Steric effects in the tuning of the diastereoselectivity of the intramolecular free-radical cyclization to an olefin as exemplified through the synthesis of a carba-pentofuranose scaffold

Article

pubs.acs.org/joc

Steric Eﬀects in the Tuning of the Diastereoselectivity of the

Intramolecular Free-Radical Cyclization to an Oleﬁn As Exempliﬁed

through the Synthesis of a Carba-Pentofuranose Scaﬀold

Mansoureh Karimiahmadabadi, Sayeh Erfan, Andras Foldesi, and Jyoti Chattopadhyaya*

̈

Program of Chemical Biology, Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, SE-75123 Uppsala,

Sweden

S

* Supporting Information

ABSTRACT: Two free-radical cyclization reactions with the

radical at the chiral C4 of the pentose sugar and the

intramolecularly C1-tethered oleﬁn (on radical precursors 8

and 17) gave a new diastereospeciﬁc C4−C8 bond in

dimethylbicyclo[2.2.1]heptane 9, whereas the new C4−C7

bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave

trans and cis diastereomers, in which the chirality of the C4

center is fully retained as that of the starting material. It has

been shown how the chemical nature of the fused carba-

pentofuranose scaﬀolds, dimethylbicyclo[2.2.1]heptane 9 vis-a-

vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in

the former versus 2-O- in the latter), dictates the stereo-

chemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure

1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of

the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the α-face) with that of the 8(R)-CH₂^•radical in

the β-face. The conversion of 17 → 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the

boat-like transition states is likely.

VIII).¹⁰The radical was always generated at a nonchiral carbon

center to avoid the generation of an intractable mixture of

diastereomers owing to epimerization during the radical addition

reaction. However, when the radical was generated at the

INTRODUCTION

■

Recently, we have shown that substitution of 2′-O- in LNA

(locked nucleic acid: 2′-O,4′-C-methylenebicyclonucleoside)^1a,b

by the 2′-CH(Me)- group, giving carbocyclic nucleosides (carba-

LNA),^1c−ienhances the nucleolytic stability of the carba-LNA-

nonchiral centers of the furanose ring (I → II), or at its side

modiﬁed oligo-DNA or RNA by ∼145 times.^1fThese carba-

chain, a diastereomeric mixture of cis and trans isomers (III → IV

and V → VI)¹¹was obtained. When the radical was generated at a

LNA-modiﬁed small interfering RNAs (siRNA) have been found

to be useful as potential therapeutic agents against HIV-1,^2,3

nonchiral carbon and had a constrained oleﬁn in the proximity,

whereas the carba-LNA-modiﬁed antisense oligonucleotides are

found to be active against allele-speciﬁc Huntington disease,⁴

owing to improved target RNA aﬃnity, single-mismatch

discrimination, and nuclease stability.^1c−e

which was part of a ring, it gave a diastereomerically pure isomer

as shown by conversion of VII → VIII (74%) and IX → X

(76%),¹¹owing to steric reasons.

A radical center generated at an achiral carbon added easily to a

CN of an oximino ether (VII) to give 1-benzyloxyaminocy-

clopentane (VIII) as a diastereomerically pure main product in

74% yield. All of these reactions, VII → VIII and IX → X, took

place by 5-exo ring closure and gave one major isomer because of

the steric eﬀect imposed by the acetonide group on the α-face of

the pentose sugar ring. However, the alkyl substitution at the

radical center and ring strain have been shown to promote the

radical 6-endo cyclization (XI → XII), thereby allowing syntheses

of carba-pyranoses from a carbohydrate precursor. Similarly, a

vinyl radical led to more 6-endo cyclization (XIII → XIV + XV,

On the other hand, the cyclopentane nucleoside derivative in

which the furanose O4′-oxygen is replaced by methylene

stabilizes the glycosidic bond and enhances the biological

stability,^5,6which in turn culminates into enhanced selectivity to

diﬀerent viral enzymes.^5e,fThus, the locked North-type (N)

methanocarba-adenosine analogues⁶showed favorable pharma-

codynamic properties in binding assays to A1, A_2A, and A3

receptors compared to the S-locked analogue.⁶The syntheses of

several carbocyclic nucleosides have been reported so far.^7a,b

They used diﬀerent (Grubb’s^7aand Schrock’s catalyst⁸)

metathesis approaches for closing the carba-ring to give

functionalized cyclopentanol. Synthesis of annulated furanoses⁹

was reported through the radical cyclization to the intra-

molecularly tethered oleﬁn (Table 1, compounds II, IV, VI, and

Received: May 9, 2012

Published: August 2, 2012

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Table 1. Formation of Annulated Furanoses and Carba-Pyranoses through the Free-Radical Cyclization Reaction in Which the

Radical Generated Is Invariably on the Nonchiral Carbon

Scheme 1. Retrosynthetic Routes

1.6:1), whereas an alkyl radical in compound IX gave only the exo

cyclization product X.

We herein report a radical ring-closure reaction in which the

radical is generated at the chiral center with an intramolecularly

tethered oleﬁn to give appropriately functionalized carba-^D-

furanose.

Beckwith,¹²Houk,¹³and Rajan Babu¹⁴have reported that hex-

5-enyl radical cyclization generally proceeds through a chair-like

or boat-like transition state with very low energy barrier.^1c

Whether a chair- or boat-like transition state would actually be

involved in the product formation depends upon many other

stereochemical eﬀectors around these two transition states,^1c,14

which may compensate for the formation of the normally

unfavorable boat-like transition state or actually provide extra

stabilization of the chair-like transition state.

RESULTS AND DISCUSSION

■

Clearly, the free-radical generated at the chiral C4 center of a D-

furanose ring by a 5-exo ring-closure reaction to an intra-

molecularly tethered oleﬁn is likely to give a ^Dand

L

diastereomeric mixture, unless the C4 center is actually a part

of a ring. Hence in order to retain the ^Dconﬁguration of the

newly formed carba-ring, we argued that construction of a C2 to

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Scheme 2. Synthesis of the (1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-[benzyloxymethyl]-1-[(4-methyloxyphenyl)methoxy]-8,7-

dimethylbicyclo[2.2.1]heptane (9)

C4 bridge as in dimethylbicyclo[2.2.1]heptanes B₁and B₂or a

furano bridge (oxabicyclo bridge [2.2.1]) as in D₁and D₂

(Scheme 1) will be necessary in order to stop the formation of

diastereomers at the chiral C4 center. It was also clear that the

intramolecular 5-exo ring closure by the C4 radical center to the

C8 of the tethered oleﬁn (A→ B₁or B₂) or to the C7 center of

the oleﬁn (C → D₁or D₂) will create two new chiral centers

across the C4−C8 or C4−C7 bond (as in B₁or B₂and D₁or D₂,

respectively). As we wish to understand the steric factors that

control the stereochemistry of the radical ring closure, we tried to

inﬂuence the participation of either chair- or boat-like forms to

give cis and/or trans cyclic products, respectively, across the C4

and C8 centers.

This prompted us to attempt two free-radical cyclization

reactions, ﬁrst, on 3-(1-hydroxyallyl)-cyclopentanol derivative

(A) to give 7,8-dimethylbicyclo[2.2.1]heptanes (B₁or B₂) and,

second, on C to give 7-methyl-2-oxabicyclo[2.2.1]heptanes (D₁

or D₂).

Synthesis of the (1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-

[benzyloxymethyl]-1-[(4-methyloxyphenyl)methoxy]-

8,7-dimethylbicyclo[2.2.1]heptane (9). The synthesis of

carbocyclic pentose 9 starts from the known 4-C-allyl-3,5-di-O-

benzyl-1,2-O-isopropylidene-α-^D-ribofuranose 1^1d(Scheme 2).

Compound 1 was treated with p-toluenesulfonic acid·H₂O in

MeOH to obtain the methyl glycoside 2 in a one-pot reaction¹⁵

as an inseparable mixture of α- and β-anomers in 86% yield. The

¹H NMR assignment approximately shows a 4:1 ratio of the two

anomers (Figure S1, Supporting Information part I). After 2-

esteriﬁcation of the α and β mixture 2 with phenyl

chlorothionoformate in dry pyridine at room temperature, the

key intermediates for the radical cyclization, 2-O-phenoxythio-

carbonyl 3a (β-isomer, 66%, [α]²_D⁵= −52) (Figures S6−S10,

Supporting Information part I) and 3b (α-isomer, 22%, [α]_D²⁵

=

−14), (Figures S11−S15, Supporting Information part I) were

separated as pure isomers. Their structures were conﬁrmed by

both coupling constant analysis and nuclear Overhauser eﬀect

(NOE) experiments. For compound 3a (β-isomer), the ³J_H1,H2

=

3

0.2 Hz (Figure S6, Supporting Information part I) suggests a

transoid orientation for H1 and H2 (Figure 1, panel A₁for

Newman projection), thereby suggesting a 1(R) conﬁguration

for 3a.

3

In a similar way, the J_H1,H2= 4.8

0.2 Hz (Figure S11,

Supporting Information part I) was assigned for the α-isomer

(Figure 1, panel B₁for Newman projection) for cis orientation

(eclipsed) between H1 and H2 [1(S) conﬁguration] for 3b. The

stereochemistry at C1 was further conﬁrmed by NOE: for the β-

isomer, the irradiation of H2 (Figure 1, panel A₁) shows 1.6%

NOE enhancement for H1 (d_H1,H2(calc)≈ 2.9 Å) which shows (R)

conﬁguration at C1. In contrast, the irradiation of H2 (Figure 1,

panel B₁) in the α-isomer gave a strong NOE enhancement for

H1, 3.4% (d_H1,H2(calc)≈ 2.3 Å), which shows that H1 and H2 are

cis and C1 is with (S) conﬁguration.

The products 3a and 3b were subjected to the radical ring

closure in degassed anhydrous toluene at reﬂux temperature in

the presence of Bu₃SnH, while azobisisobutyronitrile (AIBN)

was added dropwise as radical initiator using our procedure.^1d

Quite expectedly, the β-isomer 3a successfully aﬀorded a

diastereomeric mixture of two isomers 4a (Figures S16−S21,

Supporting Information part I) and 4b (Figures S22−S26,

Supporting Information part I) (60% yield) through the 5-exo

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Figure 1. ¹H NMR of the (A) β-isomer 3a and (B) α-isomer 3b and (A₁,B₁) NOEs observed upon irradiation of their respective H2, thereby conﬁrming

the conﬁguration at C1 to be β in 3a and α in 3b, respectively.

cyclization. The ¹H NMR assignment approximately shows a 3:1

ratio of the two isomers 4a and 4b. The major isomer 4a, [α]²_D⁵=

−21, could be isolated in the pure form, but the minor isomer 4b

contained a 30% impurity of 4a.

The radical cyclization can proceed through a chair- or a boat-

like transition state (Figure 2) where the former is favored. On

the other hand, a bulky substituent at the centers close to the

radical center might inﬂuence the stereochemical outcome in

order to increase the product with less steric interaction (the

boat-like TS), which is the result in this case.

stereochemistry of the new chiral center, C7, has been assigned

by NOE enhancement (Figure S27, panel A₁, in Supporting

Information part I) and coupling constant analysis for major

isomer 4a: irradiation of H1 led to 3.7% NOE enhancement for

7-Me (d_{H1,7‑Me(calc)}≈ 2.2 Å), but the weak NOE enhancement for

H7 (0.3%, d_H1,H7(calc)≈ 3.8 Å) suggested that the H1 and 7-Me

were oriented on the same face of the [2.2.1]-fused carba-ring,

which means that H2 and H7 are cis to each other.

This was further evidenced by the coupling constant analysis of

3

4a which shows J_H2,H7= 3 0.2 Hz (Figure S27, panel A₁, in

The boat-like TS1 is favorable due to the absence of the clash

between 7(R)-Me and the axial 3(S)-OBn which leads to the 2,7-

cis product (Figure 2, panel A). In contrast, the clash between the

7(S)-Me and the axial 3(S)-OBn makes the chair-like TS3 (gives

the 2,7-trans product) less favored (Figure 2, panel B). The

formation of the new C2−C7 bond has been corroborated by the

presence of the correlation between H2 and H7 in the COSY

experiment (Figure S21, panel A, in Supporting Information part

I). The HMBC correlation spectra (Figure S21, panel B, in

Supporting Information part I) provided further evidence

through the cross-peaks between H1 and C7 due to the long-

range ¹H−¹³C coupling over the C2−C7 bond, thereby

conﬁrming the presence of the new C2−C7 bond in 4a. The

Supporting Information part I for Newman projection), thereby

conﬁrming 7(R) and 2(R) conﬁgurations for the carbo-pentose

4a. The stereochemistry of the new chiral center at C7 for the

minor isomer 4b has also been determined by NOE (Figure S27,

panels B₁and B₂, in Supporting Information part I): irradiation of

7-Me showed a weak NOE enhancement for H1 (0.4%,

d_{H1,7‑Me(calc)}≈ 4.2 Å), but irradiation of H7 led to a strong

NOE enhancement for H1 (3.7%, d_H7,H1(calc)≈ 2.2 Å), which

suggests that H7 and H1 are oriented on the same face of the

carba-ring, thereby conﬁrming 7(S) and 2(R) conﬁgurations for

the carba-pentose 4b.

An eﬀort to produce the 5-exo-cyclized compound from the α-

isomer 3b was unsuccessful; this is likely due to the steric

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Figure 2. Mechanism of the stereoselectivity of the 5-exo radical ring-closure reaction to a tethered oleﬁn, in which the 2,7-cis addition, 4a, is favored over

the 2,7-trans addition, 4b, owing to the presence or absence of steric crowding.^1c

Figure 3. Due to the steric hindrance by the 1-methoxy group, the incipient radical at C2 in the α-isomer (in A₁/A₂) cannot attack the double bond.

hindrance of 1-methoxy group (Figure 3) on the α-face of the

pentose ring through which the radical cyclization takes place in

the β-isomer 3a → 4. Hence, the radical generated at C2 in 3b

was found to be quenched by a hydrogen atom to give the 2-

deoxygenated compound A₃before it could be captured by the

double bond (Figure 3).

Compound 4 was hydrolyzed by a 30% aqueous mixture of p-

toluenesulfonic acid·H₂O in THF at room temperature to give

the aldehyde 5 in 78% yield (Figures S28 and S29, Supporting

Information part I). The aldehyde 5 was then subjected to a

Grignard reaction using vinylmagnesium bromide (4 equiv) at

room temperature in dry THF overnight to produce the alkene-

diol 6 (71%), (Figures S30−S34, Supporting Information part I)

as an inseparable mixture of two isomers with a single spot on

TLC. The ¹H NMR assignment approximately shows 5:1 ratio of

the two isomers. Compound 6 was selectively protected at C1-

OH with a bulky p-methoxybenzyl (PMB) group using NaH and

PMB-Cl (1.2 equiv) in dry DMF at 0 °C to obtain the desired 1-

O-PMB product 7 (Figures S35−S39, Supporting Information

part I) (65%, [α]²_D⁵= −27). At this stage, we succeeded to isolate

only the major isomer 7. The stereochemistry of this compound

has been assigned by coupling constant analysis and NOE

experiments: homonuclear decoupling of H8 shows the ³J_H1,H2

=

3.5 0.2 Hz, suggesting a cis relationship between H1 and H2

(Figure S54 in Supporting Information part I) with C1(S)

3

conﬁguration. The J_H1,H8= 7.5

0.2 Hz (Figure S55 in

Supporting Information part I) was assigned for the trans

3

orientation between H1 and H8. The J_H2,H7= 8.5 0.2 Hz

shows cis relationship between H2 and H7 (Figure S57 in

Supporting Information part I), which suggests (R) conﬁg-

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Figure 4. (A) TS1a (boat-like conformation) in which there is no steric repulsion between the trans-oriented 1-(S)-O-PMB (eq) and 8-Me (ax), thereby

giving the sole 1,8-trans product 9. TS1b in panel A (boat-like conformation) shows that the steric repulsion between the cis-oriented 1-(R)-O-PMB (ax)

and 7-Me (ax) giving the thermodynamically less favorable 1,7-cis product 18b. (B) Chair-like TS3a shows that because of the steric repulsion between

the cis-oriented 1-(S)-O-PMB (eq) and 7-Me (ax), the 1,8-cis product is disfavored. On the other hand, TS3b shows that a chair-like conformation in

TS3b involves no steric clash between the trans-oriented 1-(R)-O-PMB (ax) and 7-Me (eq), thereby giving the favorable 1,7-trans product 18a.

uration at the C7 center. These results have been further

evidenced by NOE enhancements: irradiation of H8 (Figure S51

in Supporting Information part I) led to NOE enhancement for

H3 [1.4%, d_H8,H3(calc)≈ 2.7 Å] and H2 [1.4%, d_H8,H2(calc)≈ 3.4 Å ],

which conﬁrms that H8, H2, and H3 were oriented on the same

face of the pentose sugar (β-face), which means that Grignard

addition to 1-CHO takes place from the β-face, that is, from

the top of the 1-CHO, and C1 possess an (S) conﬁguration. In

contradistinction, if the Grignard addition to 1-CHO were to

take place from its α-face (i.e., from the bottom of the 1-CH

O), we should not have observed any NOE between H8 of the

oleﬁn and H3 of the sugar since d_H8,H3(calc)is ≈4.6 Å (modeled by

HyperChem, MM/Amber, and semiempirical/AM1; see Ex-

perimental Section). Further conﬁrmation comes from irradi-

ation of H1 (Figure S52 in Supporting Information part I), which

shows 3.6% NOE enhancement for H2 (d_H1,H2(calc)≈ 2.5 Å),

thereby suggesting that H1 and H2 are on the β-face with cis

orientation.

center. These assignments have been further evidenced by the

NOEs: irradiation of H1 (Figure S61 in Supporting Information

part I) shows 2.4% NOE enhancement for H2 (d_H1,H2(calc)≈ 2.4

Å), suggesting that H1 and H2 are on the same face [cis

orientation, 1(S) conﬁguration]. Irradiation of H8 (Figure S59 in

Supporting Information part I) led to NOE enhancement for H3

[1.6%, d_H8,H3(calc)≈ 2.4 Å] and H2 [1.7%, d_H8,H2(calc)≈ 3.4 Å ],

which conﬁrms that H8, H2, and H3 are oriented on the same

face of the alkene group.

The key intermediate 8 was subjected to radical cyclization in

anhydrous toluene under reﬂux by dropwise addition of Bu₃SnH

(4 equiv), utilizing AIBN as the initiator during 4 h to avoid the

C4-deoxygenation product formation. The hexenyl radical

cyclization at C8 proceeded in the 5-exo cyclization mode to

give only one [2.2.1]-fused C4−C8 trans-fused product 9, with

8(R) conﬁguration as the main product (60%, [α]²_D⁵= 32), along

with the C4-deoxygenated product. The stereospeciﬁcity of the

radical reaction is due to the absence of steric hindrance of the 1-

O-PMB group and the 7(R)-Me group which drives the 8(R)-

Compound 7 was subjected to esteriﬁcation at 4-OH with

methyl(chlorocarbonyl)formate in pyridine at 40 °C overnight

to give the key precursor 8 (68%, [α]²_D⁵= −33) for the free-radical

cyclization. The conﬁguration of the intermediate 8 was also

conﬁrmed by coupling constant and NOE experiments: the

³J_H1,H8= 7.5 0.2 Hz was found for compound 8 (Figure S62 in

Supporting Information part I), which suggests trans orientation

•

CH₂radical to the β-face (TS1a and TS2a in Figure 4). In

addition, 1D NOE experiments (Figure 5) conﬁrm the

conﬁguration which showed to be (S) at C1 and (R) at C4.

Hence, these two centers preserved their conﬁguration after

radical reaction. However, the C8 was not a chiral center in the

starting material, but after the radical reaction, the chiral center

was generated to be of (R) conﬁguration.

3

between H1 and H8. The J_H2,H7= 8 0.2 Hz indicates cis

relationship between H2 and H7 (Figure S63 in Supporting

Mechanism of the 5-exo Free-Radical Cyclization To

Information part I), which gives (R) conﬁguration at the C7

Give (1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-[benzyloxy-

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Figure 5. (A) ¹H NMR spectrum (600 MHz) of compound 9. (A₁,A₂) NOE enhancements of compound 9; irradiation of H1 showed 5.4% NOE

enhancements for H3, and irradiation of 8(R)-Me shows 1.8% NOE enhancement with H5, which indicated that 8(R)-Me and H5 are on the β-face of

the carba-sugar, thereby proving the conﬁguration of C8 to be (R). (A₃,A₄) Irradiation of 7(R)-Me shows 0.5% NOE enhancement for H8, but none for

8(R)-Me, and irradiation of H6′ shows 5.4% NOE enhancement with H8, which shows that the 8(R)-Me is on the β-face and the 7(R)-Me is on the α-

face of the carba-sugar.

methyl]-1-[4-(methyloxyphenyl)methoxy]-8,7-

dimethylbicyclo[2.2.1]heptane (9) from Methylcyclopen-

tenyl Methyl Oxalate Derivative 8. The 5-exo intramoleculer

cyclization of the radical generated at C4 to the C1-tethered

oleﬁn, as in 8 exclusively proceeded through the 4,8 ring closure

to give 9 (Scheme 2 and Figure 4). This could be explained by

Beckwith’s hypothesis,¹²which enumerates the role of steric and

thermodynamic factors dictating the formation of the more

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Scheme 3. Synthesis of (1R,2R,3R,4R,7S)-3-(Benzyloxy)-4-[(benzyloxy)methyl]-1-[(4-methoxyphenyl)methoxy]-7-methyl-2-

oxabicyclo[2.2.1]heptane (18a) and (1R,2R,3R,4R,7R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]-1-[(4-methoxyphenyl)methoxy]-7-

methyl-2-oxabicyclo[2.2.1]heptane (18b)

stable 5-exo product. Hence, no endo cyclization took place in our

studies in the course of the ring-closure reaction. After treatment

of compound 8 with AIBN and Bu₃SnH, the incipient C4 radical

adopts a boat-like transition state which can attack the double

bond at the α-face by involving transition states TS1a and TS2a,

as schematically shown in panel A of Figure 4.

also found to be correlated with H1 (Figure S50, panel C, in

Supporting Information part I). These observations along with

the disappearance of the oleﬁnic proton resonances (at δ 5.16

and 5.73 in the starting material) suggest that the radical

generated at C4 has been quenched by the terminal double bond

at C1 to give the 5-exo bicyclic product 9. This was also

conﬁrmed by the observation of a long-range connectivity

(HMBC) of 8-Me with C4 (Figure S50, panel D, in Supporting

Information part I) and H8 with C4.

Determination of Conﬁguration of All Chiral Centers in

(1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-[benzyloxymethyl]-

1-[(4-methyloxyphenyl)methoxy]-8,7-dimethylbicyclo-

[2.2.1]heptane (9) through NOE Analysis. The conﬁgu-

ration of the newly formed chiral center at the C8 in compound 9

has been identiﬁed by NOE experiments. Irradiation of H1

(Figure 5, panel A₁) shows a strong NOE enhancement for H3

(5.4%, d_H1,H3≈ 2.4 Å), 8-Me (3%, d_H1,8‑Me≈ 2.6 Å), and H2

(2.9%, d_H1,H2≈ 2.5 Å), which conﬁrmed that 8-Me is on the same

face of the newly formed carbocycle as the original H3 and H2,

which ascertained that the C8 center has (R) conﬁguration. On

the other hand, the observation of the weak NOE enhancement

for H8 (0.8%, d_H1,H8≈ 3 Å) upon H1 irradiation determined that

H1 and H8 are trans-oriented. In addition, irradiation of 8-Me

(Figure 5, panel A₂) led to 1.8% NOE enhancement for H5

(d_8‑Me,H5≈ 2.4 Å), which indicated that 8-Me and H5 are located

on the same face. Thus, this observation conﬁrmed the (R)

In fact, the radical cyclization can proceed through a chair- or

boat-like transition state, but a bulky substituent close to the

radical center may inﬂuence the stereochemical outcome in order

to promote the formation of the thermodynamically stable

product with relatively less steric interaction. The overlapping of

SOMO of C4 with the HOMO of C8 through the boat-like

transition state (Figure 4, TS1a and TS2a in panel A) drives the

•

8(R)-CH₂radical to the β-face due to absence of the steric clash

of the bulky 1-O-PMB group and the 7(R)-Me in the α-face,

thereby leading to form the 1,8-trans product. In contrast, in the

chair-like transition state, the steric bulk of the 1-O-PMB group

and 7(R)-Me makes the 1,8-cis product disfavored (Figure 4,

TS3a and TS4a in panel B).

NMR Assignments To Support the Structure of

(1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-[(benzyloxy)-

methyl]-1-[(4-methyloxyphenyl)methoxy]-8,7-

dimethylbicyclo[2.2.1]heptane (9). The 600 MHz ¹H NMR

spectrum is shown in Figure 5, panel A. The doublet at δ 0.92 for

8-Me is found to be correlated with H8 (Figure S50, panel B, in

Supporting Information part I) in the COSY spectrum, H8 was

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Figure 6. (A) ¹H NMR (500 MHz) of compound 12 and (A₁) observed NOE from the irradiation of H1, which shows NOE enhancement with H2

(1.2%, d_H7,H2(calc)= 3.0 Å), but a weak NOE with H3 (0.5%, d_H1,H3(calc)= 3.9 Å). This suggests that H1 is on the opposite face to H2 and H3, and the

conﬁguration of C1 is (R).

conﬁguration at the C8 center and (S) conﬁguration at the C1

center. Hence, the original assignment of C7(R) stereochemistry

for compound 4 has remained unchanged during the formation

of 5-exo bicyclic compound 9 by free-radical reaction.

This conﬁrmation of C7(R) stereochemistry was important as

an internal reference point for the chirality to conﬁrm the

stereochemistry of a new chiral center in compound 9.

Irradiation of 7(R)-Me (Figure 5, panel A₃) led to 0.5% NOE

enhancement for H8 (d_7‑Me,H8≈ 2.8 Å), but none for 8(R)-Me or

H1, and irradiation of H6′ (Figure 5, panel A₄) shows a strong

NOE enhancement with H8 (5.4%, d_H6,H8≈ 2.2 Å), but none for

8-Me. All of these NOE enhancements indicated (R)

conﬁguration at the C8 center and (S) conﬁguration at the C1

center.

4-[(benzyloxy)methyl]-1-[(4-methoxyphenyl)methoxy]-

7-methyl-2-oxabicyclo[2.2.1]heptane (18b) by the Radi-

cal Cyclization Approach. The synthesis of the 3-(benzyloxy)-

4-[(benzyloxy)methyl]-1-[(4-methoxyphenyl)methoxy]-7-

methyl-2-oxabicyclo[2.2.1]heptanes (18a/18b) starts from a

known intermediate 10^1d(Scheme 3), which was converted to

the crude 6-O-mesylate 11 by the treatment with methanesul-

fonyl chloride in dry pyridine.^7a

After workup, the crude 6-O-Ms-1,2-O-isopropylidene pen-

tose 11 was deprotected with p-toluenesulfonic acid·H₂O in

methanol to aﬀord compound 12 (92%, over two steps) (Figures

S1−S5, Supporting Information part II). Notably, during this

methyl glycoside formation step, only one stereoisomer 12-1(R),

[α]²_D⁵= −26.9, was obtained. In the NOE where H1 was

irradiated (Figure 6, panel A₁), NOE enhancements between H1

Determination of Dihedral Angles through Analysis of

3

3-Bond J_HHfor (1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-

with H2 (1.2%, d_H1,H2(calc)= 3.0 Å) and H3 (0.5%, d_H1,H3(calc)=

[benzyloxymethyl]-1-[(4-methyloxyphenyl)methoxy]-

8,7-dimethylbicyclo[2.2.1]heptane 9. The coupling con-

stants were also used to conﬁrm the conﬁgurations of the chiral

centers in molecule 9 (Figure S74, Supporting Information part

I). The dihedral angles across each bond were calculated through

analysis by Karplus equation²¹through the coupling constants

input.

3.9 Å) were observed.

This suggests that H1 is on the opposite face of H2 and H3,

and the conﬁguration of C1 is (R). The ³J_H2,H3= 4.8 0.2 Hz

(Figure S1, Supporting Information part II) was calculated,

which suggests that H2 and H3 are cisoid to each other. H1 is a

singlet, hence no coupling constant can be measured between H1

and H2. These data prove that the sugar is indeed of β

conﬁguration, as expected. A suspension of compound 12 and

potassium carbonate in MeOH at ∼5 °C aﬀorded the bicyclic 2-

oxo-cycloheptane derivative 13 (74%, [α]_D²⁵= −26.3) by

overnight stirring. The formation of the new 2-oxo-cycloheptane

ring, as in 13, was evidenced on the basis of the HMBC spectra

(Figure S13, Supporting Information part II), where the long-

range proton to carbon coupling gave the correlation between

C6 and H2 over the 2-oxo substituent.

Overnight hydrolysis of the locked sugar 13 by aqueous p-

toluenesulfonic acid·H₂O in THF led to 14 with the free formyl

(δ_[1‑CHO]= 9.6 ppm; 90 and 10% hemiacetal, Figure S14,

Supporting Information part II). The crude formyl compound 14

was subjected to a Grignard reaction with vinylmagnesium

bromide in dry THF overnight to aﬀord the pure alkene

diastereomer 15 [C1-(R), C4-(R)] in 62% yield ([α]²_D⁵= 10.3)

after separation. The vinyl resonances at 5.9, 5.4, and 5.2 ppm

The ³J_H8,H1of compound 9 is 5 0.2 Hz (Figure S74, panel A₁,

in Supporting Information part I), indicating that H1 and H8

have trans orientation to each other which corresponds to 8(R)

conﬁguration. The ³J_H2,H3= 4 0.2 Hz (Figure S74, panel A₂, in

Supporting Information part I) suggests that the H2 and H3 have

cis orientation [2(R),3(S) conﬁguration]. After decoupling of

3

H8, a doublet is observed for H1 with J_H1,H2= 1.4 0.2 Hz

(Figure S73, Supporting Information part I), conﬁrming that H1

and H2 have approximately cis orientation, thereby conﬁrming

1(S) conﬁguration. Moreover, the ³J_H6,H7= 11 0.2 Hz (Figure

S74, panel A₃, in Supporting Information part I) indicates a cis

relationship between H6 and H7 which conﬁrms C7(R)

conﬁguration.

Synthesis of the Diastereomeric Mixture of

(1R,2R,3R,4R,7S)-3-(Benzyloxy)-4-[(benzyloxy)methyl]-1-

[(4-methoxyphenyl)methoxy]-7-methyl-2-oxabicyclo-

[2.2.1]heptane (18a) and (1R,2R,3R,4R,7R)-3-(Benzyloxy)-

1

(Figure S16, Supporting Information part II) in the H NMR

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spectrum of 15 indicate that the vinyl group is incorporated into

the molecule. The conﬁguration at C1 was conﬁrmed by detailed

NOE and coupling constant analyses: irradiation of H7 (Figure

S22, Supporting Information part II) shows NOE enhancement

for H8 (1.6%, d_H7,H8(calc)= 2.4 Å), H2 (1.0%, d_H7,H2(calc)= 3.1 Å),

H3 (0.4%, d_H7,H3(calc)= 3.7 Å), and H1 (0.9%, d_H7,H1(calc)= 3.1 Å).

The key NOE between H8 of the oleﬁn and H3 shows that C1

has an (R) conﬁguration, resulting from an α-face attack of the

Grignard reagent to 1-CHO, that is, from the bottom of the 1-

CHO. To further prove the conﬁguration at C1, irradiation of

H1 (Figure S21, Supporting Information part II) shows NOE

enhancement for H8 (0.9%, d_H1,H8(calc)= 3.7 Å) and H2 (1.8%,

d_H1,H2(calc)= 2.6 Å). These data suggest that H1 is on the opposite

face of the alkene. The vicinal coupling constants have been

measured, showing ³J_H1,H2= 5 0.2 Hz (Figure S25, Supporting

Information part II). This means that H1 and H2 are gauche to

each other, which is also true for H2 and H3 [³J_H2,H3= 3 0.2

Hz] (Figure S23, Supporting Information part II) because they

all have the origin from the ^D-ribose sugar.

[(benzyloxy)methyl]-1-[(4-methoxyphenyl)methoxy]-7-

methyl-2-oxabicyclo[2.2.1]heptane (18a) and

(1R,2R,3R,4R,7R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]-1-

[(4-methoxyphenyl)methoxy]-7-methyl-2-oxabicyclo-

[2.2.1]heptane (18b) from Prop-2-en-1-yl]oxola-3-yl

Methyl Oxalate (17). As previously stated, the free-radical

ring closure resulted in an intractable mixture of 1,7-cis/trans

1

diastereomers (1:0.4 by H NMR), 18a (7S,1R,4R) and 18b

(7R,1R,4R). This has been explained by the steric hindrance of

the 1-(R)-O-PMB group which is occupying most of the β-face,

and therefore, the 7(R)-CH₂^•radical in the β-face is less favored

as shown in TS1b and TS2b in panel A of Figure 4. In the

Newman projections of 18b (Figure 4, panel A, arrow b), it is

shown that for 18b there is steric repulsion between the cis-

oriented 1-(R)-O-PMB (pseudoaxial) and 7(R)-Me (pseudoax-

ial) in the boat-like transition state (the less favored product). On

the other hand, compound 18a exists in the chair-like transition

state, as shown in TS3b and TS4b in panel B in Figure 4, where

the steric repulsion is absent between the trans-oriented 1-(R)-O-

PMB (pseudoaxial) and 7(S)-Me (pseudoequatorial); therefore,

18a is sterically favorable.

In conclusion, the reaction outcome is aﬀected by the

substituent 1-(R)-O-PMB which occupies the β-face, the H1

and the 7(S)-Me are on the α-face, H1 and H7 are trans in 18a,

and H1 and H7 are cis in compound 18b. This mechanism

therefore suggests that we can engineer the outcome of the ratio

of 1,7-cis/trans diastereomers by controlling the conﬁguration

and bulk of the C1 substituent.

NMR Assignments To Support the Structures of

Compounds (1R,2R,3R,4R,7S)-3-(Benzyloxy)-4-

[(benzyloxy)methyl]-1-[(4-methoxyphenyl)methoxy]-7-

methyl-2-oxabicyclo[2.2.1]heptane (18a) and

(1R,2R,3R,4R,7R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]-1-

[(4-methoxyphenyl)methoxy]-7-methyl-2-oxabicyclo-

[2.2.1]heptane (18b). In 18a, the disappearance of the vinyl

resonances (at 5.8 and 5.25 ppm) and the O4 oxalyl methyl signal

at 3.8 ppm, the chemical shift decrease of H1 (from 3.75 to 3.09

ppm) but also the appearance of the doublet 7-Me at 0.98 ppm

suggested that the ring closure had taken place (Figure S43,

Supporting Information part II). The formation of the new C4−

C7 bond was further evidenced by the correlation between H7−

C4 in the HMBC spectrum (Figure S49, panel A, in Supporting

Information part II).

The vicinal coupling constant of H1 with H7 (i.e., ³J_H1,H7= 5.5

0.2 Hz; Figure S24 in Supporting Information part II) shows

that H1 and H7 are transoid to each other.

These data suggest that the C1 center has (R) conﬁguration,

and since the C4 center is part of the locked sugar, the simple

hydrolysis step is not likely to alter its (R) conﬁguration.

The selective protection of 1-OH with p-methoxybenzyl

chloride using NaH as a base in dry DMF yielded the oleﬁn 16

[C1-(R), C4-(R), 71%] ([α]²_D⁵= −25.4). The structure of the

oleﬁn 16 has been corroborated by the COSY experiment

(Figure S29, panels A,B, in Supporting Information part II),

where correlations between H1 and H7, H7 and H8, and H1 and

H2 are found. In the long-range proton to carbon correlation

experiment (Figure S32, panels A−D, in Supporting Information

part II), the following correlations have also been found: H1 and

C8, H7/H8 and C1, H8/H1 and C7, and ﬁnally H3 and C4,

which also corroborate the structural integrity of the oleﬁn 16.

The 1D NOE is shown in Figure S33, Supporting Information

part II: irradiation of H7 shows NOE enhancement for H2

(1.3%, d_H7,H2(calc)= 3.4 Å) and H1 (1.1%, d_H7,H1(calc)= 3.1 Å). In

the coupling constant analysis, the following data are found:

³J_H1,H2= 3.5

0.2 Hz (Figure S36, panel A₁, in Supporting

3

Information part II). The J_H1,H2conﬁrms that the relationship

between H1 and H2 is gauche.

The proton to carbon and proton to proton correlations in

both HMBC and COSY experiments (Figures S45 and S49,

Supporting Information part II) give adequate proof that

oxabicyclo[2.2.1]heptane 18a is indeed formed during the

radical cyclization.

In 18b, the visual appearance of 7-Me and H7 (Figure S43,

Supporting Information part II) indicates that this is tentatively

the other isomer of the newly formed oxabicyclo[2.2.1]heptane,

which is corroborated by the following observations: The H7/7-

Me and H1/H7 correlations in the COSY spectrum (Figure S46,

panels A,B, in Supporting Information part II). In the HMBC

experiment (Figure S50, panel C, in Supporting Information part

II), it is seen that H7 and C4 are long-range coupled, this

conﬁrms that the ring closure has taken place.

Determination of Conﬁguration through NOE Analysis

and the Determination of Dihedral Angles through

Analysis of 3-Bond ³J_HHof Compounds 3-(Benzyloxy)-4-

[(benzyloxy)methyl]-1-[(4-methoxyphenyl)methoxy]-7-

methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b. The orien-

tation of the substituents (at C1 and C7) in the carbocyclic

The coupling constant between H1 and H7 is extracted from

1

3

the H decoupling spectrum, where J_H1,H7= 7.8

0.2 Hz

(Figure S35, Supporting Information part II) suggests that H7

(or vinyl-CH) and H1 are trans-oriented and the conﬁguration at

C1 is conﬁrmed to be (R). The oleﬁn 16 in dry pyridine solution

was treated with methyl(chlorocarbonyl)formate overnight at 50

°C to give the key free-radical cyclization precursor 17 in good

overall yield (73%, [α]²_D⁵= −16.4).

The free-radical cyclization^1dwas carried out under N₂in

anhydrous toluene with Bu₃SnH under reﬂux, using AIBN as an

initiator in a dropwise manner. Cyclization of 17 resulted in an

inseparable mixture of diastereomers 18a/18b in moderate

yields (47%). The chemical identity and the conﬁgurations of

18a/18b have been conﬁrmed by 1D NOEs and detailed

coupling constant analysis (Figures S51−S56, Supporting

Information part II). Detailed NMR analysis conﬁrms that they

both have exclusive β-1-O-PMB (C1-R) conﬁguration, but they

have opposite conﬁgurations at C7.

Mechanism of the Formation of the Diastereomeric

Mixture of (1R,2R,3R,4R,7S)-3-(Benzyloxy)-4-

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Figure 7. (A) ¹H NMR (500 MHz) of compound 18a. (A₁) NOE spectrum where irradiation of H1 shows strong NOE enhancement with CH₃and H2.

(A₂) NOE where irradiation of H3 again proves that H3 and H7 are on the β-face. These data show that H1 and H7 are on the opposite faces and are

trans. H1 and CH₃are on the α-face, C1 is of (R) conﬁguration, and C7 is of (S) conﬁguration.

skeleton of compounds 18a/18b was determined by 1D NOE

experiments (Figures 7 and 8) as well as from the vicinal coupling

constant evaluations.

For compound 18a, irradiation of H1 (Figure 7, panel A₁)

shows NOE enhancement for 7(S)-CH₃(2.8%, d_{H1,7‑Me(calc)}= 2.8

Å), H7 (1.1%, d_H1,H7(calc)= 3.4 Å), H3 (0.3%, d_H1,H3(calc)= 3.8 Å),

and H2 (1.9%, d_H1,H2(calc)= 2.7 Å). This indicates that H1 has the

same orientation as 7-Me, but not H3, which shows that the

stereochemistry of C1 is of (R) conﬁguration.

In compound 18b, irradiation of H7 (Figure 8, panel A₂)

shows NOE enhancement for H1 (9.5%, d_H7,H1(calc)= 2.3 Å),

which suggests that H1 and H7 are on the same face (α-face).

Irradiation of 7(R)-Me (Figure 8, panel A₁) shows NOE

enhancement for H1 (1.7%, d_{7‑Me,H1(calc)}= 3.3 Å), H3 (1.6%,

d_{7‑Me,H3(calc)}= 3 Å), and H2 (0.6%, d_{7‑Me,H2(calc)}= 4.3 Å). This

proves that 7(R)-Me and H3 are both on the β-face, which

suggests that H1 and H7 are cis-oriented.

¹H decoupling experiment of H7 (Figure S60, Supporting

Information part II) shows that 7-Me is aﬀected, but since H1 is a

multiplet and it overlaps with H6, the coupling from H1 cannot

be calculated. However, ¹H decoupling of 7-Me gives the ³J_H1,H7

= 8 0.2 Hz (Figure S61, Supporting Information part II) which

proves that H1 and H7 are cis to each other.

In a similar way, irradiation of H7 (Figure S53, Supporting

Information part II) shows NOE enhancement for 7(S)-Me

(2.7%, d_{H7,7‑Me(calc)}= 3.2 Å), H1 (1.3%, d_H7,H1(calc)= 3.4 Å), H6

(1.2 and 0.8%), H3 (3.7%, d_H7,H3(calc)= 2.5 Å), and H2 (0.2%,

d_H7,H2(calc)= 4.3 Å), which proves that H7 and H3 are on the β-

face. To further verify the conﬁguration of C1 and C7, irradiation

of H3 (Figure 7, panel A₂) was performed which showed

enhancement for 7(S)-Me (0.1%, d_{H3,7‑Me(calc)}= 4.3 Å), H7

(3.6%, d_{H3,7‑Me(calc)}= 2.2 Å), H1 (0.3%, d_H3,H1(calc)= 3.8 Å), and

H2 (1.4%, d_H3,H2(calc)= 2.8 Å). These suggest that H1 and H7 are

trans-oriented.

Steric-Dependent Origin of Diﬀerent Stereochemical

Outcome. What Is the Diﬀerence in the Outcome of the

Grignard Reaction with the Carba-Ring (5→6) in the α-Face

Compared to That of the Furano Ring (14→15)? The outcome

of the Grignard reaction on the formyl/hemiacetal group of the

furanose system (5 → 6 in Scheme 2) to give the alkene-diol 6

(1S,1R mixture) is aﬀected by the steric clash of the 7(R)-Me and

the Grignard reagent in the α-face of the 2,4-carba-ring. Hence,

the β-attack by the Grignard reagent from the “top face” is

favored in 5 → 6, which is fully supported by the NOE

(particularly NOE between H1 and H3; see Table S1,

Supporting Information part I). In contradistinction, the same

reaction on the formyl 14 (14 → 15 in Scheme 3) giving alkene-

diol 15 with the 2-O of the furane ring in the α-face resulted in an

α-attack from the α-face with (R) conﬁguration at C1 exclusively

because, given that the substituents on the β-face in 5 and 14 are

1

On the other hand, the homonuclear H decoupling of H2

3

shows that H1 is coupled to H7 with a J_H1,H7= 3 0.2 Hz

(Figure S58, Supporting Information part II), which indicates

1

that H1 and H7 are in trans relationship with each other. H

decoupling of H7 (Figure S59, Supporting Information part II)

turned H1 into a singlet, which proves that there is no coupling

observed between H1 and H2. The broad singlets of H2 and H3

indicate that these protons have too small coupling to each other

and no coupling can be measured between H2 and H3.

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Figure 8. (A) ¹H NMR (500 MHz) of compound 18b. (A₁) NOE where irradiation of H7 suggests that H1 and H7 are cis. (B) ¹H NMR (500 MHz) of

compound 18b. (A₂) NOE where irradiation of H8 suggests that CH₃and H3 are on the β-face of the fused oxabicyclo[2.2.1]heptane (18b). These data

show that both C1 and C7 have (R) conﬁguration.

identical, the furano-oxygen in 14 has been assumed to form a

Lewis acid−base complex^16a−cwith vinylmagnesium bromide,

thereby enabling the vinyl group to add to the aldehyde from the

α-face.

hindrance by the 1(R)-O-PMB group (TS1b and TS2b, panel A

in Figure 4), which is arising from the boat-like conformation,

which was competing with the chair-like transition state (TS3b

and TS4b, panel B in Figure 4).

What Is the Diﬀerence in the Outcome of the Free-Radical

Cyclization Giving 2,5-Dimethylbicyclo[2.2.1]heptane (8 →9)

Compared to 7-Methyl-2-oxabicyclo[2.2.1]heptane (17→

18a/18b)? Taking into consideration that the radical cyclization

generally proceeds via a boat- and a chair-like transition state, we

have shown that our two diﬀerent chiral carba systems, one with

2,4-carba bridge 8 in the α-face and 17 with 2-O of the furane ring

in the α-face, proceed with diﬀerent stereoselectivity. This is due

to the steric factors that control the stereochemistry of the radical

cyclization from precursors 8 and 17 to give the new C4−C8

bond in 9 (Scheme 2) and C4−C7 bond in 18a and 18b,

respectively (Scheme 3).

Determination of Dihedral Angles through Analysis of 3-

Bond ³J_HHby Karplus Equation for 9 versus 18a/18b and the

Newman Projection. In compound 9 (the sole isomer in which

H8/C5 are transoid), the Newman projections across the C1−

C8 (projection A₁), C4−C6 (projection A₂), and C7−C2

(projection A₃) bonds are shown (Figure 9, panel A). The

3

experimentally derived J_H1,H8= 5 0.2 Hz gives the dihedral

angle for the corresponding torsion, ϕ_{H1−C8−C8−H8}= 132 2°, as

can be found in projection A₁; with these torsion angles ﬁxed, we

could then calculate the other signiﬁcant torsions through

modeling in HyperChem (MM/Amber and semiempirical/

AM1) which in turn shows through projection A₂that the

In the ring closure of 8, the only product obtained is the 2,5-

dimethylbicyclo[2.2.1]heptane (9). The transition state is a boat-

like transition state resulting in the 1,8-trans product exclusively,

and this is due to the steric clash of the bulky 1(S)-O-p-

methoxybenzyl (PMB) and 7(R)-Me in the α-face (pseudoe-

quatorial orientations, Figure 4, TS1a and TS2a in panel A). In

contrast, the ring closure of 17 (Scheme 3) resulted in a

diastereomeric mixture of 1(R)-7-methyl-2-oxabicyclo[2.2.1]-

heptanes (18a/18b, 6:4), which was intractable and could not be

separated. Both the boat- and the chair-like transition states are

possible: the latter resulted in the major 1,7-trans product

observed. The 1,7-cis product [between the 1(R)-O-PMB and

7(R)-Me] was formed as a minor product because of the steric

ϕ_{8‑Me−C8−C4−C5}= 37

2°, ϕ_{8‑Me−C8−C4−C6}= 165

2°, and

ϕ_{8‑Me−C8−C4−C3}= 89 2°, thereby showing that the chirality of

the C4 center has remained unchanged. The Newman projection

A₃across the C7−C2 shows experimental ³J_H2,H7= 5.4 0.2 Hz,

giving torsion, ϕ_{H2−C2−C7−H7}= 46

discussed in the legend of Figure 9.

The Newman projections across the C8−C4 (B₁), C3−C2

(B₂), and C7−C6 (B₃) bonds are shown in Figure 9. Projection

B₂through C3−C2 shows an experimental ³J_H2,H3= 4 0.2 Hz,

giving torsion, ϕ_{H2−C2−C3−H3}= 60 2°, which is fully explained

by the legend of Figure 9: note that these torsions could be easily

obtained because we have a [2.2.1]-fused cycloheptane system

2°, which is further

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Figure 9. (A) Newman projection across the C1−C8 (A₁), C4−C6 (A₂), and C7−C2 (A₃) bonds in dimethylbicyclo[2.2.1]heptane 9. Projection A₁

through C1−C8 bond shows an experimental ³J_H1,H8= 5 0.2 Hz, giving torsion, ϕ_{H1−C1−C8−H8}= 132 2°, which in turn shows through projection A₂

that the ϕ_{8‑Me−C8−C4−C5}= 37 2°, ϕ_{8‑Me−C8−C4−C6}= 165 2°, and ϕ_{8‑Me−C8−C4−C3}= 89 2°, thereby showing that the chirality of the C4 center has

remained unchanged. Projection A₃through C7−C2 bond shows experimental ³J_H2,H7= 5.4 0.2 Hz, giving torsion, ϕ_{H2−C2−C7−H7}= 46 2°, which in

turn shows that the ϕ_{H7−C7−C2−C1}= 178 2° and ϕ_{H7−C7−C2−C3}= 78 2°. (B) Newman projections through the C8−C4 (B₁), C3−C2 (B₂), and C7−

C6 (B₃) bonds in compound 9. Projection B₂through C3−C2 bond shows an experimental ³J_H2,H3= 4 0.2 Hz, giving torsion, ϕ_{H2−C2−C3−H3}= 60 2°,

thereby showing through projection B₂that the ϕ_{H2−C2−C3−OBn}= 58 2°, ϕ_{C1−C2−C3−OBn}= 179 2° and ϕ_{C5−C4−C8−H8}= 86 2° in projection B₁.

Experimental ³J_H6,H7= 11 0.2 Hz corresponds to ϕ_{H6−C6−C7−H7}= 7 2°, and ³J_H6′,H7= 4.5 0.2 Hz corresponds to ϕ_{H6′−C6′−C7−H7}= 128 2°, thereby

showing through projection B₃that the ϕ_{H6−C6−C7−7‑Me}= 113 2°, ϕ_{H6′−C6−C7−7‑Me}= 8 2°.

with a bridgehead at C4. So that also settles the conﬁguration of

C4 to be (R), which, as expected, has remained unchanged.

On the other hand, for compound 18a (the major isomer in

which H7/C5 are cisoid), the Newman projection across the C1−

C7 (A₁) and C4−C6 (A₂) bonds are shown in Figure 10. The

experimentally derived ³J_H1,H7of 3 0.2 Hz (in projection A₁)

gives the dihedral angle for the corresponding torsion,

ϕ_{H1−C1−C7−H7}of 123 2°, and with this torsion angle ﬁxed,

we could then calculate the other signiﬁcant torsions through

modeling in HyperChem. Projection A₁shows that the

torsions through modeling in HyperChem, which in turn shows

through projection B₁that the ϕ_{H7−C7−C1−O‑PMB}= 129 2°,

ϕ_{O‑PMB−C1−C7−7‑Me}= 7

ϕ_{H1−C1−C7−C4}= 118

ϕ_{7‑Me−C7−C4−C3}= 86

2°, ϕ_{7‑Me−C7−C1−C2}= 123

2°, ϕ_{7‑Me−C7−C4−C5}= 42

2°, and ϕ_{7‑Me −C7−C4−C6}= 170

2°,

2°.

For projection B₂details, see caption of Figure 10. These show

that the chirality of C4 center has remained unchanged. The

signiﬁcant torsions were obtained because the 2-oxo-[2.2.1]-

fused cycloheptane system has a bridgehead at C4, so

conﬁguration of C4 has to be (R).

ϕ_{H7−C7−C1−O‑PMB}= 3

2°, ϕ_{O1‑PMB−C1−C7−7‑Me}= 117

2°,

CONCLUSIONS

ϕ_{H1−C1−C7−7‑Me}= 3 2°, ϕ_{H1−C1−C7−C4}= 117 2°, ϕ_{C4−C7−C1−C2}

= 3 2°, and ϕ_{C2−C1−C7−H7}= 112 2°. The bonds in projection

A₂are fully explained in the legend of Figure 10. The

conﬁguration at C4 has remained as (R). For compound 18b

(the minor isomer in which H7/C5 are transoid), the Newman

projections across the C1−C7 (B₁) and C4−C6 (B₂) bonds are

shown in Figure 10. Panel B₁shows the experimentally derived

³J_H1,H7of 8 0.2 Hz, ϕ_{H1−C1−C7−H7}of 3 2°, and with this

torsion angle ﬁxed, we could then calculate the other signiﬁcant

■

In this study, we have synthesized dimethylbicyclo[2.2.1]-

heptane (9) stereospeciﬁcally and a diastereomeric mixture of

7-methyl-2-oxabicyclo[2.2.1]heptanes (18a/18b, 6:4) by the

free-radical ring-closure reaction approach. We have speculated

that the outcome of the reaction is controlled by the

stereochemical environments around the new radical addition

center, C4 and C8−C9 oleﬁn in the radical precursor 8 to give 9

and C4 and C7−C8 oleﬁn in 17 to give 18a/18b. The role of

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Figure 10. (A) Newman projection through the C1−C7 (A₁) and C4−C6 (C₂) bonds in compound 18a. (A₁) Experimental ³J_H1,H7of 3 0.2 Hz, giving

torsion ϕ_{H1−C1−C7−H7}= 123 2°, which in turn shows through projection A₁that the ϕ_{H7−C7−C1−O‑PMB}= 3 2°, ϕ_{O‑PMB−C1−C7−7‑Me}= 117 2°,

ϕ_{H1−C1−C7−7‑Me}= 3 2°, ϕ_{H1−C1−C7−C4}= 117 2°, ϕ_{C4−C7−C1−C2}= 3 2°, ϕ_{C2−C1−C7−H7}= 112 2°, thereby showing through projection C₂,

ϕ_{C3−C4−C6−H6}= 80 2°, ϕ_{C5−C4−C6−H6}= 48 2°, ϕ_{C5−C4−C6−H6′}= 78 2°, ϕ_{H6′−C6−C4−C7}= 50 2°, ϕ_{C7−C4−C6−O2}= 73 2°, ϕ_{O2−C6−C4−C3}= 36 2°,

and ϕ_{7‑Me−C7−C4−C6}= 58 2°. (B) Newman projection of compound 18b through the C1−C7 (B₁) and C4−C6 (B₂) bonds. (B₁) Experimental ³J_H1,H7

of 8 0.2 Hz, ϕ_{H1−C1−C7−H7}of 3 2°, which in turn shows through projection B₁that the ϕ_{H7−C7−C1−O‑PMB}= 129 2°, ϕ_{O‑PMB−C1−C7−7‑Me}= 7 2°,

ϕ_{7‑Me −C7−C1−C2}= 123 2°, ϕ_{H1−C1−C7−C4}= 118 2°, ϕ_{7‑Me−C7−C4−C5}= 42 2°, and ϕ_{7‑Me −C7−C4−C6}= 170 2°, which in turn shows through

projection B₂that ϕ_{C7−C4−C6−O2}= 71 2°, ϕ_{O2−C6−C4−C3}= 36 2°, ϕ_{C3−C4−C6−H6}= 80 2°, ϕ_{H6−C6−C4−C5}= 48 2°, ϕ_{C5−C4−C6−H6′}= 79 2°,

ϕ_{H6′−C6−C4−C7}= 48 2°. Taken these torsions together, it can be found that the chirality of C4 center has remained unchanged.

steric factors for diﬀerent chair- and the boat-like transitions

states have been evaluated.

Implications. Work is in progress to exploit this new

chemistry and the products for synthesis of modiﬁed

oligonucleotides in order to explore their biological activity.

The stereochemical outcome is rationalized by the steric factors,

and having grasped this information, we believe that we are in a

position to predict successfully the stereochemistry at the centers

of the newly formed C−C bond by modifying the bulkiness of

the substituents around the sugar moiety. With less rigid

conformations and less bulky substituents around the radical

center, several isomers are likely to be formed. In contra-

distinction, with more rigid conformationally constrained

conformations and bulkier substituents around the radical

center, only one product may be obtained in a stereospeciﬁc

manner. This opens new possibilities for the syntheses of novel

chiral carba- or double carba-LNAs through the free-radical ring-

closure reaction with a transient conformationally constrained

group at the radical center, which can be removed at the end of

the free-radical ring-closure reaction. These transient groups may

include bifunctional cyclic reagents, such as tetraisopropyldisi-

loxane-1,3-diyl,¹⁷tetraisopropyldisiloxane,¹⁸isopropylidene¹⁹).

In the free-radical cyclization of 8, the single product observed

is the 2,5-dimethylbicyclo[2.2.1]heptane (9) because the

transition state adopts a boat-like conformation which resulted

in the 1,8-trans product (favored) due to the absence of steric

clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me

with 8(R)-CH₂^•radical (TS1a and TS2a in Figure 4) in the α-

face, giving an outcome of one pure bicyclo[2.2.1]heptane 9. On

the other hand, the ring closure of 17 resulted in a diastereomeric

mixture of 1(R)-7-methyl-2-oxabicyclo[2.2.1]heptanes (18a/

18b, 6:4) because both boat-like (TS1b and TS2b in Figure 4)

and the chair-like (TS3b and TS4b in Figure 4) transition states

with low energy barrier are possible. The chair-like transition

state gives the major 1,7-trans addition product. On the other

hand, the minor 1,7-cis product is formed because of the steric

clash between the 1(R)-O-PMB and 7(R)-Me.

Various 1D NMR experiments, including ¹H, ¹³C, ¹H

homodecoupling experiments, 1D nuclear Overhauser eﬀect

spectroscopy (1D NOE), 2D COSY, one-bond ¹H−¹³C

1

correlation (HMQC), and long-range H−¹³C HMBC correla-

tion have been employed to characterize the synthesized

compounds unambiguously.

EXPERIMENTAL SECTION

■

General Procedures. All reagents were the highest commercial

quality and were used without further puriﬁcation. All nonaqueous

reactions were carried out under anhydrous conditions in dry, freshly

distilled solvents under N₂(g). Reactions were monitored by TLC

carried out using UV light as visualizing agent and/or cerium

ammonium molybdate. Flash chromatography was performed using

silica gel 60 (230−400 mesh). ¹H, ¹³C NMR were obtained using 500

and 600 MHz instruments for ¹H and 125 and 150 MHz for ¹³C. The

same spectrometers were used for the acquisition of ¹H−¹H

The conﬁgurations of the substituents of the key intermediates

as well as that of the ﬁnal compounds have been determined by

1D NOE and the dihedral angles determined through analysis of

3-bond ³J_HH(experimentally derived) by Karplus equation. The

molecular structures have been studied by MM and semi-

empirical simulations in HyperChem to understand the

stereochemistry of the key intermediates and the cyclization

products.

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1

homonuclear (COSY and NOE) and H−¹³C heteronuclear (HSQC

(1R,3S,4R,7R)-3-Benzyloxy-5-benzyloxymethyl-1-methoxy-

7-methyl-8-oxa-bicyclo[2.2.1]heptane (4a) and (1R,3S,4R,7S)-3-

Benzyloxy-5-benzyloxymethyl-1-methoxy-7-methyl-8-oxa-

bicyclo[2.2.1]heptane (4b). Compound 3 (2 g, 3.73 mmol) was

dissolved in 80 mL of anhydrous toluene to which N₂was purged for 30

min. The mixture was heated to reﬂux, and Bn₃SnH (2.01 mL in 10 mL

anhydrous toluene) and AIBN (0.31 g in 10 mL anhydrous toluene)

were added dropwise in 2 h and reﬂux was continued for 2 h. Solvent was

evaporated, and the concentrate was puriﬁed by silica gel column

chromatography (0−10% EtOAc in petroleum ether, v/v) to give 0.9 g

of diastereomeric mixture of two isomers 4a and 4b as a colorless oil

(60%) in 3:1 ratio, respectively. The major isomer 4a was isolated but

the minor isomer 4b contained a 30% impurity of 4a.

and HMBC) correlations. Optical rotations were recorded on a

polarimeter, and values are reported as follows: [α]_λ(c (g/100 mL),

T

solvent). The molecular modelings have been performed using

HyperChem Pro 6.0²⁰using MM (AMBER) followed by semiempirical

(AM1) method (as implemented in HyperChem Pro. 6.0) to analyze

the structures of all products reported in the schemes. The dihedral

angles have been obtained using Karplus equation^21a,bthrough the

coupling constant (NMR data) input, whereas HyperChem was used

where no coupling constant could be obtained. High-resolution mass

spectra (HRMS) with correct masses have been obtained by MALDI-

TOF mass spectroscopy.

4-C-Allyl-3,5-di-O-benzyl-1-O-methyl-α,β-^D-ribofuranoside

(2). Compound 1 (1 g, 2.44 mmol) was stirred with 6% p-

toluenesulfonic acid·H₂O in MeOH (15 mL) at rt for 24 h; the mixture

was neutralized with saturated solution of NaHCO₃, concentrated,

diluted with H₂O, and extracted with CH₂Cl₂. After drying over MgSO₄,

it was puriﬁed by silica gel column chromatography (EtOAc/petroleum

ether 1/5−2/5) to give compound 2 as a colorless oil (800 mg, 86%) as

an inseparable mixture of anomer α:β.

4a: ¹H NMR (500 MHz, CDCl₃) δ 7.18−7.26 (10H, m, aromatic),

4.77 (1H, s, H1), 4.54 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.52 (1H, d, J_gem

12 Hz, CH₂Ph), 4.41 (1H, d, J_gem= 11.5 Hz, CH₂Ph), 4.44 (1H, d, J_gem

=

11.5 Hz, CH₂Ph), 4.14 (1H, s, H3), 3.58 (1H, d, J_gem= 11 Hz, H5′), 3.55

(1H, d, J_gem= 11 Hz, H5), 3.30 (3H, s, OCH₃), 2.37 (1H, m, H7), 2.22

(1H, d, J_2,3= 3 Hz, H2), 1.94 (1H, dd, J_gem= 11 Hz, J_6,7= 3.7 Hz, H6),

1.12 (1H, dd, J_gem= 11 Hz, J_6,7= 3.7 Hz, H6), 1.02 (3H, d, J = 9 Hz,

CH₃); ¹³C NMR (125 MHz) δ 138.6, 138.4 (aromatic), 129.6, 128.3,

127.6, 127.4, 127.3 (aromatic), 101.7 (C1), 87.1 (C4), 82.9 (C3), 73.5

(CH₂Ph), 71.7 (CH₂Ph), 69.2 (C5), 54.7 (OCH₃), 48.7 (C2), 37.6

(C6), 27.9 (C7), 15.9 (CH₃); MALDI-TOF m/z [M + Na]⁺calcd for

C₂₃H₂₈NaO₄391.189, found 391.188.

Major Isomer: ¹H NMR (600 MHz, CDCl₃) δ 7.28−7.38 (13H, m,

aromatic), 5.95 (1H, m, H7), 5.12 (2H, m, H8, H8′), 4.86 (1H, s, H1),

4.69 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.61 (1H, d, J_gem= 12 Hz, CH₂Ph),

4.56 (2H, s, CH₂Ph), 4.16 (1H, d, J_3,2= 5.4 Hz, H3), 4.08 (1H, dd, J_2,1

3 Hz, J_3,2= 5.4 Hz, H2), 3.55 (1H, d, J_gem= 9 Hz, H5), 3.28 (1H, d, J_gem= 9

Hz, H5′), 3.31 (3H, s, OCH₃), 2.55 (2H, d, J_gem= 7.2 Hz, H6, H6′); ¹³

NMR (150 MHz, CDCl₃) δ 138.7, 138.5 (aromatic), 134.4 (C7), 128.9,

128.4, 128.2, 127.9 (aromatic), 118.3 (C8), 107.6 (C1), 86.8 (C4), 82.1

(C2), 75.2 (C5), 75.1 (C3), 73.3 (CH₂Ph), 72.8 (CH₂Ph), 55.3

(OCH₃), 38.1 (C6); MALDI-TOF m/z [M + Na]⁺calcd for

C₂₃H₂₈NaO₅407.183, found 407.186.

4-C-Allyl-3,5-di-O-benzyl-1-O-methyl-2-O-phenoxythiocar-

bonyl-β-^D-ribofuranoside (3a), 4-C-Allyl-3,5-di-O-benzyl-1-O-

methyl-2-O-phenoxythiocarbonyl-α-^D-ribofuranoside (3b).

Compound 2 (5 g, 13.01 mmol) was dissolved in 100 mL of anhydrous

pyridine. The solution was cooled to 0 °C, and then phenyl

chlorothionoformate was added dropwise (3.53 mL, 26.02 mmol),

while temperature was maintained at 0 °C during the addition. After

overnight stirring at room temperature, pyridine was recovered under

reduced pressure. The residue was dissolved in CH₂Cl₂and washed with

saturated solution of NaHCO₃twice. The organic layer was separated,

dried over MgSO₄, and concentrated. The concentrate was puriﬁed by

silica gel column chromatography (0−10% EtOAc in petroleum ether,

v/v) to give compound 3 as a yellowish oil (6 g, 88%) as a separable

mixture of anomers α (3b, 22%), β (3a, 66%).

=

4b: ¹H NMR (500 MHz, CDCl₃) δ 7.24−7.34 (14H, m, aromatic),

C

4.56 (1H, s, H1), 4.67 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.61 (1H, d, J_gem

=

12 Hz, CH₂Ph), 4.49 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.59 (1H, d, J_gem= 12

Hz, CH₂Ph), 4.17 (1H, s, H3), 3.75 (1H, d, J_gem= 11 Hz, H5), 3.68 (1H,

d, J_gem= 11 Hz, H5′), 3.38 (3H, s, OCH₃), 2.2 (1H, s, H2), 1.98 (1H, m,

H6), 1.55 (1H, dd, J_gem= 12.5 Hz, J_6,7= 5 Hz, H6′), 1.88 (1H, m, H7),

1.19 (3H, d, J = 7 Hz, CH₃); ¹³C NMR (125 MHz) δ 138.3, 138.6

(aromatic), 128.3, 127.6, 127.4, 127.3 (aromatic), 106.5 (C1), 86.7

(C4), 82.3 (C3), 73.5 (CH₂Ph), 71.8 (CH₂Ph), 68.9 (C5), 54.7

(OCH₃), 48.8 (C2), 38.8 (C6), 32.6 (C7), 20.4 (CH₃); MALDI-TOF

m/z [M + Na]⁺calcd for C₂₃H₂₈NaO₄391.189, found 391.190.

(2R,3S,4R,7R)-3-Benzyloxy-5-benzyloxymethyl-4-hydroxy-7-

methylcyclopentane-1-carbaldehyde (5). To a solution of 4 (900

mg, 2.4 mmol) in the mixed solvent of THF (30 mL) and H₂O (3 mL)

was added p-toluenesulfonic acid·H₂O (1.8 g, 9.6 mmol) at room

temperature and stirred overnight. The reaction mixture was quenched

with saturated solution of NaHCO₃, and the aqueous layer was extracted

with EtOAc. The combined organic layer was washed with brine, dried

over MgSO₄, and concentrated under reduced pressure. The residue was

ﬁltered by column chromatography (25−30% EtOAc in petroleum

ether, v/v) to give 5 as a colorless crude oil (675 mg, 78%), which was

used as-is for the next step for Grignard reaction (to compound 6)

because this aldehyde decomposed on standing and also during attempts

at mass spectrography: ¹H NMR (500 MHz, CDCl₃) δ 9.77 (∼1H, d, J_1,2

= 3 Hz, H1), 7.17−7.29 (10H, m, aromatic), 4.41−4.45 (4H, m, 2 ×

CH₂Ph), 4.15 (1H, d, J_3,2= 4.2 Hz, H3), 3.67 (1H, d, J_gem= 9.6 Hz, H5),

3.40 (1H, d, J_gem= 9 Hz, H5′), 2.22 (1H, dd, J_2,3= 4.8 Hz, H2), 2.49 (1H,

1

Anomer β: H NMR (500 MHz, CDCl₃) δ 7.13−7.26 (13H, m,

aromatic), 6.90 (2H, d, J = 8.5 Hz, aromatic), 5.82 (1H, m, H7), 5.63

(1H, d, J_2,3= 5 Hz, H2), 5.01 (1H, d, J_1,2= 3 Hz, H1), 4.98 (2H, d, J_8,8′= 3

Hz, H8, H8′), 4.54 (2H, s, CH₂Ph), 4.49 (1H, d, J_gem= 11.5 Hz, CH₂Ph),

4.41 (1H, d, J_gem= 11.5 Hz, CH₂Ph), 4.35 (1H, d, J_3,2= 5 Hz, H3), 3.46

(1H, d, J_gem= 9 Hz, H5), 3.27 (1H, d, J_gem= 9 Hz, H5′), 3.26 (3H, s,

OCH₃), 2.39 (2H, m, H6, H6′); ¹³C NMR (125 MHz, CDCl₃) δ 194.4

(CS), 153.3, 151.0, 138.3, 137.9 (aromatic), 133.9 (C7), 128.3, 127.5,

126.8, 121.9, 120.9 (aromatic), 117.9 (C1), 104.4 (C8), 85.1 (C4), 84.2

(C2), 79.4 (C3), 73.9 (C5), 73.3 (CH₂Ph), 73.4 (CH₂Ph), 55.1

(OCH₃), 37.4 (C6); MALDI-TOF m/z [M + Na]⁺calcd for

C₃₀H₃₂NaO₆S 543.182, found 543.180.

m, H7), 2.11 (1H, dd, J_gem= 13.8 Hz, J_6,7= 9 Hz, H6), 1.09 (1H, dd, J_gem

13.2 Hz, J_6,7= 7.2 Hz, H6′), 1.07 (3H, d, J = 5.4 Hz, CH₃).

=

(1S,2R,3S,4R,7R)-3-Benzyloxy-5-benzyloxymethyl-1-hydrox-

yl-1-C-vinyl-7-methylcyclopentane-4-ol (6). Compound 5 (650

mg) was dissolved in THF (20 mL) under nitrogen and cooled to 0 °C.

Vinylmagnesium bromide (1.0 M solution in THF, 7.3 mL, 7.3 mmol)

was added, and then it was allowed to warm to room temperature and

kept stirring at this temperature overnight. The reaction was quenched

with water slowly. The residue was diluted with CH₂Cl₂, washed with

saturated NaHCO₃, dried over MgSO₄, and concentrated under reduced

pressure. The crude material was puriﬁed by column chromatography

on silica gel (10−30% ethyl acetate in petroleum ether, v/v) to give 6 as a

colorless oil (500 mg, 71%): ¹H NMR (600 MHz, CDCl₃) δ 7.18−7.28

(10H, m, aromatic), 5.73 (1H, m, H8), 5.23 (1H, dt, J = 1.8 Hz, H9),

5.05 (1H, dt, J = 1.8 Hz, H9′), 4.53 (1H, d, J_gem= 16.2 Hz, CH₂Ph), 4.47

(1H, d, J_gem= 16.2 Hz, CH₂Ph), 4.51 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.44

(1H, d, J_gem= 12 Hz, CH₂Ph), 4.23 (1H, app t, J_1,2= 5.4 Hz, J_1,8= 6 Hz,

H1), 3.95 (1H, d, J_3,2= 6 Hz, H3), 3.67 (1H, d, J_gem= 9 Hz, H5), 3.37

1

Anomer α: H NMR (600 MHz, CDCl₃) δ 7.19−7.35 (13H, m,

aromatic), 6.98 (2H, d, J = 7.8 Hz, aromatic), 5.80 (1H, m, H7), 5.43

(1H, dd, J_2,3= 6 Hz, J_2,1= 4.8 Hz, H2), 5.15 (1H, d, J_1,2= 4.8 Hz, H1),

4.94 (2H, m, H8, H8′), 4.61 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.47 (1H, d,

J_gem= 12 Hz, CH₂Ph), 4.49 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.33 (1H, d,

J_gem= 12 Hz, CH₂Ph), 4.29 (1H, d, J_3,2= 4.8 Hz, H3), 3.42 (3H, s,

OCH₃), 3.2 (1H, d, J_gem= 9.6 Hz, H5), 3.27 (1H, d, J_gem= 9.6 Hz, H5′),

2.68 (1H, dd, J_gem= 14.4 Hz, J_6,7= 6 Hz, H6); ¹³C NMR (150 MHz) δ

195.21 (CS), 153.9 (aromatic), 134.4 (C7), 129.0, 128.1, 128.0,

126.5, 122.2 (aromatic), 118.3 (C8), 101.7 (C1), 86.9 (C4), 79.7 (C2),

77.6 (C3), 74.9 (CH₂Ph), 73.9 (CH₂Ph), 73.6 (C5), 55.3 (OCH₃), 38.4

(C6); MALDI-TOF m/z [M + Na]⁺, calcd for C₃₀H₃₂NaO₆S 543.182,

found 543.183.

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(1H, d, J_gem= 9 Hz, H5′), 2.18 (1H, m, H7), 2.04 (1H, dd, J_gem= 11.4 Hz,

J_6,7= 3 Hz, H6), 1.92 (1H, dd, J_2,3= 6 Hz, H2), 1.44 (1H, dd, J_gem= 14.4

Hz, J_6,7= 6 Hz, H6), 1.04 (3H, d, J = 7.2 Hz, 7-CH₃); ¹³C NMR (150

MHz) δ 140.6 (C8), 138.3, 138.0, 128.9, 128.8, 128.4, 128.2 (aromatic),

115.2 (C9), 89.1 (C3), 82.4 (C4), 74.5 (CH₂Ph), 74.1 (CH₂Ph), 72.6

(C5), 72.2 (C1), 52.4 (C2), 42.2 (C6), 32.0 (C7), 16.7 (7-CH₃);

MALDI-TOF m/z [M + Na]⁺calcd for C₂₄H₃₀NaO₄405.204, found

405.203.

CH₂PMB), 3.72 (3H, s, OCH₃), 3.50 (1H, d, J_gem= 9 Hz, H5), 3.41 (1H,

d, J_gem= 8.4 Hz, H5′), 3.41 (1H, s, H3), 3.32 (1H, t, J_1,8= 5, J_1,2= 3.5 Hz,

H1), 2.46 (1H, m, J_2,7= 5.4 Hz, H7), 2.43 (1H, d, J_2,3= 4 Hz, H2), 2.08

(1H, t, J_6,6′= 11.4 Hz, J_6,7= 11, Hz, H6), 1.65 (1H, t, H8), 1.25 (3H, d, J =

5.4 Hz, 7-CH₃), 1.14 (1H, dd, J_gem= 12 Hz, J_6,7= 5.4 Hz, H6′), 0.92 (3H,

d, J = 7.2 Hz, 8-CH₃); ¹³C NMR (150 MHz) δ 159.0, 138.8, 130.9, 128.9,

128.2, 127.4, 127.3, 127.1, 113.7 (aromatic), 87.0 (C1), 84.2 (C3), 73.4

(CH₂Ph), 71.1 (C5), 70.8 (CH₂Ph), 55.3 (OCH₃), 53.0 (C4), 45.3

(C2), 45.0 (C8), 42.0 (C6), 31.4 (C7), 17.6, 17.5 (CH₃); MALDI-TOF

m/z [M + Na]⁺calcd for C₃₂H₃₈NaO₄509.267, found 509.268.

(1S,2R,3S,4R,7R)-3-Benzyloxy-5-benzyloxymethyl-1-[(4-

methoxyphenyl)methoxy]-1-C-vinyl-7-methylcyclopentane-4-

ol (7). Compound 6 (350 mg, 0.92 mmol) was dissolved in dry DMF

(10 mL) cooled to 0 °C. NaH (0.043 g, 1.84 mmol) was added, left to

stir for 1 h, PMB-Cl (0.16 mL, 1.2 mmol) was added, and then it was

allowed to warm to room temperature and kept stirring at this

temperature for 5 h. The reaction was quenched with water slowly. The

residue was diluted with EtOAc, washed with brine, dried over MgSO₄,

and concentrated under reduced pressure. The residue was puriﬁed by

silica gel column chromatography (10% EtOAc in petroleum ether, v/v)

to give 7 as a colorless oil (300 mg, 65%): ¹H NMR (500 MHz, CDCl₃)

δ 7.15−7.22 (13H, m, aromatic), 6.76 (1H, d, J = 8.4 Hz, aromatic), 5.73

3,5-Di-O-benzyl-6-O-mesyl-1-O-methyl-β-^D-ribofuranose 12.

Compound 10 (500 mg, 1.25 mmol) was dissolved in dry pyridine (8

mL). Methanosulfonyl chloride (145 μL, 1.87 mmol) was added at 0 °C.

The reaction was stirred at room temperature for 1 h. The reaction

mixture was partitioned between EtOAc and H₂O. The organic layer was

washed with brine twice and dried over anhydrous sodium sulfate,

ﬁltered, and concentrated in vacuo to give crude 11 (as a yellowish oil)

which then was dissolved in MeOH (8 mL), and p-toluenesulfonic

acid·H₂O (500 mg) was added at room temperature. The reaction

mixture was stirred at rt overnight. The mixture was diluted with

dichloromethane and washed with NaHCO₃, dried over anhydrous

sodium sulfate, ﬁltered, and evaporated. The crude 12 was puriﬁed by

silica gel column chromatography (10−40% EtOAc/petroleum ether)

(1H, m, J_{H8, H9}= 17.5 Hz, J_{H8, H9′}= 10.5 Hz, H8), 5.17 (2H, m, J_{H9, H9′}

6.5, H9, H9′), 4.52 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.41 (1H, d, J_gem= 12

Hz, CH₂Ph), 4.43 (1H, d, J_gem= 10.8 Hz, CH₂PMB), 4.16 (1H, d, J_gem

=

1

10.8 Hz, CH₂PMB), 4.49 (2H, s, CH₂Ph), 4.04 (1H, d, J_3,2= 4 Hz, H3),

3.95 (1H, dd, J_1,2= 3.5 Hz, J_1,8= 7.5 Hz, H1), 3.72 (3H, s, OCH₃), 3.59

(1H, d, J_gem= 9.6 Hz, H5), 3.46 (1H, d, J_gem= 9 Hz, H5′), 2.21 (1H, m,

J_H2,H7= 8.5 Hz, H7), 1.91 (2H, m, H2, H6), 1.37 (1H, dd, J_gem= 13.2 Hz,

J_6,7= 9.6 Hz, H6′), 0.96 (3H, d, J_7‑Me,7= 7.2 Hz, 7-CH₃); ¹³C NMR (150

MHz) δ 159.2 (aromatic), 137.8 (C8), 129.0, 129.7, 128.9, 128.4, 128.3,

128.2, 128.0, 127.7, 127.3 (aromatic), 117.1 (C9), 87.7 (C3), 82.2 (C4),

79.3 (C1), 73.6 (CH₂Ph), 73.0 (C5), 72.3 (CH₂Ph), 70.1 (CH₂PMB),

55.3 (OCH₃), 52.4 (C2), 44.9 (C6), 32.5 (C7), 16.0 (7-CH₃); MALDI-

TOF m/z [M + Na]⁺calcd for C₃₂H₃₈NaO₅525.262, found 525.262.

(1S,2R,3S,4R,7R)-3-Benzyloxy-5-benzyloxymethyl-1-[(4-

methoxyphenyl)methoxy]-1-C-vinyl-7-methylcyclopentyl

methyl oxalate (8). Methyl oxalyl chloride (0.29 mL, 3.18 mmol) was

added to a solution of compound 7 (200 mg, 0.39 mmol) in dry pyridine

(10 mL) under nitrogen. The mixture was stirred at 40 °C overnight.

The reaction was cooled, and the solvent was removed. The residue was

extracted with CH₂Cl₂and saturated NaHCO₃solution. The organic

layer was dried over MgSO₄and evaporated. The residue was puriﬁed by

silica gel column chromatography (0−10% ethyl acetate in petroleum

ether, v/v) to obtain 8 as a yellowish oil (160 mg, 68%): ¹H NMR (600

MHz, CDCl₃) δ 7.13−7.23 (15H, m, aromatic), 6.76 (1H, d, J = 8.4 Hz,

aromatic), 5.73 (1H, m, J_H1,H8= 7.5 Hz, J_H8,H9= 18 Hz, J_H8,H9′= 11.5 Hz,

H8), 5.17 (2H, m, H9, H9′), 5.17 (1H, d, J_gem= 10.8 Hz, CH₂Ph), 4.46

(1H, d, J_gem= 10.8 Hz, CH₂Ph), 4.38 (5H, m, CH₂Ph, CH₂PMB, H3),

4.15 (1H, d, J_gem= 12 Hz, H5), 4.01 (1H, d, J_gem= 12 Hz, H5′), 3.87 (1H,

dd, J_1,2= 4.8 Hz, J_1,8= 7.8 Hz, H1), 3.79 (3H, s, OCH₃), 3.73 (3H, s,

OCH₃), 2.27 (1H, dd, J_gem= 13.2 Hz, J_6,7= 7.2 Hz, H6), 2.15 (1H, m,

H7), 2.06 (1H, m, H2), 1.95 (1H, dd, J_gem= 13.8 Hz, J_6,7= 8.4 Hz, H6′),

0.94 (3H, d, J = 6.6 Hz, CH₃); ¹³C NMR (150 MHz) δ 159.3, 159.3

(CO), 156.8 (aromatic), 138.4 (C8), 131.1, 128.7, 128.5, 128.0,

127.8, 127.7, 114.0 (aromatic), 117.7 (C9), 94.9 (C4), 86.6 (CH₂Ph),

79.9 (C1), 73.8 (CH₂Ph), 72.5 (CH₂PMB), 69.7 (C5), 55.7, 53.7

(OCH₃), 52.2 (C2), 42.2 (C6), 30.1 (C7), 16.6 (CH₃); MALDI-TOF

m/z [M + Na]⁺calcd for C₃₅H₄₀NaO₈611.262, found 611.265.

to yield 12 as a colorless oil (520 mg, 92%): H NMR (600 MHz,

CDCl₃) δ 7.31−7.23 (10H, m, aromatic H), 4.86 (1H, s, H1), 4.64 (1H,

d, J = 11.4 Hz, H5), 4.59 (2H, d, J = 11.4 Hz, CH₂Ph), 4.55 (1H, d, J_gem

=

11.4 Hz, H5′), 4.51 (1H, d, J_gem= 10.8 Hz, CH₂Ph), 4.42 (1H, d, J = 10.8

Hz, CH₂Ph), 4.22 (1H, d, J_3,2= 4.8 Hz, H3), 4.04 (1H, t, H2), 3.69 (1H,

d, J = 9 Hz, H6), 3.34 (1H, d, H6′), 3.28 (3H, s, OMe), 2.98 (3H, s,

Mesyl-CH₃), 2.72 (1H, d, OH); ¹³C NMR (150 MHz, CDCl₃) δ 137.6,

137.3, 128.7, 128.6, 128.5, 128.3, 128.1, 128.0, 127.9, 127.8 (aromatic

C), 107.5 (C1), 83.2 (C4), 81.9 (C3), 74.1 (C5), 73.7 (C2), 73.4 (C6),

72.5 (CH₂Ph), 70.6 (CH₂Ph), 54.9 (CH₃), 37.2 (CH₃); MALDI-TOF

m/z [M + Na]⁺calcd for C₂₂H₂₈NaO₈S 475.140, found 475.140.

(1R,2R,3R,4R)-3-Benzyloxy-4-benzyloxymethyl-1-methoxy-

2-oxabicyclo[2.2.1.]heptane 13. Compound 12 (520 mg, 1.15

mmol) was dissolved in MeOH (20 mL). Potassium carbonate (190 mg,

1.39 mmol) was added at 0 °C. The reaction was left to stir at 5 °C

overnight. The temperature was raised to room temperature, at which

the reaction mixture was stirred for another hour. MeOH was

evaporated, and the mixture was dissolved in EtOAc and washed with

H₂O. The aqueous layer was extracted with EtOAc again, dried over

anhydrous sodium sulfate, ﬁltered, and evaporated in vacuo. The crude

compound 13 was puriﬁed by silica gel column chromatography (5−

15% EtOAc/petroleum ether) to give 13 as a colorless oil (305 mg,

74%): ¹H NMR (500 MHz, CDCl₃) δ 7.34−7.26 (10H, m, aromatic H),

4.81 (1H, s, H1), 4.65(1H, d, J_gem= 12 Hz, CH₂Ph), 4.61 (2H, s,

CH₂Ph), 4.56 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.11 (1H, s, H3), 4.08 (1H,

s, H2), 4.00 (1H, d, J = 7.5 Hz, H5), 3.81−3.75 (3H, m, H6, H6′, H5′),

3.39 (3H, s, CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 137.9, 128.4, 127.8,

127.7, 127.6 (aromatic C), 104.9 (C1), 85.2 (C4), 79.2 (C2), 76.8 (C3),

73.7 (CH₂Ph), 72.3 (C5), 72.2 (CH₂Ph), 66.6 (C6), 55.4 (CH₃);

MALDI-TOF m/z [M + Na]⁺calcd for C₂₁H₂₄NaO₅379.152, found

379.152.

(2R,3R,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]-tetrahydro-

4-hydroxyfuran-2-carbaldehyde 14. To compound 13 (300 mg,

0.84 mmol) in THF (10 mL) were added p-toluenesulfonic acid·H₂O

(641 mg, 3.37 mmol) and distilled H₂O (1 mL). The reaction was stirred

at room temperature overnight. The mixture was then quenched with

saturated NaHCO₃solution, extracted with EtOAc, dried over

anhydrous sodium sulfate, ﬁltered, and evaporated. The crude aldehyde

was puriﬁed by silica gel column chromatography (20−40% EtOAc/

petroleum ether) to give 14 as a yellowish oil (252 mg, 75%): ¹H NMR

(500 MHz, CDCl₃) δ 9.56 (1H, s, aldehyde), 7.28−7.18 (10H, m, H

aromatic), 4.61 (1H, d, CH₂Ph), 4.51 (2H, m, CH₂Ph), 5.38 (1H, m,

CH₂Ph), 4.32 (1H, s, H2), 3.91 (3H, m, H3, H6), 3.78 (1H, d, J_gem= 9.5

Hz, H5), 3.44 (1H, d, H5′); MALDI-TOF m/z [M + Na]⁺calcd for

C₂₀H₂₂NaO₅365.136, found 365.137.

(1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-(benzyloxymethyl)-1-

[(4-ethyloxyphenyl)methoxy]-8,7-dimethylbicyclo[2.2.1]-

heptane (9). Compound 8 (100 mg, 0.17 mmol) was dissolved in 6 mL

of anhydrous toluene to which N₂was purged for 30 min. The mixture

was heated to reﬂux, and Bn₃SnH (0.19 mL in 2 mL of anhydrous

toluene) and AIBN (30 mg in 2 mL of anhydrous toluene) were added

dropwise in 2 h and reﬂux was continued for 2 h. Solvent was evaporated,

and the concentrate was puriﬁed by silica gel column chromatography

(0−5% EtOAc in petroleum ether, v/v) to give compound 9 as a

colorless oil (50 mg, 60%): ¹H NMR (600 MHz, CDCl₃) δ 7.18−7.26

(15H, m, aromatic), 6.79 (2H, d, 8.4, aromatic), 4.44 (1H, d, J_gem= 11

Hz, CH₂PMB), 4.43 (2H, s, CH₂Ph), 4.38 (1H, d, J_gem= 12 Hz, CH₂Ph),

4.27 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.23 (1H, d, J_gem= 11.4 Hz,

(1R,2R,3R,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]-tetrahy-

dro-5-(1-hydroxyallyl)-furan-3-ol 15. To the aldehyde 14 (210 mg,

6870

dx.doi.org/10.1021/jo300936g | J. Org. Chem. 2012, 77, 6855−6872

The Journal of Organic Chemistry

Article

0.61 mmol) in dry THF (3 mL) was added vinylmagnesium bromide (1

M in THF, 2.5 mL, 2.5 mmol) at 0 °C. The reaction was stirred at room

temperature overnight. The reaction mixture was the quenched with

saturated NaHCO₃solution, extracted with EtOAc, dried over

anhydrous sodium sulfate, ﬁltered, and evaporated. The crude 15 was

puriﬁed by silica gel column chromatography (20−50% EtOAc/

chromatography (5−20% EtOAc/petroleum ether) to yield 18a/18b as

a yellowish oil (8 mg, 47%). Major isomer: ¹H NMR (500 MHz, CDCl₃)

δ 7.26−7.12 (12H, m, aromatic H), 6.80 (2H, d, CH₂-PMB, J = 8.5 Hz),

4.57 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.50 (1H, d, J_gem= 12 Hz, CH₂Ph),

4.47 (1H, d, J_gem= 12.5 Hz, CH₂Ph), 4.42 (1H, d, J_gem= 11.5 Hz,

CH₂Ph), 4.39 (2H, m, CH₂PMB), 3.95 (1H, br s, H2), 3.89 (1H, s, H3),

3.74 (3H, s, CH₃), 3.58 (3H, m, H5, H5′, H6), 3.36 (1H, d, J = 9.5 Hz,

H6′), 3.09 (1H, dd, J_1,7= 3 Hz, H1), 2.03 (1H, m, J_7,1= 3 Hz, H7), 0.98

(3H, d, J_8,7= 7 Hz, H8); ¹³C NMR (125 MHz, CDCl₃) δ 159.2 (C-

PMB), 138.5, 138.4, 138.3, 130.7, 129.5, 129.2, 128.3, 127.7, 127.5 (C

aromatic), 113.8 (C-PMB), 84.3 (C1), 82.3 (C3), 78.4 (C2), 73.3

(CH₂Ph), 71.9 (CH₂Ph), 71.1 (CH₂PMB), 66.3 (C6), 65.3 (C5), 55.3

(CH₃), 52.4 (C4), 39.8 (C7), 12.9 (C8); MALDI-TOF m/z [M + Na]⁺

calcd for C₃₀H₃₄NaO₅497.233, found 497.231. Minor isomer: ¹H NMR

(500 MHz, CDCl₃) δ 7.20−7.21 (m, aromatic H), 4.51−4.41 (6H, m, 2

× CH₂Bn, CH₂PMB), 3.93 (1H, s, H2), 3.71 (1H, s, H3), 3.092 (1H, m,

1

petroleum ether) to yield 15 as a yellowish oil (140 mg, 62%): H

NMR (500 MHz, CDCl₃) δ 7.38−7.28 (10H, m, aromatic H), 5.92 (1H,

m, J_7,8= 10.5 Hz, H7), 5.38 (1H, dd, J_8,8′= 17 Hz, H8), 5.24 (1H, dd, J_8,8′

= 10.5 Hz, H8′), 4.64 (2H, s, CH₂Ph), 4.59 (2H, m, CH₂Ph), 4.19 (1H,

dt, J_1,2= 5 Hz, J_1,7= 5.5 Hz, H1), 3.94 (1H, m, J_2,3= 3 Hz, H2), 3.90 (1H,

m, H3), 3.89−3.82 (3H, m, H6, H5), 3.63 (1H, d, J_gem= 9.5 Hz, H6′);

¹³C NMR (125 MHz, CDCl₃) δ 138.1 (C7), 129.0, 128.9, 128.4, 128.3

(C aromatic), 117.3 (C8), 88.0 (C2), 85.6 (C3), 82.0 (C4), 75.5 (C5),

74.3 (CH₂−Ph), 73.6 (C1), 72.9 (CH₂−Ph), 70.0 (C6); MALDI-TOF

m/z [M + Na]⁺calcd for C₂₂H₂₆NaO₅393.168, found 393.168.

(1R,2R,3R,4R)-5-(1-(4-Methoxybenzyloxy)allyl)-3-(benzyl-

oxy)-4-[(benzyloxy) methyl]tetrahydrofuran-3-ol 16. Compound

15 (80 mg, 0.22 mmol) was dissolved in dry DMF (3 mL). Then, 60%

NaH (17 mg, 0.432 mmol) was added at 0 °C and left to stir at room

temperature for 30 min at which PMB-Cl (38 μL, 0.28 mmol) was added

at 0 °C. The reaction was left to stir at room temperature for 3 h. Brine

was added to the reaction mixture, extracted with EtOAc, dried over

anhydrous sodium sulfate, ﬁltered, and evaporated followed by

puriﬁcation by silica gel column chromatography (5−15% EtOAc/

petroleum ether) to yield 16 as a yellowish oil (75 mg, 71%): ¹H NMR

(500 MHz, CDCl₃) δ 7.27−7.09 (12H, m, aromatic H), 6.79 (2H, d, J =

J_1,7= 8 Hz, H1), 2.03 (1H, m, H7), 0.91 (3H, d, J = 7.5 Hz, H8); ¹³

C

NMR (125 MHz, CDCl₃) δ 159.1 (C-PMB), 138.4, 138.3, 130.7, 129.5,

129.2, 128.9, 128.3, 127.6, 127.5 (C aromatic), 84.3 (C1), 82.3 (C3),

78.4 (C2), 73.3 (CH₂Ph), 71.9 (CH₂Ph), 71.1 (CH₂PMB), 66.3 (C6),

65.3 (C5), 55.3 (CH₃), 52.4 (C4), 39.8 (C7), 12.9 (C8); MALDI-TOF

m/z [M + Na]⁺calcd for C₃₀H₃₄NaO₅497.233, found 497.231.

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H, ¹³C NMR, COSY, HMQC, HMBC spectra for compounds

1−9 (Supporting Information part I) and 10−18a/18b (part II);

¹H homodecoupling for compounds 7, 8, and 9 (part I), 15, 16,

and 18a/18b (part II); 1D NOE spectra for compounds 7, 8, and

8.4 Hz, H- PMB), 5.84 (1H, m, J_7,8= 10.5 Hz, H7), 5.30 (1H, d, J_7,8

=

10.0 Hz, H8), 5.22 (1H, dd, J_8′,8= 1 Hz, H8′), 4.54 (2H, s, CH₂Ph), 4.52

(1H, d, J_gem= 11.4 Hz, CH₂PMB), 4.45 (1H, d, J_gem= 12 Hz, CH₂Ph),

4.34 (1H, d, J_gem= 12 Hz, CH₂Ph), 4.21 (1H, d, J_gem= 11.4 Hz,

CH₂PMB), 3.80 (1H, t, J_2,3= 3 Hz, H2), 3.77 (1H, d, J_gem= 9.6 Hz, H5),

3.72 (3H, s, CH₃PMB), 3.72−3.69 (4H, m, H3, H6, H5′), 3.64 (1H, dd,

J_1,2= 3.5 Hz, J_1,7= 7.8 Hz, H1), 3.59 (1H, d, J_gem= 9.6 Hz, H6′); ¹³C NMR

(125 MHz, CDCl₃) δ 135.2 (C7), 129.9, 129.5, 128.4, 127.9, 127.7 (C

aromatic), 119.4 (C8), 113.8 (CH₂−PMB), 87.4 (C2), 85.7 (C3), 81.4

(C4), 79.3 (C1), 75.6 (C5), 73.9 (CH₂−Ph), 72.7 (CH₂−Ph), 69.9

(C6), 55.3 (C-Me); MALDI-TOF m/z [M + Na]⁺calcd for

C₃₀H₃₄NaO₆513.225, found 513.226.

(1R,2R,3R,4R)-5-(1-(4-Methoxybenzyloxy)allyl)-3-(benzyl-

oxy)-4((benzyloxy)methyl)tetrahydrofuran-3-yl methyl oxalate

17. Methoxyoxalyl chloride (38 μL, 0.41 mmol) was added to a solution

of 16 (50 mg, 0.1 mmol) in dry pyridine (3 mL). The reaction was

stirred at 50 °C overnight at which time it was quenched with saturated

NaHCO₃solution, extracted with DCM, dried over anhydrous sodium

sulfate, ﬁltered, and evaporated. The crude 17 was puriﬁed by silica gel

column chromatography (5−15% EtOAc/petroleum ether) to yield 17

as a colorless oil (40 mg, 73%): ¹H NMR (500 MHz, CDCl₃) δ 7.21−

7.11 (12H, aromatic H), 6.78 (2H, d, J = 9 Hz, CH₂-PMB), 5.78 (1H, m,

3

9 (part I), 12, 15, 16, and 18a/18b (part II) and J_HHvicinal

coupling constant of compounds 7, 8, and 9 (part I), 15, 16, and

18a/18b (part II) along with Newman projections of these

compounds; molecular structures based on MM and semi-

empirical calculations for compounds 7, 8, and 9 (part I), 12, 16,

and 18a/18b (part II). This material is available free of charge via

the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: jyoti@boc.uu.se.

■

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

M.K. and S.E. have contributed equally. Generous ﬁnancial

support is from the Swedish Natural Science Research Council

■

H7), 5.25 (1H, d, J = 7 Hz, H8), 5.21 (1H, s, H8′), 4.59 (1H, d, J_gem

=

(Vetenskapsradet), the Swedish Foundation for Strategic

̊

11.5 Hz, CH₂Ph), 4.49 (1H, d, J_gem= 11.5 Hz, CH₂PMB), 4.47 (2H,

Research (Stiftelsen for Strategisk Forskning), and the EU-FP6

̈

ABq, J_gem= 12 Hz, CH₂Ph), 4.35 (1H, d, J_gem= 11.0 Hz, H6), 4.29 (1H, d,

funded RIGHT project (Project No. LSHB-CT-2004-005276).

M.K. and S.E. also thank Dr. O. Plashkevych of this lab for

teaching them to use the HyperChem program.

J_gem= 11.5 Hz, CH₂Ph), 4.15 (3H, m, H2, H5, H6), 3.89 (1H, d, J_gem

=

10.5 Hz, H5′), 3.80 (4H, m, CH₃, H6′), 3.75 (2H, m, H3, H1), 3.70 (3H,

s, CH₃PMB); ¹³C NMR (125 MHz, CDCl₃) δ 159.2, 157.9, (CO),

137.7 (C7), 134.9, 129.7, 128.4, 128.0, 127.8, 127.7 (C aromatic), 119.3

(C8), 113.7 (C-PMB), 92.8 (C4), 86.5 (C3), 83.4 (C2), 78.4 (C1), 73.9

(CH₂−Ph), 73.6 (C6), 73.3 (CH₂−Ph), 70.0 (CH₂−PMB), 66.4 (C5),

55.3 (OCH₃−PMB), 53.5 (CH₃); MALDI-TOF m/z [M + Na]⁺calcd

for C₃₃H₃₆NaO₉599.136, found 599.134.

(1R,2R,3R,4R,7S)-3-(Benzyloxy)-4-[(benzyloxy)methyl]-1-[(4-

methoxyphenyl)methoxy]-7-methyl-2-oxabicyclo[2.2.1]-

heptane18a and (1R,2R,3R,4R,7R)-3-(Benzyloxy)-4-

[(benzyloxy)methyl]-1-[(4methoxyphenyl)methoxy]-7-methyl-

2-oxabicyclo[2.2.1]heptane 18b. Compound 17 (20 mg, 0.036

mmol) was dissolved in dry toluene (2 mL). Bu₃SnH (40 μL, 0.146

mmol in 0.5 mL of dry toluene) and AIBN (5.9 mg, 0.036 mmol in 0.5

mL of dry toluene) were added over 1 h at reﬂux. The reaction was

stirred at reﬂux for another 2 h at which time the mixture was evaporated

in vacuo. The crude 18a/18b was puriﬁed by silica gel column

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Steric effects in the tuning of the diastereoselectivity of the intramolecular free-radical cyclization to an olefin as exemplified through the synthesis of a carba-pentofuranose scaffold

DOI: 10.1021/jo300936g

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