A Pauson-Khand approach to new carbocyclic nucleoside analogs

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A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

Andreas Lanver^[a]and Hans-Günther Schmalz*^[a]

Keywords: Cobalt / Palladium / Kinetic resolution / Nucleosides / Pauson–Khand reaction

The synthesis of three new carbocyclic nucleoside analogs

(CNAs) with the nucleobase attached to a 3Ј-hydroxymeth-

ylcyclopent-2Ј-en-1Ј-yl scaffold is reported. A variety of sym-

metric dienynes (propargylic acetals of type 11) were used

as substrates in a cobalt-mediated Pauson–Khand (PK) reac-

tion to give bicyclic cyclopentenone derivatives of type rac-

12 with high diastereoselectivity. These compounds are valu-

able building blocks for the synthesis of structurally diverse

CNAs with a high biological potential as apoptosis-inducing

agents. Starting from the PK product rac-12a, the synthesis

of 4Ј-trialkylsilyloxyethyl-substituted nucleosides rac-18 and

rac-19 (with 5-bromouracil and 6-chloropurine as a nucleo-

base, respectively) was accomplished in seven steps (28%

and 37% overall yield). The regio- and diastereoselective nu-

cleobase (NB) introduction was achieved by Pd⁰-catalyzed

allylic substitution. Starting from the PK product rac-12e, the

2Ј-phenyl-4Ј-trialkylsilyloxymethyl-substituted CNA rac-17

was prepared (6 steps, 29% yield)by exploitingan alternative

protocol − a Mitsunobu reaction − for the NB introduction.

The key intermediates 12a and 12e were obtained in vir-

tually enantiopure form by kinetic resolution by means of ox-

azaborolidine-catalyzed borane reduction (CBS reduction) in

the presence of a (R)-diphenylprolinol-derived B-methyl ox-

azaborolidine catalyst.

Germany, 2005)

Introduction

Carbocyclic nucleosides (CNAs), where the furanose

oxygen atom of the normal nucleoside is replaced by a

methylene group, have received a great deal of attention

over the last two decades. They play an important role as

antiviral or antitumoral drugs,^[1]and synthetic strategies

towards such compounds have been highlighted in various

review articles.^[2]Aristeronmycin^[3,4](1) and neplanocin A^[5]

(2) are natural products that have a carbocyclic backbone

and show antiviral and anticancer activity (Scheme 1). Due

to their biological properties and their interesting structures

they have often been chosen as target molecules for chemi-

cal syntheses. Abacavir^[6](3), which is the cyclopropylamine

derivative of Carbovir,^[7]has entered into clinical use for the

treatment of HIV. Several methods for the construction of

cyclopentyl skeletons have been developed.^[2,8]However,

many of them do not allow for a (diversity-oriented^[9]) vari-

ation of substituents at the carbocyclic backbone.

Scheme 1. Selected examples of CNAs (carbocyclic nucleoside ana-

logs). NB = nucleobase.

We have recently reported a convergent and enantioselec-

tive synthesis of monoprotected, 2Ј,3Ј-unsaturated carbocy-

clic nucleoside analogs of type 4 with a hydroxymethyl sub-

stituent in the 3Ј-position.^[10]The synthesis centrally ex-

ploits transition metal organic chemistry, i.e. a Co-mediated

Pauson–Khand (PK) reaction and a Pd-catalyzed allylic

substitution, the latter of which allows the introduction of

various nucleobases with virtually complete regio- and dia-

stereocontrol. Enantiomerically pure compounds are ac-

cessible by kinetic resolution of the PK products. The po-

tential of this new class of compounds as anti-tumoral

agents was first shown in a series of biological assays,^[10b]

with cytotoxic activities at concentrations in the lower

micromolar range resulting from apoptosis induction. Evi-

dence for an apoptotic pathway of cell death was provided

by microscope (characteristic membrane blebbing and cell

shrinkage), by measuring the DNA fragmentation (hypo-

ploidity) and by probing the activation of caspases 3, 8 and

9 (Western blot analysis).

[a] Institut für Organische Chemie, Universität zu Köln,

Greinstrasse 4, 50939 Köln, Germany

Fax: +49-221-470-3064

E-mail: schmalz@uni-koeln.de

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DOI: 10.1002/ejoc.200400886

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A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

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Scheme 2. Retrosynthetic analysis for CNAs of type 5.

Challenged by these promising results, we decided to gations are constantly being reported, also in the field of

carry out further structural variations of the above-men- catalytic PK-type reactions.^[14–16]Against this background,

tioned type of nucleosides. In this article, we now describe it was interesting to carefully evaluate the generality (and

the synthesis of further CNAs having a modified backbone, diastereoselectivity) of this reaction as a key step in our

thereby demonstrating the flexibility of our strategy and approach towards new CNAs (Scheme 2 and Scheme 3).

thus expanding the scope of possible target structures. In a

first part we focus on general investigations concerning the

selectivity of Pauson–Khand reactions in order to obtain

potential CNA precursors, and in a second part, selected

PK products are exploited as building blocks for the synthe-

sis of the envisioned target structures of type 5 (Scheme 2).

Results and Discussion

A retrosynthetic analysis revealed that compounds of

Scheme 3. General pattern of the Pauson–Khand reactions investi-

gated (see Table 1 for yields and diastereoselectivities).

type 5 could be traced back to bicyclic acetals of type 6,^[10]

thus allowing the differentiation of the two oxygen func-

tionalities after acetal hydrolysis (Scheme 2). It was envi-

sioned that the nucleobase could be introduced by Pd⁰-cata-

Pauson–Khand precursors of type 11 were synthesized

lyzed allylic substitution.^[11,12]Bicyclic compounds of type

following established acetalization protocols.^[17]In the case

7 could be derived from α,β-unsaturated ketones of type 8,

of propargylic alcohols 10a and 10b PCC oxidation^[18]gave

which should be accessible by an intramolecular PK reac-

the corresponding (highly sensitive) aldehydes, which were

tion from symmetric acetals 9. Such acetals are easily ob-

only isolated as crude products and then directly converted

into the acetals of type 11 by acid-catalyzed acetalization

tained from propargylic alcohols of type 10.

By systematically varying the substitution pattern of the

with PPTS (entries 1, 2, 5, 8, 9, and 10). A modified proto-

acetals of type 9 we wanted to evaluate the scope and

col had to be used for the synthesis of 11e because of the

limitations of our PK-based strategy. Other key issues to be

high volatility of the respective aldehyde (entry 4). Here, the

addressed concerned the preparation of the PK products 8

commercially available diethylacetal 14 was converted into

in nonracemic form, as well as the diastereoselective intro-

11e by acid-catalyzed transacetalization with azeotropic re-

moval of EtOH. For the preparation of acetal 11f, the al-

duction of the two additional stereocenters.

kyne 15 was first deprotonated with nBuLi and methyl for-

mate was added. The resulting mixture of the desired alde-

hyde and the corresponding dialkynylcarbinol (2,2,8,8-tet-

Pauson–Khand Reaction

The formation of three new bonds in an inter- or intra- ramethylnona-3,6-diyn-5-ol) was directly subjected to the

molecular [2+2+1]-cycloaddition makes the PK reaction standard acetalization procedure to afford 11f in 33% yield

one of the most powerful tools in the repertoire of organic after chromatographic purification. The ester 11g was ob-

chemists.^[13]It has found various applications in the synthe- tained from acetal 13h in a deprotonation/acylation se-

sis of complex organic molecules and extensive investi- quence (nBuLi, ClCO₂Et).

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A. Lanver, H.-G. Schmalz

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Table 1. Results of the Pauson–Khand reaction according to Scheme 3.

[a] Reported previously.^[10][b] Method A: a) PCC (1.5 equiv.), CH₂Cl₂, room temp., 3 h; b) allyl-OH (5 equiv.) or homoallyl-OH

(10 equiv.), cat. TsOH, benzene, reflux, –H₂O, 16 h. [c] Method B: TBAF (1 equiv.) in THF, H₂O/allyl-OH (2:1), room temp., 1 h. [d]

Method C: allyl-OH (5 equiv.), cat. TsOH, benzene, reflux, –EtOH, 16 h. [e] Method D: a) nBuLi (1.1 equiv.), HCO₂Me (2 equiv.), THF,

0 °C, 1.5 h; b) allyl-OH (10 equiv.), cat. TsOH, benzene, reflux, –H₂O, 16 h. [f] Method E: nBuLi (1.1 equiv.), ClCO₂Et (1.1 equiv.),

THF, –78 °C to room temp., 16 h; PK reaction: Co₂(CO)₈(1.15 equiv.), 4 Å mol. sieves (8 wt. equiv.), CH₂Cl₂, room temp., 2 h; then

TMANO (8 equiv.), air, –20 °C to room temp., 16 h.

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A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

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Having prepared a variety of dienynes (11a–j), we next

investigated the Co₂(CO)₈-mediated PK reaction using

these substrates. As a standard protocol, we used the same

conditions optimized for substrate 11b in the course of our

previous study.^[10]Here, an amine N-oxide is used as an

activator, a concept independently introduced by Jeong and

Schreiber.^[19]The N-oxide acts by oxidizing a CO ligand to

CO₂, thus generating a vacant coordination site at a cobalt

center. All reactions (Table 1) were performed by first stir-

ring the substrates with Co₂(CO)₈(1.1 equiv.) and molecu-

lar sieves (4 Å) for two hours at room temp. in dichloro-

methane (in situ formation of alkyne–Co₂(CO)₆com-

plexes), before trimethylamine N-oxide (8 equiv.) was added

at –20 °C and the mixture was exposed to air and stirring

was continued overnight.

The results of the various experiments (Table 1) show

that most of the enynes of type 11 afford the expected prod-

ucts in moderate to excellent yields. While the relative con-

figuration of rac-12b has previously been assigned by X-ray

crystallography,^[10b]the configuration of the main dia-

stereomers was assigned in all other cases by ¹H NMR

spectroscopy, especially NOE measurements and/or corre-

lation with data from known compounds. The assignments

are in agreement with those of Jeong and coworkers,^[20]who

have prepared such compounds in a related fashion starting

from isolated alkyne–Co₂(CO)₆precursors.

Scheme 4. The apoptosis-inducing CNA 16^[10a]and the envisioned

structural analogs 17–19 (as target structures).

The elaboration of the synthetic routes described here

was carried out in the racemic series. Additionally, the ac-

Two of the substrates, the electron-deficient enyne 11g cess to the nonracemic compounds was achieved by kinetic

(entry 7) and the one bearing three bulky TMS groups (11j; resolution of the PK products rac-12a and rac-12e as de-

entry 10), could not be converted into the corresponding scribed in the latter part of this paper.

PK products. The diastereoselectivities proved to be

Following our general synthetic strategy (Scheme 2), the

strongly dependant on the bulkiness of the terminal substit- PK product rac-12a was first reduced under Luche condi-

uent at the triple bond. Whereas for bulky substituents vir- tions^[21]to afford the allylic alcohol rac-20 (99%;

tually complete diastereoselectivity was obtained (TMS, Ph, Scheme 5). After removal of the TMS group by treatment

tBu, see entries 3, 4, and 9), a slight drop (dr = 98:2) was with KOtBu (81%),^[22]the resulting product (rac-21) was

observed for RЈ = Me (Scheme 3). Significantly lower selec- treated with methylchloroformate to afford the carbonate

tivities were observed for RЈ = H (dr = 72:28; entry 10), rac-22 in high yield (91%). Having thus set up the system

matching the observations made by Jeong et al.^[20]The for the planned nucleobase introduction by Pd-catalyzed al-

highest yields were achieved for the transformation of the lylic substitution,^[12]rac-22 was treated with bromouracil

1,7-dienyne 11a into the hydroindanone derivative rac-12a. and chloropurine, respectively, in the presence of 5 mol-%

[Pd₂(dba)₃] and 10 mol-% dppp. The expected substitution

products were obtained in good yields (rac-23a: 60%; rac-

23b: 73%).

Unexpectedly, the hydrolysis of the acetal moiety in com-

Synthesis of New CNAs

pounds rac-23 andrac-24 proved to be rather difficult. Un-

der the standard conditions (PPTS, acetone, H₂O, reflux^[23]

)

As reported previously, compound rac-16 (Scheme 4) ex- only low conversion was observed, possibly due to a high

hibited particularly promising results in preliminary bio- stability of the six-membered heterocycle (and the interme-

logical assays.^[10b]Therefore, we chose this compound as a diate oxenium cation) and the tendency of the lactol (hy-

starting point for further structural optimization. We envi- droxyaldehyde) to react with homoallylic alcohol back to

sioned the CNAs 17–19 as promising target structures as the starting material during workup. This problem was

they feature a silyl protecting group as well as chloropurine solved by using polymer-supported reagents, i.e. Amberlyst-

as the nucleobase (17 and 18). We were interested in how 15, as a strongly acidic catalyst^[24]in the hydrolysis step and

the backbone variation, i.e. the increased chain length of neutralization of the filtrate with an excess of poly(4-vinyl-

the substituent in the 4Ј-position (18 and 19) or the intro- pyridine) (Scheme 6). After evaporation of the solvent, the

duction of a phenyl substituent in the 2Ј-position (17) crude product was directly O-silylated by addition of pyri-

would effect the biological activity. The CNAs 17–19 were dine and thexyldimethylsilyl chloride (TDS-Cl) to afford the

derived from the readily synthesized PK products rac-12a aldehydes rac-25 and rac-26, respectively. A small amount

and rac-12e (Scheme 2, Table 1).

of remaining acetal (rac-23 or rac-24) was easily separated

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A. Lanver, H.-G. Schmalz

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Scheme 5. Synthesis of the CNA precursors rac-23 and rac-24. Reaction conditions: a) NaBH₄(5 equiv.), CeCl₃(1 equiv.), MeOH,

–20 °C to room temp., 2 h, 99%; b) tBuOK (1 equiv.), DMSO/H₂O (19:1), room temp., 2 h, 81%; c) ClCO₂Me (3 equiv.), py, 0 °C, 1 h,

91%; d) [Pd₂(dba)₃] (5 mol-%), dppp (10 mol-%), chloropurine or bromouracil (1.5 equiv.), DMF, room temp., 16 h, 60% for rac-23; 73%

for rac-24.

Scheme 6. Preparation of the CNAs rac-18 and rac-19. Reaction conditions: a) Amberlyst-15 (0.1 wt. equiv.), wet acetone, room temp.,

1 h, then poly(4-vinylpyridine) (2 wt. equiv.); b) TDSCl (3 equiv.), py, room temp., 16 h; c) NaBH₄(10 equiv.), MeOH/CH₂Cl₂, –78 °C,

1 h.

after borohydride reduction, and the CNAs rac-18 and rac- duction of the ketone rac-12e (99%) and carbonate forma-

19 were obtained in good overall yields (63–69% over three tion (84%) proceeded smoothly under these conditions, all

steps).

our attempts to introduce the nucleobase by Pd-catalyzed

The synthesis of the target compound rac-17 (Scheme 4), substitution failed.^[10b,12]Obviously, the tetra-substituted

which bears a phenyl substituent in the 2Ј-position, was at- double bond in substrate rac-28 is not sufficiently reactive

tempted following a similar strategy (Scheme 7). While re- towards the Pd⁰catalyst. As a consequence, we decided to

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A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

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Scheme 7. Synthesis of the 2Ј-phenyl-substituted nucleoside analog rac-17. Reaction conditions: a) NaBH₄(4 equiv.), CeCl₃(1 equiv.),

MeOH, –20 °C to room temp., 2 h, 99%; b) ClCO₂Me (3 equiv.), py, 0 °C, 1 h, 84%; c) [Pd₂(dba)₃] (5 mol-%), dppp (10 mol-%), chloropu-

rine (1.5 equiv.), DMF, room temp., 16 h; d) Yamamoto’s reagent (from 2,6-di-tert-butyl-4-methylphenol and DIBAH),^[27a]toluene, –

78 °C to –40 °C, 5 h; e) DEAD (5 equiv.), PPh₃(5 equiv.), p-nitrobenzoic acid (4.4 equiv.), toluene, room temp., 16 h, 79%; f) K₂CO₃

(2 equiv.), MeOH, room temp., 16 h, 82%; g) DEAD (2 equiv.), PPh₃(2 equiv.), chloropurine (2 equiv.), THF, room temp., 16 h, 62%; h)

PPTS (0.3 equiv.), wet acetone, reflux, 6 h; then TDSCl (4 equiv.), py, room temp., 16 h, 73% over 2 steps; i) NaBH₄(10 equiv.), MeOH/

CH₂Cl₂, –78 °C, 1 h, 99%.

introduce the nucleobase in this case by means of a Mitsu- then proceeded smoothly (99%) to give the desired 2Ј-

nobu-type reaction.^[25,26]To access the required epimeric phenyl-substituted CNA rac-17.

alcohol rac-29, we initially tried to reduce 12e with Yamam-

oto’s reagent, which often shows an inverted diastereoselec-

tivity in the reduction of ketones.^[27]However, this Lewis-

acidic reagent predominantly led to acetal cleavage and

none of the reduction products (rac-27 or rac-29) could be

Kinetic Resolution of the Key Intermediates rac-15a and

rac-15c

isolated (Scheme 7).

Having successfully elaborated efficient synthetic routes

To overcome these problems, alcohol rac-27 was con- towards the target compounds in the racemic series, an im-

verted into its epimer rac-29 in a Mitsunobu reaction (p- portant goal was to pave the way for the synthesis of the

nitrobenzoic acid in the presence of DIAD and tri- new CNAs in the nonracemic series as well.

phenylphosphane) and subsequent ester hydrolysis in 65%

As all attempts to perform the chirogenic step (i.e. the

overall yield (Scheme 7).^[25]Chloropurine was then intro- PK reaction of substrates of type 11; see Table 1) in an en-

duced in a second Mitsunobu reaction to yield the bicyclic antioselective manner^[14,15]were not successful, we had to

CNA precursor rac-30 (62%). Hydrolysis of the acetal ring resolve the chiral products. In analogy to our previous

was easily accomplished in this case by treatment of rac-30 work,^[10b]we investigated the possibility to kinetically re-

with PPTS in wet acetone.^[23]After removal of the solvent, solve the ketones rac-12a and rac-12e, respectively, by me-

the 5Ј-OH group was directly protected as a silyl ether. Re- ans of an asymmetric oxazaborolidine-catalyzed borane re-

duction of the aldehyde intermediate rac-31 with NaBH₄duction (CBS reduction).^[28]

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Scheme 8. Preparation of nonracemic 15a and 15c by kinetic resolution (see Table 2 for details).

Table 2. Results of the kinetic resolution by means of CBS reduction according to Scheme 8.

Entry

Substrate

Catecholborane

Unreacted ketone of

Alcohols ent-21/ent-

type 12

27

1

2

3

4

5

rac-12a

rac-12e

0.50 equiv.

0.65 equiv.

0.80 equiv.

0.65 equiv.

0.80 equiv.

62% (53% ee)

43% (83% ee)

30% (98% ee)

38% (96% ee)

29% (Ͼ99% ee)

22% (90% ee)

36% (85% ee)

51% (78% ee)

n.d.

Following our established protocol, a solution containing

The stereochemical assignments of the nonracemic prod-

the racemic ketone (rac-12a and rac-12e, respectively) and ucts were made applying the Corey model, i.e. by analyzing

the (R)-diphenylprolinol-derived B-methyl oxazaborolidine the (competing) transition states for the CBS reduction of

(20 mol-%) in toluene at –78 °C was treated with 0.5 to the two enantiomeric substrates assuming a strong catalyst

0.8 equivalents of catecholborane in THF. The mixture was control (Scheme 9).^[28a,10b]

allowed to warm up to room temp. over a period of 6 h and

then quenched by addition of MeOH (Scheme 8).

As shown in Scheme 9 for the resolution of rac-12e, the

reduction of 12e (case A) should be less favored (slower)

As the results summarized in Table 2 show, the kinetic because hydride transfer has to occur from the concave side

resolutions proceeded with high efficiency. Using of the substrate, which violates the natural preference. In

0.80 equiv. of catecholborane the recovered ketones were contrast, the reduction of ent-12e (case B) is highly favored

obtained after ca. 60% conversion in 30% isolated yield because substrate and catalyst control are matched. It

in virtually enantiopure form (Table 2). The enantiomeric should be mentioned that the configurational assignments

purities were determined by means of GLC (12a) or HPLC drawn by this type of analysis have been validated carefully

(12e) on chiral stationary phases. The enantiomeric purity in our previous work for the resolution of rac-12b.^[10b]

of the reduction product ent-21 was determined after reoxi-

dation with MnO₂. Attempts to reoxidize ent-27 under such

conditions failed (decomposition).

Conclusions

These results nicely demonstrate the generality of the

CBS protocol for the kinetic resolution of PK products of

In summary, we have developed an efficient and practical

type 8 (see also Scheme 2).

protocol for the synthesis of new, monoprotected, 2Ј,3Ј-un-

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A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

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gon using Schlenk techniques. Reactions were monitored by analyt-

ical thin-layer chromatography (TLC) using Merck silica gel 60 F

254 aluminum plates. Chromatograms were visualized either with

UV light, by staining with iodine, or with a “cerium reagent” [pre-

pared by dissolving 2 g of phosphomolybdic acid and 1 g of

Ce(SO₄)₂in 100 mL of 10% aqueous H₂SO₄] and subsequent heat-

ing. Flash chromatography:^[30]silica gel 60 (230–400 mesh) from

Merck. Gas chromatography (GLC): HP-6890, with H₂as a carrier

gas, FID (flame ionization detector). Merck–Hitachi HPLC-sys-

tem: L6200A pump, L-4000A UV-detector. NMR spectroscopy:

Bruker DPX 300, DRX 500 and AC 250 instruments. Chemical

shifts (δ) are given in ppm relative to the solvent reference. ¹³C

NMR spectra were measured with proton decoupling and the

number of bound protons (multiplicities) determined by DEPT. IR

spectroscopy: Perkin–Elmer FT-IR Paragon 1000 using the ATR

technique. Mass spectrometry: Finnigan MAT Incos 50 Galaxy

System (DIP-MS) or a Finnigan MAT 900 spectrometer; high reso-

lution mass spectra (HRMS) were recorded on a Finnigan HSQ-

30 (HR-EI-MS) or on a Finnigan MAT 900 (HR-ESI-MS). The

method of ionization is given in parentheses. Melting points were

measured on a Büchi B-545 apparatus and are uncorrected. Spe-

cific optical rotations were recordedon a Perkin–Elmer 343 plus

polarimeter; concentrations, c, are given in grams per 100 mL; the

cell length was 100 mm.

Scheme 9. Two competing transition structures for the kinetic reso-

lution of rac-12e by CBS reduction assuming catalyst control. A:

mismatched case (violation of substrate preference); B: matched

case.

saturated carbocyclic nucleoside analogs having a hy-

droxymethyl side chain in 3Ј-position, as exemplified by

structures 17, 18, and 19. Such compounds are analogs of

strongly apoptosis-inducing CNAs. The synthesis described

herein demonstrates the flexibility of our Pauson–Khand-

based approach, which allows the variation of the substitu-

tion pattern at the pseudosugar backbone. Using a variety

of dieneynes as substrates, we found high diastereoselectivi-

ties in the Co-mediated key reaction. Two of the resulting

cyclopentanoid building blocks (rac-12a and rac-12e) were

used for the elaboration of the further synthetic routes. Spe-

cial attention was given to the nucleobase introduction.

Starting from 12a, an established protocol based on Pd-

catalyzed allylic substitution was applied. In contrast, two

subsequent Mitsunobu reactions were needed to achieve a

stereocontrolled NB introduction in the 2Ј-phenyl-substi-

tuted series. Finally, we have shown that the key intermedi-

ates (12a and 12e) can be obtained in enantiomerically pure

form through a highly efficient kinetic resolution by means

of CBS reduction.

3,3-Bis(but-3-enyloxy)-1-propynyltrimethylsilane (11a): A solution

of alcohol 10a (1.00 g, 7.80 mmol) in dry CH₂Cl₂(5 mL) was added

dropwise to a stirred suspension of pyridinium chlorochromate

(2.52 g, 11.70 mmol) in dry CH₂Cl₂(15 mL) at 0 °C. The mixture

was allowed to warm to room temp. for 3 h and was then carefully

filtered through a plug of silica. After evaporation of the solvent,

the sensitive 3-trimethylsilyl-2-propyne-1-al was immediately fur-

ther converted as follows. The crude aldehyde (approx. 7.80 mmol),

homoallyl alcohol (3.40 mL, 39 mmol), and pTsOH (74 mg, 39

μmol) were dissolved in benzene (15 mL), and the mixture was

heated to reflux for 16 h with azeotropic removal of water (Dean–

Stark trap). After cooling to room temp., the mixture was neutral-

ized by addition of NaHCO₃before it was filtered through a plug

of silica and concentrated under reduced pressure. The residue was

purified by flash chromatography (CyHex/EtOAc, 20:1) to afford

the acetal 11a as a light-yellow oil (1.54 g, 78% over two steps).

TLC: R_f= 0.63 (CyHex/EtOAc, 20:1). ¹H NMR (250 MHz,

CDCl₃): δ = 5.89–5.72 (m, 2 H, CH=CH₂), 5.23 (s, 1 H, H-3), 5.07

(d, J = 17.2 Hz, 2 H, CH=CH–H_cis), 5.18 (d, J = 10.2 Hz, 2 H,

CH=CH–H_trans), 3.70 (td, J = 6.8, 9.5 Hz, 2 H, O–CH₂), 3.54 (td,

J = 6.7, 9.5 Hz, 2 H, O–CH₂), 2.33 (td, J = 6.7, 6.7 Hz, 4 H, CH₂–

CH=CH₂), 0.17 (s, 9 H, SiCH₃) ppm. ¹³C NMR (63 MHz, CDCl₃):

δ = 135.0 (CH=CH₂), 116.5 (CH=CH₂), 99.8 (C3), 91.5 and 90.7

(C1 and C2), 64.7 (O–CH₂), 33.9 (CH₂CH=CH₂), –0.3 (TMS)

The biological activity (apoptosis induction) of the new

CNAs prepared is currently under investigation. The results

will be reported separately. In any case, the (diversity-ori-

ented) synthetic schemes disclosed here will provide a reli-

able basis for the preparation of various new CNSs of type

5 in the future.

ppm. IR (ATR): ν = 2956 (m), 1640 (m), 1352 (m), 1327 (m), 1249

˜

(m), 1103 (s), 1037 (s), 913 (m), 842 (s), 759 cm^–1(m). MS (EI,

70 eV): m/z (%) = 251 (14) [M – H⁺], 181 (57), 151 (23), 123 (18),

111 (19), 99 (22), 73 (68), 59 (35), 55(100). HRMS (EI) calcd. for

[M – H⁺] C₁₄H₂₃O₂Si: 251.1467; found 251.146.

Experimental Section

1,1-Diallyloxy-2-butyne (11d): A solution of 1,1-diethoxy-2-pro-

pyne (14; 2.00 g, 14.06 mmol), allyl alcohol (4.74 mL, 70 mmol),

and pTsOH (134 mg, 0.7 mmol) in benzene (50 mL) was heated to

reflux. Using a distillation head, the benzene/ethanol azeotrope was

constantly removed from the system and benzene was added

(5×20 mL), until no further azeotrope formed (16 h). The mixture

was cooled to room temp. and neutralized by addition of K₂CO₃.

The solvent and excess of allyl alcohol were removed under reduced

pressure and the residue was purified by flash chromatography

(CyHex/EtOAc, 10:1) to give the product 11d as a colorless oil

General Remarks: Anhydrous solvents were obtained by distillation

from sodium/benzophenone (THF), from CaH₂(CH₂Cl₂), from

KOH (pyridine, Et₃N), or by storage over 4 Å mol. sieves (DMSO).

Reagents (generally Ն 99%) were used as purchased unless other-

wise stated. The concentration of organolithium reagents was de-

termined by titration against menthol in THF using 1,10-phenan-

throline as an indicator.^[29]TMANO (trimethylamine N-oxide) was

dried by azeotropic removal of water with toluene. Water- and/or

air-sensitive compounds were handled under an atmosphere of ar-

Eur. J. Org. Chem. 2005, 1444–1458

www.eurjoc.org

1451

A. Lanver, H.-G. Schmalz

FULL PAPER

(1.64 g, 70%).TLC: R_f= 0.56 (CyHex/EtOAc, 10:1). ¹H NMR

(250 MHz, CDCl₃): δ = 5.91 (dddd, J = 5.4, 11.5, 10.3, 6.0 Hz, 2

(30 mL) was added and it was extracted with EtOAc (4×30 mL).

The combined organic phases were washed with water (3×20 mL)

H, CH=CH₂), 5.31 (q, J = 1.6 Hz, 1 H, H-1), 5.26 (tdd, J = 1.6, and brine (20 mL), dried (MgSO₄), and the solvent was removed

1.6,11.5 Hz, 2 H, CH=CH–H_trans), 5.16 (tdd, J = 1.6, 1.6, 10.3 Hz,

2 H, CH=CH–H_cis), 4.18 (tdd, J = 1.6, 12.6, 5.4 Hz, 2 H, CH₂–

under reduced pressure. After purification by flash chromatography

(CyHex/EtOAc, 20:1) the product 11g was obtained as a colorless

1

CH=CH₂), 4.04 (tdd, J = 1.4, 12.6, 6.0 Hz, 2 H, CH₂–CH=CH₂), oil (1.10 g, 47% yield). TLC: R_f= 0.31 (CyHex/EtOAc, 20:1). H

1.85 (d, J = 1.6 Hz, 3 H, CCH₃) ppm. ¹³C NMR (63 MHz, CDCl₃):

δ = 134.1 (CH=CH₂), 117.3 (CH=CH₂), 90.6 (C1), 82.7 and 74.5

NMR (250 MHz, CDCl₃): δ = 5.89 (dddd, J = 5.4, 17.2, 10.3,

6.0 Hz, 2 H, CH=CH₂), 5.42 (s, 1 H, H-4), 5.29 (tdd, J = 1.3,

(C2 and C3), 66.0 (CH CH=CH ), 3.5 (C4) ppm. IR (ATR): ν = 1.7,17.2 Hz, 2 H, CH=CH–H_trans), 5.16 (tdd, J = 1.3, 1.7, 10.3 Hz,

˜

2

2875 (w), 1725 (m), 1424 (m), 1363 (m), 1246 (m), 1157 (s), 2 H, CH=CH–H_cis), 4.22 (q, J = 7.1 Hz, 2 H, O–CH₂CH₃), 4.22

1036 cm^–1(s). MS (EI, 70 eV): m/z (%) = 166 (6) [M⁺], 165 (59),

109 (100), 81 (45), 79 (51), 67 (37), 53 (38).

(m, 2 H, CH₂–CH=CH₂), 4.08 (tdd, J = 1.3, 12.6, 6.0 Hz, 2 H,

CH₂–CH=CH₂), 1.28 (t, J = 7.1 Hz, 3 H, O–CH₂CH₃) ppm. ¹³C

NMR (63 MHz, CDCl₃): δ = 152.7 (C1), 133.3 (CH=CH₂), 117.9

(CH=CH₂), 89.9 (C4), 80.4 and 76.5 (C2 and C3), 66.7

(CH₂CH=CH₂), 62.3 (OCH₂CH₃), 13.9 (OCH₂CH₃) ppm. IR

3,3-Diallyloxy-1-propynylbenzene (11e): Following the two-step

procedure described for 11a, 10b (6.00 g, 45.4 mmol) afforded the

acetal 11e (9.22 g, 80% yield) as a yellow oil. TLC: R_f= 0.58

(CyHex/EtOAc, 20:1). ¹H NMR (250 MHz, CDCl₃): δ = 7.48–7.44

(m, 2 H, H_ar), 7.33–7.29 (m, 3 H, H_ar), 5.97 (tdd, J = 5.5, 17.2,

10.3 Hz, 2 H, CH=CH₂), 5.57 (s, 1 H, H-3), 5.33 (tdd, J = 1.6,

1.6,17.2 Hz, 2 H, CH=CH–H_trans), 5.20 (tdd, J = 1.3, 1.7, 10.3 Hz,

2 H, CH=CH–H_cis), 4.29 (tdd, J = 1.4, 12.6, 5.5 Hz, 2 H, CH₂–

CH=CH₂), 4.15 (tdd, J = 1.4, 12.6, 6.0 Hz, 2 H, CH₂–CH=CH₂)

ppm. ¹³C NMR (63 MHz, CDCl₃): δ = 134.0 (CH=CH₂), 131.9,

128.9, 128.2 (d, C_ar), 121.7 (s, C_ar), 117.5 (CH=CH₂), 91.0 (C3),

(ATR): ν = 2983 (w), 1715 (s), 1366 (w), 1242 (s), 1109 (m), 1044

˜

(s), 1014 (m), 930 (m), 750 cm^–1(m). MS (EI, 70 eV): m/z (%) =

224 (2) [M⁺], 223 (7), 167 (48), 127 (24), 111 (46), 93 (100), 81 (43),

67 (26), 53 (47).

3,3-Bis(but-2-enyloxy)-1-propynyltrimethylsilane (11h): Following

the two-step procedure described for 11a [(E)-2-butenol was used

instead of allyl alcohol], 10a (2.00 g, 15.6 mmol) afforded the acetal

11h (2.12 g, 54% yield) as a colorless oil after flash chromatography

85.7 and 83.9 (C1 and C2), 66.3 (CH₂CH=CH₂) ppm. IR (ATR): (CyHex/EtOAc, 20:1). TLC: R_f= 0.42 (CyHex/EtOAc, 50:1). ¹H

ν = 2865 (w), 2228 (w), 1488 (m), 1355 (m), 1323 (m), 1254 (w),

NMR (250 MHz, CDCl₃): δ = 5.77–5.66 (m, 2 H, CH=CHCH₃),

˜

1087 (s), 1026 (s), 921 (s), 755 (s), 689 cm^–1(s). MS (EI, 70 eV): m/z 5.63–5.52 (m, 2 H, CH=CHCH₃), 5.26 (s, 1 H, H-3), 4.11 (tdd, J

(%) = 227 (5) [M – H⁺], 198 (23), 171 (24), 142 (100), 141 (94), 129

(53), 128 (96), 11 5 (24), 102 (28), 77 (14). HRMS (EI) calcd. for

[M – H]⁺C₁₅H₁₅O₂: 227.1072; found 227.106.

= 4.2, 6.4, 12.4 Hz, 2 H, O–CH₂), 3.97 (tdd, J = 1.3, 7.5, 12.4 Hz,

2 H, O–CH₂), 1.69 (dd, J = 1.2, 6.2 Hz, 6 H, CH₃), 0.16 (s, 9 H,

SiCH₃) ppm. ¹³C NMR (63 MHz, CDCl₃): δ = 130.2 and 126.9

(CH=CH), 100.0 and 90.8 (C1 and C2), 90.0 (C3), 65.9 (O–CH₂),

1,1-Diallyloxy-4,4-dimethyl-2-pentyne (11f): 3,3-Dimethyl-but-1-

yne (15; 2.00 g, 24.35 mmol) was dissolved in dry THF (25 mL)

and nBuLi (18.59 mL, 26.78 mmol) was slowly added at 0 °C. After

stirring for 30 min the mixture was added to ethyl formate

(3.92 mL, 48.69 mmol) in dry THF (25 mL) at 0 °C. After 1 h the

reaction was quenched by addition of ice water (50 mL) and acetic

acid (2.2 mL, 36.5 mmol) was added. The mixture was extracted

with MTBE (3×30 mL) and the combined organic layers were

washed with brine and dried with MgSO₄. After removal of the

solvent, the crude mixture was directly subjected to the acetali-

zation conditions, as described for the preparation of 11a, to afford

the acetal 11f (1.65 g, 33% yield) as a colorless oil after flash

17.7 (CH CH=CH ), –0.3 (TMS) ppm. IR (ATR): ν = 2958 (m),

˜

3

2

2915 (w), 1448 (w), 1350 (m), 1249 (m), 1097 (s), 1020 (s), 963 (m),

842 (s), 759 cm^–1(m). MS (EI, 70 eV): m/z (%) = 251 (1) [M – 1⁺],

237 (3) [M – CH₃⁺], 223 (4), 181 (16), 137 (18), 127 (71), 111 (19),

+

99 (26), 73 (38), 55 (100). HRMS (EI) calcd. for [M – CH₃

C₁₃H₂₁O₂Si: 237.1311; found 237.130.

]

3,3-Bis(but-2-enyloxy)-1-propynylbenzene (11i): Following the two-

step procedure as described for 11a [(E)-2-butenol was used instead

of allyl alcohol], 10b (1.00 g, 7.57 mmol) afforded the acetal 11i

(1.07 g, 63% yield) as a yellow oil. TLC: R_f= 0.47 (CyHex/EtOAc,

1

20:1). H NMR (250 MHz, CDCl₃): δ = 7.47–7.43 (m, 2 H, H_ar),

chromatography (CyHex/EtOAc, 20:1). TLC: R_f= 0.43 (CyHex/ 7.32–7.26 (m, 3 H, H_ar), 5.84–5.71 (m, 2 H, CH=CHCH₃), 5.68–

1

EtOAc, 20:1). H NMR (300 MHz, CDCl₃): δ = 5.93 (dddd, J = 5.60 (m, 2 H, CH=CHCH₃), 5.53 (s, 1 H, H-3), 4.20 (tdd, J = 1.3,

5.5, 17.3, 10.3, 6.0 Hz, 2 H, CH=CH₂), 5.31 (s, 1 H, H-1), 5.28 6.5, 12.4 Hz, 2 H, O–CH₂), 4.06 (tdd, J = 1.3, 6.2, 12.4 Hz, 2 H,

(tdd, J = 1.6, 1.7,17.3 Hz, 2 H, CH=CH–H_trans), 5.16 (tdd, J = 1.2,

1.7, 10.3 Hz, 2 H, CH=CH–H_cis), 4.17 (tdd, J = 1.5, 12.7, 5.5 Hz,

2 H, CH₂–CH=CH₂), 4.04 (tdd, J = 1.4, 12.7, 6.0 Hz, 2 H, CH₂–

CH=CH₂), 1.21 (s, 9 H, CCH₃) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 134.2 (CH=CH₂), 117.3 (CH=CH₂), 91.0 (C3), 85.7 and 83.9

O–CH₂), 1.71 (dd, J = 1.2, 6.1 Hz, 6 H, CH₃) ppm. ¹³C NMR

(63 MHz, CDCl₃): δ = 131.9, 130.3 128.8, 128.2, 126.9 (d, C_arand

CH=CH), 121.9 (s, C_ar), 90.7 (C3), 85.5 and 84.3 (C1 and C2), 66.0

(O–CH ), 17.8 (CH CH=CH ) ppm. IR (ATR): ν = 2913 (m), 2233

˜

2

3

2

(w), 1488 (m), 1442 (m), 1353 (m), 1092 (s), 1016 (s), 964 (s), 755

(C1 and C2), 66.3 (CH₂CH=CH₂), 30.7 (C5), 27.3 (C4) ppm. IR (m), 690 cm^–1(m). MS (EI, 70 eV): m/z (%) = 256 (Ͻ1) [M⁺], 195

(ATR): ν = 2968 (m), 2204 (m), 1628 (m), 1456 (w), 1362 (m), 1262 (8), 185 (15), 167 (9), 156 (41), 131 (100), 115 (41), 102 (65), 77

˜

(m), 1109 (m), 1033 (s), 922 cm^–1(m). MS (EI, 70 eV): m/z (%) = (27), 55 (79), 39 (51).

208 (1) [M⁺], 177 (10), 151 (100), 135 (21), 121 (27), 107 (46), 90

3,3-Bis(3-trimethylsilanylallyloxy)-1-propynyltrimethylsilane (11j):

(46), 81 (84), 67 (69), 57 (79), 41 (99). HRMS (EI) calcd. for [M]⁺

Following the two-step procedure described for 11a [(E)-2-(3-tri-

C₁₃H₂₀O₂: 208.1463; found 208.146.

methylsilany)propenol^[31]was used instead of allyl alcohol], 10a

Ethyl 4,4-Diallyloxy-2-butynoate (11g): Acetal 11c (1.60 g, (1.13 g, 9.08 mmol) afforded the acetal 11j (1.66 g, 50% yield) as a

10.51 mmol) was dissolved in THF (10 mL) and the mixture was

cooled to 0 °C. A 1.44 m solution of nBuLi in hexane (8.03 mL,

11.56 mmol) was added and the reaction mixture was stirred for

another 30 min, before it was added to a solution of ethyl chloro-

formate (1.10 mL, 11.56 mmol) in THF (10 mL) at –78 °C. The

mixture was allowed to warm to room temp. during 16 h. Water

colorless oil after flash chromatography (CyHex/EtOAc, 20:1).

TLC: R_f= 0.74 (CyHex/EtOAc, 20:1). ¹H NMR (250 MHz,

CDCl₃): δ = 6.09 (ddd, J = 4.7, 5.1, 18.7 Hz, 2 H, CH=CHTMS),

5.92 (td, J = 1.2, 18.7 Hz, 2 H, CH=CHTMS) 5.30 (s, 1 H, H-3),

4.22 (ddd, J = 1.2, 4.7, 13.0 Hz, 2 H, CH₂–CH=CH₂), 4.07 (ddd,

J = 1.2, 5.1, 13.0 Hz, 2 H, CH₂–CH=CH₂), 0.17 (s, 9 H, CϵC–

1452

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1444–1458

A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

FULL PAPER

SiCH₃), 0.05 (s, 18, C=CH–SiCH₃) ppm. ¹³C NMR (63 MHz, (s), 1409 (w), 1280 (m), 1151 (m), 1063 (m), 991 (s), 944 (m),

CDCl₃): δ = 141.3 and 132.8 (CH=CH), 99.6 and 91.1 (C1 and

894 cm^–1(m). MS (EI, 70 eV): m/z (%) = 193 (1) [M – 1⁺], 165 (21),

C2), 90.7 (C3), 68.3 (CH₂CH=CH), –0.3 and –1.4 (TMS) ppm. IR 137 (79), 123 (61), 109 (29), 95 (37), 79 (74), 67 (50), 53 (26), 41

(ATR): ν = 2954 (m), 1247 (s), 1103 (m), 1028 (m), 837 (s), 760

(100).

˜

(m), 699 cm^–1(m). MS (EI, 70 eV): m/z (%) = 368 (Ͻ1) [M⁺], 295

(9), 239 (6) [M – OCH₂CH=CHTMS⁺], 225 (7), 155 (19), 147 (24),

133 (27), 85 (42), 73 (100), 59 (68).

(5SR,8RS)-8-Allyloxy-2-phenyl-7-oxabicyclo[3.3.0]oct-1-ene-3-one

(rac-12e): Following the general procedure for PK reactions, com-

pound 11e (228 mg, 1 mmol) gave rac-12e (226 mg, 0.88 mmol,

88%) as a yellow oil. TLC: R_f= 0.25 (CyHex/EtOAc, 4:1). ¹H

NMR (250 MHz, CDCl₃): δ = 7.63–7.59 (m, 2 H, H_ar), 7.43–7.35

(m, 3 H, H_ar), 6.02 (dddd, J = 17.2, 10.3, 5.4, 6.3 Hz, 1 H,

CH=CH₂), 5.61 (s, 1 H, H-8), 5.36 (tdd, J = 1.6, 1.6, 17.2 Hz, 1 H,

CH=CH–H_trans), 5.26 (tdd, J = 1.2, 1.6, 10.3 Hz, 1 H, CH=CH–

H_cis), 4.45 (dd, J = 7.9, 7.9 Hz, 1 H, H-6a), 4.38 (tdd, J = 1.4, 5.4,

12.7 Hz, 1 H, CHHa–CH=CH₂), 4.21 (tdd, J = 1.2, 6.3, 12.7 Hz,

1 H, CHHb–CH=CH₂), 3.62–3.48 (m, 1 H, H-5), 3.44 (dd, J = 7.6,

8.8 Hz, 1 H, H-6b), 2.90 (dd, J = 6.4, 17.9 Hz, 1 H, H-4a), 2.35 (dd,

J = 3.3, 17.9 Hz, 1 H, H-4b) ppm. ¹³C NMR (63 MHz, CDCl₃): δ

= 207.2 (C3), 174.7 (C1), 138.2 (C2), 133.3 (CH=CH₂), 129.7,

129.1, 128.7, 128.1 (C_ar), 117.9 (CH=CH₂), 98.7 (C8), 70.3 and 69.5

General Procedure for Pauson–Khand Reactions: A 50-mL flask was

charged with dry, degassed CH₂Cl₂(25 mL), activated 4-Å molecu-

lar sieves (8 wt. equiv.), and Co₂(CO)₈(393 mg, 1.15 mmol) under

argon. [Note: the Co₂(CO)₈must be of high quality, i.e. red and

nonsticky crystals, to obtain good yields.] Then, the dieneyne

(1 mmol) was added all at once and the mixture was stirred at room

temp. for 2 h under argon. After cooling the mixture to –20 °C, dry

TMANO (600 mg, 8 mmol) was added in small portions over a

period of 10 min. A stream of air was bubbled through the dark

solution for 20 min before stirring was continued for 16 h at room

temp. (open flask). The mixture was filtered through a plug of silica

(in order to remove blue- and violet-colored cobalt by-products)

before the solvent was evaporated and the residue purified by flash

chromatography.

(C6 and CH CH=CH ), 40.1 (C5), 40.4 (C4) ppm. IR (ATR): ν =

˜

2

2914 (m), 1711 (s), 1446 (w), 1273 (m), 1122 (m), 987 (s), 907 (s),

728 (s), 697 (s), 647 cm^–1(m). MS (EI, 70 eV): m/z (%) = 256 (5)

[M⁺], 215 (14), 199 (34), 173 (27), 141 (32), 129 (50), 128 (100), 115

(34), 77 (21). HRMS (EI) calcd. for [M⁺] C₁₆H₁₆O₃: 256.1099;

found 256.110.

(5SR,9RS)-9-(But-3-enyloxy)-2-trimethylsilyl-8-oxabicyclo[3.4.0]-

non-1-ene-3-one (rac-12a): Following the general procedure for PK

reactions, compound 11a (252 mg, 1 mmol) gave rac-12a (264 mg,

0.93 mmol, 93%) as a white solid. TLC: R_f= 0.31 (CyHex/EtOAc,

2:1). ¹H NMR (300 MHz, CDCl₃): δ = 5.81 (tdd, J = 6.7, 10.4, (5SR,8RS)-8-Allyloxy-2-tert-butyl-7-oxabicyclo[3.3.0]oct-1-ene-3-

17.3 Hz, 1 H, CH=CH₂), 5.54 (s, 1 H, H-9), 5.10 (tdd, J = 1.5, 1.7,

17.3 Hz, 1 H, CH=CH–H_trans), 5.04 (dd, J = 1.5, 10.4 Hz, 1 H,

one (rac-12f): Following the general procedure for PK reactions

(carried out on a 2 mmol scale), compound 11f (416 mg, 2 mmol)

CH=CH–H_cis), 4.01 (ddd, J = 11.9, 11.4, 2.0 Hz, 1 H, H-7a), 3.83 gave rac-12f (280 mg, 1.18 mmol, 59%) as a colorless oil. TLC: R_f

(td, J = 6.9, 9.5 Hz, 1 H, O–CHHa), 3.65 (ddd, J = 1.4, 4.6, = 0.15 (CyHex/EtOAc, 4:1). ¹H NMR (300 MHz, CDCl₃): δ = 5.92

11.4 Hz, 1 H, H-7b), 3.53 (td, J = 6.7, 9.5 Hz, 1 H, O–CHHb), (dddd, J = 17.2, 10.4, 5.4, 6.6 Hz, 1 H, CH=CH₂), 5.83 (s, 1 H, H-

3.15–3.06 (m, 1 H, H-5), 2.52 (dd, J = 6.9, 18.6 Hz, 1 H, H-4a), 8), 5.31 (tdd, J = 1.9, 2.3, 17.2 Hz, 1 H, CH=CH–H_trans), 5.22 (tdd,

2.37 (ttd, J = 1.2, 6.7, 6.7 Hz, 2 H, CH₂–CH=CH₂), 2.02 (dd, J =

4.6, 11.3 Hz, 1 H, H-6a), 1.92 (dd, J = 2.9, 18.6 Hz, 1 H, H-4b),

1.56 (ddd, J = 4.6, 12.6, 12.6 Hz, 1 H, H-6b), 0.19 [s, 9 H, Si-

J = 1.9, 2.3, 10.4 Hz, 1 H, CH=CH–H_cis), 4.34 (dd, J = 7.4, 7.4 Hz,

1 H, H-6a), 4.28 (dddd, J = 1.9, 1.9, 5.4, 13.5 Hz, 1 H, CHHa–

CH=CH₂), 4.09 (dddd, J = 1.9, 1.9, 6.6, 13.5 Hz, 1 H, CHHb–

(CH₃)₃] ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 212.0 (C3), 180.1 CH=CH₂), 3.38 (dd, J = 7.4, 7.8 Hz, 1 H, H-6b), 3.36–3.30 (m, 1

(C1), 138.8 (C2), 134.8 (CH=CH₂), 116.8 (CH=CH₂), 95.2 (C9), H, H-5), 2.62 (dd, J = 6.3, 17.6 Hz, 1 H, H-4a), 2.08 (dd, J = 3.4,

66.9 and 59.0 (C7 and O–CH₂CH₂CH=CH₂), 42.0 (C4), 37.1 (C5),

35.4 and 34.0 (C6 and O–CH₂CH₂CH=CH₂), –0.6 (TMS) ppm. IR (75 MHz, CDCl₃): δ = 209.1 (C3), 168.2 (C1), 144.1 (C2), 133.9

17.6 Hz, 1 H, H-4b), 1.24 [s, 9 H, C(CH₃)₃] ppm. ¹³C NMR

(ATR): ν = 2948 (m), 2874 (w), 1694 (s), 1610 (m), 1247 (m), 1143 (CH=CH₂), 118.1 (CH=CH₂), 97.0 (C8), 71.0 and 68.8 (C6 and

˜

(m), 1102 (s), 1034 (s), 967 (m), 841 (s), 762 cm^–1(w). MS (EI,

CH₂CH=CH₂), 41.1 (C4), 39.6 (C5), 33.3 (CCH₃), 28.6 (CCH₃)

70 eV): m/z (%) = 280 (Ͻ1) [M⁺], 265 (3), 225 (90), 209 (48), 195

ppm. IR (ATR): ν = 2955 (m), 2870 (w), 1710 (s), 1361 (w), 1289

˜

(28), 151 (14), 135 (47), 109 (18), 91 (16), 75 (100), 73 (92), 59 (18), (w), 1130 (m), 1072 (m), 992 cm^–1(m). MS (EI, 70 eV): m/z (%) =

55 (58). HRMS (EI) calcd. for [M + CH₃]⁺C₁₄H₂₁O₃Si: 265.1260;

found 265.126.

236 (59) [M⁺], 179 (73), 165 (16), 137 (100), 109 (55), 91 (28), 67

(26). HRMS (EI) calcd. for [M⁺] C₁₄H₂₀O₃: 236.1412; found

236.141.

(5SR,8RS)-8-Allyloxy-2-methyl-7-oxabicyclo[3.3.0]oct-1-ene-3-one

(rac-12d): Following the general procedure for PK reactions (car-

ried out on a 2 mmol scale), compound 11d (332 mg, 2 mmol) gave

rac-12d (315 mg, 1.62 mmol, 81%) as a light-yellow oil. The dia-

(4SR,5SR,8RS)-8-(But-2-enyloxy)-4-methyl-2-trimethylsilyl-7-oxa-

bicyclo[3.3.0]oct-1-ene-3-one (rac-12h): Following the general pro-

cedure for PK reactions, compound 11h (252 mg, 1 mmol) gave rac-

1

stereomeric ratio was 98:2 according to H NMR spectroscopy.

12h (89 mg, 0.32 mmol, 32%) as a light-yellow oil. TLC: R_f= 0.31

TLC: R_f= 0.15 (CyHex/EtOAc, 4:1). ¹H NMR (250 MHz, CDCl₃): (CyHex/EtOAc, 4:1). H NMR (300 MHz, CDCl₃): δ = 5.83–5.71

1

δ = 5.90 (dddd, J = 17.2, 10.4, 6.1, 5.2 Hz, 1 H, CH=CH₂), 5.57

(s, 1 H, H-8), 5.31 (dd, J = 1.3, 17.2 Hz, 1 H, CH=CH–H_trans), 5.21 1 H, H-8), 4.40 (dd, J = 8.5, 8.5 Hz, 1 H, H-6a), 4.21 (dd, J = 6.3,

(dd, J = 1.3, 10.4 Hz, 1 H, CH=CH–H_cis), 4.36 (dd, J = 7.6, 7.6 Hz, 11.1 Hz, 1 H, O–CHHa–CH=CH), 4.02 (dd, J = 7.4, 11.1 Hz, 1 H,

(m, 1 H, CH=CHCH₃), 5.63–5.53 (m, 1 H, CH=CHCH₃), 5.58 (s,

1 H, H-6a), 4.25 (tdd, J = 1.3, 5.2, 12.7 Hz, 1 H, CHHa–CH=CH₂), O–CHHb–CH=CH), 3.50 (dd, J = 8.5, 8.5 Hz, 1 H, H-6b), 3.11

4.11 (tdd, J = 1.2, 6.1, 12.7 Hz, 1 H, CHHb–CH=CH₂), 3.42–3.35 (td, J = 8.5, 4.2 Hz, 1 H, H-5), 2.14 (qd, J = 7.3, 4.2 Hz, 1 H, H-4),

(m, 1 H, H-5), 3.35 (dd, J = 7.6, 7.6 Hz, 1 H, H-6b), 2.68 (dd, J =

6.2, 18.0 Hz, 1 H, H-4a), 2.11 (dd, J = 2.9, 18.0 Hz, 1 H, H-4b),

1.70 (dd, J = 1.4, 6.2 Hz, 3 H, CH=CHCH₃), 1.20 [d, J = 7.3 Hz, 3

H, C(4)CH₃], 0.20 (s, 9 H, TMS) ppm. ¹³C NMR (75 MHz,

1.77 (d, J = 2.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (63 MHz, CDCl₃): CDCl₃): δ = 214.9 (C3), 182.4 (C1), 136.5 (C2), 131.1, 126.6

δ = 209.4 (C3), 170.6 (C1), 133.8 (CH=CH₂), 133.2 (C2), 117.7

(CH=CH₂), 95.9 (C8), 71.4 (C6), 68.5 (CH₂CH=CH₂), 40.1 (C4),

(CH=CH), 96.5 (C8), 70.6 and 68.5 (C6 and CH₂CH=CH₂), 50.8

and 59.5 (C5 and C4), 17.9 and 14.0 (CCH₃), –1.5 (SiCH₃) ppm.

39.2 (C5), 8.9 (CH ) ppm. IR (ATR): ν = 2878 (m), 1717 (s), 1684

IR (ATR): ν = 2971 (m), 2894 (m), 1751 (s), 1704 (s), 1454 (w),

˜

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1453

A. Lanver, H.-G. Schmalz

FULL PAPER

1377 (m), 1248 (m), 1182 (s), 1057 (s), 970 (m), 844 cm^–1(m). MS

(EI, 70 eV): m/z (%) = 280 (1) [M⁺], 226 (41), 195 (35), 165 (26),

137 (32), 107 (24), 73 (100), 55 (66).

room temp. for 2 h, the reaction was quenched by addition of satu-

rated aqueous NaHCO₃(100 mL). The mixture was extracted with

MTBE (4×75 mL) and the combined organic layers were washed

with saturated aqueous NaHCO₃(2×50 mL) solution and brine

(50 mL), dried (MgSO₄) and the solvents were evaporated. After

purification by flash chromatography (CyHex/EtOAc = 2+1) com-

pound rac-20 was isolated in 99% yield (4.01 g, 14.2 mmol) as a

colorless oil. TLC: R_f= 0.34 (CyHex/EtOAc, 2:1). ¹H NMR

(300 MHz, CDCl₃): δ = 5.88–5.75 (m, 1 H, CH=CH₂), 5.23 (s, 1

H, H-9), 5.11 (tdd, J = 1.6, 1.8, 17.2 Hz, 1 H, CH=CH–H_trans),

5.02 (tdd, J = 1.2, 1.8, 10.3 Hz, 1 H, CH=CH–H_cis), 4.88 (t, J =

6.1 Hz, 1 H, H-3), 3.90 (ddd, J = 2.1, 11.8, 12.3 Hz, 1 H, H-7a),

3.76 (td, J = 7.1, 9.5 Hz, 1 H, O–CHHa), 3.57 (ddd, J = 1.6, 5.4,

11.8 Hz, 1 H, H-7b), 3.45 (td, J = 6.8, 9.5 Hz, 1 H, O–CHHb),

2.88–2.77 (m, 1 H, H-5), 2.57 (td, J = 13.3, 6.1 Hz, 1 H, H-4a),

2.39–2.32 (m, 2 H, CH₂–CH=CH₂), 1.86 (dd, J = 5.4, 12.3 Hz, 1

H, H-6a), 1.51 (tdd, J = 12.3, 12.3, 6.1 Hz, 1 H, H-6b), 1.17 (td, J

= 6.1, 13.3 Hz, 1 H, H-4b), 0.17 [s, 9 H, Si(CH₃)₃] ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 152.5 (C1), 140.8 (C2), 135.5 (CH=CH₂),

116.9 (CH=CH₂), 96.7 (C9), 82.3 (C3), 66.9 and 59.4 (C7 and O–

CH₂CH₂CH=CH₂), 42.3 (C4), 41.5 (C5), 36.0 and 34.6 (C6 and

(4SR,5SR,8RS)-8-(But-2-enyloxy)-4-methyl-2-phenyl-7-oxabicyclo-

[3.3.0]oct-1-ene-3-one (rac-12i): Following the general procedure for

PK reactions, compound 11i (256 mg, 1 mmol) gave rac-12i

(205 mg, 0.71 mmol, 71%) as a white solid. M.p. 82 °C. TLC: R_f=

1

0.26 (CyHex/EtOAc, 4:1). H NMR (300 MHz, CDCl₃): δ = 7.61

(dd, J = 8.3, 2.1 Hz, 2 H, H_ar), 7.42–7.34 (m, 3 H, H_ar), 6.02 (qd,

J = 6.9, 15.1 Hz, 1 H, CH=CHCH₃), 5.73–5.65 (m, 1 H,

CH=CHCH₃), 5.63 (s, 1 H, H-8), 4.49 (dd, J = 8.4, 8.1 Hz, 1 H,

H-6a), 4.29 (dd, J = 6.2, 11.2 Hz, 1 H, O–CHHa–CH=CH), 4.13

(dd, J = 7.3, 11.2 Hz, 1 H, O–CHHb–CH=CH), 3.53 (dd, J = 8.4,

8.4 Hz, 1 H, H-6b), 3.20 (td, J = 8.4, 3.4 Hz, 1 H, H-5), 2.35 (qd,

J = 7.2, 3.4 Hz, 1 H, H-4), 1.74 (dd, J = 1.3, 6.9 Hz, 3 H,

CH=CHCH₃), 1.32 [d, J = 7.2 Hz, 3 H, C(4)CH₃] ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 209.5 (C3), 169.3 (C1), 134.5 (C2), 131.1,

130.4, 128.9, 128.8, 128.5, 126.5 (CH=CH and C_ar), 97.1 (C8), 70.6

and 68.6 (C6 and CH₂CH=CH₂), 49.5 and 48.2 (C5 and C4), 17.9

and 14.0 (CH ) ppm. IR (ATR): ν = 2874 (w), 1711 (s), 1446 (m),

˜

3

1274 (m), 1192 (m), 1124 (m), 1089 (m), 983 (s), 903 (m), 776 (m),

696 cm^–1(m). MS (EI, 70 eV): m/z (%) = 284 (3) [M⁺], 253 (4), 228

(18), 213 (24), 141 (23), 128 (44), 115 (38), 91 (23), 77 (17), 55 (100).

HRMS (EI) calcd. for [M⁺] C₁₈H₂₀O₃: 284.1412; found 284.142.

O–CH CH CH=CH ), 0.4 (TMS) ppm. IR (ATR): ν = 3424 (w),

˜

2

2951 (m), 1721 (m), 1695 (s), 1607 (m), 1247 (s), 1100 (m), 1033

(s), 840 (s), 761 cm^–1(m). MS (EI, 70 eV): m/z (%) = 282 (11) [M⁺],

265 (10), 227 (23), 211 (13), 183 (27), 137 (67), 75 (62), 73 (100),

55 (49).

CBS Kinetic resolution of rac-12a and rac-12e: A Schlenk flask was

charged with the azeotropically dried ketone rac-12a (561 mg,

2 mmol) and a 0.1 m solution of freshly prepared (R)-diphenylproli-

nol-derived B-methyl oxazaborolidine^[28a]in toluene (4 mL) was

added at room temp. The mixture was cooled to –78 °C and after

30 min a freshly prepared solution of catecholborane (0.5 m in

THF, various amounts, see Table 2) was added within 5 min. The

mixture was allowed to warm to room temp. and stirred for another

6 h. The reaction was quenched by addition of a 2 m aqueous KOH

(10 mL). After stirring for 30 min at room temp., the mixture was

extracted with EtOAc (4×15 mL) and the combined organic layers

were washed with a 2 m solution of KOH (2×20 mL), a saturated

aqueous solution of NH₄Cl (20 mL), and CuSO₄(2×20 mL). After

repeating the washing process it was finally washed with brine

(2×20 mL). After drying (MgSO₄) and evaporation of the solvent,

the residue was purified by flash chromatography (EtOAc/CyHex,

1:4) to afford the ketone 12a and the alcohol ent-21. The kinetic

resolution of ketone rac-12e was carried out in the same way. De-

termination of the ee: For compound 12a a chiral GLC (Hydrodex

β-PM, 120 °C, isotherm, 15 psi H₂; retention times 12b: 95.65 min

and ent-12b: 97.88 min) was used; for compound 12e a chiral

HPLC (Chiralpak AD-H, acetonitrile/hexane, 5:95, 1 mLmin^–1

flow, retention times 12e: 11.07 min and ent-12e: 12.60 min) was

used. Ketone 12a (Ͼ99% ee): [α]²_D⁰= –174.3 (c = 1.045 in CHCl₃);

(3RS,5SR,9RS)-9-(But-3-enyloxy)-8-oxabicyclo[3.4.0]non-1-ene-3-ol

(rac-21):tBuOK (3.80 g, 33.9 mmol) was added to a solution of rac-

20 (4.00 g, 33.9 mmol) in a 19:1 solvent mixture of DMSO and

H₂O (50 mL) at room temp.; the color of the mixture turned imme-

diately to brown. After stirring for 2 h at room temp. the mixture

was diluted by addition of water (100 mL) and extracted with

EtOAc (4 ×50 mL). The combined organic phases were washed

with water (3×50 mL) and brine (50 mL), dried (MgSO₄), and the

solvent was removed under reduced pressure. The product rac-21,

obtained as a colorless oil (2.41 g, 81% yield), was pure according

to ¹H NMR spectroscopy and TLC and therefore no further purifi-

cation was necessary. TLC: R_f= 0.11 (CyHex/EtOAc, 2:1). ¹H

NMR (250 MHz, CDCl₃): δ = 5.89–5.70 (m, 1 H, CH=CH₂), 5.61

(s, 1 H, H-2), 5.20 (s, 1 H, H-9), 5.08 (dd, J = 2.1, 17.2 Hz, 1 H,

CH=CH–H_trans), 5.02 (dd, J = 2.1, 10.3 Hz, 1 H, CH=CH–H_cis),

4.88 (dd, J = 7.7, 7.7 Hz, 1 H, H-3), 3.91 (ddd, J = 12.2, 12.4,

2.6 Hz, 1 H, H-7a), 3.78–3.63 (m, 1 H, O–CHHa), 3.59 (dd, J =

2.8, 12.2 Hz, 1 H, H-7b), 3.54–3.45 (m, 1 H, O–CHHb), 2.90–2.77

(m, 1 H, H-5), 2.61 (td, J = 7.7, 13.4 Hz, 1 H, H-4a), 2.39 –2.29

(m, 2 H, CH₂–CH=CH₂), 1.86 (dd, J = 6.2, 12.4 Hz, 1 H, H-6a),

1.62 (br. s, 1 H, OH), 1.51 (tdd, J = 2.8, 6.2, 12.4 Hz, 1 H, H-6b),

1.29–1.19 (m, 1 H, H-4b) ppm. ¹³C NMR (63 MHz, CDCl₃): δ =

144.2 (C1), 134.8 (CH=CH₂), 127.7 (C2), 116.5 (CH=CH₂), 95.8

(C9), 76.8 (C3), 66.3 and 59.4 (C7 and O–CH₂CH₂CH=CH₂), 41.3

(C4), 38.8 (C5), 35.7 and 34.0 (C6 and O–CH₂CH₂CH=CH₂) ppm.

20

[α] = –211.5; [α] = –558.0.

546

405

Oxidation of Alcohol ent-21: A solution of alcohol ent-21 in dry

CH₂Cl₂(2 mL) was added to a stirred suspension of MnO₂

(10 equiv.) in dry CH₂Cl₂(5 mL) at 0 °C under argon. The mixture

was allowed to warm to room temp. and stirred for 2 h. The sus-

pension was filtered through a plug of Celite and the solvent was

evaporated to give the ketone ent-12a. The ee analysis of the re-

sulting ketone was carried out by chiral GLC as described pre-

viously.

IR (ATR): ν = 3412 (m), 2927 (m), 2871 (m), 1440 (m), 1321 (m),

˜

1246 (m), 1187 (m), 1162 (m), 1085 (s), 1032 (s), 1000 (s), 955 (m),

839 cm^–1(m). MS (EI, 70 eV): m/z (%) = 209 (Ͻ1) [M – 1⁺], 166

(20), 139 (60, 120 (40), 110 (19), 91 (100), 79 (29), 66 (49), 55 (29),

39 (82).

(3RS,5SR,9RS)-9-(But-3-enyloxy)-8-oxabicyclo[3.4.0]non-1-ene-3-yl

methyl carbonate (rac-22): Pyridine (5 mL) and methyl chloro-

formate (2.30 mL, 29.7 mmol) were added to a solution of alcohol

rac-21 (2.08 g, 9.90 mmol) in CH₂Cl₂(100 mL) at 0 °C and the mix-

ture was stirred for 1 h under argon. The reaction was quenched

with water (50 mL) and stirred for an additional 30 min. The

phases were separated and the aqueous phase was extracted with

(3RS,5SR,9RS)-9-(But-3-enyloxy)-2-trimethylsilyl-8-oxabicyclo-

[3.4.0]non-1-ene-3-ol (rac-20): NaBH₄(2.70 g, 71.3 mmol) was

added portionwise to a solution of rac-12a (4.00 g, 14.3 mmol) and

CeCl₃·7H₂O (5.31 g, 14.3 mmol) in MeOH (150 mL) at –20 °C (ice-

salt bath) over a period of 30 min. After stirring the mixture at

1454

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Eur. J. Org. Chem. 2005, 1444–1458

A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

FULL PAPER

1

CH₂Cl₂(3×100 mL). The combined organic phases were washed

with brine (50 mL), followed by drying (MgSO₄) and removal of

the solvent under reduced pressure. After purification by flash

chromatography (CyHex/EtOAc, 2:1) compound rac-22 was iso-

lated in 91% yield (2.41 g, 9.00 mmol) as a colorless oil. TLC: R_f

= 0.56 (CyHex/EtOAc, 2:1). ¹H NMR (250 MHz, CDCl₃): δ =

solid. M.p. 85 °C. TLC: R_f= 0.58 (EtOAc). H NMR (250 MHz,

CDCl₃): δ = 8.71 (s, 1 H, H-2), 8.16 (s, 1 H, H-8), 5.89–5.75 (m, 2

H, CH=CH₂and H-3Ј), 5.67–5.66 (m, 1 H, H-2Ј), 5.33 (s, 1 H, H-

9Ј), 5.13–5.01 (m, 2 H, CH=CH₂), 3.98 (ddd, J = 1.2, 12.3, 12.8 Hz,

1 H, H-7aЈ), 3.78 (td, J = 7.0, 9.7 Hz, 1 H, O–CHHa), 3.67 (ddd,

J = 2.1, 4.9, 12.3 Hz, 1 H, H-7bЈ), 3.53 (td, J = 6.6, 9.7 Hz, 1 H,

5.86–5.72 (m, 1 H, CH=CH₂), 5.61 (m, 1 H, H-2), 5.61–5.67 (m, 1 O–CHHb), 3.18–3.07 (m, 1 H, H-5Ј), 2.98 (ddd, J = 8.2, 8.4,

H, H-3), 5.21 (s, 1 H, H-9), 5.08 (dd, J = 1.9, 17.2 Hz, 1 H, 13.8 Hz, 1 H, H-4aЈ), 2.41 –2.34 (m, 2 H, CH₂–CH=CH₂), 1.95

CH=CH–H_trans), 5.03 (dd, J = 1.9, 10.7 Hz, 1 H, CH=CH–H_cis),

3.92 (ddd, J = 12.0, 12.0, 2.0 Hz, 1 H, H-7a), 3.74 (s, 3 H, OCH₃), 1 H, H-6bЈ), 1.61–1.49 (m, 1 H, H-4bЈ) ppm. ¹³C NMR (63 MHz,

3.76–3.62 (m, 1 H, O–CHHa), 3.60 (ddd, J = 1.4, 4.4, 12.0 Hz, 1 CDCl₃): δ = 151.8 (C2), 151.5 and 150.9 (C4 and C6), 148.1 (C1Ј),

H, H-7b), 3.49 (td, J = 6.7, 9.7 Hz, 1 H, O–CHHb), 2.95–2.82 (m, 143.1 (C8), 134.8 (CH=CH₂), 131.8 (C5), 121.2 (C2Ј), 116.7

1 H, H-5), 2.64 (td, J = 7.9, 14.1 Hz, 1 H, H-4a), 2.39–2.31 (m, 2 ( C H = C H ₂) , 9 5 . 2 ( C 9 Ј ) , 6 6 . 5 a n d 5 9 . 0 ( C 7 Ј a n d O –

(dd, J = 6.2, 12.8 Hz, 1 H, H-6aЈ), 1.63 (tdd, J = 4.9, 13.1, 13.8 Hz,

H, CH₂–CH=CH₂), 1.86 (dd, J = 5.7, 12.0 Hz, 1 H, H-6a), 1.63– CH₂CH₂CH=CH₂), 59.7 (C3Ј), 39.3 (C5Ј), 39.6 and 35.2 and 34.0

1.35 (m, 2 H, H-6b and H-4b) ppm. ¹³C NMR (63 MHz, CDCl₃): (C4 and C6 and O–CH CH CH=CH ) ppm. IR (ATR): ν = 2935

˜

2

δ = 155.4 (C=O), 147.1 (C1), 134.9 (CH=CH₂), 122.6 (C2), 116.5

(CH=CH₂), 95.6 (C9), 83.0 (C3), 66.3 and 59.3 (C7 and O–

CH₂CH₂CH=CH₂), 54.5 (CH₃), 38.7 (C5), 36.9 and 35.4 and 34.0

(w), 2358 (s), 2339 (s), 1588 (m), 1558 (m), 1334 (m), 1195 (m), 1095

(m), 1032 (m), 950 (m), 848 (m), 667 cm^–1(m). MS (EI, 70 eV): m/

z (%) = 346 (46) [M⁺], 275 (93), 219 (11), 192 (54), 155 (49), 121

(C4 and C6 and O–CH CH CH=CH ) ppm. IR (ATR): ν = 2936 (30), 93 (62), 77 (56), 66 (38), 55 (100). HRMS (EI) calcd. for [M⁺]

˜

2

(m), 1741 (s), 1441 (m), 1345 (m), 1261 (s), 1093 (m), 1037 (m), 970 C₁₇H₁₉ClN₄O₂: 346.1197; found 346.120. C₁₇H₁₉ClN₄O₂(346.81):

(m), 793 cm^–1(w). MS (EI, 70 eV): m/z (%) = 268 (8) [M⁺], 197 calcd. C 58.87, H 5.52, N 16.15; found C 59.29, H 5.92, N 15.66.

(100), 153 (11), 139 (14), 121 (53), 109 (23), 91 (37), 77 (33), 59

(27), 55 (79). HRMS (EI) calcd. for [M⁺] C₁₄H₂₀O₅: 268.1311;

found 268.129.

(1ЈRS,4ЈSR)-6-Chloro-9-[4Ј-dimethyl-(1,1,2-trimethylpropyl)silanyl-

oxyethyl]-3Ј-(hydroxymethylcyclopent-2Ј-enyl)-9H-purine (rac-18):

A solution of rac-23 (104 mg, 0.3 mmol) in wet acetone (6 mL) was

added to Amberlyst-15 (10 mg, 0.1 wt. equiv.) and the mixture was

shaken for 1 h. After removal of Amberlyst-15 by filtration, poly(4-

vinylpyridine) (208 mg, 2 wt. equiv.; 2% cross-linked) was added,

the solvent was evaporated, and the flask was flushed with argon

(3 times). Dry pyridine (2 mL) was added and, after stirring at

room temp. for 5 min, ThxMe₂SiCl (176 μL, 0.9 mmol) was added.

After stirring at room temp. for 16 h, the reaction was quenched

by addition of saturated aqueous NaHCO₃(20 mL). After stirring

the resulting mixture at room temp. for 30 min, the water phase

was extracted with EtOAc (4×20 mL) and the combined organic

layers were washed with 10% HCl (3×20 mL), saturated aqueous

NaHCO₃(20 mL), and brine (40 mL), dried (MgSO₄), and concen-

trated. After removal of the solvent the crude product was directly

used for the next step. A mixture of MeOH (3 mL) and CH₂Cl₂

(6 mL) was added to NaBH₄(113 mg, 3 mmol), the resulting mix-

ture was stirred at room temp. for 3 min, and then cooled to

–78 °C. A solution of the crude mixture in CH₂Cl₂(2 mL) was

added dropwise. After stirring the mixture at –78 °C for 1 h, ace-

tone (5 mL) was added and the mixture was allowed to warm to

room temp. and stirred for an additional 30 min. The mixture was

poured onto a plug of silica, washed with EtOAc, and the solvents

were removed under reduced pressure. After purification by flash

chromatography the CNA rac-18 was obtained (83 mg, 63%) as a

(3ЈRS,5ЈSR,9ЈRS)-9Ј-(But-3ЈЈ-enyloxy)-8Ј-oxabicyclo[3.4.0]non-1Ј-

ene-3Ј-yl)-5-bromo-1H-pyrimidine-2,4-dione (rac-24): dppp (116 mg,

0.280 mmol) was added to a solution of [Pd₂(dba)₃] (62 mg,

0.067 mmol) in dry, degassed DMF (20 mL) at room temp. under

argon. The solution was stirred for 5 min. Carbonate rac-22

(720 mg, 2.69 mmol) in DMF (2 mL) and the bromouracil (770 mg,

4.03 mmol) in DMF (2 mL) were added to the mixture. After stir-

ring at room temp. for 16 h, the reaction was quenched by addition

of water (80 mL). The layers were separated and the aqueous phase

was extracted with EtOAc (5×60 mL). The combined organic lay-

ers were washed with water (3×60 mL) and brine (30 mL), dried,

and finally the solvent was removed under reduced pressure. The

residue was purified by flash chromatography (CyHex/EtOAc, 2:1)

to afford the product rac-24 as a white solid (751 mg, 73%). M.p.

161 °C. TLC: R_f= 0.14 (CyHex/EtOAc, 2:1). ¹H NMR (250 MHz,

CDCl₃): δ = 9.36 (s, 1 H, NH), 7.51 (s, 1 H, H-6), 5.89–5.73 (m, 1

H, CH=CH₂), 5.74–5.66 (m, 1 H, H-3Ј), 5.43–5.41 (m, 1 H, H-2Ј),

5.30 (s, 1 H, H-9Ј), 5.13–5.01 (m, 2 H, CH=CH₂), 3.97 (ddd, J =

1.6, 10.2, 11.3 Hz, 1 H, H-7aЈ), 3.81–3.72 (m, 1 H, O–CHHa), 3.67

(ddd, J = 1.6, 5.7, 10.2 Hz, 1 H, H-7bЈ), 3.52 (td, J = 6.6, 9.6 Hz,

1 H, O–CHHb), 3.07–2.94 (m, 1 H, H-5Ј), 2.83 (td, J = 8.1,

13.5 Hz, 1 H, H-4aЈ), 2.40–2.32 (m, 2 H, CH₂–CH=CH₂), 1.93 (dd,

J = 5.7, 12.1 Hz, 1 H, H-6a), 1.53 (tdd, J = 5.0, 11.3, 12.1 Hz, 1

H, H-6bЈ), 1.25–1.14 (m, 1 H, H-4bЈ) ppm. ¹³C NMR (63 MHz,

CDCl₃): δ = 159.0 (C4), 150.3 and 148.8 (C2 and C1Ј), 140.0 (C6),

134.8 (CH=CH₂), 121.5 (C2Ј), 116.7 (CH=CH₂), 97.0 (C9Ј), 95.1

(C5), 66.6 and 59.0 (C7Ј and O–CH₂CH₂CH=CH₂), 61.5 (C3Ј),

38.8 (C5Ј), 38.7 and 35.2 and 33.9 (C4 and C6 and O–

1

white solid. M.p. 130 °C. TLC: R_f= 0.16 (DCM/MeOH, 20:1). H

NMR (300 MHz, CDCl₃): δ = 8.72 (s, 1 H, H-2), 8.14 (s, 1 H, H-

8), 5.83 (m, 1 H, H-2Ј), 5.73–5.70 (m, 1 H, H-1Ј), 4.48 (d, J =

15.1 Hz, 1 H, CHHaOH), 4.32 (d, J = 15.1 Hz, 1 H, CHHbOH),

3.67–3.50 (m, 2 H, SiOCH₂), 3.02–2.91 (m, 2 H, H-4Ј and H-5aЈ),

2.14 (br. s, 1 H, OH), 2.01–1.91 (m, 1 H, SiOCH₂CHHa), 1.75–

1.67 (m, 1 H,H-5bЈ), 1.61 (septet, J = 6.8, 1 H, Me₂CH), 1.47–1.36

(m, 1 H, SiOCH₂CHHb), 0.81 [d, J = 6.8 Hz, 6 H, (CH₃)₂CH],

0.77 [s, 6 H, C(CH₃)₂], 0.03 and 0.02 (2s, 6 H, SiCH₃) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 155.6 (C3Ј), 151.7 (C2), 151.5 and

150.9 (C4 and C6), 143.3 (C8), 132.0 (C5), 121.1 (C2Ј), 60.9 and

60.5 (CH₂CH₂OSi and CH₂OH), 59.3 (C1Ј), 41.6 (C4Ј), 39.1 and

36.7 (C5Ј and CH₂CH₂OSi), 34.1 [(CH₃)₂CH], 25.1 (Me₂CSi), 20.3

CH CH CH=CH ) ppm. IR (ATR): ν = 3068 (w), 1694 (s), 1616

˜

2

(m), 1442 (m), 1253 (m), 1094 (m), 1032 (m), 963 cm^–1(w). MS

(EI, 70 eV): m/z (%) = 384 (4) [M⁺], 382 (4) [M⁺], 311 (57), 313

(58), 193 (46), 139 (85), 121 (46), 109 (65), 93 (89), 77 (59), 55 (100).

HRMS (EI) calcd. for [M⁺] C₁₆H₁₉⁸¹BrN₂O₄: 384.0509; found

384.052. C₁₆H₁₉BrN₂O₄(383.24): calcd. C 50.14, H 5.00, N 7.31;

found C 50.41, H 5.28, N 7.00.

(3ЈRS,5ЈSR,9ЈRS)-9Ј-(But-3-enyloxy)-8Ј-oxabicyclo[3.4.0]non-1Ј-

ene-3Ј-yl)-9H-6-chloropurine (rac-23): Following the procedure for

the preparation of rac-24, chloropurine was introduced. Compound

rac-22 (1.97 g, 7.35 mmol) afforded rac-23 (1.55 g, 60%) as a white

[(CH ) CH], 18.4 [(CH ) CSi], –3.5 (CH Si) ppm. IR (ATR): ν =

˜

3 2

3

3359 (m), 2955 (m), 2864 (w), 1588 (s), 1558 (m), 1401 (m), 1332

(m), 1249 (m), 1200 (m), 1087 (m), 954 (m), 828 (s), 773 cm^–1(m).

Eur. J. Org. Chem. 2005, 1444–1458

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1455

A. Lanver, H.-G. Schmalz

FULL PAPER

MS (ESI): m/z (%) = 459 (25) [M + Na⁺], 402 (6), 318 (39), 262 H_ar), 7.35–7.30 (m, 3 H, H_ar), 6.28–6.22 (m, 1 H, H-3), 5.92 (dddd,

(100), 155 (7), 105 (32). HRMS (ESI) calcd. for [M + Na]⁺

J = 5.4, 6.1, 10.3, 17.2 Hz, 1 H, CH=CH₂), 5.55 (s, 1 H, H-8), 5.26

C₂₁H₃₃ClN₄O₂SiNa: 459.1959; found 459.197. C₂₁H₃₃ClN₄O₂Si (tdd, J = 1.6, 1.6, 17.2 Hz, 1 H, CH=CH–H_trans), 5.16 (tdd, J =

(437.05): calcd. C 57.71, H 7.61, N 12.82; found C 57.77, H 7.56,

N 12.65.

1.2, 1.3, 10.3 Hz, 1 H, CH=CH–H_cis), 4.30 (dd, J = 7.7, 7.7 Hz, 1

H, H-6a), 4.22 (tdd, J = 1.4, 5.4, 12.7 Hz, 1 H, CHHa–CH=CH₂),

4.05 (tdd, J = 1.3, 6.1, 12.7 Hz, 1 H, CHHb–CH=CH₂), 3.76 (s, 3

H, CH₃), 3.49 (dd, J = 7.7, 7.7 Hz, 1 H, H-6b), 3.46–3.33 (m, 1 H,

H-5), 2.95 (ddd, J = 6.7, 6.7, 12.7 Hz, 1 H, H-4a), 1.70 (ddd, J =

7.6, 7.6, 12.7 Hz, 1 H, H-4b) ppm. ¹³C NMR (63 MHz, CDCl₃): δ

= 155.0 and 146.1 and 133.2 (s, C1, C2, and C_ar), 134.1 (CH=CH₂),

128.4, 128.1, 127.9, (d, C_ar), 117.6 (CH=CH₂), 96.9 (C8), 88.2 (C3),

72.0 and 68.2 (C6 and CH₂CH=CH₂), 55.8 (CH₃), 44.2 (C5), 38.2

(1ЈRS,4ЈSR)-5-Bromo-1-[4Ј-[dimethyl-(1,1,2-trimethylpropyl)silanyl-

oxyethyl]-3Ј-(hydroxymethylcyclopent-2Ј-enyl)-1H-pyrimidine-2,4-

dione (rac-19): Following the procedure for the preparation of rac-

18, compound rac-24 (115 mg, 0.3 mmol) afforded rac-19 (99 mg,

69%) as a white solid. M.p. 134 °C. TLC: R_f= 0.15 (DCM/MeOH,

20:1). ¹H NMR (250 MHz, CDCl₃): δ = 9.06 (br. s, 1 H, NH), 7.52

(s, 1 H, H-6), 5.57–5.54 (m, 2 H, H-1Ј and H-2Ј), 4.38 (d, J =

15.4 Hz, 1 H, CHHaOH), 4.26 (d, J = 15.4 Hz, 1 H, CHHbOH),

3.70–3.51 (m, 2 H, SiOCH₂), 2.88–2.76 (m, 2 H, H-4Ј and H-5aЈ),

2.01–1.89 (m, 1 H, SiOCH₂CHHa), 1.58 (septet, J = 6.8 Hz, 1 H,

Me₂CH), 1.44–1.28 (m, 2 H,H-5bЈ and SiOCH₂CHHb), 0.84 [d, J

= 6.8 Hz, 6 H, (CH₃)₂CH], 0.81 [s, 6 H, C(CH₃)₂], 0.06 (s, 6 H,

SiCH₃) ppm. ¹³C NMR (63 MHz, CDCl₃): δ = 159.1 (C4), 156.0

(C3Ј), 150.2 (C2), 140.4 (C6), 121.3 (C2Ј), 96.5 (C5), 61.3 (C1Ј),

60.9 and 60.6 (CH₂CH₂OSi and CH₂OH), 41.2 (C4Ј), 38.5 and

36.7 (C5Ј and CH₂CH₂OSi), 34.1 [(CH₃)₂CH], 25.1 (Me₂CSi), 20.3

[(CH₃)₂CH], 18.5 [(CH₃)₂CSi], –3.4 and –3.5 (CH₃Si) ppm. IR

(C4) ppm. IR (ATR): ν = 2952 (w), 1741 (s), 1671 (m), 1441 (m),

˜

1257 (s), 1045 (m), 934 (m), 790 (m), 700 cm^–1(m). MS (EI, 70 eV):

m/z (%) = 316 (8) [M⁺], 259 (30), 210 (18), 194 (68), 169 (61), 155

(100), 141 (73), 128 (66), 115 (69), 91 (35), 77 (39), 59 (32). HRMS

(EI) calcd. for [M⁺] C₁₈H₂₀O₅: 316.1311; found 316.130.

(3RS,5SR,8RS)-8-Allyloxy-2-phenyl-7-oxabicyclo[3.3.0]oct-1-ene-3-

yl 4-Nitrobenzoate (Derived from rac-27): A mixture of rac-27

(860 mg, 3.41 mmol), 4-nitrobenzoic acid (2.50 g, 15.0 mmol), and

PPh₃(4.47 mg, 17.05 mmol) in dry toluene (50 mL) was stirred at

room temp. for 30 min. DEAD (2.65 mL, 17.05 mmol) was added

dropwise and the resulting yellow mixture was stirred for another

16 h. The solvent was evaporated and the mixture was purified by

column chromatography (CyHex/EtOAc = 4 +1) to give the p-ni-

trobenzoate as a light-yellow oil (1.096 g, 79%). TLC: R_f= 0.47

(ATR): ν = 3396 (w), 2954 (m), 1693 (s),1616 (m), 1445 (m), 1248

˜

(m), 1092 (m), 1034 (m), 828 (m), 776 cm^–1(m). MS (ESI): m/z (%)

= 633 (3), 569 (4), 495 (100) [M + Na⁺], 475 (2), 407 (7), 305 (5).

HRMS (ESI) calcd. for [M + Na⁺] C₂₀H₃₃⁷⁹BrN₂O₄SiNa:

495.1291; found 495.128.

1

(CyHex/EtOAc, 2:1). H NMR (250 MHz, CDCl₃): δ = 8.26–8.10

(m, 4 H, H_ar–NO2), 7.50–7.46 (m, 2 H, H_ar), 7.38–7.28 (m, 3 H,

H_ar), 6.82 (dd, J = 1.5, 7.0 Hz, 1 H, H-3), 6.14–5.99 (m, 1 H,

CH=CH₂), 5.51 (s, 1 H, H-8), 5.39 (tdd, J = 1.5, 1.6, 17.2 Hz, 1 H,

CH=CH–H_trans), 5.27 (tdd, J = 1.1, 1.6, 10.3 Hz, 1 H, CH=CH–

H_cis), 4.39–4.33 (m, 1 H, CHHa–CH=CH₂), 4.34 (dd, J = 8.4,

8.4 Hz, 1 H, H-6a), 4.20 (tdd, J = 1.2, 6.4, 12.5 Hz, 1 H, CHHb–

CH=CH₂), 4.03–3.96 (m, 1 H, H-5), 3.41 (dd, J = 8.4, 8.4 Hz, 1

H, H-6b), 2.36 (ddd, J = 7.0, 14.5 Hz, 1 H, H-4a), 2.15 (ddd, J =

7.0, 7.0, 14.5 Hz, 1 H, H-4b) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

= 164.6 (C=O), 150.52, 150.48, 135.4, 133.6, 132.5 (C1 and C2 and

s, C_ar), 134.1 (CH=CH₂), 130.8, 128.8, 128.5, 127.6, 123.4 (d, C_ar),

118.1 (CH=CH₂), 97.1 (C8), 85.6 (C3), 71.2 and 68.5 (C6 and

(3RS,5SR,8RS)-8-Allyloxy-2-phenyl-7-oxabicyclo[3.3.0]oct-1-ene-3-

ol (rac-27): NaBH₄(590 mg, 15.6 mmol) was added portionwise to

a solution of rac-12e (1.00 g, 3.90 mmol) and CeCl₃·7H₂O (1.45 g,

3.90 mmol) in MeOH (340 mL) at –20 °C (ice-salt bath) over a

period of 30 min. After stirring the mixture at room temp. for 2 h,

the reaction was quenched by addition of a saturated aqueous

NaHCO₃(100 mL). The mixture was extracted with MTBE

(4×100 mL) and the combined organic layers were washed with

sat. NaHCO₃(2 ×100 mL) and brine (100 mL), dried (MgSO₄),

and the solvents evaporated. The alcohol rac-27 was obtained as a

colorless oil (1.00 g, 99%) that was pure according to ¹H NMR

spectroscopy and GLC analysis. TLC: R_f= 0.21 (CyHex/EtOAc,

2:1). ¹H NMR (250 MHz, CDCl₃): δ = 7.66–7.57 (m, 2 H, H_ar),

7.38–7.28 (m, 3 H, H_ar), 6.02 (dddd, J = 17.2, 10.3, 5.4, 6.1 Hz, 1

H, CH=CH₂), 5.60 (s, 1 H, H-8), 5.47–5.39 (m, 1 H, H-3), 5.25

(tdd, J = 1.6, 1.6, 17.2 Hz, 1 H, CH=CH–H_trans), 5.16 (tdd, J =

1.3, 1.6, 10.3 Hz, 1 H, CH=CH–H_cis), 4.29 (dd, J = 8.0, 8.0 Hz, 1

H, H-6a), 4.20 (tdd, J = 1.4, 5.4, 12.7 Hz, 1 H, CHHa–CH=CH₂),

4.05 (tdd, J = 1.4, 6.1, 12.7 Hz, 1 H, CHHb–CH=CH₂), 3.48 (dd,

J = 8.0, 8.0 Hz, 1 H, H-6b), 3.37–3.25 (m, 1 H, H-5), 2.88–2.77

(m, 1 H, H-4a), 1.51 (ddd, J = 8.0, 8.0, 12.4 Hz, 1 H, H-4b) ppm.

¹³C NMR (63 MHz, CDCl₃): δ = 143.9 and 136.8 and 134.1 (s, C1,

C2, and C_ar), 134.3 (CH=CH₂), 128.4, 128.2, 127.9, (d, C_ar), 117.5

(CH=CH₂), 97.1 (C8), 83.7 (C3), 72.3 and 68.1 (C6 and

CH CH=CH ), 47.4 (C4), 36.5 (C5) ppm. IR (ATR): ν = 2919 (m),

˜

2

1718 (s), 1526 (s), 1345 (m), 1266 (s), 1099 (m), 1076 (m), 994 (m),

939 (m), 852 (m), 718 cm^–1(m). MS (EI, 70 eV): m/z (%) = 407

(16) [M⁺], 350 (9), 321 (10), 194 (16), 171 (22), 155 (53), 150 (100),

115 (25), 104 (31), 92 (18), 76 (21). HRMS (EI) calcd. for [M⁺]

C₂₃H₂₁NO₆: 407.1369; found 407.138.

(3SR,5SR,8RS)-8-Allyloxy-2-phenyl-7-oxabicyclo[3.3.0]oct-1-ene-3-

ol (rac-29): The p-nitrobenzoate derived from rac-27 (710 mg,

1.74 mmol) was dissolved in MeOH (30 mL) and K₂CO₃(480 mg,

3.48 mmol) was added. The mixture was stirred at room temp. for

16 h. Water (60 mL) and EtOAc (100 mL) were added and the or-

ganic phase was separated. After re-extracting the aqueous phase

with EtOAc (3×60 mL), the combined organic phases were washed

with water (50 mL) and brine (50 mL), and were finally dried

(MgSO₄) and concentrated in vacuo to give a colorless oil. Purifica-

tion by flash chromatography (CyHex/EtOAc, 2:1) gave alcohol

rac-29 (269 mg, 82%). TLC: R_f= 0.13 (CyHex/EtOAc, 2:1). ¹H

NMR (250 MHz, CDCl₃): δ = 7.51–7.46 (m, 2 H, H_ar), 7.40–7.29

(m, 3 H, H_ar), 6.01 (dddd, J = 5.2, 6.2, 10.3, 17.2 Hz, 1 H,

CH=CH₂), 5.57 (dd, J = 1.3, 6.4 Hz 1 H, H-3), 5.46 (s, 1 H, H-8),

5.35 (tdd, J = 1.6, 1.6, 17.2 Hz, 1 H, CH=CH–H_trans), 5.22 (tdd, J

= 1.2, 1.6, 10.3 Hz, 1 H, CH=CH–H_cis), 4.27 (tdd, J = 1.6, 5.2,

12.6 Hz, 1 H, CHHa–CH=CH₂), 4.29 (dd, J = 8.4, 8.4 Hz, 1 H,

CH CH=CH ), 43.8 (C5), 41.6 (C4) ppm. IR (ATR): ν = 3412 (m),

˜

2

2914 (m), 2876 (m), 1444 (m), 1339 (m), 1203 (w), 1064 (s), 978 (s),

938 (m), 765 (m), 698 cm^–1(m). MS (EI, 70 eV): m/z (%) = 258 (2)

[M⁺], 201 (52), 194 (56), 159 (63), 143 (64), 131 (82), 128 (89), 115

(74), 105 (59), 91 (100), 77 (57). HRMS (EI) calcd. for [M⁺]

C₁₆H₁₈O₃: 258.1256; found 258.126.

(3RS,5SR,8RS)-8-Allyloxy-2-phenyl-7-oxabicyclo[3.3.0]oct-1-ene-3-

yl Methyl Carbonate (rac-28): Following the procedure for the prep-

aration of rac-22, compound rac-27 (30 mg, 0.12 mmol) afforded

rac-28 (32 mg, 84%) as a colorless oil.TLC: R_f= 0.45 (CyHex/

1

EtOAc, 2:1). H NMR (250 MHz, CDCl₃): δ = 7.47–7.43 (m, 2 H, H-6a), 4.15 (tdd, J = 1.3, 6.2, 12.6 Hz, 1 H, CHHb–CH=CH₂),

1456

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1444–1458

A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

FULL PAPER

3.98–3.86 (m, 1 H, H-5), 3.30 (dd, J = 8.4, 8.4 Hz, 1 H, H-6b),

2.26–2.18 (m, 1 H, H-4a), 1.93 (ddd, J = 7.0, 7.0, 14.0 Hz, 1 H, H-

4b) ppm. ¹³C NMR (63 MHz, CDCl₃): δ = 147.0 and 137.4 and

133.1 (C1 and C2 and s, C_ar), 134.3 (CH=CH₂), 128.8, 128.3, 127.8

(d, C_ar), 117.7 (CH=CH₂), 97.2 (C8), 83.2 (C3), 71.6 and 68.3 (C6

[d, J = 6.8 Hz, 6 H, (CH₃)₂CH], 0.88 [s, 6 H, C(CH₃)₂], 0.15 and

0.14 (2s, 6 H, SiCH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 190.7

(CH=O), 158.1 (C2), 151.9 (C2Ј), 151.7 and 151.0 (C4Ј+C6Ј), 143.9

(C8Ј), 141.3 (C1), 130.9 and 130.6 (C5Јand s, C_ar), 130.3 and 129.0

and 128.6 (d, C_ar), 63.3 (CH₂OSi), 60.7 (C3), 45.5 (C5), 34.1

(Me₂CH), 33.5 (C4), 25.5 (Me₂CSi), 20.5 and 20.4 [(CH₃)₂CH],

and CH CH=CH ), 47.1 (C5), 38.7 (C4) ppm. IR (ATR): ν = 3387

˜

2

(m), 2880 (m), 1496 (m), 1445 (m), 1356 (m), 1287 (m), 1203 (m), 18.6 and 18.5 [(CH₃)₂CSi], –3.3 and –3.4 (CH₃Si) ppm. IR (ATR):

1091 (s), 996 (s), 969 (s), 778 (m), 694 cm^–1(m). MS (EI, 70 eV): ν = 2955 (m), 1716 (m), 1671 (s), 1588 (s), 1558 (s), 1401 (m), 1333

˜

m/z (%) = 258 (2) [M⁺], 214 (24), 201 (42), 171 (37), 159 (47), 143 (m), 1251 (m), 1197 (s), 1105 (m), 934 (m), 829 (s), 776 cm^–1(m).

(57), 131 (78), 128 (77), 115 (69), 105 (73), 91 (100), 77 (58). HRMS MS (ESI): m/z (%) = 519 (5) [M + Na⁺], 497 (44), 343 (11), 318

(EI) calcd. for [M⁺] C₁₆H₁₈O₃: 258.1256; found 258.126.

(41), 262 (100), 183 (15). HRMS (ESI) calcd. for [M + H⁺] C₂₆H₃₄:

ClN₄O₂SiNa 497.2139; found 497.213.

(3ЈRS,5ЈSR,8ЈRS)-9-(8Ј-Allyloxy-2Ј-phenyl-7Ј-oxabicyclo[3.3.0]oct-

1Ј-ene-3Ј-yl)-9H-6-chloropurine (rac-30): 6-Chloropurine (371 mg,

2.4 mmol) and PPh₃(1.57 g, 2.4 mmol) were dissolved in dry THF

(20 mL) and DEAD (467 μL, 2.4 mmol) was added dropwise. The

resulting yellow mixture was stirred for 10 min and a solution of

rac-27 (300 mg, 1.2 mmol) in THF (2 mL) was slowly added. After

stirring the reaction mixture for 15 h the solvent was evaporated

and the mixture was purified by flash chromatography (EtOAc) to

give compound rac-30 as a sticky, yellow oil (294 mg, 62%, purity

was Ϸ90 % according to ¹H NMR). TLC: R_f= 0.30 (CyHex/

(1ЈRS,4ЈSR)-9-{4Ј-[Dimethyl-(1,1,2-trimethylpropyl)silanyloxymeth-

yl]-3Ј-hydroxymethyl-2Ј-phenylcyclopent-2Ј-enyl}-9H-6-chloropurine

(rac-17): A mixture of MeOH (3 mL) and CH₂Cl₂(6 mL) was

added to NaBH₄(40 mg, 1.04 mmol), the resulting mixture was

stirred at room temp. for 3 min, and then cooled to –78 °C. A solu-

tion of rac-31 (52 mg, 0.104 mmol) in CH₂Cl₂(2 mL) was added

dropwise. After stirring the mixture at –78 °C for 1 h, acetone

(5 mL) was added and the mixture was allowed to warm to room

temp. and stirred for 30 min. The mixture was poured onto a plug

of silica, washed with EtOAc, and the solvents were removed under

reduced pressure to give the CNA rac-17 (53 mg, 99%) in a high

purity according to ¹H NMR spectroscopy and TLC. M.p. 133 °C.

TLC: R_f= 0.24 (CyHex/EtOAc, 2:1). ¹H NMR (250 MHz, CDCl₃):

δ = 8.72 (s, 1 H, H-2), 7.92 (s, 1 H, H-8),7.19–7.13 (m, 5 H, H_ar),

6.27 (dd, J = 8.6, 6.9 Hz, 1 H, H-1Ј), 4.45–4.22 (m, 2 H, CH₂OH),

3.97 (dd, J = 10.3, 3.8 Hz, 1 H, SiOCHa), 3.72 (dd, J = 10.3,

6.9 Hz, 1 H,SiOCHb), 3.43 (t, J = 5.5 Hz, 1 H, OH), 3.29–3.22 (m,

1 H, H-4Ј), 2.93 (ddd, J = 8.6, 8.6, 13.6 Hz, 1 H,H-5aЈ), 1.73 (ddd,

J = 6.9, 6.9, 13.6 Hz, 1 H, H-5bЈ), 1.65 (septet, J = 6.8, 1 H,

Me₂CH), 0.90 [d, J = 6.8 Hz, 6 H, (CH₃)₂CH], 0.89 [s, 6 H, C-

(CH₃)₂], 0.18 and 0.16 (2s, 6 H, SiCH₃) ppm. ¹³C NMR (63 MHz,

CDCl₃): δ = 151.8 (C2), 151.7 and 150.8 (C4 and C6), 145.8 (C3Ј),

143.7 (C8), 137.6 and 132.9 (C2Јand s, C_ar), 131.3 (C5), 128.7 and

128.4 and 127.8 (d, C_ar), 65.5 (CH₂OSi), 60.7 (C1Ј), 58.7 (CH₂OH),

48.1 (C4Ј), 34.2 (C5Ј), 34.1 (Me₂CH), 25.3 (Me₂CSi), 20.3 and 20.2

[(CH₃)₂CH], 18.5 [(CH₃)₂CSi], –3.4 and –3.5 (CH₃Si) ppm. IR

1

EtOAc, 1:1). H NMR (300 MHz, CDCl₃): δ = 8.73 (s, 1 H, H-2),

7.98 (s, 1 H, H-8), 7.13–7.10 (m, 2 H, H_ar), 7.00–6.97 (m, 3 H, H_ar),

6.53 (ddd, J = 1.6, 6.9, 8.7 Hz, 1 H, H-3Ј), 5.89 (s, 1 H, H-8), 5.81

(dddd, J = 17.2, 10.3, 6.1, 5.3 Hz, 1 H, CH=CH₂), 5.20 (tdd, J =

1.5, 1.6, 17.2 Hz, 1 H, CH=CH–H_trans), 5.13 (tdd, J = 1.3, 1.6,

10.3 Hz, 1 H, CH=CH–H_cis), 4.41–4.36 (m, 1 H, H-6aЈ), 4.19 (tdd,

J = 1.4, 5.3, 12.7 Hz, 1 H, CHHa–CH=CH₂), 4.03 (tdd, J = 1.3,

6.1, 12.7 Hz, 1 H, CHHb–CH=CH₂), 3.73–3.64 (m, 2 H, H-6bЈ

and H-5), 3.06 (ddd, J = 6.9, 6.9, 12.5 Hz, 1 H, H-4aЈ), 2.03 (ddd,

J = 8.7, 8.7, 12.5 Hz, 1 H, H-4bЈ) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 152.5 (C2), 144.2 (C8), 147.8, 132.5, 132.3, 131.9,

129.3, 129.0, 128.9, 128.8, 127.1 (C4, C5, C6, C1Ј, C2Ј, C_ar), 134.3

(CH=CH₂), 118.2 (CH=CH₂), 96.5 (C8Ј), 72.1 (C6Ј), 68.6

(CH₂CH=CH₂), 66.5 (C3Ј), 45.9 (C5Ј), 40.2 (C4Ј) ppm. IR (ATR):

ν = 2975 (m), 1725 (m), 1669 (m), 1588 (s), 1556 (s), 1400 (m),

˜

1334 (s), 1195 (s), 1064 (m), 982 (m), 933 (s), 721 (m), 695 cm^–1

(m). MS (EI, 70 eV): m/z (%) = 394 (6) [M⁺], 337 (11), 240 (38),

199 (19), 181 (20), 171 (37), 155 (100), 141 (64), 128 (27), 115 (44),

77 (24). HRMS (EI) calcd. for [M⁺] C₂₁H₁₉O₂N₂Cl: 394.1197;

found 394.119.

(ATR): ν = 3382 (m), 2954 (m), 2864 (m), 1692 (m), 1588 (s), 1558

˜

(m), 1333 (m), 1251 (m), 1195 (m), 1107 (m), 828 (s), 776 (s),

699 cm^–1(m). MS (ESI): m/z (%) = 705 (8), 619 (9), 521 (75) [M +

Na⁺], 367 (100), 209 (15), 185 (8). HRMS (ESI) calcd. for [M +

Na⁺] C₂₆H₃₅ClN₄O₂SiNa: 521.2115; found 521.211.

(3RS,5SR)-3-(6Ј-Chloropurin-9Ј-yl)-5-[2-dimethyl-(1,1,2-trimethyl-

propyl)silanyloxymethyl]-2-phenylcyclopent-1-enecarbaldehyde (rac-

31): A solution of rac-30 (150 mg, 0.38 mmol) and PPTS (28 mg,

0.11 mmol) in wet acetone (5 mL) was stirred under reflux for 6 h.

The solvent was evaporated and the flask was flushed with argon

(3 times). Dry pyridine (2 mL) was added and, after stirring at

room temp. for 5 min, ThxMe₂SiCl (299 μL, 1.52 mmol) was

added. After stirring at room temp. for 16 h, the reaction was

quenched by addition of saturated aqueous NaHCO₃(20 mL). Af-

ter stirring the resulting mixture at room temp. for 30 min, the

water phase was extracted with EtOAc (4×10 mL) and the com-

bined organic layers were washed with 10% HCl (3×10 mL), sat.

NaHCO₃(10 mL), and brine (10 mL), dried (MgSO₄), and concen-

trated. The residue was then purified by flash chromatography

(CyHex/EtOAc, 2:1) to give rac-31 as a white solid (139 mg, 73%).

M.p. 142 °C. TLC: R_f= 0.40 (CyHex/EtOAc, 2:1). ¹H NMR

(300 MHz, CDCl₃): δ = 9.85 (s, 1 H, HC=O), 8.72 (s, 1 H, H-2Ј),

8.20 (s, 1 H, H-8Ј), 7.28–7.22 (m, 5 H, H_ar), 6.42 (ddd, J = 6.9, 9.5,

1.8 Hz, 1 H, H-3), 4.41 (dd, J = 3.7, 9.9 Hz, 1 H, SiOCHa), 3.75

(dd, J = 2.5, 9.9 Hz, 1 H,SiOCHb), 3.50–3.42 (m, 1 H, H-5), 2.99

(ddd, J = 9.5, 9.5, 14.1 Hz, 1 H,H-4a), 2.23 (ddd, J = 6.9, 6.9,

14.1 Hz, 1 H, H-4b), 1.65 (septet, J = 6.9 Hz, 1 H, Me₂CH), 0.89

Acknowledgments

This work was supported by the “Fonds der Chemischen Industrie”

(Fonds Stipendium to A. L.). We also thank Dr. H. Schmickler,

Dr. N. Schlörer and Dr. M. Schäfer for their support in the applica-

tion of advanced NMR and MS techniques and Dipl. Ing. A. Adler

for technical assistance with HPLC and GLC measurements. Gen-

erous gifts of chemicals from Chemetall AG are highly appreciated.

Furthermore, we would like to thank Dr. Dr. A. Prokop, Charité

Berlin, for the fruitful cooperation concerning the biological evalu-

ation of synthetic nucleosides.

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Received: December 16, 2004

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A Pauson-Khand approach to new carbocyclic nucleoside analogs

DOI: 10.1002/ejoc.200400886

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