Synthesis of the cyclopentyl nucleoside (-)-neplanocin A from D-glucose via zirconocene-mediated ring contraction

Article abstract of DOI:10.1002/hlca.200590099

Two approaches for the conversion of D-glucose to (-)-neplanocin A (2), both based on the zirconocene-promoted ring contraction of a vinyl-substituted pyranoside, are herein evaluated (Scheme 1). In the first pathway (Scheme 1), the substrate possesses th

Full text of DOI:10.1002/hlca.200590099

Helvetica Chimica Acta ± Vol. 88 (2005)
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Synthesis of the Cyclopentyl Nucleoside (À)-Neplanocin A from d-Glucose
via Zirconocene-Mediated Ring Contraction
by Leo A. Paquette*, Zhenjiao Tian, Christopher K. Seekamp, and Tony Wang
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA
(phone: ‡ 1614-292-2950; fax: ‡ 1614-292-1685; e-mail: paquette.1@osu.edu)
It is a pleasure to honor Professor Rolf Huisgen on the occasion of his 85th birthday. His pioneering mechanistic
and synthetic studies in organic chemistry are exemplary of some of the most creative work in the field.
Two approaches for the conversion of d-glucose to (À)-neplanocin A( 2), both based on the zirconocene-
promoted ring contraction of a vinyl-substituted pyranoside, are herein evaluated (Scheme 1). In the first
pathway (Scheme 2), the substrate possesses the a-d-allo configuration (see 6) such that ultimate introduction
of the nucleobase would require only an inversion of configuration. However, this precursor proved
unresponsive to Cp2Zr (ˆ [ZrCl2(Cp)2]), an end result believed to be a consequence of substantive nonbonded
steric effects operating in a key intermediate (Scheme 5). In contrast, the C(2) epimer (see 7) experienced the
desired metal-promoted conversion to an enantiomerically pure polyfunctional cyclopentane (see 5 in
Scheme 3). The substituents in this product are arrayed in a manner such that conversion to the target
nucleoside can be conveniently achieved by
a double-inversion sequence (Scheme 4). Recourse to
palladium(0)-catalyzed allylic alkylation did not provide an alternate means of generating 2.
Introduction. ± The era of carbocyclic nucleoside synthesis [1] was ushered in by the
isolation from Streptomyces citricolor of the metabolite named (À)-aristeromycin (1) in
1968 [2], and was significantly advanced by the discovery in 1981 that (À)-neplanocin A
(2) is produced by Ampullariella regularis [3]. The cytotoxicity of 2 is so elevated that
its use as an effective antiviral agent is precluded [4]. The antiviral properties of 2 have
been attributed to the inhibition of S-adenosylhomocystine (AdoHcy) hydrolase [5].
Since the latter serves as a potential feedback inhibitor of cellular transmethylation by
involving S-adenosyl-l-methionine as the methyl donor, mRNAmaturation is arrested
[6].
Many synthetic analogs of 1 and 2, including abacavir [7] and carbovir [8], have
demonstrated potent anti-HIV activity. (À)-Neplanocin Aitself has served as a target
ꢀ 2005 Verlag Helvetica Chimica Acta AG, Zürich

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of opportunity for evaluating new synthetic routes to carbocyclic nucleosides [1][9],
particularly involving modern synthetic tactics of an organometallic nature. Recent
select examples include the application of a carbene chromium complex [10], Pd0-
catalyzed enantioselective allylic amination [11], and scandium(III) triflate promoted
ring expansion [12] as useful approaches. In continuation of our program to utilize the
zirconocene-mediated ring contraction [13] of vinyl-substituted pyranosides and
furanosides as a key synthetic transformation [14], we herein define a means for
transforming d-glucose (3) into enantiomerically pure natural neplanocin A.
Results. ± To secure the stereogenic centers in 2, it is necessary that the particular
vinyl-substituted pyranoside derived from d-glucose (3) possesses an a-d-allopyrano-
side configuration. Beyond that, the option exists to project the C(2)ÀO bond either
equatorially as in 6 or axially as in 7 (Scheme 1). The first of these choices was on the
attractive path to return 4 following exposure to zirconocene (Cp2Zrˆ [ZrCl2(Cp)2])
and requires only configurational inversion at the asterisked carbon to arrive at the
carbanucleoside target. Application of the same retrosynthetic analysis to 7 takes one
back to 5, where attachment of the base must necessarily be accomplished with
retention or, more likely, double inversion. Both routes have been investigated, with
success awaiting only one of the alternatives.
Scheme 1
PMB ˆ 4-MeOC6H4CH2, SEM ˆ Me3SiCH2CH2OCH2
Since 4-methoxybenzyl (PMB) and [2-(trimethylsilyl)ethoxy]methyl (SEM) pro-
tecting groups have been found to survive the deoxygenative ring-contraction
conditions reasonably well [14], they were therefore relied upon for deployment in
the present context. Progress in the forward direction was initiated by executing the
known four-step conversion of d-glucose to the 2,3-anhydropyranoside 8 [15][16]
(Scheme 2). The heating of 8 in boiling allyl alcohol that had first been treated with
sodium hydride resulted in regioselective trans-diaxial opening of the oxirane ring as
determined by NMR analysis. In preparation for configurational inversion at C(2), the
obtained intermediate was directly treated in unpurified form with triethylsilane and
CF3COOH [14b][16]. Whereas these conditions afforded 9 in 65% yield for the two
steps, we note that comparable cleavage of the benzylidene acetal with LiAlH4/AlCl3

Helvetica Chimica Acta ± Vol. 88 (2005)
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Scheme 2
Ts ˆ 4-MeC6H4SO2, Bn ˆ PhCH2, DABCO ˆ 1,4-diazabicyclo[2.2.2]octane, TPAP ˆ (Pr4N)RuO4, NMO ˆ 4-
morpholine 4-oxide, SEM ˆ Me3SiCH2CH2OCH2, TBS ˆ tBuMe2Si, PMB ˆ 4-MeOC6H4CH2, NaHMDS ˆ
Me3SiN(Na)SiMe3
[17], NaBH3CN ´ HCl [18], and others [19 ± 21] is not feasible because of the presence
of a free OH group.
Following the conversion of 9 to its acetonide, the allyl protecting group was
removed by treatment with Wilkinsonꢁs catalyst to isomerize the CˆC bond [22] in
advance of oxymercuration [23]. The resulting axial alcohol 10 was subjected to
perruthenate oxidation [24], this maneuver generating the ketone in quantitative yield.
The targeted conversion to 11 was completed by fully stereocontrolled reduction with
NaBH4 [25]. At this juncture, the SEM functionality [26] was introduced to provide 12
(Scheme 2). To achieve maximum efficiency in this step, it was imperative that the
potassium hydride be free of oil. After reaching 12, we took advantage of an ability to
cleave the acetonide in 80% acetic acid without adversely affecting the SEM
substituent. Close monitoring of the reaction progress was necessary to avoid
overreaction. Arresting progress after 4 h irrespective of scale ultimately became the
standard protocol. Athird OH group was unmasked by conventional hydrogenolysis of

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the O-benzyl substituent. The resulting polar product was conveniently monosilylated
in selective fashion. With 13 in hand, it proved an easy matter to accomplish dual PMB
protection as in 14 provided that recourse was made to an amide base such as sodium
hexamethyldisilazide. The involvement of other bases resulted in the formation of
monoalkylation mixtures as well as products of silyl migration. The last hurdle prior to
arrival at 6 involved sequential removal of the TBS group from 14 with Bu4NF (!15),
perruthenate oxidation to generate the aldehyde, and Wittig olefination. This reaction
sequence proved challenging to monitor by TLC because of the instability of the
aldehyde toward silica gel or alumina. However, direct filtration of the oxidation
mixture through a Florisil plug after 2 h and subsequent addition of methylenetri-
phenylphosphorane in THFat 08 successfully furnished 6 in 70% yield over the two steps.
With conversion of d-glucose to 6 now complete, probe experiments designed to
produce 4 were undertaken. When general conditions involving initial treatment with
the zirconocene reagent [ZrCl2(Cp)2] and subsequent addition of boron trifluoride
etherate and hydrochloride acid [14b] were screened, no evidence for the operation of a
ring contraction was found. Only epimerization at the anomeric center in 6 occurred.
Since a comparable chemical event did not materialize when 6 was admixed with either
[ZrCl2(Cp)2] or BF3 ´ OEt2 alone, this finding was interpreted to mean that the vinyl-
substituted pyranoside in question was undergoing initial conversion to a nine-
membered zirconacycle [13]. However, further advance along the reaction pathway
was either very slow or none at all, with the consequence of ultimate nonstereoselec-
tive regeneration of the pyranoside. Alternative precedent for this phenomenon is
lacking.
It seemed reasonable to suppose that the failure on the part of 6 to undergo ring
contraction might originate from steric consequences arising from cis orientation of the
oxygenated substituents at C(2), C(3), and C(4) on the a-face. Therefore, we next
addressed the consequences of inverting the configuration at C(2). To this end, 10 was
treated with sodium hydride and freshly prepared 4-methoxybenzyl bromide [27] to
give the globally protected ether 17 (Scheme 3). Selective debenzylation was
subsequently effected with carefully washed commercial W-2 Raney-Ni as catalyst
under 1 atm of H2 [28]. Frequent TLC monitoring of the reaction progress was
necessary to obtain 18 efficiently and in a high state of purity. The oxidative conversion
of 18 to aldehyde 19 proved initially to be problematic. Several protocols based on the
use of dimethyl sulfoxide, hypervalent iodine reagents, perruthenate as tetrapropyl-
ammonium perruthenate (TPAP), or chromates as pyridinium chlorochromate (PCC)
proved to be too inefficient. In contrast, recourse to o-iodoxybenzoic acid (ˆ2-
iodylbenzoic acid; IBX) in refluxing MeCN [29] and direct addition of the unstable 19
to methylenetriphenylphosphorane in the dark furnished the targeted 7 in 77% overall
yield. As before, [ZrBu2(Cp)2] was generated in situ from [ZrCl2(Cp)2] and BuLi at
À 788. Following the addition of 7 at this temperature, the reaction mixture was allowed
to warm to 208 prior to workup. These conditions brought about high levels of
acetonide deprotection, presumably induced by one or more zirconocene species
serving as a Lewis acid. One possibility was that formation of the Cp2Zr intermediate
had not occurred prior to the addition of 7. Accordingly, the mixture was allowed to
warm to 08 and maintained at 08 for 20 min. During this time period, an intense brown
coloration developed. To continue the process, this reactive species was added to 7 at

Helvetica Chimica Acta ± Vol. 88 (2005)
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Scheme 3
PMB ˆ 4-MeOC6H4CH2, Bn ˆ 1PhCH2, IBX ˆ 2-iodoxybenzoic acid
À 788, warmed to 08 for 2 ± 3 h, and treated with boron trifluoride etherate at À 258.
After conventional workup, 5 was isolated in 31% yield. Although the efficiency of this
conversion proved to be modest, it represents the first time that an acetonide group has
been successfully deployed in the Zr-catalyzed ring contraction. Noteworthy is the fact
that a single diastereoisomer was produced, the configuration of which was established
by COSY, NOSY, and NOE spectroscopy (see A) to be as depicted in 5.
We were now in a position to exploit the interesting finding made by several
research groups [30 ± 34], who demonstrated that carbocyclic nucleosides are amenable
to assembly by Pd-catalyzed allylic alkylation. To apply this reaction, 5 was first
mesylated (!20) and freed of its PMB protecting group by treatment with 4,5-
dichloro-3,6-dioxocyclohexadiene-1,2-dicarbonitrile (DDQ) [35] to generate 21
(Scheme 4). Protection of the remaining OH group was achieved by acylation with
methyl carbonocyanidate [36] in the presence of N,N-dimethylpyridin-4-amine
(DMAP). As events unfolded, the ozonolysis of 22 [37] and b-elimination in the
presence of Hünigꢁs base was carried out in a single flask to deliver the a,b-unsaturated
aldehyde 23 in 83% yield. Chemoselective Luche reduction [38] followed by O-
silylation with tert-butyldimethylsilyl triflate [39] led to 25 without difficulty and set the
stage for the impending allylic substitution. Rather unexpectedly, 25 proved to be
totally unreactive to Pd0 catalysis in the specific instances where adenine and 6-
chloropurine served as the nucleobases of choice. Examples of ineffective couplings of
this type have been reported [40][41]. Since triethylaluminium can serve to assist these

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Scheme 4
Msˆ MeSO2, DDQˆ 4,5-dichloro-3,6-dioxocyclohexadiene-1,2-carbonitrile, PMBˆ 4-MeOC6H4CH2, DMA Pˆ
t
N,N-dimethylpyridin-4-amine, TBSOTf ˆ CF3SO2SiMe2 Bu, 2,6-lutidine ˆ 2,6-dimethylpyridine, DIBAL-H ˆ
diisopropylaluminium hydride, PDC ˆ pyridinium dichromate, DIAD ˆ diisopropyl azodicarboxylate
reactions in certain cases [41], the possible efficacy of this co-additive was also
explored, but to no avail. Unreacted 25 was readily retrieved.
Despite this setback, the availability of 25 did play a crucial role in our quest of (À)-
neplanocin A( 2). In the hope that the Mitsunobu reaction [42] would serve our
purposes, configurational inversion at the carbonate-bearing C-atom first had to be
accomplished. Sequential reduction with diisopropylaluminium hydride (DIBAL-H)
and oxidation with pyridinium dichromate (PDC) [43] under conditions of catalysis by
4-Š molecular sieves [44] furnished ketone 26 efficiently. Installation of the a-hydroxyl
group was secured by DIBAL-H reduction in toluene, thus setting the stage for reaction
with adenine, diisopropyl azodicarboxylate, and triphenylphosphine [43] to form the

Helvetica Chimica Acta ± Vol. 88 (2005)
1191
penultimate intermediate 27 (90%). Final treatment with 1.0m HCl in aqueous MeOH
[43] gave rise to 2, the physical and spectral properties [43] of which proved essentially
identical to literature data [43][45][46].
Discussion. ± Successful use was made of the zirconocene-promoted vinylpyrano-
side ring contraction as a device for producing enantiomerically pure multiply
functionalized cyclopentanes. Where 5 is concerned, further chemical modification to
give (À)-neplanocin Awas feasible by way of a double-inversion protocol. An
interesting stereochemical dependence to the metal-mediated O-extrusion reaction
was noted. The unreactivity of 6 and its tendency to experience anomerization in the
presence of Cp2Zr suggests that ligand exchange to generate B operates, and that
further conversion to C may even occur [47] (Scheme 5). Seemingly, more-advanced
progression to oxocarbenium ion D does not operate due to the extensive nonbonded
steric repulsion generated as a consequence of the cis orientation of the three OR
substituents on the periphery of the nine-membered ring. In contrast, the advancement
from 7 to 5 is not similarly complicated by steric congestion, with the result that E can
Scheme 5

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isomerize via F and G to produce 5. The cyclic nature of the chair-like transition state
depicted in G serves to deliver 5 with excellent diastereoselective placement of the cis-
oriented vinyl and OH substituents in 5.
Cyclopentane 5 is a highly versatile optically active intermediate that can be further
transformed in numerous directions. The scheme outlined here leads in 12 steps to
natural levorotatory neplanocin A. Hopefully the lessons learned in this undertaking
can be fruitfully applied to other synthetic targets.
This research was supported in part by an unrestricted grant from the Yamanouchi USA Foundation, for
which we are grateful. Details for the generation of 26 from the (4R)-alcohol and its conversion to 27 were
kindly supplied by Prof. Kunio Ogasawara, Tohoku University, whom we thank.
Experimental Part
General. CC ˆ Column chromatography. IR Spectra: in cmÀ1. NMR Spectra: d in ppm, Jand Dn in Hz. Mass
spectra: in m/z.
Methyl 2-O-Allyl 6-O-benzyl-a-d-altropyranoside (9). Epoxide 8 (10.00 g, 37.8 mmol) was dissolved in allyl
alcohol (500 ml), treated with NaH (1.36 g, 56.8 mmol), and heated to reflux for 48 h. The soln. was cooled, and
excess allyl alcohol was removed by evaporation. The residue was dissolved in AcOEt (200 ml), and sat. NH4Cl
soln. (150 ml) was added. The aq. layer was extracted with AcOEt (3 Â 75 ml) and the combined org. phase
washed with brine (75 ml), dried, and evaporated. The crude material was dissolved in CH2Cl2 (500 ml), cooled
to 08, and treated with Et3SiH (30.0 ml, 189 mmol, 5 equiv.) and CF3COOH (14.6 ml, 189 mmol). The resulting
soln. was stirred at 08 for 1 h, warmed to r.t. for 2 h, and quenched slowly with sat. NaHCO3 soln. (300 ml). The
aq. layer was extracted with AcOEt (3 Â 75 ml), the combined org. phase washed with brine (75 ml), dried, and
evaporated, and the residue purified by column chromatography (CC; silica gel, hexane/Et2O 1:2): 9 (7.95 g,
65%). Colorless oil. [a]1D8 ‡ 56.3 (c ˆ 5.0, CHCl3). IR (neat): 3476, 1737. 1H-NMR (500 MHz, CDCl3): 7.37 ± 7.26
(m, 5 H); 5.92 ± 5.85 (m, 1 H); 5.31 ± 5.26 (m, 1 H); 5.21 ± 5.19 (m, 1 H); 4.75 (s, 1 H); 4.62 (s, 2 H); 4.08 ± 4.07
(m, 2 H); 3.99 (br. s, 1 H); 3.88 ± 3.84 (m, 2 H); 3.79 ± 3.73 (m, 2 H); 3.63 ± 3.62 (m, 1 H); 3.42 (s, 3 H); 3.02 (br. s,
1 H). 13C-NMR (125 MHz, CDCl3): 138.8; 134.6; 128.7 (2C); 128.0 (2 C); 127.9; 118.1; 99.8; 76.0; 73.9; 71.7;
‡
‡
70.9; 69.3; 68.5; 65.7; 55.7. ES-HR-MS: 347.1451 ([M ‡ Na] , C17H24NaO6 ; calc. 347.1465).
Methyl 6-O-Benzyl-3,4-O-isopropylidene-a-d-altropyranoside (10). Diol (1.27 g, 4.27 mmol) was
9
dissolved in acetone (12 ml) and 2,2-dimethoxypropane (0.57 ml, 4.65 mmol) and treated with a catalytic
amount of TsOH (0.012 g). The soln. was stirred for 1 h and evaporated. After CH2Cl2 (50 ml) was added, the
org. layer was washed with sat. NaHCO3 soln. (10 ml), dried, and evaporated and the residue subjected to CC
(silica gel, hexane/Et2O 2 :1): acetonide of 9 (1.27 g, 81%). Colorless oil. [a]1D8 ˆ ‡46.8 (c ˆ 1.0, CHCl3). IR
1
(neat): 1454, 1382, 1213. H-NMR (500 MHz, CDCl3): 7.41 ± 7.36 (m, 4 H); 7.34 ± 7.30 (m, 1 H); 6.02 ± 5.94 (m,
1 H); 5.35 (ddd, J ˆ 1.6, 3.2, 17.3, 1 H); 5.23 (dd, J ˆ 1.4, 10.4, 1 H); 4.66 (s, 2 H); 4.64 (d, J ˆ 4.7, 1 H); 4.30 ± 4.19
(m, 4 H); 3.92 ± 3.89 (m, 1 H); 3.78 (dd, J ˆ 2.5, 10.9, 1 H); 3.68 ± 3.65 (m, 1 H); 3.57 (dd, J ˆ 4.7, 7.2, 1 H); 3.48 (s,
3 H); 1.52 (s, 3 H); 1.39 (s, 3 H). 13C-NMR (125 MHz, CDCl3): 138.6; 135.1; 128.8 (2 C); 128.0 (2 C); 127.9;
‡
117.8; 110.6; 102.1; 79.9; 76.9; 73.8; 72.6; 72.3; 70.9; 70.4; 55.7; 28.0; 25.8. ES-HR-MS: 387.1772 ([M ‡ Na] ,
‡
C20H28NaO6 ; calc. 387.1778).
To a soln. of the acetonide of 9 (1.00 g, 1.9 mmol) in a EtOH/benzene/H2O 7 :4 :1 (92 ml), DABCO (0.09 g,
0.84 mmol) and Wilkinsonꢁs catalyst (0.23 g, 0.25 mmol) were added. The soln. was heated to reflux for 18 h,
cooled to r.t., and evaporated. The residue was dissolved in acetone/H2O 9 :1 (40 ml). Yellow mercury(II) oxide
(0.90 g) was first added followed by the slow addition of mercury (II) chloride (0.90 g). After 30 min of stirring,
the mixture was filtered through Celite, and the filtrate was evaporated. The residue was taken up in Et2O
(100 ml), washed with sat. KI soln., dried, and evaporated. The residue was purified by CC (silica gel, hexane/
Et2O 3 :2): 10 (0.52 g, 85%). Light yellow oil. [a]1D8 ˆ ‡26.7 (c ˆ 2.4, CHCl3). IR (neat): 3462, 1497, 1454.
1H-NMR (300 MHz, CDCl3): 7.37 ± 7.28 (m, 5 H); 4.62 (s, 2 H); 4.56 (d, J ˆ 5.4, 1 H); 4.31 (dd, J ˆ 7.2, 8.7, 1 H);
4.13 (t, J ˆ 7.5, 1 H); 3.92 ± 3.80 (m, 1 H); 3.78 ± 3.72 (m, 2 H); 3.62 (dd, J ˆ 5.4, 10.9, 1 H); 3.54 (s, 3 H); 2.69 (d,
J ˆ 4.4, 1 H); 1.48 (s, 3 H); 1.35 (s, 3 H). 13C-NMR (125 MHz, CDCl3): 138.4; 128.8 (2 C); 128.0 (2 C); 127.9;
‡
‡
111.0; 102.3; 77.2; 73.9; 73.4; 72.6; 70.9; 70.8; 56.0; 27.9; 25.7. ES-HR-MS: 347.1450 ([M ‡ Na] , C17H24NaO6
;
calc. 347.1465).

Helvetica Chimica Acta ± Vol. 88 (2005)
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Methyl 6-O-Benzyl-3,4-O-isopropylidene-a-d-allopyranosede (11). To a soln. of 10 (0.40 g, 1.2 mmol) in
CH2Cl2 (10 ml), 4-Š molecular sieves (0.60 g) were added, followed by 4-methylmorpholine 4-oxide (0.22 g,
1.8 mmol) and tetrapropylammonium perruthenate (0.021 g, 0.06 mmol). The mixture was stirred for 1 h and
filtered through a plug of silica gel (elution with CH2Cl2/Et2O 1:1): ketone (0.40 g, quant.). a]1D8 ˆ ‡9.8 (c ˆ 0.8,
CHCl3). IR (neat): 1794, 1759, 1673. 1H-NMR (300 MHz, CDCl3): 7.37 ± 7.31 (m, 5 H); 4.90 (s, 1 H); 4.77 ± 4.64
(m, 4 H); 3.97 ± 3.91 (m, 1 H); 3.82 ± 3.70 (m, 2 H); 3.50 (s, 3 H); 1.47 (s, 3 H); 1.38 (s, 3 H). 13C-NMR (75 MHz,
CDCl3): 201.8; 137.7; 128.4 (2 C); 127.8; 127.6 (2 C); 112.7; 99.0; 77.6; 74.7; 73.5; 72.7; 69.7; 55.9; 27.1; 25.5. ES-
‡
‡
HR-MS: 345.1302 ([M ‡ Na] , C17H22NaO6 ; calc. 345.1309).
The above ketone (0.40 g, 1.2 mmol) was dissolved in EtOH (10 ml), cooled to 08, and treated with NaBH4
(0.07 g, 2.0 mmol). After 30 min, the reaction was quenched by the addition of acetone (3 ml), and the solvent
was evaporated. The residue was taken up in Et2O (30 ml), washed with brine (10 ml), dried, and evaporated
prior to purification by CC (silica gel, hexane/Et2O 3 :2): 11 (0.35 g, 88%). Light yellow oil. [a]1D8 ˆ ‡92.4 (c ˆ
1.0, CHCl3). IR (neat): 3490, 1451. 1H-NMR (300 MHz, CDCl3): 7.37 ± 7.30 (m, 5 H); 4.76 (d, J ˆ 4.7, 1 H); 4.60
(d, J ˆ 1.8, 2 H); 4.45 (t, J ˆ 4.9, 1 H); 4.11 (dd, J ˆ 5.1, 9.6, 1 H); 3.89 ± 3.79 (m, 2 H); 3.73 (dd, J ˆ 2.2, 10.8,
1 H); 3.61 (dd, J ˆ 5.4, 10.8, 1 H); 3.46 (s, 3 H); 1.50 (s, 3 H); 1.36 (s, 3 H); OH not observed. 13C-NMR
(125 MHz, CDCl3): 138.6; 128.8 (2 C); 128.0 (3 C); 110.6; 98.7; 74.6; 74.0; 72.1; 69.9; 67.3; 67.0; 56.4; 28.7; 26.6.
‡
‡
ES-HR-MS: 347.1474 ([M ‡ Na] , C17H24NaO6 ; calc. 347.1465).
Methyl 6-O-Benzyl-3,4-O-isopropylidene-2-O-{[2-(trimethylsilyl)ethoxy]methyl}-a-d-allopyranoside (12).
To a soln of 11 (0.35 g, 1.08 mmol) in THF (20 ml), oil-free KH (0.09 g, 2.16 mmol) was added followed by
SEMCl (0.38 ml, 2.16 mmol). After 1 h, the mixture was quenched with H2O (10 ml), and the aq. layer was
extracted with Et2O (2 Â 20 ml). The combined org. phase was washed with brine (10 ml), dried, and evaporated
and the residue purified by CC (silica gel, hexane/Et2O 2 :1): 12 (0.39 g, 80%). Colorless oil. [a]1D8 ˆ ‡40.8 (c ˆ
2.4, CHCl3). IR (neat): 1497, 1454. 1H-NMR (500 MHz, CDCl3): 7.40 ± 7.30 (m, 5 H); 4.90 ± 4.84 (m, 3 H); 4.65
(AB'q', J ˆ 12.2, DnAB ˆ 10.6, 2 H); 4.57 (t, J ˆ 4.6, 1 H); 4.15 (dd, J ˆ 4.9, 9.6, 1 H); 3.92 ± 3.89 (m, 2 H); 3.79 ±
3.73 (m, 3 H); 0.99 ± 0.95 (m, 2 H); 0.05 (s, 9 H). 13C-NMR (125 MHz, CDCl3): 138.6; 128.8 (2 C); 128.0 (2 C);
127.9; 110.9; 98.2; 95.1; 74.0; 73.8; 72.4; 72.2; 69.9; 67.2; 66.2; 56.3; 29.0; 26.6; 18.7; À 1.0 (3 C). ES-HR-MS:
‡
‡
477.2250 ([M ‡ Na] , C23H38SiNaO7 ; calc. 477.2279).
Methyl 6-O-[(tert-Butyl)dimethylsilyl]-2-O-{[2-(trimethylsilyl)ethoxy]methyl}-a-d-allopyranoside (13). A
soln. of 12 (1.20 g) in 80% AcOH/H2O (30 ml) was stirred at r.t. for 4.5 h, after which the AcOH was
evaporated, and the H2O was removed by azeotropic distillation with benzene (2 Â 50 ml). The residue was
purified by CC (silica gel, hexane/Et2O 1:1): diol (0.88 g, 80%). Colorless glass. [a]1D8 ˆ ‡21.9 (c ˆ 2.6, CHCl3).
IR (neat): 3487, 1057. 1H-NMR (500 MHz, CDCl3): 7.40 ± 7.35 (m, 4 H); 7.32 ± 7.29 (m, 1 H); 4.92 (d, J ˆ 3.5,
1 H); 4.84 (AB'q', J ˆ 7.1, DnAB ˆ 26.2, 2 H); 4.65 (s, 2 H); 4.24 ± 4.21 (m, 1 H); 3.88 ± 3.85 (m, 1 H); 3.80 ± 3.59
(series of m, 6 H); 3.49 (s, 3 H); 3.40 (d, J ˆ 8.8, 1 H); 2.77 (d, J ˆ 10.3, 1 H); 1.01 ± 0.95 (m, 2 H); 0.05 (s, 9 H).
13C-NMR (125 MHz, CDCl3): 138.6; 128.8 (2 C); 128.0; 127.9 (2 C); 100.0; 94.2; 74.0; 73.1; 70.5; 69.9; 68.1; 67.4;
‡
‡
66.1; 56.2; 18.6; À 1.0. ES-HR-MS: 437.1955 ([M ‡ Na] , C20H34SiNaO7 ; calc. 437.1966).
To the above diol in abs. EtOH (75 ml), 10% Pd/C (0.05 g) was added. H2 Gas was bubbled through the
mixture for 5 min, and the mixture was stirred under a H2-filled balloon for another hour. After filtration
through a pad of Celite, solvent evaporation gave 0.57 g (84%) of crude triol, which was directly dissolved in
t
CH2Cl2 (30 ml) and treated with 1H-imidazole (0.16 g, 1.3 equiv.) and BuMe2SiCl (0.29 g, 1.1 equiv.). The
mixture was stirred for 1 h and quenched with sat. NH4Cl soln. (10 ml). The aq. layer was extracted with CH2Cl2
(10 ml), the combined org. phase was dried and evaporated and the residue subjected to CC (silica gel, hexane/
Et2O 1:1): 13 (0.69 g, 90%). Colorless oil. [a]1D8 ˆ ‡24.9 (c ˆ 0.8, CHCl3). 1H-NMR (500 MHz, CDCl3): 4.90 (d,
J ˆ 3.4, 1 H); 4.86 (AB'q', J ˆ 7.2, DnAB ˆ 25.2, 2 H); 4.22 (br. s, 1 H); 4.01 (dd, J ˆ 2.4, 11.2, 1 H); 3.88 (dd, J ˆ
5.4, 11.2, 1 H); 3.77 ± 3.62 (m, 4 H); 3.52 ± 3.49 (m, 4 H); 0.99 ± 0.94 (m, 11 H); 0.13 (s, 6 H); 0.06 (s, 9 H).
13C-NMR (125 MHz, CDCl3): 199.8; 94.3; 73.3; 70.6; 69.3; 69.3; 67.6; 66.1; 63.5; 56.0; 26.4 (3 C); 18.8; 18.6; À 1.0
‡
‡
(3 C); À 4.9 (2 C). ES-HR-MS: 461.2381 ([M ‡ Na] , C19H42NaO7Si2 ; calc. 461.2361).
Methyl 6-O-[(tert-Butyl)dimethylsilyl]-3,4-bis-O-(4-methoxybenzyl)-2-O-{[2-(trimethylsilyl)ethoxy]meth-
yl}-a-d-allopyranoside (14). Diol 13 (0.40 g, 0.91 mmol) was dissolved in THF (20 ml), cooled to 08, and
treated with sodium hexamethyldisilazanide (2.70 ml, 2.70 mmol). After 1 h, 4-methoxybenzyl bromide (0.46 g,
2.3 mmol) and a cat. amount of Bu4NI were added. The ice bath was removed, and the mixture was stirred for
3 d and quenched by the addition of H2O (10 ml). The aq. layer was extracted with Et2O (3 Â 10 ml), the
combined org. soln. dried and evaporated, and the residue subjected to CC (silica gel, hexane/Et2O 3 :1): 14
(0.43 g, 70%). Colorless oil. [a]1D8 ˆ ‡34.8 (c ˆ 2.3, CHCl3). IR (neat): 1613, 1514. 1H-NMR (300 MHz, CDCl3):
7.30 (d, J ˆ 8.7, 2 H); 7.20 (d, J ˆ 8.7, 2 H); 6.85 (d, J ˆ 8.7, 2 H); 6.79 (d, J ˆ 8.7, 2 H); 4.78 (d, J ˆ 3.6, 2 H); 4.73
(d, J ˆ 4.0, 1 H); 4.66 (AB'q', J ˆ 7.1, DnAB ˆ 13.1, 2 H); 4.43 (ABX, J ˆ 11.3, DnAB ˆ 23.7, 2 H); 4.12 ± 4.05 (m,

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Helvetica Chimica Acta ± Vol. 88 (2005)
2 H); 3.89 ± 3.69 (series of m, 10 H); 3.61 ± 3.56 (m, 2 H); 3.42 (s, 3 H); 0.90 (br. s, 11 H); 0.06 (s, 6 H); 0.02 (s,
9 H). 13C-NMR (75 MHz, CDCl3): 159.1 (2 C); 131.4; 130.5; 129.3 (2 C); 129.0 (2 C); 113.7 (2 C); 113.4 (2 C);
98.6; 93.2; 74.9; 74.0; 73.3; 72.3; 71.0; 67.2; 65.4; 62.5; 55.6; 55.2 (2 C); 26.0 (3 C); 18.3; 18.1; À 1.5 (3 C); À 5.2;
‡
‡
À 5.4. ES-HR-MS: 701.3470 ([M ‡ Na] , C35H58NaO9Si2 ; calc. 701.3512).
Methyl 3,4-Bis-O-(4-methoxybenzyl)-2-O-{[2-(trimethylsilyl)ethoxy]methyl}-a-d-allopyranoside (15). To a
soln. of 14 (0.10 g, 0.15 mmol) in THF (10 ml), 1m Bu4NF in THF (0.15 ml) was added, and the soln. was stirred
at r.t. for 2 h. The mixture was quenched by the addition of H2O (5 ml), the aq. phase extracted with Et2O (2 Â
10 ml), the combined org. phase dried (Na2SO4) and evaporated, and the residue subjected to CC (silica gel,
hexane/Et2O 3 :2): 15 (0.07 g, 88%). Colorless oil. [a]1D8 ˆ ‡37.0 (c ˆ 3.1, CHCl3). IR (neat): 3493, 1613, 1514.
1H-NMR (300 MHz, CDCl3): 7.32 (d, J ˆ 8.6, 2 H); 7.20 (d, J ˆ 8.7, 2 H); 6.85 (d, J ˆ 8.7, 2 H); 6.81 (d, J ˆ 8.6,
2 H); 4.85 ± 4.64 (series of m, 5 H); 4.40 (AB'q', J ˆ 11.5, DnAB ˆ 42.5, 2 H); 4.15 ± 4.10 (m, 2 H); 3.85 ± 3.61 (m,
10 H); 3.61 ± 3.53 (m, 1 H); 3.44 ± 3.39 (m, 4 H); 1.87 (dd, J ˆ 5.4, 7.4, 1 H); 0.96 ± 0.89 (m, 2 H); 0.01 (s, 9 H).
13C-NMR (75 MHz, CDCl3): 159.3; 158.9; 131.3; 129.4 (3 C); 129.3 (2 C); 113.8 (2 C); 113.5 (2 C); 98.9; 93.5;
‡
74.9; 74.2; 73.3; 72.0; 70.7; 66.4; 65.5; 62.2; 55.9; 55.3; 55.2; 18.2; À 1.4 (3 C). ES-HR-MS: 587.2688 ([M ‡ Na) ,
‡
C29H44NaO9Si ; calc. 587.2647).
{2-{{{6-Ethenyl-tetrahydro-2-methoxy-4,5-bis[(4-methoxybenzyl)oxy]-2H-pyran-3-yl}oxy}methoxy}ethyl}-
trimethylsilane (6). Asoln. of 15 (0.20 g, 0.35 mmol) in CH2Cl2 (5 ml) was treated with 4 Š molecular sieves
(0.20 g), NMO (0.06 g, 0.53 mmol), and TPAP (0.006 g, 0.02 mmol). The mixture was stirred for 2 h, filtered
through a plug of Florisil, and evaporated. The aldehyde was dissolved in dry THF (5 ml), and cooled to 08. Into
the cold soln. was cannulated a soln. prepared from methyltriphenylphosphonium iodide (0.36 g, 0.89 mmol)
and BuLi (0.7 ml, 0.89 mmol) in THF (5 ml), which had been stirred for 1 h at 08. The mixture was warmed to
r.t., and quenched with H2O after 3 h. The aq. layer was extracted with Et2O (2 Â 10 ml), the combined org.
phase dried and evaporated, and the residue subjected to CC (silica gel, hexane/Et2O 2 :1): 6 (0.10 g, 48%).
Colorless syrup. [a]1D8 ˆ ‡34.0 (c ˆ 0.6, CHCl3). 1H-NMR (500 MHz, CDCl3): 7.36 (d, J ˆ 8.5, 2 H); 7.23 (d, J ˆ
8.5, 2 H); 6.89 (d, J ˆ 8.6, 2 H); 6.85 (d, J ˆ 8.6, 2 H); 6.02 ± 5.95 (m, 1 H); 5.50 ± 5.46 (m, 1 H); 5.30 ± 5.28 (m,
1 H); 4.84 (s, 2 H); 4.78 (d, J ˆ 4.1, 1 H); 4.70 (ABX, J ˆ 7.1, Dn ˆ 26.6, 2 H); 4.60 ± 4.57 (m, 1 H); 4.43 (AB'q',
J ˆ 11.5, DnAB ˆ 34.1, 2 H); 4.15 ± 4.14 (m, 1 H); 3.85 (s, 3 H); 3.82 (s, 3 H); 3.80 ± 3.74 (m, 1 H); 3.69 ± 3.67 (m,
1 H); 3.63 ± 3.56 (m, 1 H); 3.47 (s, 3 H); 3.20 (dd, J ˆ 2.6, 9.7, 1 H); 1.02 ± 0.94 (m, 2 H); 0.05 (s, 9 H). 13C-NMR
(125 MHz, CDCl3): 159.6; 159.3; 136.1; 131.7; 130.6; 129.9 (2 C); 129.6 (2 C); 117.8; 114.1 (2 C); 113.9 (2 C);
99.2; 93.7; 79.4; 74.3; 73.7; 72.7; 71.6; 67.3; 65.9; 56.4; 55.7; 31.3; 18.6; À 1.0 (3 C). ES-HR-MS: 583.2690 ([M ‡
‡
‡
Na) , C30H44NaO8Si ; calc. 583.2698).
(3aR,4R,6S,7S,7aR)-4-[(Benzyloxy)methyl]-tetrahydro-6-methoxy-[(7-(4-methoxybenzyl)oxy]-2,2-di-
methyl-4H-1,3-dioxolo[4,5-c]pyran (17). To a soln. of 10 (200 mg, 062 mmol) in DMF (6.0 ml) was added NaH
(52 mg, 60% in mineral oil, 1.30 mmol) at 08. The mixture was stirred for 15 min before 4-methoxybenzyl
bromide (186 mg, 0.93 mmol) was added dropwise. The cold bath was removed after 20 min, the suspension
allowed to warm to r.t., and stirring continued until unreacted 10 was no longer detected by TLC. The mixture
was quenched by the careful addition of H2O (8 ml) and extracted with CH2Cl2 (3 Â 8 ml), the combined org.
layer washed with brine and dried, and the residue subjected to flash chromatography (silica gel, hexane/Et2O
5 :1 ! 3 :1): 17 (260 mg, 95%). Colorless oil. [a]2D0 ˆ ‡6.9 (c ˆ 0.42, CHCl3). IR (neat): 1654, 1616, 1559.
1H-NMR (300 MHz, CDCl3): 7.37 ± 7.26 (m, 7 H); 6.87 (m, 2 H); 4.73 ± 4.62 (m, 5 H); 4.28 ± 4.17 (m, 2 H); 3.86
(m, 1 H); 3.80 (s, 3 H); 3.74 (m, 1 H); 3.60 (m, 2 H); 3.45 (s, 3 H); 1.43 (s, 3 H); 1.35 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 159.2; 138.1; 130.1; 129.6 (3 C); 128.3 (2 C); 127.5 (2 C); 113.6 (2 C); 110.1; 101.6; 79.1; 77.0;
‡
‡
76.4; 73.3; 72.5; 72.0; 70.3; 69.9; 55.2; 27.5; 25.4. ES-HR-MS: 467.2038 ([M ‡ Na) , C25H32NaO7 ; calc. 467.2040).
(3aR,4R,6S,7S,7aR)-Tetrahydro-6-methoxy-7-[(4-methoxybenzyl)oxy]-2,2-dimethyl-4H-1,3-dioxolo[4,5-
c]pyran-4)methanol (18). To a soln. of 17 (64.3 mg, 0.15 mmol) in EtOH (3 ml) was added W-2 Raney Ni (from
0.12 ml rinsed with EtOH) in EtOH (2.0 ml) at 08. The mixture was stirred under 1 atm of H2 for 2 days (TLC
monitoring was very important) before it was filtered through a pad of Celite. Evaporation of the filtrate under
vacuum gave 18 (52 mg, quant.). Colorless oil. [a]2D0 ˆ ‡31.5 (c ˆ 0.74, CHCl3). IR (neat): 3435, 1652, 1637.
1H-NMR (300 MHz, CDCl3): 7.30 (m, 2 H); 6.88 (m, 2 H); 4.70 (d, J ˆ 11.4, 1 H); 4.63 (d, J ˆ 11.4, 1 H); 4.60 (d,
J ˆ 4.4, 1 H); 4.21 (m, 2 H); 3.88 (m, 1 H); 3.84 (s, 3 H); 3.73 (m, 2 H); 3.59 (m, 1 H); 3.40 (s, 3 H); 1.90 (br. s,
1 H); 1.43 (s, 3 H); 1.34 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 159.2; 130.0; 129.6 (2 C); 113.7 (2 C); 110.2; 101.5;
‡
‡
78.6; 76.1; 72.6; 71.6; 70.5; 63.3; 55.3 (2 C); 27.4; 25.4. ES-HR-MS: 377.1570 ([M ‡ Na] , C18H26NaO7 ; calc.
377.1571).
(3aS,4S,6S,7S,7aR)-Tetrahydro-6-methoxy-7-[(4-methoxybenzyl)oxy]-2,2-dimethyl-4H-1,3-dioxolo[4,5-
c]pyran-4-carboxaldehyde (19). Asuspension of 18 (460 mg, 1.30 mmol) and IBX (1.196 g, 4.27 mmol) in MeCN
(13 ml) was refluxed for 28 min. After the mixture was allowed to cool to r.t., it was further cooled in an ice/salt

Helvetica Chimica Acta ± Vol. 88 (2005)
1195
bath. The mixture was then filtered through a pad of silica gel and the solvent evaporated: 19. Colorless oil.
(458 mg, quant.). [a]2D0 ˆ ‡17.6 (c ˆ 0.49, CHCl3). IR (film): 3500 (br.), 1740, 1612. 1H-NMR (300 MHz,
CDCl3): 9.76 (s, 1 H); 7.28 (m, 2 H); 6.87 (m, 2 H); 4.69 (d, J ˆ 4.0, 1 H); 4.64 (d, J ˆ 3.5, 2 H); 4.38 (dd, J ˆ 6.6,
6.6, 1 H); 4.21 (m, 2 H); 3.80 (s, 3 H); 3.59 (m, 1 H); 3.45 (s, 3 H); 1.47 (s, 3 H); 1.37 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 198.3; 159.1; 129.4; 129.3 (2 C); 113.5 (2 C); 110.5; 102.5; 76.4; 75.4; 74.1; 72.4; 70.3; 55.6;
‡
‡
55.0; 27.3; 25.3. ES-HR-MS: 375.1404 ([M ‡ Na] , C18H24NaO7 ; calc. 375.1414).
(3aR,4R,6S,7S,7aR)-4-Ethenyl-tetrahydro-6-methoxy-7-[(4-methoxybenzyl)oxy]-2,2-dimethyl-4H-1,3-di-
oxolo[4,5-c]pyran (7). At 08, methyltriphenylphosphonium bromide (639 mg, 1.75 mmol) in dry Et2O (13 ml)
was treated with sublimed KOtBu (195 mg, 1.74 mmol) for 30 min with stirring. Asoln. of freshly prepared 19
(458 mg, 1.30 mmol) in Et2O (8.2 ml was introduced via cannula and stirred for 20 min before the cooling bath
was removed. The mixture was stirred for another hour at r.t., at which point H2O (5 ml) and sat. NaHCO3 soln.
(5 ml) were slowly added at 08. The aq. phase was extracted with Et2O (3 Â 8 ml), the combined org. soln. dried
and evaporated, and the residue submitted to CC (silica gel, hexane/Et2O 5 :1): 351 mg (77% yield for two steps)
1
of 7. White solid. M.p. 688. [a]2D0 ˆ ‡25.0 (c ˆ 0.28, CHCl3). IR (film): 1613, 1514, 1457. H-NMR (300 MHz,
CDCl3): 7.30 (m, 2 H); 6.87 (m, 2 H); 5.99 ± 5.88 (m, 1 H); 5.42 (dd, J ˆ 1.0, 16.3, 1 H); 5.27 (dd, J ˆ 1.0, 16.3,
1 H); 4.71 (d, J ˆ 11.4, 1 H); 4.65 (d, J ˆ 11.4, 1 H); 4.60 (d, J ˆ 4.7, 1 H); 4.21 (m, 1 H); 4.13 (m, 1 H); 3.80 (s,
3 H); 3.60 (dd, J ˆ 4.7, 6.0, 1 H); 3.41 (s, 3 H); 1.44 (s, 3 H); 1.35 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 159.3;
135.6; 130.1; 129.7 (2 C); 117.2; 113.7 (2 C); 110.1; 101.5; 89.0;79.2; 76.5; 75.8; 72.6; 70.6; 55.3; 27.5; 25.3. ES-HR-
‡
‡
MS: 373.1622 ([M ‡ Na] , C19H26NaO6 calc. 373.1622).
(3aR,4S,5R,6R,6aR)-4-Ethenyl-tetrahydro-4-[(4-Methoxybenzyl)oxy]-2,2-dimethyl-4H-cyclopenta[d]-1,3-
dioxol-5-ol (5). BuLi (1.9m in hexane; 2.5 ml, 4.80 mmol) was slowly added to a soln. of [ZrCl2](Cp)2 (729 mg,
2.50 mmol) in toluene (26 ml) at À 788. The mixture was stirred for 40 min at À 788 and for 20 min at 08, during
which time the color changed from yellow to bright brown. This brown soln. was slowly cannulated into a soln. of
7 (350 mg, 1.00 mmol) in toluene (19.5 ml) at À 788. After the mixture had been stirred for 25 min at À 788 and
an added 3 h at 08, the temp. was lowered to À 258, at which point freshly distilled BF3 ´ OEt2 (278 ml, 2.2 mmol)
was slowly introduced, and stirring was continued for 25 min at À 258 before 1m HCl (20 ml) was added
dropwise. The aq. layer was extracted with AcOEt (3 Â 10 ml), the combined org. layer washed with sat.
NaHCO3 soln. and brine and evaporated, and the residue subjected to CC (silica gel, hexane/Et2O 5 :1): 5
(87.5 mg, 31% based on 89% conversion). Colorless oil. [a]2D0 ˆ ‡46.9 (c ˆ 1.4, CHCl3). IR (film): 3498, 1613,
1586. 1H-NMR (300 MHz, CDCl3): 7.28 (m, 2 H); 6.89 (m, 2 H); 5.99 ± 5.87 (m, 1 H); 5.26 ± 5.18 (m, 2 H); 4.71 ±
4.64 (m, 3 H); 4.50 (d, J ˆ 11.3, 1 H); 4.26 (m, 1 H); 3.88 (m, 1 H); 3.81 (s, 3 H); 2.67 (m, 1 H); 2.39 (d, J ˆ 4.3,
1 H); 1.43 (s, 3 H); 1.31 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 134.5; 129.6 (2 C); 129.5; 118.2; 113.9 (2 C); 112.4;
‡
‡
110.1; 84.8; 83.1; 82.8; 75.8; 71.7; 55.3; 52.9; 30.3; 24.4. ES-HR-MS: 343.1516 ([M ‡ Na] , C18H24NaO5 ; calc.
343.1516).
(3aR,4R,5R,6S,6aR)-4-Ethenyl-tetrahydro-4-[(4-methoxybenzyl)oxy]-2,2-dimethyl-4H-cyclopenta[d]-1,3-
dioxol-5-ol Methanesulfonate (20). To a stirred soln. of 5 (76.3 mg, 0.24 mmol) and Et3N (167.3 ml, 1.20 mmol) in
THF (3.8 ml) was slowly added methanesulfonyl chloride (64.7 ml, 0.84 mmol) at 08. The mixture was allowed to
reach r.t. before being quenched with H2O (2.0 ml). The aq. layer was extracted with Et2O (3Â) and the
combined org. phase washed with brine and evaporated: 20 (95 mg, 98%). Pale yellow oil. [a]2D0 ˆ ‡11.2 (c ˆ
0.59, CHCl3). IR (film): 1614, 1514, 1359. 1H-NMR (300 MHz, CDCl3): 7.29 (m, 2 H); 6.89 (m, 2 H); 5.97 ± 5.89
(m, 1 H); 5.32 ± 5.17 (m, 3 H); 4.68 ± 4.55 (m, 4 H); 4.02 (m, 1 H); 3.79 (s, 3 H); 2.96 (s, 3 H); 2.83 (m, 1 H); 1.51
(s, 3 H); 1.33 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 133.0; 129.6; 129.3 (2 C); 127.0; 113.8 (2 C); 113.7; 105.6;
‡
‡
86.9; 83.6; 82.9; 82.3; 72.0; 55.3; 51.3; 39.0; 26.9; 24.5. ES-HR-MS: 421.1310 ([M ‡ Na] , C19H26NaO7S ; calc.
421.1291).
(3aS,4S,5R,6R,6aR)-6-Ethenyl-tetrahydro-2,2-dimethyl-4H-cyclopenta[d]-1,3-dioxole-4,5-diol 5-Methane-
sulfonate (21). To a soln. of 20 (58 mg, 0.15 mmol) in CH2Cl2 (10 ml) was added H2O (0.5 ml) followed by
DDQ (83 mg, 0.37 mmol). The mixture was stirred for 7 h prior to the introduction of sat. NaHCO3 soln.
(5.0 ml). The aq. layer was extracted with AcOEt (3 Â 3 ml), the combined org. phase dried and evaporated,
and the residue purified by CC (silica gel, hexane/Et2O 2 :1): 21 (41 mg, 83%). White solid. M.p. 1108. [a]D20
‡18.8 (c ˆ 0.17, CHCl3). IR (film): 3648, 1445, 1423. H-NMR (300 MHz, CDCl3): 6.00 ± 5.88 (m, 1 H); 5.29 ±
5.21 (m, 2 H); 5.13 (m, 1 H); 4.63 ± 4.55 (m, 2 H); 4.32 (m, 1 H); 3.09 (s, 3 H); 3.01 (m, 1 H); 2.39 (d, J ˆ 4.0,
1 H); 1.48 (s, 3 H); 1.30 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 133.5; 119.2; 112.6; 84.5; 83.5; 82.3; 77.2; 51.6;
ˆ
1
‡
‡
38.6; 26.6; 24.1. ES-HR-MS: 301.0713 ([M ‡ Na] , C11H18NaO6S ; calc. 301.0716).
(3aR,4S,5R,6R,6aR)-6-Ethenyl-tetrahydro-2,2-dimethyl-4H-cyclopenta[d]-1,3-dioxole-4,5-diol 5-Methane-
sulfonate 4-(Methyl Carbonate) (22). Alcohol 21 (20.0 mg, 0.072 mmol) was mixed with Et3N (73.8 ml,
0.53 mmol) and a catalytic amount of DMAP in CH2Cl2 (1.2 ml) and placed in an ice-water bath. Methyl

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Helvetica Chimica Acta ± Vol. 88 (2005)
carboncyanidate (20.0 ml, 0.25 mmol) was then added, after which the bath was removed, and stirring was
continued until the starting material was not detected by TLC (ca. 20 min). The mixture was diluted with
CH2Cl2 (5 ml), washed with 5% NaHCO3 soln. and brine, dried, and evaporated and the residue subjected to CC
(silica gel, hexane/Et2O 2.2 :1): 22 (24 mg, 99%). Colorless oil. [a]2D0 ˆ À16.4 (c ˆ 1.6, CHCl3). IR (film): 1757,
1648, 1637. 1H-NMR (300 MHz, CDCl3): 5.89 (m, 1 H); 5.33 (m, 1 H); 5.27 (m, 2 H); 5.09 (t, J ˆ 3.9, 1 H); 4.71
(m, 1 H); 4.63 (m, 1 H); 3.82 (s, 3 H); 3.02 (s, 3 H); 3.00 ± 2.94 (m, 1 H); 1.55 (s, 3 H); 1.33 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 154.6; 132.2; 119.4; 113.8; 84.0; 81.7; 81.5; 80.9; 55.4; 51.3; 38.6; 26.8; 24.3. ES-HR-MS:
‡
‡
359.0771 ([M ‡ Na] , C13H20NaO8S ; calcd 359.0771).
(3aS,4R,6aR)-3a,6a-Dihydro-4-[(methoxycarbonyl)oxy]-2,2-dimethyl-4H-cyclopenta[d]-1,3-dioxole-6-car-
boxaldehyde (23). Asoln. of 22 (23.9 mg, 71.0 mmol) in CH2Cl2 (3.2 ml) was purged with O3 at À 788 for a few
minutes until the soln. became blue, at which point N2 was introduced to remove the remaining O3. Me2S
(13.0 ml, 178 mmol) was added, the mixture allowed to reach r.t., and stirring maintained for 4 h followed by co-
evaporation with benzene. The residue was dissolved in CH2Cl2 (3 ml), cooled to 08 in an ice-water bath, and
i
treated with Pr2EtNH (18.6 ml, 107 mmol). This soln. was stirred for 10 min in the cold and evaporated. The
residue was purified by CC (silica gel, hexane/Et2O 2 :1): 23 (14 mg, 83%). Colorless oil: IR (film): 1754, 1693.
1H-NMR (300 MHz, CDCl3): 9.90 (s, 1 H); 6.78 (m, 1 H); 5.66 (m, 1 H); 5.46 (dd, J ˆ 1.6, 5.9, 1 H); 4.76 (d, J ˆ
5.9, 1 H); 3.84 (s, 3 H); 1.43 (s, 3 H); 1.37 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 188.7; 154.8; 148.6; 144.4; 113.4;
‡
‡
85.0; 83.3; 80.3; 55.3; 26.9; 25.0. ES-HR-MS: 265.0680 ([M ‡ Na] , C11H14NaO6 ; calc. 265.0683).
(3aS,4R,6aR)-3a,6a-Dihydro-4-[(methoxycarbonyl)oxy]-2,2-dimethyl-4H-cyclopenta[d]-1,3]-dioxole-6-
methanol (24). Asoln. of 23 (37.6 mg, 155 mmol) and CeCl3 ´ 7 H2O (69.3 mg, 186 mmol) in EtOH (7.9 ml) was
cooled in an ice/salt bath, treated with NaBH4 (7.0 mg, 186 mmol) in one portion, and stirred for 40 min before
the introduction of sat. NH4Cl soln. After extraction with AcOEt, the combined org. layer was, washed with sat.
NaHCO3 soln., dried, and evaporated an the residue purified by CC (silica gel, hexane/Et2O 2.2 :1): 24 (38 mg,
quant.). Colorless oil. [a]2D0 ˆ À84.6 (c ˆ 0.76, CHCl3). IR (film): 3216, 1745. 1H-NMR (300 MHz, CDCl3): 5.80
(t, J << 1, 1 H); 5.48 (br. s, 1 H); 5.19 (d, J ˆ 5.7, 1 H); 4.68 (d, J ˆ 5.7, 1 H); 4.34 (m, 2 H); 3.80 (s, 3 H); 1.82 (t,
J ˆ 4.6, 1 H); 1.42 (s, 3 H); 1.35 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 158.0; 151.2; 123.7; 112.8; 85.3; 83.6; 83.5;
‡
‡
60.2; 55.0; 27.3; 25.8. ES-HR-MS: 267.0852 ([M ‡ Na] , C11H16NaO6 ; calc. 267.0839).
(3aS,4R,6aR)-6-{{[(1,1-Dimethylethyl)dimethylsilyl]oxy}methyl}-3a,6a-dihydro-2,2-dimethyl-4H-cyclo-
penta[d]-1,3-dioxol-4-ol Methyl Carbonate (25). To a cold (08) soln. of 24 (41.5 mg, 170 mmol) in CH2Cl (6.0 ml)
was added 2,6-dimethylpyridine (49.5 ml, 425 mmol) followed by BuMe2SiOTf (78 ml, 340 mmol). The mixture
t
was stirred for 10 min, quenched with sat. NaHCO3 soln., and extracted with Et2O. The combined org. layer was
washed in turn with 1m HCl and sat. NaHCO3 soln., dried, and evaporated and the residue subjected to CC
(silica gel, hexane/Et2O 7 :1): 49 mg (95%) of 25. Colorless oil. [a]2D0 ˆ À48.2 (c ˆ 3.8, CHCl3). IR (film): 1750,
1
1442, 1372. H-NMR (300 MHz, CDCl3): 5.77 (br. s, 1 H); 5.47 (m, 1 H); 5.09 (m, 1 H); 4.66 (d, J ˆ 5.7, 1 H);
4.31 (m, 2 H); 3.79 (s, 3 H); 1.39 (s, 3 H); 1.34 (s, 3 H); 0.90 (s, 9 H); 0.07 (s, 6 H). 13C-NMR (75 MHz, CDCl3):
152.5; 125.6; 122.5; 112.5; 85.4; 83.9; 82.9; 60.3; 54.9; 27.3; 25.9; 25.8 (3 C); 18.3; À 5.5 (2 C).
(3aS,4R,6aR)-6-{{[(1,1-Dimethylethyl)dimethylsilyl]oxy}methyl}-3a,6a-dihydro-2,2-dimethyl-4H-cyclo-
penta[d]-1,3-dioxol-4-ol. To a soln. of 25 (55.8 mg, 0.16 mmol) in CH2Cl2 (3.1 ml) was added 1m DIBAL-H in
hexane (0.59 ml, 0.59 mmol) at À 788. The mixture was stirred at À 788 for 15 min before MeOH (1.5 ml) and
sat. Roschelleꢁs salt soln. (20 ml) as well as AcOEt (30 ml) were added sequentially. After the two layers became
clear, the aq. layer was extracted with AcOEt (3 Â 10 ml), the combined org. layer washed with brine (2 ml Â2),
dried, and evaporated, and the crude product purified by CC (silica gel, hexane/Et2O 5 :1): (4R)-alcohol (47 mg,
quant.). Colorless oil. [a]2D0 ˆ À13.5 (c ˆ 0.26, CHCl3). IR (film): 3385, 1659, 1462. 1H-NMR (300 MHz, CDCl3):
5.75 (d, J < 1, 1 H); 5.12 (dd, J ˆ 5.3, < 1, 1 H); 4.73 (d, J < 1, 1 H); 4.55 (d, J ˆ 5.6, 1 H); 4.32 (d, J ˆ 15.8, 1 H);
4.27 (d, J ˆ 15.8, 1 H); 1.34 (s, 3 H); 1.30 (s, 3 H); 0.91 (s, 9 H); 0.09 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 149.8;
126.5; 111.9; 86.7; 83.1; 79.9; 60.3; 27.3; 25.9; 25.8 (3C); 18.4; À 5.4; À 5.5.
(3aR,6aR)-6-{{[(1,1-Dimethylethyl)dimethylsilyl]oxy}methyl}-3a,6a-dihydro-2,2-dimethyl-4H-cyclopen-
ta[d]-1,3-dioxol-4-one (26). Pyridinium dichromate (152 mg, 0.41 mmol) was added in several portions to a
stirred suspension of the above (4R)-alcohol (49 mg, 0.16 mmol) and 4-Š molecular sieves (109 mg) in CH2Cl2
(10.8 ml). After an additional hour, Et2O (20 ml) was added, and the mixture was stirred for 45 min prior to
filtration through a pad of Celite and washing with Et2O. The combined filtrate and washings were evaporated,
and the residue was subjected to CC (silica gel, hexane/Et2O 6 :1): 26 (42 mg, 89%). Colorless oil. [a]2D0 ˆ À7.5
(c ˆ 0.81, CHCl3). IR (film): 1726, 1630, 1443. 1H-NMR (300 MHz, CDCl3): 6.16 (m, 1 H); 5.05 (d, J ˆ 5.6, 1 H);
4.66 (dd, J ˆ 1.9, 18.8, 1 H); 4.51 (d, J ˆ 5.6, 1 H); 4.47 (dd, J ˆ 1.2, 18.8, 1 H); 1.40 (s, 6 H); 0.91 (s, 9 H); 0.10 (s,
6 H); 13C-NMR (75 MHz, CDCl3): 201.6; 177.2; 127.7; 115.4; 78.0; 77.6; 61.6; 27.4; 26.2; 25.7 (3 C); 18.2; À 5.5
(2 C).

Helvetica Chimica Acta ± Vol. 88 (2005)
1197
(3aS,4S,6aR)-6-{{[(1,1-Dimethylethyl)dimethylsilyl]oxy}methyl}-3a,6a-dihydro-2,2-dimethyl-4H-cyclopen-
ta[d]-1,3-dioxol-4-ol. Asoln. of 26 (42.1 mg, 0.14 mmol) in toluene (3.0 ml) was treated with 1.0m DIBAL-H in
toluene (0.35 ml, 0.35 mmol) dropwise at À 788, stirred for 1.5 h, and quenched with MeOH (5 ml) and H2O
(5 ml). The aq. layer was extracted with CHCl3 (3 Â 3 ml), the combined org. extract washed with brine (5 ml),
dried, and evaporated, and the residue purified by CC (silica gel, 0 ± 10% Et2O/CH2Cl2): (4S)-alcohol (38 mg,
90%). Colorless oil. [a]2D0 ˆ ‡22.5 (c ˆ 0.53, CHCl3). IR (film): 3504, 1513, 1472. 1H-NMR (300 MHz, CDCl3):
5.72 (d, J ˆ 0.9, 1 H); 4.89 (d, J ˆ 5.6, 1 H); 4.75 (t, J ˆ 5.5, 1 H); 4.54 (m, 1 H); 4.34 (dd, J ˆ 15.1, < 1, 1 H); 4.23
(dd, J ˆ 15.1, < 1, 1 H); 2.68 (d, J ˆ 10.0, 1 H); 1.41 (s, 3 H); 1.38 (s, 3 H); 0.91 (s, 9 H); 0.07 (s, 6 H). 13C-NMR
(75 MHz, CDCl3): 145.6; 129.2; 112.5; 82.7; 77.9; 73.2; 59.9; 27.6; 26.6; 25.9 (3 C); 18.3; À 5.4; À 5.5.
9-{(3aS,4R,6aR)-6-{{[(1,1-Dimethylethyl)dimethylsilyl]oxy}methyl}-3a,6a-dihydro-2,2-dimethyl-4H-cyclo-
penta[d]-1,3-dioxol-4-yl}-9H-purin-6-amine (27). Asoln. of the above (4 S)-alcohol (38 mg, 0.13 mmol),
triphenylphosphine (140 mg, 0.53 mmol), and adenine (72 mg, 0.51 mmol) in THF (24 ml) was cooled at an ice-
water bath, and diisopropyl diazocarboxylate (105 ml, 0.53 mmol) was slowly introduced. The mixture was
allowed to warm to r.t., and stirring was continued overnight. The volatiles were evaporated, and the residue was
subjected to CC (silica gel, hexane/AcOEt 1:2 containing 1% MeOH): 27 (48 mg, 90%). Thick oil. [a]D20
ˆ
À30.0 (c ˆ 0.33, CHCl3). IR (film): 3331, 1652, 1635. 1H-NMR (300 MHz, CDCl3): 8.38 (s, 1 H); 7.67 (s, 1 H);
5.90 (s, 2 H); 5.78 (s, 1 H); 5.59 (s, 1 H); 5.30 (d, J ˆ 5.7, 1 H); 4.71 (d, J ˆ 5.7, 1 H); 4.42 (m, 2 H); 1.48 (s, 3 H);
1.35 (s, 3 H); 0.92 (s, 9 H); 0.10 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 153.1; 152.6; 150.0; 138.5; 132.2; 128.6;
121.0; 112.7; 84.8; 83.6; 64.4; 60.4; 27.4; 25.9; 25.8 (3 C); 14.2; À 5.4 (2 C).
(À)-Neplanocin A (ˆ(1S,2R,5R)-5-(6-Amino-9H-purin-9-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol;
2). Asoln. of 27 (48 mg, 0.12 mmol) in MeOH (5 ml) was treated with 1.0m HCl (5 ml) and stirred at r.t. for
‡
3.5 h. The solvent was evaporated and the residue purified by ion exchange (Dowex 50WX4-400; H form), aq.
ammonia: 2 (29 mg, 95%). White solid. M.p. 217 ± 2198. [a]2D0 ˆ À155.5 (c ˆ 0.20, H2O). IR (film): 3326, 3151,
1649, 1643. 1H-NMR (300 MHz, (D6)DMSO/D2O): 8.10 (s, 1 H); 8.05 (s, 1 H); 5.68 (d, J ˆ 1.3, 1 H); 5.33 (br. s,
1 H); 4.41 (d, J ˆ 5.5, 1 H); 4.25 (t, J ˆ 5.5, 1 H); 4.09 (s, 2 H). 13C-NMR (300 MHz, (D6)DMSO/D2O): 56.1;
152.8; 150.2; 149.9; 140.2; 124.0; 119.2; 76.9; 72.5; 64.7; 58.8.
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Received November 10, 2004