A modular approach to aryl-C-ribonucleosides via the allylic substitution and ring-closing metathesis sequence. A stereocontrolled synthesis of all four α-/β- and D-/L-C-nucleoside stereoisomers

ARTICLE

pubs.acs.org/joc

A Modular Approach to Aryl-C-ribonucleosides via the Allylic

Substitution and Ring-Closing Metathesis Sequence. A

Stereocontrolled Synthesis of All Four α-/β- and ^D-/L-C-Nucleoside

Stereoisomers^†

‡,z

‡,§

^

‡

,^

ꢀ

Jan Stambaskꢁy, Vojtꢀech Kapras, Martin Stefko, Ondꢀrej Kysilka, Michal Hocek,*

Andrei V. Malkov,*^,‡,rand Pavel Koꢀcovskꢁy*^,‡

^‡Department of Chemistry, WestChem, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K.

^{^}Institute of Organic Chemistry and Biochemistry, Gilead Sciences & IOCB Research Center, Academy of Sciences of the

Czech Republic, CZ-16610, Prague 6, Czech Republic

S Supporting Information

b

ABSTRACT:

Iridium(I)-catalyzed allylation of the enantiopure monoprotected copper(I) alkoxide, generated from (S)-5a, with the enantiopure

allylic carbonates (R)-9a,b has been developed as the key step in a new approach to C-nucleoside analogues. The anomeric center

was thus constructed via a stereocontrolled formation of the CꢀO rather than CꢀC bond with retention of conﬁguration. The

resulting bisallyl ethers 15a,b (g90% de and >99% ee) were converted into C-ribosides 29a,b via the Ru-catalyzed ring-closing

metathesis, followed by a diastereoselective dihydroxylation catalyzed by OsO₄or RuO₄and deprotection. Variation of the absolute

conﬁguration of the starting segments 5a and 9a,b allowed a stereocontrolled synthesis of all four α/β-^D/L-combinations.

’ INTRODUCTION

with a glycal;⁹and (5) opening of glycal-derived epoxides

(anhydrosugars) with organometallics.¹⁰However, none of these me-

thods is truly general, and many of them suﬀer from poor stereo-

selectivity, low yields, or lability of the starting materials. We are

currently involved in the development of modular methodologies

allowing a generation of a series of diverse derivatives. Thus, we have

recently developed modular syntheses of substituted phenyl,¹¹pyridyl

and pyrimidyl,¹²and thienyl¹³C-nucleosides. This methodology was

based on the preparation of halogenated aryl C-nucleoside inter-

mediates and subsequent displacement of the halogen with alkyl, aryl,

or amino substituents by cross-coupling reactions. However, even in

this approach, the C-glycosidation step represents a bottleneck in the

whole synthesis in terms of eﬃciency and anomeric selectivity.

Therefore, our next goal was to develop a new general strategy for

the construction of aryl-C-nucleosides in all stereochemical combina-

tions at will (^Dand L series, as well as α- and β-anomers) by

stereoselective and/or stereoconserved synthesis starting from simple

chiral building blocks available in both enantiomeric forms. Herein,

we report on a modular stereocontrolled synthesis of all four 1,4-

stereoisomeric aryl-C-nucleosides via building-up the carbohy-

drate moiety by a stereospeciﬁc iridium-catalyzed allylic substitu-

tion reaction of the enantiopure arylpropenyl carbonates with

Aryl-C-nucleosides attract a great deal of attention as corner-

stones in the pursuit of extension of the genetic alphabet.¹These

aromatic derivatives form pairs selectively with the same or

other hydrophobic nucleobases in oligonucleotide duplexes as

a result of an increased propensity to π-stacking and favorable

desolvation energy (as compared to canonical hydrophilic

nucleobases).²Triphosphates of some of the C-nucleosides have

been eﬃciently incorporated into DNA by DNA polymerase.³

Recently, an artiﬁcial base-pair, consisting of 2-methoxy-4-

methylphenyl C-nucleoside and thioisocarbostyril base, has been

reported⁴to be selectively replicated and the growing DNA chain

was eﬃciently extended, which previously constituted a serious

problem with the existing artiﬁcial base pairs. This new genera-

tion of base-pairs was recently successful even in the PCR

ampliﬁcation.^4cTherefore, it would be highly desirable to build

on these promising results and expand the portfolio of artiﬁcial

base-pairs, from which new, eﬃcient combinations can be

expected to emerge. However, this program will require devel-

opment of a robust modular methodology that would allow the

synthesis of libraries of new C-nucleoside derivatives.

There are several synthetic approaches⁵to C-nucleosides: (1)

addition of organometallics to a ribono- or 2-deoxyribonolactone;^3,6

(2) coupling of a halogenose with organometallics;⁷(3) electro-

philic, Lewis acid-catalyzed substitution of electron-rich aromatics

with a carbohydrate;⁸(4) Heck-type coupling of aryl iodides

Received: June 3, 2011

Published: August 12, 2011

r

2011 American Chemical Society

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enantiopure allylic alcohols as O-nucleophiles, followed by ring-

closing metathesis (RCM) and dihydroxylation.

Chart 1. Strategic Bond Disconnection

’ RESULTS AND DISCUSSION

As discussed in the previous paragraph, the methodology

available for the synthesis of C-nucleosides is generally conﬁned

to those approaches that rely on the construction of the CꢀC

bond at the anomeric center of a suitable carbohydrate derivative

(A in Chart 1).⁵We envisaged that a stereocontrolled formation

of the endocyclic CꢀO bond (B or C) could serve as an attractive

alternative that may eliminate some of the deﬁciencies in the

existing synthetic arsenal and open a new avenue toward these

important targets.

Scheme 1. Retrosynthetic Analysis

We reasoned that transition metal-catalyzed allylic substitu-

tion with an appropriate O-nucleophile could serve as a perfect

tool for the stereo- and regiocontrolled construction of one of the

CꢀO bonds (Scheme 1) to generate the bisallyl ether G.

Subsequent cyclization of the latter intermediate via ring-closing

metathesis would then provide the dihydrofuran derivative H,

whose dihydroxylation would produce the desired C-riboside.

Four approaches to the key intermediate G can be considered:

thus, alkoxide D, generated from the monoprotected enantio-

pure 3-butene-1,2-diol, can be expected to react with the non-

chiral allylic substrate E (pathway a) or its enantiopure isomer F

(pathway b). Alternatively, the enantiopure allylic alkoxide J

could be utilized as a nucleophile in the reaction with the allylic

substrate I or K (pathways c and d). In this scheme, pathways a

and c would require the use of one enantiopure reactant each and

a chiral catalyst, whereas pathways b and d would make use of two

enantiopure reactants each and a nonchiral metal catalyst.

All the required types of starting materials are, a priori, readily

available: thus, the enantiopure 3-butene-1,2-diol, as a precursor

of the monoprotected alkoxide D and of carbonate K, is

commercially available in both enantiomeric forms (from

butadiene), whereas the nonchiral, monoprotected allylic sub-

strate I can be obtained from the commercially available 2-bu-

tene-1,4-diol. The nonchiral cinnamyl-type substrates E are a

textbook target for the Wittig-type methodology and can also be

prepared by the methods recently developed by us that are

based on either SuzukiꢀMiyaura coupling or cross-metathesis.¹⁴

Finally, a very eﬃcient synthesis of several enantiopure carbonates

F and the corresponding alcohols (as precursors of alkoxides J),

which hinges on an enzymatic resolution of the corresponding

1-arylprop-2-en-1-ols, has recently been developed by us.¹⁵

Transition metal-catalyzed allylic substitution (Scheme 2) is

known to proceed via the corresponding π-allyl complexes in a

stereo- and regiocontrolled manner.¹⁶Nonsymmetrically sub-

stituted complexes, such as 2, which can be generated either from

the linear esters 1 or from their branched isomers 3,¹⁷are

inherently chiral. Therefore, an enantioselective reaction starting

with 1 requires the use of a chiral catalyst (with a chiral ligand

L*),¹⁸whereas a nonchiral catalyst is suﬃcient when the en-

antiopure branched isomer 3 is used.^16,19ꢀ21While both allylic

esters and carbonates have been frequently employed as sub-

strates, in some instances the tert-butyl carbonyl leaving group

[R²= O(t-Bu)] is required for the catalytic substitution reaction

to occur eﬃciently (vide infra).

Scheme 2. Transition Metal-Catalyzed Asymmetric Allylic

Substitution

whereas Mo,²⁴W,^25,26Ru,²⁷Rh,²⁸and Ir^29ꢀ31exhibit the

opposite tendency, aﬀording the branched isomer as the major

product. However, in the Rh-catalyzed reactions with symme-

trical substrates, the nucleophile enters at the site to which the

leaving group was orriginally attached.^28bFinally, Fe³²complexes

are preferentially attacked by nucleophiles at the leaving group

site with retention of conﬁguration. Of this portfolio of transition

metal catalysts, Ir and Rh appear to be particularly suitable for the

construction of the CꢀO (and CꢀN) bonds, whereas other

metal catalysts have proven to be less successful here and are

mainly used in the realm of CꢀC bond formation. Therefore, we

focused on these two metals in the present study.

Synthesis of Protected Butenediols. One of the main

advantages of our new strategy toward C-nucleosides is the oppor-

tunity to employ a common building block for the nucleophilic

partner in the allylic substitution reaction. 3-Butene-1,2-diol (4),

commercially available in both enantiomeric forms, was selected as a

starting material (Scheme 3), bearing in mind that, if used as a

Regioselectivity of the nucleophilic attack by nucleophiles at

the nonsymmetrically substituted η³-complexes is mainly gov-

erned by the nature of the metal. Thus, Pd complexes are

preferentially attacked at the less substituted terminus,^16,17,22,23

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Scheme 3. Synthesis of the Protected Butenediols 5aꢀd

Chart 2. Allylic Derivatives

nucleophile (pathways a and b in Scheme 1), (S)-4 would produce

the natural ^D-C-nucleosides, whereas (R)-4 would give rise to their

non-natural ^L-enantiomers. The chemistry to be involved required

protection of the latter diol at the primary hydroxyl, leaving free the

secondary hydroxyl function. Various protecting groups were

investigated,³³and racemic diol 4 was first employed to optimize

the protecting group and reaction conditions. The protecting groups

were selected with a view of attaining the highest selectivity toward

the primary hydroxyl, also bearing in mind their behavior in the

subsequent reactions. Four protecting groups were explored,

namely tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl

(TBDPS), triphenylmethyl (Trt), and pivaloyl (Piv). Diol 4 was

treated with the respective derivatizing agent R-Cl (neat, or 2 M

solution in the case of solids) in the presence of Et₃N (4ꢀ5 equiv)

and 4-(dimethylamino)pyridine (DMAP, 10 mol %) in an appro-

priate solvent at room temperature for 24 h: THF was used for the

alkylchlorosilanes, whereas dichloromethane was found to be the

solvent of choice for the trityl and pivaloyl chlorides. The isolated

yields of the monoprotected products, shown in Scheme 3, reflect

the selectivity of the individual reactions. Later, during the course of

the investigation of the metal-catalyzed allylic substitution and the

subsequent transformations, the tert-butyldimethylsilyl and, to some

extent, tert-butyldiphenylsilyl group, were identified as an optimum

(vide infra). Protection of the enantiopure diol (R)-4 and (S)-4

(both g99% ee) proceeded in a similar way without any loss of

enantiopurity. The monoprotected diols (()-5b and (R)-5b were

converted into the corresponding tert-butyl carbonates (()-6b

(94%) and (R)-6b (95%, g99% ee) by using our protocol,^14,15

involving deprotonation of the free hydroxyl with n-BuLi at 0 ꢀC,

followed by treatment with Boc anhydride at room temperature.

Under these conditions, the possible migration of the protecting

group from the primary to the secondary hydroxyl was minimized.

Synthesis of Cinnamyl- and Isocinnamyl-Type tert-Butyl

Carbonates. Hartwig has found allylic carbonates, in particular

tert-butyl carbonates, to be superior to esters as substrates for the

Ir-catalyzed allylic substitution.²⁹The synthesis of a series of

cinnamyl-type carbonates was reported by us in another paper,¹⁴

in which we compared three approaches: (1) the WittigꢀHorner-

Emmons olefination of aldehydes ArCHO to produce the corre-

sponding α,β-unsaturated esters ArCHdCHCO₂Et, followed by

reduction with DIBAL-H and conversion of the resulting allylic

alcohols ArCHdCHCH₂OH into the desired carbonates upon

reaction with n-BuLi and Boc₂O; (2) SuzukiꢀMiyaura coupling of

aryl iodides ArI with trans-vinyl pinacolboronate (RO)₂BCHd

CHCH₂OCO₂(t-Bu), which in turn was obtained by hydroboration

of propargyl carbonate HCtCCH₂OCO₂(t-Bu) with pinacolbor-

ane; (3) cross metathesis of vinyl aromatics ArCHdCH₂with the

Boc-protected allyl alcohol CH₂dCHCH₂OCO₂(t-Bu), catalyzed

Chart 3. Phosphoramidite Ligands

by the Grubbs second-generation complex.¹⁴Of this series, only the

phenyl derivative 7 was used as a model compound in the present

investigation (Chart 2).

Racemic isocinnamyl-type alcohols 8aꢀe (Chart 2) were

prepared via addition of vinylmagnesium bromide to the corre-

sponding aldehydes ArCHO.¹⁵Their optimized resolution by

using an enantioselective acetylation with isopropenyl acetate,

catalyzed by Novozyme 435, aﬀorded both enantiomeric series in

g99% ee.¹⁵Conversion of the latter alcohols into the Boc

derivatives 9aꢀe was carried out under optimized conditions,

involving deprotonation with n-BuLi in THF, followed by treat-

ment with Boc anhydride at room temperature for 3 h;^15,34,35this

protocol was found to minimize side reactions, in particular the

allylic rearrangement.¹⁵

Iridium-Catalyzed Allylic Substitution with Oxygen Nu-

cleophiles. Rhodium- and iridium-catalyzed allylic nucleophilic

substitution of the cinnamyl-type carbonates 1 and 3 with

MeOH, PhCH₂OH, and other simple alcohols has been shown

by Evans,²⁸Hartwig,²⁹and Helmchen^30qto require the use of the

corresponding Cu(I) alkoxide as the O-nucleophile, which in

turn can be generated from the respective alcohol by deprotona-

tion with n-BuLi, followed by transmetalation with CuI. Both

isomeric carbonates 1 and 3 give predominantly the branched

product, irrespective of the alcoholate nucleophile.^28ꢀ30Reac-

tions of the chiral allylic substrates 3, catalyzed by both Rh and Ir,

are known to proceed with overall retention of configuration

with C-, N-, and O-nucleophiles.^28ꢀ31Furthermore, Helmchen

has demonstrated a double inversion mechanism for stabilized

C-nucleophiles, such as NaCH(CO₂Me)₂;³⁰ⁱin this, Ir parallels

the stereochemical behavior of Pd^16,19,36but differs from that of

Mo, where a double retention pathway is followed.^20,21,37

Iridium-Catalyzed Reaction of Cinnamyl Carbonate 7 with

Monoprotected Diols 5. In the reactions of allylic carbonates

with simple copper(I) alkoxides, catalyzed by either rhodium or

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Scheme 4. Allylic Substitution Employing Racemic

Substrates^a

Scheme 5. Allylic Substitution Employing Enantiopure

Substrates^a

^aTBS = (t-Bu)Me₂Si, TBDPS = (t-Bu)Ph₂Si, Trt = Ph₃C, Piv = t-BuCO.

iridium, various chiral ligands, in particular FeringaꢀAlexakis

phosphoramidites (Chart 3),^28c,29,30have been reported to

induce high enantioselectivity. According to the original proce-

dure developed by Hartwig for the iridium-catalyzed intermole-

cular allylic etherification with simple alcohols,^29lsolid aliphatic

lithium alkoxide and copper(I) iodide are mixed, followed by

addition of a solvent at 0 ꢀC; a solution of a mixture of the

precatalyst and the ligand is then added at 0 ꢀC, followed by

addition of the allyl carbonate at 0 ꢀC.

Our reaction system required further development and opti-

mization owing to the steric bulk of alcohol 5b, which was

utilized as the ﬁrst model compound. This endeavor included

ﬁnding the right conditions for the deprotonation of the alcohol

(to avoid the migration of the protecting group from the primary

to secondary hydroxyl), optimization of the copper source for the

alkoxide formation, the time required for full conversion, the reac-

tion temperature proﬁle, and assessment of the inﬂuence of the

ligand, additives, and the nature of the precatalyst and its loading.

Various methods for the formation of the alkoxide from (()-

5b were investigated, namely deprotonation with n-butyllithium,

vinylmagnesium bromide, phenylmagnesium bromide, and phe-

nylzinc bromide in THF (Scheme 4). A solution of the alkoxide

thus generated was then directly transferred to a suspension of

^aTBS = (t-Bu)Me₂Si; COD = 1,5-cyclooctadiene.

(to 73% conversion, based on 7) with high selectivity for the

branched product 12ba but required higher temperature (20 ꢀC)

than that originally recommended by Hartwig,^29lpresumably

owing to the increased steric bulk of the protecting group in

alcohol 5b. The latter success clearly demonstrated the key role

of the phosphoramidite ligand. However, no stereochemical

preference was observed, and the bisallyl ether 12ba was isolated

as a ∼1:1 mixture of two diastereoisomers. With the catalyst

generated from ligand 11 (2 mol %), the reaction of (()-5b (1

equiv) with 7 (0.55 equiv) reached 95% conversion at 20 ꢀC over

16 h and aﬀorded 12ba as a 65:35 mixture of diastereoisomers in

which the anti-isomer (i.e., S,S/R,R) dominated over its syn-

counterpart (i.e., S,R/R,S).³⁸Substrates 5c and 5d were found to

be less suitable than 5b as the conversions to 12ca/12da were

substantially lower (25% and 12%, respectively).³⁹The reaction

of (()-5a (1 equiv) with 7 (0.55 equiv), catalyzed by

[(COD)IrCl]₂(2 mol %), in the presence of the phosphorami-

dite ligand 10 (2 mol %) furnished 12aa as a ∼1:1 mixture of

diastereoisomers in a rather lower yield (38%). Interestingly, in

the case of 5a, partial migration of the protecting group was

observed in some cases, giving rise to the isomer 13 as a minor

contaminant along with the main product 12aa (see the follow-

ing paragraph).⁴⁰

The latter experiments deﬁned the reaction conditions and

demonstrated the diﬀerence in reactivity of the individual

enantiomers of racemic 5bꢀd when ligand 11 was employed,

which is quite remarkable in its own right but not suﬃcient for

the production of the stereochemically pure targets. Therefore,

the reaction of the enantiopure 5a (2 equiv) with the cinnamyl

substrate 7 (1 equiv) was explored next (THF at ꢀ40 ꢀC for 16 h).

In the presence of the catalyst generated from [(COD)IrCl]₂

(2 mol %) and ligand 11 (3 mol %), (S)-5a aﬀorded 15a

(Scheme 5) at ꢀ40 ꢀC as the major product,⁴¹accompanied

by its diastereoisomer 16a (97:3 dr) and the rearranged product

13 (6%).^40,42The opposite enantiomer (R)-5a also reacted

CuI or CuBr Me₂S in THF at 0 ꢀC or at 20 ꢀC. For the formation

3

of the alkoxide from (()-5b, the protocol using n-BuLi at 0 ꢀC

for 10 min, followed by transmetalation with CuI at 20 ꢀC for 30

min, proved to be optimal. The appearance of a bright yellow

solution of the corresponding copper alkoxide was indicative of a

successful transmetalation. The quality of the CuI proved to be of

key importance; the optimal procedure for its preparation

included rigorous drying of a perfectly ground CuI in the reaction

ﬂask at 140 ꢀC overnight and until the reaction was set up. No

diﬀerence was noticed when nondegassed solvent was used.

With a successful procedure for the copper alkoxide formation

in hand, we endeavored to work out the conditions for the

reaction of 5b with the cinnamyl derivative 7 (Scheme 4). In the

initial experiments, racemic (()-5b was employed as a precursor

of the required nucleophile (vide supra). However, an attempted

reaction of the copper(I) alkoxide generated from (()-5b or

(R)-5b with the cinnamyl carbonate 7 in the presence of

[(COD)IrCl]₂(3 mol %) failed. On the other hand, when the

catalyst was prepared (in situ) from the latter Ir(I) complex

(2 mol % based on the metal) and the chiral ligand 10 (2 mol %),

the reaction of (()-5b (1 equiv) with 7 (0.55 equiv) did proceed

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readily with 7 under the same conditions and in the presence of

the same ligand (11) aﬀorded the diastereoisomeric 17a (97:3

dr)⁴¹together with the rearranged product 13 (10%).^40,42ꢀ44

Hence, ligand (R_a,R_c,R_c)-11 promotes the construction of the

(R)-stereocenter in the “eastern” part of the molecule with the

same eﬃciency for both enantiomers of the nucleophilic “western”

moiety. Therefore, it can be assumed that the enantiomeric

ligand ent-11 would give access to the remaining members of the

series, i.e., 16 and 18.

Iridium- and Rhodium-Catalyzed Reaction of Isocinna-

myl-Type Carbonates 9 with Protected Diols 5. The reaction

of (()-5b or (R)-5b (1 equiv) with (()-9a (0.55 equiv),

catalyzed by [(COD)IrCl]₂(4 mol %), proceeded readily

(unlike with 7) and produced 12ba (52% and 54%, respectively)

as a 1:1 mixture of diastereoisomers in each case (Scheme 4),

showing that no kinetic resolution took place. The 4-fluorophe-

nyl analogue (()-9e proved to be slightly more reactive, furnish-

ing 12be (77%). The analogous reaction catalyzed by [(COD)-

RhCl]₂gave 12ba (12%) along with olefin 14a (23%).⁴⁵The

corresponding reaction of (()-9e catalyzed by [(COD)RhCl]₂

gave a mixture of 12be (31%) and olefin 14b (43%).

Table 1. Stereocontrolled Synthesis of Bisallyl Ethers 15ꢀ18

from the Monoprotected Diol 5a and Branched Allylic

Carbonates 9ad (Scheme ⁵)^a

entry

alcohol^b

carbonate^b

product^c

yield (%)^d,e,f

1

2

(S)-5a

(R)-5a

(R)-9a

(R)-9b

(S)-9a

(S)-9b

(R)-9a

(R)-9b

(S)-9a

(S)-9b

(S)-9c

(S)-9d

15a

15b

16a

16b

17a

17b

18a

18b

18c

18d

82

74

79

78

83

72

77

73

85

70

3

4

5

6

7

8

9

10

^aThe reaction was carried out at 6ꢀ17 mmol scale in THF at 20 ꢀC for

20 h, using 1 equiv of 5a, 0.9 equiv of 9, and 2 mol % of the catalyst (mol %

c

based on the metal) unless stated otherwise. ^bPurity >99% ee. The

relative conﬁguration was determined after cyclization (vide infra).

^dIsolated yield. ^eThe enantiopurity determined by chiral HPLC was

f

>99% ee in all cases. According to the NMR spectra of the crude

An improvement in the reactivity (but not in stereoselectivity)

was observed when the phosphoramidite ligand 10 (2 mol %)

and [(COD)IrCl]₂(2 mol %) was used as the reaction of (()-5b

with (()-9a aﬀorded 12ba (66%), again as an almost 1:1

diastereoisomeric mixture (6% de). A similar result (62%) was

obtained when (t-BuO)₂PN(i-Pr)₂was employed as the added

ligand. Interestingly, only traces of 12ba (5%) were obtained

when the reaction of (R)-5b with (()-9a was carried out in the

presenceof[(COD)IrCl]₂(2.5mol%) and(S)-BINAP(2.5mol%),

the major product being oleﬁn 14a (33%).⁴⁵The latter product

dominated (e46%) in the reaction of (()-5b with (()-9a

catalyzed by (Ph₃P)₃RhCl or [(COD)RhCl]₂, regardless of

whether an additional ligand [e.g., BINAP, (MeO)₃P, or

(t-BuO)₂PN(i-Pr)₂] was added or not, with no 12ba obtained;

instead, the starting carbonate (()-9a was recovered (e51%),

demonstrating the inferiority of the Rh-based catalysts in this

particular system.

Improved yields were obtained with the silyl derivative 5a.

Thus, the reaction of (()-5a or (R)-5a (1 equiv) with (()-9a

(0.55 equiv), catalyzed by [(COD)IrCl]₂(2 mol %), aﬀorded the

bisallyl ether 12aa as a 1:1 mixture of diastereoisomers in 84%.

The combination of (R)-5a (1 equiv) and (S)-9a (0.55 equiv),

catalyzed by [(COD)IrCl]₂(2 mol %), aﬀorded the bisallyl ether

12aa as a single diastereoisomer in 79% yield. With higher

amounts of carbonate (()-9a (0.8 equiv), a slight decrease in

the yield (74%) was observed. The 4-ﬂuorinated carbonate (()-

9e (0.9 and 1.0 equiv) and the 4-brominated carbonate (()-9c

(0.55 equiv) behaved in a similar way, aﬀording the correspond-

ing products in good yields (74%, 65%, and 75%, respectively).

Similarly, in the presence of the phosphoramidite ligand 10 (2

mol %), 12aa was obtained as a ∼1:1 mixture in a rather lower

yield (41%), showing that neither kinetic resolution nor stereo-

chemical isomerization of the intermediate η³-Ir-complex took

place.⁴⁶With the catalyst generated from [(COD)IrCl]₂, (2 mol %)

and (t-BuO)₂PN(i-Pr)₂(2 mol %), the same conversion to 12aa

was attained (84%) but with no eﬀect on diastereoselectivity.

By contrast, only the starting carbonates were detected in the

attempted reaction of (()-5a (1 equiv) with (()-9a or 7 (0.55

equiv), catalyzed by [(COD)RhCl]₂(2 mol %), clearly demon-

strating the superiority of the Ir catalyst.

products, the diastereoisomeric ratio was at least 95:5 in all cases; this

ratio might actually be even higher (see the main text below for

discussion of accuracy).

Attempted Iridium-Catalyzed Reaction of Isocinnamyl

Alcohol 8a with the Allylic Carbonate 6b. The reversed

disconnection, according to pathway c in Scheme 1, proved

unsuccessful. Thus, the attempted reaction of carbonate (()-6b

with the Cu(I) alkoxide generated from the isocinnamyl alcohol

(()-8a, carried out in the presence of either [(COD)IrCl]₂,

[(COD)RhCl]₂, or (Ph₃P)₃RhCl (4ꢀ5 mol %) with or without

added (MeO)₃P, only led to a slow decomposition, with no 12

being detected. This behavior clearly shows that the isocinnamyl-

type carbonates 9 are the electrophilic partners of choice in terms

of reactivity, which favors pathway b over c (and consequently d)

in the disconnection diagram (Scheme 1).

Stereocontrolled Synthesis of Bisallyl Ethers 15ꢀ18. All

the above experiments allow the following conclusions to be

made: (1) The linear carbonate 7 (in pathway a; Scheme 1) gives

diastereoisomerically almost pure products (97% de) in the

presence of the chiral ligand 11, which are however contaminated

with various amounts of byproducts that are rather difficult to

remove.⁴³(2) The branched carbonate 9a (pathway b) is more

reactive than its linear isomer 7. (3) The stereocontrol with the

chiral ligand 11 is excellent for pathway a, whereas pathway c

(and presumably d) is not suitable because of the low reactivity;

the reaction has to be carried out at ꢀ40 ꢀC to minimize the

formation of byproducts. (4) For the formation of the bisallyl

ether 12 from 5 and 9 (pathway b), the use of ([Ir(COD)Cl]₂)

(2 mol %) without any additional ligand gives the best conversion

at 20 ꢀC in g16 h in a clean reaction. (5) Rh catalysts proved

inferior. (6) Silyl protecting groups, as in 5a,b, proved superior to

trityl and pivaloyl (5c,d). Furthermore, 5a proved to be superior

to 5b for pathway b. (7) Path b appears to be the most promising;

here, the optimal ratio of the alcohol to carbonate 5:9 was found

to be 1:0.8 to 1:0.9.

In view of these ﬁndings, we focused on the Ir(I)-catalyzed

reaction of the enantiopure alcohol 5a (>99% ee) with the

enantiopure branched carbonates 9aꢀd (>99% ee), aiming at a

high-yielding stereospeciﬁc process (Scheme 5 and Table 1);

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Scheme 6. Ring-Closing Metathesis^a

Scheme 7. O-Deprotection^a

^aTBS = (t-Bu)Me₂Si.

^aTBS = (t-BU)Me₂Si.

considerable amounts of byproducts.^51aIt is pertinent to note

that the latter deprotected nucleoside analogues 23ꢀ26 thus

obtained represent, in fact, products of potential biological

interest in their own right.⁵²

the substitution was expected to proceed predominantly with

retention of conﬁguration (vide supra). The reactions were carried

out under our standard conditions, i.e., with 5a (1.0 equiv) and

9aꢀd (0.9 equiv) and with [(COD)IrCl]₂as catalyst (2.0 mol %,

based on the metal) in THF at 20 ꢀC for 20 h (Table 1). All

stereochemical combinations of the (R)- and (S)-substrates

turned out to be successful, aﬀording the respective enantiopure

products 15ꢀ18 (>99% ee) in good isolated yields (73ꢀ85%).

The substitution itself was highly stereospeciﬁc, giving the

products of retention of conﬁguration in g95:5 ratio in all cases,

as evidenced by the NMR spectra of the crude products. Hence,

this protocol appears to be the method of choice for the

construction of the bisallylic ethers required as precursors for

the ring-closing metathesis. However, in contrast to the success-

ful reactions of meta- and para-substituted phenyl derivatives 9,

their ortho-substituted congeners (e.g., 2-methyl- 2-ﬂuoro-, 2,4-

dimethyl-, and 2,4-diﬂuorophenyl) reacted sluggishly, whereas

the 3-pyridyl analogue failed to react; in both cases the corre-

sponding carbonates gradually decomposed.

The absolute conﬁguration at C-4 of the deprotected products

(Scheme 7) reﬂects the absolute conﬁguration of the starting

monoprotected diol 5a, as no reaction occurred at this center.

The conﬁguration at C-1 (the anomeric center) is dictated by the

conﬁguration of the starting isocinnamyl carbonate 9, as the Ir-

catalyzed allylic substitution is known^28ꢀ31to proceed with

retention of conﬁguration. Thus, for instance, the conﬁguration

of 23a, originating from (S)-5a and (R)-9a, should be cis as

shown, which is consistent with the NOE enhancement (1ꢀ2%)

of 1-H and 4-H in the ¹H NMR spectrum. By contrast, anomers

24, which should be trans-conﬁgured, exhibited no NOE eﬀect.

The relative conﬁguration was eventually conﬁrmed by X-ray

crystallography for the products of dihydroxylation (vide infra).

The deprotection step not only represents a divergent route,

broadening the synthetic utility of our new approach to

C-nucleosides, but also oﬀers an opportunity to accurately establish

the stereochemical purity of our products, as the protected

derivatives were not suitable for HPLC or GC analysis, owing

either to their instability or to poor resolution. The expected

appropriate NOE eﬀect was only observed after the deprotec-

tion. All four stereoisomers of 1⁰-phenyl-substituted D4 nucleo-

side analogue 23aꢀ26a were then subjected to GC analysis. The

results were compared with the chromatograms recorded for the

corresponding racemic diastereoisomers (obtained from racemic

starting materials). All samples of 23aꢀ26a showed high diaster-

eo- and enantiopurity (>99% de and >99% ee). On the basis of

these values, we can assume that the diastereoselectivity of the

allylic substitution (Table 1) might have been higher than the ¹H

NMR spectroscopy allowed to estimate (>90% de). However, we

have to bear in mind that three chromatographic puriﬁcation

steps were used in the sequence from the allylic substitution to

the deprotected derivatives 23ꢀ26, which may have slightly

enhanced the diastereoisomeric purity.

Synthesis of Protected 2⁰,3⁰-Didehydro-2⁰,3⁰-Dideoxy-C-

Nucleosides by Ring-Closing Metathesis. The bisallyl ethers

15a,bꢀ18a,b were subjected to the standard ring-closing me-

tathesis (RCM) reaction (Scheme 6).⁴⁸A brief screening of the

reaction conditions was carried out, employing Grubbs first- and

second-generation catalysts. Because no significant difference

was observed in the performance of these two catalysts, Grubbs

first-generation complex was chosen. Catalyst loadings as low as

1% was found to be sufficient, and the optimized reaction

conditions comprised a heating to reflux in CH₂Cl₂for 3 h.⁴⁹

The desired 1,5-dihydrofuran derivatives 19a,bꢀ22a,b were

obtained as pure stereoisomers in 78ꢀ97% isolated (with one

exception, where the yield dropped to 56% due to the inefficient

isolation procedure).

The sensitive⁵⁰dihydrofuryl derivatives 19ꢀ22 were depro-

tected by treatment with Et₃N HF (3 equiv) as the opti-

3

mized reagent (20 ꢀC, 16 h) to aﬀord alcohols 23a,bꢀ26a,b in

good isolated yields (Scheme 7).⁵¹The analogous TBDPS

derivatives could be deprotected under similar conditions, but

the yields, as a rule, were by ca. 20% lower due to the formation of

Construction of Ribofuranosides and Completion of the

Synthesis. Dihydroxylation of the double bond in the dihydro-

furan derivatives resulting from the RCM should readily afford

the desired vicinal diols. However, since only the cis-derivatives

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Scheme 8. Dihydroxylation of Dihydrofurans^a

loading (10 mol %).⁵³In our hands, neither of the ﬁrst two

modiﬁcations was overwhelmingly successful, and we feel that

the main problem was the ineﬃcient phase transfer in this

heterogeneous system. Following the third protocol, the dihy-

drofuran derivative 19b in a mixture of AcOEt and MeCN (1:1)

was oxidized with aqueous NaIO₄in the presence of RuCl₃H₂O

3

(12 mol %) at 0 ꢀC for 45 s to aﬀord 27b (61%) as the major

diastereoisomer. On the other hand, extending the reaction time

to 80 s resulted in a dramatic decrease of the yield to 16%, owing

to the oxidation of the product with excess of NaIO₄. Again, the

results here were very dependent on the level of homogeneity.

Finally, the one-pot experiment, combining the RCM accord-

ing to Blechert, followed by Hudlickꢁy’s procedure, was carried

out as follows: the bisallyl ether 18b was subjected to RCM

[Grubbs ﬁrst-generation catalyst (1.5 mol %), CH₂Cl₂, reﬂux

for 3 h]. When the RCM was complete, the solvent was changed

(CH₂Cl₂was evaporated, and the residue was dissolved in a 1:1

mixture of AcOEt and MeCN), and the oxidation was carried out

via Hudlickꢁy’s procedure (i.e., without a Lewis acid), and with

RuCl₃H₂O (up to 10% Ru in total) as an additional ruthenium

3

source. With NaIO₄as the stoichiometric oxidant at 0 ꢀC for 15 s,

the latter protocol aﬀorded 28b in 34% yield over the two steps.

Analogous results were obtained for the one-pot reaction of

bisallyl ethers 15a and 18c, furnishing diols 27a (24%) and 28c

(31%) respectively.

Clearly, the protocol employing the ruthenium catalyst and

NaIO₄suﬀers from the propensity of the resulting diol to an

oxidative cleavage by excess of NaIO₄(which can be assumed to

be faster for ﬁve-membered ring systems than for the correspon-

ing six-memberd rings due to the inherent dihedral angle).

Therefore, the reaction must be carried out like a titration, where

an aqueous solution of NaIO₄is added dropwise to a solution

containing the reactant and Ru catalyst; the change of color from

dark-brown into yellow indicates the completion of the reaction,

and the mixture needs to be quenched immediately with a 50%

aqueous solution of Na₂S₂O₃to prevent further oxidation.

Hence, in view of the diﬃculties associated with controlling

^aTBS = (t-Bu)Me₂Si.

19 and 22 can be expected to react stereoselectively, the trans-

derivatives 20 and 21 were excluded from the study. Two

possible tactics can be considered (Scheme 8): (1) vicinal

dihydroxylation of the isolated dihydrofuran derivatives 19 and

22,^48,53catalyzed either by osmium tetroxide (method A), or by

the less toxic and far more reactive ruthenium tetroxide (method

B);^53,54or (2) a direct, one-pot procedure involving the ring-

closing metathesis of 15 and 18, followed by oxidation of the

ruthenium in the reaction mixture to RuO₄, which would then

catalyze the dihydroxylation of the intermediate dihydrofuran

derivative (method C).⁵⁵

These tactics were explored in various combinations of the

reaction conditions. Oxidation of the enantiomers 19a and 22a

with osmium tetroxide as catalyst (1 mol %) and N-methylmor-

pholine N-oxide as a stoichiometric oxidant (1.3 equiv) was

carried out in a mixture of acetone and water (10:1) at room

temperature. The reaction proceeded readily and was complete

within 12 h, furnishing the enantiomeric ^D- and L-ribo-diols 27a

(80%) and 28a (78%), respectively. Alongside these desired

ribonucleosides, their lyxo-diastereoisomers 31 (14%) and 33

(13%) were obtained, respectively, which were readily separated

by column chromatography.

For the dihydroxylation catalyzed by ruthenium tetroxide, the

following protocols were reported previously: (1) Plietker’s

procedure, utilizing a catalytic amount of a ruthenium source

together with certain amounts of a Lewis acid (e.g., CeCl₃) and a

stoichiometric inorganic oxidant, most frequently NaIO₄.⁵⁶(2)

A modiﬁcation of this method, recently reported by Blechert,

combines the RCM procedure with subsequent utilization of the

remaining ruthenium complex in the Plietker-type oxidation as a

one-pot protocol.⁵⁵(3) Hudlickꢁy’s procedure, which does not

utilize any Lewis acidic additive but requires a higher catalyst

ꢀ

the Ru/IO₄protocols, the OsO₄-catalyzed procedure can be

regarded as much more reliable, robust, and reproducible. The

formation of a small amount of the lyxo-derivative does not

constitute a signiﬁcant problem, as the two disatereoisomers can

be readily separated by chromatography.

The TBS derivatives 27a and 28a were deprotected by

treatment with 2 M aqueous hydrochloric acid at 45 ꢀC (by

coevaporation in vacuo), followed by a reverse phase column

chromatography to produce the free ribonucleoside 29a (86%)

and 30a (79%), respectively. Slightly lower yields were attained

when Et₃N 3HF in THF was employed (75% and 72%, re-

3

spectively). The m-ﬂuoro derivatives 27b and 28b were depro-

tected by using the latter method; chromatographic puriﬁcation

aﬀorded triols 29b (65%) and 30b (62%). The TBS-protected

lyxo-nucleoside 31 was transformed into the free nucleoside 32

upon treatment with 2 M HCl in the same way. Direct deprotec-

tion of the crude reaction mixtures after dihydroxylation of 19a

was also explored, but the resulting mixture of the free ribo- and

lyxo-nucleosides was not separable. Therefore, the optimum

deprotection sequence involves the separation of the diastereoi-

someric silylated nucleosides, followed by deprotection of pure

isomers. Of the two methods employed, namely 2 M HCl and

Et₃N 3HF, the former gave slightly higher yields.⁵⁷

3

The enantiomeric β-1-phenyl ribofuranoses 29a and 30a were

isolated as crystalline compounds suitable for X-ray diﬀraction

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ARTICLE

analysis, which conﬁrmed the relative conﬁguration. Since the

absolute conﬁguration of the starting monoprotected diol 5a was

known, the absolute conﬁguration of 29a and 30a can thus be

regarded as fully established. The latter conclusion can be

extrapolated to the ﬂuoro derivatives 29b and 30b and other

intermediates of the whole sequence.

Solvents and solutions were transferred by syringeꢀseptum and cannula

techniques. All solvents for the reactions were of reagent grade and were

dried and distilled immediately before use as follows: tetrahydrofuran

(THF) from sodium/benzophenone; dichloromethane from calcium

hydride. Solvents for the palladium- and ruthenium-catalyzed reactions

were degassed in vacuo and stored over molecular sieves (4 Å) under

argon atmosphere. Yields are given for isolated products showing one

spot on a TLC plate and no impurities detectable in the NMR spectrum.

The identity of the products prepared by different methods was checked

by comparison of their ¹H NMR spectra, and ultimate elemental

composition (microanalysis).

General Procedure A: Regioselective Protection of Butene-

1,2-diols. A solution of the chosen protecting agent (TBSCl, TBDPSCl,

or Ph₃CCl, 30.87 mmol) in THF (20 mL) was added slowly to a solu-

tion of butene-1,2-diol 4 (2.721 g, 30.87 mmol) and DMAP (400 mg,

3.27 mmol) in a mixture of Et₃N (15 mL) and THF (60 mL) at 0 ꢀC, and

the mixture was stirred overnight at 20 ꢀC. The reaction was then

quenched with water, diluted with Et₂O (200 mL), three times washed

with brine, dried (Na₂SO₄), and evaporated. Chromatography on a

column of silica gel with a mixture of hexanes and ethyl acetate gave the

respective protected butenol 5 as a colorless oil.

’ CONCLUSIONS

A conceptually new synthetic route to C-nucleosides has been

developed, comprising a divergent reaction sequence with three

strategic steps followed by deprotection. The anomeric center

was constructed via a stereocontrolled formation of the “endo-

cyclic” CꢀO bond as the key step (route b in Scheme 1). Thus,

iridium(I)-catalyzed reaction of the isocinnamyl carbonate (R)-

9a with the copper(I) alkoxide, generated from the monopro-

tected diol (S)-5a, produced the bisallylic ether (S,R)-15a as a

result of the stereo- and regiospeciﬁc allylic substitution that

occurred with retention of conﬁguration (>90% de) owing to a

double inversion mechanism. The alternative strategy, employ-

ing the Ir-catalyzed reaction of the nonchiral cinnamyl carbonate

7 (instead of 9) and the chiral ligand 11 (path a in Scheme 1) was

also found to be highly stereoselective but less eﬃcient, owing to

the formation of byproducts that were rather diﬃcult to separate.

Subsequent ring-closing metathesis, catalyzed by the Grubbs

ﬁrst-generation catalyst, aﬀorded the dihydrofuran derivative 19a

(>99% de; >99% ee), whose dihydroxylation, catalyzed by OsO₄,

resulted in the formation of diol 27a as the major diastereo-

isomer. The ﬁnal deprotection produced the enantiopure β-^D-

ribofuranoside 29a. Variation of the absolute conﬁguration of the

starting segments 5a and 9a,b allowed a stereocontrolled synth-

esis of all four α/β-^D/L-combinations 29/30. Each reaction step

was investigated in detail and optimized. Our approach is suitable

for the synthesis of aryl C-nucleosides lacking ortho-substituents

and/or a coordinating nitrogen atom. Application of our proto-

col can be expected in the area of lipophilic isosters of ribonucleo-

sides for RNA studies,⁵⁸α- and β-aryl C-nucleosides for

ﬂuorescent oligonucleotide arrays,⁵⁹and unnatural L-C-ribonu-

cleosides⁶⁰for studies of biological activity. This strategy for the

de novo construction of carbohydrate molecules is likely to be

general⁶¹and should also be suitable for the synthesis C-

deoxyribonucleosides, which would extend its application from

the RNA to DNA realm.

(()-1-(tert-Butyldimethylsilyloxy)but-3-en-2-ol (()-(5a).

Butene-1,2-diol (()-4 (2.721 g, 30.87 mmol) was protected with tert-

butyl(chloro)dimethylsilane following general procedure A. Chroma-

tography on column of silica gel (5 ꢁ 10 cm) with a mixture of hexanes

and ethyl acetate (98:2) gave the butenol (()-5a as a yellowish liquid

(5.081 g, 81%): ¹H NMR (400.1 MHz, CDCl₃) δ 0.07 (s, 6H, CH₃),

3

0.90 (s, 9H, t-Bu), 2.60 (d, J_OH,2-CH= 3.4 Hz, 1H, OH), 3.44 (dd,

²J_1-Ha,1-Hb= 10.0 Hz, ³J_1-Ha,2-H= 7.6 Hz, 1H, 1-Ha), 3.64 (dd, ²J_1-Hb,1-Ha

=

10.0 Hz, ³J_1-Hb,2-H= 3.8 Hz, 1H, 1-Hb), 4.15 (m, 1H, 2-H), 5.17 (ddd,

³J_4-Ha,3-H= 10.6 Hz, ²J_4-Ha,4-Hb= 1.5 Hz, ⁴J_4-Ha,2-H= 1.4 Hz, 1H, 4-Ha),

3

4

2

5.33 (ddd, J_4-Hb,3-H= 17.3 Hz, J_4-Hb,2-H= 1.6 Hz, J_4-Hb,4-Ha= 1.5

3

Hz, 1H, 4-Hb), 5.80 (ddd, J_3-H,4-Hb= 17.3 Hz, J_3-H,4-Ha= 10.6 Hz,

³J_3-H,2-H= 5.7 Hz, 1H, 3-H); ¹³C NMR (100.6 MHz, CDCl₃): δ ꢀ5.42

(CH₃), ꢀ5.39 (CH₃), 18.3 (C(CH₃)₃), 25.8 (C(CH₃)₃), 66.9 (CH₂-1),

73.0 (CH-2), 116.4 (CH₂-4), 136.7 (CH-3). Anal. Calcd for C₁₀H₂₂O₂Si:

C, 59.35; H, 10.96. Found: C, 59.36; H, 11.07.

(R)-1-(tert-Butyldimethylsilyloxy)but-3-en-2-ol (R)-(5a).

Butene-1,2-diol (R)-4 (2.53 g, 28.6 mmol) was protected with tert-

butyl(chloro)dimethylsilane following general procedure A. Chro-

matography on column of silica gel (5 ꢁ 10 cm) with a mixture of

hexanes and ethyl acetate (98:2) gave the butenol (R)-5a as a

colorless oil (3.83 g, 66%) with chemical purity >99% (GC) and

>99% ee (chiral GC): ¹H NMR (400.1 MHz, CDCl₃) δ 0.05 (s, 6H,

3

CH₃), 0.88 (s, 9H, t-Bu), 2.65 (d, J_2-OH,2-H= 3.6 Hz, 1H, 2-OH),

3.43 (dd, ²J_1-Ha,1-Hb= 9.9 Hz, ³J_1-Ha,2-H= 7.6 Hz, 1H, 1-Ha), 3.62 (dd,

’ EXPERIMENTAL SECTION

3

²J_1-Hb,1-Ha= 9.9 Hz, J_1-Hb,2-H= 3.8 Hz, 1H, 1-Hb), 4.10ꢀ4.15 (m,

3

2

1H, 2-H), 5.15 (dd, J_4-Ha,3-H= 10.6 Hz, J_4-Ha,4-Hb= 1.2 Hz, 1H,

4-Ha), 5.31 (dd, ³J_4-Hb,3-H= 17.3 Hz, ²J_4-Hb,4-Ha= 1.2 Hz, 1H, 4-Hb),

5.78 (ddd, ³J_3-H,4-Hb= 17.3 Hz, ³J_3-H,4-Ha= 10.6 Hz, ³J_3-H,2-H= 5.7 Hz,

1H, 3-H) in agreement with an authentic sample of the racemate.

Anal. Calcd for C₁₀H₂₂O₂Si: C, 59.35; H, 10.96. Found: C, 59.21; H,

11.13. Chiral GC showed >99% ee (Supelco β-DEX 120 column,

oven 70 ꢀC for 5 min then gradient 1 ꢀC.min^ꢀ1to 105 ꢀC) t_R= 31.48

min ((S)-5a), t_R= 32.68 min ((R)-5a). Fraction distillation of the

crude product obtained by the above procedure (131 mmol scale)

gave (R)-5a as a colorless liquid (21.35 g, 80%): bp 43ꢀ45 ꢀC at

270 Pa.

(S)-1-(tert-Butyldimethylsilyloxy)but-3-en-2-ol (S)-(5a).

Butene-1,2-diol (S)-4 (5.28 g, 59.9 mmol) was protected with tert-

butyl(chloro)dimethylsilane following general procedure A. Chro-

matography on a column of silica gel (8 ꢁ 10 cm) with a mixture of

hexanes and ethyl acetate (98:2) gave butenol (S)-5a as a colorless oil

(9.29 g, 76%) with chemical purity >99% (GC) and >99% ee (chiral

General Methods. Melting points were determined on a Kofler

block and are uncorrected. Optical rotations were recorded in CHCl₃at

25 ꢀC unless otherwise indicated with an error of <(0.1. The [α]_D

values are given in 10^ꢀ1deg cm²g^ꢀ1. The NMR spectra were measured

in chloroform-d. Residual solvent peaks (δ 7.26, ¹H; δ 77.00, ¹³C) and

CCl₃F (δ 0.00, ¹⁹F) were used as internal standards unless otherwise

indicated. Chemical shifts are given in ppm (δ-scale), coupling constants

(J) in hertz. Complete assignment of all NMR signals was performed

using a combination of H,H-COSY, H,C-HSQC, and H,C-HMBC

experiments. IR spectra were recorded for a thin film between NaCl

plates or for CHCl₃solutions. Mass spectra (EI or CI-isobutane, unless

otherwise specified) were measured on a dual sector mass spectrometer

using direct inlet and the lowest temperature enabling evaporation. All

reactions were performed under an atmosphere of dry, oxygen-free

argon in oven-dried glassware three times evacuated and backfilled with

the argon three times. Reaction temperature ꢀ83 ꢀC refers to the

cooling bath filled with an ethyl acetateꢀliquid nitrogen mixture.

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GC): ¹H NMR (400.1 MHz, CDCl₃) δ 0.05 (s, 6H, CH₃), 0.88 (s, 9H,

105 (40), 77 (25), consistent with the literature data.⁶³Anal. Calcd for

C₂₃H₂₂O₂: C,83.60; H, 6.71. Found: C, 83.43; H, 6.58.

3

2

t-Bu), 2.65 (d, J_2-OH,2-H= 3.6 Hz, 1H, 2-OH), 3.43 (dd, J_1-Ha,1-Hb

=

3

2

(()-2-Hydroxybut-3-enyl Pivalate (5d).⁶²Pivaloyl chloride

(2.40 g, 19.9 mmol) was slowly added to a cold (0 ꢀC) solution of diol

(()-4 (1.78 g, 20.2 mmol), Et₃N (10 mL), and DMAP (100 mg, 0.82

mmol) in dichloromethane (20 mL), and the reaction mixture was

stirred at room temperature for 24 h and then quenched with saturated

aqueous NaCl (50 mL), extracted with ethyl acetate (3 ꢁ 100 mL), dried

(Na₂SO₄), and evaporated. Gradient chromatography on a column of

silica gel (5 ꢁ 10 cm) with a mixture of hexanes and ethyl acetate (95:5

to 80:20) gave (()-5d as a colorless oil (1.81 g, 53%): ¹H NMR (400.1

MHz, CDCl₃) δ 1.13 (s, 9H, t-Bu), 2.94 (s, 1H, 2-OH), 3.99 (dd,

9.9 Hz, J_1-Ha,2-H= 7.6 Hz, 1H, 1-Ha), 3.62 (dd, J_1-Hb,1-Ha= 9.9

Hz, ³J_1-Hb,2-H= 3.8 Hz, 1H, 1-Hb), 4.10ꢀ4.15 (m, 1H, 2-H), 5.15 (dd,

³J_4-Ha,3-H= 10.6 Hz, ²J_4-Ha,4-Hb= 1.2 Hz, 1H, 4-Ha), 5.31 (dd, ³J_4-Hb,3-H

=

2

3

17.3 Hz, J_4-Hb,4-Ha= 1.2 Hz, 1H, 4-Hb), 5.78 (ddd, J_3-H,4-Hb

3

17.3 Hz, J_3-H,4-Ha= 10.6 Hz, J_3-H,2-H= 5.7 Hz, 1H, 3-H) in

agreement with an authentic sample of the racemate. Anal. Calcd

for C₁₀H₂₂O₂Si: C, 59.35; H, 10.96. Found: C, 59.13; H, 11.13.

Chiral GC (Supelco β-DEX 120 column, oven 70 ꢀC for 5 min then

gradient 1 ꢀC.min^ꢀ1to 105 ꢀC) showed >99% ee (t_R= 31.48 min, t_R=

32.68 min). Fraction distillation of the crude product obtained by the

above procedure (156 mmol scale) gave (S)-5a as a colorless liquid

(25.16 g, 80%): bp 46ꢀ48 ꢀC at 300 Pa.

²J_1-Ha,1-Hb= 11.4 Hz, ³J_1-Ha,2-H= 6.6 Hz, 1H, 1-Ha), 4.04 (dd, ²J_1-Hb,1-Ha

=

11.4 Hz, ³J_1-Hb,2-H= 4.3 Hz, 1H, 1-Hb), 4.26ꢀ4.31 (m, 1H, 2-H), 5.14

(ddd, ³J_4-Ha,3-H= 10.6 Hz, ²J_4-Ha,4-Hb= 1.4 Hz, ⁴J_4-Ha,2-H= 1.4 Hz, 1H,

(()-1-(tert-Butyldiphenylsilyloxy)but-3-en-2-ol (()-(5b).⁶²

Butene-1,2-diol (()-4 (5.0 g, 56.8 mmol) was protected with tert-butyl-

(chloro)diphenylsilane following general procedure A. Chromatography on

column of silica gel (8 ꢁ 10 cm) with a mixture of hexanes and ethyl acetate

(95:5) gave the butenol (()-5b as a colorless oil (17.68 g, 95%): ¹H NMR

(400.1 MHz, CDCl₃) δ 1.14 (s, 9H, t-Bu), 2.73 (d, ³J_2-OH,2-H= 3.9 Hz, 1H,

2-OH), 3.62 (dd, ²J_1-Ha,1-Hb= 10.2 Hz, ³J_1-Ha,2-H= 7.4 Hz, 1H, 1-Ha), 3.76

(dd, ²J_1-Hb,1-Ha= 10.2 Hz, ³J_1-Hb,2-H= 3.9 Hz, 1H, 1-Hb), 4.27ꢀ4.32 (m,

1H, 2-H), 5.21 (ddd, ³J_4-Ha,3-H= 10.6 Hz, ²J_4-Ha,4-Hb=1.5Hz,⁴J_4-Ha,2-H=1.5

Hz, 1H, 4-Ha), 5.37 (ddd, ³J_4-Hb,3-H= 17.3 Hz, ²J_4-Hb,4-Ha=1.5Hz,⁴J_4-Hb,2-H

= 1.5 Hz,1H, 4-Hb), 5.89 (ddd, ³J_3-H,4-Hb= 17.3 Hz, ³J_3-H,4-Ha= 10.6 Hz,

³J_3-H,2-H= 5.6 Hz, 1H, 3-H), 7.40ꢀ7.48 (m, 6H, H-arom), 7.72ꢀ7.74 (m, 4H,

H-arom); ¹³C NMR (100.6 MHz, CDCl₃): δ 19.2 (C(CH₃)₃), 26.8

(C(CH₃)₃), 67.6 (CH₂-1), 73.0 (CH-2), 116.4 (CH₂-4), 127.7 (CH-arom),

129.8 (CH-arom), 133.0 (CH-arom), 135.48 (C-arom), 136.59 (CH-3);

consistent with the literature data.⁶²

4-Ha), 5.29 (ddd, ³J_4-Hb,3-H= 17.2 Hz, ²J_4-Hb,4-Ha= 1.4 Hz, ⁴J_4-Hb,2-H

=

1.4 Hz,1H, 4-Hb), 5.78 (ddd, ³J_3-H,4-Hb= 17.2 Hz, ³J_3-H,4-Ha= 10.6 Hz,

³J_3-H,2-H= 5.6 Hz, 1H, 3-H); ¹³C NMR (100.6 MHz, CDCl₃) δ 27.0

(C(CH₃)₃), 38.6 (C(CH₃)₃), 67.3 (CH₂-1), 70.7 (CH-2), 116.6 (CH₂-4),

136.4 (CH-3), 178.6 (CO carbonyl); MS (CI) m/z (%) 173 (98, M +

H⁺), 155 (100, M⁺ꢀ OH), 103 (22, M⁺ꢀ tBu ꢀ H₂O); HRMS (CI)

173.1180 [C₉H₁₇O₃(M + H⁺) requires 173.1178]; consistent with the

literature data.⁶²

(()-tert-Butyl 1-(tert-Butyldiphenylsilyloxy)but-3-en-2-yl

Carbonate (()-(6b). A solution of n-butyllithium (5.0 mL, 2.0 M

in pentane) was added slowly to a solution of silylated diol (()-5b

(3.260 g, 9.98 mmol) in THF (10 mL) at 0 ꢀC. The resulting solution

was stirred at 0 ꢀC for 20 min and than transferred, at room temperature

(via canula), to a solution of Boc anhydride (2.45 g, 11.2 mmol) in THF

(30 mL) and stirred at room temperature overnight. The reaction was

quenched with brine (20 mL), diluted with ethyl acetate (100 mL),

washed with brine (3 ꢁ 50 mL), dried (Na₂SO₄), and evaporated.

Chromatography on a column of silica gel (5 ꢁ 15 cm) with a mixture of

hexanes and ethyl acetate (95:5) gave (()-6b as a yellowish oil (4.03 g,

94%): ¹H NMR (400.1 MHz, CDCl₃) δ 1.06 (s, 9H, t-Bu), 1.51 (s, 9H, t-

Bu), 3.70 (dd, ²J_1-H,1-H= 10.9 Hz, ³J_1-H,2-H= 4.5 Hz, 1H, 1-H), 3.77 (dd,

(R)-1-(tert-Butyldiphenylsilyloxy)but-3-en-2-ol (R)-(5b).

Butene-1,2-diol (R)-4 (2.18 g, 24.7 mmol) was protected with tert-

butyl(chloro)diphenylsilane following general procedure A. Chro-

matography on column of silica gel (8 ꢁ 10 cm) with a mixture of

hexanes and ethyl acetate (95:5) gave the butenol (R)-5b as a

colorless oil (7.06 g, 88%). [α]_D+5.2 (c 0.9, CHCl₃). Anal. Calcd

for C₂₀H₂₆O₂Si: C, 73.57; H, 8.03. Found: C, 73.49; H, 8.13. For

further characterization of the corresponding racemate, see the

previous paragraph and the literature.⁶²

²J_1-H,1-H= 10.9 Hz, ³J_1-H,2-H= 7.3 Hz, 1H, 1-H), 5.23 (dt, ³J_cis-4-H,3-H

=

2

10.7 Hz, J_4-H,4-H= 1.2 Hz, 1H, 4-H), 5.26 (m, 1H, 2-H), 5.34 (dt,

³J_{trans-4-H,3-H}= 17.3 Hz, ²J_4-H,4-H= 1.2 Hz, 1H, 4-H), 5.81 (ddd, ³J_{3-H,trans-4-H}

=

17.1 Hz, ³J_3-H,cis-4-H= 10.6 Hz, ³J_3-H,2-H= 6.4 Hz, 1H, 3-H), 7.37ꢀ7.46

(m, 6H, H-arom), 7.68ꢀ7.72 (m, 4H, H-arom); ¹³C NMR (100.6 MHz,

CDCl₃) δ 19.2 (C(CH₃)₃), 26.7 (C(CH₃)₃), 27.8 (C(CH₃)₃), 65.4

(CH₂-1), 77.9 (CH-2), 81.9 (C(CH₃)₃), 118.2 (CH₂-4), 127.6 (CH-arom),

129.7 (CH-arom), 133.2 (CH-3), 133.3 (C-arom), 135.6 (CH-arom),

153.0 (CO carbonate); IR (neat) ν 2932 (m), 2858 (m), 1743 (s, CO

carbonate), 1428 (m), 1368 (m), 1276 (s), 1254 (s), 1165 (s), 1113 (s),

(S)-1-(tert-Butyldiphenylsilyloxy)but-3-en-2-ol (S)-(5b).⁶²

Butene-1,2-diol (S)-4 (2.20 g, 25.0 mmol) was protected with tert-

butyl(chloro)diphenylsilane following general procedure A. Chroma-

tography on column of silica gel (5 ꢁ 10 cm) with a mixture of hexanes

and ethyl acetate (95:5) gave the butenol (S)-5b as a colorless oil (7.02 g,

86%). [α]_Dꢀ4.9 (c 1.2, CHCl₃). Anal. Calcd for C₂₀H₂₆O₂Si: C, 73.57;

H, 8.03. Found: C, 73.31; H, 8.39. For further characterization of the

corresponding racemate, see the previous paragraph and the literature.⁶²

(()-1-(Trityloxy)but-3-en-2-ol (5c).⁶³Butene-1,2-diol (()-4

(1.76 g, 20.0 mmol) was protected with chloro(triphenyl)methane

following general procedure A. Reaction time was prolonged to 24 h.

Chromatography on column of silica gel (5 ꢁ 10 cm) with a mixture of

hexanes and ethyl acetate (95:5) gave the butenol (()-5c as a colorless

+

702 (s) cm^ꢀ1; MS (CI-NH₃) m/z (%) 444 (M + NH₄, 100), 388 ([M +

+

NH₄] ꢀ C₄H₈, 15), 371 (5), 326 (5), 309 (MH⁺ꢀ C₄H₈ꢀCO₂ꢀ

H₂O, 20), 216 (8). Anal. Calcd for C₂₅H₃₄O₄Si: C, 70.38; H, 8.03.

Found: C, 70.31; H, 8.12.

(R)-tert-Butyl 1-(tert-Butyldiphenylsilyloxy)but-3-en-2-yl

Carbonate (R)-(+)-(6b). A solution of n-butyllithium (2.5 mL, 2.0

M in pentane) was added slowly to a solution of silylated diol (R)-5b

(1.630 g, 4.99 mmol) in THF (10 mL) at 0 ꢀC. The resulting solution

was stirred at 0 ꢀC for 20 min and than transferred, at room temperature

(via canula), to a solution of Boc anhydride (1.230 g, 5.63 mmol) in THF

(20 mL), and the mixture was stirred at room temperature overnight.

The reaction was quenched with brine, diluted with ethyl acetate

(100 mL), washed with brine (3 ꢁ 50 mL), dried (Na₂SO₄), and

evaporated. Chromatography on a column of silica gel (5 ꢁ 15 cm) with

a mixture of hexanes and ethyl acetate (95:5) gave (R)-6b as a yellowish

oil (5.82 g, 88%): ¹H NMR (400.1 MHz, CDCl₃) δ 2.44 (d, ³J_2-OH,2-H

3.9 Hz, 1H, 2-OH), 3.14 (dd, ²J_1-Ha,1-Hb= 9.4 Hz, ³J_1-Ha,2-H= 7.5 Hz, 1H,

=

2

3

1-Ha), 3.24 (dd, J_1-Hb,1-Ha= 9.4 Hz, J_1-Hb,2-H= 3.7 Hz, 1H, 1-Hb),

4.27ꢀ4.33 (m, 1H, 2-H), 5.18 (ddd, ³J_4-Ha,3-H= 10.6 Hz, ²J_4-Ha,4-Hb= 1.4

4

3

Hz, J_4-Ha,2-H= 1.4 Hz, 1H, 4-Ha), 5.32 (ddd, J_4-Hb,3-H= 17.2 Hz,

²J_4-Hb,4-Ha= 1.4 Hz, ⁴J_4-Hb,2-H= 1.4 Hz, 1H, 4-Hb), 5.83 (ddd, ³J_3-H,4-Hb

=

17.2 Hz, ³J_3-H,4-Ha= 10.6 Hz, ³J_3-H,2-H= 5.7 Hz, 1H, 3-H), 7.25ꢀ7.29 (m,

3H, H-arom), 7.31ꢀ7.35 (m, 6H, H-arom), 7.44ꢀ7.48 (m, 6H,

H-arom); ¹³C NMR (100.6 MHz, CDCl₃): δ 67.4 (CH₂-1), 72.0

(CH-2), 86.7 (CPh₃), 116.3 (CH₂-4), 127.1 (CH-arom), 127.9 (CH-

arom), 128.6 (CH-arom), 136.9 (CH-3), 143.7 (C-arom); MS (EI) m/z

(%) 330 (1, M⁺) 243 (100, Trt), 228 (15), 215 (15), 183 (22), 165 (90),

oil (2.02 g, 95%): [α]_D+17.0 (c 1.7, CHCl₃); ¹H NMR (400.1 MHz,

2

CDCl₃) δ 1.06 (s, 9H, t-Bu), 1.51 (s, 9H, t-Bu), 3.70 (dd, J_1-H,1-H

=

3

2

10.9 Hz, J_1-H,2-H= 4.5 Hz, 1H, 1-H), 3.77 (dd, J_1-H,1-H= 10.9 Hz,

7789

dx.doi.org/10.1021/jo201110z |J. Org. Chem. 2011, 76, 7781–7803

The Journal of Organic Chemistry

ARTICLE

³J_1-H,2-H= 7.3 Hz, 1H, 1-H), 5.23 (dt, ³J_cis-4-H,3-H= 10.7 Hz, ²J_4-H,4-H= 1.2

([Ir(COD)Cl]₂(14.0 mg, 0.020 mmol) and ligand (R_a,R_c,R_c)-11 (14.0 mg,

0.044 mmol) in THF (1 mL) and allyl carbonate 7(120 mg, 0.51 mmol, neat)

were added, respectively. The cooling bath was then removed, and the reaction

mixture was stirred at room temperature for 16 h. The catalyst was precipitated

by adding hexane (5 mL), the mixture was filtered through a pad of silica

(3 ꢁ 3 cm), and the product was eluted with a mixture of hexanes and ethyl

acetate (90:10). Chromatography on a column of silica gel (3 ꢁ 10 cm) with a

mixture of hexanes and Et₂O (95:5) gave 12ba as a colorless oil (198 mg,

93%): ¹H NMR (400.1 MHz, CDCl₃, a mixture of diastereoisomers in a 1:1.8

ratio, the minor diastereoisomer is marked with * where possible) δ 1.07* 1.10

(s, 9H, t-Bu), 3.28*ꢀ3.50* 3.62ꢀ3.86 (m, 2H, CH₂), 3.92*ꢀ3.97* 4.14ꢀ4.18

(m,1H,CH₂CH),4.98(d,J_HH= 7.2 Hz, 0.6H, PhCH), 5.06* (d, J_HH= 7.5 Hz,

0.4H, PhCH), 5.11ꢀ5.36 (m, 4H, CH₂=CH), 5.72ꢀ5.80 and 5.77*ꢀ5.84*

and 5.86ꢀ5.96 and 5.95*ꢀ6.04* (m, 2H, CH₂dCH), 7.22ꢀ7.47 and

7.66ꢀ7.76 (m, 15H, Ph); ¹³C NMR (100.6 MHz, CDCl₃) δ 26.8 and 27.0

(tBu), 66.8 (CH₂CH), 78.4 and 78.5 (CH₂CH), 79.7 and 80.2 (PhCH), 115.1

and 116.6 and 117.9 and 118.1 (CH₂dCH), 126.7, 127.2, 127.6, 129.5, 129.6,

133.5, 133.6, 135.6, 135.7, 135.9, 136.0, 136.1, 141.0, 141.5. MS (CI-NH₃,

150 ꢀC) m/z (%) 460 ([M + NH₄⁺], 95), 444 (5), 364 (10), 252 (30), 193

(15), 52 (100); HRMS (CI-NH₃, 100 ꢀC) 460.2670 [C₂₉H₃₈NO₂Si (M +

NH₄⁺) requires 460.2672].

3

Hz, 1H, 4-H), 5.26 (m, 1H, 2-H), 5.34 (dt, J_{trans-4-H,3-H}= 17.3 Hz,

²J_4-H,4-H= 1.2 Hz, 1H, 4-H), 5.81 (ddd, ³J_{3-H,trans-4-H}= 17.1 Hz, ³J_3-H,cis-4-H

=

3

10.6 Hz, J_3-H,2-H= 6.4 Hz, 1H, 3-H), 7.37ꢀ7.46 (m, 6H, H-arom),

7.68ꢀ7.72 (m, 4H, H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ 19.2

(C(CH₃)₃), 26.7 (C(CH₃)₃), 27.8 (C(CH₃)₃), 65.4 (CH₂-1), 77.9

(CH-2), 81.9 (C(CH₃)₃), 118.2 (CH₂-4), 127.6 (CH-arom), 129.7

(CH-arom), 133.2 (CH-3), 133.3 (C-arom), 135.6 (CH-arom), 152.95

(CO carbonate). Anal. Calcd for C₂₅H₃₄O₄Si: C, 70.38; H, 8.03. Found:

C, 70.15; H, 8.10.

tert-Butyl(dimethyl)(2-(1⁰-(phenyl)allyloxy)but-3-enyloxy)-

silane (12aa). n-Butyllithium (0.5 mL, 1.0 mmol, 2.0 M solution in

pentane) was added slowly to a solution of protected butenediol (()-5a

(206 mg, 1.00 mmol) in THF (1 mL), and the mixture was stirred at 0 ꢀC

for 15 min. The lithium alkoxide thus generated was transferred (via

cannula) to a suspension of copper(I) iodide (200 mg, 1.05 mmol) in

THF (2 mL) at room temperature. The mixture turned light yellow and

was then stirred for 30 min.⁶⁴The resulting mixture was cooled to 0 ꢀC,

a cold (0 ꢀC) solution of [Ir(COD)Cl]₂(7.8 mg, 0.011 mmol) and

(t-BuO)₂PN(iPr)₂(6.0 mg, 0.021 mmol) in THF (1 mL) and allyl

carbonate (()-9a (124 mg, 0.53 mmol, neat) were added consecutively.

The cooling bath was then removed, and the reaction mixture was stirred

at room temperature for 16 h. The catalyst was precipitated by adding

hexane (5 mL), the mixture was filtered through a pad of silica (3 ꢁ

3 cm), and the product was eluted with a mixture of hexanes and ethyl

acetate (90:10). Chromatography on a column of silica gel (3 ꢁ 10 cm)

with a mixture of hexanes and ethyl acetate (98.5:1.5) gave silane 12aa as

a colorless oil (142 mg, 84%, an equimolar mixture of diastereoisomers A

and B): ¹H NMR (400.1 MHz, CDCl₃) δ 0.03 (s, 6H, CH₃), 0.08 (s, 3H,

CH₃), 0.09 (s, 3H, CH₃), 0.89 (s, 9H, t-Bu), 0.92 (s, 9H, t-Bu), 3.57 (dd,

²J_1A-Ha,1A-Hb= 10.5 Hz, ³J_1A-Ha,2A-H= 5.3 Hz, 1H, 1A-Ha), 3.63 (dd, ²J_1B-

tert-Butyl(2-(1⁰-(4⁰⁰-bromophenyl)allyloxy)but-3-enyloxy)-

diphenylsilane (12bc). n-BuLi (1.2 mL, 3.0 mmol, 2.5 M solution

in hexanes) was slowly added to a solution of the protected butenediol

(()-5b (920 mg, 2.82 mmol) in THF (3 mL) at 0 ꢀC, and the mixture

was stirred for 15 min at 0 ꢀC and then transferred (via cannula) to a

suspension of copper(I) iodide (600 mg, 1.15 mmol) in THF (6 mL) at

room temperature. The mixture turned to light yellow and was stirred for

30 min. The resulting mixture was cooled to 0 ꢀC, and a cold (0 ꢀC)

solution of [Ir(COD)Cl]₂(19.7 mg, 0.029 mmol)) in THF (2 mL) was

added, followed by allyl carbonate (()-9c (674 mg, 2.15 mmol, neat).

The cooling bath was removed, and the reaction mixture was stirred at

room temperature for 16 h. The catalyst was precipitated by adding

hexane (5 mL), and the mixture was filtered through a pad of silica

(3 ꢁ 3 cm), using a mixture of hexanes and AcOEt (9:1) as eleuent.

Chromatography of the crude product on a column of silica gel

(3 ꢁ 10 cm) with a mixture of hexanes and AcOEt (98.5:1.5) afforded

pure silane 12bc as a colorless oil (711 mg, 62%, mixture of diastereoi-

somers A, B): ¹H NMR (400.1 MHz, CDCl₃) δ 1.05 (s, 9H, t-Bu), 1.08

(s, 9H, t-Bu), 3.62 (dd, ²J_1A-Ha,1A-Hb= 10.5 Hz, ³J_1A-Ha,2A-H= 4.7 Hz, 1H,

1A-Ha), 3.69 (dd, ²J_1B-Ha,1B-Hb= 10.5 Hz, ³J_1B-Ha,2B-H= 4.8 Hz, 1H, 1B-

3

2

= 10.5 Hz, J_1B-Ha,2B-H= 5.3 Hz, 1H, 1B-Ha), 3.70 (dd, J_1A-

Ha,1B-Hb

= 10.5 Hz, ³J_1A-Hb,2A-H= 6.6 Hz, 1H, 1A-Hb), 3.76 (dd, J_1B-

2

Hb,1A-Ha

_Hb,1B-Ha= 10.5 Hz, ³J_1B-Hb,2B-H= 6.6 Hz, 1H, 1B-Hb), 3.83 (ddddd, ³J_2-

_H,3-H= 6.9 Hz, ³J_2-H,1-Hb= 6.6 Hz, ³J_2-H,1-Ha= 5.3 Hz, ⁴J_2-H,4-Ha= 1.0 Hz,

⁴J_2-H,4-Hb= 1.0 Hz, 1H, 2A-H or 2B-H), 4.06 (ddddd, ³J_2-H,3-H= 6.9 Hz,

³J_2-H,1-Hb= 6.6 Hz, ³J_2-H,1-Ha= 5.3 Hz, ⁴J_2-H,4-Ha= 1.0 Hz, ⁴J_2-H,4-Hb= 1.0

Hz, 1H, 2B-H or 2A-H), 4.95 (d, ³J_{1 -H,2 -H}= 7.2 Hz, 1H, 1⁰A-H or 1⁰B-H),

0

4.95 (d, ³J_{1 -H,2 -H}= 6.1 Hz, 1H, 1⁰B-H or 1⁰A-H), 5.10ꢀ5.34 (m, 8H,

0

3

4A-H, 3⁰A-H, 4B-H, and 3⁰B-H), 5.74 (ddd, J_3-H,4-Ha= 17.3 Hz,

³J_3-H,4-Hb= 10.4 Hz, ³J_3-H,2-H= 6.9 Hz, 1H, 3A-H or 3B-H), 5.77 (ddd,

³J_3-H,4-Ha= 16.2 Hz, ³J_3-H,4-Hb= 11.5 Hz, ³J_3-H,2-H= 6.9 Hz, 1H, 3B-H or

Ha), 3.75 (dd, J_1A-Hb,1A-Ha= 10.5 Hz, J_1A-Hb,2A-H= 6.9 Hz, 1H, 1A-

2

3

2

3

0

3A-H), 5.90(ddd, J_{2 -H,3 -Ha}= 17.3 Hz, J_{2 -H,3 -Hb}=10.2Hz, J_{2 -H,1 -H}=7.2

Hb), 3.81 (dd, J_1B-Hb,1B-Ha= 10.5 Hz, J_1B-Hb,2B-H= 6.7 Hz, 1H, 1B-

Hb), 3.87 (dddt, ³J_2A-H,1A-Hb= 6.9 Hz, ³J_2A-H,3A-H= 5.7 Hz, ³J_2A-H,1A-Ha

= 4.7 Hz, ⁴J_2A-H,4A-H= 1.0 Hz, 1H, 2A-H), 4.11 (tdt, ³J_2B-H,1B-Hb= 6.7

Hz, ³J_2B-H,3B-H= 6.7 Hz, ³J_2B-H,1B-Ha= 4.8 Hz, ⁴J_2B-H,4B-H= 1.0 Hz, 1H,

2B-H), 4.90ꢀ4.92 (m, 2H, 1⁰A-H, and 1⁰B-H), 5.12ꢀ5.33 (m, 8H, 3⁰A-H,

3⁰B-H, 4A-H, and 4B-H), 5.68ꢀ5.97 (m, 4H, 2⁰A-H, 2⁰B-H, 3A-H,

and 3B-H), 7.22ꢀ7.51 (m, 20H, H-arom), 7.65ꢀ7.74 (m, 8H, H-arom).

Anal. Calcd for C₂₉H₃₃BrO₂Si: C, 66.78; H, 6.38. Found: C, 66.64;

H, 6.72.

Hz, 1H, 2⁰A-H or 2⁰B-H), 5.98 (ddd, J_{2 -H,3 -Ha}= 17.2 Hz, ³J_{2 -H,3 -Hb}

=

3

0

10.3 Hz, ³J_{2 -H,1 -H}= 6.1 Hz, 1H, 2⁰B-H or 2⁰A-H), 7.23ꢀ7.38 (m, 10H,

H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.37 (CH₃), ꢀ5.31

(CH₃), ꢀ5.28 (CH₃), ꢀ5.18 (CH₃), 18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃),

66.2, and 66.3 (CH₂-1), 78.5, and 78.8 (CH-2), 79.9, and 80.3 (CH-1⁰),

115.3, 116.7, 117.9, and 118.1 (CH₂-4, and CH₂-3⁰), 126.7, 127.2,

127.34, 127.5, 128.25, and 128.35 (CH-arom), 136.1, and 136.3 (CH-3),

138.8, and 139.5 (CH-2⁰), 141.0, and 141.5 (C-arom); IR (NaCl, neat) ν

2956 (s), 2929 (s), 2857 (s), 1472 (m), 1257 (s), 1087 (s), 838

0

tert-Butyl(2-(1⁰-(4⁰⁰-fluorophenyl)allyloxy)but-3-enyloxy)-

diphenylsilane (12be). n-Butyllithium (1.2 mL, 3.0 mmol, 2.5 M

solution in hexanes) was added slowly to a solution of protected

butenediol (()-5b (986 mg, 3.02 mmol) in THF (3 mL), and the

mixture was stirred at 0 ꢀC for 15 min. The lithium alkoxide thus

generated was transferred (via cannula) to a suspension of copper(I)

iodide (600 mg, 3.15 mmol) in THF (6 mL) at room temperature. The

mixture turned light yellow and was then stirred for 30 min.⁶³The

resulting mixture was cooled to 0 ꢀC, and a cold (0 ꢀC) solution of

[Ir(COD)Cl]₂(20.7 mg, 0.031 mmol) in THF (3 mL) and allyl

carbonate (()-9e (508 mg, 2.01 mmol, neat) were added consecutively.

The cooling bath was then removed, and the reaction mixture was stirred

at room temperature for 16 h. The catalyst was precipitated by adding

+

(s) cm^ꢀ1; MS (CI-NH₃, 160 ꢀC) m/z (%) 336 ([M + NH₄], 30),

117 (100); HRMS (CI-NH₃, 100 ꢀC) 336.2357 [C₁₉H₃₄NO₂Si (M +

+

NH₄) requires 336.2359]. Anal. Calcd for C₁₉H₃₀O₂Si: C, 71.64; H,

9.49. Found: C, 71.26; H, 9.57.

tert-Butyl(2-(1⁰-(phenyl)allyloxy)but-3-enyloxy)diphenylsilane

(12ba). n-Butyllithium (0.4 mL, 1.0 mmol, 2.5 M solution in hexanes) was

added slowly to a solution of protected butenediol (()-5b (326 mg, 1.00

mmol) in THF (1 mL), and the mixture was stirred at 0 ꢀC for 15 min. The

lithium alkoxide thus generated was transferred (via cannula) to a suspension of

copper(I) iodide (200 mg, 1.05 mmol) in THF (2 mL) at room temperature.

The mixture turned light yellow and was then stirred for 30 min.⁶⁴The resulting

mixture was cooled to 0 ꢀC, and a cold (0 ꢀC) solution of catalyst

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hexane (5 mL), the mixture was filtered through a pad of silica

(3 ꢁ 3 cm), and the product was eluted with a mixture of hexanes

and ethyl acetate (90:10). Chromatography on a column of silica gel

(3 ꢁ 10 cm) with a mixture of hexanes and ethyl acetate (98.5:1.5) gave

silane 12be as a colorless oil (733 mg, 79%, mixture of diastereoisomers

A, B: ¹H NMR (400.1 MHz, CDCl₃) δ 1.06 (s, 9H, t-Bu), 1.09 (s, 9H,

t-Bu), 3.63 (dd, ²J_1A-Ha,1A-Hb= 10.5 Hz, ³J_1A-Ha,2A-H= 4.7 Hz, 1H, 1A-

Ha), 3.70 (dd, ²J_1B-Ha,1B-Hb= 10.5 Hz, ³J_1B-Ha,2B-H= 4.9 Hz, 1H, 1B-Ha),

3.76 (dd, ²J_1A-Hb,1A-Ha= 10.5 Hz, ³J_1A-Hb,2A-H= 6.8 Hz, 1H, 1A-Hb), 3.83

6.19 (dt, ³J_2-H,1-H= 15.7 Hz, ³J_2-H,3-H= 6.8 Hz, 1H, 2-H), 6.33 (d, ³J_1-H,2-H

=

15.7 Hz, 1H, 1-H), 6.87ꢀ6.92 (m, 2H, H-arom), 7.12ꢀ7.25 (m, 6H,

H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ 38.2 (CH₂-3), 114.8 (d,

²J_CF= 21.7 Hz, CH-3⁰⁰), 115.3 (d, ²J_CF= 22.9 Hz, CH-3⁰), 126.3 (CH-

2), 130.1 (d, ³J_CF= 8.1 Hz, CH-2⁰), 130.3 (d, ³J_CF= 8.2 Hz, CH-2⁰⁰),

130.9 (CH-1), 133.7 (d, ⁴J_CF= 1.1 Hz, C-1⁰), 136.8 (d, ⁴J_CF= 3.1 Hz,

C-1⁰⁰), 160.3 (d, ¹J_CF= 249.2 Hz, CF-4⁰), 162.1 (d, ¹J_CF= 246.1 Hz, CF-4⁰⁰);

HRMS (EI) 230.0910 [C₁₅H₁₂F₂(M⁺) requires 230.0907].

General Procedure B: Iridium-Catalyzed Allylic Substitu-

tion with Chiral Precursors. n-Buthyllithium (3.0 mL, 6.0 mmol, 2.0

M solution in pentane) was added slowly to a solution of the protected

enantiopure butenediol 5 (1.236 g, 6.11 mmol) in THF (6 mL), and the

mixture was stirred at 0 ꢀC for 15 min. The lithium alkoxide thus

generated was transferred (via cannula) to a suspension of copper(I)

iodide (1.200 g, 6.30 mmol) in THF (12 mL) at room temperature. The

mixture turned light yellow and was then stirred for 30 min.⁶⁴The

resulting mixture was cooled to 0 ꢀC, and a cold (0 ꢀC) solution of

[Ir(COD)Cl]₂(40.0 mg, 0.060 mmol) in THF (3.5 mL) and enantio-

pure allyl carbonate 9 (1.133 g, 4.84 mmol, neat) were added consecu-

tively. The cooling bath was then removed, and the reaction mixture

was stirred at room temperature for 16 h. The catalyst was precipitated

by adding hexane (5 mL), the mixture was filtered through a pad of silica

(3 ꢁ 3 cm), and the product was eluted with a mixture of hexanes and

ethyl acetate (90:10). Chromatography on a column of silica gel (3 ꢁ

10 cm) with a mixture of hexanes and ethyl acetate (98.5:1.5) gave

respective silane (15ꢀ18) as a colorless oil.

2

3

(dd, J_1B-Hb,1B-Ha= 10.5 Hz, J_1B-Hb,2B-H= 6.6 Hz, 1H, 1B-Hb), 3.89

(dddt, ³J_2A-H,1A-Hb= 6.8 Hz, ³J_2A-H,3A-H= 5.7 Hz, ³J_2A-H,1A-Ha= 4.7 Hz,

3

⁴J_2A-H,4A-H= 1.0 Hz, 1H, 2A-H), 4.13 (dddt, J_2B-H,1B-Hb= 6.6 Hz,

³J_2B-H,3B-H= 5.9 Hz, ³J_2B-H,1B-Ha= 4.9 Hz, ⁴J_2B-H,4B-H= 1.1 Hz, 1H, 2B-H),

4.93ꢀ4.96 (m, 2H, 1⁰A-H, and 1⁰B-H), 5.12ꢀ5.34 (m, 8H, 3⁰A-H, 3⁰B-

H, 4A-H, and 4B-H), 5.70ꢀ6.00 (m, 4H, 2⁰A-H, 2⁰B-H, 3A-H, and 3B-

H), 6.98ꢀ7.05 (m, 4H, H-arom), 7.31ꢀ7.47 (m, 16H, H-arom),

7.65ꢀ7.76 (m, 8H, H-arom); HRMS (CI-NH₃, 100 ꢀC) 478.2576

+

[C₂₉H₃₇FNO₂Si (M + NH₄) requires 478.2578].

(E)-1,3-Diphenylpropene (14a). n-Butyllithium (0.5 mL, 1.0

mmol, 2.0 M solution in pentane) was added slowly to a solution of

protected butenediol 5b (326 mg, 1.00 mmol) in THF (1 mL), and the

mixture was stirred at 0 ꢀC for 15 min. The lithium alkoxide thus

generated was transferred (via cannula) to a suspension of copper(I)

iodide (200 mg, 1.05 mmol) in THF (2 mL) at room temperature. The

mixture turned light yellow and was then stirred for 30 min.⁶⁴The

resulting mixture was cooled to 0 ꢀC, and a cold (0 ꢀC) solution of

Rh(PPh)₃Cl (61.1 mg, 0.066 mmol) and P(OMe)₃(25.0 mg, 0.201

mmol) in THF (1.0 mL) and allyl carbonate 9a (136 mg, 0.58 mmol,

neat) were added, respectively. The cooling bath was then removed, and

the reaction mixture was stirred at room temperature for 16 h. The

catalyst was precipitated by adding hexane (5 mL), the mixture was

filtered through a pad of silica (3 ꢁ 3 cm), and the product was eluted

with a mixture of hexanes and ethyl acetate (90:10). Chromatography on

a column of silica gel (3 ꢁ 10 cm) with hexanes gave 14a as a colorless oil

(26 mg, 46% of theory, 77% based on recovered carbonate). Subsequent

elution with a mixture of hexanes and ethyl acetate (98.5:1.5) gave

carbonate 9a as a colorless oil (55 mg, 40% recovered). 14a: ¹H NMR

(400.1 MHz, CDCl₃) δ 3.47 (d, ³J_3-H,2-H= 6.6 Hz, 2H, 3-H), 6.28 (dt,

³J_2-H,1-H= 15.8 Hz, ³J_2-H,3-H= 6.6 Hz, 1H, 2-H), 6.38 (d, ³J_1-H,2-H= 15.8

Hz, 1H, 1-H), 7.10ꢀ7.29 (m, 10H, H-arom); ¹³C NMR (100.6 MHz,

CDCl₃) δ 39.3 (CH₂-3), 126.1, 126.2, 127.1, 128.47, 128.48, and 128.65

(CH-arom), 129.2 (CH-2), 131.1 (CH-1), 137.5 (C-1⁰), 140.1 (C-1⁰⁰);

MS (EI) m/z (%) 194 (M⁺, 40), 179 (15), 115 (20), 83 (100); HRMS

(EI) 194.1094 [C₁₅H₁₄(M⁺) requires 194.1096], consistent with the

literature data.⁶⁵

(2S,1⁰R)-tert-Butyl(dimethyl)(2-(1⁰-(phenyl)allyloxy)but-3-

enyloxy)silane (2S,1⁰R)-(15a). Method 1. Following general pro-

cedure B, the protected butenediol (S)-5a (1.236 g, 6.11 mmol) was

coupled with allyl carbonate (R)-9a (1.133 g, 4.84 mmol, neat) to obtain

ether (2S,1⁰R)-15a as a colorless oil (1.263 g, 82%, as a single

diastereoisomer): [α]_D+25.3 (c 1.11, MeOH); ¹H NMR (400.1

MHz, CDCl₃) δ 0.04 (s, 6H, CH₃), 0.89 (s, 9H, t-Bu), 3.58 (dd,

²J_1-Ha,1-Hb= 10.5 Hz, ³J_1-Ha,2-H= 5.3 Hz, 1H, 1-Ha), 3.71 (dd, ²J_1-Hb,1-Ha

=

10.5 Hz, ³J_1-Hb,2-H= 6.6 Hz, 1H, 1-Hb), 3.84 (ddddd, ³J_2-H,3-H= 7.0 Hz,

³J_2-H,1-Hb= 6.6 Hz, ³J_2-H,1-Ha= 5.3 Hz, ⁴J_2-H,4-Ha= 0.8 Hz, ⁴J_2-H,4-Hb= 0.8

Hz, 1H, 2-H), 4.96 (d, ³J_{1 -H,2 -H}= 6.1 Hz, 1H, 1⁰-H), 5.12ꢀ5.28 (m, 4H,

0

3

4-H, and 3⁰-H), 5.78 (ddd, J_3-H,4-Ha= 16.2 Hz, J_3-H,4-Hb= 11.4 Hz,

3

J_3-H,2-H= 7.0 Hz, 1H, 3-H), 5.98 (ddd, ³J_{2 -H,3 -Ha}= 17.1 Hz, ³J_{2 -H,3 -Hb}

=

0

10.4 Hz, ³J_{2 -H,1 -H}= 6.1 Hz, 1H, 2⁰-H), 7.25ꢀ7.38 (m, 5H, H-arom);

¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.37 (CH₃), ꢀ5.28 (CH₃), 18.3

(C(CH₃)₃), 25.9 (C(CH₃)₃), 66.2 (CH₂-1), 78.5 (CH-2), 79.9 (CH-

1⁰), 115.3, and 118.1 (CH₂-4, and CH₂-3⁰), 127.2, 127.5, and 128.3

(CH-arom), 136.1 (CH-3), 139.5 (CH-2⁰), 141.0 (C-arom); IR (NaCl,

neat) ν 2955 (s), 2928 (s), 2857 (s), 1471 (m), 1255 (s), 1121 (s), 1083

0

(E)-1,3-Bis(4⁰-fluorophenyl)propene (14b). n-Butyllithium

(0.4 mL, 1.0 mmol, 2.5 M solution in hexanes) was added slowly to a

solution of protected butenediol 5b (326 mg, 1.00 mmol) in THF

(1 mL), and the mixture was stirred at 0 ꢀC for 15 min. The lithium

alkoxide thus generated was transferred (via cannula) to a suspension of

copper(I) iodide (200 mg, 1.05 mmol) in THF (2 mL) at room

temperature. The mixture turned light yellow and was then stirred for

30 min.⁶⁴The resulting mixture was cooled to 0 ꢀC, and a cold (0 ꢀC)

solution of [Rh(COD)Cl]₂(10.1 mg, 0.020 mmol) in THF (1.0 mL)

and allyl carbonate 9e (136 mg, 0.54 mmol, neat) were added,

respectively. The cooling bath was then removed, and the reaction

mixture was stirred at room temperature for 16 h. The catalyst was

precipitated by adding hexane (5 mL), the mixture was filtered through a

pad of silica (3 ꢁ 3 cm), and the product was eluted with a mixture of

hexanes and ethyl acetate (90:10). Chromatography on a column of

silica gel (3 ꢁ 10 cm) with hexanes gave 14b as a colorless oil (27 mg,

43%). Subsequent elution with a mixture of hexanes and ethyl acetate

(98.5:1.5) gave diallyl ether 12be as a colorless oil (78 mg, 31%). 14b:

¹H NMR (400.1 MHz, CDCl₃) δ 3.45 (d, ³J_3-H,2-H= 6.8 Hz, 2H, 3-H),

+

(s), 838 (s) cm^ꢀ1; MS (CI-NH₃, 150 ꢀC) m/z (%) 336 ([M + NH₄],

100), 134 (90), 117 (60). Anal. Calcd for C₁₉H₃₀O₂Si: C, 71.64; H, 9.49.

Found: C, 71.80; H, 9.52.

Method 2. n-Butyllithium (1.25 mL, 2.0 mmol, 1.6 M solution in

hexanes) was added dropwise to a solution of the protected butenediol

(S)-5a (419 mg, 2.07 mmol) in THF (2 mL), and the mixture was stirred

at ꢀ40 ꢀC for 30 min. The lithium alkoxide thus generated was rapidly

transferred to a suspension of copper(I) iodide (400 mg, 2.10 mmol) in

THF (4 mL) at ꢀ40 ꢀC. The mixture was stirred for 30 min at ꢀ40 ꢀC,

placed in an ice bath, and stirred for another 30 min. Finally, a cold

(0 ꢀC) solution of [Ir(COD)Cl]₂(13.8 mg, 0.040 mmol) and the chiral

ligand (R_a,R_c,R_c)-11 (37.0 mg, 0.060 mmol) in THF (2 mL) and

cinnamyl carbonate 7 (235 mg, 1.00 mmol, neat) were added consecu-

tively. The cooling bath was then removed, and the reaction mixture

was stirred at room temperature for 16 h. The catalyst was precipitated

by adding hexane (5 mL), the mixture was ﬁltered through a pad of silica

(3 ꢁ 3 cm), and the product was eluted with a mixture of hexanes and

ethyl acetate (90:10). Chromatography on a column of silica gel (15 g)

with a mixture of hexanes, ether, and acetone (250:1:1) aﬀorded silane

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ARTICLE

(2S,1⁰R)-15a as a colorless oil together with its diastereoisomer (2S,1⁰S)-

16a and the rearranged silane 13 (195 mg, 61% combined yield; in a

91:3:6 ratio as shown by GC): ¹H NMR (400.1 MHz, CDCl₃) δ 0.04 (s,

1255 (s), 1128 (s), 1086 (s) cm^ꢀ1; MS (CI-NH₃, 150 ꢀC) m/z (%)

+

336 ([M + NH₄], 95), 117 (100). Anal. Calcd for C₁₉H₃₀O₂Si: C,

71.64; H, 9.49. Found: C, 71.75; H, 9.57.

6H, CH₃), 0.89 (s, 9H, t-Bu), 3.58 (dd, ²J_1-Ha,1-Hb= 10.5 Hz, ³J_1-Ha,2-H

=

Method 2. n-Butyllithium (0.625 mL, 1.0 mmol, 1.6 M solution in

pentane) was added slowly to a solution of protected butenediol (S)-5a

(205 mg, 1.01 mmol) in THF (1 mL), and the mixture was stirred at 0 ꢀC

for 15 min. The lithium alkoxide thus generated was transferred (via

cannula) to a suspension of copper(I) iodide (205 mg, 1.05 mmol) in

THF (2 mL) at room temperature. The mixture turned light yellow and

was then stirred for 30 min. The resulting mixture was cooled to 0 ꢀC,

and a cold (0 ꢀC) solution of [Ir(COD)Cl]₂(7.5 mg, 0.011 mmol) and

ligand (S_a,S_c,S_c)-10 (12.5 mg, 0.023 mmol) in THF (2 mL) and

cinnamyl carbonate 7 (190 mg, 0.81 mmol, neat) were added consecu-

tively. The cooling bath was then removed, and the reaction mixture was

stirred at room temperature for 48 h. The catalyst was precipitated by

adding hexane (5 mL), the mixture was ﬁltered through a pad of silica

(1.5 ꢁ 1.5 cm), and the product was eluted with a mixture of hexanes

and ethyl acetate (90:10). Chromatography on a column of silica gel

(1 ꢁ 15 cm) with a mixture of hexanes and ethyl acetate (98.5:1.5) aﬀorded

silane (2S,1⁰S)-16a as a colorless oil together with its diastereoisomer

(2S,1⁰R)-15a and the rearranged silane 13 (102 mg, 40% combined

yield; in 73:3:24 ratio as shown by ¹H NMR): ¹H NMR (400.1 MHz,

CDCl₃, the regioisomer 13 is marked with * where possible) δ 0.08 0.09

0.10* (s, 6H, CH₃), 0.92 (s, 9H, t-Bu), 3.31* (dd, ²J_1-Ha,1-Hb= 9.6 Hz,

³J_1-Ha,2-H= 5.6 Hz, 1H, 1-H_a), 3.41* (dd, ²J_1-Hb,1-Ha= 9.6 Hz, ³J_1-Hb,2-H= 6.9

Hz, 1H, 1-H_b), 3.63 (dd, ²J_1-Ha,1-Hb= 10.5 Hz, ³J_1-Ha,2-H= 5.3 Hz, 1H,

1-H_a), 3.76 (dd, ²J_1-Hb,1-Ha= 10.5 Hz, ³J_1-Hb,2-H= 6.6 Hz, 1H, 1-H_b), 4.06

5.3 Hz, 1H, 1-H_a), 3.71 (dd, ²J_1-Hb,1-Ha= 10.5 Hz, ³J_1-Hb,2-H= 6.6 Hz, 1H,

1-H_b), 3.84 (ddddd, ³J_2-H,3-H= 7.0 Hz, ³J_2-H,1-Hb= 6.6 Hz, ³J_2-H,1-Ha= 5.3

Hz, ⁴J_2-H,4-Ha= 0.8 Hz, ⁴J_2-H,4-Hb= 0.8 Hz, 1H, 2-H), 4.96 (d,³J_{1 -H,2 -H}

6.1 Hz, 1H, 1⁰-H), 5.12ꢀ5.28 (m, 4H, 4-H, and 3⁰-H), 5.78(ddd, ³J_3-H,4-Ha

=

0

3

16.2 Hz, J_3-H,4-Hb= 11.4 Hz, J_3-H,2-H= 7.0 Hz, 1H, 3-H), 5.98

3

0

(ddd, J_{2 -H,3 -Ha}= 17.1 Hz, J_{2 -H,3 -Hb}= 10.4 Hz, J_{2 -H,1 -H}= 6.1 Hz,

1H, 2⁰-H), 7.25ꢀ7.38 (m, 5H, H-arom); ¹³C NMR (100.6 MHz,

CDCl₃) δ ꢀ5.37 (CH₃), ꢀ5.28 (CH₃), 18.3 (C(CH₃)₃), 25.9

(C(CH₃)₃), 66.2 (CH₂-1), 78.5 (CH-2), 79.9 (CH-1⁰), 115.3, and

118.1 (CH₂-4, and CH₂-3⁰), 127.2, 127.5, and 128.3 (CH-arom), 136.1

(CH-3), 139.5 (CH-2⁰), 141.0 (C-arom); MS (CI-NH₃, 150 ꢀC) m/z

+

(%) 336 ([M + NH₄], 100), 134 (90), 117 (60); chiral GC (Supelco γ-

DEX 120 column, oven for 1 min at 160 ꢀC, then 0.5 deg min^ꢀ1

)

3

showed 97:3 dr (t_SR= 16.4 min, t_SS= 18.3 min) and 6% of the rearranged

product (t_xSR= 18.5 min).

(2S,1⁰R)-tert-Butyl(2-(1⁰-(3⁰⁰-fluorophenyl)allyloxy)but-3-

enyloxy)dimethylsilane (2S,1⁰R)-(15b). Following general proce-

dure B, the protected butenediol (S)-5a (3.440 g, 17.00 mmol) was

coupled with allyl carbonate (R)-9b (3.605 g, 14.29 mmol, neat) to

obtain ether (2S,1⁰R)-15b as a colorless oil (3.557 g, 74%): [α]_D+18.3

(c 3.06, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.06 (s, 6H, CH₃),

0.90 (s, 9H, t-Bu), 3.60 (dd, ²J_1-Ha,1-Hb= 10.6 Hz, ³J_1-Ha,2-H= 4.9 Hz, 1H,

1-Ha), 3.71 (dd, ²J_1-Hb,1-Ha= 10.6 Hz, ³J_1-Hb,2-H= 6.8 Hz, 1H, 1-Hb),

(ddddd, ³J_2-H,3-H= 6.9 Hz, ³J_2-H,1-Hb= 6.6 Hz, ³J_2-H,1-Ha= 5.3 Hz, ⁴J_2-H,4-Ha

=

3.85 (ddddd, ³J_2-H,3-H= 7.0 Hz, ³J_2-H,1-Hb= 6.8 Hz, ³J_2-H,1-Ha= 4.9 Hz,

4

3

J_HH=1.0Hz, J_HH= 1.0 Hz, 1H, 2-H), 4.96 (d, J_{1 -H,2 -H}= 6.1 Hz, 1H, 1⁰-H),

5.15 (ddd, J_HH= 10.4 Hz, J_HH= 1.4 Hz, J_HH= 1.4 Hz, 1H, 3⁰⁰⁰⁰-Ha or

3⁰-Hb), 5.21ꢀ5.29 (m, 3H, 3⁰-Hb or 3⁰-Ha, 4-Ha, and 4-Hb), 5.76 (ddd,

J_HH= 17.4 Hz, J_HH= 10.8 Hz, ³J_3-H,2-H= 7.0 Hz, 1H, 3-H), 5.94 (ddd,

0.9 Hz, J_2-H,4-Hb= 0.9 Hz, 1H, 2-H), 4.34ꢀ4.38* (m, 1H, 2-H),

0

3

4.78* (d, J_{1 -H,2 -H}= 6.7 Hz, 1H, 1⁰-H), 4.95 (d, J_{1 -H,2 -H}= 7.3 Hz,

1H, 1⁰-H), 5.10ꢀ5.35 (m, 4H, 4-H_a, 4-H_b, 3⁰-H_a, and 3⁰-H_b), 5.74 (ddd,

³J_3-H,4-Ha= 17.3 Hz, ³J_3-H,4-Hb= 10.4 Hz, ³J_3-H,2-H= 6.9 Hz, 1H, 3-H),

5.82ꢀ5.97 (m, 1H, 2⁰-H, 2⁰-H*, 3-H*), 7.23ꢀ7.38 (m, 5H, H-arom);

¹³C NMR (100.6 MHz, CDCl₃) δ -5.3 (CH₃), ꢀ5.2 (CH₃), ꢀ4.7*

(CH₃), 18.32* 18.35 (C(CH₃)₃), 25.85* 25.91 (C(CH₃)₃), 66.3 (CH₂-1),

72.8* (CH₂-2), 73.2* (CH₂-1), 78.8 (CH-2), 80.3 (CH-1⁰), 83.4*

(CH-1⁰), 114.9*, 116.0* (CH₂-4, and CH₂-3⁰), 116.7 (CH₂-3⁰), 117.8

(CH₂-4), 126.7, 126.8*, 127.3, 127.5*, 128.25 and 128.34 (CH-arom),

136.3 (CH-3), 138.6* (CH-double bond) 138.8 (CH-2⁰), 138.98* (CH-

double bond), 141.06*, 141.53 (C-arom).

0

J_HH= 17.1 Hz, J_HH= 10.3 Hz, ³J_{2 -H,1 -H}= 6.1 Hz, 1H, 2⁰-H), 6.94ꢀ6.99

(m, 1H, 4⁰⁰-H), 7.10ꢀ7.14 (m, 2H, 2⁰⁰-H, and 6⁰⁰-H), 7.27ꢀ7.32 (m, 1H,

5⁰⁰-H); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.39 (CH₃), ꢀ5.30 (CH₃),

18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃), 66.3 (CH₂-1), 78.4 (d, ⁴J_CF= 1.7 Hz,

0

CH-1⁰), 79.0 (CH-2), 114.0 (d, ²J_CF= 21.7 Hz, CH-2⁰⁰), 114.4 (d, ²J_CF

=

21.3 Hz, CH-4⁰⁰), 115.7 (CH₂-3⁰), 118.2 (CH₂-4), 122.7 (d, ⁴J_CF= 2.8

3

Hz, CH-6⁰⁰), 129.8 (d, J_CF= 8.1 Hz, CH-5⁰⁰), 136.9 (CH-3), 139.0

(CH-2⁰), 143.9 (d, ³J_CF= 6.6 Hz, C-1⁰⁰), 163.0 (d, ¹J_CF= 245.9 Hz, CF-

3⁰⁰); ¹⁹F NMR (376.5 MHz, CDCl₃) δ ꢀ113.6; IR (NaCl, neat) ν 2955

(s), 2929 (s), 2858 (s), 1614 (m), 1592 (m), 1296 (s), 1126 (s), 1086

(s) cm^ꢀ1; MS (CI) m/z (%) 337 ([M + H⁺], 5), 135 (100); HRMS (CI)

337.1997 [C₁₉H₃₀FO₂Si (M + H⁺) requires 337.1999]. Anal. Calcd for

C₁₉H₂₉FO₂Si: C, 67.81; H, 8.69. Found: C, 67.55; H, 8.70.

(2S,1⁰S)-tert-Butyl(dimethyl)(2-(1⁰-(3⁰⁰-fluorophenyl)allyloxy)-

but-3-enyloxy)silane (2S,1⁰S)-(16b). Following general procedure B,

the protected butenediol (S)-5a (1.641 g, 8.11 mmol) was coupled with allyl

carbonate (S)-9b (1.700 g, 6.73 mmol, neat) to obtain ether (2S,1⁰S)-16b as

a colorless oil (1.765 g, 78%): [α]_D+15.2 (c 3.10, CHCl₃); ¹H NMR (400.1

MHz, CDCl₃) δ 0.10 (s, 3H, CH₃), 0.11 (s, 3H, CH₃), 0.94 (s, 9H, t-Bu),

(2S,1⁰S)-tert-Butyl(dimethyl)(2-(1⁰-(phenyl)allyloxy)but-3-

enyloxy)silane (2S,1⁰S)-(16a). Method 1. Following general pro-

cedure B, the protected butenediol (S)-5a (556 mg, 2.74 mmol) was

coupled with allyl carbonate (S)-9a (436 mg, 1.86 mmol, neat) to obtain

ether (2S,1⁰S)-16a as a colorless oil (468 mg, 79%, as a single

diastereoisomer): [α]_D+11.5 (c 0.78, MeOH); ¹H NMR (400.1

MHz, CDCl₃) δ 0.08 (s, 3H, CH₃), 0.09 (s, 3H, CH₃), 0.92 (s, 9H, t-

Bu), 3.63 (dd, ²J_1-Ha,1-Hb= 10.5 Hz, ³J_1-Ha,2-H= 5.3 Hz, 1H, 1-Ha), 3.76

(dd, ²J_1-Hb,1-Ha= 10.5 Hz, ³J_1-Hb,2-H= 6.6 Hz, 1H, 1-Hb), 4.06 (ddddd,

³J_2-H,3-H= 6.9 Hz, ³J_2-H,1-Hb= 6.6 Hz, ³J_2-H,1-Ha= 5.3 Hz, ⁴J_2-H,4-Ha= 0.9

2

3

3.66 (dd, J_1-Ha,1-Hb= 10.5 Hz, J_1-Ha,2-H= 5.1 Hz, 1H, 1-Ha), 3.78 (dd,

²J_1-Hb,1-Ha=10.5Hz,³J_1-Hb,2-H= 6.6 Hz, 1H, 1-Hb), 4.07 (ddddd, ³J_2-H,1-Hb=6.6

Hz, ³J_2-H,3-H= 6.2 Hz, ³J_2-H,1-Ha= 5.1 Hz, ⁴J_2-H,4-Ha= 1.2 Hz, ⁴J_2-H,4-Hb= 1.0

3

Hz, 1H, 2-H), 4.96 (d, J_{1 -H,2 -H}= 7.3 Hz, 1H, 1⁰-H), 5.25 (ddd, J_4-Hb,3-H

=

0

2

4

10.4 Hz, J_4-Hb,4-Ha= 1.9 Hz, J_4-Hb,2-H= 1.0 Hz, 1H, 4-Hb), 5.28 (ddd,

3

J_{3 -Hb,2 -H}=10.2Hz, J_{3 -Hb,3 -Ha}=1.7Hz,J_HH= 0.8 Hz, 1H, 3⁰-Hb), 5.29 (ddd,

0

³J_4-Ha,3-H= 17.4 Hz, ³J_4-Ha,4-Hb= 1.9 Hz, ⁴J_4-Ha,2-H= 1.2 Hz, 1H, 4-Ha), 5.35

3

(ddd, J_{3 -Ha,2 -H}= 17.4 Hz, J_{3 -Ha,3 -Hb}= 1.7 Hz, J_HH= 1.1 Hz, 1H, 3⁰-Ha),

0

5.75 (ddd, ³J_3-H,4-Ha= 17.4 Hz, ³J_3-H,4-Hb= 10.4 Hz, ³J_3-H,2-H= 6.2 Hz, 1H,

3

Hz, ⁴J_2-H,4-Hb= 0.9 Hz, 1H, 2-H), 4.95 (d, ³J_{1 -H,2 -H}= 7.3 Hz, 1H, 1⁰-H),

5.20ꢀ5.35 (m, 4H, 4-Ha, 4-Hb, 3⁰-Ha, and 3⁰-Hb), 5.74 (ddd, ³J_3-H,4-Ha

0

3-H), 5.88 (ddd, J_{2 -H,3 -Ha}= 17.4 Hz, J_{2 -H,3 -Hb}= 10.2 Hz, J_{2 -H,1 -H}= 7.3

0

Hz, 1H, 2⁰-H), 6.93ꢀ6.98 (m, 1H, 4⁰⁰-H), 7.11ꢀ7.14 (m, 1H, 2⁰⁰-H),

4

7.14ꢀ1.16 (m, 1H, 6⁰⁰-H), 7.30 (ddd, J_HH= 8.1 Hz, J_HH= 8.1 Hz, J_{5 -H,F}

=

= 17.3 Hz, ³J_3-H,4-Hb= 10.4 Hz, ³J_3-H,2-H= 6.9 Hz, 1H, 3-H), 5.90 (ddd,

00

0

5.9 Hz, 1H, 5⁰⁰-H); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.3 (CH₃), ꢀ5.2

3

J_{2 -H,3 -Ha}= 17.3 Hz, ³J_{2 -H,3 -Hb}= 10.2 Hz, ³J_{2 -H,1 -H}= 7.3 Hz, 1H, 2⁰-

H), 7.23ꢀ7.38 (m, 5H, H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ

ꢀ5.3 (CH₃), ꢀ5.2 (CH₃), 18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃), 66.3

(CH₂-1), 78.8 (CH-2), 80.3 (CH-1⁰), 116.7, 117.8 (CH₂-4, and CH₂-

3⁰), 126.7, 127.3, and 128.3 (CH-arom), 136.3 (CH-3), 138.8 (CH-2⁰),

141.5 (C-arom); IR (NaCl, neat) ν 2955 (s), 2928 (s), 2857 (s), 1471 (m),

(CH₃), 18.4 (C(CH₃)₃), 25.9(C(CH₃)₃), 66.3(CH₂-1), 79.0 (CH-2), 79.6

(d, ⁴J_CF= 1.8 Hz, CH-1⁰), 113.6 (d, ²J_CF= 22.1 Hz, CH-2⁰⁰), 114.1 (d, ²J_CF

=

21.2 Hz, CH-4⁰⁰), 117.2 (CH₂-3⁰), 118.0 (CH₂-4), 122.3 (d, ⁴J_CF= 2.9 Hz,

CH-6⁰⁰), 129.6 (d, ³J_CF= 8.2 Hz, CH-5⁰⁰), 136.1 (CH-3), 138.3 (CH-2⁰),

144.3 (d, ³J_CF= 6.9 Hz, C-1⁰⁰), 162.9 (d, ¹J_CF= 245.5 Hz, CF-3⁰⁰); ¹⁹F NMR

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The Journal of Organic Chemistry

ARTICLE

(376.5 MHz, CDCl₃) δ ꢀ113.8; IR (NaCl, neat) ν 2958 (s), 2931 (s), 2858

(s), 2360 (s), 1593 (m), 1253 (s), 1128 (s) cm^ꢀ1; MS (CI) m/z (%) 337

([M + H⁺], 10), 135 (100); HRMS (CI) 337.1998 [C₁₉H₃₀FO₂Si (M +

H⁺) requires 337.1999]. Anal. Calcd for C₁₉H₂₉FO₂Si: C, 67.81; H, 8.69.

Found: C, 67.74; H, 8.79.

(2R,1⁰R)-tert-Butyl(dimethyl)(2-(1⁰-(phenyl)allyloxy)but-

3-enyloxy)silane (2R,1⁰R)-(17a). Method 1. Following general

procedure B, the protected butenediol (R)-5a (1.236 g, 6.11 mmol)

was coupled with allyl carbonate (R)-9a (1.226 g, 5.23 mmol, neat) to

obtain ether (2R,1⁰R)-17a as a colorless oil (1.388 g, 83%, as a single

diastereoisomer): [α]_Dꢀ10.2 (c 3.73, CHCl₃); ¹H NMR (400.1

MHz, CDCl₃) δ 0.08 (s, 3H, CH₃), 0.09 (s, 3H, CH₃), 0.92 (s, 9H,

t-Bu), 3.63 (dd, ²J_1-Ha,1-Hb= 10.5 Hz, ³J_1-Ha,2-H= 5.3 Hz, 1H, 1-Ha),

(2R,1⁰R)-tert-Butyl(dimethyl)(2-(1⁰-(3⁰⁰-fluorophenyl)allyloxy)-

but-3-enyloxy)silane (2R,1⁰R)-(17b). Following general procedure B,

the protected butenediol (R)-5a (1.209 g, 5.97 mmol) was coupled with allyl

carbonate (R)-9b (1.208 g, 4.79 mmol, neat) to obtain ether (2R,1⁰R)-17b as

a colorless oil (1.161 g, 72%): [α]_Dꢀ14.7 (c 1.84, CHCl₃); ¹H NMR (400.1

MHz, CDCl₃) δ0.10 (s, 3H, CH₃),0.11(s,3H,CH₃),0.94(s,9H,t-Bu), 3.66

(dd, ²J_1-Ha,1-Hb=10.5Hz, ³J_1-Ha,2-H= 5.1 Hz, 1H, 1-Ha), 3.78 (dd, ²J_1-Hb,1-Ha

=

3

10.5 Hz, J_1-Hb,2-H= 6.6 Hz, 1H, 1-Hb), 4.07 (ddddd, J_2-H,1-Hb= 6.6 Hz,

³J_2-H,3-H=6.2Hz,³J_2-H,1-Ha= 5.1 Hz, ⁴J_2-H,4-Ha= 1.2 Hz, ⁴J_2-H,4-Hb= 1.0 Hz, 1H,

3

2-H), 4.96 (d, J_{1 -H,2 -H}= 7.3 Hz, 1H, 1⁰-H), 5.25 (ddd, J_4-Hb,3-H= 10.4 Hz,

0

J_4-Hb,4-Ha=1.9Hz,⁴J_4-Hb,2-H=1.0Hz,1H,4-Hb),5.28(ddd, J_{3 -Hb,2 -H}=10.2

2

3

0

3

Hz, J_{3 -Hb,3 -Ha}=1.7Hz,J_HH= 0.8 Hz, 1H, 3⁰-Hb), 5.29 (ddd, J_4-Ha,3-H=17.4

0

Hz, ³J_4-Ha,4-Hb= 1.9 Hz, ⁴J_4-Ha,2-H= 1.2 Hz, 1H, 4-Ha), 5.35 (ddd, J_{3 -Ha,2 -H}

=

3

0

3

17.4 Hz, J_{3 -Ha,3 -Hb}=1.7Hz, J_HH=1.1Hz, 1H, 3⁰-Ha), 5.75 (ddd, J_3-H,4-Ha

2

3

0

3.76 (dd, J_1-Hb,1-Ha= 10.5 Hz, J_1-Hb,2-H= 6.6 Hz, 1H, 1-Hb), 4.06

17.4 Hz, ³J_3-H,4-Hb=10.4Hz,³J_3-H,2-H= 6.2 Hz, 1H, 3-H), 5.88 (ddd, J_{2 -H,3 -Ha}

3

0

(ddddd, J_2-H,3-H= 6.9 Hz, J_2-H,1-Hb= 6.6 Hz, J_2-H,1-Ha= 5.3 Hz,

3

17.4 Hz, J_{2 -H,3 -Hb}= 10.2 Hz, J_{2 -H,1 -H}= 7.3 Hz, 1H, 2⁰-H), 6.93ꢀ6.98

J_2-H,4-Ha= 0.9 Hz, ⁴J_2-H,4-Hb= 0.9 Hz, 1H, 2-H), 4.95 (d, ³J_{1 -H,2 -H}= 7.3

Hz, 1H, 1⁰-H), 5.20ꢀ5.35 (m, 4H, 4-Ha, 4-Hb, 3⁰-Ha, and 3⁰-Hb),

5.74 (ddd, ³J_3-H,4-Ha= 17.3 Hz, ³J_3-H,4-Hb= 10.4 Hz, ³J_3-H,2-H= 6.9 Hz,

4

0

(m, 1H, 4⁰⁰-H), 7.11ꢀ7.14 (m, 1H, 2⁰⁰-H), 7.14ꢀ1.16 (m, 1H, 6⁰⁰-H), 7.30

(ddd, J_HH= 8.1 Hz, J_HH= 8.1 Hz, J_{5 -H,F}= 5.9 Hz, 1H, 5⁰⁰-H); ¹³C NMR

4

00

3

(100.6 MHz, CDCl₃) δ ꢀ5.3 (CH₃), ꢀ5.2 (CH₃), 18.4 (C(CH₃)₃), 25.9

(C(CH₃)₃), 66.3 (CH₂-1), 79.0 (CH-2), 79.6 (d, ⁴J_CF= 1.8 Hz, CH-1⁰),

113.6 (d, ²J_CF= 22.1 Hz, CH-2⁰⁰), 114.1 (d, ²J_CF= 21.2 Hz, CH-4⁰⁰), 117.2

0

1H, 3-H), 5.90 (ddd, J_{2 -H,3 -Ha}= 17.3 Hz, J_{2 -H,3 -Hb}= 10.2 Hz,

J_{2 -H,1 -H}= 7.3 Hz, 1H, 2⁰-H), 7.23ꢀ7.38 (m, 5H, H-arom); ¹³C NMR

(100.6 MHz, CDCl₃) δ ꢀ5.3 (CH₃), ꢀ5.2 (CH₃), 18.4 (C(CH₃)₃),

25.9 (C(CH₃)₃), 66.3 (CH₂-1), 78.8 (CH-2), 80.3 (CH-1⁰), 116.7,

117.8 (CH₂-4, and CH₂-3⁰), 126.7, 127.3, and 128.3 (CH-arom),

136.3 (CH-3), 138.8 (CH-2⁰), 141.5 (C-arom); IR (NaCl, neat) ν

2955 (s), 2928 (s), 2857 (s), 1471 (m), 1255 (s), 1128 (s), 1086

(s) cm^ꢀ1; MS (CI-iso, 150 ꢀC) m/z (%) 319 ([M + H⁺], 5), 117

(100); HRMS (CI) 319.2091 [C₁₉H₃₁O₂Si (M + H⁺) requires

319.2093]. Anal. Calcd for C₁₉H₃₀O₂Si: C, 71.64; H, 9.49. Found:

C, 71.45; H, 9.54.

3

0

(CH₂-3⁰), 118.0 (CH₂-4), 122.3 (d, ⁴J_CF= 2.9 Hz, CH-6⁰⁰), 129.6 (d, ³J_CF

=

8.2 Hz, CH-5⁰⁰), 136.1 (CH-3), 138.3 (CH-2⁰), 144.3 (d, ³J_CF=6.9Hz,C-1⁰⁰),

162.9 (d, ¹J_CF= 245.5 Hz, CF-3⁰⁰);¹⁹F NMR (376.5 MHz, CDCl₃) δꢀ113.8;

IR (NaCl, neat) ν2958(s), 2931(s), 2858(s), 2360(s), 1593(m), 1253(s),

1128 (s) cm^ꢀ1; MS (CI) m/z (%) 337 ([M + H⁺], 10), 135 (100); HRMS

(CI) 337.1998 [C₁₉H₃₀FO₂Si (M + H⁺) requires 337.1999]. Anal. Calcd for

C₁₉H₂₉FO₂Si: C, 67.81; H, 8.69. Found: C, 67.71; H, 8.55.

(2R,1⁰S)-tert-Butyl(dimethyl)(2-(1⁰-(phenyl)allyloxy)but-3-

enyloxy)silane (2R,1⁰S)-(18a). Method 1. Following general pro-

cedure B, the protected butenediol (R)-5a (1.252 g, 6.19 mmol) was

coupled with allyl carbonate (S)-9a (1.180 g, 5.04 mmol, neat) to obtain

ether (2R,1⁰S)-18a as a colorless oil (1.232 g, 77%, as a single

diastereoisomer): [α]_Dꢀ23.3 (c 2.62, CHCl₃); ¹H NMR (400.1

MHz, CDCl₃) δ 0.04 (s, 6H, CH₃), 0.89 (s, 9H, t-Bu), 3.58 (dd,

Method 2. n-Butyllithium (1.25 mL, 2.0 mmol, 1.6 M solution in

hexanes) was added dropwise to a solution of the protected butenediol

(R)-5a (419 mg, 2.07 mmol) in THF (2 mL), and the mixture was

stirred at ꢀ40 ꢀC for 30 min. The lithium alkoxide thus generated was

rapidly transferred to a suspension of copper(I) iodide (400 mg, 2.10

mmol) in THF (4 mL) at ꢀ40 ꢀC. The mixture was stirred for 30 min at

ꢀ40 ꢀC, placed in an ice bath, and stirred for another 30 min. Finally, a

cold (0 ꢀC) solution of [Ir(COD)Cl]₂(13.8 mg, 0.040 mmol) and the

chiral ligand (R_a,R_c,R_c)-11 (37.0 mg, 0.060 mmol) in THF (2 mL) and

cinnamyl carbonate 7 (235 mg, 1.00 mmol, neat) were added consecu-

tively. The cooling bath was then removed, and the reaction mixture was

stirred at room temperature for 16 h. The catalyst was precipitated by

adding hexane (5 mL), the mixture was ﬁltered through a pad of silica (3

ꢁ 3 cm), and the product was eluted with a mixture of hexanes and ethyl

acetate (90:10). Chromatography on a column of silica gel (15 g) with a

mixture of hexanes, ether, and acetone (250:1:1) gave silane (2R,1⁰R)-

17a as a colorless oil, together with its diastereoisomer (2R,1⁰S)-18a and

the rearranged silane 13 (187 mg, 59% combined yield; in an 88:2.5:9.5

ratio as shown by GC): ¹H NMR (400.1 MHz, CDCl₃) δ 0.08 (s, 3H,

CH₃₃), 0.09 (s, 3H, CH₃), 0.92 (s, 9H, t-Bu), 3.63 (dd, ²J_1-Ha,1-Hb= 10.5

²J_1-Ha,1-Hb= 10.5 Hz, ³J_1-Ha,2-H= 5.3 Hz, 1H, 1-Ha), 3.71 (dd, ²J_1-Hb,1-Ha

=

10.5 Hz, ³J_1-Hb,2-H= 6.6 Hz, 1H, 1-Hb), 3.84 (ddddd, ³J_2-H,3-H= 7.0 Hz,

³J_2-H,1-Hb= 6.6 Hz, ³J_2-H,1-Ha= 5.3 Hz, ⁴J_2-H,4-Ha= 0.8 Hz, ⁴J_2-H,4-Hb= 0.8

Hz, 1H, 2-H), 4.96 (d, ³J_{1 -H,2 -H}= 6.1 Hz, 1H, 1⁰-H), 5.12ꢀ5.28 (m, 4H,

0

3

4-H, and 3⁰-H), 5.78 (ddd, J_3-H,4-Ha= 16.2 Hz, J_3-H,4-Hb= 11.4 Hz,

J_3-H,2-H= 7.0 Hz, 1H, 3-H), 5.98 (ddd, ³J_{2 -H,3 -Ha}= 17.1 Hz, ³J_{2 -H,3 -Hb}

=

3

0

10.4 Hz, ³J_{2 -H,1 -H}= 6.1 Hz, 1H, 2⁰-H), 7.25ꢀ7.38 (m, 5H, H-arom);

¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.37 (CH₃), ꢀ5.28 (CH₃), 18.3

(C(CH₃)₃), 25.9 (C(CH₃)₃), 66.2 (CH₂-1), 78.5 (CH-2), 79.9 (CH-1⁰),

115.3, and 118.1 (CH₂-4, and CH₂-3⁰), 127.2, 127.5, and 128.3

(CH-arom), 136.1 (CH-3), 139.5 (CH-2⁰), 141.0 (C-arom); IR (NaCl,

neat) ν 2955 (s), 2928 (s), 2857 (s), 1471 (m), 1255 (s), 1121 (s), 1083

(s), 838 (s) cm^ꢀ1; MS (CI-Iso, 150 ꢀC) m/z (%) 319 ([M + H⁺], 3), 185

(10), 117 (100); HRMS (CI) 319.2092 [C₁₉H₃₁O₂Si (M + H⁺) requires

319.2093]. Anal. Calcd for C₁₉H₃₀O₂Si: C, 71.64; H, 9.49. Found: C,

71.45; H, 9.57.

0

2

Hz, J_1-Ha,2-H= 5.3 Hz, 1H, 1-H_a), 3.76 (dd, J_1-Hb,1-Ha= 10.5 Hz,

³J_1-Hb,2-H= 6.6 Hz, 1H, 1-H_b), 4.06 (ddddd, ³J_2-H,3-H= 6.9 Hz, ³J_2-H,1-Hb

=

6.6 Hz, ³J_2-H,1-Ha= 5.3 Hz, ⁴J_2-H,4-Ha= 0.9 Hz, ⁴J_2-H,4-Hb= 0.9 Hz, 1H,

Method 2. n-Butyllithium (0.625 mL, 1.0 mmol, 1.6 M solution in

pentane) was added slowly to a solution of protected butenediol (R)-5a

(205 mg, 1.01 mmol) in THF (1 mL), and the mixture was stirred at 0 ꢀC

for 15 min. The lithium alkoxide thus generated was transferred (via

cannula) to a suspension of copper(I) iodide (205 mg, 1.05 mmol) in

THF (2 mL) at room temperature. The mixture turned light yellow and

was then stirred for 30 min. The resulting mixture was cooled to 0 ꢀC,

and a cold (0 ꢀC) solution of [Ir(COD)Cl]₂(7.5 mg, 0.011 mmol) and

ligand (S_a,S_c,S_c)-10 (12.5 mg, 0.023 mmol) in THF (1 mL) and

cinnamyl carbonate 7 (120 mg, 0.51 mmol, neat) were added consecu-

tively. The cooling bath was then removed, and the reaction mixture was

stirred at room temperature for 48 h. The catalyst was precipitated by

adding hexane (5 mL), the mixture was ﬁltered through a pad of silica

2-H), 4.95 (d, ³J_{1 -H,2 -H}= 7.3 Hz, 1H, 1⁰-H), 5.20ꢀ5.35 (m, 4H, 4-H_a,

0

4-H_b, 3⁰-H_a, and 3⁰-H_b), 5.74 (ddd, ³J_3-H,4-Ha= 17.3 Hz, ³J_3-H,4-Hb= 10.4

3

0

Hz, J_3-H,2-H= 6.9 Hz, 1H, 3-H), 5.90 (ddd, J_{2 -H,3 -Ha}= 17.3 Hz,

J_{2 -H,3 -Hb}= 10.2 Hz, ³J_{2 -H,1 -H}= 7.3 Hz, 1H, 2⁰-H), 7.23ꢀ7.38 (m, 5H,

H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.3 (CH₃), ꢀ5.2 (CH₃),

18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃), 66.3 (CH₂-1), 78.8 (CH-2), 80.3

(CH-1⁰), 116.7, 117.8 (CH₂-4, and CH₂-3⁰), 126.7, 127.3, and 128.3

(CH-arom), 136.3 (CH-3), 138.8 (CH-2⁰), 141.5 (C-arom); MS (CI-

3

0

+

NH₃, 150 ꢀC) m/z (%) 336 ([M + NH₄], 95), 117(100); chiral GC

(Supelco γ-DEX 120 column, oven for 1 min at 160 ꢀC, then 0.5

deg min^ꢀ1) showed 3:97 dr (t_RS= 16.4 min, t_RR= 18.3 min) and 10% of

3

the rearranged product (t_xRR= 19.1 min).

7793

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The Journal of Organic Chemistry

ARTICLE

(1.5 ꢁ 1.5 cm), and the product was eluted with a mixture of hexanes

and ethyl acetate (90:10). Chromatography on a column of silica gel

(1 ꢁ 15 cm) with a mixture of hexanes and ethyl acetate (98.5:1.5) aﬀorded

silane (2R,1⁰S)-18a as a colorless oil together with its diastereoisomer

(2R,1⁰R)-17a and the rearranged silane 13 (61 mg, 38% combined yield;

in 71:4:24 ratio as shown by ¹H NMR): ¹H NMR (400.1 MHz, CDCl₃,

the regioisomer 13 is marked with * where possible) δ 0.04, 0.07* (s, 6H,

CH₃), 0.89, 0.91* (s, 9H, t-Bu), 3.34ꢀ3.41* (m, 2H, CH₂-1), 3.58 (dd,

²J_1-Ha,1-Hb= 10.5 Hz, ³J_1-Ha,2-H= 5.3 Hz, 1H, 1-H_a), 3.71 (dd, ²J_1-Hb,1-Ha

= 10.5 Hz, ³J_1-Hb,2-H= 6.6 Hz, 1H, 1-H_b), 3.84 (ddddd, ³J_2-H,3-H= 7.0 Hz,

³J_2-H,1-Hb= 6.6 Hz, ³J_2-H,1-Ha= 5.3 Hz, ⁴J_2-H,4-Ha= 0.8 Hz, ⁴J_2-H,4-Hb= 0.8

(CH-1⁰), 115.7 (CH₂-3⁰), 118.3 (CH₂-4), 121.3 (C-4⁰⁰), 128.9 (CH-2⁰⁰,

and CH-6⁰⁰), 131.4 (CH-3⁰⁰, and CH-5⁰⁰), 135.8 (CH-3), 139.0 (CH-2⁰),

140.1 (C-1⁰⁰); IR (NaCl, neat) ν 2954 (s), 2928 (s), 2857 (s), 1487 (m),

1472 (m), 1255 (s), 1121 (s), 1073 (s) cm^ꢀ1; MS (CI) m/z (%) 397/399

([M + H⁺], 10), 369 (30), 195/197 (100); HRMS (CI) 397.1156/

399.1200 [C₁₉H₃₀BrO₂Si (M + H⁺) requires 397.1198/399.1180].

(2R,1⁰S)-tert-Butyl(dimethyl)(2-(1⁰-(3⁰⁰,4⁰⁰-dimethoxyphe-

nyl)allyloxy)but-3-enyloxy)silane (2R,1⁰S)-(18d). Following

general procedure B, the protected butenediol (R)-5a (2.022 g, 9.99

mmol) was coupled with allyl carbonate (S)-9d (2.511 g, 8.53 mmol,

neat) to obtain silane (2R,1⁰S)-18d as a colorless oil (2.267 g, 70%):

[α]_Dꢀ20.4 (c 2.30, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ ꢀ0.04

Hz, 1H, 2-H), 4.34ꢀ4.39* (m, 1H, 2H), 4.79* (d, ³J_{1 -H,2 -H}= 6.3 Hz, 1H,

0

(s, 3H, CH₃), ꢀ0.01 (s, 3H, CH₃), 0.84 (s, 9H, t-Bu), 3.54 (dd, ²J_1-Ha,1-Hb

=

3

1⁰-H), 4.96 (d, J_{1 -H,2 -H}= 6.1 Hz, 1H, 1⁰-H), 5.11ꢀ5.33 (m, 4H, 4-H,

and 3⁰-H), 5.78 (ddd, ³J_3-H,4-Ha= 16.2 Hz, ³J_3-H,4-Hb= 11.4 Hz, ³J_3-H,2-H

= 7.0 Hz, 1H, 3-H), 5.84ꢀ6.03 (m, 1H, 2⁰-H, 2⁰-H*, 3-H*), 7.25ꢀ7.38

(m, 5H, H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.36, ꢀ5.27,

ꢀ4.8* (CH₃), 18.4 (C(CH₃)₃), 25.8*, 25.9 (C(CH₃)₃), 66.3 (CH₂-1),

72.7* (CH-2), 73.1* (CH₂-1), 78.5 (CH-2), 79.9 (CH-1⁰), 83.4* (CH-

1⁰), 114.9*, 115.3, 115.9, and 118.1 (CH₂-4, and CH₂-3⁰), 126.8, 127.2,

127.5, 128.3, and 128.4 (CH-arom), 136.2 (CH-3), 138.6*, 139.1* (CH-

2⁰and CH-3), 139.5 (CH-2⁰), 141.0 (C-arom).

0

3

2

10.4 Hz, J_1-Ha,2-H= 5.6 Hz, 1H, 1-Ha), 3.66 (dd, J_1-Hb,1-Ha= 10.4

Hz, ³J_1-Hb,2-H= 6.3 Hz, 1H, 1-Hb), 3.77ꢀ3.82 (m, 1H, 2-H), 3.84 (s, 3H,

CH₃O), 3.85 (s, 3H, CH₃O), 4.87 (d, ³J_{1 -H,2 -H}= 5.9 Hz, J_HH= 1.3 Hz,

0

3

J_HH= 1.3 Hz, 1H, 1⁰-H), 5.08 (ddd, J_{3 -Hb,2 -H}= 10.4 Hz, J_HH= 1.7 Hz,

J_HH= 1.3 Hz, 1H, 3⁰-Hb), 5.16ꢀ5.24 (m, 3H, 3⁰-Ha, 4-Ha, and 4-Hb),

5.75 (ddd, ³J_3-H,4-Ha= 16.3 Hz, ³J_3-H,4-Hb= 11.4 Hz, ³J_3-H,2-H= 7.0 Hz,

0

3

0

1H, 3-H), 5.95 (ddd, J_{2 -H,3 -Ha}= 17.2 Hz, J_{2 -H,3 -Hb}= 10.4 Hz, J_{2 -H,1 -H}

=

3

5.9 Hz, 1H, 2⁰-H), 6.80 (d, J_{5 -H,6 -H}= 8.0 Hz, 1H, 5⁰⁰-H), 6.84 (d,

00

J_{2 -H,6 -H}= 1.8 Hz, 1H, 2⁰⁰-H), 6.86 (ddd, J_{6 -H,5 -H}= 8.0 Hz, ⁴J_{6 -H,2 -H}

=

4

3

(2R,1⁰S)-tert-Butyl(dimethyl)(2-(1⁰-(3⁰⁰-fluorophenyl)allyloxy)-

but-3-enyloxy)silane (2R,1⁰S)-(18b). Following general procedure B,

the protected butenediol (R)-5a (2.024 g, 10.02 mmol) was coupled with allyl

carbonate (S)-9b (2.005 g, 7.94 mmol, neat) to obtain ether (2R,1⁰S)-18b as a

colorless oil (1.951 g, 73%): [α]_Dꢀ18.4 (c 1.96, CHCl₃); ¹H NMR (400.1

00

1.8 Hz, J_HH= 0.4 Hz, 1H, 6⁰⁰-H); ¹³C NMR (100.6 MHz, CDCl₃) δ

ꢀ5.47 (CH₃), ꢀ5.40 (CH₃), 18.2 (C(CH₃)₃), 25.8 (C(CH₃)₃), 55.65,

and 55.68 (2 ꢁ CH₃O), 66.2 (CH₂-1), 78.1 (CH-2), 79.5 (CH-1⁰),

110.0 (CH-2⁰⁰), 110.7 (CH-5⁰⁰), 114.9 (CH₂-3⁰), 117.9 (CH₂-4), 119.6

(CH-6⁰⁰), 133.4 (C-1⁰⁰), 136.2 (CH-3), 139.4 (CH-2⁰), 148.4, and 148.9

(C-3⁰⁰, and C-4⁰⁰); IR (NaCl, neat) ν 2955 (s), 2928 (s), 2858 (s), 1614

(m), 1256 (s) cm^ꢀ1; MS (EI) m/z (%) 378 ([M⁺], 80), 321 (100), 265

(90), 246 (60); HRMS (CI) 378.2225 [C₂₁H₃₄O₄Si (M⁺) requires

378.2226].

General Procedure C: Ring Closure by Metathesis. Grubbs

first-generation catalyst C1 (6.9 mg, 0.008 mmol) was added to a

solution of silane 15ꢀ18 (0.83 mmol) in dichloromethane (10 mL)

under a stream of argon atmosphere, and the mixture was stirred at 40 ꢀC

for 5 h. The resulting solution was evaporated, and the residue was

chromatographed on a column of silica gel (3 ꢁ 10 cm) with a mixture of

hexanes and ethyl acetate (98.5:1.5) to give, respectively, silane 19ꢀ22

as a colorless oil.

MHz, CDCl₃) δ 0.06 (s, 6H, CH₃), 0.90 (s, 9H, t-Bu), 3.60 (dd, ²J_1-Ha,1-Hb

10.6 Hz, ³J_1-Ha,2-H= 4.9 Hz, 1H, 1-Ha), 3.71 (dd, ²J_1-Hb,1-Ha= 10.6 Hz, ³J_1-Hb,2-H

=

6.8 Hz, 1H, 1-Hb), 3.85 (ddddd, ³J_2-H,3-H=7.0Hz,³J_2-H,1-Hb=6.8Hz,³J_2-H,1-Ha

3

0

4.9 Hz, J_HH= 1.0 Hz, J_HH= 1.0 Hz, 1H, 2-H), 4.96 (d, J_{1 -H,2 -H}= 6.1

Hz, 1H, 1⁰-H), 5.15 (ddd, J_HH= 10.4 Hz, J_HH= 1.4 Hz, J_HH= 1.4 Hz, 1H, 3⁰-

Ha or 3⁰-Hb), 5.21ꢀ5.29 (m, 3H, 3⁰-Hb or 3⁰-Ha, 4-Ha, and 4-Hb), 5.76

(ddd, J_HH= 17.4 Hz, J_HH= 10.8 Hz, ³J_3-H,2-H= 7.0 Hz, 1H, 3-H), 5.94 (ddd,

3

J_HH= 17.1 Hz, J_HH= 10.3 Hz, J_{2 -H,1 -H}= 6.1 Hz, 1H, 2⁰-H), 6.94ꢀ6.99 (m,

1H, 4⁰⁰-H), 7.10ꢀ7.14 (m, 2H, 2⁰⁰-H, and 6⁰⁰-H), 7.27ꢀ7.32 (m, 1H, 5⁰⁰-H);

¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.39 (CH₃), ꢀ5.30 (CH₃), 18.4

(C(CH₃)₃), 25.9 (C(CH₃)₃), 66.3 (CH₂-1), 79.0 (CH-2), 78.4 (d, ⁴J_CF=1.7

Hz, CH-1⁰), 114.0 (d, ²J_CF= 21.7 Hz, CH-2⁰⁰), 114.4 (d, ²J_CF= 21.3 Hz, CH-

4⁰⁰), 115.7 (CH₂-3⁰), 118.2 (CH₂-4), 122.7 (d, ⁴J_CF= 2.8 Hz, CH-6⁰⁰), 129.8

(d, ³J_CF=8.1 Hz, CH-5⁰⁰), 136.9 (CH-3), 139.0 (CH-2⁰), 143.9 (d, ³J_CF=6.6

0

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-2⁰,3⁰-didehydro-2⁰,3⁰-di-

deoxy-1⁰-phenyl-β-D-ribofuranose (19a). Employing general

procedure C, the silane (2S,1⁰R)-15a (483 mg, 1.52 mmol) was

converted to dihydrofuran 19a (441 mg, 78%): [α]_Dꢀ35.5 (c 1.24,

CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.09 (s, 6H, CH₃), 0.93 (s,

9H, t-Bu), 3.73 (dd, ²J_5-Ha,5-Hb= 10.3 Hz, ³J_5ꢀHa,4-H= 5.9 Hz, 1H, 5-Ha),

1

Hz, C-1⁰⁰), 163.0 (d, J_CF= 245.9 Hz, CF-3⁰⁰); ¹⁹F NMR (376.5 MHz,

CDCl₃) δꢀ113.6; IR (NaCl, neat) ν2955 (s), 2929 (s), 2858 (s), 1614 (m),

1592 (m), 1296 (s), 1126 (s), 1086 (s) cm^ꢀ1; MS (CI) m/z (%) 337 ([M +

H⁺], 5), 135 (100); HRMS (CI) 337.1997 [C₁₉H₃₀FO₂Si (M + H⁺) requires

337.1999]. Anal. Calcd for C₁₉H₂₉FO₂Si: C, 67.81; H, 8.69. Found: C, 67.64;

H, 8.80.

2

3

3.85 (dd, J_5-Hb,5-Ha= 10.3 Hz, J_5-Hb,4-H= 4.8 Hz, 1H, 5-Hb), 4.96

3

4

(2R,1⁰S)-(2-(1⁰-(4⁰⁰-Bromophenyl)allyloxy)but-3-enyloxy)-

(tert-butyl)dimethylsilane (2R,1⁰S)-(18c). Following general pro-

cedure B, the protected butenediol (R)-5a (2.022 g, 9.99 mmol) was

coupled with allyl carbonate (S)-9c (2.527 g, 8.07 mmol, neat) to obtain

ether (2R,1⁰S)-18c as yellowish oil (2.724 g, 85%): [α]_Dꢀ18.8 (c 2.02,

CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.11 (s, 6H, CH₃), 0.95 (s,

9H, t-Bu), 3.63 (dd, ²J_1-Ha,1-Hb= 10.5 Hz, ³J_1-Ha,2-H= 4.9 Hz, 1H, 1-Ha),

(ddddd, J_4-H,5-Ha= 5.9 Hz, J_4-H,5-Hb= 4.8 Hz, J_4-H,1-H= 4.0 Hz,

³J_4-H,3-H= 2.1 Hz, ⁴J_4-H,2-H= 1.4 Hz, 1H, 4-H), 5.80 (ddd, ⁴J_1-H,4-H= 4.0

Hz, ³J_1-H,2-H= 2.4 Hz, ⁴J_1-H,3-H= 1.6 Hz, 1H, 1-H), 5.92 (ddd, ³J_3-H,2-H

6.1 Hz, ³J_3-H,4-H= 2.1 Hz, ⁴J_3-H,1-H= 1.6 Hz, 1H, 3-H), 6.02 (ddd, ³J_2-H,3-H

=

6.1 Hz, ³J_2-H,1-H= 2.4 Hz, ⁴J_2-H,4-H= 1.4 Hz, 1H, 2-H), 7.27ꢀ7.40 (m,

5H, H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.4 (CH₃), 18.4

(C(CH₃)₃), 25.9 (C(CH₃)₃), 66.4 (CH₂-5), 87.2 (CH-4), 88.0 (CH-1),

126.8, 127.8, and 128.27 (CH-arom), 128.33 (CH-2), 131.0 (CH-3),

141.7 (C-arom); IR (NaCl, CHCl₃) ν 2954 (s), 2930 (s), 2858 (s), 1726

2

3

3.73 (dd, J_1-Hb,1-Ha= 10.5 Hz, J_1-Hb,2-H= 6.9 Hz, 1H, 1-Hb), 3.85

(ddddd, ³J_2-H,3-H= 7.0 Hz, ³J_2-H,1-Hb= 6.9 Hz, ³J_2-H,1-Ha= 4.9 Hz, ⁴J_2-H,4-Ha

=

0

(m), 1257 (s), 1113 (s), 836 (s) cm ;

^{ꢀ1 66}MS (CI) m/z (%) 305 (100),

4

3

1.0 Hz, J_2-H,4-Hb= 1.0 Hz, 1H, 2-H), 4.97 (d, J_{1 -H,2 -H}= 6.1 Hz,

0

291 ([M⁺], 50); HRMS (CI) 291.1778 [C₁₇H₂₇O₂Si (M⁺) requires

291.1780].

J_{1 -H,3 -Ha}= 1.2 Hz, ⁴J_{1 -H,3 -Hb}= 1.2 Hz, 1H, 1⁰-H), 5.19 (ddd, J_{3 -Hb,2 -H}

4

3

= 10.3 Hz, J_HH= 1.7 Hz, ⁴J_{3 -Hb,1 -H}= 1.2 Hz, 1H, 3⁰-Hb), 5.24ꢀ5.34 (m,

0

3H, 3⁰-Ha, 4-Ha, and 4-Hb), 5.79 (ddd, ³J_3-H,4-Ha= 16.9 Hz, ³J_3-H,4-Hb

=

(+)-5⁰-O-(tert-Butyldimethylsilyl)-2⁰,3⁰-didehydro-1⁰,2⁰,3⁰-

trideoxy-1⁰-(3-fluorophenyl)-β-D-ribofuranose (19b). Em-

ploying general procedure C, the silane (2S,1⁰R)-15b (1.346 g, 4.00

mmol) was converted to dihydrofuran 19b (1.185 g, 96%): [α]_D+8.0 (c

2.63, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.09 (s, 6H, CH₃), 0.93

10.8 Hz, ³J_3-H,2-H= 7.0 Hz, 1H, 3-H), 5.97 (ddd, ³J_{2 -H,3 -Ha}= 17.2 Hz,

0

J_{2 -H,3 -Hb}= 10.3 Hz, ³J_{2 -H,1 -H}= 6.1 Hz, 1H, 2⁰-H), 7.30 (d, J_{2 -H,3 -H}

=

3

0

00

3

8.2 Hz, 2H, 2⁰⁰-H, and 6⁰⁰-H), 7.52 (d, J_{3 -H,2 -H}= 8.2 Hz, 2H, 3⁰⁰-H, and

5⁰⁰-H); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.38 (CH₃), ꢀ5.27 (CH₃),

18.3 (C(CH₃)₃), 25.9 (C(CH₃)₃), 66.2 (CH₂-1), 78.8 (CH-2), 79.2

00

(s, 9H, t-Bu), 3.71 (dd, ²J_{5 -Ha,5 -Hb}= 10.5 Hz, ³J_{5 -Ha,4 -H}= 5.5 Hz, 1H,

0

7794

dx.doi.org/10.1021/jo201110z |J. Org. Chem. 2011, 76, 7781–7803

The Journal of Organic Chemistry

ARTICLE

2

5⁰-Ha), 3.77 (dd, J_{5 -Hb,5 -Ha}= 10.5 Hz, ³J_{5 -Hb,4 -H}= 4.9 Hz, 1H, 5⁰-Hb),

5H, H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.33 (CH₃), ꢀ5.28

(CH₃), 18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃), 66.0 (CH₂-5), 87.2 (CH-4),

88.0 (CH-1), 126.4, and 127.8 (CH-arom), 128.1 (CH-2), 128.4 (CH-

arom), 131.3 (CH-3), 141.9 (C-arom); IR (NaCl, neat) ν 2931 (s),

0

3

0

4.89ꢀ4.95 (m, 1H, 4 -H), 5.73ꢀ5.75 (m, 1H, 1 -H), 5.94 (ddd, J_{3 -H,2 -H}

=

3

6.1 Hz, J_HH= 1.8 Hz, J_HH= 1.2 Hz, 1H, 3⁰-H), 5.97 (ddd, J_{2 -H,3 -H}

0

6.1 Hz, J_HH= 2.2 Hz, J_HH= 1.1 Hz, 1H, 2⁰-H), 6.98ꢀ7.11 (m, 3H, 2-H,

4-H, and 6-H), 7.30ꢀ7.32 (m, 1H, 5-H); ¹³C NMR (100.6 MHz,

CDCl₃) δ ꢀ5.4 (CH₃), 18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃), 63.0 (CH₂-

5⁰), 87.2 (d, ⁴J_CF= 1.8 Hz, CH-1⁰), 87.3 (CH-4⁰), 113.8 (d, ²J_CF= 21.7

Hz, CH-2), 114.8 (d, ²J_CF= 21.2 Hz, CH-4), 122.4 (d, ⁴J_CF= 2.9 Hz,

CH-6), 129.5 (CH-2⁰), 130.0 (d, ³J_CF= 8.1 Hz, CH-5), 130.2 (CH-3⁰),

2858 (s), 1730 (m), 1467 (m), 1257 (s), 1113 (s), 837 (s) cm ;

^{ꢀ1 66}MS

(CI) m/z (%) 291 ([M + H⁺], 100); HRMS (CI) 291.1779

[C₁₇H₂₇O₂Si (M + H⁺) requires 291.1780].

(+)-5⁰-O-(tert-Butyldimethylsilyl)-2⁰,3⁰-didehydro-1⁰,2⁰,3⁰-

trideoxy-1⁰-(3-fluorophenyl)-α-L-ribofuranose (21b). Em-

ploying general procedure C, the silane (2R,1⁰R)-17b (650 mg, 1.93

mmol) was converted to dihydrofuran 21b (580 mg, 97%), obtained as a

144.4 (d, J_CF= 6.6 Hz, C-1), 163.0 (d, J_CF= 246.3 Hz, CF-3); ¹⁹F

3

1

NMR (376.5 MHz, CDCl₃) δ ꢀ113.3; IR (NaCl, neat) ν 2954 (s), 2931

(s), 2858 (s), 1742 (m), 1592 (m), 1258 (s) cm ;

^{ꢀ1 66}MS (CI) m/z (%)

1

colorless oil: [α]_D+147.1 (c 2.40, CHCl₃); H NMR (400.1 MHz,

309 ([M + H⁺], 100); HRMS (CI) 309.1687 [C₁₇H₂₆FO₂Si (M + H⁺)

requires 309.1686].

CDCl₃) δ 0.09 (s, 3H, CH₃), 0.10 (s, 3H, CH₃), 0.93 (s, 9H, t-Bu), 3.70

(dd, ²J_{5 -Ha,5 -Hb}= 10.4 Hz, ³J_{5 -Ha,4 -H}= 5.5 Hz, 1H, 5⁰-Ha), 3.80 (dd,

0

J_{5 -Hb,5 -Ha}= 10.4 Hz, ³J_{5 -Hb,4 -H}= 4.6 Hz, 1H, 5⁰-Hb), 5.05ꢀ5.11 (m,

2

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-2⁰,3⁰-didehydro-2⁰,3⁰-di-

deoxy-1⁰-phenyl-α-D-ribofuranose (20a). Employing general

procedure C, the silane (2S,1⁰S)-16a (266 mg, 0.83 mmol) was

converted to dihydrofuran 20a (136 mg, 56%): [α]_Dꢀ69.6 (c 1.02,

CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.06 (s, 3H, CH₃), 0.07 (s,

0

3

1H, 4⁰-H), 5.81ꢀ5.82 (m, 1H, 1⁰-H), 5.93 (ddd, J_{3 -H,2 -H}= 6.1 Hz, J_HH

0

3

= 2.0 Hz, J_HH= 1.6 Hz, 1H, 3⁰-H), 6.01 (ddd, J_{2 -H,3 -H}= 6.1 Hz, J_HH

=

0

2.3 Hz, J_HH= 1.5 Hz, 1H, 2⁰-H), 6.96 (dddd, ³J_4-H,F= 9.5 Hz, ³J_4-H,5-H

8.5 Hz, ⁴J_4-H,2-H= 2.6 Hz, ⁴J_4-H,6-H= 1.0 Hz, 1H, 4-H), 7.03 (ddd, ³J_2-H,F

= 9.7 Hz, ⁴J_2-H,4-H= 2.6 Hz, ⁴J_2-H,6-H= 1.6 Hz, 1H, 2-H), 7.07ꢀ7.10 (m,

1H, 6-H), 7.30 (ddd, ³J_5-H,4-H= 8.5 Hz, ³J_5-H,6-H= 7.7 Hz, ⁴J_5-H,F= 5.8

Hz, 1H, 5-H); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.34 (CH₃), ꢀ5.30

(CH₃), 18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃), 65.9 (CH₂-5⁰), 87.4 (d, ⁴J_CF

= 1.8 Hz, CH-1⁰), 87.5 (CH-4⁰), 113.2 (d, ²J_CF= 21.8 Hz, CH-2), 114.6

(d, ²J_CF= 21.3 Hz, CH-4), 121.8 (d, ⁴J_CF= 2.9 Hz, CH-6), 128.5 (CH-

2⁰), 129.9 (d, ³J_CF= 8.1 Hz, CH-5), 130.9 (CH-3⁰), 144.7 (d, ³J_CF= 6.5

3H, CH₃), 0.90 (s, 9H, t-Bu), 3.66 (dd, ²J_5-Ha,5-Hb= 10.3 Hz, ³J_5-Ha,4-H

=

5.7 Hz, 1H, 5-Ha), 3.77 (dd, ²J_5-Hb,5-Ha= 10.3 Hz, ³J_5-Hb,4-H= 4.6 Hz,

1H, 5-Hb), 5.02ꢀ5.07 (m, 1H, 4-H), 5.78ꢀ5.80 (m, 1H, 1-H), 5.92

(ddd, ³J_3-H,2-H= 6.1 Hz, J_HH= 2.1 Hz, J_HH= 1.4 Hz, 1H, 3-H), 5.97 (ddd,

³J_2-H,3-H= 6.1 Hz, J_HH= 2.2 Hz, J_HH= 1.5 Hz, 1H, 2-H), 7.22ꢀ7.36 (m,

5H, H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.33 (CH₃), ꢀ5.28

(CH₃), 18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃), 66.0 (CH₂-5), 87.2 (CH-4),

88.0 (CH-1), 126.4, and 127.8 (CH-arom), 128.1 (CH-2), 128.4 (CH-

arom), 131.3 (CH-3), 141.9 (C-arom); IR (NaCl, neat) ν 2954 (s),

1

Hz, C-1), 163.0 (d, J_CF= 246.1 Hz, CF-3); ¹⁹F NMR (376.5 MHz,

CDCl₃) δ ꢀ113.6; IR (NaCl, neat) ν 2955 (s), 2930 (s), 2858 (s), 1730

(m), 1593 (s), 1258 (s) cm^{ꢀ1 66}MS (CI) m/z (%) 309 ([M + H⁺],

;

2930 (s), 2858 (s), 1725 (m), 1257 (s), 1113 (m), 836 (s) cm ;

^{ꢀ1 66}MS

100); HRMS (CI) 309.1682 [C₁₇H₂₆FO₂Si (M + H⁺) requires

309.1686].

(CI) m/z (%) 291 ([M + H⁺], 70), 149 (100); HRMS (CI) 291.1776

[C₁₇H₂₇O₂Si (M + H⁺) requires 291.1780].

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-2⁰,3⁰-didehydro-2⁰,3⁰-di-

deoxy-1⁰-phenyl-β-L-ribofuranose (22a). Employing general

procedure C, the silane (2R,1⁰S)-18a (1.129 g, 3.54 mmol) was

converted to dihydrofuran 22a (880 mg, 86%): [α]_Dꢀ24.6 (c 1.83,

CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.09 (s, 6H, CH₃), 0.93 (s,

9H, t-Bu), 3.73 (dd, ²J_5-Ha,5-Hb= 10.3 Hz, ³J_5-Ha,4-H= 5.9 Hz, 1H, 5-Ha),

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-2⁰,3⁰-didehydro-1⁰,2⁰,3⁰-

trideoxy-1⁰-(3-fluorophenyl)-α-D-ribofuranose (20b). Em-

ploying general procedure C, the silane (2S,1⁰S)-16b (329 mg, 0.97

mmol) was converted to dihydrofuran 20b (285 mg, 95%): [α]_D

ꢀ

154.4 (c 1.80, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.09 (s,

3H, CH₃), 0.10 (s, 3H, CH₃), 0.93 (s, 9H, t-Bu), 3.70 (dd, ²J_{5 -Ha,5 -Hb}

=

0

2

3

10.4 Hz, ³J_{5 -Ha,4 -H}= 5.5 Hz, 1H, 5⁰-Ha), 3.80 (dd, J_{5 -Hb,5 -Ha}= 10.4 Hz,

2

3.85 (dd, J_5-Hb,5-Ha= 10.3 Hz, J_5-Hb,4-H= 4.8 Hz, 1H, 5-Hb), 4.96

0

(ddddd, ³J_4-H,5-Ha= 5.9 Hz, ³J_4-H,5-Hb= 4.8 Hz, ⁴J_4-H,1-H= 4.0 Hz, ³J_4-H,3-H

2.1 Hz, ⁴J_4-H,2-H= 1.4 Hz, 1H, 4-H), 5.80 (ddd, ⁴J_1-H,4-H= 4.0 Hz, ³J_1-H,2-H

=

3

J_{5 -Hb,4 -H}= 4.6 Hz, 1H, 5⁰-Hb), 5.05ꢀ5.11 (m, 1H, 4⁰-H), 5.81ꢀ5.82

0

3

(m, 1H, 1⁰-H), 5.93 (ddd, J_{3 -H,2 -H}= 6.1 Hz, J_HH= 2.0 Hz, J_HH= 1.6 Hz,

0

4

3

1H, 3⁰-H), 6.01 (ddd, J_{2 -H,3 -H}= 6.1 Hz, J_HH= 2.3 Hz, J_HH= 1.5 Hz, 1H,

2⁰-H), 6.96 (dddd, ³J_4-H,F= 9.5 Hz, ³J_4-H,5-H= 8.5 Hz, ⁴J_4-H,2-H= 2.6 Hz,

⁴J_4-H,6-H= 1.0 Hz, 1H, 4-H), 7.03 (ddd, ³J_2-H,F= 9.7 Hz, ⁴J_2-H,4-H= 2.6

Hz, ⁴J_2-H,6-H= 1.6 Hz, 1H, 2-H), 7.07ꢀ7.10 (m, 1H, 6-H), 7.30 (ddd, ³J_5-

_H,4-H= 8.5 Hz, ³J_5-H,6-H= 7.7 Hz, ⁴J_5-H,F= 5.8 Hz, 1H, 5-H); ¹³C NMR

(100.6 MHz, CDCl₃) δ ꢀ5.34 (CH₃), ꢀ5.30 (CH₃), 18.4 (C(CH₃)₃),

2.4 Hz, J_1-H,3-H= 1.6 Hz, 1H, 1-H), 5.92 (ddd, J_3-H,2-H= 6.1 Hz,

³J_3-H,4-H= 2.1 Hz, ⁴J_3-H,1-H= 1.6 Hz, 1H, 3-H), 6.02 (ddd, ³J_2-H,3-H= 6.1

Hz, ³J_2-H,1-H= 2.4 Hz, ⁴J_2-H,4-H= 1.4 Hz, 1H, 2-H), 7.27ꢀ7.40 (m, 5H,

H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.4 (CH₃), 18.4

(C(CH₃)₃), 25.9 (C(CH₃)₃), 66.4 (CH₂-5), 87.2 (CH-4), 88.0 (CH-1),

126.8, 127.8, and 128.27 (CH-arom), 128.33 (CH-2), 131.0 (CH-3),

141.7 (C-arom); IR (NaCl, neat) ν 2954 (s), 2931 (s), 2858 (s), 1468

(m), 1255 (s), 1103 (s), 839 (s) cm^ꢀ1; MS (CI) m/z (%) 291 ([M +

H⁺], 100); HRMS (CI) 291.1760 [C₁₇H₂₇O₂Si (M + H⁺) requires

291.1780].

0

4

25.9 (C(CH₃)₃), 65.9 (CH₂-5⁰), 87.4 (d, J_CF= 1.8 Hz, CH-1⁰), 87.5

(CH-4⁰), 113.2 (d, ²J_CF= 21.8 Hz, CH-2), 114.6 (d, ²J_CF= 21.3 Hz, CH-4),

4

3

121.8 (d, J_CF= 2.9 Hz, CH-6), 128.5 (CH-2⁰), 129.9 (d, J_CF= 8.1

Hz, CH-5), 130.9 (CH-3⁰), 144.7 (d, ³J_CF= 6.5 Hz, C-1), 163.0 (d, ¹J_CF

= 246.1 Hz, CF-3); ¹⁹F NMR (376.5 MHz, CDCl₃) δ ꢀ113.6; IR

(NaCl, neat) ν 2955 (s), 2930 (s), 2858 (s), 1730 (m), 1593 (s), 1258

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-2⁰,3⁰-didehydro-1⁰,2⁰,3⁰-

trideoxy-1⁰-(3-fluorophenyl)-β-L-ribofuranose (22b). Employ-

ing general procedure C, the silane (2R,1⁰S)-18b (1.088 g, 3.23 mmol)

was converted to dihydrofuran 22b (946 mg, 95%): [α]_Dꢀ7.7 (c 1.14,

CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.09 (s, 6H, CH₃), 0.93 (s,

(s) cm^{ꢀ1 66}MS (CI) m/z (%) 309 ([M + H⁺], 100); HRMS (CI)

;

309.1687 [C₁₇H₂₆FO₂Si (M + H⁺) requires 309.1686].

(+)-5⁰-O-(tert-Butyldimethylsilyl)-2⁰,3⁰-didehydro-2⁰,3⁰-di-

deoxy-1⁰-phenyl-α-L-ribofuranose (21a). Employing general

procedure C, the silane (2R,1⁰R)-17a (1.226 g, 3.85 mmol) was

converted to dihydrofuran 21a (1.019 g, 91%): [α]_D+202.6 (c 1.90,

CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.06 (s, 3H, CH₃), 0.07 (s,

9H, t-Bu), 3.71 (dd, ²J_{5 -Ha,5 -Hb}= 10.5 Hz, ³J_{5 -Ha,4 -H}= 5.5 Hz, 1H, 5⁰-

0

Ha), 3.77 (dd, ²J_{5 -Hb,5 -Ha}= 10.5 Hz, ³J_{5 -Hb,4 -H}= 4.9 Hz, 1H, 5⁰-Hb),

0

3

4.89ꢀ4.95 (m, 1H, 4⁰-H), 5.73ꢀ5.75 (m, 1H, 1⁰-H), 5.94 (ddd, J_{3 -H,2 -}

0

3

_H= 6.1 Hz, J_HH= 1.8 Hz, J_HH= 1.2 Hz, 1H, 3⁰-H), 5.97 (ddd, J_{2 -H,3 -H}

=

0

3H, CH₃), 0.90 (s, 9H, t-Bu), 3.66 (dd, ²J_5-Ha,5-Hb= 10.3 Hz, ³J_5-Ha,4-H

=

6.1 Hz, J_HH= 2.2 Hz, J_HH= 1.1 Hz, 1H, 2⁰-H), 6.98ꢀ7.11 (m, 3H, 2-H,

4-H, and 6-H), 7.30ꢀ7.32 (m, 1H, 5-H); ¹³C NMR (100.6 MHz,

CDCl₃) δ ꢀ5.4 (CH₃), 18.4 (C(CH₃)₃), 25.9 (C(CH₃)₃), 63.0 (CH₂-

5⁰), 87.2 (d, ⁴J_CF= 1.8 Hz, CH-1⁰), 87.3 (CH-4⁰), 113.8 (d, ²J_CF= 21.7

Hz, CH-2), 114.8 (d, ²J_CF= 21.2 Hz, CH-4), 122.4 (d, ⁴J_CF= 2.9 Hz,

5.7 Hz, 1H, 5-Ha), 3.77 (dd, ²J_5-Hb,5-Ha= 10.3 Hz, ³J_5-Hb,4-H= 4.6 Hz,

1H, 5-Hb), 5.02ꢀ5.07 (m, 1H, 4-H), 5.78ꢀ5.80 (m, 1H, 1-H), 5.92

(ddd, ³J_3-H,2-H= 6.1 Hz, J_HH= 2.1 Hz, J_HH= 1.4 Hz, 1H, 3-H), 5.97 (ddd,

³J_2-H,3-H= 6.1 Hz, J_HH= 2.2 Hz, J_HH= 1.5 Hz, 1H, 2-H), 7.22ꢀ7.36 (m,

7795

dx.doi.org/10.1021/jo201110z |J. Org. Chem. 2011, 76, 7781–7803

The Journal of Organic Chemistry

ARTICLE

CH-6), 129.5 (CH-2⁰), 130.0 (d, ³J_CF= 8.1 Hz, CH-5), 130.2 (CH-3⁰),

IR (NaCl, neat) ν 3406 (s, OH), 2868 (s), 1493 (m), 1454 (m), 1065

(s) cm^ꢀ1; MS (CI) m/z (%) 177 ([M + H⁺], 95), 159 ([M + H⁺] ꢀ

H₂O, 100); HRMS (CI) 177.0917 [C₁₁H₁₃O₂(M + H⁺) requires

177.0916]. Anal. Calcd for C₁₁H₁₂O₂: C, 74.98; H, 6.86. Found: C,

74.82; H, 6.96.

3

1

144.4 (d, J_CF= 6.6 Hz, C-1), 163.0 (d, J_CF= 246.3 Hz, CF-3); ¹⁹F

NMR (376.5 MHz, CDCl₃) δ ꢀ113.3; IR (NaCl, neat) ν 2954 (s), 2931

(s), 2858 (s), 1742 (m), 1592 (m), 1258 (s) cm ;

^{ꢀ1 66}MS (CI) m/z (%)

309 ([M + H⁺], 100); HRMS (CI) 309.1687 [C₁₇H₂₆FO₂Si (M + H⁺)

requires 309.1686].

(ꢀ)-2⁰,3⁰-Didehydro-1⁰,2⁰,3⁰-trideoxy-1⁰-(3-fluorophenyl)-

α-^D-ribofuranose (24b). Silane 20b (178 mg, 0.57 mmol) was

deprotected using general procedure D to obtain alcohol 24b (97 mg,

88%): [α]_Dꢀ236.8 (c 1.90, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ

General Procedure D: Removal of the TBS Group. Complex

Et₃N 3HF (1.0 mL, 6.1 mmol) was added to a solution of silane 19ꢀ22

3

(1.52 mmol) in THF (10 mL), and the reaction mixture was stirred at

20 ꢀC overnight and then evaporated. Gradient chromatography on a

column of silica gel (3 ꢁ 10 cm) with a mixture of hexanes and ethyl

acetate (95:5 to 67:33) gave alcohol 23ꢀ26 as a colorless oil.

2.05 (bs, 1H, OH), 3.65 (dd, ²J_{5 -Ha,5 -Hb}= 11.7 Hz, ³J_{5 -Ha,4 -H}= 5.2 Hz,

0

1H, 5⁰-Ha), 3.81 (dd, J_{5 -Hb,5 -Ha}= 11.7 Hz, ³J_{5 -Hb,4 -H}= 3.2 Hz, 1H, 5⁰-

2

0

3

Hb), 5.14ꢀ5.18 (m, 1H, 4⁰-H), 5.85 (ddd, J_{1 -H,F}= 5.8 Hz, J_HH= 2.1

0

3

Hz, J_HH= 2.1 Hz, 1H, 1⁰-H), 5.92 (ddd, J_{2 -H,3 -H}= 6.1 Hz, J_HH= 2.3 Hz,

(+)-2⁰,3⁰-Didehydro-1⁰,2⁰,3⁰-trideoxy-1⁰-phenyl-β-D-ribo-

furanose (23a). Silane 19a (203 mg, 0.70 mmol) was deprotected

using general procedure D to obtain alcohol 23a (84 mg, 68%): [α]_D

0

3

J_HH= 1.5 Hz, 1H, 2⁰-H), 6.00 (ddd, J_{3 -H,2 -H}= 6.1 Hz, J_HH= 2.2 Hz, J_HH

= 1.6 Hz, 1H, 3⁰-H), 6.95ꢀ7.13 (m, 3H, 2-H, 4-H, and 6-H), 7.31 (ddd,

0

3

4

³J_HH= 7.9 Hz, J_HH= 7.7 Hz, J_5-H,F= 5.8 Hz, 1H, 5-H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 65.0 (CH₂-5⁰), 87.4 (d, ⁴J_CF= 1.8 Hz, CH-1⁰),

87.5 (CH-4⁰), 113.1 (d, ²J_CF= 21.9 Hz, CH-2), 114.7 (d, ²J_CF= 21.3 Hz,

1

+77.5 (c 1.28, CHCl₃); H NMR (400.1 MHz, CDCl₃) δ 1.96 (t,

2

³J_5-OH,5-H= 6.0 Hz, 1H, 5-OH), 3.67 (ddd, J_5-Ha,5-Hb= 11.6 Hz,

³J_5-Ha,5-OH= 6.1 Hz, ³J_5-Ha,4-H= 5.2 Hz, 1H, 5-Ha), 3.78 (ddd, ²J_5-Hb,5-Ha

=

CH-4), 121.8 (d, ⁴J_CF= 2.9 Hz, CH-6), 126.9 (CH-2⁰), 130.1 (d, ³J_CF

=

11.6 Hz, ³J_5-Hb,5-OH= 5.9 Hz, ³J_5-Hb,4-H= 3.3 Hz, 1H, 5-Hb), 5.00ꢀ5.03

8.1 Hz, CH-5), 131.8 (CH-3⁰), 144.1 (d, ³J_CF= 6.4 Hz, C-1), 163.0 (d,

¹J_CF= 246.3 Hz, CF-3); ¹⁹F NMR (376.5 MHz, CDCl₃) δ ꢀ113.3; IR

(NaCl, neat) ν 3405 (s, OH), 2928 (m), 2874 (m), 1615 (s), 1592 (s),

1488 (s), 1449 (s), 1264 (s) cm^ꢀ1; MS (CI) m/z (%) 195 ([M + H⁺],

15), 177 ([M + H⁺] ꢀ H₂O, 100); HRMS (CI) 195.0816 [C₁₁H₁₂FO₂

(M + H⁺) requires 195.0821].

3

(m, 1H, 4-H), 5.80ꢀ5.82 (m, 1H, 1-H), 5.94 (ddd, J_3-H,2-H

=

6.1 Hz, J_HH= 2.4 Hz, J_HH= 1.4 Hz, 1H, 3-H), 6.00 (ddd, ³J_2-H,3-H

6.1 Hz, J_HH= 2.2 Hz, J_HH= 1.5 Hz, 1H, 2-H), 7.29ꢀ7.38 (m, 5H,

H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ 65.0 (CH₂-5), 87.2 (CH-

4), 87.9 (CH-1), 127.0 (CH-arom), 127.7 (CH-3), 128.1 (CH-arom),

128.6 (CH-arom), 131.5 (CH-2), 141.1 (C-arom); IR (NaCl, neat) ν

3365 (m, OH), 2929 (m), 2858 (m), 2360 (s), 1454 (m) cm^ꢀ1; MS

(CI) m/z (%) 177 ([M + H⁺], 80), 159 ([M + H⁺] ꢀ H₂O, 100);

HRMS (CI) 177.0918 [C₁₁H₁₃O₂(M + H⁺) requires 177.0916].

(+)-2⁰,3⁰-Didehydro-1⁰,2⁰,3⁰-trideoxy-1⁰-(3-fluorophenyl)-

β-^D-ribofuranose (23b). Silane 19b (459 mg, 1.49 mmol) was

deprotected using general procedure D to obtain alcohol 23b (176 mg,

61%): [α]_D+64.2 (c 1.90, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ

(+)-2⁰,3⁰-Didehydro-1⁰,2⁰,3⁰-trideoxy-1⁰-phenyl-α-L-ribo-

furanose (25a). Silane 21a (463 mg, 1.59 mmol) was deprotected

using general procedure D to obtain alcohol 25a (199 mg, 71%): [α]_D

+334.6 (c 1.79, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 2.42 (s, 1H,

OH), 3.59 (dd, ²J_{5 -Ha,5 -Hb}= 11.7 Hz, ³J_{5 -Ha,4 -H}= 5.2 Hz, 1H, 5⁰-Ha),

0

3.74 (dd, ²J_{5 -Hb,5 -Ha}= 11.7 Hz, ³J_{5 -Hb,4 -H}= 3.2 Hz, 1H, 5⁰-Hb), 5.10

0

4

(m, 1H, 4⁰-H), 5.81 (ddd, J_{1 -H,4 -H}= 5.7 Hz, J_HH= 2.3 Hz, J_HH= 1.6

0

3

Hz, 1H, 1⁰-H), 5.85 (ddd, J_{3 -H,2 -H}= 6.1 Hz, J_HH= 2.3 Hz, J_HH= 1.6

2.19 (bs, 1H, OH), 3.66 (dd, ²J_{5 -Ha,5 -Hb}= 11.8 Hz, ³J_{5 -Ha,4 -H}= 5.2 Hz,

0

3

Hz, 1H, 3⁰-H), 5.95 (ddd, J_{2 -H,3 -H}= 6.1 Hz, J_HH= 2.3 Hz, J_HH= 1.6

Hz, 1H, 2⁰-H), 7.24ꢀ7.33 (m, 5H, H-arom); ¹³C NMR (100.6 MHz,

CDCl₃) δ 65.0 (CH₂-5⁰), 87.4 (CH-4⁰), 88.0 (CH-1⁰), 126.3 (CH-

arom), 126.5 (CH-3⁰), 128.0, and 128.5 (CH-arom), 132.2 (CH-2⁰),

141.3 (C-arom); IR (NaCl, neat) ν 3406 (s, OH), 2868 (s), 1493 (m),

1454 (m), 1065 (s) cm^ꢀ1; MS (CI) m/z (%) 177 ([M + H⁺], 95), 159

([M + H⁺] ꢀ H₂O, 100); HRMS (CI) 177.0918 [C₁₁H₁₃O₂(M + H⁺)

requires 177.0916]. Anal. Calcd for C₁₁H₁₂O₂: C, 74.98; H, 6.86.

Found: C, 74.73; H, 6.95.

1H, 5⁰-Ha), 3.78 (dd, J_{5 -Hb,5 -Ha}= 11.8 Hz, ³J_{5 -Hb,4 -H}= 3.4 Hz, 1H, 5⁰-

2

0

3

Hb), 4.98ꢀ5.02 (m, 1H, 4⁰-H), 5.78 (d, J_{1 -H,F}= 5.9 Hz, 1H, 1⁰-H),

0

5.93 (ddd, ³J_{2 -H,3 -H}= 6.1 Hz, J_HH= 2.1 Hz, J_HH= 1.1 Hz, 1H, 2⁰-H),

0

5.96 (ddd, ³J_{3 -H,2 -H}= 6.1 Hz, J_HH= 2.1 Hz, J_HH= 1.2 Hz, 1H, 3⁰-H),

0

3

4

6.99 (dddd, J_4-H,F= 8.4 Hz, J_4-H,5-H= 8.0 Hz, J_4-H,2-H= 2.6 Hz,

⁴J_4-H,6-H= 1.0 Hz, 1H, 4-H), 7.07 (ddd, ³J_2-H,F= 9.7 Hz, ⁴J_2-H,4-H= 2.6 Hz,

⁴J_2-H,6-H= 1.6 Hz, 1H, 2-H), 7.12 (dddd, ³J_6-H,5-H= 7.7 Hz, ⁴J_6-H,2-H

1.6 Hz, ⁴J_6-H,4-H= 1.0 Hz, ⁵J_6-H,F= 0.5 Hz, 1H, 6-H), 7.32 (ddd, ³J_5-H,4-H

=

3

4

8.0 Hz, J_5-H,6-H= 7.7 Hz, J_5-H,F= 5.8 Hz, 1H, 5-H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 65.0 (CH₂-5⁰), 87.2 (d, ⁴J_CF= 1.8 Hz, CH-1⁰),

87.4 (CH-4⁰), 113.8 (d, ²J_CF= 21.8 Hz, CH-2), 115.0 (d, ²J_CF= 21.2

Hz, CH-4), 122.4 (d, ⁴J_CF= 2.9 Hz, CH-6), 127.9 (CH-2⁰), 130.1 (d,

(+)-2⁰,3⁰-Didehydro-1⁰,2⁰,3⁰-trideoxy-1⁰-(3-fluorophenyl)-

α-^L-ribofuranose (25b). Silane 21b (455 mg, 1.48 mmol) was

deprotected using general procedure D to obtain alcohol 25b (218

mg, 76%): [α]_D+288.2 (c 2.04, CHCl₃₂); ¹H NMR (400.1 MHz,

3

³J_CF= 8.1 Hz, CH-5), 131.2 (CH-3⁰), 143.8 (d, J_CF= 6.5 Hz, C-1),

3

163.0 (d, ¹J_CF= 246.5 Hz, CF-3); ¹⁹F NMR (376.5 MHz, CDCl₃) δ ꢀ

113.1; IR (NaCl, neat) ν 3406 (s, OH), 2929 (m), 2870 (m), 1615

(s), 1592 (s), 1488 (s), 1449 (s), 1263 (s) cm^ꢀ1; MS (CI) m/z (%) 195

([M + H⁺], 30), 177 ([M + H⁺] ꢀ H₂O, 100); HRMS (CI) 195.0819

[C₁₁H₁₂FO₂(M + H⁺) requires 195.0821]. Anal. Calcd for

C₁₁H₁₁FO₂: C, 68.03; H, 5.71. Found: C, 68.23; H, 5.72.

0

CDCl₃) δ 2.05 (bs, 1H, OH), 3.65 (dd, J_{5 -Ha,5 -Hb}= 11.7 Hz, J_{5 -}

2

_{Ha,4 -H}= 5.2 Hz, 1H, 5⁰-Ha), 3.81 (dd, J_{5 -Hb,5 -Ha}= 11.7 Hz, ³J_{5 -Hb,4 -H}

=

0

3

3.2 Hz, 1H, 5⁰-Hb), 5.14ꢀ5.18 (m, 1H, 4⁰-H), 5.85 (ddd, J_{1 -H,F}= 5.8

0

3

Hz, J_HH= 2.1 Hz, J_HH= 2.1 Hz, 1H, 1⁰-H), 5.92 (ddd, J_{2 -H,3 -H}= 6.1 Hz,

0

3

J_HH= 2.3 Hz, J_HH= 1.5 Hz, 1H, 2⁰-H), 6.00 (ddd, J_{3 -H,2 -H}= 6.1 Hz, J_HH

= 2.2 Hz, J_HH= 1.6 Hz, 1H, 3⁰-H), 6.95ꢀ7.13 (m, 3H, 2-H, 4-H, and

0

3

4

(ꢀ)-2⁰,3⁰-Didehydro-1⁰,2⁰,3⁰-trideoxy-1⁰-phenyl-α-D-ribo-

furanose (24a). Silane 20a (441 mg, 1.52 mmol) was deprotected

using general procedure D to obtain alcohol 24a (176 mg, 66%): [α]_Dꢀ

332.4 (c 1.71, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 2.42 (s, 1H,

6-H), 7.31 (ddd, J_HH= 7.9 Hz, J_HH= 7.7 Hz, J_5-H,F= 5.8 Hz, 1H,

5-H); ¹³C NMR (100.6 MHz, CDCl₃) δ 65.0 (CH₂-5⁰), 87.4 (d, ⁴J_CF

=

1.8 Hz, CH-1⁰), 87.5 (CH-4⁰), 113.1 (d, ²J_CF= 21.9 Hz, CH-2), 114.7 (d,

²J_CF= 21.3 Hz, CH-4), 121.8 (d, ⁴J_CF= 2.9 Hz, CH-6), 126.9 (CH-2⁰),

130.1 (d, ³J_CF= 8.1 Hz, CH-5), 131.8 (CH-3⁰), 144.1 (d, ³J_CF= 6.4 Hz,

C-1), 163.0 (d, ¹J_CF= 246.3 Hz, CF-3); ¹⁹F NMR (376.5 MHz, CDCl₃)

δ ꢀ113.3; IR (NaCl, neat) ν 3405 (s, OH), 2928 (m), 2874 (m), 1615

(s), 1592 (s), 1488 (s), 1449 (s), 1264 (s) cm^ꢀ1; MS (CI) m/z (%) 195

([M + H⁺], 40), 177 ([M + H⁺] ꢀ H₂O, 100); HRMS (CI) 195.0824

[C₁₁H₁₂FO₂(M + H⁺) requires 195.0821].

OH), 3.59 (dd, ²J_{5 -Ha,5 -Hb}= 11.7 Hz, ³J_{5 -Ha,4 -H}= 5.2 Hz, 1H, 5⁰-Ha),

0

3.74 (dd, ²J_{5 -Hb,5 -Ha}= 11.7 Hz, ³J_{5 -Hb,4 -H}= 3.2 Hz, 1H, 5⁰-Hb), 5.10

0

4

(m, 1H, 4⁰-H), 5.81 (ddd, J_{1 -H,4 -H}= 5.7 Hz, J_HH= 2.3 Hz, J_HH= 1.6 Hz,

0

3

1H, 1⁰-H), 5.85 (ddd, J_{3 -H,2 -H}= 6.1 Hz, J_HH= 2.3 Hz, J_HH= 1.6 Hz, 1H,

0

3

3⁰-H), 5.95 (ddd, J_{2 -H,3 -H}= 6.1 Hz, J_HH= 2.3 Hz, J_HH= 1.6 Hz, 1H, 2⁰-

H), 7.24ꢀ7.33 (m, 5H, H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ

65.0 (CH₂-5⁰), 87.4 (CH-4⁰), 88.0 (CH-1⁰), 126.3 (CH-arom), 126.5

(CH-3⁰), 128.0, and 128.5 (CH-arom), 132.2 (CH-2⁰), 141.3 (C-arom);

0

(ꢀ)-2⁰,3⁰-Didehydro-1⁰,2⁰,3⁰-trideoxy-1⁰-phenyl-β-L-ribo-

furanose (26a). Silane 22a (254 mg, 0.87 mmol) was deprotected

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The Journal of Organic Chemistry

ARTICLE

using general procedure D to obtain alcohol 26a (82 mg, 54%): [α]_D

afford silane 27a as a colorless oil (83 mg, 24%): [α]_Dꢀ10.2 (c 0.74,

CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.10 (s, 3H, CH₃), 0.11 (s,

1

ꢀ78.8 (c 1.32, CHCl₃); H NMR (400.1 MHz, CDCl₃) δ 1.96 (t,

2

³J_5-OH,5-H= 6.0 Hz, 1H, 5-OH), 3.67 (ddd, J_5-Ha,5-Hb= 11.6 Hz,

3H, CH₃), 0.92 (s, 9H, t-Bu), 3.28 (bs, 2H, OH), 3.85 (dd, ²J_{5 -Ha,5 -Hb}

=

0

³J_5-Ha,5-OH= 6.1 Hz, ³J_5-Ha,4-H= 5.2 Hz, 1H, 5-Ha), 3.78 (ddd, ²J_5-Hb,5-Ha

=

2

10.8 Hz, ³J_{5 -Ha,4 -H}= 4.3 Hz, 1H, 5⁰-Ha), 3.89 (dd, J_{5 -Hb,5 -Ha}= 10.8 Hz,

0

11.6 Hz, ³J_5-Hb,5-OH= 5.9 Hz, ³J_5-Hb,4-H= 3.3 Hz, 1H, 5-Hb), 5.00ꢀ

5.03 (m, 1H, 4-H), 5.80ꢀ5.82 (m, 1H, 1-H), 5.94 (ddd, ³J_3-H,2-H= 6.1

Hz, J_HH= 2.4 Hz, J_HH= 1.4 Hz, 1H, 3-H), 6.00 (ddd, ³J_2-H,3-H= 6.1 Hz,

J_HH= 2.2 Hz, J_HH= 1.5 Hz, 1H, 2-H), 7.29ꢀ7.38 (m, 5H, H-arom);

¹³C NMR (100.6 MHz, CDCl₃) δ 65.0 (CH₂-5), 87.2 (CH-4), 87.9

(CH-1), 127.0 (CH-arom), 127.7 (CH-3), 128.1 (CH-arom), 128.6

(CH-arom), 131.5 (CH-2), 141.1 (C-arom); IR (NaCl, neat) ν

3365 (m, OH), 2929 (m), 2858 (m), 2360 (s), 1454 (m) cm^ꢀ1; MS

(CI) m/z (%) 177 ([M + H⁺], 80), 159 ([M + H⁺] ꢀ H₂O, 100);

HRMS (CI) 177.0918 [C₁₁H₁₃O₂(M + H⁺) requires 177.0916]. Anal.

Calcd for C₁₁H₁₂O₂: C, 74.98; H, 6.86. Found: C, 74.59; H, 6.82.

(ꢀ)-2⁰,3⁰-Didehydro-1⁰,2⁰,3⁰-trideoxy-1⁰-(3-fluorophenyl)-

β-^L-ribofuranose (26b). Silane 22b (100 mg, 0.32 mmol) was

deprotected using general procedure D to obtain alcohol 26b (42 mg,

67%): [α]_Dꢀ63.4 (c 1.90, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ

J_{5 -Hb,4 -H}= 3.4 Hz, 1H, 5⁰-Hb), 4.00 (dd, J_{2 -H,1 -H}= 6.4 Hz, ³J_{2 -H,3 -H}

3

0

= 5.5 Hz, 1H, 2⁰-H), 4.06 (dd, J_{4 -H,5 -Ha}= 4.3 Hz, ³J_{4 -H,5 -Hb}= 3.4 Hz,

3

0

3

1H, 4⁰-H), 4.21 (dd, J_{3 -H,2 -H}= 5.5 Hz, J_HH= 4.0 Hz, 1H, 3⁰-H), 4.76 (d,

0

3

J_{1 -H,2 -H}= 6.4 Hz, 1H, 1⁰-H), 7.28ꢀ7.37 (m, 3H, H-arom), 7.42ꢀ7.44

(m, 2H, H-arom); NMR (100.6 MHz, CDCl₃) δ ꢀ5.53 (CH₃), ꢀ5.4

(CH₃), 18.3 (C(CH₃)₃), 25.9 (C(CH₃)₃), 63.7 (CH₂-5⁰), 72.8 (CH-3⁰),

78.0 (CH-2⁰), 84.2 (CH-4⁰), 84.3 (CH-1⁰), 126.1, 127.8, and 128.4 (CH-

arom), 140.0 (C-arom); IR (NaCl, neat) ν 3421, 2929 (s), 2858 (s),

2360 (s), 1255 (s) cm^ꢀ1; MS (CI) m/z (%) 325 ([M + H⁺], 100);

HRMS (CI) 325.1837 [C₁₇H₂₉O₄Si (M + H⁺) requires 325.1835].

Method 2. Dihydroxylation of alkene 19a (207 mg, 0.713 mmol)

with OsO₄(general Procedure E) aﬀorded a mixture of diastereoiso-

meric diols, which was separated by column chromatography to furnish

ﬁrst diol 31 (32 mg, 14%) as a yellowish oil, followed by diol 27a (86 mg,

80%) as a colorless oil, whose spectra data were identical to those of the

0

2.22 (bs, 1H, OH), 3.64 (dd, ²J_{5 -Ha,5 -Hb}= 11.8 Hz, ³J_{5 -Ha,4 -H}= 5.2 Hz,

1

0

product obtained by Method 1. 31: [α]_D+33.2 (c 0.30, MeOH); H

1H, 5⁰-Ha), 3.75 (dd, J_{5 -Hb,5 -Ha}= 11.8 Hz, ³J_{5 -Hb,4 -H}= 3.4 Hz, 1H, 5⁰-

2

0

NMR (600.1 MHz, CDCl₃): 0.15 and 0.16 (2 ꢁ s, 2 ꢁ 3H, CH₃Si); 0.91

3

Hb), 4.95ꢀ5.00 (m, 1H, 4⁰-H), 5.76 (d, J_{1 -H,F}= 5.9 Hz, 1H, 1⁰-H), 5.91

0

(s, 9H, (CH₃)₃C); 3.04 (d, 1H, J_OH,3= 9.4, OH-3); 3.58 (d, 1H, J_OH,2

=

(ddd, ³J_{2 -H,3 -H}= 6.1 Hz, J_HH= 2.1 Hz, J_HH= 1.1 Hz, 1H, 2⁰-H), 5.95

0

11.2, OH-2); 3.89 (dd, 1H, J_gem= 11.1, J_5b,4= 1.7, H-5b); 3.97 (dd, 1H,

J_gem= 11.1, J_5a,4= 3.1, H-5a); 4.10 (ddd, 1H, J_2,OH= 11.2, J_2,3= 4.8, J_2,1

(ddd, ³J_{3 -H,2 -H}= 6.1 Hz, J_HH= 2.1 Hz, J_HH= 1.2 Hz, 1H, 3⁰-H), 6.96

0

=

(dddd, ³J_4-H,F= 8.4 Hz, ³J_4-H,5-H= 8.0 Hz, ⁴J_4-H,2-H= 2.6 Hz, ⁴J_4-H,6-H

=

3.3, H-2); 4.23 (ddd, 1H, J_4,3= 8.1, J_4,5= 3.1, 1.7, H-4); 4.66 (ddd, 1H,

J_3,OH= 9.4, J_3,4= 8.1, J_3,2= 4.8, H-3); 4.91 (d, 1H, J_1,2= 3.3, H-1); 7.26 (m,

1H, H-p-Ph); 7.33 (m, 2H, H-m-Ph); 7.36 (m, 2H, H-o-Ph). ¹³C NMR

(150.9 MHz, CDCl₃): ꢀ5.7 and ꢀ5.6 (CH₃Si); 18.2 (C(CH₃)₃); 25.8

((CH₃)₃C); 62.4 (CH₂-5); 73.3 (CH-2); 74.4 (CH-3); 78.6 (CH-4);

81.3 (CH-1); 126.5 (CH-o-Ph); 127.6 (CH-p-Ph); 128.0 (CH-m-Ph);

136.9 (C-i-Ph); HRMS (ESI) 325.1831 [C₁₇H₂₉O₄Si (M + H) requires

325.1830]; IR (CCl₄) ν 3549, 3379, 3090, 3067, 3032, 2957, 1606, 1497,

1471, 1461, 1453, 1406, 1392, 1363, 1316, 1259, 1208, 1167, 1142, 1128,

1110, 1080, 1030, 939, 909, 839, 726, 697, 673 cm^ꢀ1; HRMS (ESI)

347.1647 [C₁₇H₂₈O₄NaSi: (M + Na) requires 347.1649].

1.0 Hz, 1H, 4-H), 7.05 (ddd, ³J_2-H,F= 9.7 Hz, ⁴J_2-H,4-H= 2.6 Hz, ⁴J_2-H,6-H

= 1.6 Hz, 1H, 2-H), 7.11 (dddd, ³J_6-H,5-H= 7.7 Hz, ⁴J_6-H,2-H= 1.6 Hz,

⁴J_6-H,4-H= 1.0 Hz, ⁵J_6-H,F= 0.5 Hz, 1H, 6-H), 7.29 (ddd, ³J_5-H,4-H= 8.0 Hz,

³J_5-H,6-H= 7.7 Hz, ⁴J_5-H,F= 5.8 Hz, 1H, 5-H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 65.0 (CH₂-5⁰), 87.2 (d, ⁴J_CF= 1.8 Hz, CH-1⁰), 87.4 (CH-4⁰),

113.8 (d, ²J_CF= 21.8 Hz, CH-2), 115.0 (d, ²J_CF= 21.2 Hz, CH-4), 122.4

(d, ⁴J_CF= 2.9 Hz, CH-6), 127.9 (CH-2⁰), 130.1 (d, ³J_CF= 8.1 Hz, CH-5),

131.2 (CH-3⁰), 143.8 (d, ³J_CF= 6.5 Hz, C-1), 163.0 (d, ¹J_CF= 246.5 Hz,

CF-3); ¹⁹F NMR (376.5 MHz, CDCl₃) δ ꢀ113.1; IR (NaCl, neat) ν

3406 (s, OH), 2929 (m), 2870 (m), 1615 (s), 1592 (s), 1488 (s), 1449

(s), 1263 (s) cm^ꢀ1, MS (CI) m/z (%) 195 ([M + H⁺], 30), 177 ([M +

H⁺] ꢀ H₂O, 100); HRMS (CI) 195.0820 [C₁₁H₁₂FO₂(M + H⁺)

requires 195.0821]. Anal. Calcd for C₁₁H₁₁FO₂: C, 68.03; H, 5.71.

Found: C, 68.19; H, 5.77.

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-1⁰-deoxy-1⁰-(3-fluorop-

henyl)-β-^D-ribofuranose (27b). Silane 19b (313 mg, 1.01 mmol)

was dissolved in a mixture of ethyl acetate (5 mL) and acetonitrile

(5 mL) and cooled to 0 ꢀC, and a cold (0 ꢀC) solution of RuCl₃H₂O

3

General Procedure E: OsO₄-Catalyzed Dihydroxylation. A

solution of OsO₄(0.01 mmol) in water (0.127 mL) [prepared as a stock

solution of OsO₄(100 mg) in water (5 mL)] was added to a solution of

the respective alkene 19a or 22a (1 mmol, 290.5 mg) in a mixture of

acetone (2.3 mL), water (0.2 mL), and an aqueous solution of

4-methylmorpholine 4-oxide (NMO) (1.3 mmol, 0.274 mL of a 50%

solution in water), and the resulting solution was stirred at room

temperature overnight. The solution was then evaporated at reduced

pressure, and the residue was chromatographed on a column of silica gel

(3 ꢁ 20 cm) with a mixture of chloroform and methanol (50:1) to afford

the corresponding silanes.

(30 mg, 0.12 mmol) and NaIO₄(320 mg, 1.50 mmol) in water (4 mL)

was added in one portion. After 45 s, the reaction was quenched with a

50% aqueous solution of Na₂S₂O₃(15 mL). The aqueous layer was

separated and extracted with ethyl acetate (3 ꢁ 50 mL). The combined

organic phase was dried (Na₂SO₄), evaporated, and chromatographed

on a column of silica gel (3 ꢁ 10 cm) with a mixture of hexanes and

ethyl acetate (80:20) to afford diol 27b as a colorless oil (211 mg, 61%):

[α]_Dꢀ16.7 (c 1.20, CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.10 (s,

3H, CH₃), 0.11 (s, 3H, CH₃), 0.91 (s, 9H, t-Bu), 2.56 (bs, 2H, OH), 3.86

(dd, ²J_{5 -Ha,5 -Hb}= 10.8 Hz, ³J_{5 -Ha,4 -H}= 4.0 Hz, 1H, 5⁰-Ha), 3.89 (dd,

0

2

J_{5 -Hb,5 -Ha}= 10.8 Hz, ³J_{5 -Hb,4 -H}= 3.2 Hz, 1H, 5⁰-Hb), 3.97ꢀ4.01 (m,

0

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-1⁰-phenyl-β-D-ribofura-

nose (27a). Method 1. Grubbs first-generation catalyst C1 (42.4 mg,

0.051 mmol) was added to a solution of silane (2S,1⁰R)-15a (328 mg,

1.03 mmol) in dichloromethane (20 mL) under a stream of argon

atmosphere, and the mixture was stirred at 40 ꢀC for 3 h, and then

evaporated. The resulting residue was dissolved in a mixture of ethyl

acetate (5 mL) and acetonitrile (5 mL), cooled to 0 ꢀC, and a cold (0 ꢀC)

1H, 2⁰-H), 4.08 (dd, J_{4 -H,5 -Ha}= 4.0 Hz, ³J_{4 -H,5 -Hb}= 3.2 Hz, 1H, 4⁰-H),

3

0

3

4.22ꢀ4.25 (m, 1H, 3⁰-H), 4.76 (d, J_{1 -H,2 -H}= 6.5 Hz, 1H, 1⁰-H), 6.97

(dddd, ³J_4-H,F= 8.4 Hz, J_HH= 8.3 Hz, J_HH= 2.2 Hz, J_HH= 1.5 Hz, 1H,

4-H), 7.11ꢀ7.16 (m, 1H, 2-H), 7.18ꢀ7.21 (m, 1H, 6-H), 7.27ꢀ7.33 (m,

1H, 5-H); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.6 (CH₃), ꢀ5.4 (CH₃),

18.3 (C(CH₃)₃), 25.9 (C(CH₃)₃), 63.6 (CH₂-5⁰), 72.8 (CH-3⁰), 78.1

0

(CH-2⁰), 83.6 (d, ⁴J_CF= 1.9 Hz, CH-1⁰), 84.4 (CH-4⁰), 112.8 (d, ²J_CF

=

22.3 Hz, CH-2), 114.6 (d, ²J_CF= 21.2 Hz, CH-4), 121.6 (d, ⁴J_CF= 2.9

Hz, CH-6), 129.8 (d, ³J_CF= 8.2 Hz, CH-5), 143.9 (d, ³J_CF= 6.6 Hz, C-1),

solution of RuCl₃H₂O (30 mg, 0.12 mmol), and NaIO₄(357 mg, 1.67

3

mmol) in water (4 mL) was added in one portion. After 15 s, the reaction

was quenched with a 50% aqueous solution of Na₂S₂O₃(10 mL). The

aqueous layer was separated and extracted with ethyl acetate (3 ꢁ

50 mL). The combined organic phase was dried (Na₂SO₄) and

evaporated, and the residue was chromatographed on a column of silica

gel (3 ꢁ 10 cm) with a mixture of hexanes and ethyl acetate (80:20) to

163.0 (d, J_CF= 246.7 Hz, CF-3); ¹⁹F NMR (376.5 MHz, CDCl₃) δ

1

ꢀ113.6; IR (NaCl, neat) ν 3398 (s, OH), 2929 (s), 2858 (s), 1617 (s),

1592 (s) cm^ꢀ1; MS (CI) m/z (%) 343 ([M + H⁺], 100); HRMS (CI)

343.1740 [C₁₇H₂₈FO₄Si (M + H⁺) requires 343.1741]. Anal. Calcd for

C₁₇H₂₇FO₄Si: C, 59.62; H, 7.95. Found: C, 59.47; H, 8.06.

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The Journal of Organic Chemistry

ARTICLE

(+)-5⁰-O-(tert-Butyldimethylsilyl)-1⁰-deoxy-1⁰-phenyl-β-L-

ribofuranose (28a). Method 1. Silane 22a (337 mg, 1.16 mmol) was

dissolved in a mixture of ethyl acetate (5 mL) and acetonitrile (5 mL)

(CI) m/z (%) 343 ([M + H⁺], 100); HRMS (CI) 343.1740

[C₁₇H₂₈FO₄Si (M + H⁺) requires 343.1741]. Anal. Calcd for

C₁₇H₂₇FO₄Si: C, 59.62; H, 7.95. Found: C, 59.47; H, 8.06.

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-1⁰-(4-bromophenyl)-1⁰-

deoxy-β- ^L-ribofuranose (28c). Grubbs first-generation catalyst C1

(72.0 mg, 0.087 mmol) was added to a solution of silane (2R,1⁰S)-18c

(2.483 g, 6.25 mmol) in dichloromethane (60 mL) under a stream of

argon atmosphere, and the mixture was stirred at 40 ꢀC for 3 h and then

evaporated. The resulting residue was dissolved in a mixture of ethyl

acetate (30 mL) and acetonitrile (30 mL), cooled to 0 ꢀC, and

intensively stirred with mechanical overhead stirrer. A cold (0 ꢀC)

and cooled to 0 ꢀC, and a cold (0 ꢀC) solution of RuCl₃H₂O (30 mg,

3

0.12 mmol) and NaIO₄(400 mg, 1.87 mmol) in water (5 mL) was

added in one portion. After 15 s, the reaction was quenched with 50%

aqueous solution of Na₂S₂O₃(15 mL). The aqueous layer was

separated and extracted with ethyl acetate (3 ꢁ 50 mL). The combined

organic phase was dried (Na₂SO₄), evaporated, and the residue was

chromatographed on a column of silica gel (3 ꢁ 10 cm) with a mixture

of hexanes and ethyl acetate (80:20) to afford starting silane 22a (232

mg, 69% of starting mass), followed by diol 28a (colorless oil, 103 mg,

27%; 87% based on the recovered silane): [α]_D+10.8 (c 0.37, CHCl₃);

¹H NMR (400.1 MHz, CDCl₃) δ 0.10 (s, 3H, CH₃), 0.11 (s, 3H, CH₃),

solution of RuCl₃H₂O (166 mg, 0.67 mmol) and NaIO₄(1.656 g, 7.74

3

mmol) in water (25 mL) was added in one portion. After 15 s, the

reaction was quenched with a 50% aqueous solution of Na₂S₂O₃

(50 mL). The aqueous layer was separated and extracted with dichlor-

omethane (3 ꢁ 300 mL). The combined organic phase was dried

(Na₂SO₄) and evaporated. Chromatography on a column of silica gel

(3 ꢁ 10 cm) with a mixture of hexanes and ethyl acetate (80:20) gave diol

28c (colorless oil, 786 mg, 31%): [α]_Dꢀ35.1 (c 0.74, CHCl₃); ¹H NMR

(400.1 MHz, CDCl₃) δ 0.04 (s, 3H, CH₃), 0.05 (s, 3H, CH₃), 0.90 (s,

9H, t-Bu), 2.57 (bs, 2H, OH), 3.55ꢀ3.76 (m, 4H), 4.54ꢀ4.56 (m, 1H),

7.34 (d, ³J_2-H,3-H= 8.4 Hz, 2H, 2-H, and 6-H), 7.50 (d, ³J_3-H,2-H= 8.4 Hz,

2H, 3-H, and 5-H); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ5.42 (CH₃), ꢀ

5.40 (CH₃), 18.3 (C(CH₃)₃), 25.8 (C(CH₃)₃), 66.0 (CH₂-5⁰), 73.1

(CH-3⁰), 74.3 (CH-2⁰), 79.3 (CH-1⁰), 79.7 (CH-4⁰), 120.1 (C-4), 129.2

(CH-2, and CH-6), 131.6 (CH-3, and CH-5), 137.4 (C-1); IR (NaCl,

neat) ν 3420 (s, OH), 2954 (s), 2928 (s), 2857 (s), 1255 (s) cm^ꢀ1; MS

(CI) m/z (%) 403/405 ([M + H⁺], 100); HRMS (CI) 403.0916/

405.0774 [C₁₇H₂₈BrO₄Si (M + H⁺) requires 403.0940/405.0922].

(ꢀ)-1⁰-Deoxy-1⁰-phenyl-β-D-ribofuranose (29a).^58bMeth-

od 1. Following general procedure D, 27a (76 mg, 0.23 mmol) was

deprotected, and flash chromatography on a column of silica gel (3 ꢁ

10 cm) with ethyl acetate gave 29a (36 mg, 75%) as a white crystalline

solid: mp 112ꢀ113 ꢀC (ethyl acetate), (lit.^58bmp 121ꢀ122 ꢀC); [α]_Dꢀ

0.92 (s, 9H, t-Bu), 3.28 (bs, 2H, OH), 3.85 (dd, ²J_{5 -Ha,5 -Hb}= 10.8 Hz,

0

3

2

J_{5 -Ha,4 -H}= 4.3 Hz, 1H, 5⁰-Ha), 3.89 (dd, J_{5 -Hb,5 -Ha}= 10.8 Hz,

0

J_{5 -Hb,4 -H}= 3.4 Hz, 1H, 5⁰-Hb), 4.00 (dd, J_{2 -H,1 -H}= 6.4 Hz, ³J_{2 -H,3 -H}

=

3

0

5.5 Hz, 1H, 2⁰-H), 4.06 (dd, J_{4 -H,5 -Ha}= 4.3 Hz, ³J_{4 -H,5 -Hb}= 3.4 Hz,

3

0

3

1H, 4⁰-H), 4.21 (dd, J_{3 -H,2 -H}= 5.5 Hz, J_HH= 4.0 Hz, 1H, 3⁰-H), 4.76

0

3

(d, J_{1 -H,2 -H}= 6.4 Hz, 1H, 1⁰-H), 7.28ꢀ7.37 (m, 3H, H-arom),

7.42ꢀ7.44 (m, 2H, H-arom); ¹³C NMR (100.6 MHz, CDCl₃) δ ꢀ

5.53 (CH₃), ꢀ5.40 (CH₃), 18.31 (C(CH₃)₃), 25.90 (C(CH₃)₃),

63.71 (CH₂-5⁰), 72.75 (CH-3⁰), 77.97 (CH-2⁰), 84.15 (CH-4⁰), 84.33

(CH-1⁰), 126.05, 127.82, and 128.35 (CH-arom), 140.02 (C-arom);

0

IR (NaCl, neat) ν 3421, 2929 (s), 2858 (s), 2360 (s), 1255 (s) cm^ꢀ1

;

MS (CI) m/z (%) 325 ([M + H⁺], 100); HRMS (CI) 325.1836

[C₁₇H₂₉O₄Si (M + H⁺) requires 325.1835].

Mehtod 2. Dihydroxylation of alkene 22a (0.709 mmol, 206 mg) with

OsO₄(general procedure E) aﬀorded a mixture of diastereoisomeric

diols, which was separated by column chromatography to furnish ﬁrst

the diol 33 (30 mg, 13%) as a yellowish oil, followed by diol 28a (179

mg, 78%) as a colorless oil, whose spectra data were identical to those of

the product obtained by Method 1.

(ꢀ)-5⁰-O-(tert-Butyldimethylsilyl)-1⁰-deoxy-1⁰-(3-fluorop-

henyl)-β-^L-ribofuranose (28b). Grubbs first-generation catalyst C1

(71.0 mg, 0.090 mmol) was added to a solution of silane (2R,1⁰S)-18b

(1.951 g, 5.80 mmol) in dichloromethane (50 mL) under a stream of

argon atmosphere, and the mixture was stirred at 40 ꢀC for 3 h and then

evaporated. The resulting residue was dissolved in a mixture of ethyl

acetate (25 mL) and acetonitrile (25 mL), cooled to 0 ꢀC, and

intensively stirred with a mechanical overhead stirrer. A cold (0 ꢀC)

1

24.8 (c 0.44, MeOH); H NMR (400.1 MHz, CD₃OD) δ 3.73 (dd,

2

3

2

J_{5 -Ha,5 -Hb}= 12.1 Hz, J_{5 -Ha,4 -H}= 4.8 Hz, 1H, 5⁰-Ha), 3.79 (dd, J_{5 -}

0

_{Hb,5 -Ha}= 12.1 Hz, ³J_{5 -Hb,4 -H}= 3.9 Hz, 1H, 5⁰-Hb), 3.88 (dd, J_{2 -H,1 -H}

=

0

3

0

6.4 Hz, ³J_{2 -H,3 -H}= 5.8 Hz, 1H, 2⁰-H), 3.95 (ddd, J_{4 -H,3 -H}= 4.8 Hz, ³J_{4 -}

3

0

_{H,5 -Ha}= 4.8 Hz, ³J_{4 -H,5 -Hb}= 3.9 Hz, 1H, 4⁰-H), 4.03 (dd, J_{3 -H,2 -H}= 5.8

3

0

Hz, ³J_{3 -H,4 -H}= 4.8 Hz, 1H, 3⁰-H), 4.69 (d, J_{1 -H,2 -H}= 6.4 Hz, 1H, 1⁰-H),

3

0

5.28 (s, 3H, OH), 7.22ꢀ7.32 (m, 3H, H-arom), 7.36ꢀ7.39 (m, 2H,

13

H-arom); C NMR (100.6 MHz, CD₃OD) δ 62.7 (CH₂-5⁰), 71.5

solution of RuCl₃H₂O (140 mg, 0.60 mmol) and NaIO₄(1.430 g, 6.69

3

(CH-3⁰), 77.4 (CH-2⁰), 84.78 (CH-4⁰), 84.81 (CH-1⁰), 126.3, 128.1, and

128.6 (CH-arom), 140.0 (C-arom); MS (CI) m/z (%) 211 ([M + H⁺],

25), 193 ([M + H⁺] ꢀ H₂O, 100); HRMS (CI) 211.0973 [C₁₁H₁₅O₄

(M + H⁺) requires 211.0970]; consistent with the literature data.^58b

Method 2. Aqueous HCl (2M, 20 mL) was added to a solution of the

silyloxy derivative 27a (135 mg, 0.416 mmol) in toluene (10 mL), and

the resulting heterogeneous mixture was evaporated on a rotavap

(45 ꢀC, 20 mBar) to aﬀord a white solid, which was puriﬁed on a

column of reverse phase silica gel (HPFC) (C18HS 25+M, 2.5 ꢁ 15 cm)

using a gradient, starting with water and continuing with up to a mixture

of water and MeOH (80:20) to obtain nucleoside 29a (75 mg, 86%) as a

white powder, whose spectral data were identical to those obtained in

the previous experiment.

mmol) in water (20 mL) was added in one portion. After 15 s, the

reaction was quenched with a 50% aqueous solution of Na₂S₂O₃

(50 mL), and the aqueous layer was separated and extracted with ethyl

acetate (3 ꢁ 250 mL). The combined organic phase was dried

(Na₂SO₄), evaporated, and chromatographed on a column of silica gel

(3 cm ꢁ10 cm) with a mixture of hexanes and ethyl acetate (80:20) to

afford diol 28b as a colorless oil (667 mg, 34%): [α]_Dꢀ15.7 (c 1.15,

CHCl₃); ¹H NMR (400.1 MHz, CDCl₃) δ 0.10 (s, 3H, CH₃), 0.11 (s,

3H, CH₃), 0.91 (s, 9H, t-Bu), 2.56 (bs, 2H, OH), 3.86 (dd, ²J_{5 -Ha,5 -Hb}

=

0

2

10.8 Hz, ³J_{5 -Ha,4 -H}= 4.0 Hz, 1H, 5⁰-Ha), 3.89 (dd, J_{5 -Hb,5 -Ha}= 10.8 Hz,

0

3

J_{5 -Hb,4 -H}= 3.2 Hz, 1H, 5⁰-Hb), 3.97ꢀ4.01 (m, 1H, 2⁰-H), 4.08 (dd,

0

J_{4 -H,5 -Ha}= 4.0 Hz, ³J_{4 -H,5 -Hb}= 3.2 Hz, 1H, 4⁰-H), 4.22ꢀ4.25 (m, 1H,

3

0

3

3⁰-H), 4.76 (d, J_{1 -H,2 -H}= 6.5 Hz, 1H, 1⁰-H), 6.97 (dddd, J_4-H,F= 8.4 Hz,

0

(ꢀ)-1⁰-Deoxy-1⁰-(3-fluorophenyl)-β-D-ribofuranose (29b).

Following general procedure D, silane 27b (118 mg, 0.34 mmol) was

deprotected, and flash chromatography on a column of silica gel (3 ꢁ

10 cm) with ethyl acetate gave 29b (50 mg, 65%) as a white solid: mp

J

_HH= 8.3 Hz, J_HH= 2.2 Hz, J_HH= 1.5 Hz, 1H, 4-H), 7.11ꢀ7.16 (m, 1H,

2-H), 7.18ꢀ7.21 (m, 1H, 6-H), 7.27ꢀ7.33 (m, 1H, 5-H); ¹³C NMR

(100.6 MHz, CDCl₃) δ ꢀ5.6 (CH₃), ꢀ5.4 (CH₃), 18.3 (C(CH₃)₃),

25.9 (C(CH₃)₃), 63.6 (CH₂-5⁰), 72.8 (CH-3⁰), 78.1 (CH-2⁰), 83.6 (d,

⁴J_CF= 1.9 Hz, CH-1⁰), 84.4 (CH-4⁰), 112.8 (d, ²J_CF= 22.3 Hz, CH-2),

114.6 (d, ²J_CF= 21.2 Hz, CH-4), 121.6 (d, ⁴J_CF= 2.9 Hz, CH-6), 129.8

1

92ꢀ93 ꢀC (ethyl acetate); [α]_Dꢀ31.6 (c 0.35, MeOH); H NMR

(400.1 MHz, CD₃OD) δ 3.32ꢀ3.33 (bs, 3H, OH), 3.74 (dd, ²J_{5 -Ha,5 -Hb}

0

(d, ³J_CF= 8.2 Hz, CH-5), 143.9 (d, ³J_CF= 6.6 Hz, C-1), 163.0 (d, ¹J_CF

=

= 11.9 Hz, ³J_{5 -Ha,4 -H}= 4.7 Hz, 1H, 5⁰-Ha), 3.81 (dd, J_{5 -Hb,5 -Ha}= 11.9

2

0

246.7 Hz, CF-3); ¹⁹F NMR (376.5 MHz, CDCl₃) δ ꢀ113.6; IR (NaCl,

neat) ν 3398 (s, OH), 2929 (s), 2858 (s), 1617 (s), 1592 (s) cm^ꢀ1; MS

Hz, J_{5 -Hb,4 -H}= 3.7 Hz, 1H, 5⁰-Hb), 3.85 (dd, J_{2 -H,1 -H}= 6.8 Hz,

3

0

3

0

J_{2 -H,3 -H}= 5.7 Hz, 1H, 2 -H),4.00(ddd, J_{4 -H,5 -Ha}=4.7Hz, J_{4 -H,3 -H}=4.2Hz,

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The Journal of Organic Chemistry

ARTICLE

3

J_{4 -H,5 -Hb}= 3.7 Hz, 1H, 4⁰-H), 4.05 (ddd, J_{3 -H,2 -H}= 5.7 Hz, ³J_{3 -H,4 -H}

=

(+)-1⁰-Deoxy-1⁰-phenyl-β-D-lyxofuranose (32). Aqueous

HCl (2 M, 14 mL) was added to a solution of the silyloxy derivative

31 (87 mg, 0.268 mmol) in toluene (7 mL), and the resulting

heterogeneous mixture was evaporated on a rotavap (45 ꢀC, 20 mBar)

to afford a white solid, which was purified on a column of reverse phase

silica gel (HPFC) (C18HS 25+M, 2.5 ꢁ 15 cm) using a gradient,

starting with water and continuing with up to a mixture of water and

MeOH (80:20) to obtain nucleoside 32 (56 mg, 79%) as a white

powder: [α]_D+51.4 (c 0.23, MeOH); ¹H NMR (500 MHz, DMSO-d₆)

δ 3.59 (ddd, 1H, J_gem= 11.6, J_5b-H,OH= 4.9, J_5b-H,4-H= 4.6, H-5b), 3.67

(ddd, 1H, J_gem= 11.6, J_5a-H,OH= 5.4, J_5a-H,4-H= 3.8, H-5a), 3.97 (ddd,

1H, J_4-H,3-H= 7.1, J_4-H,5-H= 4.6, 3.8, H-4), 4.03 (ddd, 1H, J_2-H,OH= 7.6,

0

4

3

4.2 Hz, J_{3 -H,1 -H}= 0.5 Hz, 1H, 3⁰-H), 4.73 (dd, J_{1 -H,2 -H}= 6.8

0

4

3

Hz, J_{1 -H,3 -H}= 0.5 Hz, 1H, 1⁰-H), 6.99 (dddd, J_4-H,F= 9.0 Hz, J_4-

_H,5-H= 7.9 Hz, J_HH= 2.7 Hz, J_HH= 1.0 Hz, 1H, 4-H), 7.21ꢀ7.26 (m, 1H,

0

2-H, and 6-H), 7.33 (ddd, ³J_5-H,6-H= 8.0 Hz, ³J_5-H,4-H= 7.9 Hz, ⁴J_5-H,F

=

6.0 Hz, 1H, 5-H); ¹³C NMR (100.6 MHz, CDCl₃) δ 63.4 (CH₂-5⁰), 72.6

(CH-3⁰), 78.9 (CH-2⁰), 84.5 (d, ⁴J_CF= 1.6 Hz, CH-1⁰), 86.2 (CH-4⁰),

113.7 (d, ²J_CF= 22.4 Hz, CH-2), 115.1 (d, ²J_CF= 21.5 Hz, CH-4), 122.8

(d, ⁴J_CF= 2.7 Hz, CH-6), 130.7 (d, ³J_CF= 8.3 Hz, CH-5), 143.0 (d, ³J_CF

=

6.8 Hz, C-1), 164.3 (d, ¹J_CF= 244.3 Hz, CF-3); ¹⁹F NMR (376.5 MHz,

CDCl₃) δ ꢀ113.8, all in agreement with the literature data;⁶⁷MS (CI)

m/z (%) 229 ([M + H⁺], 55), 211 ([M + H⁺] ꢀ H₂O, 100) HRMS (CI)

229.0878 [C₁₁H₁₄FO₄(M + H⁺) requires 229.0876]. Anal. Calcd for

C₁₁H₁₃FO₄: C, 57.89; H, 5.74. Found: C, 57.61; H, 5.75.

J_2-H,3-H= 4.7, J_2-H,1-H= 4.2, H-2), 4.39 (ddd, 1H, J_3-H,4-H= 7.1, J_3-H,OH

=

5.5, J_3-H,2-H= 4.7, H-3), 4.73 (d, 1H, J_OH,2-H= 7.6, OH-2), 4.79 (d, 1H,

J_1-H,2-H= 4.2, H-1), 4.88 (d, 1H, J_OH,3-H= 5.5, OH-3), 4.99 (dd, 1H,

(+)-1⁰-Deoxy-1⁰-phenyl-β- L-ribofuranose (30a). Method 1.

Following general procedure D, silane 28a (77 mg, 0.24 mmol) was

deprotected and a flash chromatography on a column of silica gel (3 ꢁ

10 cm) with ethyl acetate gave 30a (36 mg, 72%) as a white crystalline

solid: mp 112ꢀ113 ꢀC (ethyl acetate), (lit.^58bgives mp 121ꢀ122 ꢀC for

the ^D-enantiomer); [α]_D+25.0 (c 0.48, MeOH); ¹H NMR (400.1 MHz,

J

_OH,5-H= 5.4, 4.9, OH-5), 7.21 (m, 1H, H-p-Ph), 7.28 (m, 2H, H-m-Ph),

7.35 (m, 2H, H-o-Ph); ¹³C NMR (125.7 MHz, DMSO-d₆) δ 60.3 (CH₂-5),

72.4 (CH-3), 72.9 (CH-2), 80.1 (CH-4), 81.7 (CH-1), 126.9 (CH-p-

Ph), 127.5 (CH-m-Ph), 127.7 (CH-o-Ph), 139.1 (C-i-Ph); IR (KBr) ν

3296, 3064, 3031, 1604, 1587, 1495, 1455, 1310, 1210, 1178, 1130, 1062,

1029, 1001, 909, 737, 700 cm^ꢀ1; HRMS (ESI) 233.0785 [C₁₁H₁₄O₄Na

(M + Na) requires 233.0784].

CD₃OD) δ 3.73 (dd, ²J_{5 -Ha,5 -Hb}= 12.1 Hz, ³J_{5 -Ha,4 -H}= 4.8 Hz, 1H, 5⁰-

0

Ha), 3.79 (dd, ²J_{5 -Hb,5 -Ha}= 12.1 Hz, ³J_{5 -Hb,4 -H}= 3.9 Hz, 1H, 5⁰-Hb),

0

3.88 (dd, ³J_{2 -H,1 -H}= 6.4 Hz, ³J_{2 -H,3 -H}= 5.8 Hz, 1H, 2⁰-H), 3.95 (ddd,

0

3

J_{4 -H,3 -H}= 4.8 Hz, ³J_{4 -H,5 -Ha}= 4.8 Hz, ³J_{4 -H,5 -Hb}= 3.9 Hz, 1H, 4⁰-H),

0

3

4.03 (dd, J_{3 -H,2 -H}= 5.8 Hz, J_{3 -H,4 -H}= 4.8 Hz, 1H, 3⁰-H), 4.69 (d,

0

’ ASSOCIATED CONTENT

3

J_{1 -H,2 -H}= 6.4 Hz, 1H, 1⁰-H), 5.28 (s, 3H, OH), 7.22ꢀ7.32 (m, 3H,

H-arom), 7.36ꢀ7.39 (m, 2H, H-arom); ¹³C NMR (100.6 MHz,

CD₃OD) δ 62.7 (CH₂-5⁰), 71.5 (CH-3⁰), 77.4 (CH-2⁰), 84.8 (CH-4⁰),

84.8 (CH-1⁰), 126.3, 128.1, and 128.6 (CH-arom), 140.0 (C-arom); MS

(CI) m/z (%) 211 ([M + H⁺], 80), 193 ([M + H⁺] ꢀ H₂O, 100); HRMS

(CI) 211.0972 [C₁₁H₁₅O₄(M + H⁺) requires 211.0970]; consistent

with the literature data for the ^D-enantiomer.^58b

0

S

Supporting Information. Procedures for racemic pro-

b

ducts, copies of ¹H NMR and ¹³C NMR spectra, and HPLC/GC

traces. This material is available free of charge via the Internet at

http://pubs.acs.org.

’ AUTHOR INFORMATION

Method 2. Aqueous HCl (2M, 16 mL) was added to a solution of the

silyloxy derivative 28a (87 mg, 0.268 mmol) in toluene (8 mL), and the

resulting heterogeneous mixture was evaporated on a rotavap (45 ꢀC, 20

mBar) to aﬀord a white solid, which was puriﬁed on a column of reverse

phase silica gel (HPFC) (C18HS 25+M, 2.5 ꢁ 15 cm) using gradient,

starting with water and continuing with up to a mixture of water and

MeOH (80:20) to obtain ribonucleoside 30a (44 mg, 79%) as a white

powder, whose spectral data were identical to those obtained in the

previous experiment.

Corresponding Author

*E-mail: (M.H.) hocek@uochb.cas.cz; (A.V.M.) a.malkov@

lboro.ac.uk; (P.K.) pavelk@chem.gla.ac.uk.

Present Addresses

^zNovaEnergo Ltd., Nꢁam. 14.ꢀríjna 1307/2, 15000 Prague, Czech

Republic.

^§Exchange Erasmus student from Department of Chemistry,

Charles University, 12840 Prague 2, Czech Republic.

^rDepartment of Chemistry, Loughborough University, Lough-

borough, Leicestershire LE11 3UT, UK.

(+)-1⁰-Deoxy-1⁰-(3-fluorophenyl)-β-L-ribofuranose (30b).

Following general procedure D, silane 28b (666 mg, 1.94 mmol) was

deprotected, and flash chromatography on a column of silica gel (3 ꢁ

10 cm) with ethyl acetate gave 30b (276 mg, 62%) as a white solid: mp

1

92ꢀ93 ꢀC (ethyl acetate); [α]_D+27.1 (c 0.48, MeOH); H NMR

(400.1 MHz, CD₃OD) δ 3.32ꢀ3.33 (bs, 3H, OH), 3.74 (dd, ²J_{5 -Ha,5 -Hb}

0

2

= 11.9 Hz, ³J_{5 -Ha,4 -H}= 4.7 Hz, 1H, 5⁰-Ha), 3.81 (dd, J_{5 -Hb,5 -Ha}= 11.9

’ ACKNOWLEDGMENT

0

3

Hz, J_{5 -Hb,4 -H}= 3.7 Hz, 1H, 5⁰-Hb), 3.85 (dd, J_{2 -H,1 -H}= 6.8 Hz,

0

ꢀ

We thank the University of Glasgow for a fellowship to J.S. and

3

J_{2 -H,3 -H}= 5.7 Hz, 1H, 2⁰-H), 4.00 (ddd, J_{4 -H,5 -Ha}=4.7 Hz, J_{4 -H,3 -H}= 4.2

0

O.K., The Erasmus exchange program for a scholarship to V.K.,

the Academy of Sciences of the Czech Republic (Z4 055 905),

the Ministry of Education (LC 512), and the Grant Agency of the

ASCR (IAA400550902) for additional support, and Eastman for

a generous gift of the pure enantiomers, from which the

enantiomeric diols 4 were readily obtained. We also thank the

late Dr. Andy Parkin of the University of Glasgow for the X-ray

analysis.

3

Hz, J_{4 -H,5 -Hb}= 3.7 Hz, 1H, 4⁰-H), 4.05 (ddd, J_{3 -H,2 -H}= 5.7 Hz,

0

J_{3 -H,4 -H}= 4.2 Hz, ⁴J_{3 -H,1 -H}= 0.5 Hz, 1H, 3⁰-H), 4.73 (dd, J_{1 -H,2 -H}= 6.8

3

0

Hz, ⁴J_{1 -H,3 -H}= 0.5 Hz, 1H, 1⁰-H), 6.99 (dddd, J_4-H,F= 9.0 Hz, ³J_4-H,5-H

= 7.9 Hz, J_HH= 2.7 Hz, J_HH= 1.0 Hz, 1H, 4-H), 7.21ꢀ7.26 (m, 1H, 2-H,

and 6-H), 7.33 (ddd, ³J_5-H,6-H= 8.0 Hz, ³J_5-H,4-H= 7.9 Hz, ⁴J_5-H,F= 6.0 Hz,

3

0

13

1H, 5-H); C NMR (100.6 MHz, CDCl₃) δ 63.4 (CH₂-5⁰), 72.6

(CH-3⁰), 78.9 (CH-2⁰), 84.5 (d, ⁴J_CF= 1.6 Hz, CH-1⁰), 86.2 (CH-4⁰),

113.7 (d, ²J_CF= 22.4 Hz, CH-2), 115.1 (d, ²J_CF= 21.5 Hz, CH-4), 122.8

(d, ⁴J_CF= 2.7 Hz, CH-6), 130.7 (d, ³J_CF= 8.3 Hz, CH-5), 143.0 (d, ³J_CF

=

6.8 Hz, C-1), 164.3 (d, ¹J_CF= 244.3 Hz, CF-3); ¹⁹F NMR (376.5 MHz,

CDCl₃) δ ꢀ113.8; IR (NaCl, neat) ν 3376 (s, OH), 2932 (s), 2883 (s),

2501 (s), 1615 (s), 1591 (s), 1488 (s), 1450 (s) cm^ꢀ1; MS (CI) m/z (%)

229 ([M + H⁺], 50), 211 ([M + H⁺] ꢀ H₂O, 100); HRMS (CI)

229.0875 [C₁₁H₁₄FO₄(M + H⁺) requires 229.0876].

’ DEDICATION

^†Dedicated to Professor Antonín Holꢁy on the occasion of his

75th birthday and in appreciation of his life work in the area of

nucleosides and antiviral drugs.

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The Journal of Organic Chemistry

ARTICLE

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J. F. Org. Lett. 2007, 9, 3949. (h) Yamashita, Y.; Gopalarathnam, A.;

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CꢀO bonds: (j) Lꢁopez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc.

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formation of the corresponding metallacycle, see: (n) Leitner, A.; Shu,

C.; Hartwig, J. F. Org. Lett. 2005, 7, 1093. For a recent overview, see:

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(35) These carbonates are rather sensitive compounds that readily

undergo allylic rearrangement. For a detailed discussion of the problems

associated with their preparation, see ref 15.

(36) Fiaud, J.-C.; Legros, J.-Y. J. Org. Chem. 1987, 52, 1907.

(37) For further comparison: the Rh-catalyzed substitution with

stabilized C-nucleophiles is known to aﬀord products of overall reten-

tion of conﬁguration,²⁸so that double inversion can be assumed. This

mechanism is further supported by the observation that organometallics,

such as PhZnBr, give products of overall inversion,^28gwhich can be

rationalized by inversion in the ﬁrst step, followed by transmetalation

and intramolecular delivery via retention, mirroring the behavior of Pd

and Ni catalysts.¹⁶

(38) The relative conﬁguration of the major diastereoisomer of 12

obtained in the presence of ligand 11 was deduced from the conﬁgura-

tion of the product of the subsequent ring-closing metathesis, which

proved to be trans (Scheme 6).

(39) (a) No signiﬁcant improvement was observed here when the

“activated” catalyst²⁹ⁿwas used. The catalyst was “activated” by heating

[Ir(COD)Cl]₂and ligand (R_a,R_c,R_c)-11 with propylamine at 50 ꢀC for

20 min to generate the corresponding metalacyclic species,²⁹ⁿfollowed

by evaporation of the volatile materials before the addition of the

reaction solvent and the two reagents. (b) Attempted reaction in the

absence of the iridium exhibited very low conversion (e10%). (c)

Conversion of the bisallyl ethers 12ca and 12da to the respective

products was based on the ¹H NMR spectroscopy integrals of the

worked-up reaction mixture (based on the carbonate). These two

compounds were not isolated.

(40) In fact, formation of the rearranged product 13 is proportional

to the time that is used for the generation of the alkoxide from the

monoprotected diol 5a. Thus, if 5a is ﬁrst left with n-BuLi for a longer

period of time before CuI is added, the initially generated secondary

alkoxide tends to slowly rearrange to the primary isomer, which then,

(30) For further examples of the Ir-catalyzed formation of the CꢀC

bonds, see, for example: (a) Bartels, B.; García-Yerba, C.; Helmchen, G.

Eur. J. Org. Chem. 2003, 1097. (b) García-Yerba, C.; Jansen, J. P.;

Rominger, F.; Helmchen., G. Organometallics 2004, 23, 5459. (c)

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after transmetalation with CuI, reacts in the subsequent Ir-catalyzed

reaction with the allylic partner, so that 13 becomes a visible impurity in

the product. On the other hand, shortening the time allowed between

the alkoxide generation and its subsequent reaction with the allylic

partner to the minimum, prevents the formation of 13 entirely. For an

optimized protocol, see the Experimental Section.

(41) The relative conﬁguration was conﬁrmed for the product of

ring-closing metathesis (Scheme 6).

(42) The ratios were established by chiral HPLC; see the Experi-

mental Section for details.

However, removal of the TBS group from the cyclized products turned

out to be substantially easier than that of its TBDPS counterpart, so that

only the TBS derivatives were used in the experiments involving pure

diastereoisomers.

(50) Kumamoto, H.; Tanaka, H. J. Org. Chem. 2003, 67, 3541.

(51) (a) The racemic 1:1 mixture of diastereoisomers of the TBDPS

(rather than TBS) derivatives, obtained from the reaction of (()-5b and

(()-9a (Scheme 4), followed by ring-closing metathesis, was used for

optimization of the reagent and conditions. Thus for instance, the

standard treatment with Bu₄NF (TBAF, 3.5 equiv, 20 ꢀC, 16 h) gave the

corresponding alcohol in 44% yield along with a number of decomposi-

(43) By contrast, inferior results were obtained with ligand (S_a,S_c,

S_c)-10: Although the diastereoselectivity was still high [94% dr for (R)-

5a and 96% dr for (S)-5a], the formation of the rearranged product 13

and other unidentiﬁed byproducts rose to unacceptable levels (24% in

both series), as revealed by the ¹H NMR spectra of the crude products.⁴⁰

(44) The lower temperature (ꢀ40 ꢀC) is required here to suppress

the formation of the byproduct; at 0 ꢀC, 15% of 13 was formed.

(45) The mechanism of the formation of 1,3-diphenylpropene 14 is

rather obscure. Hartwig reported on an interesting migration of one of

the phenyls of the OCPh₃group in the σ-complex [Rh]ꢀOꢀCPh₃to

form the new complex [Rh]ꢀPh and Ph₂CdO: Zhao, P.; Incarvito,

C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 3124. In view of

this observation, it can be speculated that the allylic complex [Rh]ꢀ

(C₃H₄Ph), initially generated from 9, loses the allyl group with a

concomitant migration of the phenyl to the coordination sphere of

the metal, generating [Rh]ꢀPh. The reaction of the latter complex with

another molecule of the substrate 9 would then eﬀect a standard allylic

substitution, where the Ph would migrate from the metal to the organic

ligand, giving rise to 14. It is noteworthy that we did not observe the

formation of this byproduct in the case of the Ir-based catalyst, unless a

phosphine ligand (such as BINAP) was added to the reaction mixture.

(46) By contrast, the reaction of racemic arylpropenyl carbonates

with dimethyl sodiomalonate, catalyzed by chiral molybdenum com-

plexes, is known to be stereoconvergent, i.e., both enantiomers are

converted into the same enantiomer of the product, demonstrating

epimerization of the intermediate Mo-complex.²¹Note, however, that

other Mo-complexes may react nonselectively: (a) Malkov, A. V.;

Baxendale, I. R.; Dvoꢀrꢁak, D.; Mansﬁeld, D. J.; Koꢀcovskꢁy, P. J. Org. Chem.

1999, 64, 2737. (b) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell,

W. L.; Koꢀcovskꢁy, P. J. Org. Chem. 1999, 64, 2751. (c) Koꢀcovskꢁy, P.;

tion products, which made the separation tedious. By contrast, Py HF

3

(3 equiv, 20 ꢀC, 16 h) failed completely. On the other hand, with 11

equiv of the latter reagent (20 ꢀC, 16 h), the alcohol was obtained in

52%. Finally, Et₃N 3HF (3 equiv, 20 ꢀC, 16 h) aﬀorded the alcohol in

3

56% yield. (b) It is pertinent to note that unlike their silylated precursors,

the diastereoisomeric free alcohols can be readily separated by ﬂash

chromatography. Therefore, in principle, an enantiopure diastereoiso-

meric mixture, e.g., 15a/16a, obtained from (S)-5a and (()-9a via the

Ir(I)-catalyzed allylic substitution, can also be used if both anomers of

C-nucleosides are the target. The ring-closing metathesis of the latter

mixture would produce a ∼1:1 mixture of 19a/20a, deprotection of

which, followed by chromatography, would provide pure, readily separ-

able enantiomers 23a and 24a.

(52) (a) Riddler, S. A.; Anderson, R. E.; Mellors, J. W. Antiviral Res.

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(54) For a recent review on RuO₄-catalyzed oxidations, see: Plietker,

B. Synthesis 2005, 2453.

(55) Beligny, S.; Eibauer, S.; Maechling, S.; Blechert, S. Angew.

Chem., Int. Ed. 2006, 45, 1900.

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dx.doi.org/10.1021/jo201110z |J. Org. Chem. 2011, 76, 7781–7803

The Journal of Organic Chemistry

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7803

dx.doi.org/10.1021/jo201110z |J. Org. Chem. 2011, 76, 7781–7803

Article Doi

A modular approach to aryl-C-ribonucleosides via the allylic substitution and ring-closing metathesis sequence. A stereocontrolled synthesis of all four α-/β- and D-/L-C-nucleoside stereoisomers

DOI: 10.1021/jo201110z

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