Toward a total synthesis of macrocyclic jatrophane diterpenes - Concise route to a highly functionalized cyclopentane key intermediate

Article abstract of DOI:10.1002/hlca.200590124

A total synthesis of the biologically potent jatrophane diterpenes pepluanin A (1) and euphosalicin A (2) is being aimed at. En route to these targets, a concise synthesis of the nonracemic cyclopentane building block 74 was developed. Key steps were a Cl

Full text of DOI:10.1002/hlca.200590124

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Toward a Total Synthesis of Macrocyclic Jatrophane Diterpenes ± Concise
Route to a Highly Functionalized Cyclopentane Key Intermediate
by Johann Mulzer*a), Gerald Giesterb), and Michael Gilberta)
a) Institut für Organische Chemie der Universität Wien, Währinger Strasse 38, A-1090 Wien
(phone: ‡ 431-4277-52190; fax: ‡ 431-4277-52189; e-mail: johann.mulzer@univie.ac.at)
b) Institut für Mineralogie und Kristallographie, Universität Wien, Geozentrum, Althanstr.14, A-1090 Wien
Dedicated to Professor Rolf Huisgen on the occasion of his 85th birthday
A total synthesis of the biologically potent jatrophane diterpenes pepluanin A (1) and euphosalicin A (2) is
being aimed at. En route to these targets, a concise synthesis of the nonracemic cyclopentane building block 74
was developed. Key steps were a Claisen ± Eschenmoser rearrangement of the enantiomerically enriched allylic
alcohol 14 to amide 34 (Scheme 7), a hydroxy-lactonization of 40 to 43 (Scheme 9), followed by trans-
lactonization to 72, which was subjected to a Davis hydroxylation to 69 (Scheme 17). Eventually, compound 69
was converted into the enol triflate 74. This material should prove suitable for an annulation of the macrocyclic
ring characteristic of the desired jatrophanes 1 and 2. Less-successful approaches are also discussed due to their
intrinsically valuable information content.
Introduction. ± Any kind of cancer chemotherapy is threatened by intrinsic or
acquired multidrug resistance (MDR1). Nearly 50% of human cancers are either
completely resistant to chemotherapy or respond only transiently, whereafter they are
no longer affected by commonly used anticancer drugs. The phenomenon of MDR was
first discovered by Shapiro and Ling, who observed that human tumors treated
sequentially with different chemotherapeutics became resistant to further chemo-
therapy [1]. Thus, certain kinds of cancer cannot be treated successfully by means of
chemotherapy. A primary mechanism of MDR is attributed to the overexpression of P-
glycoprotein (P-gp) in the plasma membrane or in resistant cells, where the P-gp acts as
an energy-dependent efflux pump, reducing intracellular accumulation of anticancer
drugs [2]. A number of drugs such as calcium channel blockers, calmodulin inhibitors,
and certain indole alkaloids are known to reverse MDR by competing with anticancer
drugs for binding to P-gp. However, they have not been proven clinically useful yet. For
example, Verapamilꢀ, the most extensively studied MDR-reversing agent, induces
cardiovascular toxicity at the concentration that is needed to reverse MDR [3]. Clearly,
there is a need for new classes of MDR-reversing agents with less toxicity to the host.
In a search for MDR-reversing compounds from natural sources, the secondary
metabolites of Euphorbia species, perennial herbs distributed throughout Central and
South-East Europe, were investigated [4]. The Euphorbiaceae (spurge) family is
known to produce various highly functionalized, structurally unique macrocyclic
diterpenes. The MDR-reversing effect of lipophilic extracts of Euphorbia esula l., E.
1
)
For abbreviations, see Exper. Part.
ꢁ 2005 Verlag Helvetica Chimica Acta AG, Zürich

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peplus l., E. salicifolia, and E. serrulata were tested on mouse lymphoma cells. From
the active extracts, a series of structurally related compounds with significant P-gp
inhibitory activities were isolated, including pepluanin A (1) and euphosalicin (2).
Results and Discussion. ± To gain deeper insight into structure ± activity relation-
ship (SAR), we [5] and others [6] thought about a general synthetic access to pepluanin
A (1) and euphosalicin (2), as well as other structurally related jatrophane natural
products. Structural analysis of 1 and 2 revealed that the differences in the oxygenation
patterns and carbon skeletons lie primarily in the C(7 ± 14) segment of the larger ring.
Therefore, we envisaged a C(15 ± 6) segment (3) common to both targets, which should
then be coupled to a tailor-made C(7 ± 14) segment (4).
A retrosynthetic analysis of 1 suggested that formation of the bonds C(14)ÀC(15)
and C(6)ÀC(7) at a late stage might be achieved via McMurry [7] and Nozaki ±
Hiyama ± Kishi (NHK) type [8] couplings, respectively (Scheme 1). The stereochem-
ical implications of a McMurry type coupling for the ring closure of keto aldehyde 5
were then considered. The approach of the aldehyde moiety from the a-side of the ring
should be favored for steric reasons, as illustrated in 6, affording a diol with the desired
relative configuration. If this expectation should not be borne out experimentally,
recourse to the free 3-OH group would be expected to undergo the McMurry coupling
from the desired a-side (see 7) [7]. The next disconnection of C(6)ÀC(7) leads back to
vinyl triflate 8 and the aldehyde segment 9, which represent suitable substrates for a
NHK-type coupling. Fragment A, the CÀ(15)ÀC(6) segment, could, thus, serve as an
advanced intermediate coupling partner, and allow synthetic access to several natural
products upon coupling with the corresponding C(7)(14) segments, i.e., fragment B.

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Scheme 1. Retrosynthetic Analysis of 1. For abbreviations, see Exper. Part.
Naturally, the first target of our synthetic study was fragment A, the segment
common to both proposed syntheses. A straightforward retrosynthetic analysis
suggested that vinyl triflate 8 should be available from lactone 10 via methyl ketone
11 (Scheme 2). In turn, lactone 10 should be accessible from alkene 12 via epoxidation
of the CˆC bond, followed by regioselective opening of the newly formed epoxide. We
envisaged acid 12 to be the main product of a Claisen type rearrangement of ester 13,
which in turn, should be readily accessible from diol 14.
Scheme 2. Retrosynthetic Analysis of 8

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Diol 14 was prepared in racemic form from 2,5-dimethylfuran (15) via 16 and the
known ketone 17 [9] (Scheme 3). It should be noted that prolonged reaction times for
the production of 17 lead to formation of the thermodynamically more-stable
constitutional isomer 18, conceivably via 19a,b as shown in Scheme 3. The desired
hydroxy ketone 17 was then subjected to a Luche reduction to furnish cis-diol 14. To
test the validity of our concept, the following transformations were performed with
racemic 14.
Scheme 3
With racemic diol 14 in hand, the proposed Ireland ± Claisen rearrangement [10]
was investigated. Selective PMB (ˆꢂp-methoxybenzylꢃ) protection of the secondary
alcohol function was followed by acetylation of the tertiary alcohol to give 20
(Scheme 4). Treatment of the latter with potassium hexamethyldisilazane (KHMDS)
and Me3SiCl (TMSCl) afforded one major product, which, on the basis of NMR studies,
was expected to be acid 21. Epoxidation of the CˆC bond in 21 with ꢂmeta-
chloroperbenzoic acidꢃ (MCPBA) gave what we thought to be compound 22. However,
to our disappointment, all attempts at inducing an epoxide-opening lactonization with
the neighboring COOH moiety to 23 failed. This result was quite surprising, as
literature precedence suggested that this reaction usually proceeds under very mild
conditions. However, the reason for this discrepancy soon became clear, when X-ray
crystallographic studies were performed on crystals of the putative epoxy acid 21.
Indeed, the structure we had assigned to 22 was inconsistent with the X-ray data, which
showed this compound to have structure 24 (Fig. 1).
Both the relative configurations of the side chain with the benzyl ether and the
epoxide on the ring were wrong in our original assignment. This certainly explained
why we were unable to open the epoxide with the COOH moiety! Clearly, the
predicted stereochemical outcomes for both the Ireland ± Claisen rearrangement and
the epoxidation had been false.

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Scheme 4. Attempted Preparation of 21 and 22 (see text)
Fig. 1. X-Ray crystal structure of 24 (one enantiomer shown)
An analysis of the stereochemical outcome of the Ireland ± Claisen rearrangement
[10] is shown in Scheme 5. It is fairly well-established that deprotonation of a BnO-
substituted acetate (20) under kinetically controlled conditions with KHMDS, followed
by quenching of the resulting enolate with TMSCl, should afford the (Z)-configured
enol ether (25). However, the next step of the reaction, the [3,3]-sigmatropic
rearrangement, is not so well-established for five-membered rings. In most cases, the
rearrangement involves a boat-like transition state similar to 26, which would then
afford the desired product 21. However, in some cases, namely in our case, the

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Scheme 5. Stereochemical Course of the Ireland ± Claisen rearrangement of 20
rearrangement can adopt a chair-like transition state similar to 27, in which the isomer
28 is obtained. Literature precedence [10b,c] has shown that, under certain conditions,
the corresponding (E)-configured enol ether of 25 can be prepared to access a
rearrangement product with the alternate configuration. However, the yields for these
reactions tend to be lower, and we decided to abandon this approach.
The, at first sight, contradictory outcome of the epoxidation at 28 is most likely due
to a Henbest effect exerted by the pseudo-axial COOH function in a conformation such
as 29 [11], which is in equilibrium with 30 (Scheme 5).
At this point in the study, a new retrosynthetic plan was considered. As in the
previous plan, triflate 8 was thought to be accessible from ketone 11 (Scheme 6). But
this time, access to the ketone would be attempted by opening lactone 31. We then
envisaged that 32 could serve as a template to introduce the challenging oxygenation
pattern with the desired configuration in 31. Thus, we believed that both the
epoxidation of the CˆC bond and the hydroxylation next to the lactone could be
directed to take place from the sterically less-hindered, convex face. Lactone 32 could
then be obtained from 33, the product of an Eschenmoser ± Claisen rearrangement [12].
Once again, the first steps of the planned sequence were attempted with racemic
diol 14 (Scheme 7). The secondary OH group in 14 was protected as the corresponding

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Scheme 6. Alternative Retrosynthesis of 8
tert-butyl(diphenyl)silyl (TBS) ether. Subjection of the resulting material to the
Eschenmoser ± Claisen protocol [12] afforded the amide rearrangement product 34 in
good yield. TBS Removal and a subsequent lactonization step were then smoothly
effected under acidic aqueous conditions. The resulting material, 32, was then treated
with KHMDS, followed by a solution of the Davis oxaziridine [13]. As predicted, the
cis-fused bicycle underwent hydroxylation completely stereoselectively from the convex
Scheme 7. Synthesis of the Bicyclic Lactone 35 (racemic series)

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a-face. The newly introduced OH function was then protected as the TBS ether to yield
35.
The next step in the envisaged strategy foresaw a diastereoselective epoxidation of
35. However, even under the most-favorable conditions tested, at best, a 1:1-mixture of
36/37 resulted. The same outcome was observed when 32 served as the starting material
to give mixtures of 38/39 (Scheme 8).
Scheme 8
As the epoxidation of the cis-fused bicyclic systems did not proceed with the
anticipated stereoselectivity, we investigated other precursors as substrates for this key
epoxidation step. Gratifyingly, treatment of the Eschenmoser ± Claisen rearrangement
product 34 with in situ generated dimethyldioxirane (DMDO) afforded exclusively the
desired epoxide 40 (Scheme 9). In this case, both the silyl ether and amide side chain
moieties on the b-face of 34 were sufficient to direct the attack of the peracid to the a-
face. With the epoxide and amide moieties on opposing faces of the ring in 40, the
system was perfectly set up for an intramolecular epoxide-opening lactonization.
Indeed, simple flash chromatography of crude 40 produced, via 41 and 42, lactone 43 in
80% overall yield from 34 (Scheme 9).
In concurrent studies, ample quantities of enantiomerically enriched starting
materials had been prepared. Since all attempts at resolving diol 14 or its derivatives
failed in our hands, an alternative approach to prepare enantiomerically enriched 44
was developed (Scheme 10). Employing a sequence reported by Curran and co-
workers [14], commercially available furfuryl alcohol (45) was converted in four steps
to a separable mixture of acetate 46 (13%, 98% ee) and alcohol 47 (13%, 98% ee).
By well-established chemistry [15], compounds 46 and 47 were then converted to a

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Scheme 9. Synthesis of Lactone 43 (racemic series)
common intermediate, ketone 48 [16], in two and five steps, respectively2). Finally,
treatment of 48 with MeLi yielded the desired tertiary alcohol 44 [17] in good yield.
This enantiomerically enriched material was then carried through the next two newly
developed steps to give lactone 43 (98% ee) in good yield.
Scheme 10. Preparation of Enantiomerically Enriched 44
The next challenge in our synthesis was the introduction of an OH substituent a to
the lactone function with the desired (R)-configuration. To utilize the convex/concave
handle inherent to cis-fused bicycles, it would be necessary to first migrate the lactone
function in 43 from the oxygenated 2-position on the ring to the oxygenated 5-position
2
)
All spectra obtained for intermediates 46 ± 48 matched those previously reported in the literature [14 ± 17].

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(Scheme 11). First, the OH group of 43 was protected as the corresponding
methoxymethyl (MOM) ether 49. The lactone in 49 was opened with pyrrolidine,
and the resulting alcohol was protected as benzoyl ester 50. Removal of the TBS
protection group liberated the 5-OH group, which was then used for the formation of
the desired lactone 51.
Scheme 11
The following step, a-hydroxylation of the lactone moiety of 51, was investigated
next (Scheme 12). Once more, we were faced with disappointment, as treatment of 51
with KHMDS, followed by a solution of the Davis oxaziridine reagent, afforded alcohol
(52) with the undesired (S)-configuration. The relative configuration of the newly
introduced PMB-protected OH group in 53 was confirmed by two-dimensional
1H-NMR NOESYexperiments. Among the noted cross-peaks, strong correlations were
detected between the Hb-atom, adjacent to the newly introduced PMB-protected OH
group, and the ring-fusion Ha-atom. Surprisingly, the Davis reagent approached the
enolate derived from lactone 51 from the concave b-face of the cis-fused system. In an
attempt to understand the unexpected stereoselectivity of the hydroxylation, we
considered conformers C and D with molecular models. According to these studies, the
attack should have occurred from the convex a-face. The only possibility we could
imagine was that D, with the benzoyl (Bz) group in pseudo-equatorial position, might
be the preferred conformer. Presumably, the Bz group is wrapped around the ring
fusion, and lies beneath the enolate, thus blocking the bottom face. Therefore, we
sought to attempt the a-hydroxylation on substrate 54 lacking the Bz group.
Unfortunately, attempted removal of the Bz group of 51 under basic conditions
resulted in complex mixtures, likely due to competing lactone opening. Therefore, an
alternative preparation of the desired alcohol 54 was developed, by introducing a 3-
(AcO) group (vide infra).

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Scheme 12. Stereochemical Course of the Davis Hydroxylation of 51
As shown in Scheme 13, lactone 49 was treated with pyrrolidine, and the resulting
alcohol was acetylated to 55. The TBS group was removed with Bu4NF (TBAF), and
the lactone was formed. In contrast to the previous Bz protecting group (vide supra),
the AcO group could be smoothly cleaved to give alcohol 54. a-Hydroxylation of the
latter was then effected by treatment with excess of KHMDS, followed by addition of
the Davis reagent. In this case, the OH group was successfully introduced from the
convex a-face to give alcohol 56 with the desired (R)-configuration.
Scheme 13

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With all the stereogenic centers set, the final steps in the synthesis of fragment A
were investigated. The newly introduced OH group in 56 was protected as the PMB
ether (Scheme 14). The next step, MeLi addition to the lactone, proceeded smoothly,
yielding the hemi-acetal 57 in good yield. We envisaged that 57 would exist in an
equilibrium with hydroxy ketone 57a, and that the latter, under the right conditions,
could be trapped as silyl ether 58. However, in our hands, using a variety of silylating
reagents (R3SiCl, R3SiTf), we were unable to obtain 58. The only products were mono-
silylated compounds of type 59. Additional attempts to trap the ketone 58, from these
intermediates, also failed.
Scheme 14
As an alternative to a direct MeLi addition to the lactone derived from 56, we
investigated the possibility of opening this lactone with an amine, and subsequently
preparing the desired methyl ketone 58. Heating 60 with pyrrolidine gave the amide 61,
which was then subjected to various silylating conditions (Scheme 15). We were able to
introduce larger silyl groups (TBS, TIPS) at the less-hindered 5-position to give 62, but
we were limited to smaller protecting groups such as Me3Si and Et3Si (TES) for the
more-hindered OH-group at C(2) to give species of type 63. Attempted protection of
the 2-OH group with larger groups under more-forcing conditions simply resulted in
lactonization to give 64. The next step, conversion of the amide to a methyl ketone also
proved difficult. Under various conditions, treatment of 63 with MeLi simply resulted
in recovered starting material. Since we had samples of 64 on hand, we once again
looked for a direct conversion of the lactone unit to the methyl ketone. However, as in
the previous examples (vide supra), MeLi addition proceeded well to give 65, but this
hemi-acetal could not be trapped as ketone 58.
Whilst carrying material though the presently favored synthesis-to-date, we were
constantly trying to optimize the involved steps. In one particular example, this proved
to be quite rewarding (Scheme 16). For the requisite transformation of lactone 49 to
lactone 54, a five-step sequence had been developed. However, we were pleased to find
that simply treating 49 with TBAF overnight also accomplished the same task in good
yield. From a mechanistic point of view, it would seem that the alkoxide generated upon

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Scheme 15
Scheme 16

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desilylation might exist in two major conformations. On the basis of molecular-model
studies, conformer 66 conceivably can undergo an intramolecular lactone-opening to
67, which reacts to 54.
In continuing with the scale-up procedure, lactone 49 was converted to lactone 68
via the new TBAF procedure (Scheme 17). a-Hydroxylation then gave 69, and
subsequent PMB protection afforded 70 in good yield.
Scheme 17
The relative configuration of the newly introduced OH group in 70 was confirmed
1
by H-NMR NOESY experiments. Among the observed cross-peaks, strong correla-
tions were noticed between the Ha-atom adjacent to the newly introduced OH group,
and the ring Mea group (Fig. 2).
Fig. 2. Sole significant NOE effect in compound 69
With lactone 70 at hand, we investigated the formation of the requisite methyl
ketone (Scheme 18). Lactone 70 was opened with pyrrolidine to give 71, and the
resulting alcohol was trapped as TES ether 72. With a TES ether on one side and a
MOM ether on the other, MeLi addition to 72 proceeded smoothly to give methyl
ketone 73. Although more than 2 equiv. of MeLi were required for this reaction to go to
completion, no double-addition product was detected. The final step in this sequence,
regioselective vinyl triflate formation, was accomplished by first deprotonating the
methyl ketone 73 under kinetically controlled conditions, and then treating the
resulting enolate with a solution of PhN(Tf)2. The resulting material was fully
characterized and shown to be vinyl triflate 74, the target of the present synthetic study.

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Scheme 18
Conclusions. ± In summary, we have prepared the highly functionalized building
block 74 from the enantiomerically enriched alcohol 44 via an eleven-step sequence
that involves a highly stereoselective epoxidation and a subsequent intramolecular ring
opening reaction. This allowed a quick establishment of the required oxygenation
pattern combined with the desired relative configuration at all stereogenic centers. The
advanced intermediate 74 trades well for a rational synthetic access to a multitude of
jatrophane natural products. The preparation of the coupling partners required for a
synthesis of the polyesters pepluanin A (1) and euphosalicin (2) is currently underway
in our laboratories.
Experimental Part
Abbreviations. Ac, acetyl; Bn, benzyl (ˆ phenylmethyl); Bz, benzoyl (ˆ phenylcarbonyl); CSA,
chlorosulfonic acid; DIPEA, ꢂdiisopropylethylamineꢃ (Et(i-Pr)2N); DMAP, 4-(dimethylamino)pyridine;
DMDO, dimethyldioxirane; DMF, N,N-dimethylformamide; Im, 1H-imidazole; KHMDS, potassium hexa-
methyldisilazane; MCPBA, ꢂmetachloroperbenzoic acidꢃ (ˆ 3-chlorobenzeneperoxoic acid); MDR, multidrug
resistance; MOM, methoxymethyl; MPPA, monoperoxyphthalic acid magnesium salt; Nic, nicotinoyl
(ˆ pyridyl-3-carbonyl); PDC, pyridinium dichromate; PG, protecting group; PMB, ꢂparamethoxybenzylꢃ
(ˆ(4-methoxyphenyl)methyl); TBAF, tetrabutylammonium fluoride (Bu4NF); TBS, tert-butyl(dimethyl)silyl
(t-BuMe2Si); TES, triethylsilyl (Et3Si); Tf, trifluoromethylsulfonyl (ˆCF3SO2); THF, tetrahydrofuran; TIPS,
triisopropylsilyl (i-Pr3Si); TMS, trimethylsilyl (Me3Si).
General. All moisture-sensitive reactions were carried out under Ar atmosphere. Anhydrous (anh.) THF
was distilled from Na/benzophenone ketyl. All other solvents were of HPLC grade. Flash chromatography (FC)
[18] was performed with Merck silica gel (0.04 ± 0.63 mm, 240 ± 400 mesh) under medium pressure. Thin-layer
chromatography (TLC) was carried out with Merck silica gel 60-F254 plates. Optical rotations were measured on
a Perkin-Elmer P-341 polarimeter. NMR Spectra were recorded on either a Bruker Avance DPX-250 or -400
apparatus. Unless otherwise stated, all NMR spectra were recorded in CDCl3 soln. and referenced to the
residual CHCl3 signal (d(H) 7.26, d(C) 77.0 ppm). Chemical shifts d are given in ppm, coupling constants J are
expressed in Hz, and multiplicities are abbreviated as s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet.
Assignments of H-atom resonances were confirmed, when possible, by selective homonuclear decoupling
experiments, or by correlated spectroscopy. Electron-impact (EI) mass spectra were measured on a Micro Mass

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Trio-200 mass spectrometer (Fisions Instruments, UK). High-resolution mass spectra (HR-MS) were
performed with a Finnigan MAT-8230 apparatus at a resolution of 10000; in m/z (rel. %).
(2S)-(Benzyloxy){(1S,5R)-5-[(4-methoxybenzyl)oxy]-3-methylcyclopent-2-en-1-yl}acetic Acid (28). To a
cooled (08), stirred soln. of 14 (3.0 g, 26.3 mmol) in DMF (60 ml) was portion-wise added NaH (55% suspension
in oil; 2.41g, 55.2 mmol) over 15 min. PMBCl (4.1g, 26.3 mmol) and Bu 4NI (100 mg, 0.3 mmol) were then
added. The resulting dark mixture was allowed to warm to r.t., and stirred for 3 h. The mixture was then added to
a 2 :1mixture of sat. aq. NH 4Cl soln./Et2O (300 ml). The resulting layers were separated, and the aq. layer was
washed with Et2O (3 Â 100 ml). The volatile components were removed under reduced pressure, and the
resulting crude material was dissolved in pyridine (30 ml). 2-(Benzyloxy)acetyl chloride (4.9 g, 26.5 mmol) and
DMAP (20 mg, 0.16 mmol) were added, and the resulting mixture was stirred for 18 h. The mixture was diluted
with Et2O (100 ml), and washed with aq. 1n HCl soln. (100 ml), followed by sat. aq. NaHCO3 soln. (2 Â 50 ml).
The solvents were removed under reduced pressure, and the resulting material was subjected to FC (hexane/
AcOEt 5 :1) to afford the desired 2-(benzyloxy)acetate 20 (7.25 g, 18.9 mmol, 72% yield) as a clear colorless oil.
To a cold (À 788), stirred soln. of 20 (471mg, 1.23 mmol) and TMSCl (0.67 g, 6.2 mmol) in anh. THF (50 ml)
was added a 0.5m soln. of KHMDS in toluene (12.3 ml, 6.2 mmol). The mixture was stirred for 1 h at À 788,
allowed to warm to r.t. over 1h, and stirred for 2 h at r.t. Then., sat. aq. NH 4Cl soln. (50 ml) was added, and the
resulting layers were separated. The aq. layer was extracted with AcOEt (3 Â 50 ml), and the combined org.
layers were dried (MgSO4). The solvents were removed under reduced pressure, and the resulting material was
subjected to FC (hexane/AcOEt/AcOH 60 :30 :1) to afford 28 (358 mg, 76%). Clear, colorless oil. 1H-NMR
(CDCl3, 400 MHz): 1.75 (s, 3 H); 2.35 ± 2.55 (m, 2 H); 3.28 (br. s, 1H); 3.80 ( s, 3 H); 4.17 (d, J ˆ 4.0, 1H); 4.35 ±
4.80 (m, 5 H); 5.29 (br. s, 1H); 6.85 ( d, J ˆ 8.7, 2 H); 7.19 (d, J ˆ 8.7, 2 H); 7.29 ± 7.37 (m, 5 H); 10.65 (br. s, 1 H).
13C-NMR (CDCl3, 100.6 MHz): 16.1; 42.4; 52.0; 55.3; 71.8; 73.2; 77.9; 79.1; 113.9; 122.1; 127.9; 128.1; 128.4;
129.1; 129.5; 137.5; 140.8; 159.5; 172.7.
(2S)-(Benzyloxy){(1R,2R,3R,5S)-3-[(4-methoxybenzyl)oxy]-5-methyl-6-oxabicyclo[3.1.0]hex-2-yl}acetic
Acid (24). To a cold (À158), stirred soln. of 28 (302 mg, 0.79 mmol) in anh. CH2Cl2 (30 ml) was added MCPBA
(77%; 177 mg, 0.79 mmol). The mixture was stirred for 30 min at À 158. Then, sat. aq. NaHCO3 soln. (30 ml)
was added, and the resulting layers were separated. The aq. layer was extracted with CH2Cl2 (3 Â 30 ml), and the
combined org. layers were dried (MgSO4). The solvents were removed under reduced pressure, and the
resulting material was subjected to FC (hexane/AcOEt/AcOH 50 :50 :1) to afford 24 (264 mg, 84%). Colorless
solid. 1H-NMR (CDCl3, 400 MHz): 1.43 (s, 3 H); 1 .83 (dd, J ˆ 15.1, 6.5, 1 H); 2.14 (d, J ˆ 15.1, 1 H); 2.66 (br. t,
J ˆ 8.3, 1H); 3.31(br. s, 1H); 3.77 ( s, 3 H); 4.03 (dd, J ˆ 6.7, 6.5, 1H); 4.33 ( d, J ˆ 11.7, 1 H); 4.42 ± 4.48 (m,
3 H); 4.66 (d, J ˆ 10.9, 1 H); 6.80 (d, J ˆ 8.7, 2 H); 7.18 (d, J ˆ 8.7, 2 H); 7.27 ± 7.35 (m, 5 H); 8.96 (br. s, 1 H).
13C-NMR (CDCl3, 100.6 MHz): 17.5; 38.0; 49.6; 55.2; 62.7; 63.6; 71.9; 72.8; 75.7; 76.7; 113.7; 127.8; 128.0; 128.3;
129.4; 129.9; 137.4; 159.1; 175.9. X-Ray crystal structure: see Fig. 1 and crystallographic section below.
2-[(1S,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-3-methylcyclopent-2-en-1-yl]-N,N-dimethylacetamide (34).
To a stirred soln. of alcohol 44 (13.9 g, 61.0 mmol) in toluene (30 ml), N,N-dimethylacetamide dimethoxy
acetal (24.6 g, 183 mmol) was added dropwise. The mixture was heated to reflux for 48 h, during which time the
generated MeOH was allowed to distill out. The volatiles were removed under reduced pressure, and the
resulting crude material was purified by FC (hexane/AcOEt 5 :1) to afford 34 (15.5 g, 85%). Clear, yellow oil. Rf
0.31(hexane/AcOEt 2 :1). [ a]2D0 ˆ ‡24.4 (c ˆ 1.1, acetone). IR (film): 3035, 2929, 2856, 1652, 1471, 1397.
1H-NMR (CDCl3, 400 MHz): 0.01( s, 3 H); 0.03 (s, 3 H); 0.86 (s, 9 H); 1.68 (s, 3 H); 2.10 ± 2.25 (m, 2 H); 2.43
(dd, J ˆ 16.0, 6.7, 1 H); 2.62 (dd, J ˆ 16.0, 6.8, 1 H); 2.92 (s, 3 H); 2.97 (s, 3 H); 3.09 ± 3.17 (m, 1H); 4.48 ± 4.54
(m, 1H); 5.25 ± 5.30 ( m, 1 H). 13C-NMR (CDCl3, 100.6 MHz): À 5.1; À 4.7; 17.0; 18.1; 25.8; 32.3; 35.3; 37.1;
‡
45.6; 46.1; 73.6; 127.0; 137.7; 172.8. EI-MS (70 eV): 297 (1, M ), 240 (42), 72 (100). HR-EI-MS (70 eV): 297.2127
‡
‡
(M , C16H31NO2Si ; calc. 297.2124).
(3aS,4R,6R,6aR)-4-{[tert-Butyl(dimethyl)silyl]oxy}-3,3a,4,5,6,6a-hexahydro-6-hydroxy-6-methyl-2H-cy-
clopenta[b]furan-2-one (43). To a cooled (08), stirred soln. of 34 (15.0 g, 50.3 mmol) and 18-crown-6 (1.0 g,
3.8 mmol) in a 1:1:1mixture of CH 2Cl2/acetone/H2O (450 ml) was added NaHCO3 (32.0 g, 381mmol)
portionwise over 20 min. A soln. of Oxone ( ˆ potassium peroxymonosulfate; 60.0 g, 100 mmol) in H2O
(300 ml) was added dropwise over 1h. The resulting mixture was stirred for another 2 h at 0 8. Then, AcOEt
(200 ml) was added, and the layers were separated. The aq. layer was extracted with AcOEt (2 Â 200 ml), and
the combined org. layers were dried (MgSO4). The solvents were removed under reduced pressure, and the
resulting material was subjected to FC (hexane/AcOEt 2 :1) to afford 43 (11.5 g, 80%). Clear, colorless oil. Rf
0.17 (hexane/AcOEt 2 :1). [a]2D0 ˆ À26.6 (c ˆ 0.95, acetone). IR (film): 3440, 2957, 2931, 1778, 1472. 1H-NMR
(CDCl3, 400 MHz): 0.04 (s, 6 H); 0.88 (s, 9 H); 1 .40 (s, 3 H); 1.53 ± 1.65 (m, 2 H); 1 .97 (dd, J ˆ 13.6, 6.3, 1 H);
2.44 (dd, J ˆ 18.8, 10.9, 1 H); 2.98 (dd, J ˆ 18.8, 2.9, 1 H); 3.09 ± 3.18 (m, 1H); 4.41 ( dd, J ˆ 6.6, 1.5, 1 H);

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Helvetica Chimica Acta ± Vol. 88 (2005)
4.52 ± 4.59 (m, 1 H). 13C-NMR (CDCl3, 100.6 MHz): À 5.0; À 4.8; 18.0; 23.6; 25.7; 28.0; 41.4; 45.3; 71.1; 78.4;
t
‡
89.9; 177.6. EI-MS (70 eV): 229 (41), [M À Bu] ), 137 (42), 75 (100). HR-EI-MS (70 eV): 229.0901
t
‡
‡
([M À Bu] ), C10H17O4Si ; calc. 229.0896).
(3aS,4R,6R,6aR)-4-{[tert-Butyl(dimethyl)silyl]oxy}-3,3a,4,5,6,6a-hexahydro-6-(methoxymethoxy)-6-meth-
yl-2H-cyclopenta[b]furan-2-one (49). To a cooled (08), stirred soln. of 43 (11.2 g, 39.3 mmol) and DIPEA
(25.2 g, 194 mmol) in anh. CH2Cl2 (100 ml) was dropwise added MOMCl (9.50 g, 118 mmol) over 15 min. The
resulting mixture was allowed to warm to r.t. and stirred for 48 h. Then, sat. aq. NaHCO3 soln. (25 ml) was
added, and the layers were separated. The aq. layer was extracted with CH2Cl2 (3 Â 50 ml), and the combined
org. layers were dried (MgSO4). The solvents were removed under reduced pressure, and the resulting material
was subjected to FC (hexane/AcOEt 3 :1) to afford 49 (10.5 g, 81%). Clear, colorless oil. Rf 0.39 (hexane/
1
AcOEt 2 :1). [a]2D0 ˆ À21.3 (c ˆ 1.2, acetone). IR (film): 2957, 2823, 1789, 1471. H-NMR (CDCl3, 400 MHz):
0.05 (s, 6 H); 0.88 (s, 9 H); 1 .37 (s, 3 H); 1 .50 (dd, J ˆ 13.9, 9.3, 1 H); 2.18 (dd, J ˆ 13.9, 6.4, 1 H); 2.45 (dd, J ˆ
18.7, 10.9, 1 H); 2.98 (dd, J ˆ 18.7, 2.9, 1 H); 3.05 ± 3.08 (m, 1H); 3.37 ( s, 3 H); 4.50 (ddd, J ˆ 9.3, 8.3, 6.4, 1H);
4.58 (dd, J ˆ 6.6, 1.5, 1 H); 4.65 ± 4.70 (m, 2 H). 13C-NMR (CDCl3, 100.6 MHz): À 5.1; À 4.7; 18.0; 18.9; 25.7;
t
‡
28.0; 41.4; 43.7; 55.7; 71.0; 83.8; 88.5; 91.3; 177.4. EI-MS (70 eV): 273 (21, [M À Bu] ), 243 (100). HR-EI-MS
t
‡
‡
(70 eV): 273.1161 ([M À Bu] , C12H21O5Si ; calc. 273.1158).
(3S,4R,5R,6aR)-3,3a,4,5,6,6a-Hexahydro-3-[(4-methoxybenzyl)oxy]-5-(methoxymethoxy)-5-methyl-2-
oxo-2H-cyclopenta[b]furan-4-yl Benzoate (53). To a stirred soln. of 52 (618 mg, 1.83 mmol) in anh. CH2Cl2
(25 ml) was added PMBÀOC(ˆNH)CCl3 (780 mg, 2.74 mmol) and CSA (42 mg, 0.18 mmol). The resulting
mixture was stirred for 18 h at r.t. Then, sat. aq. NaHCO3 soln. (10 ml) was added, and the resulting layers were
separated. The aq. layer was extracted with CH2Cl2 (3 Â 20 ml), and the combined org. layers were dried
(MgSO4). The solvents were removed under reduced pressure, and the resulting material was subjected to FC
(hexane/AcOEt 2 :1) to afford 53 (698 mg, 72%). Clear, colorless oil. 1H-NMR (CDCl3, 400 MHz): 1.30 (s,
3 H); 2.13 (dd, J ˆ 3.2, 15.5, 1 H); 2.67 (ddd, J ˆ 1.3, 7.3, 15.4, 1 H); 3.36 (s, 3 H); 3.37 ± 3.42 (m, 1H); 3.78 ( s,
3 H); 4.34 (d, J ˆ 8.9, 1H); 4.57 ± 4.75 ( m, 4 H); 4.93 (ddd, J ˆ 3.2, 6.8, 6.9, 1H); 5.69 ( d, J ˆ 4.6, 1H); 6.80 ( d,
J ˆ 8.7, 2 H); 7.18 (d, J ˆ 8.6, 2 H); 7.45 (br. t, J ˆ 7.6, 2 H); 7.56 (br. t, J ˆ 7.4, 2 H); 7.93 ± 7.97 (m, 1 H). 13C-NMR
(CDCl3, 100.6 MHz): 17.9; 44.9; 46.1; 55.2; 55.8; 72.4; 72.5; 77.4; 80.3; 87.7; 91.6; 113.8; 128.4; 128.7; 128.8; 129.4;
129.8; 129.9; 133.2; 159.5; 165.1; 174.6.
(3aS,4R,5R,6aR)-3,3a,4,5,6,6a-Hexahydro-4-hydroxy-5-(methoxymethoxy)-5-methyl-2H-cyclopenta[b]-
furan-2-one (54). To a stirred soln. of 49 (9.50 g, 28.8 mmol) in anh. THF (40 ml) was added TBAF (1m soln. in
THF; 43.2 ml, 43.2 mmol). The mixture was stirred at r.t. for 18 h. The solvent was removed under reduced
pressure, and the resulting crude was subjected to FC (hexane/AcOEt 1:1) to afford 54 (5.47 g, 88%). Clear,
colorless oil. Rf 0.3 (AcOEt). [a]2D0 ˆ À15.1 (c ˆ 1.2, CDCl3). IR (film): 3443, 2940, 2825, 1769, 1644, 1454.
1H-NMR (CDCl3, 400 MHz): 1.35 (s, 3 H); 2.03 (dd, J ˆ 14.8, 3.5, 1 H); 2.39 (dd, J ˆ 14.8, 6.8, 1 H); 2.56 (dd, J ˆ
18.4, 11.1, 1 H); 2.60 (br. s, 1H); 2.81( dd, J ˆ 18.4, 2.8, 1 H); 3.18 ± 3.26 (m, 1H); 3.38 ( s, 3 H); 3.97 (dd, J ˆ 6.5,
2.6, 1H); 4.63 ( d, J ˆ 7.6, 1H); 4.75 ( d, J ˆ 7.6, 1H); 4.99 ( ddd, J ˆ 7.5, 6.8, 3.5, 1H). 13C-NMR (CDCl3,
‡
100.6 MHz): 17.8; 28.7; 41.3; 42.4; 55.8; 77.9; 83.2; 86.7; 91.3; 177.9. EI-MS (70 eV): 216 (1, M ), 171 (46), 153
‡
‡
(65), 57 (100). HR-EI-MS (70 eV): 216.0993 (M , C10H16O5 ; calc. 216.0998).
(3aS,4R,5R,6aR)-3,3a,4,5,6,6a-Hexahydro-4,5-bis(methoxymethoxy)-5-methyl-2H-cyclopenta[b]furan-2-
one (68). To a cooled (08), stirred soln. of 54 (950 mg, 4.40 mmol) and DIPEA (2.84 g, 22.0 mmol) in anh.
CH2Cl2 (20 ml) was dropwise added MOMCl (1.06 g, 13.2 mmol) over 15 min. Then, NaI (20 mg, 0.13 mmol)
was added, and the resulting mixture was heated at reflux for 18 h. The mixture was allowed to cool to r.t., sat.
aq. NaHCO3 soln. (10 ml) was added, and the layers were separated. The aq. layer was extracted with CH2Cl2
(3 Â 20 ml), and the combined org. layers were dried (MgSO4). The solvents were removed under reduced
pressure, and the resulting material was subjected to FC (hexane/AcOEt 1:1) to afford 68 (984 mg, 86%). Clear,
colorless oil. Rf 0.38 (AcOEt). [a]2D0 ˆ ‡28.5 (c ˆ 1.1, CDCl3). IR (film): 2947, 2896, 1772, 1451. 1H-NMR
(CDCl3, 400 MHz): 1.36 (s, 3 H); 1 .93 (dd, J ˆ 14.8, 4.2, 1 H); 2.44 (ddd, J ˆ 14.8, 7.2, 1.3, 1 H); 2.58 (dd, J ˆ
18.0, 10.1, 1 H); 2.68 (dd, J ˆ 18.0, 2.8, 1 H); 3.10 ± 3.25 (m, 1H); 3.33 ( s, 3 H); 3.41( s, 3 H); 3.86 (d, J ˆ 5.8,
1H); 4.55 ± 4.70 ( m, 4 H); 4.97 (dd, J ˆ 7.5, 7.5, 4.3 1H). 13C-NMR (CDCl3, 100.6 MHz): 18.4; 29.5; 41.6; 42.7;
‡
55.7; 56.6; 83.7; 85.3; 87.3; 91.4; 98.2; 177.5. EI-MS (70 eV): 260 (2, M ), 240 (25), 215 (74), 198 (100). HR-EI-
‡
‡
MS (70 eV): 260.1264 (M , C12H20O6 ; calc. 260.1260).
(3R,3aS,4R,5R,6aR)-3,3a,4,5,6,6a-Hexahydro-3-hydroxy-4,5-bis(methoxymethoxy)-5-methyl-2H-cyclo-
penta[b]furan-2-one (69). To a cooled (À 788), stirred soln. of lactone 68 (850 mg, 3.27 mmol) in anh. THF
(40 ml) was added a 0.5m soln. of KHMDS in toluene (9.80 ml, 4.90 mmol). The mixture was stirred for 1h at
À 788. Then. a cold (À 788) soln. of Davis reagent (ˆ 3-(3-nitrophenyl)-2-(phenylsulfonyl)-1,2-oxaziridine;
1.28 g, 4.90 mmol) in anh. THF (5 ml) was added via a cannula. The mixture was stirred for an additional 30 min

Helvetica Chimica Acta ± Vol. 88 (2005)
1577
at À 788. Then, a soln. of CSA (1.14 g, 4.90 mmol) in anh. THF (5 ml) was addedvia a cannula, and the resulting
mixture was allowed to warm to r.t. over 1h. Then, sat. aq. NH 4Cl soln. (15 ml) was added, the layers were
separated, and the aq. layer was extracted with AcOEt (3 Â 20 ml). The combined org. layers were dried
(MgSO4) and evaporated under reduced pressure. The resulting material was subjected to FC (hexane/AcOEt
1:1) to afford 69 (665 mg, 74%). Clear, colorless oil. Rf 0.36 (AcOEt). [a]2D0 ˆ ‡21.6 (c ˆ 1.1, CDCl3). IR
(film): 3385, 2948, 1770, 1640, 1567, 1447. 1H-NMR (CDCl3, 400 MHz): 1.33 (s, 3 H); 1.86 (dd, J ˆ 14.5, 5.2, 1 H);
2.42 (dd, J ˆ 14.5, 7.2, 1.3, 1 H); 2.88 (br. s, 1H); 3.16 ( ddd, J ˆ 7.9, 6.6, 3.3, 1H); 3.35 ( s, 3 H); 3.42 (s, 3 H); 4.08
(dd, J ˆ 6.6, 1.1, 1 H); 4.59 (d, J ˆ 3.3, 1H); 4.65 ± 4.72 ( m, 4 H); 5.10 (ddd, J ˆ 7.9, 7.2, 5.2, 1H). 13C-NMR
(CDCl3, 100.6 MHz): 18.4; 42.2; 49.7; 55.8; 56.5; 68.9; 82.1; 83.4; 87.0; 91.4; 97.9; 177.6. EI-MS (70 eV): 276 (2,
‡
‡
‡
M ), 231 (25), 214 (51), 77 (100). HR-EI-MS (70 eV): 276.1217 (M , C12H20O7 ; calc. 276.1209).
(3R,3aR,4R,5R,6aR)-3,3a,4,5,6,6a-Hexahydro-3-[(4-methoxybenzyl)oxy]-4,5-bis(methoxymethoxy)-5-
methyl-2H-cyclopenta[b]furan-2-one (70). To a stirred soln. of 69 (505 mg, 1.83 mmol) in anh. CH2Cl2 (25 ml)
was added PMBÀOC(ˆNH)CCl3 (780 mg, 2.74 mmol) and CSA (42 mg, 0.18 mmol). The resulting mixture
was stirred for 18 h at r.t. Then, sat. aq. NaHCO3 soln. (10 ml) was added, and the resulting layers were
separated. The aq. layer was extracted with CH2Cl2 (3 Â 20 ml), and the combined org. layers were dried
(MgSO4) and evaporated under reduced pressure. The resulting material was subjected to FC (hexane/AcOEt
2 :1) to afford 70 (630 mg, 87%). Clear, colorless oil. Rf 0.16 (hexane/AcOEt 2 :1). [a]2D0 ˆ ‡48.6 (c ˆ 1.1,
CDCl3). IR (film): 3277, 2948, 1769, 1731, 1613, 1586, 1447. 1H-NMR (CDCl3, 400 MHz): 1.32 (s, 3 H); 1.90 (dd,
J ˆ 14.9, 4.3, 1 H); 2.44 (ddd, J ˆ 14.9, 7.3, 1.2, 1 H); 3.12 (ddd, J ˆ 7.4, 5.9, 1.5, 1 H); 3.30 (s, 3 H); 3.32 (s, 3 H);
3.80 (s, 3 H); 3.97 (d, J ˆ 6.3, 1H); 4.20 ( d, J ˆ 1.5, 1 H); 4.4 ± 4.8 (m, 6 H); 5.1 0 (ddd, J ˆ 7.4, 7.4, 4.2, 1H); 6.9 ( d,
J ˆ 8.6, 2 H); 7.3 (d, J ˆ 8.6, 2 H). 13C-NMR (CDCl3, 100.6 MHz): 18.2; 42.4; 49.5; 55.3; 55.8; 56.6; 71.7; 74.4;
‡
82.9; 84.3; 87.4; 91.4; 98.0; 113.9; 129.2; 130.1; 159.5; 175.0. EI-MS (70 eV): 396 (1, M ), 275 (3), 137 (24), 121
‡
‡
(100). HR-EI-MS (70 eV): 396.1775 (M , C20H28O8 ; calc. 396.1786).
(1R,2R,3R,4R)-2-{(1R)-1-[(4-Methoxybenzyl)oxy]-2-oxo-2-pyrrolidin-1-ylethyl}-3,4-bis(methoxymeth-
oxy)-4-methylcyclopentanol (71). To a stirred soln. of 70 (504 mg, 1.27 mmol) in anh. toluene (5 ml) was added
pyrrolidine (524 ml, 6.40 mmol). The resulting mixture was heated to reflux for 18 h. The mixture was allowed to
cool to r.t., and the volatiles were removed under reduced pressure. The resulting crude material was subjected
to FC (AcOEt) to afford 71 (541mg, 91%), with trace-amounts of pyrrolidine. Clear, orange oil. Rf 0.1
(AcOEt). [a]2D0 ˆ À13.3 (c ˆ 1.0, CDCl3). IR (film): 3450, 2957, 2882, 1774, 1631, 1514, 1449. 1H-NMR (CDCl3,
400 MHz): 1.44 (s, 3 H); 1.72 ± 1.95 (m, 5 H); 2.44 (dd, J ˆ 14.6, 7.1, 1 H); 2.77 (m, 1H); 3.31( s, 3 H); 3.32 ± 3.38
(m, 1H); 3.40 ( s, 3 H); 3.45 ± 3.60 (m, 4 H); 3.79 (s, 3 H); 4.03 (d, J ˆ 3.8, 1H); 4.12 ± 4.20 ( m, 1H); 4.40 ( d, J ˆ
10.9, 1 H); 4.48 (d, J ˆ 10.9, 1 H); 4.53 (d, J ˆ 11.1, 1 H); 4.62 ± 4.69 (m, 3 H); 4.76 (d, J ˆ 6.6, 1H); 6.86 (br. d,
J ˆ 8.8, 2 H); 7.24 (br. d, J ˆ 8.8, 2 H). 13C-NMR (CDCl3, 100.6 MHz): 21.0; 23.9; 26.8; 46.7; 46.9; 48.2; 50.0;
55.7; 55.9; 57.0; 71.2; 72.9; 76.9; 86.8; 86.9; 91.9; 99.0; 114.2; 129.7; 130.0; 159.7; 171.2. EI-MS (70 eV): 422 (1,
‡
‡
‡
[M À MOM] ), 210 (13), 137 (27), 121 (100). HR-EI-MS (70 eV): 422.2191 ([M À MOM] , C22H32NO7 ; calc.
422.2179).
1-{(2R)-2-{(1R,2R,3R,5R)-2,3-Bis(methoxymethoxy)-3-methyl-5-[(triethylsilyl)oxy]cyclopentyl}-2-[(4-
methoxybenzyl)oxy]acetyl}pyrrolidine (72). To a stirred soln. of 71 (392 mg, 0.840 mmol) in anh. CH2Cl2
(10 ml) was first added pyridine (200 ml, 2.5 mmol), then TESCl (212 ml, 1.26 mmol), and the resulting mixture
was stirred at r.t. for 1h. Then, sat. aq. NH 4Cl soln. (5 ml) was added, and the layers were separated. The aq.
layer was extracted with CH2Cl2 (3 Â 10 ml), and the combined org. layers were dried (MgSO4) and evaporated
under reduced pressure. The resulting material was subjected to FC (hexane/AcOEt 2 :1) to afford 72 (430 mg,
88%). Clear, colorless oil. Rf 0.21(hexane/AcOEt 2 :1). [ a]2D0 ˆ À34.0 (c ˆ 0.6, CDCl3). IR (film): 3854, 3822,
1
1646, 1613, 1586, 1441. H-NMR (CDCl3, 400 MHz): 0.51( q, J ˆ 7.9, 6 H); 0.91( t, J ˆ 7.9, 9 H); 1.40 (s, 3 H);
1.73 (dd, J ˆ 13.8, 5.4, 1 H); 1.75 ± 1.95 (m, 4 H); 2.38 (dd, J ˆ 13.8, 6.8, 1 H); 3.28 ± 3.35 (m, 1H); 3.38 ( s, 3 H);
3.39 (s, 3 H); 3.40 ± 3.55 (m, 3 H); 3.58 ± 3.68 (m, 1H); 3.78 ( s, 3 H); 3.85 (d, J ˆ 4.3, 1H); 4.29 ( d, J ˆ 10.8, 1 H);
4.49 (d, J ˆ 10.8, 1 H); 4.51 ± 4.58 (m, 1H); 4.61± 4.72 ( m, 4 H); 4.83 (d, J ˆ 6.3, 1H); 6.84 ( d, J ˆ 8.7, 2 H); 7.20
(d, J ˆ 8.7, 2 H). 13C-NMR (CDCl3, 100.6 MHz): 4.8; 6.8; 19.7; 24.2; 26.1; 45.3; 45.5; 45.8; 47.6; 55.2; 55.7; 56.4;
‡
66.6; 72.6; 73.7; 85.2; 86.3; 91.4; 98.44; 113.6; 129.3; 130.9; 158.9; 168.3. EI-MS (70 eV): 582 (2, M ), 552 (9,
‡
‡
‡
[M À Et] ), 324 (34), 121 (100). HR-EI-MS (70 eV): 552. 2881 ([M À Et] , C28H46NO8Si , calc. 552.2883).
(1R)-1-[(1R,2R,3R,5R)-2,3-Bis(methoxymethoxy)-3-methyl-5-[(triethylsilyl)oxy]cyclopentyl]-1-[(4-meth-
oxyphenyl)methoxy]propan-2-one (73). To a cooled (08), stirred soln. of 72 (362 mg, 0.623 mmol) in anh. THF
(10 ml) was dropwise added a 1.6m soln. of MeLi in Et2O (0.780 ml, 1.24 mmol) over 30 min. The mixture was
stirred for an additional 15 min at 08. Then, sat. aq. NH4Cl soln. (5 ml) was added, the aq. layer was extracted
with AcOEt (3 Â 10 ml), and the combined org. layers were dried (MgSO4) and evaporated under reduced
pressure. The resulting material was subjected to FC (hexane/AcOEt 5 :1) to afford 73 (265 mg, 81%). Colorless

1578
Helvetica Chimica Acta ± Vol. 88 (2005)
oil. Rf 0.42 (hexane/AcOEt 2 :1). [a]2D0 ˆ À5.5 (c ˆ 1.7, CDCl3). IR (film): 2955, 2878, 1715, 1613, 1586, 1515,
1458. 1H-NMR (CDCl3, 400 MHz): 0.58 (q, J ˆ 8.0, 6 H); 0.95 (t, J ˆ 8.0, 9 H); 1.34 (s, 3 H); 1.82 (dd, J ˆ 13.6,
7.6, 1H); 2.20 ± 2.29 ( m, 4 H); 3.00 (m, 1H); 3.33 ( s, 3 H); 3.35 (s, 3 H); 3.80 (s, 3 H); 3.98 (d, J ˆ 5.8, 1H); 4.18
(d, J ˆ 7.8, 1H); 4.38 ( ddd, J ˆ 7.6, 7.5, 7.3, 1H); 4.42 ( s, 2 H); 4.52 ± 4.72 (m, 4 H); 6.87 (d, J ˆ 8.6, 2 H); 7.25 (d,
J ˆ 8.6, 2 H). 13C-NMR (CDCl3, 100.6 MHz): 4.8; 6.7; 20.0; 26.9; 47.0; 49.0; 55.2; 55.4; 56.3; 70.8; 71.1; 81.4; 85.1;
‡
86.0; 91.5; 97.8; 113.8; 129.5; 130.1; 159.2; 210.0. EI-MS (70 eV): 497 (0.5, [M À MeO] ), 465 (1), 390 (3), 121
‡
‡
(100). HR-EI-MS (70 eV): 497.2559 ([M À MeO] , C25H41O8Si ; calc. 497.2571).
1-{(R)-{(1S,2R,3R,5R)-2,3-Bis(methoxymethoxy)-3-methyl-5-[(triethylsilyl)oxy]cyclopentyl}[(4-methoxy-
benzyl)oxy]methyl}ethenyl Trifluoromethanesulfonate (74). To a cooled (À 788), stirred soln. of 73 (201mg,
0.381mmol) in anh. THF (10 ml) was added a 0.5 m soln. of KHMDS in toluene (0.84 ml, 0.42 mmol), and the
mixture was stirred for 1h at À 788. Then, a cold (À 788) soln. of PhN(Tf)2 (204 mg, 0.57 mmol) in anh. THF
(1ml) was added via a cannula. The mixture was stirred for an additional 10 min at À 788, and then allowed to
warm to r.t. over 1h. Then, sat. aq. NH 4Cl soln. (5 ml) was added, and the resulting layers were separated. The
aq. layer was extracted with AcOEt (3 Â 10 ml), and the combined org. layers were dried (MgSO4). The
solvents were removed under reduced pressure, and the resulting material was subjected to FC (hexane/AcOEt/
Et3N 50 :10 :1) to afford 74 (229 mg, 91%). Clear, colorless oil. Rf 0.55 (hexane/AcOEt 2 :1). [a]2D0 ˆ À3.3 (c ˆ
1
0.9, CDCl3). IR (film): 2956, 1664, 1613, 1515, 1443, 1417. H-NMR (CDCl3, 400 MHz): 0.56 (q, J ˆ 7.9, 6 H);
0.96 (t, J ˆ 7.9, 9 H); 1.39 (s, 3 H); 1.77 (dd, J ˆ 14.2, 4.2, 1 H); 2.39 (dd, J ˆ 14.2, 6.4, 1 H); 2.71 ± 2.78 (m, 1 H);
3.31( s, 3 H); 3.38 (s, 3 H); 3.79 (s, 3 H); 3.89 (d, J ˆ 4.5, 1H); 4.18 ( d, J ˆ 10.1, 1 H); 4.32 (d, J ˆ 10.4, 1 H); 4.37
(ddd, J ˆ 6.9, 6.4, 4.2, 1H); 4.59 ± 4.71( m, 5 H); 5.24 (d, J ˆ 3.4, 1H); 5.39 ( d, J ˆ 3.4, 1H); 6.86 (br. d, J ˆ 8.6,
2 H); 7.28 (br. d, J ˆ 8.6, 2 H). 13C-NMR (CDCl3, 100.6 MHz): 4.9; 6.8; 20.0; 48.3; 48.5; 55.2; 55.5; 56.3; 69.9;
71.6; 76.6; 85.9; 86.7; 91.4; 98.9; 108.5; 113.7; 118.4 (q, F3C); 129.5; 129.9; 152.7; 159.1. EI-MS (70 eV): 613 (1,
‡
‡
M À MOM] ), 283 (3), 181 (5), 135 (8), 121 (100). HR-EI-MS (70 eV): 613.2097 ([M À MOM] ,
‡
C26H40F3O9SSi ; calc. 613.2114).
X-Ray Crystal-Structure Analysis of 243). Formula, C23H26O6; Mr 398.461; crystal system, monoclinic; cell
constants: a ˆ 17.858(4), b ˆ 5.2318(10), c ˆ 22.836(5) Š, b ˆ 107.91(3)8, Vˆ 2030.2(7) Š3; space group, P21/c;
Z ˆ 4; F(000) ˆ 848, 1calc. ˆ 1.304 g/cm3; crystal size 0.03  0.11  0.56 mm; MoKa radiation (l ˆ 07107 Š);
exper. absorption coefficient, 0.09 mmÀ1; temperature, 120 K; data collection, Nonius Kappa CCD instrument;
dx ˆ 35 mm, w scans with 450 frames, scan width of 1.58; data-collection range, 2q ˆ 7.0 to 50.08 (h À 20, 20;
k À 5, 6; l À 27, 26); number of reflections collected, 7004; unique reflections, 3587; unique reflections with Fo >
2s(Fo), 2783; no absorption corrections; least-squares refinement; number of parameters refined, 367; largest d/
s, final cycle < 0.001; extinction correction, largest residual peaks (e/A3) À 0.16/0.19; final R value, 0.0327;
Rw ˆ 0.0869, S ˆ 1.03.
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3
)
The crystallographic data of 24 were deposited with the Cambridge Crystallographic Data Centre as
CCDC-262614. The data can be obtained, free of charge, via the internet at http://www.ccdc.cam.ac.uk/
data_request/cif.

Helvetica Chimica Acta ± Vol. 88 (2005)
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Received February 27, 2005