridine, rt, 15 h, 39, 85%; (iii) t-BuOK

(4.8 equiv), Ph₃PMeBr (5 equiv), toluene, 80 °C; then 38, rt; 40, 91%; (iv) t-BuOK (2.4 equiv), Ph₃PMeBr (2.5 equiv), toluene, 80 °C; then 39,

0 °C?rt; then NaOMe (1 equiv), MeOH; 37, 92%; (v) (COCl)₂(2.2 equiv), Me₂SO (4.4 equiv), CH₂Cl₂, ꢂ60 °C; then Et₃N (5 equiv), ꢂ60 °C?rt; (vi)

vinylmagnesium bromide (2 equiv), THF, 0 °C?rt, (17:18, 2:1) 79% from 37; (vii) Grubbs’ second generation catalyst (3 ꢁ 0.01 equiv), toluene,

60 °C, 19 h; 19, 53%; 20, 21%.

Our best procedure for the Wittig reaction–deprotec-

tion, then, was to take the benzoate-protected ketone

39 and methylenate under standard Wittig conditions.

Following complete conversion of the ketone to a mix-

ture of the benzoate-protected 41 and free alcohol 37

oleﬁnated compounds, the mixture was ﬁltered and a so-

dium methoxide solution added, which eﬀected cleavage

of any remaining benzoate protection. The free alcohol

37 could in this way be isolated in good yield over two

steps.

diastereomers were not separated at this stage, but

underwent ring-closing metathesis mediated by Grubbs’

second generation catalyst to give the cyclohexenes 19

and 20, which could now be separated by column

chromatography.

2.1. Conclusions

An advanced precursor to valienamine has been syn-

thesised starting from ^D-glucose and from L-sorbose.

The sorbose route is the shorter and more eﬃcient, giv-

ing the Fukase intermediate 19 in eight steps from sor-

bose, and in 30% overall yield; it relies on a reaction

in which a hemiketal is forced open by acyl protection,

Oxidation of the primary alcohol in 37 under Swern

conditions gave the aldehyde 42, which was not isolated,

but treated directly with vinylmagnesium bromide to

give the dienes 17 and 18 as an epimeric mixture. The

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

1681

exposing the naked carbonyl group, which was more

amenable to Wittig methylenation than the original

hemiketal. The behaviour of some carbohydrate deriva-

tives diﬀering only in the substituent at one allylic posi-

tion in the ring-closing metathesis reaction is compared:

their reactivity followed a trend that could be explained

on steric grounds, with compounds bearing an allylic

alcohol reacting fastest, and those with a doubly pro-

tected nitrogen completely unreactive. However, an

alternative electronic explanation cannot be ruled out.

The minor diastereomer from Grignard addition was

converted into 1-epi-valienamine 2.

3.2. (2R,3R,4R,5S,6R)-1,3,4,5-Tetra-O-benzyl-oct-7-ene-

1,2,3,4,5,6-hexaol (4) and (2R,3R,4R,5S,6S)-1,3,4,5-

tetra-O-benzyl-oct-7-ene-1,2,3,4,5,6-hexaol (5)

Hemiacetal 3 (3.1 g, 5.6 mmol) was suspended in THF

(10 mL) and cooled to 0 °C under N₂. Vinylmagnesium

bromide (22 mL, 1 M in THF, 22 mmol) was added and

the resulting solution stirred. After 22 h, NH₄Cl (satd

aq) was added dropwise. The mixture was diluted with

EtOAc (100 mL) and washed with brine (100 mL). The

organic phase was dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The residue was puriﬁed by ﬂash col-

umn chromatography (CH₂Cl₂–Et₂O 12:1?5:1) to give

one diastereoisomer 5 (932 mg, 29%) as a pale yellow

21

3. Experimental

oil. ½aꢃ_D+1.5 (c 1.0, CHCl₃); IR (ﬁlm); m 3460 (OH)

cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): 3.60 (1H, dd,

0

3.1. General methods

J_1,2= 4.9 Hz, J_1;1¼ 10:0 Hz, H-1), 3.62 (1H, dd,

J_{1 ;2}¼ 3:8 Hz, H-1⁰), 3.70 (1H, dd, J_5,6= 5.2 Hz,

0

Melting points were measured using a Gallenkamp melt-

ing point apparatus and are uncorrected. Proton nuclear

magnetic resonance (¹H) spectra were recorded on Bru-

ker Avance II 400 (400 MHz), Varian 300 (300 MHz) or

Varian Mercury 400 (400 MHz) spectrometers; multi-

plicities are quoted as singlet (s), doublet (d), doublet

of doublets (dd), triplet (t), apparent triplet (at) or

apparent triplet of doublets (atd). Carbon nuclear mag-

netic resonance (¹³C) spectra were recorded on Bruker

Avance II 400 (100 MHz), Varian Mercury 300

(75 MHz) or Varian Mercury 400 (100 MHz) spectro-

meters. Spectra were assigned using COSY, HSQC and

DEPT experiments. All chemical shifts are quoted on

the d-scale in parts per million (ppm). Residual solvent

signals were used as an internal reference. NMR spectra

of the di-N-substituted carbamates showed a mixture of

two rotamers and two diastereomers, and therefore

assignments are not reported. Low- (ESI⁺) and high-re-

solution electrospray mass spectra were recorded using a

Bruker Microtof instrument or at the mass spectrometry

unit, Universidad de Santiago de Compostela, Spain.

MALDI spectra were recorded on a Bruker Biﬂex III

spectrometer using 2⁰,4⁰,6⁰-trihydroxyacetophenone tri-

hydrate (THAP) as matrix. Optical rotations were mea-

sured on a Perkin–Elmer 241 polarimeter with a path

length of 1 dm; concentrations are given in g/100 mL.

Thin layer chromatography (TLC) was carried out on

Merck Kieselgel sheets, pre-coated with 60F₂₅₄silica.

Plates were visualised with UV light and developed

using 10% sulfuric acid, or an ammonium molybdate

(10% w/v) and cerium (IV) sulfate (2% w/v) solution

in 10% sulfuric acid. Flash column chromatography

was carried out on silica gel (35–70 lm, Grace). CH₂Cl₂

was distilled from calcium hydride. Et₂O and THF were

distilled from sodium benzophenone ketyl radical. Tolu-

ene was distilled from sodium. Reactions performed un-

der an atmosphere of nitrogen or argon were maintained

by an inﬂated balloon.

J_4,5= 4.2 Hz, H-5), 3.83 (1H, dd, J_3,4= 4.3 Hz,

J_2,3= 7.0 Hz, H-3), 3.91 (1H, at, J = 4.3 Hz, H-4),

4.00 (1H, m, H-2), 4.40 (1H, atat, J = 5.2 Hz,

J = 1.6 Hz, H-6), 4.50, 4.56 (2H, ABq, J_AB= 11.9 Hz,

PhCH₂), 4.57 (2H, s, PhCH₂), 4.61, 4.70 (2H, ABq,

J_AB= 11.2 Hz, PhCH₂), 4.62, 4.67 (2H, ABq,

J_AB= 11.7 Hz, PhCH₂), 5.20 (1H, dat, J_cis= 10.4 Hz,

J = 1.6 Hz, H-8_cis), 5.34 (1H, dat, J_trans= 17.2 Hz,

J = 1.6 Hz, H-8_trans), 5.84 (1H, ddd, J_6,7= 5.4 Hz, H-

7), 7.21–7.37 (20H, m, Ar-H); ¹³C NMR (100 MHz,

CDCl₃): 71.2, 73.2, 73.6, 74.0 (4 ꢁ t, C-1, 4 ꢁ PhCH₂),

71.3, 72.4, 77.0, 78.8, 79.7 (5 ꢁ d, C-2, C-3, C-4, C-5,

C-6), 116.5 (t, C-8), 127.9, 128.0, 128.0, 128.0, 128.1,

128.1, 128.2, 128.3, 128.5, 128.6, 128.7 (11 ꢁ d, Bn–

CH), 137.6, 138.0, 138.0, 138.2 (4 ꢁ s, 4 ꢁ Bn–C),

137.6 (d, C-7). MALDI m/z 607 [M+K]⁺, 591

[M+Na]⁺. ESIMS m/z: [M+Na]⁺calcd for

C₃₆H₄₀O₆Na, 591.2717; found, 591.2734.

And its epimer 4 (2.09 g, 65%) as a pale yellow oil,

which solidiﬁed on standing. Recrystallisation was diﬃ-

cult, but gave some white crystals, mp 143–145 °C

21

(MeOH); ½aꢃ_D+11.6 (c 1.0, CHCl₃); IR (ﬁlm); m 3453

(OH) cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): 3.64 (1H,

0

dd, J_1,2= 5.0 Hz, J_1;1¼ 9:8 Hz, H-1), 3.67 (1H, dd,

J_{1 ;2}¼ 3:8 Hz, H-1⁰), 3.77–3.80 (2H, m, H-3, H-5), 4.00

0

(1H, dd, J = 3.4 Hz, J = 7.4 Hz, H-4), 4.08 (1H, m,

J_2,3= 7.0 Hz, H-2), 4.17 (1H, m, H-6), 4.52, 4.57 (2H,

ABq, J_AB= 12.0 Hz, PhCH₂), 4.54, 4.60 (2H, ABq,

J_AB= 11.5 Hz, PhCH₂), 4.62, 4.77 (2H, ABq,

J_AB= 11.1 Hz, PhCH₂), 4.64, 4.74 (2H, ABq,

J_AB= 11.2 Hz, PhCH₂), 5.13 (1H, dat, J_cis= 10.6 Hz,

J = 1.5 Hz, H-8_cis), 5.26 (1H, dat, J_trans= 17.2 Hz,

J = 1.5 Hz, H-8_trans), 5.80 (1H, ddd, J_6,7= 4.9 Hz, H-

7), 7.23–7.38 (20H, m, Ar-H); ¹³C NMR (100 MHz,

CDCl₃): 70.9, 72.3, 77.5, 79.4, 81.7 (5 ꢁ d, C-2, C-3,

C-4, C-5, C-6), 71.4, 73.2, 73.6, 75.0, 75.2 (5 ꢁ t, C-1,

4 ꢁ PhCH₂), 115.6 (t, C-8), 127.9, 128.0, 128.1, 128.3,

128.4, 128.5, 128.5, 128.6, 128.6 (9 ꢁ d, Bn–CH),

1682

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

137.9, 138.1, 138.3 (3 ꢁ s, 4 ꢁ Bn–C), 136.8 (d, C-7).

MALDI m/z 607 [M+K]⁺, 591 [M+Na]⁺. ESIMS m/z:

[M+Na]⁺calcd for C₃₆H₄₀O₆Na, 591.2717; found,

591.2746.

J = 11.0 Hz, ArCHH⁰), 4.71 (1H, d, J = 11.5 Hz, ArCH-

H⁰), 4.76 (1H, d, J = 11.5 Hz, ArCHH⁰), 5.09 (1H, dat,

J_cis= 10.4 Hz, J = 1.5 Hz, H-8_cis), 5.22 (1H, dat,

J_trans= 17.3 Hz, J = 1.6 Hz, H-8_trans), 5.71 (1H, ddd,

J_6,7= 5.0 Hz, H-7), 6.77 (1H, d, J = 8.1 Hz, DMB–H),

6.82 (1H, dd, J = 1.6 Hz, J = 8.1 Hz, DMB–H), 6.87

(1H, d, J = 1.6 Hz, DMB–H), 7.23–7.34 (20H, m, Ar-

H). MALDI m/z 757 [M+K]⁺, 741 [M+Na]⁺. ESIMS

m/z: [M+Na]⁺calcd for C₄₅H₅₀O₈Na, 741.3398; found,

741.3385.

3.3. (2R,3S,4R,5S,6R)-1,3,4,5-Tetra-O-benzyl-2-O-(3,4-

dimethoxybenzyl)-oct-7-ene-1,2,3,4,5,6-hexaol (6a),

(2R,3R,4S,5R,6R)-1,3,4,5-tetra-O-benzyl-6-O-(3,4-dime-

thoxybenzyl)-oct-7-ene-1,2,3,4,5,6-hexaol (6b) and

(2R,3S,4R,5R,6R)-1,3,4,5-tetra-O-benzyl-2,6-bis-O-(3,4-

dimethoxybenzyl)-oct-7-ene-1,2,3,4,5,6-hexaol

And recovered starting material 4 (261 mg, 17%), as a

colourless oil.

Diol 4 (1.50 g, 2.64 mmol) was dissolved in DMF

(20 mL) and cooled to 0 °C under N₂. Dimethoxybenzyl

chloride (516 mg, 2.77 mmol) and NaH (60% in oil,

211 mg, 5.28 mmol) were added, and the mixture was

stirred at 0 °C. After 1 h 30 min, TLC (CH₂Cl₂–Et₂O

19:1) showed the formation of mono- (R_f= 0.4) and

disubstituted (R_f= 0.6) products, along with remaining

starting material (R_f= 0.3). The mixture was diluted

with Et₂O (200 mL), and washed with brine (200 mL).

The aqueous phase was re-extracted with Et₂O

(200 mL), and the combined organic extracts were dried

(Na₂SO₄), ﬁltered and concentrated in vacuo. The resi-

due was puriﬁed by ﬂash column chromatography

(CH₂Cl₂–Et₂O 19:1?9:1) to give the disubstituted com-

3.4. (2R,3S,4S,5R,6R)-1,3,4,5-Tetra-O-benzyl-2-O-(3,4-

dimethoxybenzyl)-6-O-pivalyl-oct-7-ene-1,2,3,4,5,6-hexa-

ol (8a), (2R,3S,4R,5R,6R)-1,3,4,5-tetra-O-benzyl-6-O-

(3,4-dimethoxybenzyl)-2-O-pivalyl-oct-7-ene-1,2,3,4,5,6-

hexaol (8b)

Mixture 6a/b (2.24 g, 3.12 mmol) was dissolved in pyri-

dine. Pivalyl chloride (1.5 mL, 12.5 mmol) and DMAP

(230 mg, 1.6 mmol) were added and the mixture was

stirred at rt. After 22 h, TLC (pentane–EtOAc 3:1)

showed the formation of a major product (R_f= 0.7)

and the complete consumption of starting material

(R_f= 0.2). The mixture was diluted with EtOAc

(200 mL), washed with HCl (1 M, 200 mL), dried

(Na₂SO₄), ﬁltered and concentrated in vacuo. The resi-

due was puriﬁed by ﬂash column chromatography (pen-

tane–EtOAc 4:1) to give the fully protected compounds

8a/b (2.41 g, 96%) as a colourless oil. MALDI m/z 842

[M+K]⁺, 826 [M+Na]⁺. ESIMS m/z: [M+Na]⁺calcd

for C₅₀H₅₈O₉Na, 825.3973; found, 825.3967.

21

pound (589 mg, 26%) as a colourless oil. ½aꢃ_Dꢂ11.6 (c

1.0, CHCl₃); ¹H NMR (300 MHz, CDCl₃): 3.65–3.94

(6H, m, H-1, H-1⁰, H-2, H-3, H-4, H-5), 3.71, 3.73,

3.83, 3.85 (12H, 4 ꢁ s, 4 ꢁ OCH₃), 4.03 (1H, at,

J = 6.7 Hz, H-6), 4.25 (1H, d, J = 11.3 Hz, ArCHH⁰),

4.40 (1H, d, J = 11.5 Hz, ArCHH⁰), 4.45–4.76 (9H, m,

9 ꢁ benzylic-H), 4.83 (1H, d, J = 11.5 Hz, ArCHH⁰),

5.10 (1H, d, J_trans= 17.3 Hz, H-8_trans), 5.19 (1H, d,

J_cis= 10.2 Hz, H-8_cis), 5.69 (1H, ddd, J_6,7= 7.7 Hz, H-

7), 6.72–6.84 (6H, m, DMB–H), 7.21–7.32 (20H, m,

Bn–H); ¹³C NMR (75 MHz, CDCl₃): 55.8, 55.8, 56.0,

56.0 (4 ꢁ q, 4 ꢁ OCH₃), 70.4, 70.5, 71.9, 73.4, 74.0,

74.7, 74.9 (7 ꢁ t, C-1, 4 ꢁ PhCH₂, 2 ꢁ DMPCH₂),

79.4, 79.4, 79.7, 80.7, 82.2 (5 ꢁ d, C-2, C-3, C-4, C-5,

C-6), 110.9, 111.0, 111.1, 111.7, 120.0, 120.8 (6 ꢁ d,

6 ꢁ DMB–H), 119.0 (t, C-8), 127.3, 127.5, 127.6,

127.8, 128.0, 128.3, 128.3, 128.4 (8 ꢁ d, Bn–CH),

130.8, 131.4 (2 ꢁ s, 2 ꢁ DMB–C), 135.8 (d, C-7),

138.5, 138.9, 139.0, 139.2 (4 ꢁ s, 4 ꢁ Bn–C), 148.4,

148.6, 148.9, 149.0 (4 ꢁ s, DMB–C). MALDI m/z 908

[M+K]⁺, 892 [M+Na]⁺. ESIMS m/z: [M+Na]⁺calcd

for C₅₄H₆₀O₁₀Na, 891.4079; found, 891.4114.

3.5. (2R,3R,4S,5R,6R)-1,3,4,5-Tetra-O-benzyl-6-O-piv-

alyl-oct-7-ene-1,2,3,4,5,6-hexaol (9a), (2R,3S,4R,5S,6R)-

1,3,4,5-tetra-O-benzyl-2-O-pivalyl-oct-7-ene-1,2,3,4,5,6-

hexaol (9b)

Mixture 8a/b (2.41 g, 3.0 mmol) was dissolved in MeCN

(27 mL), and water (3 mL) was added. The mixture was

cooled to 0 °C under N₂. Cerium ammonium nitrate

(3 ꢁ 1.38 g, 3.0 mmol) was added in three portions at

hourly intervals. After the ﬁnal addition, the mixture

was stirred at 0 °C for 1 h, after which time it was re-

moved from the ice-bath and stirred for a further 2 h

at rt. After this time, TLC (pentane–EtOAc 4:1) showed

the formation of a major product (R_f= 0.5) and the

complete consumption of starting material (R_f= 0.4).

The mixture was diluted with CH₂Cl₂(200 mL) and

washed with NH₄Cl (satd aq, 200 mL). The aqueous

phase was re-extracted with CH₂Cl₂(100 mL), and the

combined organic extracts were dried (Na₂SO₄), ﬁltered

and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (pentane–EtOAc 5:1) to

give the deprotected compounds 9a/b (1.73 g, 88%) as

The monoprotected compounds 6a/b (1.04 g, 55%) as

1

a colourless oil (6a:6b ratio ca. 10:1). H NMR data for

6a (300 MHz, CDCl₃): 3.65 (1H, dd, J = 2.9 Hz,

J = 6.4 Hz, H-5), 3.74–3.79 (4H, m, OCH₃), 3.86 (s,

OCH₃), 3.91–3.96 (4H, m), 4.16 (1H, m, H-6), 4.42,

4.60 (2H, ABq, J_AB= 12.1 Hz, ArCH₂), 4.56 (1H, d,

J = 11.3 Hz, ArCHH⁰), 4.62 (1H, d, J = 11.5 Hz, ArCH-

H⁰), 4.64 (1H, d, J = 11.3 Hz, ArCHH⁰), 4.70 (1H, d,

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

1683

a colourless oil. MALDI m/z 691 [M+K]⁺, 675

[M+Na]⁺. ESIMS m/z: [M+Na]⁺calcd for

C₄₁H₄₈O₇Na, 675.3292; found, 675.3312.

ESIMS m/z: [M+Na]⁺calcd for C₄₁H₄₆O₇Na,

673.3136; found, 673.3139.

3.7. (3R,4S,5R,6R)-1,3,4,5-Tetra-O-benzyl-6-O-pivalyl-

2-methylene-oct-7-ene-1,3,4,5,6-pentaol (12)

3.6. (3S,4R,5R,6R)-1,3,4,5-Tetra-O-benzyl-6-O-pivalyl-

1,3,4,5,6-pentahydroxy-oct-7-en-2-one (10)

Methyltriphenylphosphonium

bromide

(3.3 g,

Oxalyl chloride (0.51 mL, 5.83 mmol) was dissolved in

CH₂Cl₂(6 mL) and cooled to ꢂ60 °C. Me₂SO

(0.83 mL, 11.7 mmol) was dissolved in CH₂Cl₂(6 mL)

and added, and the mixture was stirred at ꢂ60 °C. After

30 min, alcohols 9a/b were added by cannula under N₂,

and the mixture was stirred at ꢂ60 °C. After 1 h, Et₃N

(1.84 mL, 13.3 mmol) was added. The mixture was re-

moved from the cooling bath and stirred further at rt.

After 2 h, TLC (pentane–EtOAc 5:1) showed the forma-

tion of major (R_f= 0.4) and minor (R_f= 0.5) products,

and the complete consumption of the starting material

(R_f= 0.3). The mixture was diluted with CH₂Cl₂

(200 mL) and washed with water (200 mL). The aqueous

phase was re-extracted with CH₂Cl₂(100 mL), and the

combined organic extracts were dried (Na₂SO₄), ﬁltered

and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (pentane–EtOAc 6:1) to

give the ketone 10 (1.43 g, 83%) as a colourless oil.

9.23 mmol) and potassium tert-butoxide (984 mg,

8.78 mmol) were suspended in toluene (20 mL) and the

mixture was stirred at 80 °C. After 3 h, the mixture

was removed from the heat bath and allowed to cool

to rt. Ketone 10 (1.20 g, 1.85 mmol) was dissolved in tol-

uene (20 mL) and added by cannula under N₂and the

mixture was stirred at rt. After 2 h, TLC (pentane–

EtOAc 6:1) showed the formation of a major product

(R_f= 0.4), and the complete consumption of starting

material (R_f= 0.3). The mixture was ﬁltered through

Celite and concentrated in vacuo. The residue was puri-

ﬁed by ﬂash column chromatography (pentane–EtOAc

9:1) to give the diene 12 (1.02 g, 85%) as a colourless

21

oil. ½aꢃ_Dꢂ17.9 (c 1.0, CHCl₃); IR (ﬁlm); m 1729 (C@O)

cm^ꢂ1

;

¹H NMR (300 MHz, CDCl₃): 1.18 (9H, s,

C(CH₃)₃), 3.73–3.80 (2H, m, H-4, H-5), 3.96 (1H, d,

J_1;1¼ 13:0 Hz, H-1), 4.04 (1H, d, H-1⁰), 4.26 (1H, d,

0

J_3,4= 5.2 Hz, H-3), 4.31, 4.56 (2H, ABq, J_AB= 11.5 Hz,

PhCH₂), 4.48, 4.53 (2H, ABq, J_AB= 12.1 Hz, PhCH₂),

4.63, 4.78 (2H, ABq, J_AB= 11.0 Hz, PhCH₂), 4.63,

4.76 (2H, ABq, J_AB= 11.5 Hz, PhCH₂), 5.06 (1H, dat,

J_cis= 10.2 Hz, J = 1.1 Hz, H-8_cis), 5.12 (1H, dat,

J_trans= 17.3 Hz, J = 1.3 Hz, H-8_trans), 5.26 (1H, s, H-

2a), 5.40–5.45 (2H, m, H-6, H-2a⁰), 5.69 (1H, ddd,

J_6,7= 6.3 Hz, H-7), 7.23–7.38 (20H, m, Ar-H); ¹³C

NMR (75 MHz, CDCl₃): 27.3 (q, C(CH₃)₃), 39.0 (s,

C(CH₃)₃), 70.0, 71.1, 72.8, 74.1, 74.8 (5 ꢁ t, C-1,

4 ꢁ PhCH₂), 74.5, 80.1, 80.5, 81.7 (4 ꢁ d, C-3, C-4, C-

5, C-6), 117.0, 117.8 (2 ꢁ t, C-2a, C-8), 127.4, 127.5,

127.8, 128.0, 128.3, 128.3, 128.4, 128.5, 128.5 (9 ꢁ d,

Bn–CH), 134.0 (d, C-7), 138.2, 138.3, 138.8, 139.0

(4 ꢁ s, 4 ꢁ Bn–C), 142.7 (s, C-2), 177.4 (s, C@O). MAL-

DI m/z 687 [M+K]⁺, 671 [M+Na]⁺. ESIMS m/z:

[M+Na]⁺calcd for C₄₂H₄₈O₆Na, 671.3343; found,

671.3360.

21

½aꢃ_Dꢂ4.7 (c 1.0, CHCl₃); IR (ﬁlm); m 1731 (C@O)

cm^ꢂ1

;

¹H NMR (300 MHz, CDCl₃): 1.22 (9H, s,

C(CH₃)₃), 3.84 (1H, at, J = 5.2 Hz, H-5), 3.91 (1H, at,

J = 4.5 Hz, H-4), 4.09 (1H, d, J_3,4= 3.8 Hz, H-3),

4.22, 4.34 (4H, 2 ꢁ s, H-1, H-1⁰, PhCH₂), 4.41, 4.68

(2H, ABq, J_AB= 11.6 Hz, PhCH₂), 4.46 (1H, d,

J = 11.0 Hz, PhCHH⁰), 4.59–4.63 (2H, m, PhCHH⁰,

PhCHH⁰), 4.67 (1H, d, J = 11.3 Hz, PhCHH⁰), 5.11–

5.21 (2H, m, H-8, H-8⁰), 5.40 (1H, at, J = 5.6 Hz, H-

6), 5.80 (1H, ddd, J_cis= 10.7 Hz, J_trans= 17.3 Hz,

J_6,7= 6.0 Hz, H-7), 7.17–7.39 (20H, m, Ar-H); ¹³C

NMR (75 MHz, CDCl₃): 27.3 (q, C(CH₃)₃), 39.1 (s,

C(CH₃)₃), 73.3, 73.8, 74.5, 74.5, 74.6 (5 ꢁ t, C-1,

4 ꢁ PhCH₂), 73.7, 79.4, 80.1, 81.1 (4 ꢁ d, C-3, C-4, C-

5, C-6), 117.4 (t, C-8), 127.8, 128.0, 128.0, 128.3,

128.4, 128.4, 128.4, 128.5, 128.7 (9 ꢁ d, Bn–CH), 133.7

(d, C-7), 137.1, 137.5, 137.6, 138.3 (4 ꢁ s, 4 ꢁ Bn–C),

177.5 (s, OC@O), 206.7 (s, C-2). MALDI m/z 689

[M+K]⁺, 673 [M+Na]⁺. ESIMS m/z: [M+Na]⁺calcd

for C₄₁H₄₆O₇Na, 673.3136; found, 673.3155.

3.8. (1R,2R,3S,4R)-2,3,4-Tri-O-benzyl-1-O-pivalyl-5-

(benzyloxymethyl)-cyclohex-5-ene-1,2,3,4-tetrol (15)

The a,b-unsaturated ketone 11 was also isolated for

characterisation. A colourless oil; IR (ﬁlm); m 1729

Diene 12 (154 mg, 0.24 mmol) was dissolved in toluene

(6 mL), and Grubbs’ second generation catalyst (12%

in wax, 168 mg, 0.024 mmol)⁴⁰was added. The mixture

was stirred at 60 °C under Ar. After 24 h, TLC (pen-

tane–EtOAc 7:1) showed consumption of the starting

material (R_f= 0.8) and the formation of a major prod-

uct (R_f= 0.7). The mixture was concentrated in vacuo,

and the residue was puriﬁed by ﬂash column chromatog-

raphy (pentane–EtOAc 12:1) to give the carbocycle 15

(92 mg, 62%) as white crystals, mp 92–93 °C (MeOH);

(OC@O), 1698 (C@C–C@O) cm^ꢂ1

;

¹H NMR

(300 MHz, CDCl₃): 1.19 (9H, s, C(CH₃)₃), 3.65 (1H,

0

dd, J_7,8= 5.8 Hz, J_8;8¼ 10:2 Hz, H-8), 3.90 (1H,

dd, J_7;8¼ 5:2 Hz, H-8⁰), 4.03–4.04 (2H, m, H-5, H-6),

0

4.22 (1H, br s, H-4), 4.33–4.71 (8H, m, 4 ꢁ PhCH₂),

0

5.23 (m, H-7), 5.52 (1H, dd, J_1;1¼ 1:6 Hz,

J_cis= 10.4 Hz, H-1_cis), 6.23 (1H, dd, J_trans= 17.6 Hz,

H-1_trans), 6.66 (1H, dd, H-2), 7.13–7.36 (20H, m,

Ar-H). MALDI m/z 689 [M+K]⁺, 673 [M+Na]⁺.

1684

21

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

½aꢃ_Dꢂ71.2 (c 1.0, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): 1.21 (9H, s, C(CH₃)₃), 3.81 (1H, dd,

J_1,2= 7.9 Hz, J_2,3= 10.4 Hz, H-2), 3.89 (1H, dd,

3.9.2. Method 2: oxidation of alcohol 37 and subsequent

Grignard reaction. Oxalyl chloride (0.87 mL,

10.0 mmol) was dissolved in CH₂Cl₂(5 mL) and cooled

to ꢂ60 °C. Me₂SO (1.42 mL, 20.0 mmol) was dissolved

in CH₂Cl₂(5 mL) and added, and the mixture was stir-

red at ꢂ60 °C. After 30 min, alcohol 37 (2.45 g,

4.55 mmol) in CH₂Cl₂(10 mL) was added by cannula

under N₂, and the mixture was stirred at ꢂ60 °C. After

40 min, Et₃N (3.16 mL, 22.8 mmol) was added. The

mixture was allowed to warm up slowly: After 2 h, it

had reached ꢂ40 °C, and it was removed from the cool-

ing bath and stirred further at rt. After 1 h at rt, TLC

(pentane–EtOAc 3:1) showed the formation of a major

product (R_f0.6), and the complete consumption of the

starting material (R_f= 0.4). The mixture was poured

into water (100 mL) and extracted with CH₂Cl₂

(2 ꢁ 100 mL). The organic extracts were dried

(Na₂SO₄), ﬁltered and concentrated in vacuo.

0

J_3,4= 7.5 Hz, H-3), 3.92 (1H, d, J_6;6¼ 12:4 Hz, H-6),

4.22 (1H, d, H-6⁰), 4.35 (1H, d, H-4), 4.48, 4.52 (2H,

ABq, J_AB= 11.8 Hz, PhCH₂), 4.72, 4.85 (2H, ABq,

J_AB= 11.0 Hz, PhCH₂), 4.74, 4.85 (2H, ABq,

J_AB= 11.0 Hz, PhCH₂), 4.80, 4.95 (2H, ABq,

J_AB= 10.9 Hz, PhCH₂), 5.55–5.58 (2H, m, H-1, H-5a),

7.25–7.36 (20H, m, Ar-H); ¹³C NMR (75 MHz, CDCl₃):

27.3 (q, C(CH₃)₃), 38.9 (s, C(CH₃)₃), 70.0, 72.7, 75.0,

75.4, 75.6 (5 ꢁ t, C-6, 4 ꢁ PhCH₂), 74.2, 79.8, 82.0,

84.3 (4 ꢁ d, C-1, C-2, C-3, C-4), 124.2 (d, C-5a), 127.7,

127.7, 127.8, 127.8, 127.9, 128.0, 128.1, 128.5, 128.5,

128.6 (10 ꢁ d, Bn–CH), 138.0, 138.1, 138.4, 138.5,

138.6 (5 ꢁ s, 4 ꢁ Bn–C, C-5), 178.1 (s, C@O). MALDI

m/z 659 [M+K]⁺, 643 [M+Na]⁺. ESIMS m/z:

[M+Na]⁺calcd for C₄₀H₄₄O₆Na, 643.3030; found,

643.3011.

The residue was dissolved in THF (5 mL) and cooled

to 0 °C under N₂, and vinylmagnesium bromide (0.7 M,

13 mL, 9.1 mmol) was added. After 90 min, the reaction

was quenched with NH₄Cl (100 mL) and extracted with

EtOAc (2 ꢁ 100 mL). The combined organic extracts

were dried (Na₂SO₄), ﬁltered and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatogra-

phy (pentane–EtOAc 6:1) to give the dienes 17 and 18

(2.02 g, 79%) as a colourless oil (17:18, 2:1).

3.9. (3R,4S,5S,6R)-1,3,4,5-Tetra-O-benzyl-2-methylene-

oct-7-ene-1,3,4,5,6-pentaol (17)

3.9.1. Method 1: deprotection of pivalate 12. Sodium

(112 mg, 4.87 mmol) was dissolved in MeOH (10 mL)

and added to a solution of diene 12 (1.02 g, 1.57 mmol)

in MeOH (10 mL), and the mixture was stirred at 45 °C.

After 48 h, TLC (pentane–EtOAc 5:1) showed little

remaining starting material (R_f= 0.9) and the formation

of a major product (R_f= 0.5). Silica was added, the mix-

ture concentrated in vacuo, and the residue dry-loaded

onto a column and puriﬁed by ﬂash column chromatog-

raphy to give the allylic alcohol 17 (786 mg, 89%) as a

3.10. (1R,2S,3S,4R)-2,3,4-Tri-O-benzyl-5-(benzyloxy-

methyl)-cyclohex-5-ene-1,2,3,4-tetrol (19)

3.10.1. Method 1: ring-closing metathesis after deacyla-

tion. Diene 17 (669 mg, 1.19 mmol) was dissolved in tol-

uene (50 mL). Grubbs second generation catalyst (12% in

wax, 126 mg, 0.018 mmol)⁴⁰was added, and the mixture

was stirred at 60 °C under Ar. After 3 h, TLC (pentane–

EtOAc 3:1) showed the formation of a major product

(R_f= 0.3), and the near-complete consumption of start-

ing material (R_f= 0.8). The mixture was ﬁltered and con-

centrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (pentane–EtOAc 3:1) to give

the carbocycle 19 (569 mg, 89%) as white crystals, mp

22

colourless oil. ½aꢃ_Dꢂ12.0 (c 1.0, CHCl₃); IR (ﬁlm); m

3464 (OH) cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): 2.59

;

(1H, br s, OH-6), 3.67 (1H, dd, J_4,5= 6.0 Hz,

J_5,6= 3.0 Hz, H-5), 3.85 (1H, dd, J_3,4= 4.4 Hz, H-4),

4.00–4.03 (2H, m, H-1, H-6), 4.09 (1H, d,

J_1;1¼ 12:8 Hz, H-1⁰), 4.27 (1H, d, H-3), 4.33 (1H. d,

0

J = 11.9 Hz, PhCHH⁰), 4.51, 4.56 (2H, ABq,

J_AB= 12.0 Hz, PhCH₂), 4.63–4.73 (5H, m, 2 ꢁ PhCH₂,

PhCHH⁰), 5.10 (1H, dd, J_cis= 10.6 Hz, J_gem1.5 Hz, H-

8_cis), 5.20 (1H, dd, J_trans= 17.2 Hz, H-8_trans), 5.40, 5.49

(2H, 2 ꢁ s, H-2a, H-2a⁰), 5.78 (1H, ddd, J_6,7= 5.3 Hz,

H-7), 7.24–7.39 (20H, m, Ar-H); ¹³C NMR (100 MHz,

CDCl₃): 70.6 (t, C-1), 70.9, 72.8, 74.9, 75.3 (4 ꢁ t,

4 ꢁ PhCH₂), 72.3 (d, C-6), 80.1 (d, C-3), 81.0 (d, C-4),

81.8 (d, C-5), 115.6 (t, C-8), 116.8 (t, C-2a), 127.7,

127.7, 127.8, 127.8, 127.9, 128.0, 128.3, 128.4, 128.5,

128.5, 128.6 (11 ꢁ d, Ar-CH), 137.9, 138.3, 138.5,

138.6 (4 ꢁ s, 4 ꢁ Ar-C), 138.7 (d, C-7), 142.5 (s, C-2);

ESI⁺m/z 582 [M+NH₄]⁺, 100%. ESIMS m/z:

[M+NH₄]⁺calcd for C₃₇H₄₄O₅N, 582.3214; found,

582.3206.

21

73–74 °C (EtOAc/pentane), lit.²⁶74–75 °C. ½aꢃ_Dꢂ72.8

(c 0.5, CHCl₃), lit.²⁶ꢂ66.9; ¹H NMR (400 MHz, CDCl₃):

3.57 (1H, dd, J_1,2= 7.4 Hz, J_2,3= 9.8 Hz, H-2), 3.85 (1H,

0

dd, J_3,4= 7.0 Hz, H-3), 3.91 (1H, d, J_6;6¼ 12:4 Hz, H-6),

4.25 (1H, d, H-6⁰), 4.29–4.34 (2H, m, H-1, H-4), 4.46, 4.52

(2H, ABq, J_AB= 11.9 Hz, PhCH₂), 4.70, 4.80 (2H, ABq,

J_AB= 10.9 Hz, PhCH₂), 4.73, 4.97 (2H, ABq, J_AB

11.5 Hz, PhCH₂), 4.82, 4.93 (2H, ABq, J_AB= 11.1 Hz,

PhCH₂), 5.74 (1H, s, H-5a), 7.26–7.36 (20H, m, Ar-H).

=

3.10.2. Method 2: deacylation after ring clo-

sure. Sodium methoxide (3 mL of a 1 M solution,

3 mmol) was added to a solution of carbocycle 15

(162 mg, 0.26 mmol) in MeOH (3 mL), and the mixture

Also recovered starting material 12 (55 mg, 5%) as a

colourless oil.

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

1685

was stirred at 45 °C. After 48 h, TLC (pentane–EtOAc

5:1) showed little remaining starting material

(R_f= 0.8) and the formation of a major product

(R_f= 0.1). AcOH (0.3 mL) was added, and the mixture

concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography to give the alcohol 19 (123 mg,

88%) as a white solid, identical to that described above.

4.40, 4.56 (2H, ABq, J_AB= 11.4 Hz, ArCH₂), 4.47–4.50

(3H, m, ArCH₂, ArCHH⁰), 4.63–4.73 (5H, m,

2 ꢁ ArCH₂, ArCHH⁰), 4.80 (1H, d, J = 11.3 Hz, ArCH-

H⁰), 5.33–5.39 (2H, m, H-8_trans, H-8_cis), 5.98 (1H, ddd,

J_cis= 10.2 Hz, J_trans= 17.6 Hz, H-7), 6.72–6.83 (6H,

m, DMB–H), 7.22–7.32 (20H, m, Bn–H); ¹³C NMR

(100 MHz, CDCl₃): 55.8, 55.8, 56.0, 56.0 (4 ꢁ q,

4 ꢁ OCH₃), 70.0, 70.4, 72.0, 73.4, 74.1, 74.2, 75.2

(7 ꢁ t, C-1, 6 ꢁ ArCH₂), 79.3, 79.8, 80.9, 81.8 (4 ꢁ d,

C-2, C-3, C-4, C-5, C-6), 110.9, 111.0, 111.2, 111.2,

120.1 (5 ꢁ d, 6 ꢁ DMB–CH), 119.5 (t, C-8), 127.4,

127.5, 127.6, 127.6, 127.7, 127.9, 128.0, 128.1, 128.3,

128.3, 128.4 (11 ꢁ d, Bn–CH), 131.2, 131.4 (2 ꢁ s,

2 ꢁ DMB–C), 136.1 (d, C-7), 138.6, 138.8, 139.0, 139.1

(4 ꢁ s, 4 ꢁ Bn–C), 148.5, 148.9 (2 ꢁ s, DMB–C); ESI⁺

m/z 891 [M+Na]⁺, 100%. ESIMS m/z: [M+Na]⁺calcd

for C₅₄H₆₀O₁₀Na, 891.4079; found, 891.4054.

3.10.3. Method 3: starting from a diastereomeric mixture

of dienes. Dienes 17 and 18 (2:1, 1.73 g, 3.06 mmol)

were dissolved in toluene (130 mL), and Grubbs’ second

generation catalyst (26 mg, 0.03 mmol) was added. The

mixture was stirred at 60 °C. Further catalyst (26 mg,

0.03 mmol) was added after 2 h, and again after a fur-

ther 12 h. After a total of 19 h, TLC (pentane–EtOAc

3:1) showed little starting material (R_f= 0.6) and the

formation of two products (R_f= 0.15 and 0.2). The mix-

ture was concentrated and puriﬁed by ﬂash column

chromatography (pentane–EtOAc 3:1?2:1) to give the

major diastereomer 19 (879 mg, 53%) as a white solid

and the minor diastereomer 20 (343 mg, 21%) as a pale

brown oil, identical to those described above. A further

amount of a colourless oil was isolated and found to be

a diastereomeric mixture of the two products (157 mg,

10%, 19:20, 3:2).

The monoprotected compound, major component 7a

(374 mg, 18%, 7a:7b, 7:1) as a colourless oil. IR (ﬁlm);

1

m 3491 (OH) cm^ꢂ1; H NMR (400 MHz, CDCl₃): 3.22

(1H, d, J_OH,6= 6.2 Hz, OH-6), 3.58 (1H, dd, J_4,5

=

4.1 Hz, J_5,6= 5.3 Hz, H-5), 3.70–3.79 (4H, m, OCH₃,

H-1), 3.81–3.91 (5H, m, OCH₃, H-1⁰, H-2), 3.94 (1H,

dd, J_3,4= 5.9 Hz, H-4), 4.12 (1H, dd, J_2,3= 3.9 Hz, H-

3), 4.39 (1H, m, H-6), 4.45–4.82 (10H, m, 5 ꢁ ArCH₂),

5.18 (1H, dat, J_cis= 10.6 Hz, J = 1.7 Hz, H-8_cis), 5.36

(1H, dat, J_trans= 17.2 Hz, J = 1.7 Hz, H-8_trans), 5.79

(1H, ddd, J_6,7= 5.1 Hz, H-7), 6.78 (3H, m, DMB–H),

7.20–7.38 (20H, m, Ar-H); ¹³C NMR (100 MHz,

CDCl₃): 55.8, 56.0 (2 ꢁ q, 2 ꢁ OCH₃), 69.8 (t, C-1),

71.9, 72.6, 73.5, 74.3, 74.6 (5 ꢁ t, 5 ꢁ ArCH₂), 72.1 (d,

C-6), 79.1, 79.2 (2 ꢁ d, C-2, C-3), 79.7 (d, C-4), 80.1 (d,

C-5), 110.9, 111.1, 120.1 (3 ꢁ d, 3 ꢁ DMB–CH), 116.1

(t, C-8), 127.6, 127.7, 127.8, 127.8, 127.8, 128.1, 128.2,

128.3, 128.3, 128.4, 128.5 (11 ꢁ d, Bn–CH), 131.2 (s,

DMB–C), 137.9 (d, C-7), 138.2, 138.2, 138.3, 138.6

(4 ꢁ s, 4 ꢁ Bn–C), 148.5, 148.9 (2 ꢁ s, 2 ꢁ DMB–C);

ESI⁺m/z 741 [M+Na]⁺, 100%. ESIMS: [M+Na]⁺calcd

for C₄₅H₅₀O₈Na, 741.3398; found, 741.3396.

3.11. (3S,4R,5R,6S)-1,3,4,5-Tetra-O-benzyl-6-O-(3,4-

dimethoxybenzyl)-1,3,4,5,6-pentahydroxy-oct-7-en-2-one

(13)

3.11.1. (2R,3S,4R,5S,6S)-1,3,4,5-Tetra-O-benzyl-2-O-

(3,4-dimethoxybenzyl)-oct-7-ene-1,2,3,4,5,6-hexaol (7a),

(2R,3R,4S,5R,6S)-1,3,4,5-tetra-O-benzyl-6-O-(3,4-dime-

thoxybenzyl)-oct-7-ene-1,2,3,4,5,6-hexaol

(2R,3S,4R,5R,6S)-1,3,4,5-tetra-O-benzyl-2,6-bis-O-(3,4-

(7b)

and

dimethoxybenzyl)-oct-7-ene-1,2,3,4,5,6-hexaol. Diol

(1.66 g, 2.90 mmol) was dissolved in DMF (15 mL)

and cooled to 0 °C under N₂. Dimethoxybenzyl chloride

(516 mg, 2.77 mmol) and NaH (60% in oil, 232 mg,

5.8 mmol) were added, and the mixture was stirred at

0 °C. After 1 h 45 min, TLC (CH₂Cl₂–Et₂O 19:1)

showed the formation of three products (R_f= 0.4, 0.6

and 0.7), along with remaining starting material

(R_f= 0.3). The mixture was diluted with Et₂O

(200 mL) and washed with brine (200 mL). The aqueous

phase was re-extracted with Et₂O (200 mL), and the

combined organic extracts were washed with brine

(200 mL), dried (Na₂SO₄), ﬁltered and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chro-

matography (CH₂Cl₂–Et₂O 40:1, more than one column

was necessary) to give the disubstituted compound

5

Monoprotected compound, major component 7b

(701 mg, 33%, 7a:7b, 1:5.5) as a colourless oil. IR (ﬁlm);

1

m 3499 (OH) cm^ꢂ1; H NMR (400 MHz, CDCl₃): 3.03

(1H, d, J_OH,2= 4.5 Hz, OH-2), 3.60 (1H, dd, J_1,2

=

0

5.4 Hz, J_1;1¼ 10:0 Hz, H-1), 3.63 (1H, dd, J_{1 ;2}

¼

3:7 Hz, H-1), 3.75 (1H, dd, J = 4.1 Hz, J = 6.9 Hz),

3.79, 3.86 (6H, 2 ꢁ s, 2 ꢁ OCH₃), 3.90 (1H, m), 3.99–

4.05 (3H, m), 4.19 (1H, d, J = 11.5 Hz, ArCHH⁰),

4.49–4.73 (8H, m, 3 ꢁ ArCH₂, ArCHH⁰, ArCHH⁰),

4.85 (1H, d, J = 11.2 Hz, ArCHH⁰), 5.34 (1H, dd,

J_trans= 17.4 Hz, J = 1.4 Hz, H-8_trans), 5.39 (1H, dd,

J_cis= 10.2 Hz, J = 1.7 Hz, H-8_cis), 6.00 (1H, ddd,

J_6,7= 7.3 Hz, H-7), 6.78–6.88 (3H, m, DMB–H), 7.20–

7.38 (20H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃):

55.8, 56.0 (2 ꢁ q, 2 ꢁ OCH₃), 70.0, 71.4, 73.1, 73.5,

74.4, 74.6 (6 ꢁ t, C-1, 5 ꢁ ArCH₂), 71.0 (d, C-2), 77.5,

78.9, 80.8, 81.1 (4 ꢁ d, C-3, C-4, C-5, C-6), 111.0,

23

(223 mg, 9%) as a colourless oil. ½aꢃ_D+6.8 (c 1.0,

1

CHCl₃); H NMR (400 MHz, CDCl₃): 3.70–3.78 (7H,

m, H-1, 2 ꢁ OCH₃), 3.83–3.98 (11H, m, H-1⁰, H-2, H-

3, H-4, H-5, 2 ꢁ OCH₃), 4.02 (1H, dd, J_5,6= 4.3 Hz,

J_6;6¼ 7:7 Hz, H-6), 4.13 (1H, d, J = 11.3 Hz, ArCHH⁰),

0

1686

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

111.2, 120.2 (3 ꢁ d, 3 ꢁ DMB–CH), 119.6 (t, C-8),

127.5, 127.7, 127.7, 127.9, 127.9, 128.1, 128.2, 128.3,

128.4, 128.4, 128.4, 128.4, 128.5, 128.5 (14 ꢁ d, Bn–

CH), 131.2 (s, DMB–C), 135.8 (d, C-7), 138.2, 138.2,

138.4, 138.7 (4 ꢁ s, 4 ꢁ Bn–C), 148.5, 149.0 (2 ꢁ s,

2 ꢁ DMB–C); ESI⁺m/z 741 [M+Na]⁺, 100%. ESIMS

m/z: [M+Na]⁺calcd for C₄₅H₅₀O₈Na, 741.3398; found,

741.3388.

3.47 mmol) were suspended in toluene (10 mL) and the

mixture was stirred at 80 °C. After 2 h, the mixture

was allowed to cool to rt. Ketone 13 (521 mg,

0.73 mmol) was dissolved in toluene (10 mL) and added

by cannula under N₂and the mixture was stirred at rt.

After 2 h, TLC (pentane–EtOAc 7:1) showed the forma-

tion of a major product (R_f= 0.2), and the complete

consumption of starting material (R_f= 0.1). The

mixture was ﬁltered through Celite and concentrated

in vacuo. The residue was puriﬁed by ﬂash column

chromatography (pentane–EtOAc 7:1?5:1) to give

And recovered starting material 5 (301 mg, 18%) as a

colourless oil.

22

3.11.2. (3S,4R,5R,6S)-1,3,4,5-Tetra-O-benzyl-6-O-(3,4-

dimethoxybenzyl)-1,3,4,5,6-pentahydroxy-oct-7-en-2-one

the diene 14 (456 mg, 88%) as a colourless oil. ½aꢃ_D

ꢂ19.5 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃):

3.79–3.90 (9H, m, H-4, H-5, H-6, 2 ꢁ CH₃), 4.01–

4.08 (3H, m, H-1, H-1⁰, ArCHH⁰), 4.25 (1H, d,

J_3,4= 5.5 Hz, H-3), 4.33, 4.59 (2H, ABq, J_AB= 11.8 Hz,

PhCH₂), 4.43 (1H, d, J = 11.5 Hz, ArCHH⁰), 4.48,

4.52 (2H, ABq, J_AB= 12.0 Hz, ArCH₂), 4.61, 4.75

(2H, ABq, J_AB= 11.2 Hz, ArCH₂), 4.64, 4.85 (2H,

ABq, J_AB= 11.3 Hz, ArCH₂), 5.26 (1H, dd,

J_trans= 17.4 Hz, J_gem= 1.6 Hz, H-8_trans), 5.27 (1H, d,

J_gem= 1.1 Hz, H-2a), 5.33 (1H, dd, J_cis= 10.4 Hz,

H-8_cis), 5.45 (1H, d, H-2a⁰), 5.97 (1H, m, H-7), 6.77–

6.83 (3H, m, DMB–H), 7.24–7.38 (20H, m, Ar-H);

¹³C NMR (100 MHz, CDCl₃): 55.8, 56.0 (2 ꢁ q,

2 ꢁ CH₃), 69.9, 70.1, 70.8, 72.7, 74.2, 75.3 (6 ꢁ t, C-1,

5 ꢁ ArCH₂), 80.3, 80.8, 81.2, 81.5 (4 ꢁ d, C-3, C-4, C-

5, C-6), 111.0, 111.1, 120.0 (3 ꢁ d, DMB–CH), 116.5,

119.4 (2 ꢁ t, C-2a, C-8), 127.3, 127.4, 127.6, 127.8,

128.2, 128.2, 128.2, 128.4, 128.5 (9 ꢁ d, Bn–CH), 131.4

(s, DMB–C), 136.0 (d, C-7), 138.2, 138.4, 139.1, 139.2

(4 ꢁ s, 4 ꢁ Bn–C), 142.7 (s, C-2), 148.4, 148.9 (2 ꢁ s,

2 ꢁ DMB–C); ESI⁺m/z 737 [M+Na]⁺, 100%. ESIMS

m/z: [M+Na]⁺calcd for C₄₆H₅₀O₇Na, 737.3449; found,

737.3440.

˚

(13). 4 A Molecular sieves (ca. 350 mg) were sus-

pended in CH₂Cl₂(6 mL) and sodium acetate (34 mg,

0.42 mmol) and pyridinium chlorochromate (90 mg,

0.42 mmol) were added. Alcohol 7a:7b, 5.5:1 (232 mg,

0.32 mmol) was dissolved in CH₂Cl₂(6 mL) and added

to the reaction mixture. The mixture was stirred at rt un-

der N₂. Further PCC (2 ꢁ 273 mg, 1.27 mmol) was

added after 1 h and after a further 1 h 30 min. After a

further 1 h 15 min, TLC (pentane–EtOAc 4:1) showed

the formation of a product (R_f= 0.4), and the complete

consumption of starting material (R_f= 0.3). The mix-

ture was loaded directly onto a silica column and puri-

ﬁed by ﬂash column chromatography (CH₂Cl₂–Et₂O

20:1) to give the ketone 13 (190 mg, 82%) as a colourless

24

oil. ½aꢃ_Dꢂ6.8 (c 1.0, CHCl₃); IR (ﬁlm); m 1729 (C@O)

cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): 3.81, 3.85 (6H,

;

2 ꢁ s, 2 ꢁ CH₃), 3.86–3.95 (2H, m, H-5, H-6), 4.02

(1H, at, J = 4.9 Hz, H-4), 4.16 (1H, d, J_3,4= 4.4 Hz,

H-3), 4.17, 4.51 (2H, ABq, J_AB= 11.3 Hz, ArCH₂),

4.21, 4.33 (4H, 2 ꢁ s, H-1, H-1⁰, ArCH₂), 4.37, 4.54

(2H, ABq, J_AB= 11.7 Hz, ArCH₂), 4.44, 4.65 (2H,

ABq, J_AB= 11.2 Hz, ArCH₂), 4.61, 4.70 (2H, ABq,

J_AB= 10.8 Hz, ArCH₂), 5.32–5.40 (2H, m, H-8, H-8⁰),

5.92 (1H, ddd, J_cis= 10.2 Hz, J_trans= 17.4 Hz, J_6,7

=

3.13. (1S,2R,3S,4R)-2,3,4-Tri-O-benzyl-1-O-(3,4-dime-

thoxybenzyl)-5-(benzyloxymethyl)-cyclohex-5-ene-

1,2,3,4-tetrol (16)

7.4 Hz, H-7), 6.78–6.86 (3H, m, DMB–H), 7.15–7.34

(20H, m, Ar-H); ¹³C NMR (75 MHz, CDCl₃): 55.9,

56.0 (2 ꢁ q, 2 ꢁ OCH₃), 70.1, 73.3, 73.5, 74.4, 74.5,

75.1 (6 ꢁ t, C-1, 5 ꢁ PhCH₂), 80.1, 80.7, 80.9, 82.1

(4 ꢁ d, C-3, C-4, C-5, C-6), 111.0, 111.3, 120.4 (3 ꢁ d,

DMB–CH), 120.0 (t, C-8), 127.5, 127.8, 127.8, 128.0,

128.2, 128.2, 128.3, 128.4, 128.4, 128.6 (10 ꢁ d, Bn–

CH), 130.9 (s, DMB–C), 135.8 (d, C-7), 137.1, 137.6,

138.0, 138.6 (4 ꢁ s, 4 ꢁ Bn–C), 148.6, 149.0 (2 ꢁ s,

2 ꢁ DMB–C), 207.0 (s, C-2); ESI⁺m/z 739 [M+Na]⁺,

100%, 734 [M+NH₄]⁺, 15%. ESIMS m/z: [M+Na]⁺

calcd for C₄₅H₄₈O₈Na, 739.3241; found, 739.3216.

Diene 14 (52 mg, 0.073 mmol) was dissolved in dichloro-

ethane (3 mL), and Grubbs’ second generation catalyst

(6 mg, 0.006 mmol) was added. The mixture was stirred

at 60 °C under Ar. After 48 h, TLC (pentane–EtOAc

7:1) showed consumption of starting material

(R_f= 0.3) and the formation of a major product

(R_f= 0.2). The mixture was concentrated in vacuo,

and the residue puriﬁed by ﬂash column chromatogra-

phy (pentane–EtOAc 5:1) to give the carbocycle 15

23

(27 mg, 54%) as a colourless oil; ½aꢃ_D+32.1 (c 1.0,

3.12. (3R,4S,5R,6S)-1,3,4,5-Tetra-O-benzyl-6-O-(3,4-

dimethoxybenzyl)-2-methylene-oct-7-ene-1,3,4,5,6-pen-

taol (14)

CHCl₃); ¹H NMR (400 MHz, CDCl₃): 3.59 (1H, dd,

J_1,2= 3.7 Hz, J_2,3= 10.1 Hz, H-2), 3.80, 3.89 (6H,

0

2 ꢁ s, 2 ꢁ OCH₃), 3.96 (1H, d, J_6;6¼ 12:4 Hz, H-6),

4.10 (1H, at, J = 4.4 Hz, H-1), 4.19–4.22 (2H, m, H-4,

H-6⁰), 4.32 (1H, dd, J_3,4= 7.1 Hz, H-3), 4.44, 4.49

(2H, ABq, J_AB= 11.9 Hz, ArCH₂), 4.63–4.72 (3H, m,

Methyltriphenylphosphonium

bromide

(1.30 g,

3.64 mmol) and potassium tert-butoxide (388 mg,

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

1687

ArCH₂, ArCHH⁰), 4.72, 4.76 (2H, ABq, J_AB= 12.1 Hz,

3.15. (1S,2S,3S,4R)-2,3,4-Tri-O-benzyl-5-(benzyloxy-

methyl)-cyclohex-5-ene-1,2,3,4-tetrol (20)

ArCH₂), 4.81, 5.05 (2H, ABq, J_AB= 11.0 Hz, ArCH₂),

4.82 (1H, d, J = 11.2 Hz, ArCHH⁰), 5.90 (1H, d,

J_1,5a= 5.3 Hz, H-5a), 6.82 (1H, d, J = 8.1 Hz, DMB–

H), 6.89 (1H, dd, J = 1.5 Hz, DMB–H), 6.97 (1H, d,

DMB–H), 7.26–7.38 (20H, m, Ar-H); ¹³C NMR

(100 MHz, CDCl₃): 55.9, 56.0 (2 ꢁ q, 2 ꢁ OCH₃), 70.4

(t, C-6), 70.6 (d, C-1), 71.7, 72.6, 72.8, 73.9, 75.1

(5 ꢁ t, 5 ꢁ ArCH₂), 79.8, 80.1 (2 ꢁ d, C-2, C-4), 80.8

(d, C-3), 110.9, 111.4, 120.5 (3 ꢁ d, 3 ꢁ DMB–CH),

123.6 (d, C-5a), 127.6, 127.7, 127.8, 127.8, 127.8,

127.9, 128.1, 128.4, 128.5, 128.5 (10 ꢁ d, Bn–CH),

131.4 (s, DMB–C), 138.2, 138.7, 138.8, 139.0 (4 ꢁ s,

4 ꢁ Bn–C), 138.6 (s, C-5), 148.7, 149.2 (2 ꢁ s,

2 ꢁ DMB–C).

3.15.1. Method 1: ring-closing metathesis after deprotec-

tion. Diene 18 (149 mg, 0.26 mmol) was dissolved in

toluene (12 mL). Grubbs second generation catalyst

(12% in wax, 19 mg, 0.0026 mmol)⁴⁰was added, and

the mixture was stirred at 60 °C under Ar. After 3 h,

TLC (pentane–EtOAc 4:1) showed the formation of a

major product (R_f= 0.1), and the near-complete con-

sumption of starting material (R_f= 0.5). The mixture

was ﬁltered and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (pen-

tane–EtOAc 3:1) to give carbocycle 20 (128 mg, 90%)

21

as a colourless oil; ½aꢃ_Dꢂ7.8 (c 0.5, CHCl₃); IR (ﬁlm);

1

Also recovered starting material 14 (20 mg, 38%).

m 3448 (OH) cm^ꢂ1; H NMR (400 MHz, CDCl₃): 2.59

(1H, br s, OH-1), 3.61 (1H, dd, J_1,2= 3.8 Hz, J_2,3

=

0

3.14. (3R,4S,5S,6S)-1,3,4,5-Tetra-O-benzyl-2-methylene-

oct-7-ene-1,3,4,5,6-pentaol (18)

9.2 Hz, H-2), 3.95 (1H, d, J_6;6¼ 12:1 Hz, H-6), 4.07

(1H, dd, J_3,4= 6.8 Hz, H-3), 4.16 (1H, d, H-4), 4.24

(1H, d, H-6⁰), 4.32 (1H, br m, H-1), 4.44, 4.50 (2H,

ABq, J_AB= 11.8 Hz, PhCH₂), 4.65–4.82 (5H, m, 2 ꢁ

PhCH₂, PhCHH⁰), 4.89 (1H, d, J = 11.0 Hz, PhCHH⁰),

5.92 (1H, d, J_1,5a= 4.2 Hz, H-5a), 7.26–7.33 (20H, m,

Ar-H); ¹³C NMR (100 MHz, CDCl₃): 65.2 (d, C-1),

70.4 (t, C-6), 72.7, 73.0, 74.2, 74.9 (4 ꢁ t, 4 ꢁ PhCH₂),

78.9, 79.0, 79.2 (3 ꢁ d, C-2, C-3, C-4), 124.8 (d, C-5a),

127.7, 127.8, 127.8, 127.9, 128.1, 128.1, 128.2, 128.5,

128.5, 128.6, 128.7 (11 ꢁ d, Ar-CH), 138.1, 138.2,

138.7, 138.7 (4 ꢁ s, 4 ꢁ Bn–C), 139.9 (s, C-5); ESI⁺

m/z 559 [M+Na]⁺, 100%. ESIMS m/z: [M+Na]⁺calcd

for C₃₅H₃₆O₅Na, 559.2455; found, 559.2461.

Diene 14 (252 mg, 0.35 mmol) was dissolved in CH₂Cl₂

(12 mL) and water (0.6 mL) was added. The mixture

was cooled to 0 °C under N₂. DDQ (96 mg, 0.42 mmol)

was added, and the mixture was stirred at 0 °C. After 1 h

20 min, NaHCO₃(satd aq, ca. 5 mL) was added. The

mixture was stirred for 5 min, then diluted with CH₂Cl₂

(50 mL) and washed with water (50 mL). The aqueous

phase was re-extracted with CH₂Cl₂(50 mL) and the

combined organic extracts dried (Na₂SO₄), ﬁltered and

concentrated in vacuo. TLC (pentane–EtOAc 4:1)

showed the formation of a major product (R_f= 0.4),

and the complete consumption of starting material

(R_f= 0.3). The residue was puriﬁed by ﬂash column

chromatography (pentane–EtOAc 5:1) to give the diene

3.15.2. Method 2: deprotection after ring closure. Car-

bocycle 16 (33 mg, 0.048 mmol) was dissolved in a mix-

ture of MeCN (1.8 mL) and water (0.2 mL). CAN

(90 mg, 0.165 mmol) was added in three portions over

1 h. After a further 90 min, TLC (pentane–EtOAc 3:1)

showed the conversion of the starting material

(R_f= 0.3) into a major product (R_f= 0.2). The reaction

mixture was added to ammonium bicarbonate (satd aq,

25 mL), and extracted with CH₂Cl₂(2 ꢁ 25 mL). The

combined organic extracts were dried (Na₂SO₄), ﬁltered

and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (CH₂Cl₂–Et₂O 30:1?

20:1) to give the deprotected carbocycle 20 (19 mg,

74%), identical to that described above.

22

18 (150 mg, 75%) as a colourless oil. ½aꢃ_Dꢂ35.2 (c 1.0,

CHCl₃); IR (ﬁlm); m 3474 (OH) cm^ꢂ^{1 1}H NMR

;

(400 MHz, CDCl₃): 3.26 (1H, d, J_OH,66.6 Hz, OH-6),

3.58 (1H, dd, J_4,5= 3.6 Hz, J_5,6= 4.7 Hz, H-5), 3.94

(1H, dd, J_3,4= 6.7 Hz, H-4), 3.97 (1H, d,

J_1;1¼ 12:4 Hz, H-1), 4.06 (1H, d, H-1⁰), 4.32–4.40

0

(3H. m, H-3, H-6, PhCHH⁰), 4.47–4.56 (4H, m, PhCH₂,

PhCHH⁰,

PhCHH⁰),

4.64,

4.86

(2H,

ABq,

J_AB= 10.8 Hz, PhCH₂), 4.70 (1H, d, J = 11.5 Hz,

PhCHH⁰), 5.13 (1H, dat, J_cis= 10.5 Hz, J = 1.5 Hz, H-

8_cis), 5.29–5.33 (2H, m, H-2a, H-8_trans), 5.43 (1H, d,

J = 1.1 Hz, H-2a⁰), 5.74 (1H, ddd, J_6,7= 5.1 Hz,

J_trans= 17.1 Hz, H-7), 7.24–7.39 (20H, m, Ar-H); ¹³C

NMR (100 MHz, CDCl₃): 70.0 (t, C-1), 70.9, 72.4,

73.0, 74.9 (4 ꢁ t, 4 ꢁ PhCH₂), 71.8 (d, C-6), 79.9 (d,

C-5), 80.7 (d, C-4), 82.7 (d, C-3), 116.0 (t, C-8), 117.8

(t, C-2a), 127.7, 127.8, 127.8, 127.9, 127.9, 128.3,

128.4, 128.5, 128.5, 128.6 (10 ꢁ d, Ar-CH), 137.9 (d,

C-7), 138.2, 138.2, 138.3, 138.4 (4 ꢁ s, 4 ꢁ Ar-C),

142.7 (s, C-2); m/z (ESI⁺) 582 [M+NH₄]⁺, 100%.

ESIMS m/z: [M+NH₄]⁺calcd for C₃₇H₄₄O₅N,

582.3214; found, 582.3206.

3.16. (1R,2S,3S,4R)-2,3,4-Tri-O-benzyl-5-(benzyloxy-

methyl)-1-phthalimidocyclohex-5-ene-2,3,4-triol (29)

Alcohol 20 (94 mg, 0.18 mmol) was dissolved in THF.

Phthalimide (52 mg, 0.35 mmol) and triphenyl phos-

phine (371 mg, 1.41 mmol) were added. The mixture

was cooled to 0 °C and then DIAD (0.27 mL,

1.41 mmol) was added. The mixture was then allowed

to return to rt and stirred under N₂. After 24 h, the reac-

1688

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

tion mixture was concentrated in vacuo and the residue

was puriﬁed by ﬂash column chromatography (CH₂Cl₂–

Et₂O 40:1) to give the phthalimide derivative 29 (94 mg,

blue, and after the blue colour disappeared (10 min),

further sodium (ca. 30 mg) was added. After a further

10 min, NH₄Cl was added to quench the reaction, then

the mixture was allowed to warm to rt, and then concen-

trated in vacuo. The residue was taken up in MeOH

(6 mL) and ﬁltered, and the ﬁltrate concentrated to dry-

ness. The residue was dissolved in water (6 mL) and

Dowex 50WX8 (H⁺form) was added. After 10 min,

the mixture was ﬁltered, and the resin washed with

water. The resin was then washed with ammonia (2%

aq, 30 mL), and the ﬁltrate concentrated to give the

deprotected compound 2 (17 mg, 78%) as an oﬀ-white

21

81%) as a colourless oil. ½aꢃ_Dꢂ155 (c 0.5, CHCl₃); IR

(ﬁlm); m 1714 (C@O) cm^ꢂ1

;

¹H NMR (400 MHz,

0

CDCl₃): 3.89 (1H, d, J_6;6¼ 13:0 Hz, H-6), 4.00 (1H,

dd, J = 8.1 Hz, J = 10.2 Hz, H-3), 4.28–4.36 (2H, H-2,

H-6⁰), 4.43, 4.59 (2H, ABq, J_AB= 12.0 Hz, PhCH₂),

4.48–4.51 (2H, m, H-4, PhCHH⁰), 4.79–4.94 (5H, m,

H-1, PhCH₂, PhCHH⁰, PhCHH⁰), 5.05 (1H, d,

J = 11.0 Hz, PhCHH⁰), 5.46 (1H, s, H-5a), 6.76 (1H, t,

J = 7.4 Hz, Bn–H), 6.85 (2H, at, J = 7.3 Hz, Bn–H),

7.03 (2H, d, J = 7.0 Hz, Bn–H), 7.23–7.41 (15H, m,

Ar-H), 7.68 (4H, s, Phth-H); ¹³C NMR (100 MHz,

CDCl₃): 52.6 (d, C-1), 69.5 (t, C-6), 71.5, 74.9, 75.3,

75.8 (4 ꢁ t, 4 ꢁ PhCH₂), 78.5 (d, C-2), 80.3 (d, C-4),

86.2 (d, C-3), 123.3, 133.8 (2 ꢁ d, Phth-CH), 123.9 (d,

C-5a), 127.4, 127.6, 127.8, 128.0, 128.1, 128.1, 128.2,

128.4, 128.4, 128.5, 128.6 (11 ꢁ d, Ar-CH), 132.0 (s,

Phth-C), 137.6, 138.0, 138.5, 138.6, 138.7 (5 ꢁ s,

4 ꢁ Bn–C, C-5), 167.7 (s, C@O); ESI⁺m/z 683

[M+NH₄]⁺, 100%. ESIMS m/z: [M+NH₄]⁺calcd for

C₄₃H₄₃O₆N₂, 683.3116; found, 683.3106.

1

solid. H NMR (500 MHz, D₂O) 3.53–3.60 (2H, m, H-

2, H-3), 3.82 (1H, m, H-1), 4.07–4.17 (3H, m, H-4, H-

6, H-6⁰), 5.57 (1H, m, H-5a); ¹³C NMR (125 MHz,

D₂O) 54.1 (d, C-1), 61.4 (t, C-6), 72.0, 72.2 (2 ꢁ d, C-

2, C-4), 76.1 (d, C-3), 117.5 (d, C-5a), 143.7 (s, C-5).

ESIMS m/z: [M+Na]⁺calcd for C₇H₁₃O₄NNa,

198.0737; found, 198.0734.

3.18. 1,3,4,5-Tetra-O-benzyl-6-O-trityl-^L-iditol and

1,3,4,5-tetra-O-benzyl-6-O-trityl-L-gulitol (34)

3.18.1. 1,3,4,5-Tetra-O-benzyl-^L-iditol and 1,3,4,5-Tetra-

O-benzyl-L-gulitol (33). Hemiacetal 32³⁹(2.96 g,

5.47 mmol) was suspended in MeOH (30 mL). The mix-

ture was cooled to 0 °C, NaBH₄(0.63 g, 16.6 mmol) was

added, and the mixture was stirred at rt. After 3 h, TLC

(toluene–EtOAc 6:1) indicated the complete consump-

tion of starting material (R_f= 0.6) and the formation

of the product (R_f= 0.1). The reaction mixture was

poured into water, neutralised with NH₄Cl (10% aq,

10 mL), concentrated to less than half of its volume

and extracted with EtOAc (100 mL, 2 ꢁ 30 mL). The or-

ganic extracts were dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (toluene–EtOAc 9:1) to aﬀord

the alcohols 33 (2.32 g, 85%) as a yellow oil, as a mix-

ture. The isomers were partially separated by chroma-

3.17. 1-epi-Valienamine (2)

3.17.1. (1R,2S,3S,4R)-1-Amino-2,3,4-tri-O-benzyl-5-(benz-

yloxymethyl)cyclohex-5-ene-2,3,4-triol (30). Phthali-

mide derivative 29 (94 mg, 0.14 mmol) was dissolved in

EtOH (8 mL) and ethylene diamine (0.8 mL), and the

mixture was stirred at 70 °C. After 3 h, TLC (EtOAc)

showed the presence of a single compound (R_f0.3).

The reaction mixture was concentrated in vacuo and

the residue was puriﬁed by ﬂash column chromatogra-

phy (EtOAc; 1% triethylamine) to give the amine 30

22

(67 mg, 89%) as a colourless oil. ½aꢃ_Dꢂ82.3 (c 1.0,

CHCl₃); ¹H NMR (400 MHz, CDCl₃): 3.37 (1H, at

J = 9.0 Hz, H-2), 3.47 (1H, d, J_1,2= 8.6 Hz, H-1), 3.85

(1H, dd, J_2,3= 9.7 Hz, J_3,4= 7.7 Hz, H-3), 3.88 (1H,

23

d, J_6;6¼ 11:9 Hz, H-6), 4.23 (1H, d, H-6⁰), 4.34 (1H,

tography for characterisation. Isomer 1 ½aꢃ_D+13.8 (c

0

1

d, H-4), 4.45, 4.51 (2H, ABq, J_AB= 11.8 Hz, PhCH₂),

4.68–4.71 (2H, m, 2 ꢁ PhCHH⁰), 4.80–4.85 (2H, m,

PhCHH⁰, PhCHH⁰), 4.94 (1H, d, J = 11.2 Hz,

PhCHH⁰), 5.00 (1H, d, J = 11.4 Hz, PhCHH⁰), 5.65

(1H, s, H-5a), 7.23–7.35 (20H, m, Ar-H); ¹³C NMR

(100 MHz, CDCl₃): 53.7 (d, C-1), 70.4 (t, C-6), 72.6,

74.7, 75.3, 75.4 (4 ꢁ t, 4 ꢁ PhCH₂), 80.5 (d, C-4), 84.9

(d, C-3), 85.2 (d, C-2), 127.8, 127.8, 127.9, 128.0,

128.0, 128.3, 128.5, 128.6, 128.7 (9 ꢁ d, Ar-CH), 135.9

(s, C-5), 138.3, 138.6 (2 ꢁ s, Bn–C).

1.0, CHCl₃); H NMR (400 MHz, CDCl₃): 2.19 (1H,

br s, OH-6), 2.99 (1H, d, J_OH,2= 5.1 Hz, OH-2), 3.56

(1H, m, H-6), 3.64 (2H, m, H-1, H-1⁰), 3.51–3.81 (3H,

m, H-3, H-5, H-6⁰), 3.89 (1H, dd, J= 3.7 Hz,

J = 6.4 Hz, H-4), 4.03 (1H, m, H-2), 4.49, 4.53 (2H,

ABq, J_AB= 11.9 Hz, PhCH₂), 4.54, 4.58 (2H, ABq,

J_AB= 11.5 Hz, PhCH₂), 4.61, 4.66 (2H, ABq,

J_AB= 11.6 Hz, PhCH₂), 4.65, 4.71 (2H, ABq,

J_AB= 11.3 Hz, PhCH₂), 7.20–7.36 (20H, m, Ar-H);

¹³C NMR (100 MHz, CDCl₃): 62.0 (t, C-6), 70.9 (d,

C-2), 71.3 (t, C-1), 73.2, 73.4, 73.6, 74.7 (4 ꢁ t,

4 ꢁ PhCH₂), 77.5, 79.7 (2 ꢁ d, C-3, C-5), 79.3 (d, C-4),

127.9, 128.0, 128.1, 128.1, 128.1, 128.3, 128.6, 128.6,

128.6, 128.6 (10 ꢁ d, 10 ꢁ Ar-CH), 138.0, 138.0, 138.1,

138.3 (4 ꢁ s, 4 ꢁ Ar-C). ESIMS m/z: [M+Na]⁺calcd

for C₃₄H₃₈O₆Na, 265.2561; found, 265.2561.

3.17.2. 1-epi-Valienamine (2). Benzyl ether protected

compound 30 (67 mg, 0.12 mmol) was dissolved in

THF (2 mL), and the solution cooled to ꢂ78 °C under

N₂. Ammonia (ca. 10 mL) was condensed into the ﬂask,

and sodium (ca. 80 mg) was added. The mixture turned

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

1689

23

Isomer 2 ½aꢃ_D+16.3 (c 1.0, CHCl₃); ¹H NMR

138.6 (6 ꢁ s, Ar-C) 144.1 (s, Tr-C). ESIMS m/z:

[M+Na]⁺calcd for C₅₃H₅₂O₆Na, 807.3656; found,

807.3660.

(400 MHz, CDCl₃): 2.20 (1H, br s, OH-6), 2.64 (1H, d,

0

J_OH,2= 6.7 Hz, OH-2), 3.37 (1H, dd, J_1;1¼ 9:3 Hz,

0

J_1,2= 6.1 Hz, H-1), 3.46 (1H, dd, J_1;1¼ 9:3 Hz;

J_{1 ;2}¼ 6:4 Hz, H-1⁰), 3.67 (1H, m, H-6), 3.70 (1H, m,

3.19. 1,3,4,5-Tetra-O-benzyl-6-O-trityl-^L-sorbose (35)

0

H-5), 3.78 (1H, m, H-6⁰), 3.85 (1H, dd, J_3,4= 6.9 Hz,

J_2,3= 2.4 Hz, H-3), 3.91 (1H, m, H-4), 3.94 (1H, m,

H-2), 4.40, 4.46 (2H, ABq, J_AB= 11.9 Hz, PhCH₂),

4.54, 4.75 (2H, ABq, J_AB= 11.2 Hz, PhCH₂), 4.59,

4.63 (2H, ABq, J_AB= 11.6 Hz, PhCH₂), 4.65, 4.71

(2H, ABq, J_AB= 11.4 Hz, PhCH₂), 7.20–7.36 (20H, m,

Ar-H); ¹³C NMR (100 MHz, CDCl₃): 61.8 (t, C-6),

69.7 (d, C-2), 71.4 (t, C-1), 72.7, 73.4, 74.8, 74.8 (4 ꢁ t,

4 ꢁ PhCH₂), 78.3 (C-3), 78.8 (C-5), 79.4 (C-4), 127.9,

128.0, 128.0, 128.0, 128.3, 128.4, 128.5, 128.6, 128.6

(9 ꢁ d, 9 ꢁ Ar-CH), 138.1, 138.2, 138.2 (3 ꢁ s, 3 ꢁ Ar-

C). ESIMS m/z: Calcd [M+Na]⁺for C₃₄H₃₈O₆Na,

565.2561; found, 565.2556.

Alcohols 34 (2.33 g, 2.96 mmol) were suspended in

CH₂Cl₂(100 mL). Pyridinium dichromate (7.80 g,

˚

21.0 mmol) and molecular sieves (4 A, 14 g) were added

under nitrogen. After 22 h, TLC (toluene–EtOAc 6:1)

indicated complete consumption of starting material

(R_f= 0.6) and the formation of a major product

(R_f= 0.7). The mixture was ﬁltered through silica,

washed with CH₂Cl₂and concentrated to aﬀord ketone

23

35 (2.13 g, 92%) as a pale yellow oil. ½aꢃ_Dꢂ1.1 (c 1.0,

CHCl₃); ¹H NMR (400 MHz, CDCl₃): 3.15 (1H, dd,

J_6;6¼ 10:4 Hz; J_5;6¼ 5:1 Hz, H-6), 3.46 (1H, m, H-6⁰),

0

3.90 (1H, m, H-5), 3.95, 4.27 (2H, ABq, J_AB= 11.4 Hz,

PhCH₂), 4.00 (1H, d, J_3,4= 3.7 Hz, H-3), 4.09, 4.17 (2H,

ABq, J_AB= 17.8 Hz, H-1, H-1⁰), 4.18 (1H, dd,

J_4,5= 5.8 Hz, H-4), 4.30, 4.35 (2H, ABq, J_AB= 12.0 Hz,

PhCH₂), 4.43, 4.63 (2H, ABq, J_AB= 11.3 Hz, PhCH₂),

4.55, 4.63 (2H, ABq, J_AB= 11.3 Hz, PhCH₂), 7.23–

7.44 (35H, m, Ar-CH); ¹³C NMR (100 MHz, CDCl₃):

62.9 (t, C-6), 73.3, 73.4, 73.8, 74.5, 74.8 (5 ꢁ t, C-1,

4 ꢁ PhCH₂), 79.0 (d, C-5), 80.1 (d, C-4), 82.9 (d, C-3),

127.2, 127.8, 128.0, 128.0, 128.0, 128.1, 128.1, 128.2,

128.3, 128.5, 128.5, 128.6, 128.8, 128.9, 129.2, 130.0

(16 ꢁ d, 16 ꢁ Ar-CH), 137.1, 137.6, 137.9 (3 ꢁ s, 3 ꢁ Ar-

C), 144.0 (s, Tr-C), 207.6 (C-2). ESIMS m/z: [M+Na]⁺

calcd for C₅₃H₅₀O₆Na, 805.3500; found, 805.3516.

3.18.2. 1,3,4,5-Tetra-O-benzyl-6-O-trityl-^L-iditol and

1,3,4,5-tetra-O-benzyl-6-O-trityl-^L-gulitol (34). Diols

33 (2.32 g, 4.28 mmol) were suspended in pyridine

(40 mL). Trityl chloride (1.79 g, 6.41 mmol) and DMAP

(15 mg, 0.13 mmol) were added, and the mixture was

stirred at rt and 10 h at 80 °C. After 14 h, TLC (tolu-

ene–EtOAc 6:1) indicated the complete consumption

of starting material (R_f= 0.5) and the formation of ma-

jor (R_f= 0.7) and minor (R_f= 0.9) products. The reac-

tion mixture was concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (tolu-

ene–EtOAc 1:0?9:1) to aﬀord alcohols 34 (2.33 g,

69%) as a pale yellow oil. (X and Y denote the two alco-

hols arbitrarily.) ¹H NMR (400 MHz, CDCl₃): 2.54 (1H,

d, J_OH,2= 6.2 Hz, OH-2^X), 2.88 (1H, d, J_OH,2= 5.5 Hz,

3.20. (3R,4R,5S) 1,3,4,5-Tetra-O-benzyl-2-methylene-6-

O-trityl-hexane-1,3,4,5,6- pentaol (36)

OH-2^Y), 3.20 (1H, dd, J_6;6¼ 10:3 Hz; J_5;6¼ 5:2 Hz, H-

0

6^Y), 3.27 (1H, dd, J_1;1¼ 9:4 Hz; J_1;2¼ 5:6 Hz, H-1^X),

Methyltriphenylphosphonium

bromide

(5.85 g,

0

3.37–3.40 (3H, m, H-1⁰, H-6^X, H-6⁰), 3.43 (1H, dd,

16.4 mmol) and potassium tert-butoxide (1.78 g,

15.8 mmol) were suspended in toluene (50 mL). The

mixture was stirred at 80 °C for 3 h, then a solution of

ketone 35 (2.14 g, 2.73 mmol) in toluene (25 mL) was

added. After 1 h, TLC (toluene–EtOAc 6:1) indicated

the complete consumption of starting material

(R_f= 0.5) and the formation of a major product

(R_f= 0.6). The mixture was diluted with toluene, ﬁltered

through silica and concentrated in vacuo to aﬀord al-

X

Y

J_{6 ;6}¼ 10:3 Hz; J_5;6¼ 4:0 Hz, H-6⁰), 3.54–3.56 (2H,

0

m, H-1^Y, H-1⁰), 3.60 (1H, dd, J_3,4= 3.7 Hz,

Y

J_2,3= 6.8 Hz, H-3^Y), 3.71 (1H, dd, J_2,3= 2.7 Hz,

J_3,4= 7.0 Hz, H-3^X), 3.73–3.77 (1H, m, H-2^X), 3.79–

3.83 (1H, m, H-5^X), 3.91 (2H, m, H-2^Y, H-5^Y), 3.97

(1H, dd, J_4,5= 3.7 Hz, J_3,4= 7.0 Hz, H-4^X), 4.05 (1H,

dd, J_2,3= 5.6 Hz, J_3,4= 3.7 Hz, H-4^Y), 4.15, 4.36 (2H,

ABq, J_AB= 11.4 Hz, PhCH₂), 4.37, 4.41 (2H, ABq,

J_AB= 12.0 Hz, PhCH₂), 4.46–4.68 (12H, m, PhCH₂),

7.10–7.44 (70H, m, Ar-CH); ¹³C NMR (100 MHz,

CDCl₃): 63.1 (t, C-6^Y), 63.4 (t, C-6^X), 70.1 (d, C-2^X),

70.9 (d, C-2^Y), 71.4 (t, C-1^Y), 71.5 (t, C-1^X), 73.0,

73.2, 73.3, 73.4, 74.5, 74.9, 75.0 (7 ꢁ t, PhCH₂), 77.9

(d, C-3^Y), 78.1 (d, C-5^X), 78.6 (d, C-3^X), 78.6 (d, C-

4^X), 79.3 (d, C-5^Y), 79.4 (d, C-4^Y), 127.2, 127.2, 127.6,

127.7, 127.8, 127.8, 127.8, 127.8, 127, 9, 127.9, 128.0,

128.0, 128.0, 128.2, 128.3, 128.4, 128.4, 128.4, 128.5,

128.5, 128.5, 128.5, 128.6, 128.6, 128.9, 128.9, 129.2

(27 ꢁ d, Ar-CH), 138.2, 138.3, 138.4, 138.4, 138.5,

23

1

kene 36 (2.13 g, >99%). ½aꢃ_Dꢂ5.8 (c 1.0, CHCl₃); H

0

NMR (400 MHz, CDCl₃): 3.16 (1H, dd, J_6;6

10:0 Hz; J_5;6¼ 4:7 Hz, H-6), 3.43 (1H, dd, J_5;6

¼

0

4:5 Hz, H-6⁰), 3.77 (1H, aq, J = 4.6 Hz, H-5), 3.93,

4.37 (2H, ABq, J_AB= 11.3 Hz, H-1, H-1⁰), 3.94, 3.99

(2H, ABq, J_AB= 13.5 Hz, PhCH₂), 3.96 (1H, m, H-4),

4.12 (1H, d, J_3,4= 5.5 Hz, H-3), 4.40, 4.45 (2H, ABq,

J_AB= 12.1 Hz, PhCH₂), 4.46, 4.60 (2H, ABq,

J_AB= 11.6 Hz, PhCH₂), 4.62, 4.72 (2H, ABq,

J_AB= 11.1 Hz, PhCH₂), 5.19 (1H, s, H-2a), 5.37 (1H,

s, H-2a⁰), 7.24–7.41 (35H, m, Ar-CH); ¹³C NMR

1690

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

(100 MHz, CDCl₃): 63.0 (t, C-6), 70.2 (t, C-1), 71.3,

72.8, 73.2, 75.4 (4 ꢁ t, 4 ꢁ PhCH₂), 79.8 (d, C-5), 80.4

(d, C-4), 82.2 (d, C-3), 116.1 (t, C-2a), 127.2, 127.5,

127.6, 127.7, 128.0, 128.1, 128.2, 128.4, 128.4, 128.4,

128.6, 128.7, 128.9 (13 ꢁ d, Ar-CH), 138.5, 138.5,

138.8, 138.9 (4 ꢁ s, 4 ꢁ Ar-C), 144.2 (s, C-2), 143.0 (s,

Tr-C). ESIMS m/z: [M+Na]⁺calcd for C₅₄H₅₂O₅Na,

803.3707; found, 803.3697.

3.21.2. Method 2: Wittig reaction/deprotection of ketone

39. Methyltriphenylphosphonium bromide (4.23 g,

11.9 mmol) and potassium tert-butoxide (1.27 g,

11.4 mmol) were suspended in toluene (10 mL). The

mixture was stirred at 80 °C for 90 min, then the mixture

was removed from the heat and cooled to 0 °C. (Cooling

the reaction mixture during the addition of ylid was

necessary on larger scales to avoid elimination, presum-

ably occurring via initial cleavage of the benzoate to re-

store the elimination-prone hemiketal.) A solution of

ketone 39 (3.05 g, 4.73 mmol) in toluene (15 mL) was

added. After addition was complete, the mixture was al-

lowed to stir at rt. After 30 min, TLC (pentane–EtOAc

4:1) indicated the complete consumption of starting

material (R_f= 0.5) and the formation of two products

(R_f= 0.8 and 0.4). MeOH (ca. 6 mL) was added, and

the mixture was ﬁltered through Celite and concentrated

in vacuo.

The residue was dissolved in MeOH (15 mL) and a so-

dium methoxide solution generated from sodium

(109 mg, 4.74 mmol) and MeOH (10 mL) was added.

After 1 h, TLC (pentane–EtOAc 4:1) showed the pres-

ence of a single major product (R_f= 0.4). The mixture

was added to HCl (100 mL) and extracted with EtOAc

(2 ꢁ 100 mL). The combined organic extracts were dried

(Na₂SO₄), ﬁltered and concentrated in vacuo. The resi-

due was puriﬁed by ﬂash column chromatography (pen-

tane–EtOAc 3:1) to give alkene 37 (2.34 g, 92%),

identical to that described above.

3.21. (3R,4R,5S) 1,3,4,5-Tetra-O-benzyl-2-methylene-

hexane-1,3,4,5,6-pentaol (37)

3.21.1. Method 1: deprotection of trityl ether 36. Pro-

tected alkene 36 (100 mg, 0.13 mmol) was dissolved in

a mixture of formic acid and Et₂O (1:1, 0.5 mL). The

mixture was stirred at rt. After 4 h, TLC (toluene–

EtOAc 6:1) indicated complete consumption of starting

material (R_f= 0.7) and the formation of major

(R_f= 0.2) and minor (R_f= 0.6) products. The mixture

was concentrated and the residue was puriﬁed by ﬂash

column chromatography (CH₂Cl₂?CH₂Cl₂–EtOAc

30:1) to aﬀord deprotected alkene 37 (46 mg, 66%);

22

½aꢃ_Dꢂ13.3 (c 1.0, CHCl₃); IR (ﬁlm); m 3458 (OH)

1

cm^ꢂ1; H NMR (400 MHz, CDCl₃): 3.46 (1H, m, H-

6), 3.61–3.64 (2H, m, H-5, H-6⁰), 3.78 (1H, at,

J = 4.7 Hz, H-4), 3.98, 4.07 (2H, ABq, J_AB= 12.7 Hz,

H-1, H-1⁰), 4.27 (1H, d, J_3,4= 4.8 Hz, H-3), 4.33, 4.57

(2H, ABq, J_AB= 11.5 Hz, PhCH₂), 4.46, 4.51 (2H,

ABq, J_AB= 11.9 Hz, PhCH₂), 4.53, 4.58 (2H, ABq,

J_AB= 11.6 Hz, PhCH₂), 4.67, 4.73 (2H, ABq,

J_AB= 11.3 Hz, PhCH₂), 5.33 (1H, s, H-2a), 5.43 (1H,

s, H-2a⁰), 7.21–7.27 (20H, m, Ar-CH); ¹³C NMR

(100 MHz, CDCl₃): 61.8 (t, C-6), 70.6 (t, C-1), 71.2,

72.8, 72.9, 75.1 (4 ꢁ t, 4 ꢁ PhCH₂), 79.3 (d, C-5), 80.7

(d, C-4), 81.0 (d, C-3), 117.0 (t, C-2a), 127.8, 127.8,

127.9, 127.9, 128.0, 128.4, 128.5, 128.6, 12.6, 128.8

(10 ꢁ d, 10 ꢁ Ar-CH), 138.1, 138.4, 138.4, 138.7

(4 ꢁ s, 4 ꢁ Ar-C), 142.7 (C-2). ESIMS m/z: [M+Na]⁺

calcd for C₃₅H₃₈O₅Na, 561.2611; found, 561.2590.

And the 6-O-formate compound (25 mg, 34%) as a

pale yellow oil. ¹H NMR (400 MHz, CDCl₃): 3.73–

3.81 (2H, m, H-3, H-4), 3.97, 4.07 (2H, 2 ꢁ d,

Working up the reaction after the Wittig reaction but

before methoxide deacylation allowed the isolation of

the protected alkene 41 as well as the deprotected alkene

37. Data for the benzoate-protected alkene 41 follow:

21

colourless oil; ½aꢃ_Dꢂ19.7 (c 1.0, CHCl₃); ¹H NMR

(500 MHz, CDCl₃): 3.88 (1H, dd, J_3,4= 6.1 Hz, J_4,5

=

4.0 Hz, H-4), 3.94–4.01 (2H, m, H-1, H-5), 4.08 (1H, d,

J_1;1¼ 12:6 Hz, H-1⁰), 4.36–4.42 (4H, m, H-3, H-6, H-6⁰,

0

PhCHH⁰), 4.45, 4.49 (2H, ABq, J_AB= 12.1 Hz, PhCH₂),

4.57 (1H, d, J = 11.6 Hz, PhCHH⁰), 4.58 (1H, d,

J = 11.5 Hz, PhCHH⁰), 4.71–4.72 (2H, m, PhCHH⁰,

PhCHH⁰), 4.84 (1H, d, J = 11.4 Hz, PhCHH⁰), 5.30

(1H, m, H-2a), 5.43 (1H, m, H-2a⁰), 7.24–7.96 (25H, m,

Ar-H); ¹³C NMR (125 MHz, CDCl₃): 64.3 (t, C-6), 70.1

(t, C-1), 71.1, 72.7, 73.2, 75.1 (4 ꢁ t, 4 ꢁ PhCH₂), 77.4

(d, C-5), 79.5 (d, C-4), 82.0 (d, C-3), 117.3 (d, C-2a),

127.6, 127.7, 127.7, 127.8, 127.8, 127.9, 128.2, 128.3,

128.4, 128.4, 128.5, 128.5, 128.7 (13 ꢁ d, Ar-CH), 129.7

(d, Bz-CH), 130.2 (s, Bz-C), 133.1 (d, Bz-CH), 138.2,

138.5 (4 ꢁ s, Bn–C), 142.6 (s, C-2), 166.2 (s, C@O);

ESI⁺m/z 665 [M+Na]⁺, 100%. ESIMS m/z: [M+Na]⁺

calcd for C₄₂H₄₂O₆Na, 665.2874; found, 665.2878.

J_1;1¼ 12:3 Hz, H-1, H-1⁰), 4.13–4.20 (2H, m, H-6, H-

0

6⁰), 4.30 (1H, m, H-5), 4.34, 4.56 (2H, ABq,

J_AB= 11.7 Hz, PhCH₂), 4.46, 4.51 (2H, ABq,

J_AB= 11.8 Hz, PhCH₂), 4.55, 4.60 (2H, ABq,

J_AB= 11.5 Hz, PhCH₂), 4.64, 4.76 (2H, ABq,

J_AB= 11.3 Hz, PhCH₂), 5.26 (1H, d, J = 1.0 Hz, H-

2a), 5.41 (1H, d, J = 1.3 Hz, H-2a⁰), 7.21–7.35 (20H,

m, Ar-CH), 7.76 (1H, s, CHO); ¹³C NMR (100 MHz,

CDCl₃): 63.3 (t, C-6), 70.5 (t, C-1), 71.1, 72.9, 73.3,

75.2 (4 ꢁ t, 4 ꢁ PhCH₂), 77.4, 79.4 (2 ꢁ d, C-3, C-4),

81.5 (d, C-5), 117.5 (t, C-2a), 127.8, 128.0, 128.3,

128.4, 128.5, 128.5, 128.6, 128.8 (8 ꢁ d, Ar-CH), 138.2,

138.3, 138.4, 138.5 (4 ꢁ s, 4 ꢁ Ar-C), 142.6 (s, C-2),

160.8 (d, CHO).

3.22. 1,3,4,5-Tetra-O-benzyl-6-O-pivalyl-^L-sorbose (38)

Hemiacetal 32 (200 mg, 0.37 mmol) was dissolved in

pyridine (1.6 mL) and pivalyl chloride (0.23 mL,

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

1691

1.85 mmol) added. The mixture was stirred at 60 °C for

17 h. After this time, TLC (pentane–EtOAc 3:1) showed

complete conversion of starting material (R_f= 0.4) into

a single product (R_f= 0.8). The mixture was diluted

with CH₂Cl₂(25 mL) and washed with HCl (1 M,

25 mL) and NaHCO₃(satd aq, 25 mL). The organic

phase was dried (Na₂SO₄), ﬁltered and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chro-

matography (pentane–EtOAc 6:1) to give the ketone

(4 ꢁ s, 4 ꢁ Bn–C), 166.3 (s, Bz-C@O), 207.4 (s, C-2);

ESI⁺m/z 1311 [2M+Na]⁺, 5%, 667 [M+Na]⁺, 100%.

ESIMS m/z: [M+Na]⁺calcd for C₄₁H₄₀O₇Na,

667.2666; found, 667.2633.

3.24. (3R,4R,5S) 1,3,4,5-Tetra-O-benzyl-2-methylene-6-

O-pivalyl-hexane-1,3,4,5,6- pentaol (40)

Methyltriphenylphosphonium

bromide

(544 mg,

23

38 (192 mg, 83%) as a colourless oil. ½aꢃ_Dꢂ18.0 (c 1.0,

1.52 mmol) and potassium tert-butoxide (161 mg,

1.44 mmol) were suspended in toluene (2 mL). The mix-

ture was stirred at 80 °C for 90 min, then the mixture

was removed from the heat and allowed to cool to rt.

A solution of ketone 38 (190 mg, 0.30 mmol) in toluene

(4 mL) was added and the mixture was stirred at rt.

After 90 min, TLC (pentane–EtOAc 6:1) indicated com-

plete consumption of the starting material and the for-

mation of a single product. The mixture was ﬁltered

through Celite and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (pen-

tane–EtOAc 8:1) to give the alkene 40 (172 mg, 91%).

CHCl₃); ¹H NMR (500 MHz, CDCl₃): 1.22 (9H, s,

C(CH₃)₃), 3.90 (1H, m, H-5), 3.95 (1H, m, H-4), 4.18

0

(1H, dd, J_5,6= 6.4 Hz, J_6;6¼ 11:9 Hz, H-6), 4.23–4.26

(3H, m, H-3, H-1, H-1⁰), 4.36 (1H, dd, J_5;6¼ 3:2 Hz,

0

H-6⁰), 4.37, 4.43 (2H, ABq, J_AB= 12.0 Hz, PhCH₂),

4.50–4.65 (6H, m, 3 ꢁ PhCH₂), 7.22–7.35 (20H, m,

Ar-H); ¹³C NMR (125 MHz, CDCl₃): 27.3 (q,

C(CH₃)₃), 38.8 (s, C(CH₃)₃), 63.8 (t, C-6), 73.3, 73.3,

73.7, 74.3, 74.4 (5 ꢁ t, 4 ꢁ PhCH₂, C-1), 76.7 (d, C-5),

79.2 (d, C-4), 81.3 (d, C-3), 127.8, 127.9, 127.9, 128.1,

128.1, 128.3, 128.4, 128.4, 128.5, 128.5, 128.6 (11 ꢁ d,

Ar-CH), 136.9, 137.4, 137.4, 137.9 (4 ꢁ s, Ar-C), 178.1

(s, Piv-C@O), 207.1 (s, C-2); ESI⁺m/z 1271

[2M+Na]⁺, 5%, 647 [M+Na]⁺, 100%. ESIMS m/z:

[M+Na]⁺calcd for C₃₉H₄₄O₇Na, 647.2979; found,

647.2970.

21

½aꢃ_Dꢂ18.0 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃):

1.19 (9H, s, C(CH₃)₃), 3.76 (1H, dd, J_3,4= 6.1 Hz,

J_4,5= 4.2 Hz, H-4), 3.81 (1H, aq, J = 5.0 Hz, H-5),

4.02 (1H, d, J_1;1¼ 13:0 Hz, H-1), 4.08 (1H, d, H-1⁰),

0

4.18 (1H, dd, J_5,6= 5.7 Hz, J_6,6= 11.5 Hz, H-6), 4.21

(1H, dd, J_5;6¼ 5:0 Hz, H-6⁰), 4.35 (1H, d, H-3), 4.39,

0

3.23. 1,3,4,5-Tetra-O-benzyl-6-O-benzoyl-^L-sorbose (39)

4.59 (2H, ABq, J_AB= 12.1 Hz, PhCH₂), 4.50–4.54

(3H, m, PhCHH⁰, PhCH₂), 4.66–4.72 (2H, m, PhCHH⁰,

PhCHH⁰), 4.57 (1H, d, J = 11.6 Hz, PhCHH⁰), 4.58 (1H,

d, J = 11.5 Hz, PhCHH⁰), 4.83 (1H, d, J = 11.3 Hz,

PhCHH⁰), 5.29 (1H, m, H-2a), 5.46 (1H, m, H-2a⁰),

7.28–7.37 (20H, m, Ar-H); ¹³C NMR (125 MHz,

CDCl₃): 27.3 (q, C(CH₃)₃), 38.8 (s, C(CH₃)₃), 63.9 (t,

C-6), 70.0 (t, C-1), 71.1, 72.8, 73.1, 75.2 (4 ꢁ t,

4 ꢁ PhCH₂), 77.7 (d, C-5), 79.8 (d, C-4), 81.9 (d, C-3),

116.9 (d, C-2a), 127.6, 127.7, 127.7, 127.8, 127.8,

128.3, 128.4, 128.4, 128.5, 128.5, 128.6 (11 ꢁ d, Ar-

CH), 138.2, 138.3, 138.5, 138.6 (4 ꢁ s, 4 ꢁ Bn–C),

142.7 (s, C-2), 178.2 (s, C@O); ESI⁺m/z 645

[M+Na]⁺, 100%. ESIMS m/z: [M+Na]⁺calcd for

C₄₀H₄₆O₆Na, 645.3187; found, 645.3201.

Hemiacetal 32 (3.02 g, 5.55 mmol) was dissolved in pyr-

idine (15 mL) and benzoyl chloride (1.92 mL,

16.7 mmol) added. The mixture was stirred at rt for

15 h. After this time, TLC (pentane–EtOAc 4:1) showed

complete conversion of starting material (R_f= 0.3) into

a single product (R_f= 0.4). The mixture was diluted

with EtOAc (100 mL) and washed with HCl (1 M,

100 mL). The aqueous phase was re-extracted with

EtOAc (100 mL), and the combined organic extracts

washed with NaHCO₃(satd. aq., 100 mL) then dried

(Na₂SO₄), ﬁltered, and concentrated in vacuo. The resi-

due was puriﬁed by ﬂash column chromatography (pen-

tane–EtOAc 5:1?4:1?7:2) to give the ketone 39

23

(3.05 g, 85%) as a colourless oil. ½aꢃ_Dꢂ24.8 (c 1.0,

1

CHCl₃); H NMR (500 MHz, CDCl₃): 4.04–4.06 (2H,

m, H-4, H-5), 4.25 (2H, s, H-1, H-1⁰), 4.33 (1H, d,

J_3,4= 3.6 Hz, H-3), 4.38–4.41 (2H, m, H-6, PhCHH⁰),

4.44 (1H, d, J = 11.9 Hz, PhCHH⁰), 4.53 (1H, d,

J = 11.5 Hz, PhCHH⁰), 4.56 (1H, d, J = 11.5 Hz,

PhCHH⁰), 4.58–4.67 (5H, m, H-6⁰, 2 ꢁ PhCHH⁰,

PhCH₂), 7.23–8.00 (25H, m, Ar-H); ¹³C NMR

(125 MHz, CDCl₃): 64.5 (t, C-6), 73.3, 73.4, 73.9, 74.3

(4 ꢁ t, 4 ꢁ PhCH₂), 74.5 (t, C-1), 76.5, 79.0 (2 ꢁ d, C-

4, C-5), 81.6 (d, C-3), 127.9, 128.0, 128.0, 128.0, 128.1,

128.3, 128.3, 128.5, 128.5, 128.5, 128.5, 128.5, 128.6,

128.6, 128.7 (15 ꢁ d, Ar-CH), 129.7 (d, Bz-CH), 130.1

(s, Bz-C), 133.1 (d, Bz-CH), 136.9, 137.3, 137.4, 137.8

Acknowledgements

˚

Financial support from Vetenskapsradet (the Swedish

research council) and Carl Tryggers Stiftelse is gratefully

acknowledged.

Supplementary data

Supplementary data associated with this article can be

found, in the online version, at doi:10.1016/j.carres.

2008.04.010.

1692

I. Cumpstey et al. / Carbohydrate Research 343 (2008) 1675–1692

22. Gomez, A. M.; Moreno, E.; Valverde, S.; Lopez, J. C.

Tetrahedron Lett. 2002, 43, 7863–7866.

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Article Doi

Studies on the synthesis of valienamine and 1-epi-valienamine starting from d-glucose or l-sorbose

DOI: 10.1016/j.carres.2008.04.010

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