Synthesis of vinylcyclopentanes via samarium(II) mediated tandem reactions

Tetrahedron 60 (2004) 8113–8130

Synthesis of vinylcyclopentanes via samarium(II) mediated

tandem reactions

*

Mounira Bent Sadok Ferjani, Zhihong Zhou and Sharon M. Bennett

´ ´ ´

Departement de chimie et de biochimie, Universite du Quebec a Montreal, Case postale 8888, succursale Centre-Ville,

`

´ ´

Montreal, Quebec, Canada H3C 3P8

´

Received 16 February 2004; revised 8 June 2004; accepted 18 June 2004

Available online 4 August 2004

Abstract—In the presence of either visible light or HMPA, SmI₂reacts with some carbohydrate derived u-iodoallylic alcohols, and their

acetylated derivatives, to give vinylcyclopentanediol and vinylcyclopentanetriol derivatives.

1. Introduction

photoirradiation of SmI₂reaction mixtures;^4,5the absor-

bance of visible light by SmI₂in the 560–700 nm range was

attributed to a 4f⁶to 4f⁵5d¹electronic transition and the

observed reactivity enhancement associated with an efﬁ-

cient electron transfer between photoexcited SmI₂and the

organic halides.^4aMore recently, Hilmersson and collabor-

ators have found that mixtures of SmI₂/H₂O/amine can also

be successfully used to reduce alkyl halides.⁶

Samarium(II) iodide is a versatile reducing reagent that has

been the subject of a large number of scientiﬁc papers over

the past two decades.¹The reduction of organic halides by

SmI₂in THF was ﬁrst described by Kagan’s group²and

several years later Inanaga and coworkers reported that

these reactions are faster when hexamethylphosphoramide

(HMPA) is added to the reaction mixtures.^3aElectro-

chemical studies on SmI₂/THF/HMPA solutions^3band

As well as being a popular reducing reagent for individual

transformations, samarium(II) iodide is useful in promoting

sequential or tandem reactions.^1d,eIn a preliminary

communication from our group we reported that E and Z

u-iodoallylic acetates 1a and 1b react with SmI₂in a

stereodivergent manner to give the vinylcyclopentanetriol

derivatives 3a and 3b [Fig. 1 and Table 1 (entries g and h)].⁷

The vinylcyclopentane derivatives 3a and 3b are formed by

a sequence of Sm(II) mediated steps and, at the time of our

ﬁrst report, our best results were obtained for reactions run

at low temperature with an excess of SmI₂in the presence of

both HMPA and MeOH. In contrast, the Bu₃SnH mediated

reactions of 1a and 1b gave the reductive cyclization

compounds 6a and 6b [Table 3, entries a and b]. Reaction of

the corresponding u-iodoallylic alcohol 2b with SmI₂in

THF–HMPA–MeOH under similar conditions was incom-

plete (Table 1, entry d); initial attempts to improve the

efﬁciency resulted in the formation of complex mixtures and

in a lower overall mass balance⁸but we have since

overcome these difﬁculties. We have expanded our

investigation so as to establish the generality of this method

and to identity the factors that are important with respect to

the efﬁciency and selectivity of these transformations.

3c

3d

X-ray structures of SmI₂(hmpa)₄and [Sm(hmpa)₆]I₂

have since been published. Kinetic studies comparing SmI₂

in THF with SmI₂in THF/HMPA,^3eand studies on the

mechanism of electron transfer (inner-sphere-type versus

outer-sphere-type) between Sm(II) and organic substrates,^3f,g

have been reported. An article describing the structure and

energetics of the SmI₂–HMPA complex in THF has also

appeared in the literature.^3hTogether these papers have

given us an appreciation of the role HMPA plays in

changing the redox properties of divalent samarium.

While the addition of HMPA to SmI₂reaction mixtures is

now fairly common, signiﬁcant efforts have been directed

towards ﬁnding safer promoters of SmI₂reductions. Several

years ago, the groups of Ogawa,^4aScaiano^4band Molander⁵

reported that irradiation of SmI₂reaction mixtures of

organic halides with visible light results in a signiﬁcant

reactivity enhancement. Literature reports described the

efﬁcient reduction of organic chlorides by the

Keywords: Alkenyl halides; Cyclisation; Samarium and compounds;

Tandem or sequential reactions.

* Corresponding author. Tel.: C1-514-987-3000-4320; fax: C1-514-987-

4054; e-mail: bennett.sharon_m@uqam.ca

The synthesis of functionalized cyclopentane molecules

doi:10.1016/j.tet.2004.06.099

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M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

Figure 1. Reaction of 1a, 1b and 2b with SmI₂and Bu₃SnH.⁷

Table 1. SmI₂reactions of u-iodoallylic acetates 1a and 1b and u-iodoallylic alcohols 2a and 2b

Exp.

S. mat and method^a

SmI₂/MeOH/HMPA

ratio

Isolated yields^b(%)

Tandem_cis

Tandem_trans

Diene

S. mat.

a

b

c

d

e

f

g

h

i

2b

2a

1a

1b

A2 (3 h)

A2 (4 h)

D (2.5 h)

A1

B2

3:0:0

4a:11

4a:34

4b:3

4b:13

5:3^c

50

3:9:0

4:10:0

5:19^c

5:14

36^c

e,f

—

4aC4b:57^d(4a/4bZ89/11)

4a:51

g

5:11:20

6:10:14.4

6:10:14.6

5:13:21

5:10:20

5:0:0

4b —^g

—

e,f

—

30

e,f

—

4a:76

4aC4b:62^d(4a/4bZ53/47)

3a:26

3a:76

3a:34

4b —^e,f

e,f

—

g

A1

3b:65

3b:6

3b:18

—

g

—

g

—

39

g

A2 (o.night)

—

a

With the exception of entries a and i, reactions were run in THF with 1 equiv of substrate, 9–13 equiv of MeOH, 3–6 equiv of SmI₂and 0–21 equiv of

HMPA; entries a and i were run in the absence of MeOH. See Section 4 for details of Sm(II) methods.

Compounds 4a and 4b are somewhat volatile and care must be taken to avoid loss during solvent removal steps.

Isolated as a slightly impure sample as determined by NMR.

b

c

d

e

f

In this experiment compounds 4a and 4b were isolated as a mixture; the trans/cis ratio was determined by ¹H NMR.

Compound not detected by TLC analysis of crude products before chromatography.

Not detected by GC–MS analysis of crude products before chromatography.

g

Not detected by either TLC or NMR analysis of the crude products before chromatography.

using SmI₂mediated annulation reactions is a research

Kan et al.^9bfound that aldehydes tethered to an allyl sulﬁde

or sulfone are also reduced with samarium(II) iodide in the

presence of HMPA to give vinylcyclopentanol products in a

stereoselective fashion. Unsubstituted 7-(phenylthio)-5-

heptenal or 7-(phenylsulfonyl)-5-heptenal substrates give

the corresponding trans vinylcyclopentanol. Substrates with

additional functional groups may react to give cis products

preferentially as illustrated below (Scheme 2).

objective that is shared by many groups. A number of

excellent methods have been reported in the literature but

only a few of these Sm(II) mediated cyclizations give direct

access to vinylcyclopentanes.^1,9Gillmann^9areported that

intramolecular reductive coupling of an aldehyde with an

allenic ester gives vinylcyclopentanols. The selectivity of

the reaction was attributed to chelation with a samarium ion

thus favoring formation of the diastereoisomer with the

hydroxyl and ester groups cis to one another (Scheme 1).

Molander and Harris^9chave described the synthesis of

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

8115

Scheme 1.

Scheme 2.

vinylcyclopentanes via a one pot, three step, nucleophilic

acyl substitution/ketyl-oleﬁn coupling/b-elimination

sequence. Cyclopentanones with a pendant enol ether are

generated after the ﬁrst step. Samarium(II) initiated ketyl-

oleﬁn coupling is then either followed by b-elimination or

by competitive protonation (Scheme 3).

not involve an addition to a carbonyl carbon. Because we

have used primary alkyl iodides as substrates, our cycliza-

tion reactions result in the formation of only one new

stereocenter. The following section describes the synthesis

of vinylcyclopentanediol and vinylcyclopentanetriol deriva-

tives from u-iodoallylic alcohol substrates, or their

acetylated derivatives, via a sequence of samarium(II)

iodide mediated transformations using either visible light or

HMPA as a promoter. The chemoselectivity and the

stereoselectivity of these Sm(II) reactions were compared

to those with Bu₃SnH. Reactions with Bu₃SnH gave the

expected 5-exo radical cyclization products whereas

vinylcyclopentanes were the major products of the Sm(II)

mediated tandem reactions.

9d

Aurrecoechea and Lopez found that ring contraction of

´

6-enopyranosides to form diastereomeric mixtures of

vinylcyclopentanols is possible using SmI₂and a catalytic

amount of Pd(0); the major products are those in which the

vinyl and hydroxyl groups of the newly formed stereo-

centers are trans to one another. A representative example is

shown below. These reactions are thought to involve Pd(0)-

mediated ring opening and formation of an aldehyde

tethered to a p-allyl palladium complex. Reduction of the

palladium complex with SmI₂and coupling of the resulting

allylsamarium species with the aldehyde function gives the

vinylcyclopentanol reaction products (Scheme 4).

2. Results and discussion

The substrates for this present study were prepared by

1,2-reduction of known carbohydrate-derived conjugated

tert-butyl esters with DIBAL.¹⁰After workup and chroma-

tography the desired allylic alcohols 2a, 2b, 10a, 10b and 11

Our approach to vinylcyclopentanes differs from those of

other groups (vide supra) in that our annulation reactions do

Scheme 3.

Scheme 4.

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M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

Figure 2. Preparation of u-iodoallylic alcohols and acetates.

were isolated in moderate to good yields. Acetylation of the

free hydroxyl groups of 2a, 2b and 10a under standard

conditions gave compounds 1a, 1b and 13. The acetonide

group of 10a was removed by treatment with MeOH and an

acidic resin to give the triol 12 in good yield (Fig. 2).

or changing the nature of the Sm(II) reductant by in situ

coordination with HMPA ligands. Our mass balance

improved when the reaction was run in the presence of

MeOH but the reaction was non selective and still

incomplete after 4 h at room temperature. There is an

marked improvement in stereoselectivity when the Sm(II)

reductions were run with either visible light or HMPA as a

promoter. Photoirradiation of the reaction mixture, using a

xenon lamp, allowed us to push the reduction to completion

and to improve the stereoselectivity of the reaction.

Unfortunately, an appreciable amount of compound 5 was

formed under these conditions. We had more success using

HMPA as a promoter for the sequenced reactions of 2b but

light was successfully used with some of the other substrates

described in this paper (vide infra).

The experimental conditions and results of reactions with

Sm(II) for 1a, 1b, 2a and 2b are shown in Table 1 and those

for compounds 10a, 10b, 11, 12 and 13 are summarized in

Table 2. We used commercially available solutions of SmI₂

for our experiments. The SmI₂solution was transferred

dropwise, using a cannula, over ca. 10 min to a solution of

the u-iodoallylic alcohol in THF/MeOH or in THF/HMPA/

MeOH under an argon atmosphere. The ﬁnal concentration

of the starting material was 0.015 M. It should be noted that,

at the time reactions were quenched, the reaction mixtures

were still either the deep blue color associated with SmI₂in

THF or the purple color associated with solutions of SmI₂in

THF/HMPA. This was also true for experiments where the

reduction was incomplete, as judged by the presence of

either unreacted starting material or simple reductive

cyclization compounds.

Reaction of 2b at low temperature with 5 equiv of SmI₂and

20 equiv of HMPA was stereoselective but incomplete

(Table 1, entry d); attempts to push the reduction to

completion by simply increasing the quantity of SmI₂from

5 to 7 equiv, while keeping the SmI₂–HMPA ratio at ca. 1:4,

resulted in the formation of some of compound 5.⁸This loss

of chemoselectivity is presumably due to an increase in the

rate of the b-elimination reaction due to the increase in the

Sm(II) concentration. This pathway, leading to 5, is

competitive with that leading to 4a (Scheme 5). We have

since found that a more successful and convenient approach

is to run the reaction at room temperature with a different

molar ratio of substrate, SmI₂, and HMPA (vide infra). The

selectivity of the reaction was excellent and the isolated

yield of 4a was good (Table 1, entry e).

Our initial investigations focused on compound 2b. Room

temperature reactions with an excess of SmI₂in THF under

ambient lighting conditions are incomplete after 3 h and

gave complex mixtures of starting material, vinylcyclopen-

tanes (4a and 4b) and non-cyclized b-elimination product 5

(Table 1, entry a). The stereoselectivity of the tandem

cyclization-reductive elimination process was poor. One of

the reaction condition changes that we considered involved

adding a proton source. We also considered either

irradiating our reaction mixtures with a visible light source

As one might expect, based on considerations of A-strain,¹¹

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

Table 2. Reactions of 2-deoxy-D-ribose derived substrates with SmI₂–HMPA and SmI₂–hn

8117

Exp.

S.mat.

Method^aand

SmI₂/HMPA ratio

Tandem (T_trans,T_cis) and simple (S_trans,S_cis) reaction product ratios^b

Yield (%) of

vinylcyclo-

pentanes

T_trans

T_cis

S_trans

S_cis

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

10a

10b

13

11

12

C

4:19

83

85

82

87

58

61

16

28

90

95

91

82

83

84

83

80

53

82

67

78

92

84

40

28

11

13

12

2

7

8

2

11

3

5

15

10

16

8

20

9

6

0

3

2

0

3

0

7

0

6

0

13

39^c

B1

C

B1

B2

D

4:19

4:9.5

4:4.8

4:0

2

6

91^d

n.d.

72^d

46^d

44^d,e

n.d.^f

n.d.^g

58^d,h

60^d,h

65^d

84^d

90^d

50^c

11

32

21

9

13

7

2

4

3

7

0

9

0

31

18

20

0

2

4:0

4:19

6:14

4:0

D

4:0

B2

B1

D

B2

B1

D

6:14

4:19

4:0

6:14

4:9.5

4:19

4:0

56^d

80^d

48^d

n.d.

51^d

79^c

0

7

s

t

u

v

x

y

22

8

14

60

51

B2

D

6:14

4:19

4:0

77^c

74^c

0

7

73^c

B2ⁱ

6:14

56^c,j

a

With the exception of entry c, reactions were run in THF with 1 equiv of substrate, 10 equiv of MeOH, 4–6 equiv of SmI₂and 0–19 equiv of HMPA; entry c

was run in the absence of MeOH. See Section 4 for details on Sm(II) methods.

Ratios determined by GC–MS after workup and before concentration of the dried organic phase.

Isolated yield of puriﬁed compounds.

GC yields are reported for 14a and 14b (volatile compounds); these values were determined after chromatography but before evaporation of solvents. The

error associated with these values is less than or equal to 5%.

Incomplete; GC–MS of crude indicated that 10a accounted for 8% of reaction products.

Incomplete; GC–MS of crude indicated that 10a accounted for 71% of reaction products. Trace amounts of two unidentiﬁed compounds were also detected

in the crude products.

Incomplete; GC–MS of crude indicated that 10a accounted for 45% of reaction products.

The organic phase was washed several times with aq. CuSO₄to remove residual HMPA.

Reaction products for this experiment with 12 were isolated as their acetylated derivatives; product ratios were determined by ¹H NMR.

Simple cyclization products 22aC22b were also isolated (14%).

b

c

d

e

f

g

h

i

j

leads to the trans product while cyclization via conformer

Ib is expected to be the minor pathway and leads to

formation of the cis products. Reaction of 2a, under the

the Sm(II)-mediated cyclization of the Z u-iodoallylic

alcohol 2b is more stereoselective than that of the

corresponding E isomer 2a. Cyclization via conformer Ia

Table 3. Reductive cyclizations with Bu₃SnH

Entry

S. mat. and method^a

Simple reductive cyclization products

Diastereomeric ratios (trans/cis)^b

Isolated yields (%)^c

a

b

c

d

e

f

1b

1a

2b

10a

10b

13

Method E

Method F^d

Method F

Method F^d

79/21

37/63

93/7

82/18

90/10

76/24

89/11

42/58

6aC6b:72

6aC6b:25; 1a:10

6aC6b:61

18aC18b:75

18aC18b:63

20aC20b:86

19aC19b:73

22aC22b:62

g

h

11

12

a

Method E: Bu₃SnH, AIBN, reﬂuxing benzene. Method F: Bu₃SnH, Et₃B, toluene (d–g) or THF (c, h), room temperature.

1

Ratios determined by H NMR and/or GC–MS after workup and chromatography.

Isolated yield of puriﬁed compounds.

Products of reactions of 12 and 2b were isolated as their acetylated derivatives.

b

c

d

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M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

Scheme 5. Possible mechanistic pathways.

room temperature SmI₂–HMPA conditions, resulted in the

formation of both trans and cis-cyclized products 4a and 4b

in almost equal proportions (Table 1, entry f).

either (1) cyclize in a 5-exo fashion to give the cyclic

secondary radical IIa or (2) be reduced by a second

equivalent of Sm(II) to give organosamarium species III.

Cyclization via conformer Ia would eventually give the

trans product in which the C-4 substituent is on the opposite

side as all the other ring substituents. In the Bu₃SnH

mediated reaction, H-atom abstraction allows for the

transformation of IIa to the simple reductive cyclization

compound. In the samarium(II) mediated conversion, this is

also a possibility if H-atom abstraction from THF is

competitive with further reduction. Alternatively, the cyclic

secondary radical IIa may be reduced by Sm(II) to give

an organosamarium intermediate IVa; b-elimination

results in formation of 4a. If intermediate III is formed, it

may then either (1) undergo b-elimination to give diene 5 or

Reduction of the acetylated derivatives 1a and 1b with SmI₂

in the presence of HMPA also results in the formation of

vinylcyclopentane products. While the stereoselectivity for

the u-iodoallylic acetate 1b is slightly less than that

observed for the u-iodoallylic alcohol 2b, both of these Z

substrates give predominantly the trans tandem products.

Once again, as expected, the double bond geometry has a

marked effect on the stereoselectivity of these reactions and

reduction of the E diastereoisomer 1a gives predominantly

the cis derivative 3b (Table 1, entry g).

0

Two possible mechanisms, that may explain our obser-

vations for substrate 2b, are illus₀trated in Scheme 5. They

involve either a radical or a S_Ntype cyclization.¹²It is

relevant to note that reduction of 2b with Bu₃SnH (Table 3,

entry c) gives the 5-exo radical cyclization products;

compounds 5, 4a and 4b were not detected in our Bu₃SnH

reaction mixture. This observation together with the

requirement of an excess of Sm(II) suggests that organo-

samarium intermediates are involved at some stage in our

reactions and result in the formation of b-elimination

products.^13–15Scheme 5 presents two possible pathways

available to compound 2b.

(2) cyclize in a S_Ntype fashion to give the vinylcyclo-

pentane derivatives 4a and 4b. Elimination may be assisted

by coordination of the departing hydroxyl groups with

Sm(III).

Both the Z double bond geometry of 1b and 2b and the

presence of a substituent at the g-position are factors that

favor formation of trans vinylcyclopentanetriol derivatives

3a and 4a. Reductions of the E isomer 1a with Sm(II) were

less stereoselective than those with 1b and the major

product was the cis derivative 3b. The E u-iodoallylic

alcohol 2a gave almost equal amounts of the trans and cis

compounds 4a and 4b. This same tendency for stereodiver-

gence was not, however, seen with the simpler compounds

Sm(II) reduction of 2b gives a primary radical which may

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

8119

Scheme 6.

10a and 10b; these two u-iodoallylic alcohols lack a

substituent at the g-position. Reduction of either 10a or 10b

with Sm(II) gives the same trans vinylcyclopentane

derivative 14a as the major reaction product (Scheme 6).

after chromatography using a calibration curve. Reaction

products of substrate 11 are less volatile and yields reported

in entries t–v are for the isolated compounds 15a and 15b.

The isolation of reaction products of substrate 12 with

Sm(II)–HMPA was complicated by the solubility of

compounds 16a and 16b in water and so the yield reported

for the last entry of Table 2 corresponds to that of the

peracetylated derivatives 17a and 17b.

Compound 14a is the major product formed when Sm(II)

reacts with either 10a, 10b or 13 (see Table 2). It is not the

only product however and small quantities of other

compounds were detected by GC–MS analysis of our

crude reaction products before chromatography; one of

these minor components is the expected cis isomer 14b.

Based on our results with compound 2b we considered the

possibility that uncyclized b-elimination products (Fig. 3)

might be present as minor reaction products. This proved to

be incorrect as the minor reaction products were actually the

simple reductive cyclization compounds. Reactions run

with Bu₃SnH and our substrates (Table 3) allowed us to

prepare authentic samples of compounds 18–22; NMR and

GC–MS data for these compounds matched those of the

minor reaction products of the Sm(II) reactions.

Either visible light or HMPA can be used to facilitate these

reactions. Reactions using visible light as a promoter were

carried out at room temperature using a xenon lamp with

appropriate ﬁlters. Reaction conditions involving the

photoirradiation of SmI₂reaction mixtures with a visible

light source offered some practical advantages over the

HMPA conditions. In addition to the obvious safety

consideration of using visible light as a promoter, rather

than HMPA, isolated yields of vinylcyclopentanediol

derivatives were higher for substrates 11–13. Isolation of

the major reaction products was easier due, in part, to a

simpler workup procedure and because reactions run under

the SmI₂-hn conditions favored the exclusive (Table 2,

entries p, t, x) or near exclusive (entries k and l) formation of

the vinylcyclopentanediol compounds. The stereochemistry

of the SmI₂–hn reactions, of the Figure 3 substrates, was

equivalent or slightly less than that observed under our best

Sm(II)–HMPA conditions.

Crude and puriﬁed products were analyzed by TLC, GC–

MS and by NMR. The product ratios were determined after

reaction workup but before chromatography. The vinyl-

cyclopentane derivatives 14a and 14b are somewhat volatile

and so, with the exception of entries a and n of Table 2, the

yields given for these compounds are GC yields determined

Figure 3. Conversion of u-iodoallylic alcohols to tandem and simple cyclization products.

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M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

The results of the Sm(II)–HMPA mediated reactions of

substrates 10–13 (Table 2) show that the diastereoselectivity

and the product distribution vary with the reaction

conditions and the substrate characteristics. Reactions with

SmI₂-HMPA were run at either room temperature (Method

B2) or at K78 8C (Methods B1 and C) under ambient

lighting conditions in the presence of MeOH and with either

4 or 6 equiv of SmI₂per equivalent of alkenyl iodide.

Although the sequenced reactions formally require only

2 equiv of Sm(II), we routinely ran these reactions in the

presence of excess reagent. We found that both the quantity

of HMPA and its order of addition are key factors in the

determining the outcome of these Sm(II)–HMPA mediated

reductions. The proportion of unreacted starting material

and simple reductive cyclization products increases as the

quantity of HMPA is reduced for both the K78 8C and the

room temperature reactions. As we decreased the quantity

of HMPA (entries b, d, f, g) we observed a drop in the

proportion of vinylcyclopentanediol products; in the

absence of HMPA at K78 8C (entry g) the major reaction

component is unreacted starting material 10a. Removal of

methanol from the reaction mixture does not have an

appreciable effect on the ratio of tandem–simple cyclization

products (entries b and c).

of vinylcyclopentanes formed if the THF solution of SmI₂is

added dropwise to a solution of 10a in THF–MeOH–

HMPA? We noticed that, during the initial phase of the

transfer process, the deep blue color of the SmI₂/THF

solution rapidly dissipates and the deep purple color

associated with SmI₂/THF/HMPA solutions persisted only

after addition of ca. two molar equivalents of Sm(II). One

possible explanation for this observation and for the

differences observed for Methods B1 and C (entries d and

e) is that during the addition of the ﬁrst 2 equiv of SmI₂, to

the solution of the substrate in THF–MeOH–HMPA, the

ratio of HMPA–SmI₂is actually greater than 4:1 and so the

Sm(II)–HMPA species that initially forms and rapidly reacts

with 10a has a greater number of HMPA ligands

coordinated to Sm(II) than does the reagent formed under

the Method C conditions.

Entry j (Table 2) summarizes a set of convenient reaction

parameters for 10a that allowed us to achieve both a high

ratio of tandem–simple reductive cyclization products as

well as a high level of diastereoselectivity. The reaction was

run at room temperature and does not require premixing of

SmI₂and HMPA. These conditions, as well as the SmI₂–hn

conditions, were then used for the reactions of the other

substrates of this series. Both the isopropylidene and the

isopentylidene substrates 10a and 11 give excellent ratios of

tandem–simple cyclization products under these conditions

(entries j and u, Table 2) with a slightly better diastereo-

selectivity observed for 10a. Acetylation of the hydroxyl

group of 10a to give 13 had a detrimental effect on the

Sm(II)–HMPA sequenced reactions (entry q), however

reaction of 13 under the SmI₂–hn conditions exclusively

gave compounds 14a and 14b in an 80:20 ratio (entry p).

Removal of the protecting group of the 1,2-diol group

had a bigger impact on product distribution; reductions

of 12 with either SmI₂–hn or Sm(II)–HMPA gave

slightly more cis cyclization products than trans

cyclization products. We observed a similar level of

diastereoselectivity for the Bu₃SnH mediated reaction

of 12 (entry h, Table 3). The trans/cis ratio was 42/58 for

the reductive cyclization products of the Bu₃SnH reaction

and 40/60 for the tandem products of the SmI₂–hn reaction

of 12.

One might expect a decrease in the ratio of tandem–simple

cyclization products under conditions where the Sm(II)

reducing reagent is not reactive enough to ensure that

reduction of the cyclized radical and b-elimination, to give

vinylcyclopentanes, is favored over hydrogen-atom abstrac-

tion (Scheme 5). The redox potential of Sm(II)–HMPA

complexes varies with the number of coordinated HMPA

ligands³and so it is not surprising that our results vary with

the SmI₂–HMPA ratios. The nature of the Sm(II)–HMPA

complexes formed in solution, when SmI₂in THF is mixed

with HMPA, depends on the HMPA–SmI₂molar ratio. It

has been proposed that, in the presence of more than

10 equiv of HMPA, the species formed is [Sm(HMPA)₆]I₂.

At 4 equiv, the principal species is [Sm(HMPA)₄(THF)₂]I₂

and at intermediate concentrations of HMPA (4–10 equiv)

both species are present. The exact nature of the Sm(II)–

HMPA complexes formed in solution in the presence of less

than 4 equiv of HMPA is not well understood.^3f

With the exception of entries a and e, all of the Sm(II)–

HMPA reactions summarized in Table 2 involve the

dropwise addition of SmI₂in THF to solutions of our

substrates in THF/MeOH/HMPA (Methods B1 and B2).

The order of addition of HMPA had little effect on results of

reactions of 10a with SmI₂when the 10a–SmI₂–HMPA

ratio was 1:4:19 (entries a and b). This was not true for

reactions with a lower HMPA–SmI₂ratio. If HMPA and the

THF solution of SmI₂were ﬁrst pre-mixed, before

transferring the resulting purple solution to a cooled solution

of 10a in THF–MeOH (Method C), we observed a decrease

in the ratio of tandem–simple cyclization products and in the

ratio of trans:cis products (entries d and e). Precomplexa-

tion, of Sm(II) with less than 4 equiv of HMPA per

equivalent of SmI₂, should result in the formation of

Sm(II)–HMPA complexes, with fewer HMPA ligands, that

are weaker reducing reagents than the complex or

complexes formed when the HMPA–SmI₂ratio is greater

than 4:1 (entry a). Why do we see an increase in the amount

2.1. Structure assignment for tandem and simple

cyclization products

The u-iodoallylic alcohols that we used in this study

originate from either ^D-(C)-ribonic g-lactone (1a, 1b, 2a,

2b) or 2-deoxy-^D-ribose (10–13). The relative conﬁguration

of C₄for compounds 4a and 4b was determined using the

known conﬁguration of C₁, C₂and C₃together with NMR

data from NOE and COSY experiments, vicinal coupling

constants, and simple ¹H–¹H decoupling experiments.

Analysis of the coupling constants associated with the H₃

1

and H₄protons is complicated by the fact that, for the H

NMR spectrum of 4a in CDCl₃, H₄appears as a complex

multiplet and the H₃and H₂signals overlap to give an

apparent doublet. ¹H NMR spectra of 4a were also recorded

in acetone-d₆and benzene-d₆. Although the use of acetone-

d₆did give a better resolution of some signals (i.e. H_2a,

0

H_2b, H_5aand H_5b) it did not allow us to resolve the H₂and

0

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

8121

H₃signals; separation of these signals was achieved,

however, using benzene-d₆.

Therefore, the relative conﬁgurations of compounds 3a

(trans isomer) and 3b (cis isomer) are as shown. Our NOE

experiments supported this stereochemical assignment.

Upon irradiation of the H₃signal of 3a we observed a

smaller NOE effect for H₄(2.0%) than we did in the

corresponding experiment for 3b (i.e. 4.3% enhancement

for H₄upon irradiation at H₃). Irradiation of H₄resulted in a

smaller NOE effect for the H₃proton of 3a (1.6%) than for

the H₃proton of 3b (5.7%).

The ¹H NMR spectrum of 4b in CDCl₃was easier to analyze

as, unlike 4a, the H₂and H₃protons have different chemical

shifts; the signals, of these two protons present as apparent

triplets due to similar coupling between H₃and either H₂or

H₄as well as between H₂and either H₃or H₁. The vicinal

coupling constants that we measured (J_3,2and J_3,4are both

ca. 5 Hz) are consistent with the H₃and H₄protons syn to

one another. We therefore assigned structure 4b to the minor

diastereoisomer isolated from the reaction of 2b with SmI₂

in THF/MeOH (Table 1, entry b).

The relative conﬁgurations of the simple cyclization

products 6a (trans isomer) and 6b (cis isomer) were also

determined by using the known conﬁgurations of C₁, C₂and

C₃together with NOE experiments. Upon irradiation of the

H₃signal of compound 6a, we observed a 8.4% enhance-

ment for the H₂signal but did not observe an effect for the

The NOE experiments that we ran support our structural

assignments for compounds 4a and 4b. We saw a smaller

NOE between the signals of H₄and of H₂CH₃in the case of

isomer 4a (where H₄and H₃are anti and the H₂and H₃

signals overlap) than we saw in the case of isomer 4b (where

H₄and H₃are syn). Irradiation of 4a in acetone-d₆at

2.60 ppm (H₄) resulted in a total NOE of 1.3% for the

overlapping H₂CH₃signals. Irradiation of 4b (CDCl₃C

D₂O) at 2.28 ppm (H₄) resulted in a total NOE of 4.6% for

the combined H₂CH₃signals.

0

H₄signal. A 5.1% effect was also noted for the H_{1 a}

multiplet. Upon irradiation of the H₂signal, we observed

enhancements for the H₃(7.4%) and H₁(6.3%) signals. In

the case of diastereoisomer 6b, irradiation of the H₃signal

resulted in enhancements for the signals at 4.66 ppm (H₂

0

and H₁, 8.9%) and 1.78 ppm (H₄and H_{1 b}, 4.8%). We

therefore assigned structure 6a to the major diastereoisomer

isolated from the reaction of 1b with Bu₃SnH and 6b to

We determined the relative conﬁguration of C₄of

compounds 3a and 3b in a similar fashion. The J_3,4value

of 3a (1.3 Hz) was determined with the help of decoupling

experiments and is consistent with H₃and H₄anti to one

another. The COSY spectrum of 3a showed only a weak

correlation between H₄and H₃. The J_3,4coupling constant

the structure of the major isomer from the Bu₃SnH reaction

of 1a.

The NMR spectra of the tandem cyclization products 14–17

and the simple cyclization products 18–22 were simpler

than those of the previously described compounds but the

absence of a stereogenic center at C₃or C₅made

assignment of the relative conﬁgurations at C₄slightly

more complicated. The C₃and C₅carbons are equivalent

1

(4.8 Hz) of 3b was determined with the help of H–¹H

decoupling and HOM2DJ experiments and was consistent

with the H₃and H₄protons of 3b syn to one another.

8122

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

and each have 2 diastereotopic protons with distinct

chemical shifts; assignments of the diastereotopic protons

were made using the known conﬁguration of C₁and C₂

together with NMR data and NOE experiments. Once the

identity of the Hb and Ha signals of each isomer was

established, additional NOE experiments then allowed us to

determine the conﬁguration at C₄for each of the

diastereoisomers. Details for the NOE experiments are

included in the Supplementary information.

Fisher–Johns apparatus and are uncorrected. GC–MS

analysis were run on a Hewlett–Packard GCD Plus

instrument (HP-5 column, 30 m length, 0.25 mm diameter,

1 mL/min ﬂow rate; electron ionization detector); oven

ramp initial temperature 50 8C, ﬁnal temperature 275 8C,

rateZ22 8C/min. Optical rotations were measured at

589 nm in ethanol (100%) with a JASCO P-1010 Digital

or a JASCO DIP-370 polarimeter. The reported concen-

trations are in g/100 mL. Radial chromatography was

carried out with a Harrison Research Chromatotron and

silica gel plates.

3. Conclusions

4.1.1. (2E)-2,3,7-Trideoxy-7-iodo-4,5-O-(1-methylethyli-

dene)-^D-ribo-hept-2-enitol (2a). A solution of 7a (0.1511 g,

0.3794 mmol) in THF (9.1 mL) was prepared under a

nitrogen atmosphere and cooled in a dry ice–acetone bath

(K25 to K35 8C). To this solution was added, dropwise

over 10 min, a solution of DIBAL (2.30 mL, 1.0 M solution

in hexanes, 2.30 mmol).¹⁶The reaction mixture was stirred

under these conditions for 1.5 h and then quenched with a

saturated aqueous solution of NH₄Cl (5.0 mL). The mixture

was stirred and the white cloudy solution was then ﬁltered

through a short pad of silica gel. The heterogeneous ﬁltrate

was transferred to a separatory funnel and the layers

separated; the aqueous layer was extracted with EtOAc

(20 mL!3) and the combined organic phases were washed

with H₂O (30 mL) and brine (30 mL). The organic layer was

then dried over MgSO₄, ﬁltered and concentrated. The

residue was puriﬁed by radial chromatography [2 mm silica

plate] to give 0.0934 g (75.7%) of 2a (oil): R_fZ0.20 (1:1

The experiments described in this manuscript demonstrate

that vinylcyclopentanes can be efﬁciently and stereoselec-

tively synthesized by the reduction of carbohydrate derived

u-iodoallylic alcohols with an excess of Sm(II). In contrast,

reductions of these same u-iodoallylic alcohols with

Bu₃SnH gave (2-hydroxyethyl)cyclopentanediol and -triol

derivatives. The sequenced or tandem reactions, leading to

vinylcyclopentane formation, are favored when the Sm(II)

reaction mixtures are either irradiated with a xenon lamp or

when HMPA is added. The quantity of HMPA used and the

order of addition of HMPA and SmI₂are important reaction

parameters. Reactions can be run at either K78 8C or at

room temperature. In general, the diastereomeric ratios of

the trans–cis cyclization products for reactions run with

HMPA were equal, or slightly higher, than those found for

either the SmI₂–hn or Bu₃SnH reactions. The chemoselec-

tivity of the Bu₃SnH reactions is different of course from the

Sm(II) mediated reactions and we isolated only the simple

reductive cyclization products from these reactions. For the

substrates originating from 2-deoxy-^D-ribose, reactions run

under the SmI₂–hn conditions presented several advantages

over those run with Sm(II)–HMPA. In addition to the

obvious safety advantage of using visible light as a

promoter, rather than HMPA, isolated yields of vinylcyclo-

pentanediol derivatives were higher for substrates 11–13

due, in part, to a simpler workup procedure and because

reactions run under the SmI₂–hn conditions gave exclu-

sively (11–13), or nearly exclusively (10a, 10b), the tandem

cyclization products.

1

EtOAc–hexanes). [a]_DZK5.4 (c 0.91, 15.7 8C). H NMR

d: 6.00 (ddt, JZ15.5, 0.8, 4.9 Hz, 1H, H₂), 5.84 (ddt, JZ

15.5, 6.9 Hz, 1.4 Hz, 1H, H₃), 4.74 (apparent t, J_app

Z

6.6 Hz, 1H, H₄), 4.20 (apparent d, JZ4.7 Hz, 2H, H₁), 3.98

(dd, JZ6.4, 8.0 Hz, 1H, H₅), 3.41–3.62 [m, 3H; H₆, H_7a, and

OH. Upon D₂O exchange this region integrates for 2H and

simpliﬁes to a dd at 3.55 ppm (JZ2.4, 10.1 Hz, 1H, H_7a)

and a partially resolved ddd at 3.47 ppm (JZ2.5, 8.7,

7.0 Hz, 1H, H₆), 3.35 (dd, JZ6.5, 10 Hz, 1H, H_7b), 2.83

(broad singlet, 1H, OH; D₂O exchangeable), 1.46 (s, 3H,

CH₃), 1.37 (s, 3H, CH₃). ¹³C NMR d: 132.7 (C₂), 126.4 (C₃),

108.9 (C(CH₃)₂), 80.0 (C₅), 77.6 (C₄), 68.9 (C₆), 62.5 (C₁),

27.8 (CH₃), 25.2 (CH₃), 14.2 (C₇). FTIR (cast): 3383 (s,

br) cm^K1. GC–MS: t_RZ10.75 min; m/z: 313 (0.6%, MK

CH₃), 157 (8.8%, MKICH₂CHOH), 128 (9.5%), 125

(4.7%), 99 (24.1%), 59 [100%, (CH₃)₂COH^C]. HRMS:

found 312.9934; calcd for MKCH₃]C₉H₁₄IO₄: 312.9937.

4. Experimental

4.1. General experimental

Unless otherwise noted, ¹H NMR (300 MHz) and ¹³C NMR

(75 MHz) spectra were recorded in CDCl₃on a Varian

Gemini 300 BB instrument. The symbols s⁰, d⁰, t⁰, and q⁰,

used for ¹³C NMR data, represent carbons having zero, one,

two and three attached hydrogens, respectively. HMQC and

NOE NMR experiments were run on a Bru¨ker AMX2 500

instrument. FTIR spectra were recorded on either a Bomem

MB series instrument or a Perkin–Elmer Series 1600

instrument. Mass spectra were run on a Kratos 25

RFA instrument.^†Melting points were recorded on a

4.1.2. (2E) 2,3,7-Trideoxy-7-iodo-4,5-O-(1-methylethyli-

dene)-^D-ribo-hept-2-enitol diacetate (1a). A solution of 2a

(0.0935 g, 0.285 mmol) and DMAP (0.0017 g,

0.0139 mmol) in CH₂Cl₂(1.5 mL) was prepared under

anhydrous conditions and cooled at K78 8C. Acetic

anhydride (0.12 mL, 1.27 mmol) and NEt₃(0.17 mL,

1.22 mmol) were then simultaneously added dropwise

(over 3 min) to this mixture.¹⁷The reaction mixture was

stirred for 10 min, quenched with a mixture of H₂O–ether

(5 mL, 1:1 v/v) and then warmed up to room temperature.

The aqueous layer was extracted with EtOAc (3!10 mL)

and the combined organic layers were washed with aqueous

citric acid (20 mL, 10%), saturated aqueous NaHCO₃

(20 mL) and brine (20 mL). The organic phase was then

dried over MgSO₄, ﬁltered and concentrated. Puriﬁcation of

^†Most of our compounds do not give detectable molecular ions in EI mode

but they do give an intense MKCH₃fragment that is a well known

characteristic of O-isopropylidene molecules;²³we were able to obtain an

accurate mass for these MK15 fragments.

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

8123

the residue by radial chromatography [(1 mm silica plate,

eluant: 18% EtOAc–hexanes (100 mL) followed by 1:1

EtOAc–hexanes (50 mL)] gave 1a (0.1094 g, 93.1%). R_fZ

0.24 (16% EtOAc–hexanes); mp 58–59 8C. [a]_DZK35 (c

0.0499 mmol) in CH₂CH₂(2.7 mL) was prepared under

anhydrous conditions and cooled to K78 8C. Ac₂O

(0.21 mL, 2.226 mmol) and NEt₃(0.30 mL, 2.2 mmol)

were then simultaneously added dropwise (over 3 min).¹⁷

The reaction mixture was stirred for 1.5 h, quenched with a

mixture of H₂O–ether (5 mL, 1:1 v/v) and then warmed up

to room temperature. The mixture was extracted with

EtOAc (3!10 mL) and the combined organic layers were

washed with aqueous citric acid (20 mL, 10%), saturated

aqueous NaHCO₃(20 mL) and brine (20 mL). The organic

phase was then dried, ﬁltered and concentrated. Puriﬁcation

by radial chromatography (20% EtOAc–hexanes, 2 mm

silica plate) gave pure 1b (0.2017 g, 95%) as a pale yellow

oil. R_fZ0.34 (TLC, 20% EtOAc–hexanes). [a]_DZ15.0 (c

1.69, 25 8C). ¹H NMR d: 5.78 (m, 1H, H₂), 5.60 (m, 1H, H₃),

5.02 (ddd, JZ1.1, 6.2, 8.6 Hz, 1H, H₄), 4.74 [ddd, JZ1.1,

7.1, 13.3 Hz, 1H, H_1a), 4.61 (ddd, JZ1.6, 6.2, 13.3 Hz, 1H,

H_1b), 4.43 (m, 1H, H₆), 4.25 (dd, JZ6.2, 8.3 Hz, 1H, H₅),

3.46–3.55 [2H, H_7aCH_7b; overlapping signals at 3.53 ppm

(dd, JZ3.4, 11.1 Hz) and 3.49 ppm (dd, JZ3.9, 11.1 Hz)],

2.09 (s, 3H, CH₃CO), 2.05 (s, 3H, CH₃CO), 1.48 (s, 3H,

1

1.12, 25 8C). H NMR d: 5.92 (apparent ddt, JZ15.5, 1.0,

5.7 Hz, 1H, H₂), 5.69 (apparent ddt, JZ15.5, 6.8, 1.4 Hz,

1H, H₃), 4.70 (apparent t, J_appZ6.3 Hz, 1H, H₄), 4.60–4.50

[2H, overlapping signals of H_1a(4.58 ppm, dd, JZ5.5,

13.6 Hz) and H_1b(4.52 ppm, dd, JZ5.9, 13.6 Hz)], 4.33

(apparent dt, JZ8.6, 3.4 Hz, 1H, H₆), 4.25 (dd, JZ5.9,

8.6 Hz, 1H, H₅), 3.51 [2H, overlapping signals of H_7a

(3.54 ppm, dd, JZ3.2, 11.1 Hz) and H_7b(3.49 ppm, dd, JZ

3.5, 11.0 Hz)], 2.08 (s, 3H, CH₃CO), 2.05 (s, 3H, CH₃CO),

1.48 (s, 3H, CH₃), 1.39 (s, 3H, CH₃). ¹³C NMR d: 170.5

(C]O), 169.3 (C]O), 127.9 (C₃and C₂, conﬁrmed by

HMQC experiment), 109.3 (C(CH₃)₂), 77.8 (C₅), 76.9 (C₄),

68.9 (C₆), 63.6 (C₁), 27.7 (C(CH₃)₂), 25.2 (C(CH₃)₂), 20.9

(CH₃CO), 20.8 (CH₃CO), 7.5 (C₇). FTIR (solution in

CH₂Cl₂) 1741 (s), 1736 (s) cm^K1. MS [EI] m/z: 397 (23.2%,

MKCH₃), 235 (28%), 211 (51.6%), 170 (51.3%), 141

(40.3%), 43 (100%, CH₃CO^C). HRMS: found 397.0152;

calcd for MKCH₃]C₁₃H₁₈IO₆: 397.0148. MS [CI, NH₃]

m/z: 430 (20.6%, MCNH₄), 397 (19.7%), 355 (74.1%), 43

(100%).

13

CH₃), 1.40 (s, 3H, CH₃). C NMR d: 170.5 (s⁰, C]O),

169.4 (s⁰, C]O), 128.6 (d⁰, C₃), 128.1 (d⁰, C₂), 109.4 (s⁰,

C(CH₃)₂), 77.8 (d⁰, C₅), 73.0 (d⁰, C₄), 68.8 (d⁰, C₆), 59.8 (t⁰,

C₁), 27.6 (q⁰, C(CH₃)₂), 25.1 (q⁰, C(CH₃)₂), 20.91 (q⁰,

COCH₃), 20.86 (q⁰, COCH₃), 7.3 (t⁰, C₇). FTIR (ﬁlm) 1741

(s) cm^K1. MS [EI] m/z: 397 (6.6%, MKCH₃), 43 (100%,

CH₃CO^C). HRMS: found 397.0153; calcd for MK

CH₃]C₁₃H₁₈IO₆: 397.0148.

4.1.3. (2Z)-2,3,7-Trideoxy-7-iodo-4,5-O-(1-methylethyli-

dene)-^D-ribo-hept-2-enitol (2b). A solution of DIBAL

(6.2 mL, 1.0 M in hexanes, 6.2 mmol) was added, dropwise

over 10 min, to a cooled (K25 to K35 8C) solution of 7b

(0.4097 g, 1.0288 mmol) in THF (23.3 mL) under a

nitrogen atmosphere.¹⁶After an additional 55 min the

reaction mixture was quenched with MeOH (8.5 mL).

Ether (6.5 mL), NaF (0.18 g, 4.3 mmol) and H₂O (1 mL)

were added and the cloudy solution was ﬁltered. The ﬁlter

cake was washed with EtOAc (3!5 mL) and the combined

ﬁltrates were concentrated. Puriﬁcation by radial chroma-

tography (1:1 EtOAc–hexanes, 4 mm silica plate) allowed

for the separation of 7b (0.0509 g, 12.4% recovery) from 2b

(0.2319 g, 68.7% yield of pure sample and 0.0162 g, 4.8%

yield of a slightly impure sample as determined by ¹H

NMR). Compound 2b: mp 88–90 8C, R_fZ0.27 (silica, 1:1

4.1.5. (2E) 2,3,4,7-Tetradeoxy-7-iodo-5,6-O-(1-methyl-

ethylidene)-^D-ribo-hept-2-enitol (10a). The method used

for the reduction of 8a is based on a procedure described in

the literature.¹⁸A solution of DIBAL (1.0 M in toluene,

1.05 mL, 1.05 mmol) was added dropwise over 10 min to a

cooled (0 8C) solution of compound 8a (0.200 g,

0.523 mmol) in anhydrous toluene (10 mL) under an

argon atmosphere. The reaction mixture was stirred at

0 8C for 2 h and then quenched by the addition of tert-

butanol (1.2 mL). The mixture was stirred for 30 min, water

(0.10 mL) was added and stirring continued for another

30 min. To this mixture was added an aqueous solution of

NaOH (2 M, 1.5 mL), CH₂Cl₂(20) mL and H₂O (10 mL).

The layers were separated and the aqueous phase was

neutralized by the addition of dilute aqueous HCl (0.1 M)

and re-extracted with CH₂Cl₂(3!40 mL). The combined

organic extracts were washed successively with saturated

aqueous solutions of NaHCO₃(25 mL) and NaCl (25 mL).

The organic phase was dried over MgSO₄, ﬁltered and

concentrated. Radial chromatography of the crude residue

gave 0.007 g (3.5% recovery) of starting material, 0.013 g

(8% yield) of the corresponding conjugated aldehyde (GC

purity 95%, contaminated with the saturated aldehyde) and

0.097 g (60% yield) of the allylic alcohol 10a (GC purity

98%) as a colorless oil (R_fZ0.35 silica, 4:1:1 CH₂Cl₂–

1

EtOAc–hexanes). [a]_DZ30.4 (c 1.5, 25 8C). H NMR d:

5.97 (partially resolved dddd, JZ11.2, 1.1, 7.4, 6.4 Hz, 1H,

H₂), 5.67 (partially resolved ddd, JZ1.3, 9.5, 11.1 Hz, 1H,

H₃), 5.15 (ddd, JZ1.0, 6.1, 9.4 Hz, 1H, H₄), 4.29 (ddd, JZ

1.5, 7.4, 12.4 Hz, 1H, H_1a), 4.13 (dd, JZ6.4, 12.3 Hz, 1H,

H_1b), 4.04 (dd, JZ6.2, 8.7 Hz, 1H, H₅), 3.58 (m, 1H, H_7a),

3.35–3.50 (m, 3H, H₆, H_7b, OH; upon D₂O exchange this

region integrates for 2H), 2.40 (broad s, 1H, OH; D₂O

exchangeable), 1.49 (s, 3H, CH₃), 1.38 (s, 3H, CH₃). ¹³C

NMR d: 131.4 (d⁰), 130.8 (d⁰), 109.5 (s⁰₀), 80.4 (d⁰), 73.5

(d⁰), 68.3 (d⁰), 57.9 (t⁰), 28.1 (q⁰), 25.5 (q ), 13.7 (t⁰). FTIR

(ﬁlm): 3357 (s, br) cm^K1. MS [CI] m/z: 346 (1.0%, MC

NH₄), 329 (2.3%, MC1), 253 (100%, loss of H₂O and

CH]CHCH₂OH). MS [EI] m/z: 313 (4.7%, MKCH₃), 295

[6.7%, MK(CH₃and H₂O], 171 (12.4%, ICH₂CHOH^C),

157 (13.2%, MKICH₂CHOH), 99 (81.0%), 59 [100%,

(CH₃)₂COH^C]. HRMS: found 312.9934; calcd for MK

CH₃]C₉H₁₄IO₄: 312.9937.

1

Et₂O–hexanes). [a]_DZ87.7 (c 0.18, CH₂Cl₂, 20.7 8C). H

NMR d: 5.77 (m, 2H, H₂and H₃), 4.37 (partially resolved

ddd,^*JZ5.5, 6, 8 Hz, 1H, H₆), 4.19 (ddd, JZ5.5, 6, 7 Hz,

1H, H₅), 4.14 (m which simpliﬁes after resolution enhance-

ment to a partially resolved dd, JZ1, 1 Hz, 1H, H_1a), 4.13

(m that simpliﬁes to a dd after resolution enhancement, JZ

1, 2 Hz, 1H, H_1b), 3.20 (dd, JZ8, 10 Hz, 1H, H_7a), 3.15 (dd,

JZ6, 10 Hz, 1H, H_7b), 2.35 (m, 2H, H_4aand H_4b), 1.63 (s

4.1.4. (2Z)-2,3,7-Trideoxy-7-iodo-4,5-O-(1-methylethyli-

dene)-^D-ribo-hept-2-enitol diacetate (1b). A solution of

2b (0.1697 g, 0.5173 mmol) and DMAP (0.0061 g,

8124

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

13

large, 1H, 1!OH), 1.48 (s, 3H, CH₃), 1.36 (s, 3H, CH₃). ^*J

values calculated after resolution enhancement. ¹³C NMR d:

132.1 (d, C₂/C₃), 127.7 (d, C₂/C₃), 108.7 (s, C(CH₃)₂), 78.2

(d⁰, C₅/C₆), 77.2 (d⁰, C₅/C₆), 63.5 (t⁰, C₁), 32.3 (t⁰, C₄), 28.4

(q⁰, CH₃), 25.7 (q⁰, CH₃), 3.4 (t⁰, C₇). FTIR (ﬁlm): 3405

(broad, OH), 1675 (w) cm^K1. GC–MS: t_RZ8.21 min,

(EI) m/z: 297 (9.1%, MKCH₃), 241 (100%, MK

CH₂CH]CHCH₂OH), 185 (38.5%, MKI), 183 (58%),

155 (24.6%), 59 (23.6%), 43(60.9%). HRMS (EI) found

296.9985; calcd for MKCH₃]C₉H₁₄IO₃: 296.9988.

CH₃). C NMR d: 170.7 (s⁰, C]O), 130.9 (d⁰, C₂/C₃),

126.9 (d⁰, C₂/C₃), 108.7 (s⁰, C(CH₃)₂), 78.1 (d⁰, C₅/C₆),

76.98 (d⁰, C₅/C₆), 64.7 (t⁰, C₁), 32.4 (t⁰, C₄), 28.4 (q⁰, CH₃),

25.7 (q⁰, CH₃), 20.9 (q⁰, CH₃), 3.1 (t⁰, C₇). FTIR (ﬁlm) 1738

(w), 1673 (w) cm^K1. GC–MS: t_RZ8.75 min, (EI) m/z: 339

(6.1%, MKCH₃), 241 (100%, MKCH₂CHCHCH₂OAc),

185 (38.2%), 183 (57.7%, ICH₂CHCHO), 43 (78.8%,

CH₃CO). HRMS (EI) found 339.0090; calcd for MK

CH₃]C₁₁H₁₆IO₄: 339.0093.

4.1.8. (2E) 2,3,4,7-Tetradeoxy-7-iodo-5,6-O-(1-ethylpro-

pylidene)-^D-ribo-hept-2-enoic acid tert-butyl ester (9). A

mixture of pentan-3-one (5.72 mL, 54.0 mmol), tert-butyl

(2E) 2,3,4,7-tetradeoxy-7-iodo-^D-ribo-hept-2-enoate¹⁰

(0.500 g, 1.46 mmol), pTSA$H₂O (0.003 g, 0.2 mmol) and

molecular sieves were stirred under an argon atmosphere at

70 8C for 24 h. The mixture was ﬁltered and the ﬁltrate

diluted with ether (15 mL) and successively washed with

saturated aqueous solutions of NaHCO₃(15 mL) and NaCl

(15 mL). The organic phase was dried over MgSO₄, ﬁltered

and concentrated. The crude residue was puriﬁed by radial

chromatography (4 mm silica plate) to give 0.253 g (51%)

of starting material and 0.209 g (35%) of 9 (R_fZ0.90, 2:2:3

CH₂Cl₂–EtOAc–hexanes) as a white solid, mp 44–45 8C.

[a]_DZK24 (c 0.18, CH₂Cl₂, 20.1 8C). ¹H NMR d: 6.88 (dt,

JZ15.5, 7 Hz, 1H, H₃), 5.86 (dt, JZ15.5, 1.5 Hz, 1H, H₂),

4.43 (partially resolved ddd, JZ6, 6, 8 Hz, 1H, H₆), 4.27

(partially resolved ddd, JZ5.5, 5.5, 8 Hz, 1H, H₅), 3.21 (dd,

JZ7.5, 10 Hz, 1H, H_7a), 3.10 (dd, JZ6.5, 10 Hz, 1H, H_7b),

2.45 (m, 2H, H_4aand H_4b), 1.68 (q, JZ7.5 Hz, 2H,

C(CH₂CH₃)₂), 1.64 (q, JZ7.5 Hz, 2H, C(CH₂CH₃)₂), 1.49

(s, 9H, C(CH₃)₃), 0.94 (t, JZ7.5 Hz, 3H, C(CH₂CH₃)₂),

0.90 (t, JZ7.5 Hz, 3H, C(CH₂CH₃)₂). ¹³C NMR d: 165.5

(s⁰, C₁), 142.8 (d⁰, C₃), 125.5 (d⁰, C₂), 112.8 (s⁰,

C(CH₂CH₃)₂), 80.4 (s⁰, C(CH₃)₃), 77.9 (d⁰, C₅/C₆), 76.0

(d⁰, C₅/C₆), 32.4 (t⁰, C₄), 30.1 (t⁰, CH₂CH₃), 29.1 (t⁰,

CH₂CH₃), 28.1 (q⁰, C(CH₃)₃), 8.6 (q⁰, CH₂CH₃), 8.0 (q⁰,

CH₂CH₃), 3.1 (t⁰, C₇). FTIR (KBr) 1700 (s), 1650 (m), 1160

(s) cm^K1. GC–MS: t_RZ10.04 min, (EI) m/z: 381 (24.6%,

MKEt), 251 (26.8%), 213 [20.1%, MK(ICH₂and C₄H₈)],

123 (17.2%), 57 (100%, tBu). HRMS (EI) found 381.0559;

mass calcd for M–Et]C₁₄H₂₂IO₄: 381.0563.

4.1.6. (2Z) 2,3,4,7-Tetradeoxy-7-iodo-5,6-O-(1-methyl-

ethylidene)-^D-ribo-hept-2-enitol (10b). A solution of

DIBAL (1.0 M toluene, 1.57 mL, 1.57 mmol) was added

dropwise over 15 min to a cooled solution (0 8C) of 8b

(0.272 g, 0.712 mmol) in anhydrous toluene (14 mL) under

argon. The mixture was stirred at 0 8C for 5 h and then

worked up as per compound 10a. After radial chromato-

graphy we isolated 0.164 g (74%) of allylic alcohol 10b (GC

purityZ98%) as a colorless oil. R_fZ0.31 (silica, 4:1:1

CH₂Cl₂-Et₂O–hexanes). [a]_DZ12.9 (c 0.26, CH₂Cl₂,

1

20.7 8C). H NMR d: 5.86 (m, 1H, H₂; decoupling of H₄

protons transformed the signal to an apparent dt with JZ11,

7 Hz), 5.65 (m, 1H, H₃; decoupling of H₄protons simpliﬁes

this signal to an apparent dt, JZ11, 1 Hz), 4.40 (apparent dt,

JZ6, 7 Hz, 1H, H₆), 4.29–4.09 [m, 3H, H_1a, H_1band H₅;

signal is simpliﬁed upon decoupling of H₄protons to a ddd

centered at 4.25 ppm (JZ1, 7, 12.5 Hz, 1H, H_1a), a

multiplet at 4.17 ppm (1H, H₅) and a ddd centered at

4.12 ppm (JZ1, 6.5, 12.5 Hz, 1H, H_1b)], 3.22 (dd, JZ

7,10 Hz, 1H, H_7a), 3.17 (dd, JZ6.5, 10 Hz, 1H, H_7b), 2.42

(m, 2H, H_4aand H_4b), 1.71 (s large, 1H, OH), 1.49 (s, 3H,

13

CH₃), 1.36 (s, 3H, CH₃). C NMR d: 131.4 (d⁰, C₂/C₃),

128.0 (d⁰, C₂/C₃), 108.7 (s⁰, C(CH₃)₂), 78.1 (d⁰, C₅/C₆), 76.8

(d⁰, C₅/C₆), 58.1 (t⁰, C₁), 28.1 (q⁰, CH₃), 27.7 (t⁰, C₄), 25.5

(q⁰, CH₃), 3.2 (t⁰, C₇). FTIR (ﬁlm): 3410 (s, br), 1650 (w),

1040 (s) cm^K1. GC–MS: t_RZ8.17 min, (EI) m/z: 297 (5.6%,

MKCH₃), 241 (100%, MKCH₂CHCHCH₂OH), 185

(36.3%, MKI), 183 (71.7%), 155 (30.9%), 85 (20.6%), 59

(27.6%), 43 (61.3%). HRMS (EI) found 296.9990; calcd for

MKCH₃]C₉H₁₄IO₃: 296.9987.

4.1.7. (2E) 2,3,4,7-Tetradeoxy-7-iodo-5,6-O-(1-methyl-

ethylidene)-^D-ribo-hept-2-enitol acetate (13). Pyridine

(5.5 mmol, 0.44 mL) and Ac₂O (4.6 mmol, 0.43 mL) were

added to a cooled (0 8C) solution of 10a (0.2862 g,

0.9148 mmol) in CH₂Cl₂(10 mL) under an argon atmo-

sphere. The mixture was stirred 0 8C for 1 h and at room

temperature for 12 h. Water (10 mL) was added, the phases

separated and the aqueous layer was extracted with CH₂Cl₂

(3!20 mL). The combined organic layers were washed

successively with aqueous HCl (0.1 M, 10 mL) and

saturated aqueous solutions of NaHCO₃(20 mL) and

NaCl (20 mL), dried over MgSO₄, ﬁltered and concentrated.

The crude was puriﬁed by radial chromatography to give

0.290 g (89%) of 13 as a colorless oil. R_fZ0.91 silica, 4:1:1

CH₂Cl₂–Et₂O–hexanes. [a]_DZ12.5 (c 0.17, CH₂Cl₂,

20.4 8C). ¹H NMR d: 5.76 (m, 2H, H₂and H₃), 4.54

(apparent dd, 2H, JZ6, 1 Hz, 2H₁), 4.36 (partially resolved

ddd, 1H, JZ6, 6, 8 Hz, H₆), 4.18 (partially resolved ddd,

1H, JZ6, 7, 5.5 Hz, H₅), 3.18 (dd, 1H, JZ10, 8 Hz, H_7b),

3.13 (dd, 1H, JZ10, 6 Hz, H_7a), 2.35 (m, 2H, H_4aand H_4b),

2.07 (s, 3H, C]OCH₃), 1.47 (s, 3H, CH₃), 1.36 (s, 3H,

4.1.9. (2E) 2,3,4,7-Tetradeoxy-7-iodo-5,6-O-(1-ethylpro-

pylidene)-^D-ribo-hept-2-enitol (11). A solution of DIBAL

(1.0 M toluene, 1.22 mL, 1.22 mmol) was added dropwise

over 12 min to a cooled (0 8C) solution of 9 (0.227 g,

0.554 mmol) in anhydrous toluene (12 mL) under an argon

atmosphere. The reaction mixture was stirred at 0 8C for 5 h

and then worked up as previously described for compound

10a. Radial chromatography (2 mm silica plate) of the crude

products allowed for the separation of 0.118 g (63%) of

allylic alcohol 11 from the minor reaction products.

Compound 11 was isolated as a colorless oil (GC purityZ

96%). R_fZ0.44 silica, 4:1:1 CH₂Cl₂–ether–hexanes. ¹H

NMR d: 5.77 (m, 2H, H₂and H₃), 4.40 (partially resolved

ddd, JZ6, 6, 8 Hz, 1H, H₆), 4.21 (m, 1H, H_5;signal

simpliﬁes to a partially resolved ddd after resolution

enhancement, JZ8, 6, 6 Hz), 4.14 (m, 2H, H_1aand H_1b),

3.20 (dd, JZ8, 10 Hz, 1H, H_7a), 3.15 (dd, JZ6, 10 Hz, 1H,

H_7b), 2.35 (m, 2H, H_4aand H_4b), 1.68 (m, 4H, 2!CH₂CH₃),

1.56 (s large, OH and H₂O), 0.95 (t, JZ7.5 Hz, 3H,

CH₂CH₃), 0.90 (t, JZ7.5 Hz, 3H, CH₂CH₃). ¹³C NMR d:

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

8125

131.9 (d⁰, C₂/C₃), ₀127.9 (d⁰, C₂/C₃), 112.5 (s⁰,

C(CH₂CH₃)₂), 78.0 (d , C₅/C₆), 77.0^*(d⁰, C₅/C₆, ^*This

signal is masked by the CDCl₃signal and was detected by

a DEPT experiment.), 63.5 (t⁰, C₁), 32.5 (t⁰, C₄), 30.2

(t⁰, CH₂CH₃), 29.1 (t⁰, CH₂CH₃), 8.6 (q⁰, CH₂CH₃), 8.0

(q⁰, CH₂CH₃), 3.8 (t⁰, C₇). FTIR (ﬁlm) 3395 (l), 1677

(w) cm^K1. GC–MS: t_RZ9.11 min, (EI) m/z: 311 (17.6%, M

-Et), 269 (11.1%, MKCH₂CH]CHCH₂OH), 213 (14.6%,

MKI), 81 (27.1%), 57 (100%, CH]CHCH₂OH). HRMS

(EI) found 311.0141; mass calcd for MKEt]C₁₀H₁₆IO₃:

311.0144.

(20 mL), dried over MgSO₄, ﬁltered and concentrated. The

crude products were puriﬁed by radial chromatography

(silica gel or Adsorbosil plates, with a mixture of EtOAc and

hexanes).

Method A2. As per Method A1, except that reactions were

run at room temperature.

Methods B1 and B2. A solution of the substrate

(0.348 mmol) in THF (8 mL), HMPA (1.16 mL,

6.67 mmol), and MeOH (0.14 mL, 3.5 mmol) was prepared

under an argon atmosphere and either cooled to K78 8C

(Method B1) or kept at room temperature (Method B2). To

this solution was added, dropwise (ca. 1.2 mL/min), a

commercial solution of SmI₂in THF (0.1 M, 13.9 mL,

1.39 mmol). The reaction was run under ambient lighting

conditions and the ﬁnal concentration of substrateZ

0.015 M. The reaction mixture was stirred under an argon

atmosphere for 1.75 h and then quenched by the addition of

dilute aqueous HCl (0.1 M, 20 mL). The mixture was

diluted with ether (20 mL), the phases separated and the

aqueous layer re-extracted with ether (3!30 mL). The

combined organic phases were washed successively with

saturated aqueous solutions of CuSO₄(3!30 mL),

Na₂S₂O₃(30 mL) and NaCl (30 mL), dried over MgSO₄,

ﬁltered. The ﬁltrate was analyzed by GC–MS, concentrated

and the crude residue puriﬁed by radial chromatography.

4.1.10. (2E) 2,3,4,7-Tetradeoxy-7-iodo-^D-ribo-hept-2-eni-

tol (12). Deprotection was accomplished using the protocol

of Hillier et al.¹⁹A mixture of 10a (0.151 g, 0.485 mmol),

MeOH (1 mL) and an acidic resin (Amberlite IR-120) was

stirred at room temperature for 24 h under an argon

atmosphere. The mixture was ﬁltered using Celite and the

ﬁltrate concentrated. Radial chromatography (2 mm silica

plate) gave 0.112 g (85%) of pure 12: solid, mp 78–79 8C.

R_fZ0.30 (silica, 19:1 CH₂Cl₂-MeOH). [a]_DZ16.1 (c 0.19,

1

21.4 8C). H NMR (300 MHz, DMSO-d₆) d: 5.58 (m, 2H,

H₂and H₃), 5.13 (d, 1H, JZ6 Hz, C₅–OH), 4.69(d, 1H, JZ

6 Hz, C₆-OH), 4.56 (dd, 1H, JZ5, 5.5 Hz, C₁–OH), 3.87

(apparent t, 2H, H_1band H_1athat simpliﬁes to a d with JZ

4 Hz after D₂O exchange), 3.46 (dd, JZ3, 10 Hz, 1H, H_7a),

3.28 (dd, JZ6, 10 Hz, 1H, H_7b), 3.21 (m, 1H, H₅), 3.04 (m,

1H, H₆; simpliﬁes to a ddd after D₂O exchange and

resolution enhancement, JZ3, 6, 7.5 Hz), 2.35 (m, 1H, H_4a),

2.04 (m, 1H, H_4b). ¹³C NMR (75 MHz, DMSO-d₆) d: 132.3

(d⁰, C₂/C₃), 127.2 (d⁰, C₂/C₃), 73.3 (d⁰, C₅/C₆), 72.8 (d⁰, C₅/

C₆), 61.6 (t⁰, C₁), 36.0 (t⁰, C₄), 15.7 (t⁰, C₇). FTIR (KBr)

3304 (br, OH) cm^K1. FTIR (solution in CCl₄–MeOH)

1669 (very weak) cm^K1. GC–MS: t_RZ8.28 min, (EI) m/

z: 254 (1.6%, MKH₂O), 183 (11.2%), 84 [24.5%, MK

(ICH₂CHOH and OH)], 83 (60.1%, MK(ICH₂CHOH and

H₂O)], 57 (32.3%, CH]CHCH₂OH), 55 (100%), 54

(50.1%), 44 (19.7%), 43 (26.5%). MS (CI, NH₃) m/z: 290

[3.3%, MC18 (M]C₇H₁₃IO₃)], 255 [3.3%, (MC1)-H₂O],

254 (16.2%, MKH₂O), 83 [100%, MK(ICH₂CHOH and

H₂O)]. HRMS (EI) found 253.9800; calcd for MK

H₂O]C₇H₁₁IO₂: 253.9804.

Method C. As per Method B1, with the following

exceptions: a solution of the substrate (0.385 mmol) in

THF (8.8 mL) and MeOH (0.16 mL, 3.9 mmol) was

prepared under an argon atmosphere and cooled to

K78 8C. In a second ﬂask, a solution of HMPA (1.28 mL,

7.36 mmol) and SmI₂in THF [0.1 M, 15.4 mL, 1.54 mmol]

was stirred at room temperature under an argon atmosphere

for 20 min and then transferred dropwise, by cannula (ca.

1.2 mL/min), to the ﬂask containing the iodide substrate.

Method D. A solution of the substrate (0.340 mmol) in THF

(8.9 mL) and MeOH (0.14 mL, 3.4 mmol) was prepared

under an argon atmosphere in a pyrex ﬂask at room

temperature. To this mixture was transferred, via cannula, a

solution of SmI₂in THF [0.1 M, 13.6 mL, 1.36 mmol]. The

resulting reaction mixture was irradiated for 4 h in the

visible range with a xenon lamp and appropriate ﬁlters. A

water ﬁlter [quartz cylinder dimensionsZ55 mm (length)!

28 mm (diameter)] and a Schott GG 375 nm ﬁlter were

placed between the Sciencetech 150 W xenon lamp and the

reaction ﬂask at spacing intervals of ca. 0.7, 2.0 and 3.5 cm

respectively. Workup as per Method B1 but without the

aqueous CuSO₄wash.

4.2. General procedures for reactions with samarium(II)

iodide

Method A1. A ﬂask containing the substrate (0.15 mmol)

and a magnetic stirring bar was closed with a septum and

purged with argon using a Firestone valve. Distilled THF

(2.5–5.5 mL) was added followed by HMPA and/or MeOH

where appropriate; reaction ﬂasks for experiments run at

K78 8C were cooled in a dry ice–acetone bath. A

commercial solution of SmI₂in THF (0.1 M, 4.5–7.5 mL,

0.45–0.75 mmol) was transferred via cannula to the reaction

mixture. The ﬁnal concentration of the iodide substrate was

0.015 M. The solution was stirred at K78 8C for 2 h and

then at 0 8C for 1.3–2 h under ambient lighting conditions.

The reaction was quenched by addition of a dilute aqueous

solution of HCl (0.1 M, 5 mL). The mixture was diluted

with water (5 mL) and extracted with EtOAc (3!10 mL).

The combined organic extracts were washed successively

with water (20 mL or 3!20 mL when HMPA was used),

saturated aqueous solutions Na₂S₂O₃(20 mL) and NaCl

4.3. Characterization of the vinylcyclopentanetriol

derivatives

Reaction of 2b with SmI₂in THF/MeOH (Method A):

preparation of 4a, 4b and 5a. A THF solution of SmI₂

(6.8 mL, 0.1 M, 0.68 mmol) was added to a solution of 2b

(0.0743 g, 0.2264 mmol), MeOH (0.085 mL, 2.1 mmol) and

THF (8.5 mL). After 4 h at room temperature reaction was

worked up and the crude residue puriﬁed by radial

chromatography [using the following series of eluants: 6%

EtOAc–CH₂Cl₂(80 mL), 26% EtOAc–CH₂Cl₂(100 mL),

8126

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

50% EtOAc–CH₂Cl₂(50 mL); 2 mm silica plate] in order to

separate 2b (0.0268 g, 36.1%, slightly impure by ¹H NMR)

from two other fractions (A and B). Further puriﬁcation of

fraction A (20% EtOAc–hexenes, 1 mm plate) allowed for

the separation of 4a (0.0144 g, 34.5%) and 4b (0.0055 g,

13.2%). Attempts to further purify fraction B (26% EtOAc–

CH₂Cl₂, 1 mm plate) were only partially successful; we

isolated 5 (0.0078 g, 18.7% yield) as a slightly impure

sample. Although compounds 4a and 4b are separable by

TLC, they are not separable using our GC method as both

compounds have a t_RZ6.5 min.

resolved ddd, JZ1, 7, 9 Hz, 1H, H₄), 4.58 (m, 1H, H₅), 4.22

(m, 1H, H_1a), 4.05 (m, 1H, H_1b), 3.75 (apparent t, J_app

5.5 Hz, 1H, OH), 1.42 (s, 3H, CH₃), 1.32 (s, 3H, CH₃]. ¹³

NMR (CDCl₃, 75 MHz): 134.2, 132.4, 128.3, 118.4, 109.0,

80.0, 74.4, 58.8, 28.0, 25.5. FTIR (ﬁlm): 3421(s) cm^K1

Z

C

.

GC–MS: t_RZ7.09 min; [EI] m/z: 169 (5.8%, MK15), 109

(26.3%), 98 (100%).

4.3.4. Compound 3a. Compound 3a: pale yellow oil. R_f₁Z

0.29 (TLC, 12% EtOAc–hexanes). [a]_DZ95.5 (c 1.49). H

0

NMR d: 5.77 (ddd, JZ6.4, 10.6, 17 Hz, 1H, H₁), 5.07–5.16

0

[2H, overlapping signals for H_2b(d 5.12, partially resolved

0

4.3.1. Compound 4a. Oil. R_fZ0.26 (TLC, 20% EtOAc–

hexanes). [a]_DZ16.6 (c 1.22). ¹H NMR (CDCl₃, 300 MHz)

ddd, JZ17, 1.2, 1.7 Hz) and H_2a(d 5.10, partially resolved

ddd, JZ10.6, 1.4, 1.3 Hz)], 4.91 (m, 1H, H₁), 4.67 (apparent

t, J_appZ5.5 Hz (J_2,3yJ_2,1), 1H, H₂), 4.48 [apparent d (J_2,3Z

0

d: 5.75 (ddd, JZ6.5, 10.5, 17.2 Hz, 1H, H₁), 5.09 [2H,

0

overlapping ddd signals; H_2b(5.09 ppm, JZ17.3, 1.4,

5.7 Hz), 1H, H₃; this signal is actually more complex.

Decoupling at 1.95 ppm (H_5b) results in a change of the

signal to a dd (J_2,3Z5.7, J_3,4Z1.3 Hz).], 2.77 (broad m, 1H,

H₄), 2.09–2.22 (4H, s at d 2.12 (OCOCH₃) and m for H_5a],

0

1.6 Hz) and H_2a(5.07 ppm, JZ10.6, 1.4, 1.5 Hz)], 4.49

[2H, apparent d, H₂and H₃. Upon decoupling at 4.08 ppm

(H₁), this signal collapses to an apparent singlet but

decoupling at 2.75 ppm (H₄) or at 1.90 (H_5aand H_5b) had

no obvious effect on the H₂CH₃signal.], 4.08 (broad m, 1H,

H₁), 2.75 (m, 1H, H₄), 2.40 (broad, 1H, OH, D₂O

exchangeable), 1.90 (m, 2H, H_5aCH_5b), 1.52 (s, 3H,

1.95 (m, 1H, H_5b), 1.50 (s, 3H, CH₃), 1.33 (s, 3H, CH₃). ¹³

C

NMR d: 170.7 (C]O); 137.7 (CH]CH₂), 115.5

(CH]CH₂), 111.4 (C(CH₃)₂), 84.1 (C₃), 77.9 (C₂), 73.3

(C₁), 43.8 (C₄), 31.7 (C₅), 26.1 (CH₃), 24.5 (CH₃), 20.9

(CH₃CO). FTIR (ﬁlm): 1739 (s), 1637 (w) cm^K1. MS [EI]

m/z: 226 (0.6%, M^C$), 211 (72.3%, MKCH₃), 43 (100%,

CH₃CO^C). HRMS: found 211.0973; calcd for

MKCH₃]C₁₁H₁₅O₄: 211.0970.

1

CH₃), 1.36 (s, 3H, CH₃). H NMR (benzene-d₆, 300 MHz)

0

d: 5.42 (ddd, JZ10.2, 17.5, 6.7 Hz, 1H, H₁), 4.86–4.79 (m,

0

2H, overlapping signals of H_2aand H_2b), 4.13 [dd, 1H,

J_3,2Z5.9 Hz, J_3,4Z1.8 Hz, H₃. Upon decoupling at

2.74 ppm (H₄), this H₃dd collapses to a d (JZ6 Hz)],

4.02 [apparent t (J_appZca. 6 Hz) which is a partially

resolved dd, 1H, H₂], 3.94 (broad m, 1H, H₁), 2.74 (broad m,

1H, H₄), 2.42 (broad, 1H, OH, D₂O exchangeable), 1.90 [m,

1H, H₅; upon decoupling at 2.74 ppm (H₄), this multiplet

collapses to a dd, JZ13, 8 Hz], 1.65 [m, 1H, H₅; upon

decoupling at 2.74 ppm (H₄), this multiplet collapses to a

4.3.5. Compound 3b. Compound 3b: pale yellow oil. R_fZ

0.21 (TLC, 12% EtOAc–hexanes) ¹H NMR d: 5.93 (m, 1H,

0

H₁), 5.10–5.17 (m, 2H, overlapping H_2aand H_2bsignals),

4.70 [m, 2H, overlapping H₁and H₂signals.], 4.53 [1H, H₃.

This signal appears to be a dd with line overlap (J_3,2Z5.1,

J_3,4Z4.8 Hz) but is actually more complex. Decoupling at d

2.35 (H₄) collapses the signal to an apparent d, J_3,2Z5.2 Hz.

Decoupling at d 4.70 (H₁CH₂) changes this signal to a m.],

2.35 (m, 1H, H₄), 2.13 (s, 3H, CH₃CO), 1.95 (m, 2H, H_5aC

H_5b), 1.49 (s, 3H, CH₃), 1.32 (s, 3H, CH₃). ¹³C NMR d:

170.9 (C]O); 135.7 (CH]CH₂), 116.4 (CH]CH₂), 110.8

(C(CH₃)₂), 81.3 (C₃), 77.8 (C₁or C₂), 73.7 (C₁or C₂), 42.5

(C₄), 31.5 (C₅), 25.7 (CH₃), 24.2 (CH₃), 20.9 (CH₃CO).

FTIR (ﬁlm): 1738 (s) cm^K1. MS [EI] m/z: 226 (1.1%, M^C$),

211 (100%, MKCH₃). HRMS: found 211.0968; calcd for

MKCH₃]C₁₁H₁₅O₄: 211.0970.

dd, JZ13, 5 Hz], 1.33 (s, 3H, CH₃), 1.12 (s, 3H, CH₃). ¹³

C

NMR (CDCl₃, 75 MHz) d: 138.0 (CH]CH₂), 115.3

(CH]CH₂), 111.6 (s⁰, C(CH₃)₂), 84.3 (d⁰, C₂or C₃), 79.0

(d⁰, C₂or C₃), 71.1 (C₁), 44.3 (C₄), 36.0 (C₅), 26.1 (CH₃),

24.3 (CH₃). FTIR (ﬁlm): 3457 (s) cm^K1. MS [EI] m/z: 184

(0.5%, M^C$), 169 (100%, MKCH₃). HRMS: found:

169.0862; calcd for MKCH₃]C₉H₁₃O₃: 169.0865.

4.3.2. Compound 4b. Oil. R_fZ0.18 (TLC, 20%

1

EtOAc–hexanes). H NMR d: 5.91 (m, 1H, H₁), 5.08–

0

5.16 (m, 2H, H_2aCH_2b), 4.54 [dd that presents as an

apparent t, J_appZ5 Hz, 1H, H₃. Decoupling at 2.28 ppm

(H₄) simpliﬁes the H₃signal to a d (J_2,3Z5 Hz).], 4.47 [dd

that presents as an apparent t, J_appZ5.5 Hz, 1H, H₂.

Decoupling at 3.91 ppm (H₁) simpliﬁes the H₂signal to a

d (J_2,3Z5 Hz).], 3.91 (broad m, 1H, H₁), 2.41 (d, JZ11 Hz,

1H, OH, D₂O exchangeable), 2.28 (m, 1H, H₄), 1.94 (m, 1H,

H_5b), 1.63 (m, 1H, H_5a), 1.50 (s, 3H, CH₃), 1.35 (s, 3H,

CH₃). ¹³C NMR d: 135.8 (CH]CH₂), 116.2 (CH]CH₂),

110.6 (s⁰, C(CH₃)₂), 81.6 (C₃), 78.8 (C₂), 72.2 (C₁), 42.8

(C₄), 35.5 (C₅), 25.6 (CH₃), 24.1 (CH₃). MS [EI] m/z: 183

(11.3%, MK1), 169 (100%, MKCH₃). HRMS: found:

169.0862; calcd for MKCH₃]C₉H₁₃O₃: 169.0865.

4.4. Characterization of the vinylcyclopentanediol

derivatives

In most instances cis and trans vinylcyclopentanediol

diastereoisomers were isolated as an inseparable (by radial

chromatography) mixture.

4.4.1. NMR and GC–MS analysis of mixtures of 14a

(trans) and 14b (cis) isolated from reactions with 10a,

10b or 13. Compounds 14a and 14b. Colorless oil (mixture

of cis and trans). R_fZ0.91 (silica, 1:2:3 Et₂O–CH₂Cl₂–

pentane). GC–MS: t_RZ4.2 min, trans compound 14a. [EI]

m/z: 153 (100%, MKCH₃), 111 (19.5%), 93 (86.4%, MK

C₃H₇O₂), 91 (35.5%), 77 (25%), 59 (16.4%, (CH₃)₂COH),

43 (60.4%). t_RZ4.4 min, cis compound. [EI] m/z: 153

(98.9%, MKCH₃), 111 (17.6%), 93 (100%, MKC₃H₇O₂),

91 (39.5%), 77 (29.2%), 67 (21.2%), 59 (20.8%,

(CH₃)₂COH), 43 (69.8%). ¹³C NMR (125 MHz, CDCl₃)

4.3.3. Compound 5. Compound 5 was isolated as a slightly

impure pale yellow oil. R_fZ0.39 (TLC, 26% EtOAc–

CH₂Cl₂). ¹H NMR (acetone-d₆, 300 MHz) d: 5.81–5.64 (m,

2H, H₂and H₆), 5.36 (m, 1H, H₃), 5.23 (ddd, JZ1, 2, 17 Hz,

1H, H₇), 5.11 (ddd, JZ1, 2, 10 Hz, 1H, H₇), 5.03 (partially

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

8127

chemical shifts assigned to the trans isomer 14a: d: 140.4

t_RZ4.62 min, trans isomer 16a. [EI] m/z: 110 (41.9%,

MKH₂O), 95 (46.7%), 83 (100%, C₅H₇O), 82 (47.7%), 67

(30.2%), 56 (33.9%), 55 (89.9%), 43 (27.3%), 41 (32.9%),

29 (24.1%), 28 (22.6%), 27 (20.9%); t_RZ4.58 min, cis

isomer 16b. [EI] m/z: 110 (37.5%, MKH₂O), 95 (42.4%),

83 (100%, C₅H₇O), 82 (42.4%), 81 (20%), 69 (21%), 67

(31.1%), 56 (37.5%), 55 (93.9%), 43 (28.2%), 41 (33.6%),

39 (27%). ¹³C NMR chemical shifts assigned to t₀he trans

0

(d , C₁), 113.9 (t , C₂), 108.8 (s , C(CH₃)₂), 80.4 (d ,

C₁/C₂), 39.8 (d⁰, C₄), 39.5 (t⁰, C₃/C₅), 26.1 (q⁰, CH₃), 23.7

(q⁰, CH₃); chemical shifts assigned to t₀he cis isomer 10b: d:

0

142.1 (d , C₁), 113.1 (t , C₂), 111.3 (s , C(CH₃)₂), 81.0 (d ,

C₁/C₂), 43.0 (d⁰, C₄), 38.7 (t⁰, C₃/C₅), 26.9 (q⁰, CH₃), 24.4

(q⁰, CH₃). ¹H NMR (300 MHz, CDCl₃) chemical shifts

assigned to the trans isomer 14a: d 5.74 (partially resolved

0

ddd, 1H, J_{1 –4}Z7 Hz, J_{1 –2a}Z10 Hz and J_{1 –2b}Z17 Hz,

isomer 16a: d 142.6 (d , C₁), 112.8 (t , C₂), 73.5 (d , C₁and

*

H₁), 5.04 (ddd, 1H, J_{2b –4}Z1 Hz, J_{2b –2a}Z2 Hz and

J_{2b –1}Z17 Hz, H_2b), 4.94 (ddd, 1H, J_{2a –4}Z1Hz,

C₂), 38.6 (d⁰, C₄), 38.3^*(t⁰, C₃and C₅; both isomers have

0

the same chemical shift for their C₃/C₅carbons); chemical

0

(t , C₂), 73.2 (d , C₁and C₂), 38.3 (t , C₃and C₅), 37.9 (d ,

0

shifts assigned to the cis isomer 16b: d 142.8 (d , C₁), 112.9

J_{2a –2b}Z2 Hz and J_{2a –1}Z10 Hz, H_2a), 4.62 (m, 2H, H₁/

H₂), 2.80 (m, 1H, H₄), 1.95 (apparent dd, 2H, J_4–3a/5aZ6 Hz

and J_gemZ14 Hz, H_3a/H_5a), 1.44 (s, 3H, CH₃), 1.33 (m, 2H,

H_3b/H_5b), 1.27 (s, 3H, CH₃); chemical shifts assigned to the

0

*

0

C₄). H NMR chemical shifts assigned to the trans isomer

0

1

0

16a: d 5.76 (partially resolved ddd, 1H, J_{1 –4}Z8 Hz,

*

0

cis isomer 14b: d 5.96 (partially resolved ddd, 1H, J_{1 –4}

Z

J_{1 –2a}Z10 Hz, J_{1 –2b}Z17 Hz, H₁), 4.99 (ddd, 1H,

J_gemZ1 Hz, J_{2b –4}Z3 Hz, J_{2b –1}Z17 Hz, H_2b), 4.91

*

0

8 Hz, J_{1 –2a}Z10 Hz and J_{1 –2b}Z17 Hz, H₁), 4.97 (ddd,

1H, J_{2b –4}Z1 Hz, J_{2b –2a}Z2 Hz and J_{2b –1}Z17 Hz, H_2b),

4.88 (ddd, 1H, J_{2a –4}Z1 Hz, J_{2a –2b}Z2 Hz and J_{2a –1}Z

10 Hz, H_2a), 4,62 (m, 2H, H₁/H ), 2.59 (m, 1H, H₄), 2.03

0

;

(ddd, 1H, J_gemZ1 Hz, J_{2a –4}Z2 Hz, J_{2a –1}Z10 Hz, H_2a

^*the cis and trans isomers have the same chemical shifts

0

signals for the H_2aand H_2bprotons.), 4.18 (m, 2H, H₁and

H₂), 2.98 (m, 1H, H₄), 2.18 [s large, 2H, 2!OH; the OH

signals for the cis and trans isomers overlap to give a broad

singlet centred at 2.18 ppm (exchanges with D₂O) that

partially overlaps with the multiplet assigned to the H_3band

H_5bprotons of the cis isomer], 1.93 (m, 2H, H_3aand H_5a),

1.68 (m, 2H, H_3band H_5b); chemical shifts assigned to the

0

2

(m, 2H, H_3b/H_5b), 1.69 (m, 2H, H_3a/H_5a), 1.48 (s, 3H, CH₃),

1.30 (s, 3H, CH₃).

4.4.2. NMR and GC–MS analysis of mixtures of 15a

(trans) and 15b (cis) isolated from reactions with

11. Compounds 15a and 15b. Colorless oil (mixture of cis

and trans). R_fZ0.46 (silica, 2:5 CH₂Cl₂–pentane). GC–MS:

t_RZ5.6 min, trans compound 15a. [EI] m/z: 167 (100%,

MKEt), 93 (80.1%, MKC₅H₁₁O₂), 91 (33.7%), 77

(22.6%), 57 (76.3%). t_RZ5.7 min, cis compound 15b. [EI]

m/z: 167 (76.3%, MKEt), 93 (86.4%, MKC₅H₁₁O₂), 91

(37.4%), 77 (26.1%), 57 (100%). ¹³C NMR chemical shifts

cis isomer 16b: d 5.84 (partially resolved ddd, 1H, J_{1 -4}

Z

*

0

7 Hz, J_{1 -2a}Z17 Hz, J_{1 –2 b}Z10 Hz, H₁), 4.99 (ddd, 1H,

*

0

J_gemZ1 Hz, J_{2b –4}Z3 Hz, J_{2b –1}Z17 Hz, H_2b), 4.91 (ddd,

*

0

1H, J_gemZ1 Hz, J_{2a –4}Z2 Hz, J_{2a –1}Z10 Hz, H_2a; the cis

and trans isomers have the same chemical shifts signals for

0

the H_2aand H_2bprotons.), 4.05 (m, 2H, H₁and H₂), 2.46

(m, 1H, H₄), 2.18 [broad s, 2H, 2!OH; the OH signals for

the cis and trans isomers overlap to give a broad singlet

centred at 2.18 ppm (exchanges with D₂O) that partially

overlaps with the multiplet assigned to the H_2band H_5b

protons of the cis isomer], 2.16 (m, 2H, H_3band H_5b), 1.55

(m, 2H, H_3aand H_5a).

0

assigned to the trans isomer 15a: d 140.7 (d , C₁), 113.8 (t₀,

0

C₂), 112.8 (s , C(CH₂CH₃)₂), 80.4 (d , C₁and C₂), 40.1 (d ,

C₄), 39.5 (t⁰, C₃and C₅), 28.2 (t⁰, CH₂CH₃), 27.8 (t⁰,

CH₂CH₃), 8.8 (q⁰, CH₂CH₃), 7.6 (q⁰, CH₂CH₃); chemical

0

shifts assigned to₀the cis isomer 15b: d: 141.3 (d , C₁), 113.4

0

(t , C₂), 116.5 (s , C(CH₂CH₃)₂), 80.8 (d , C₁and C₂), 43.0

(d⁰, C₄), 38.7 (t⁰, C₃and C₅), 28.8 (t⁰, CH₂CH₃), 28.5 (t⁰,

1

CH₂CH₃), 8.6 (q⁰, CH₂CH₃), 7.9 (q⁰, CH₂CH₃); H NMR

chemical shifts assigned to the trans isomer 15a: d 5.76

4.4.4. NMR and GC–MS analysis of mixtures of 17a

(trans) and 17b (cis) obtained by acetylation of mixtures

of 16a and 16b. Compounds 17a and 17b. Oil (mixture of

cis and trans), R_fZ0.87 (silica, 4:1:1CH₂Cl₂–hexanes–

ether). GC–MS: t_RZ6.3 min, the cis and trans isomers were

not separable using our method; [EI] m/z: 212 (2.9%,

0

(partially resolved ddd, 1H, J_{1 –4}Z7 Hz, J_{1 –2a}Z10 Hz

0

and J_{1 –2b}Z17 Hz, H₁), 5.06 (partially resolved ddd, 1H,

0

J_{2b –4}Z2 Hz, J_{2b –2a}Z2 Hz and J_{2b –1}Z17 Hz, H_2b), 4.96

0

(partially resolved ddd, 1H, J_{2a –4}Z1 Hz, J_{2a –2b}Z2 Hz,

M

(10%), 110 (17.7%), 92 [38.8%, MK2!CH₃COOH

^$C]), 152 [3.5%, MKCH₃COOH (McLafferty)], 127

0

J_{2a –1}Z10 Hz, H_2a), 4.63 (m, 2H, H₁and H₂; same

chemical shift for both 15a and 15b), 2.87 (m, 1H, H₄),

(McLafferty)], 83 (13.8%), 43 (100%, CH₃CO). ¹³C NMR

2.01 (partially resolved ddd, 2H, J_4–3a/5aZ6 Hz, J_1/2–3a/5a

Z

chemical shifts assigned to the trans isomer: d: 170.34 (s⁰,

1 Hz, J_gemZ13 Hz, H_3aand H_5a), 1.71 (q, 2H, JZ7 Hz,

CH₂CH₃), 1.58 (q, 2H, JZ7 Hz, CH₂CH₃), 1.33 (m, 2H,

H_3band H_5b; this signal overlaps with the H_3a/H_5amultiplet

of the cis isomer), 0.97 (t, 3H, CH₂CH₃), 0.88 (t, 3H,

CH₂CH₃); the chemical shifts of 15b overlap with those of

15a with the exception of the following signals assigned

to the cis isomer 15b: d 5.90 (partially resolved ddd, 1H,

*

0

2!CH₃C]O), 141.7 (d , C₁), 113.6 (t , C₂), 73.8 (d , C₁

and C₂_*), 38.0 (d⁰, C₄), 35.1 (t⁰, C₃and C₅), 20.9₀^*(q⁰, 2!

CH₃). Same chemical shift for CH₃CO and C₂for both

isomers. Chemical shifts assigned to the cis isomer: d

0

*

170.29 (s , 2!CH₃C]O), 142.0 (d , C₁), 113.6 (t , C₂),

0

73.3 (d⁰, C₁and C₂), 37.2 (d⁰, C₄), 35.2 (t⁰, C₃and C₅), 20.9^*

*

(q⁰, 2!CH₃). Same chemical shift for carbons C₂and

0

J_{1 -4}Z7 Hz, J_{1 –2a}Z10 Hz, J_{1 –2b}Z17 Hz, H₁), 2.11 (m,

1H, H₄), 1.72 (q, 2H, JZ7 Hz, CH₂CH₃), 0.96 (t, 3H,

CH₂CH₃), 0.87 (t, 3H, CH₂CH₃).

CH₃CO for both isomers. ¹H NMR chemical shifts assigned

to the trans isomer 17a: d 5.76 (partially resolved ddd, 1H,

0

J_{1 -4}Z7.5 Hz, J_{1 –2a}Z10 Hz and J_{1 –2b}Z16.5 Hz, H₁],

*

5.25 (m, 2H, H₁and H₂), 5.01 (m, 1H, H_2b), 4.94 (m, 1H,

0

4.4.3. NMR and GC–MS analysis of mixtures of

16a(trans) and 16b(cis) isolated from reactions with

12. Compounds 16a and 16b. Solid (mixture of cis and

trans). R_fZ0.39 (silica, 1:19 MeOH–CH₂Cl₂). GC–MS:

*

H_2a), 2.97 (m, 1H, H₄), 2.05 (s, 2!CH₃of trans and cis

0

isomers), 2.02 [m, 2H, H_3aand H_5a(overlaps with the CH₃

singlet of cis and trans isomers)], 1.79 (m, 2H, H_3band H_5b).

8128

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

^*The signals for protons H_2aand H_2bof the cis and trans

isomers overlap. Chemical shifts assigned to the cis isomer

0

and H_{2 b}), 2.11 [s, 3H, OCOCH₃], 2.00 (s, 3H, OCOCH₃),

0

1.93 (m, 2H, 1!H₅and 1!H_{1 a}), 1.78 (m, 2H, H₄and 1!

0

17b: d 5.82 (partially resolved ddd, 1H, J_{1 –4}Z8 Hz,

H_{1 b}), 1.63–1.70 (m, 1H, 1!H₅), 1.47 (s, 3H, CH₃), 1.31 (s,

3H, CH₃). ¹³C NMR d: 171.1 (C]O), 170.9 (C]O), 110.6

(C(CH₃)₂), 79.8 (C₃), 77.6 (C₂or C₁), 73.6 (C₂or C₁), 63.2

0

J_{1 –2a}Z17 Hz and J_{1 –2b}Z10 Hz, H₁), 5.13 (m, 2H, H₁

*

and H₂), 5.01 (m, 1H, H_2b), 4.94 (m, 1H, H_2a), 2.56 (m,

0

1H, H₄), 2.23 (m, 2H, H_3band H_5b), 2.05 (s, 2!CH₃for

trans and cis isomers), 1.65 (m, 2H, H_3aand H_5a). The

(C₂), 35.2 (C₄), 31.8 (C₅), 27.6 (C₁); 25.7 (CH₃), 24.2

(CH₃), 21.0 (CH₃CO), 20.9 (CH₃CO). FTIR (ﬁlm): 1735 (s,

br), 1260 (s), 1094 (s), 1023 (s) cm^K1. MS (EI) m/z: 271

(100%, MKCH₃), 169 (10.7%), 151 (61.6%), 109 (32.3%),

108 (18.3%), 91 (65.5%). HRMS (EI) m/z: found: 271.1183;

calcd for MK15ZC₁₃H₁₉O₆: 271.1182.

*

0

signals of the H_2aand H_2bprotons of the cis and trans

isomers overlap.

4.5. Typical procedure for reactions with Bu₃SnH/AIBN

(Bu₃SnH Method E)

4.6. Typical procedure for reactions run with

Bu₃SnH/Et₃B (Bu₃SnH Method F)

A solution of 1b (0.2275 g, 0.5519 mmol) in freshly

distilled benzene (9 mL) was prepared under an argon

atmosphere at room temperature. Solutions of AIBN

(7.5 mg, 0.046 mmol in 2 mL benzene) and Bu₃SnH

(0.613 mmol in 2 mL benzene) were then simultaneously

added (dropwise over ca. 2 min) to this solution. The

reaction mixture was heated at reﬂux for 4 h, cooled, and

concentrated. The residue was diluted with ether (10 mL)

and DBU (0.15 mL, 1.0 mmol) was added.²⁰The mixture

was titrated with a 1 M solution of iodine in ether (2 mL, ca.

2 mmol) and the yellow precipitate that formed was

removed by ﬁltration through a short column of silica gel

(2!3 cm). The silica was washed with ether (3!10 mL)

and the combined ﬁltrates concentrated. The residue was

dissolved in ether (10 mL) and the solution stirred with a

30% aqueous solution of KF (10 mL) for 3 h.²¹The

heterogeneous mixture was ﬁltered twice, the layers

separated and the organic layer was then reﬁltered through

a short pad of silica gel and concentrated. The crude

products were puriﬁed by radial chromatography [2 mm

plate with the following series of eluants: 10% EtOAc–

hexanes (50 mL), 20% EtOAc–hexanes (50 mL), 30%

EtOAc–hexanes (50 mL)] to give 0.0196 g of 6b (12.4%),

0.0793 g of 6a (50.2%) and 0.0150 g of a mixture of 6b

(0.0044 g, 2.8%) and 6a (0.0106 g, 6.7%).

The method used is an adaptation of a literature procedure.²²

A solution of Et₃B in hexanes (1 M, 0.37 mL, 0.37 mmol,

1.1 equiv) was added to a solution of 10a (0.106 g,

0.339 mmol) in anhydrous toluene (3 mL) under an argon

atmosphere. A solution of Bu₃SnH in toluene was prepared

and slowly added to the reaction mixture over 2 h (0.18 mL,

0.67 mmol, 2 equiv of Bu₃SnH in 0.72 mL toluene). After

4 h of stirring at room temperature, the mixture was diluted

with hexanes (5 mL) and treated with TBAF (1.0 mL, 1.0 M

in THF, 1.0 mmol). Stirring was continued at room

temperature for 30 min before ﬁltering the mixture through

a short pad of silica gel. The silica was washed with ether

(100 mL) and the combined ﬁltrates concentrated. Tin

compounds were still present and so the residue was next

taken up in ether (10 mL) and treated with DBU

(0.67 mmol, 0.10 mL) and an ether solution of I₂(1 M,

1 mL). The mixture was ﬁltered through a short pad of silica

and the silica washed with ether (3!10 mL). The combined

ﬁltrates were treated with a 30% aqueous solution of KF

(5 mL) and the mixture stirred for 3 h at room temperature.

The layers were separated and the organic layer was dried

over MgSO₄, ﬁltered and concentrated. Radial chroma-

tography of the residue [1 mm plate, Et₂O–hexanes 1:3 gave

0.0475 g (75%) of compounds 18a and 18b in a 4.4:1 ratio

determined by GC–MS. The mixture of 18a and 18b was

rechromatographed and the collected fractions were ﬁrst

analyzed by GC–MS before being combined and concen-

trated. In this way we were able to isolate a pure sample of

the trans isomer 18a for characterization purposes; although

we were not able to isolate a pure sample of the cis isomer

18b we were able to obtain an enriched sample (trans–cisZ

1:6) for characterization purposes.

4.5.1. Compound 6a. Compound 6a (trans): pale yellow

oil, R_fZ0.26 (30% EtOAc–hexanes). [a]_DZ73.5 (c 0.83,

25 8C). H NMR d: 4.92 (m, 1H, H₁), 4.66 [apparent t,

1

J_appZ6 Hz (J_1,2yJ_2,3), 1H, H₂], 4.34 (d, J_2,3Z5.8 Hz,

0

J_4,3y0 Hz, 1H, H₃), 4.11 (m, 2H, H_2aand H_2b), 2.01–2.22

(m, 8H; H₄, 1!H₅, and both OCOCH₃singlets at 2.10 and

2.04 ppm.), 1.44–1.81 [m, 6H; CH₃(s,1.47 ppm) and

0

multiplets for H₅!1, H_{1 a}and H_{1 b}. The multiplets are

better separated in the 500 MHz spectrum i.e. d 1.76 (1!

0

H₅), 1.68 (m, H_{1 a}) and 1.55 (m, H_{1 b}).], 1.30 (s, 3H, CH₃).

4.6.1. Compound 18a. Compound 18a (trans): isolated as

an oil; R_fZ0.38 (silica, 3:1 Et₂O–hexanes). ¹H NMR d: 4.63

(m, 2H, H₁and H₂), 3.67 (t, 2H, J_{2 ,1}Z7 Hz, H₂protons),

2.24 (m, 1H, H₄), 1.99 (m, 2H, H_3aand H_5a; in the 500 MHz

spectrum this signal appears as a dd with JZ6 and 14 Hz),

¹³C NMR d: 170.9 (C]O), 170.7 (C]O), 111.8 (C(CH₃)₂),

0

84.5 (C₃), 78.1 (C₂), 73.1 (C₁), 62.6 (C₂), 38.1 (C₄), 32.6

0

(C₅), 31.2 (C₁), 26.1 (CH₃), 24.5 (CH₃), 20.92 (CH₃C]O),

0

20.90 (CH₃C]O). FTIR (ﬁlm): 1732 (s), 1371 (s), 1238

(s, br), 1071 (s) 1044 (s) cm^K1. MS (EI) m/z: 271 (100%,

MKCH₃), 229 (11.6%), 169 (15.7%), 151 (28.6%), 127

(11.6%), 109 (25.7%), 108 (11.3%), 91 (39.6%). HRMS

(EI) found: 271.1180; calcd for MK15ZC₁₃H₁₉O₆:

271.1182.

0

1.61(apparent quadruplet, 2H, J_4,1Z7 Hz, J_{2 ,1}Z7 Hz, H₁

protons), 1.57 (broad s, OH), 1.45 (s, 3H, CH₃), 1.29 (s, 3H,

13

CH₃), 1.14 (m, 2H, H_3band H_5b). C NMR d: 1₀08.7 (s⁰,

0

C(CH₃)₂), 80.4 (d , C₁and C₂), 62.1 (t , C₂), 39.8 (t , C₃and

0

C₅), 37.1 (t , C₁), 32.8 (d , C₄), 26.0 (q , CH₃), 23.7 (q ,

CH₃). GC–MS: t_RZ6.3 min, (EI) m/z: 171 (79.6%, MK

CH₃), 111 (53.5%), 93 (100%), 91 (24.3%), 83 (25.7%), 81

(23.7%), 67 (55.9%), 59 (18.7%), 55 (21.1%), 43 (54.2%).

4.5.2. Compound 6a. Compound 6b (cis): pale yellow oil.

R_fZ0.29 (30% EtOAc–hexanes). [a]_DZ46.4 (c 0.38,

25 8C). ¹H NMR d: 4.66 (m, 2H, H₁and H₂), 4.50 [apparent

0

t, J_appZ4 Hz (J_2,3yJ_3,4), 1H, H₃], 4.05–4.24 (m, 2H, H_{2 a}

4.6.2. GC–MS and NMR chemical shifts attributed to

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

8129

18b (cis). R_fZ0.38 (silica, 3:1 Et₂O–hexanes). GC–MS:

t_RZ6.4 min, (EI) m/z: 171 (76.3%, MKCH₃), 111 (22.9%),

93 (100%), 91 (21%), 83 (24.3%), 67 (56.8%), 59 (19.5%),

55 (20.7%), 43 (47.5%). Chemical shifts attributed to 18b:

3H, JZ7.5 Hz, CH₂CH₃), 0.87 (t, 3H, JZ7.5 Hz, CH₂CH₃).

¹³C NMR d: 112.8 (s⁰, C(CH₂CH₃)₂), 80.4 (d⁰₀, C₁/C₂), 62.2

0

(t , C₂), 39.9 (t , C₃/C₅), 37.4 (t , C₁), 33.1 (d , C₄), 28.2 (t ,

CH₂CH₃), 27.7 (t⁰, CH₂CH₃), 8.8 (q⁰, CH₂CH₃), 7.6 (q⁰,

CH₂CH₃). GC–MS: t_RZ7.3 min, (EI) m/z: 185 (64.5%,

MKEt), 111 (51.5%), 93 (100%), 91 (23.1%), 81 (26.7%),

67 (67.9%), 57 (90%).

¹H NMR d: 4.63 (m, 2H, H₁and H₂), 3.68 (t, 2H, J_{2 ,1}

Z

6 Hz, H₂protons), 2.12 (m, 1H, H₄), 1.99 (m, 2H, H_3b/H_5b),

0

*

0

1.79 (partially resolved dt, JZ6.5, 7 Hz, 2H, H₁protons),

1.63 (m, 2H, H_3a/H^*_5a), 1.53 (broad s, OH), 1.50 (s, 3H,

CH₃), 1.31 (s, 3H, CH₃). ^*Tentative assignment of these two

GC–MS and NMR chemical shifts attributed to 19b

(cis). GC–MS: t_RZ7.5 min, (EI) m/z: 185 (50.7%, MK

Et), 111 (28.4%), 93 (100%), 91 (20.6%), 67 (65.6%),

signals. ¹³C NMR d: 81.1 (d , C₁and C₂), 61.9 (t , C₂), 39.8

0

(t , C₃and C₅), 38.0 (t , C₁), 35.5 (d , C₄), 26.9 (q , CH₃),

24.2 (q⁰, CH₃). We were not able to detect a signal for the

quaternary carbon (C(CH₃)₂) of 18b.

1

57 (87.2%). H NMR: The signals of the cis isomer 19b

overlap with those of the trans isomer 19a with the

0

following exceptions: d: 3.66 (t, 2H, J_{2 ,1}Z6.5 Hz, H₂),

2.10 (m, 3H, H_3b/H_5band H₄), 0.95 (t, 3H, JZ7.5 Hz,

CH₂CH₃), 0.86 (t, 3H, JZ7.5 Hz, CH₂CH₃). ¹³C NMR

d: 116.2 (s⁰, C(CH₂CH₃)₂), 80.8 (d⁰, C₁/C₂), 61.8 (t⁰,

4.6.3. Compounds 20a and 20b. Reaction of 13 with

Bu₃SnH/Et₃B in toluene gave an inseparable mixture of

compounds 20a and 20b [oil, R_fZ0.76 (silica, 4:1:1

CH₂Cl₂–Et₂O–hexanes; 86% yield, 20a (trans): 20b

(cis)Z3.1:1.0 (GC ratio)]. GC–MS (20a) t_RZ6.9 min,

(EI) m/z: 213 (43.5%, MKCH₃), 111 (15.4%), 93 (100%),

43 (46.9%). GC–MS (20b): t_RZ7.1 min, (EI) m/z: 213

(40.5%, MKCH₃), 111 (14%), 93 (100%), 43 (49.1%).

NMR chemical shifts attributed to 20a (trans) and 20b (cis).

¹H NMR d: 4.61 (m, 2H, H₁/H₂, cis and trans), 4.07 (t, 2H,

0

C₂), 38.4 (t , C₃/C₅), 38.1 (t , C₁), 35.6 (d , C₄), 28.8

(t⁰, CH₂CH₃), 28.23 (t⁰, CH₂CH₃), 8.6 (q⁰, CH₂CH₃), 8.0

(q⁰, CH₂CH₃).

Compounds 22a and 22b were prepared by ﬁrst carrying out

a reductive cyclization on compound 12 with Bu₃SnH/Et₃B

in THF and by then adding, after 24 h, an excess of Ac₂O

(15 equiv) and pyridine (10 equiv) directly to the reaction

mixture. The resulting mixture was stirred at room

temperature overnight before workup, under our usual

conditions, and radial chromatography. Compounds 22a

and 22b were isolated as a mixture [oil, R_fZ0.68 (silica,

4:1:1 CH₂Cl₂–Et₂O–hexanes), 62% yield, NMR ratio of

22a–22bZ1.0:1.4]. GC–MS: t_RZ8.4 min, the cis and trans

isomers were not separable by our method. (EI) m/z: 229

(0.05%), 213 (0.14%), 212 (0.15%), 169 (16%), 152 (4%),

127 (23.1%), 110 (54.2%), 92 (11.6%), 83 (43.2%), 43

(100%). NMR chemical shifts attributed to 22a (trans) and

0

J_{2 ,1}Z7 Hz, H₂protons, cis and trans), 2.21 (m, 1H, H₄,

trans), 2.03 (s, 3H, OCOCH₃of cis and trans), 1.98 (m, 2H,

H_3a/H_5asignal of trans overlaps with the H_3b/H_5bsignal of

0

the cis), 1.83 (apparent q, 2H, J_4,1ZJ_{1 ,2}Z6,5 Hz, H₁, cis),

0

1.65 (apparent q, 2H, J_4,1ZJ_{2 ,1}Z7 Hz, H₁protons trans

isomer; partially overlaps with H_3a/H_5asignal of cis isomer),

0

1.63 (m, 2H, H_3aand H_5apartial overlap with H₁protons of

trans isomer), 1.48 (s, 3H, CH₃, cis), 1.43 (s, 3H, CH₃,

trans), 1.275–1.295 (m, 1H, H₄overlaps with CH₃singlets

of trans and cis at 1.280 and 1.278 ppm respectively), 1.13

13

(m, 2H, H_3b/H_5b, trans). C NMR (20b,₀cis) d: 171.14 (s⁰₀,

C]O, Ac), ₀111.0 (s⁰, C(CH₃)₂), 81.0 (d , C₁/C₂), 63.6 (t₀,

1

22b (cis): H NMR d: 5.23 (m, 2H, H₁/H₂, 22a), 5.12 (m,

0

C₂), 38.0 (t , C₃/C₅), 35.8 (d , C₄), 33.9 (t , C₁), 26.9 (q ,

CH₃), 24.1 (q⁰, CH₃), 21.0^*(q⁰, OCOCH₃). ¹³C NMR (20a,

trans) d: 171.08 (s⁰, C]O, Ac), 108.7 (s⁰, C(CH₃)₂), 80.3

0

2H, H₁/H₂, 22b), 4.074 (t, 2H, J_{2 ,1}Z7 Hz, H₂, 22a), 4.067

0

(t, 2H, J_{2 ,1}Z7 Hz, H₂, 22b), 2.39 (m, 1H, H₄, 22a), 2.22

(m, 2H, H_3b/H_5b, 22b), 2.11–1.95 (m, H_3a/H_5asignal of 22a

overlaps with the H₄multiplet of 22b and the CH₃singlets

of both isomers at 2.053 and 2.046 ppm), 1.77 (apparent q,

0

(d , C₁/C₂), 63.8 (t , C₂), 39.7 (t , C₃/C₅), 33.2 (d , C₄), 32.8

*

0

(t , C₁), 26.0 (q , CH₃), 23.7 (q , CH₃), 21.0 (q , OCOCH₃).

^*A single signal was observed for both cis and trans

isomers.

0

2H, J_4,1ZJ_{2 ,1}Z7 Hz, H₁protons, 22b), 1.64 [m, 4H, H₁

and H_3b/H_5bprotons, 22a. After resolution enhancement the

0

signal for the H₁protons appears as a quadruplet at

4.6.4. Compounds 19a (trans) and 19b (cis). Reaction of

11 with Bu₃SnH/Et₃B in toluene gave a mixture of

compounds 19a and 19b [oil, R_fZ0.38 (silica, 2:3:2

CH₂Cl₂–hexanes–EtOAc; 73% yield, 19a (trans): 19b

(cis)Z7.7:1.0 (GC ratio)]. The mixture of 19a and 19b

was rechromatographed and the collected fractions were

ﬁrst analyzed by GC–MS before being combined and

concentrated. In this way, we were able to isolate a pure

sample of the trans isomer 19a for characterization

purposes; although we were not able to isolate a pure

sample of the cis isomer 19b we were able to obtain an

enriched sample (trans–cisZ2.8:1.0) for characterization

purposes. Compound 19a (trans): isolated as an oil, R_fZ

0

1.68 ppm (J_4,1ZJ_{2 ,1}Z7 Hz)], 1.50 (m, 2H, H_3a/H_5a, 22b).

¹³C NMR d: 171.1, 170.4 and 170.3 (s⁰, C]O, 22a and

22b), 73.9 (d⁰, C₁/C₂, 22a), 73.3 (d⁰, C₁/C₂, 22b), 63₀.2 (t⁰,

0

C₂, 22a), 63.1 (t , C₂, 22b), 35.7 (t , C₁, 22b), 35.4 (t , C₁,

22a), 35.1 (t⁰, C₃/C₅, 22a), 35.0 (t⁰, C₃/C₅, 22b), 31.3 (d⁰, C₄,

22a), 30.0 (d⁰, C₄, 22b), 20.98 and 20.94 (q⁰, CH₃of 22a and

22b).

Acknowledgements

1

We are grateful to the Natural Sciences and Engineering

´

Research Council of Canada (NSERC) and the Universite

0.38 (silica, 2:3:2 CH₂Cl₂–hexanes–EtOAc). H NMR d:

0

4.61 (m, 2H, H₁/H₂), 3.67 (t, 2H, J_{2 ,1}Z7 Hz, H₂), 2.27 (m,

1H, H₄), 2.02 (apparent ddd, 2H, JZ6, 1, 13 Hz, H_3a/H_5a),

1.69 (q, 2H, JZ7.5 Hz, CH₂CH₃), 1.60 (apparent q, 2H,

´

du Quebec a Montreal for ﬁnancial support of our research.

We thank Mr. Nadim Saade of McGill University for mass

`

´

`

0

spectra results and Dr. Hoa Le Thanh of UQAM for help

with NMR experiments.

J_{2 ,1}ZJ_{4, 1}Z7 Hz, H₁), 1.57 (q, 2H, JZ7.5 Hz, CH₂CH₃),

1.51 (s large, 1H, 1!OH), 1.15 (m, 2H, H_3b/H_5b), 0.94 (t,

8130

M. B. S. Ferjani et al. / Tetrahedron 60 (2004) 8113–8130

10. We have studied the SmI₂mediated reductive cyclization of

Supplementary data

most of these esters. See: (a) Bennett, S. M.; Biboutou,

R. K.; Zhou, Z.; Pion, R. Tetrahedron 1998, 54, 4761–4786.

(b) Samin Firouz Salari, B.; Kouya Biboutou, R.; Bennett,

S. M. Tetrahedron 2000, 56, 6385–6400.

Supplementary data associated with this article can be found

at doi:10.1016/j.tet.2004.06.099.

11. Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of

Radical Reactions VCH: New York, 1996, Chapter 2.

12. Vinylcyclopentanes have been formed through intramolecular

0

S_Ndisplacement of an allylic methoxy substituent by an

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Article Doi

Synthesis of vinylcyclopentanes via samarium(II) mediated tandem reactions

DOI: 10.1016/j.tet.2004.06.099

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