Stereoselective functionalization of dihydropyran-3-ols: Application to the synthesis of enantiopure ethyl deoxymonate B

Article abstract of DOI:10.1002/ejoc.200801133

The behavior of readily available enantiopure cis and trans 3,6-disubstituted dihydropyran-3-ols and derivatives in epoxidation, osmium-catalyzed dihydroxylations, S_N2 and Claisen-related processes has been examined. The highly diastereoselective dihydroxylation of a suitably functionalized cis 3,6-disubstituted dihydropyran-3-ol has been used in the synthesis of ethyl deoxymonate B from a 3-sulfinyl- dihydropyran intermediate.

Full text of DOI:10.1002/ejoc.200801133

FULL PAPER
DOI: 10.1002/ejoc.200801133
Stereoselective Functionalization of Dihydropyran-3-ols:
Application to the Synthesis of Enantiopure Ethyl Deoxymonate B
Roberto Fernández de la Pradilla,*[a] Nadia Lwoff,[a] and Alma Viso[a]
Keywords: Oxygen heterocycles / Epoxidation / Dihydroxylation / Rearrangement / Metathesis
The behavior of readily available enantiopure cis and trans
3,6-disubstituted dihydropyran-3-ols and derivatives in
epoxidation, osmium-catalyzed dihydroxylations, SN2Ј, and
Claisen-related processes has been examined. The highly
diastereoselective dihydroxylation of a suitably function-
alized cis 3,6-disubstituted dihydropyran-3-ol has been used
in the synthesis of ethyl deoxymonate B from a 3-sulfinyl-
dihydropyran intermediate.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
the reactivity of the isomers 3,6-trans-1 and 3,6-cis-2 in sim-
ple epoxidation and dihydroxylation processes which would
lead to more functionalized structures. The epoxidation of
the free alcohol 1a with m-CPBA[5] led to a mixture of dia-
stereoisomers (Table 1, entry 1) with the syn epoxy alcohol
as the major product as expected.[6] In an attempt to invert
the selectivity by preventing coordination of the alcohol
with the reagent and at the same time introducing steric
hindrance, we prepared the silyl ether derivatives first by
using a TBS group (Table 1, entry 2) and then by increasing
the volume of the protecting group with a TIPS group. In
both cases we obtained the opposite selectivity relative to
the free alcohol, but only with moderate selectivity. There
was no clear improvement in the selectivity as a result of
increasing the steric hindrance by replacing the TBS group
with TIPS (Table 1, entries 2 and 3).
Introduction
Enantiomerically pure allylic alcohols are useful building
blocks in organic synthesis,[1] widely used for the prepara-
tion of natural products and bioactive compounds.[2] We
have recently studied the transformation of readily available
cis- and trans-2,3-disubstituted 3-sulfinyldihydropyrans (A)
into 3,6-disubstituted dihydropyran-3-ols (B) by an efficient
[2,3]-sigmatropic rearrangement of allylic sulfoxides with
complete stereoselectivity (Scheme 1).[3] Usually, (2S,3S)
derivatives are easily transformed with P(OMe)3 in MeOH,
whereas (2S,3R) isomers require other thiophiles like
DABCO or DBU in toluene at a higher temperature. The
resulting products presented a dihydropyran core contain-
ing an allylic alcohol moiety with a defined stereochemistry
that could be susceptible to further chemical transforma-
tions. In this paper we report some unoptimized model
studies of the behavior of these substrates in selected pro-
cesses such as epoxidation, dihydroxylation, SN2Ј, and
Claisen-related processes, as well as the application of these
methodologies to the synthesis of methyl and ethyl deoxy-
monates B.[4]
Table 1. Epoxidation of 3,6-trans-dihydropyranols 1.
Entry
Substrate
R1
3/4 Ratio
Yield [%]
1
2
3
1a
1b
1c
H
TBS
TIPS
88:12
23:77
20:80
65
81
76
Scheme 1. [2,3]-Sigmatropic rearrangement of allylic sulfoxides.
Results and Discussion
Allylic alcohols obtained by the above route can be use-
ful synthetic intermediates, hence we decided to study first
The results for the epoxidation of the 3,6-cis alcohols are
shown in Table 2. The free alcohol 2a led to the syn isomer
5a as the major product (Table 2, entry 1), and again pro-
tection of the hydroxy group inverted the selectivity but
gave slightly lower ratios than the free alcohol. In this case,
we prepared silyl ether 2b (Table 2, entry 2) and acetate 2d
(Table 2, entry 3), which gave only poor selectivity.
[a] Instituto de Química Orgánica, CSIC,
Juan de la Cierva, 3, 28006 Madrid, Spain
Fax: +34-915644853
E-mail: iqofp19@iqog.csic.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Stereoselective Functionalization of Dihydropyranols
Table 2. Epoxidation of 3,6-cis-dihydropyranols 2.
the reaction of the free alcohol 2a with a pseudoaxial hy-
droxy group,[3] as well as the reactions of the protected sub-
strates 1b,c and 2b,d. On the other hand, the low syn selec-
tivity found for 1a with a pseudoequatorial hydroxy group
is somewhat unexpected,[11] although there are examples in
the literature that show similar behavior.[12]
Entry
Substrate
R1
5/6 Ratio
Yield [%]
To broaden the scope of reactivity of 3-dihydropyranols,
the transformation of alcohols 1a and 2a into suitable pre-
cursors for SN2Ј displacement and sigmatropic rearrange-
ment was also studied. In these processes the chirality of
the oxygenated center is transferred to the allylic position,
leading to 2,3-disubstituted dihydropyrans, an interesting
core present in some natural products.[13] The SN2Ј dis-
placement of allylic phosphates with cyanocuprates in the
presence of LiCl is a well-established protocol.[14] Thus,
phosphate 10 was prepared from 1a by using diethyl chloro-
phosphate and LDA because milder conditions with Et3N
were not effective in this case (Scheme 2). To our dismay,
the reaction between 10 and MeCu(CN)MgBr in the pres-
ence of LiCl just gave recovered starting material whereas
the use of MeCu(CN)MgBr afforded a low yield of the
product of SN2 displacement by bromide along with start-
ing material (see the Supporting Information). The use of
BuCu(CN)Li proved equally fruitless leading to recovery of
the starting material. Finally, a low yield of the desired
product 11a was obtained upon reaction with Bu2CuLi·LiI.
At this stage we explored briefly the preparation of the re-
lated mesylate, but the product was too unstable to be iso-
lated and therefore we chose to abandon these studies.
1
2
3
2a
2b
2d
H
TBS
CH3CO
77:23
30:70
45:55
62
100
53
We next examined the OsO4-catalyzed dihydroxylation of
the cis and trans isomers of the free alcohols and silyl
ethers.[7] Dihydroxylation of the 3,6-trans isomer 1 (Table 3)
gave mixtures of syn-7 and anti-8 diastereoisomers with
selectivities ranging from 60:40 for the free alcohol (Table 3,
entry 1) to about 20:80 for the more hindered substrates
(Table 3, entries 2 and 3), all with moderate-to-good yields.
Table 3. Dihydroxylation of 3,6-trans-dihydropyranols 1.
Entry
Substrate
R1
7/8 Ratio
Yield [%]
1
2
3
1a
1b
1c
H
TBS
TIPS
60:40
17:83
21:79
67
94
70
On the other hand, the 3,6-cis isomers 2 gave only the
anti dihydroxylation products 9 with moderate-to-excellent
yields (Table 4), showing parallel behavior to other struc-
tures with related substitution patterns described in the lit-
erature, which could also be accessible by this methodology,
as will be described later.[8]
Table 4. Dihydroxylation of 3,6-cis dihydropyranols 2.
Scheme 2. Synthesis of the allylic phosphate 10 and SN2Ј reaction
with alkyl cuprates.
We next focused our attention on the Claisen–Johnson
rearrangement with triethyl orthoacetate and propionic
acid of both cis- and trans-dihydropyranols (Scheme 3) via
a ketene acetal intermediate.[15] Assuming the process pro-
ceeded with retention of configuration, hence transferring
the chirality of the oxygenated center to the allylic position,
we expected functionalized 2,3-disubstituted dihydropyrans
Entry
Substrate
R1
Yield [%]
1
2
3
2a
2b
2d
H
TBS
CH3CO
82
100
43
Although it has been reported that directive effects in 12 and 13 to be formed. Unfortunately we were unable to
osmylation reactions are predominantly steric,[9] it has been obtain 12 or 13 under the conditions studied, obtaining
suggested that at least in some allylic systems the stereo- complex reaction mixtures and in the case of 2a, a low yield
chemistry of the process is relatively insensitive to steric fac- of the dihydropyranyl propionate derivative 1f.
tors and is governed by stereoelectronic effects.[10] An em-
Because the substitution pattern and the functionalities
pirical rule states that usually osmium tetroxide preferen- of esters 12 and 13 were attractive from a synthetic point
tially approaches the alkene anti to the hydroxy group.[9a] of view, we decided to explore the Claisen rearrangement[16]
This effect is more pronounced for substrates with a pseu- as an alternative approach to accessing similar targets. En-
doaxial hydroxy group, with more steric hindrance to the couraged by previous results in our group,[17] we chose to
approach of the reagent. This would explain the result of examine the rearrangements of the trans- and cis-acrylates
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R. Fernández de la Pradilla, N. Lwoff, A. Viso
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could increase the yield of the rearrangement product.[19]
Unfortunately, problems concerning the availability of the
starting material prevented the study of the process under
these modified conditions.
The results obtained show that the trans derivatives are
more reactive in the sigmatropic processes. These findings
may be tentatively rationalized on the basis of the confor-
mational analysis of alcohol 1a, which shows the hydroxy
group to be pseudoequatorial, whereas the cis alcohol 2a
adopts a conformation in which the alcohol is in a pseu-
doaxial arrangement.[3b] For the sigmatropic process to oc-
cur, the oxygen of the acrylate or imidate must adopt a qua-
siaxial orientation to bring the reactive centers within bond-
ing distance.[18f] Thus, the trans substrates (14, 16) require
the conversion from one chair conformer to another. In
contrast, although the preferred chair-type conformer of
the cis alcohol 2a places the hydroxy group pseudoaxial,
the acrylate 15a and imidate 17 derivatives might suffer un-
favorable steric interactions with the cis substituents and
this could account for their lower reactivity in these pro-
cesses (Figure 1).
Scheme 3. Attempts at Claisen–Johnson rearrangement of 1a and
2a.
14a,e and 15a, which were prepared uneventfully from
alcohols 1a,e and 2a, respectively (Scheme 4). These acryl-
ates were heated in DMF in the presence of a catalytic
amount of butylated hydroxytoluene to yield products of a
Claisen rearrangement and a concurrent decarboxylation
with complete stereoselectivity but in variable yields
(Scheme 4). Note that for acrylate 15a with a cis relative
stereochemistry, the reaction was much slower, and the
yield was considerably lower than that of the trans isomer
14a.
Scheme 4. Synthesis and Claisen rearrangement of acrylates 14 and
15.
Figure 1. Possible conformations of the trichloroacetimidates 16
and 17.
In a similar manner we also considered the possibility of
carrying out the aza-Claisen process to obtain dihydro-
pyranyl amides and therefore we also prepared trichloroace-
timidates 16 and 17 in good yields (Scheme 5).[18] In this
case, the substrates were heated in xylene between 100 and
140 °C to produce complex reaction mixtures from which a
small amount of the expected trichloroacetamide 20 was
isolated (Scheme 5). Acid-catalyzed decomposition of the
allylic trichloroacetimidate could be a competing process,
and usually the addition of sodium or potassium carbonate
Stereochemical Assignments
To confirm the stereochemistries of the diols and triols,
7a, 8a,b, and 9a were acetylated to give the triacetates 7aЈ,
8aЈ, and 9aЈ, and the diacetate 8bЈ (Scheme 6). The coupling
constants measured for the acetylated derivatives confirmed
the stereochemistry assigned to the precursors.
To correlate the oxirane structures obtained in the epox-
idation of the free alcohols and silyl ethers, some epoxy
alcohols were protected (Scheme 7). Silylation of epoxy
alcohol 3a afforded 3b, which was the minor product ob-
tained from the epoxidation of silyl ether 1b (Table 1, en-
try 2). Similarly, silylation of an 80:20 mixture of 5a and 6a
(Table 2, entry 1) gave an 82:18 mixture of protected oxir-
anes 5b and 6b with identical data but in an opposite ratio
to the results of the epoxidation of 2b (Table 2, entry 2).
Scheme 5. Synthesis and aza-Claisen rearrangement of trichloro-
acetimidates 16 and 17.
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Stereoselective Functionalization of Dihydropyranols
acids present a tetrahydropyran ring α-cis disubstituted at
C-5 and C-8 and β-cis hydroxy groups at C-6 and C-7.
Pseudomonic acid B presents an additional hydroxy at C-
8, and pseudomonic acids C and D present E alkenes in the
side-chains (Scheme 8). Their challenging structural fea-
tures, along with their potent biological activity, have at-
tracted the attention of many groups and their efforts have
led to several synthetic approaches.[21] The key tetra-
hydropyran core has been prepared from carbohydrates by
Diels–Alder processes or from acyclic precursors. The
stereocenters were installed by Claisen rearrangements, Pd-
catalyzed alkylations, and free-radical processes. The side-
chains were homologated by Wittig and Julia protocols
and, recently, by cross-metathesis.
Scheme 6. Acetylation of the diols and triols 7a, 8a,b, and 9a.
Scheme 8. Structure of the pseudomonic acids.
Our early approach to these products arose from our ini-
tial results of SN2Ј displacements of allylic sulfones such
as 27 (Scheme 9) and related sulfoximines with magnesium
bromodialkylcuprates, which led to the expected γ-substitu-
tion products.[3] A model SN2Ј product underwent a com-
pletely selective osmium-catalyzed dihydroxylation to afford
a tetrahydropyranyl diol with the correct stereochemistry of
the core of pseudomonic acid C. These promising results
encouraged us to pursue the preparation of model com-
pound 28, which could allow us to test the viability of the
cross-metathesis reaction between the allyl moiety and the
C11–C15 fragment and also explore the selective dihydrox-
ylation of the pyran double bond. This last process would
be a challenge because the problem of regioselectivity has
to be overcome, but if successful the core of pseudomonic
acid C could be accessed expediently. Unfortunately, we
were unable to introduce an allyl substituent cleanly, ob-
taining only traces of the desired product in complex reac-
tion mixtures and thus we decided to abandon this ap-
proach and explore an alternative route.
Scheme 7. Silylation of epoxy alcohols.
The stereochemistries of the SN2Ј and Claisen products
were tentatively assigned on the basis of coupling constant
values and in some cases were confirmed by NOE experi-
ments (Figure 2).
Figure 2. Stereochemical assignments for 11a, 18a, and 19a.
Synthetic Applications
Scheme 9. Model studies for the preparation of pseudomonic acid
C.
The pseudomonic acids are C-glycopyranosides pro-
duced by a strain of Pseudomonas fluorescens, which present
a potent antibiotic activity against Gram-positive aerobic
Because the dihydroxylation of readily available cis 3,6-
bacteria;[20] pseudomonic acid A (22; Scheme 8) is used as disubstituted dihydropyranyl-3-ols is highly stereoselective
a topical antibacterial agent (Bactroban). The pseudomonic (see before), we considered an approach to pseudomonic
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R. Fernández de la Pradilla, N. Lwoff, A. Viso
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acid B, with an additional hydroxy group at C-8, from a
sulfinyldihydropyran intermediate with the appropriate
functionalization at C-2. Note that the preparation of pseu-
domonic acid B and related compounds with a hydroxy
group at C-8 is comparatively less studied.[21g,22] Scheme 10
shows our retrosynthetic analysis for methyl and ethyl de-
oxymonates B (29 and 30), which should be available by
homologation of the side-chain at C-8 of intermediate C by
a cross-metathesis reaction in the presence of a free hydroxy
group at C-8, inspired by the work of Markó and co-
workers,[21h] followed by olefination to build the C-5 side-
chain. Intermediate C would derive from allylic alcohol D
by stereoselective dihydroxylation, protection, and an oxi-
dation/allylation sequence. [2,3]-sigmatropic rearrangement
of allylic sulfoxide E would lead to alcohol D. Sulfinyldihy-
dropyran E would result from the base-mediated cyclization
of dienyl sulfoxide F, in turn available from 4-pentyn-2-ol
H through iodovinyl sulfoxide G. In this paper we report in
full our efforts to synthesize methyl and ethyl deoxymonates
B from a sulfinyldihydropyran intermediate by [2,3]-sigma-
tropic rearrangement of an allylic sulfoxide to install the
hydroxy functionality at C-8, taking advantage of the di-
recting effect of the allylic alcohol in the dihydroxylation
reaction.
Scheme 11. Model study for the conversion of D into C.
gioisomeric stannanes 38a and 38b. Treatment of 38a with
iodine led to vinyl iodide 39, which readily underwent Stille
coupling with stannane 40 to give the sulfinyl diene 41 in
excellent yield. The key cyclization of 41 with LDA pro-
duced 2,3-trans-sulfinyldihydropyran 42, with the pyran
core of the target suitably substituted at C-5,[24] as a single
isomer in excellent yield.
Scheme 10. Retrosynthetic analysis for methyl and ethyl deoxymon-
ates B (29 and 30).
Scheme 12. Synthesis of sulfinyldihydropyran 42.
Because we had previously obtained similar intermedi-
Allylic sulfoxide 42 readily underwent a [2,3]-sigmatropic
ates in the development of a formal synthesis of ent-dysiher- rearrangement to afford trans-allylic alcohol 43 as a single
baine,[23] a substrate similar to D was available to carry out isomer (Scheme 13), which was inverted by a Mitsunobu
a preliminary study of the viability of the sequence to trans- protocol via p-nitrobenzoate 44 to produce cis-alcohol 45.
form D into C (Scheme 11). Stereoselective dihydroxylation The osmium-catalyzed dihydroxylation of 45 afforded triol
of 31 and protection of the resulting diol as an isopropylid- 46, which was protected as an isopropylidene ketal under
ene ketal afforded 33. Oxidation of the secondary alcohol standard conditions to give 47a. Oxidation of 47a with
to give ketone 34, followed by stereoselective Grignard ad- PCC gave ketone 48a and addition of allylmagnesium bro-
dition to the ketone afforded 35 as a single isomer. This mide afforded exclusively the tertiary alcohol 49a
result encouraged us to follow the same approach to access (Scheme 13).[22b] Deprotection of the secondary alcohol on
key intermediate C starting from the appropriate substrate. the side-chain at C-5 led to diol 50a. The process was quite
Commercially available rac-4-pentyn-2-ol (Scheme 12) slow and to our surprise after the first test reactions, we
was protected as the TBDPS ether, and the resulting alkyne observed that the isolated product slowly isomerized to 51a
36 was treated with EtMgBr and (–)-menthyl p-toluenesulf- in which the isopropylidene ketal had migrated from the
inate to produce alkynyl sulfoxide 37. Pd-catalyzed hydro- secondary to the tertiary hydroxy group. Our approach to
stannylation of 37 afforded an 86:14 mixture of the re- deoxymonates B implies the oxidation of the hydroxy group
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Stereoselective Functionalization of Dihydropyranols
Scheme 13. Synthesis of diol 50a.
on the side-chain without affecting the tertiary alcohol in
The cross-metathesis of 53 and 54, available in four steps
the process. Because 51a has another secondary alcohol from ethyl (S)-3-hydroxybutyrate,[25] afforded 55 predomi-
that could compete in oxidation reactions, this substrate nantly as the E isomer at C-2/C-3 and with just the E geom-
could not be used further in the synthesis of deoxymonates etry at the newly formed C-10/C-11 bond. Practically pure
B.
(E)-55, contaminated with traces of the Z isomer at C-2,
Nonetheless, once alcohol 50a was isolated, it could be was obtained by careful chromatographic purification.
rapidly used before 51a was formed. Thus, 51a was con- Treatment of 55 with TBAF led to cleavage of the silyl ether
verted into ketone 52a as a single product that appeared to to give alcohol 56, which was fully deprotected with
be stable (Scheme 14). Wittig reaction of 52a with methyl DOWEX resin to give methyl deoxymonate B (29) with
(triphenylphosphoranylidene)acetate afforded 53 as an traces of the Z isomer (1.4%) in an 18-linear-step sequence
86:14 mixture of E/Z isomers. Because this step was per- (22 steps in total) from commercially available 4-pentyn-2-
formed on a small scale, the two isomers could not be sepa- ol.
rated and the product was used as a mixture in the next
Although we had completed the synthesis of 29, we had
step. Homologation of the C-8 side-chain was carried out found major drawbacks in the sequence that affected the
using the conditions described by Markó and co-workers efficiency of the route. The first one was the isomerization
for a related system lacking the extra hydroxy group at the of the isopropylidene ketal in alcohol 50a leading to 51a,
homoallylic position.[21h]
which could not be further transformed into the next inter-
Scheme 14. Synthesis of methyl deoxymonate B, 29.
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R. Fernández de la Pradilla, N. Lwoff, A. Viso
FULL PAPER
mediate, and the second one was the Wittig reaction, which Horner–Wadsworth–Emmons conditions, previously used
led to the desired unsaturated ester but in a low yield. We for related substrates. Unfortunately we were unable to im-
tried to improve these results by changing the protecting prove on the results obtained for the isopropylidene series,
group on the cis diol from an isopropylidene to a cyclohex- and the reaction of 52b with the sodium anion of triethyl
ylidene ketal with the expectation that ketal migration phosphonoacetate afforded 57 in low yield as an 80:20 mix-
would be more difficult, and also by trying different condi- ture of E/Z isomers,[8] which was used as a mixture in the
tions for the Wittig step. Therefore we protected cis-diol next step. Although it is likely that these results could be
46 as the cyclohexylidene ketal to obtain 47b, which was improved through a thorough study of this step, at this
transformed into ketone 48b (Scheme 15). Grignard ad- point, the lack of time and material prevented us from
dition to the ketone afforded alcohol 49b, which was depro- achieving this goal and we decided to continue the se-
tected with TBAF in a mixture of THF/DMF, accelerating quence. Homologation of the C-8 side-chain again was car-
the reaction to form diol 50b, which proved stable to ketal ried out as before by cross-metathesis of 57 and fragment
migration upon standing neat or in solution.
54 to afford 58 as an E/Z mixture at C-2 with the E isomer
Next we focused our attention on the low-yielding Wittig as the major product and again the E geometry at the C-
step. The required ketone 52b was obtained by oxidation of 10/C-11 alkene. Subsequent purification afforded (E)-58
alcohol 50b (Scheme 16) and then we explored the use of contaminated with traces of the Z isomer at C-2. The spec-
troscopic data for 58 (1H NMR) was almost identical to
that of a similar product described in the literature.[22b] The
synthetic sequence was completed by cleavage of the silyl
ether and cyclohexylidene ketal in one step by treatment of
58 with DOWEX resin to afford ethyl deoxymonate B (30;
2.2%) in 17 linear steps (21 steps in total) from the commer-
cially available 4-pentyn-2-ol. A previous synthesis gave the
related methyl deoxypseudomonate B in 21 linear steps (29
steps in total) from -lyxose.[22b]
Conclusions
The behavior of the readily available enantiopure cis- and
trans-3,6-disubstituted dihydropyran-3-ols and their deriva-
tives in epoxidation, osmium-catalyzed dihydroxylations,
SN2Ј, and Claisen-related processes has been examined. As
a result, a variety of potentially useful pyran building
Scheme 15. Synthesis of intermediate 50b.
blocks have been prepared. The highly diastereoselective di-
Scheme 16. Final steps for the synthesis of ethyl deoxymonate B (30).
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Stereoselective Functionalization of Dihydropyranols
chromatography (10–50% CH2Cl2/hexane) afforded 3b (11 mg,
0.038 mmol, 66%) as a colorless oil.
hydroxylation of a suitably functionalized cis-3,6-disubsti-
tuted dihydropyran-3-ol, obtained by [2,3]-sigmatropic re-
arrangement of a 3-sulfinyldihydropyran, has been used in
the synthesis of ethyl deoxymonate B, which also features
the homologation of the C-8 side-chain by the cross-me-
tathesis of a homoallylic free alcohol fragment.
From protected alcohol 1b (18 mg, 0.067 mmol) and m-CPBA
(17 mg, 0.067 mmol, 1 equiv.), according to the general procedure
described in the Supporting Information (20 h), a 77:23 mixture of
epoxides 4b and 3b was obtained. Purification by chromatography
(15–50% CH2Cl2/hexane) afforded an inseparable 77:23 mixture of
4b and 3b (16 mg, 0.054 mmol, 81%), along with recovered starting
material (4 mg, 0.013 mmol, 19%) as colorless oils.
Experimental Section
Data for 3b: Rf = 0.21 (50% CH2Cl2/hexane). [α]2D0 = +45.1 (c =
General: Reagents and solvents were handled using standard sy-
ringe techniques. All reactions were carried out under argon. Hex-
ane, toluene, CH3CN, and CH2Cl2 were distilled from CaH2, and
THF and Et2O from sodium. Crude products were purified by flash
chromatography on 230–400 mesh silica gel with distilled solvents.
Analytical TLC was carried out on silica gel plates with detection
by UV light, iodine, acidic vanillin solution, 10% phosphomolybdic
acid solution in ethanol, and 0.3% ninhydrin solution with 3%
AcOH. All reagents were commercial products. Throughout this
section, the volume of solvents is reported in mL/mmol of the start-
1
1.02, CHCl3). H NMR (300 MHz, CDCl3, COSY): δ = 0.08 (s, 3
H, CH3 TBS), 0.11 (s, 3 H, CH3 TBS), 0.89 (br. s, 12 H, tBu, CH3),
1.26–1.44 (m, 4 H, 2 CH2), 1.54–1.62 (m, 2 H, CH2), 3.14 (d, J =
4.2 Hz, 1 H, 6-H), 3.20 (d, J = 10.3 Hz, 1 H, 4-H), 3.29 (d, J =
3.9 Hz, 1 H, 1-H), 3.49 (ddd, J = 11.0, 6.1, 0.7 Hz, 1 H, 4-H), 3.66
(t, J = 6.6 Hz, 1 H, 2-H), 4.09 (ddd, J = 10.0, 6.0, 1.9 Hz, 1 H, 5-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.6 (2 C), 14.0, 18.2,
22.6, 25.8 (3 C), 27.4, 33.3, 54.2, 58.3, 64.3, 66.6, 73.6 ppm. IR
(film): ν = 2956, 2931, 2860, 1471, 1464, 1388, 1361, 1259, 1114,
˜
1032, 875, 838, 777 cm–1. MS (ES): m/z (%) = 309 [M + Na]+, 280
(100) [M + 1 – 2Me]+.
1
ing material. H and 13C NMR spectra were recorded at 25 °C at
200, 300, 400, or 500 MHz (1H) using CDCl3 as solvent and with
the residual solvent signal as the internal reference (CDCl3, 7.24
and 77.0 ppm) unless otherwise noted. The following abbreviations
are used to describe multiplicities when appropriate: s (singlet), d
(doublet), t (triplet), q (quartet), qui (quintet), m (multiplet), br.
(broad). Melting points are uncorrected. Optical rotations were
measured in CHCl3 solution at 20 °C by using a sodium lamp.
Low-resolution mass spectra were recorded by using the electronic
impact technique with an ionization energy of 70 eV or by using
the atmospheric pressure chemical ionization (APCI) or electro-
spray (ES) chemical ionization techniques in the positive or nega-
tive mode.
Partial Data for 4b (from the Mixture): Rf = (50% CH2Cl2/hexane).
1H NMR (300 MHz, CDCl3): δ = 0.07 (s, 3 H), 0.10 (s, 3 H), 0.88
(br. s, 12 H), 1.26–1.50 (m, 4 H), 1.54–1.68 (m, 2 H), 2.95 (dd, J =
11.0, 9.0 Hz, 1 H), 3.06 (dd, J = 3.9, 0.7 Hz, 1 H), 3.20 (dd, J =
3.9, 1.0 Hz, 1 H), 3.69 (td, J = 6.7, 1.0 Hz, 1 H), 3.80 (ddd, J =
10.9, 6.1, 1.0 Hz, 1 H), 3.90 (dd, J = 9.0, 6.1 Hz, 1 H) ppm.
(–)-(2S,3R,4R,5S)-2-Butyltetrahydro-2H-pyran-3,4,5-triol (9a):
From alcohol 2a (15 mg, 0.096 mmol, 1 equiv.), Me3NO·2H2O
(27 mg, 0.240 mmol, 2.5 equiv.), and OsO4 [63 µL (2.5 %),
0.005 mmol, 0.05 equiv.], according to the general procedure de-
scribed in the Supporting Information (22 h), triol 9a was obtained
as a single isomer. Purification by chromatography (0–10% MeOH/
CH2Cl2) afforded 9a (15 mg, 0.079 mmol, 82%) as a colorless oil.
Rf = (10% MeOH/CH2Cl2). [α]2D0 = –11.1 (c = 1.06, CHCl3). 1H
NMR (300 MHz, CDCl3, COSY): δ = 0.89 (t, J = 7.2 Hz, 3 H,
CH3), 1.20–1.70 (m, 5 H), 1.75 (m, 1 H), 2.03 (br. s, 2 H, 2 OH),
2.32 (br. s, 1 H, OH), 3.42 (td, J = 8.8, 2.8 Hz, 1 H, 2-H), 3.62 (dd,
J = 6.9, 3.5 Hz, 1 H, 6-H), 3.65 (dd, J = 9.4, 2.9 Hz, 1 H, 3-H),
3.81 (m, 1 H, 6-H), 3.85 (dd, J = 11.9, 1.8 Hz, 1 H, 4-H), 3.97 (td,
J = 3.5, 0.9 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
(+)-(1S,2S,5R,6R)-2-Butyl-3,7-dioxabicyclo[4.1.0]heptan-5-ol (3a)
and (1R,2S,5R,6S)-2-Butyl-3,7-dioxabicyclo[4.1.0]heptan-5-ol (4a):
From alcohol 1a (19 mg, 0.122 mmol) and m-CPBA (30 mg,
0.122 mmol, 1 equiv.), according to the general procedure described
in the Supporting Information (23 h), an 88:12 mixture of epoxides
3a and 4a was obtained. Purification by chromatography (0–20%
EtOAc/CH2Cl2) afforded 3a (11 mg, 0.064 mmol, 52%) and a 73:27
mixture of 3a and 4a (3 mg, 0.017 mmol, 13%) as colorless oils.
Data for 3a: Rf = 0.26 (20% EtOAc/CH2Cl2). [α]2D0 = +28.6 (c =
14.0, 22.7, 27.6, 30.9, 66.4, 69.5, 69.9, 70.4, 76.6 ppm. IR (film): ν
˜
1
1.03, CHCl3). H NMR (300 MHz, CDCl3, COSY): δ = 0.89 (t, J
= 3369, 2956, 2926, 2861, 1650, 1453, 1259, 1109, 1070, 1032 . MS
= 7.2 Hz, 3 H, CH3), 1.29–1.43 (m, 4 H, 2 CH2), 1.55–1.62 (m, 2
H, CH2), 1.79 (br. s, 1 H, OH), 3.10 (dd, J = 11.2, 9.5 Hz, 1 H, 4-
H), 3.23 (dd, J = 4.4, 0.5 Hz, 1 H, 1-H), 3.44 (m, 1 H, 6-H), 3.65
(app. dd, J = 5.9, 0.7 Hz, 1 H, 4-H), 3.67 (app. dd, J = 7.2, 6.1 Hz,
1 H, 2-H), 4.04 (m, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 13.9, 22.6, 27.4, 32.7, 53.7, 59.0, 64.4, 65.2, 73.4 ppm. IR (film):
(ES): m/z (%) = 213 (100) [M + Na]+.
(–)-(2S,3R,4R,5S)-2-[2-(tert-Butyldiphenylsilyloxy)propyl]tetra-
hydro-2H-pyran-3,4,5-triol (46): From alcohol 45 (205 mg,
0.517 mmol, 1 equiv.), Me3NO·2H2O (144 mg, 1.293 mmol,
2.5 equiv.), and OsO4 [0.33 mL (2.5%), 0.026 mmol, 0.05 equiv.],
according to the general procedure described in the Supporting In-
formation (15 h), triol 46 was obtained. Purification by chromatog-
raphy (0–5% MeOH/CH2Cl2) afforded 46 (213 mg, 0.495 mmol,
96%) as a colorless oil. Rf = 0.15 (5% MeOH/CH2Cl2). [α]2D0 = –3.9
ν = 3401, 2961, 2926, 2862, 1644, 1460, 1412, 1379, 1260, 1099,
˜
1068, 1035, 893, 868, 805 cm–1. MS (ES): m/z (%) = 195 (100) [M
+ Na]+, 173 [M + 1]+.
Partial Data for 4a (from the Mixture): Rf = 0.24 (20% EtOAc/
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 3.18 (dd, J = 4.2,
2.0 Hz, 1 H), 3.18 (dd, J = 11.7, 5.6 Hz, 1 H), 3.31 (dd, J = 4.1,
1.3 Hz, 1 H), 3.83 (dd, J = 11.5, 3.8 Hz, 1 H) ppm.
1
(c = 0.89, CHCl3). H NMR (300 MHz, CDCl3, COSY): δ = 1.03
(s, 9 H, tBu 1 isom.), 1.03 (d, J = 6.5 Hz, 3 H, CH3 1 isom.), 1.06
(s, 9 H, tBu 1 isom.), 1.10 (d, J = 6.3 Hz, 3 H, CH3 1 isom.), 1.47
[ddd, J = 14.3, 8.8, 2.9 Hz, 1 H, CH2CH(CH3)OTBDPS], 1.64 (br.
(+)-tert-Butyl[(1S,2S,5R,6S)-2-butyl-3,7-dioxabicyclo[4.1.0]heptan- s, 1 H, OH), 1.77 [dt, J = 14.4, 4.2 Hz, 1 H, CH2CH(CH3)-
5-yloxy]dimethylsilane (3b): From epoxy alcohol 3a (10 mg,
0.058 mmol), TBDMSCl (11 mg, 0.070 mmol, 1.2 equiv.), imid-
OTBDPS], 1.86–2.10 [m, 2 H, CH2CH(CH3)OTBDPS], 2.15 (br. s,
1 H, OH), 2.38 (br. s, 1 H, OH), 2.75 (br. s, 1 H, OH), 3.48 (dd, J
azole (5 mg, 0.070 mmol, 1.2 equiv.), and DMAP (1 crystal, = 13.7, 1.5 Hz, 2 H, 2-H 2 isom.), 3.55 (m, 1 H, OH), 3.61 (d, J =
0.05 equiv.), according to the general procedure described in the
Supporting Information (22 h), 3b was obtained. Purification by
12.2 Hz, 2 H, 6-H 2 isom.), 3.57–3.69 (m, 3 H, 3-H 1 isom, 4-H 2
isom.), 3.75 (t, J = 1.7 Hz, 1 H, 3-H 1 isom.), 3.82 (app. d, J =
Eur. J. Org. Chem. 2009, 2312–2322
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2319

R. Fernández de la Pradilla, N. Lwoff, A. Viso
FULL PAPER
9.5 Hz, 1 H, 6-H 1 isom.), 3.83 (d, J = 11.0 Hz, 1 H, 6-H 1 isom.),
3.92 (app. s, 1 H, 5-H 1 isom.), 4.02 (app. d, J = 2.7 Hz, 1 H, 5-H
(m, 12 H), 7.62–7.68 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 19.2 (2 C), 23.2, 23.7 (2 C), 23.8 (2 C), 24.3, 24.9 (2 C), 27.0 (12
1 isom.), 4.07–4.17 [m, 2 H, CH2CH(CH3)OTBDPS], 4.71 (br. s, 1 C), 34.8 (2 C), 36.8, 36.9, 43.0, 44.3, 65.9, 66.4, 73.0, 77.2, 78.0,
H, OH), 7.33–7.47 (m, 12 H, Ar-H), 7.62–7.72 (m, 8 H, Ar-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.0, 19.3, 21.7, 24.5,
26.9 (3 C), 27.0 (3 C), 42.6, 42.7, 66.6, 66.8, 67.0, 67.8, 69.4, 69.5,
69.8 (2 C), 70.0, 72.4, 73.1, 127.4 (2 C), 127.5 (2 C), 127.7 (2 C),
78.3, 112.2 (2 C), 127.4 (3 C), 127.5 (3 C), 127.5 (2 C), 127.6 (2 C),
129.5, 129.6, 129.7, 134.1, 134.2, 134.5, 134.6, 135.9 (3 C), 135.9 (2
C), 207.1 (2 C) ppm. IR (film): ν = 3049, 3072, 2935, 2858, 1739,
˜
1428, 1372, 1217, 1111, 998, 940, 822, 758, 703 cm–1. MS (ES): m/z
127.8 (2 C), 129.5, 129.6, 129.9, 130.0, 132.9, 133.2, 134.1, 134.6, (%) = 563 (100) [M + Na + MeOH]+.
135.9 (8 C) ppm. IR (film): ν = 3401, 3068, 2962, 2930, 2855, 1665,
˜
(–)-(3aS,4S,7R,7aS)-7-Allyl-4-[2-(tert-butyldiphenylsilyloxy)propyl]-
tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1Ј-cyclohexan]-7-ol
(49b): From ketone 48b (70 mg, 0.138 mmol) and allylmagnesium
bromide (1.7 mL, 0.33 , 0.552 mmol, 4 equiv.), according to the
general procedure described in the Supporting Information (1 h
40 min), alcohol 49b was obtained. Purification by chromatography
(5–20% EtOAc/hexane) afforded 49b (53 mg, 0.096 mmol, 70%) as
a colorless oil along with recovered starting material (3 mg,
0.006 mmol, 4%). Rf = 0.37 (20% EtOAc/hexane). [α]2D0 = –18.9 (c
= 0.19, CHCl3). 1H NMR (300 MHz, CDCl3, COSY): δ = 0.97 (d,
J = 6.1 Hz, 3 H, CH3 isom. A), 1.02 (s, 9 H, tBu 1 isom.), 1.03 (s,
9 H, tBu 1 isom.), 1.06 (d, J = 6.1 Hz, 3 H, CH3 isom. B), 1.29–
1.41 [m, 5 H, CH2 cyclohexyl, 1 H CH2CH(CH3)OTBDPS isom.
A], 1.43–1.70 [m, 17 H, CH2 cyclohexyl, 1 H CH2CH(CH3)-
OTBDPS isom. B], 1.79 [ddd, J = 13.9, 8.5, 2.2 Hz, 1 H,
CH2CH(CH3)OTBDPS isom. B], 1.89 [ddd, J = 14.0, 9.3, 2.5 Hz,
1 H, CH2CH(CH3)OTBDPS isom. A], 2.30 (m, 5 H, CH2=CHCH2
2 isom., OH), 3.17 (d, J = 11.2 Hz, 1 H, 6-H 1 isom.), 3.22 (d, J =
11.2 Hz, 1 H, 6-H 1 isom.), 3.24 (td, J = 9.0, 2.4 Hz, 1 H, 4-H
isom. B), 3.42 (d, J = 10.7 Hz, 1 H, 6-H 1 isom.), 3.44 (d, J =
10.5 Hz, 1 H, 6-H 1 isom.), 3.48 (dd, J = 9.8, 2.2 Hz, 1 H, 4-H
isom. A), 3.59 (dd, J = 9.0, 6.6 Hz, 1 H, 3a-H isom. A), 3.61 (dd,
J = 9.2, 6.3 Hz, 1 H, 3a-H isom. B), 4.05 [app. dd, J = 10.9, 5.0 Hz,
3 H, 7a-H 2 isom., CH2CH(CH3)OTBDPS isom. B], 4.18 [ddd, J
= 9.3, 6.3, 3.2 Hz, 1 H, CH2CH(CH3)OTBDPS isom. A], 5.07–5.16
1588, 1471, 1428, 1376, 1111, 1065, 821, 702 cm–1. MS (ES): m/z
(%) = 453 (100) [M + Na]+. C24H34O5Si (430.61): calcd. C 66.94,
H 7.96; found C 67.15, H 8.21.
(–)-(3aS,4S,7S,7aR)-4-[2-(tert-Butyldiphenylsilyloxy)propyl]tetra-
hydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1Ј-cyclohexan]-7-ol
(47b): Cyclohexanone (0.19 mL, 1.86 mmol, 8 equiv.) and p-tolu-
enesulfonic acid (2 mg, 0.012 mmol, 0.05 equiv.) were added to a
solution of triol 46 (100 mg, 0.232 mmol, 1 equiv.) in toluene
(2.3 mL, 0.1 ) under argon at room temp. and the reaction was
stirred until disappearance of the starting material was observed
(TLC, 18 h.) The reaction was quenched by the addition of solid
NaHCO3 and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography on silica gel
(5–20% EtOAc/hexane) to afford 47b (102 mg, 0.20 mmol, 86%) as
a colorless oil. Rf = 0.18 and 0.12 (20% EtOAc/hexane). [α]2D0
=
1
–21.1 (c = 0.96, CHCl3). H NMR (500 MHz, CDCl3, COSY): δ
= 0.99 (d, J = 6.1 Hz, 3 H, CH3 isom. A), 1.03 (s, 18 H, tBu 2
isom.), 1.07 (d, J = 6.1 Hz, 3 H, CH3 isom. B), 1.28–1.43 [m, 7 H,
CH2CH(CH3)OTBDPS isom. A, 3 CH2 cyclohexane], 1.56–1.70
[m, 15 H, CH2CH(CH3)OTBDPS isom. B, 7 CH2 cyclohexane],
1.84 [m, 1 H, CH2CH(CH3)OTBDPS isom. B], 1.94 [m, 2 H,
CH2CH(CH3)OTBDPS isom. A, OH], 3.26 (t, J = 8.6 Hz, 1 H, 4-
H isom. B), 3.45 (td, J = 8.6, 2.2 Hz, 1 H, 4-H isom. A), 3.50 (d,
J = 12.5 Hz, 1 H, 6-H 1 isom.), 3.58 (d, J = 12.2 Hz, 1 H, 6-H 1
isom.), 3.64 (app. dd, J = 12.2, 7.3 Hz, 2 H, 6-H 2 isom.), 3.73 (dd,
J = 9.6, 5.0 Hz, 1 H, 3a-H isom. A), 3.75 (dd, J = 10.3, 4.9 Hz, 1
H, 3a-H isom. B), 3.90 (d, J = 8.8 Hz, 2 H, 7-H 2 isom.), 4.06 [m,
1 H, CH2CH(CH3)OTBDPS isom. B], 4.12–4.22 [m, 3 H, 7a-H 2
isom., CH2CH(CH3)OTBDPS isom. A], 7.32–7.40 (m, 12 H, Ar-
H), 7.67 (m, 8 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
19.2, 19.4, 22.9, 23.7 (2 C), 24.0 (2 C), 24.4, 25.0 (2 C), 27.0 (9 C),
29.7, 35.6 (2 C), 38.0, 38.1, 42.4, 43.8, 65.6, 66.6, 66.8, 68.2 (2 C),
74.3 (2 C), 74.9, 75.3, 76.2, 110.1 (2 C), 127.3 (2 C), 127.4, 129.4,
134.2, 134.5, 134.7, 135.0, 135.8 (4 C), 135.9 (10 C) ppm. IR (film):
(m, 4 H, CH2=CHCH2 2 isom.), 5.91 (m, 2 H, CH2=CHCH2
2
isom.), 7.30–7.42 (m, 12 H, Ar-H), 7.64–7.69 (m, 8 H, Ar-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 19.2, 19.4, 22.8, 23.6 (2 C), 24.0
(2 C), 24.4, 25.0 (3 C), 27.0 (8 C), 29.7, 35.7 (2 C), 38.0 (2 C), 41.1
(3 C), 42.5, 43.7, 65.8, 66.8, 69.7 (2 C), 70.1 (2 C), 74.6, 75.5, 76.2,
110.4 (2 C), 119.0 (2 C), 127.3 (2 C), 127.4 (4 C), 127.5 (3 C), 129.4
(3 C), 132.4 (2 C), 135.9 (10 C) ppm. IR (film): ν = 3445, 3068,
˜
2933, 2857, 1471, 1462, 1447, 1428, 1365, 1269, 1159, 1111, 1085,
1047, 997, 936, 822, 759, 702 cm–1. MS (ES): m/z (%) = 573 (100)
[M + Na]+. C33H46O5Si (550.80): calcd. C 71.96, H 8.42; found C
72.21, H 8.77.
ν = 3401, 2932, 2857, 1652, 1449, 1428, 1112, 1046, 822, 702 cm–1.
˜
MS (ES): m/z (%) = 533 [M + Na]+, 527 (100), 511 [M + 1]+, 433
[M – Ph]+. C30H42O5Si (510.74): calcd. C 70.55, H 8.29; found C
70.82, H 7.94.
(–)-(3aS,4S,7R,7aS)-7-Allyl-4-(2-hydroxypropyl)tetrahydro-3aH-spi-
ro[[1,3]dioxolo[4,5-c]pyran-2,1Ј-cyclohexan]-7-ol (50b): From
alcohol 49b (52 mg, 0.094 mmol) and TBAF (0.28 mL, 1 ,
0.282 mmol, 3 equiv.) in a THF/DMF (8:2) mixture, according to
the general procedure A described in the Supporting Information
[5 d, with an addition of 1 equiv. of TBAF (0.1 mL) after 4 d] diol
50b was obtained. Purification by chromatography (0–40% EtOAc/
CH2Cl2) afforded 50b (21 mg, 0.067 mmol, 72%) as a colorless oil
along with recovered starting material (3 mg, 0.006 mmol, 6%). A
second purification of a smaller fraction (0–40% EtOAc/CH2Cl2)
afforded both isomers of 50b separately.
(+)-(3aS,4S,7aS)-4-[2-(tert-Butyldiphenylsilyloxy)propyl]dihydro-
3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1Ј-cyclohexan]-7(4H)-one
(48b): From alcohol 47b (102 mg, 0.20 mmol), PCC (88 mg,
0.40 mmol, 2 equiv.), and 4 Å molecular sieves (600 mg, 3 g/mmol),
according to the general procedure described in the Supporting In-
formation (22 h), ketone 48b was obtained. Purification by
chromatography (5–20 % EtOAc/hexane) afforded 48b (73 mg,
0.144 mmol, 72%) as a colorless oil. Rf = 0.22 (20% EtOAc/hex-
ane). [α]2D0 = +5.6 (c = 1.53, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.03 (s, 18 H), 1.09 (d, J = 6.3 Hz, 3 H), 1.11 (d, J = 6.1 Hz, 3
Data for Isomer 50b-A: Rf = 0.38 (40% EtOAc/CH2Cl2). [α]2D0
=
1
H), 1.37 (m, 4 H), 1.54–1.66 (m, 18 H), 1.88 (m, 1 H), 2.00 (ddd, –16.2 (c = 0.13, CHCl3). H NMR (300 MHz, CDCl3, COSY): δ
J = 14.3, 8.6, 2.7 Hz, 1 H), 3.42 (dd, J = 9.2, 3.0 Hz, 1 H), 3.50
(m, 1 H), 3.51 (dd, J = 18.1, 1.5 Hz, 1 H), 3.91 (dd, J = 17.8,
= 1.17 (d, J = 6.1 Hz, 3 H, CH3), 1.38 (m, 3 H, CH2 cyclohexyl,
OH), 1.52–1.73 [m, 9 H, 4 CH2 cyclohexyl, CH2CH(CH3)OH], 1.81
1.2 Hz, 1 H), 4.03 (dd, J = 17.8, 0.7 Hz, 1 H), 4.10 (m, 2 H), 4.14 [app. dt, J = 14.2, 3.0 Hz, 1 H, CH2CH(CH3)OH], 2.27 (m, 3 H,
(d, J = 17.3 Hz, 1 H), 4.21 (t, J = 8.5 Hz, 1 H), 4.34 (t, J = 8.1 Hz, CH2=CHCH2, OH), 3.41 (d, J = 11.2 Hz, 1 H, 6-H), 3.43 (td, J =
1 H), 4.48 (d, J = 8.1 Hz, 1 H), 4.53 (d, J = 8.1 Hz, 1 H), 7.31–7.44 9.3, 3.6 Hz, 1 H, 4-H), 3.61 (d, J = 11.0 Hz, 1 H, 6-H), 3.75 (dd, J
2320
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2312–2322

Stereoselective Functionalization of Dihydropyranols
= 9.0, 5.1 Hz, 1 H, 3a-H), 4.00 [ddd, J = 9.2, 6.3, 2.7 Hz, 1 H,
CH2CH(CH3)OH], 4.11 (d, J = 4.9 Hz, 1 H, 7a-H), 5.10–5.18 (m,
2 H, CH2=CHCH2), 5.92 (ddt, J = 17.4, 10.0, 7.2 Hz, 1 H,
CH2=CHCH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.2, 23.6,
24.1, 24.9, 35.5, 38.0, 41.0, 41.8, 67.5, 69.5, 70.0, 76.0, 77.8, 78.9,
2.47 (dd, J = 14.7, 2.0 Hz, 1 H), 3.35 (d, J = 11.2 Hz, 1 H), 3.40
(td, J = 9.3, 2.9 Hz, 1 H), 3.57 (d, J = 11.2 Hz, 1 H), 3.72 (dd, J
= 9.0, 4.9 Hz, 1 H), 4.11 (d, J = 4.2 Hz, 1 H), 4.12 (q, J = 7.3 Hz,
2 H), 5.11–5.17 (m, 2 H), 5.72 (s, 1 H), 5.92 (ddt, J = 17.4, 10.0,
7.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3, 19.1,
23.6, 24.0, 24.9, 35.6, 38.1, 41.1, 43.9, 59.5, 69.6, 70.5, 75.5, 77.0,
110.7, 119.3, 132.1 ppm. IR (film): ν = 3435, 2926, 2854, 1642,
˜
1452, 1367, 1263, 1161, 1110, 1037, 927 cm–1. MS (ES): m/z (%) =
77.2, 110.6, 117.7, 119.1, 132.2, 156.0, 166.9 ppm. IR (film): ν =
˜
335 (100) [M + Na]+.
3480, 3077, 2936, 2860, 1716, 1650, 1450, 1367, 1347, 1276, 1225,
1151, 1109, 1043, 927, 758 cm–1. MS (ES): m/z (%) = 403 (100) [M
+ Na]+, 381 [M + 1]+.
Partial Data for (Z)-57 (from the Mixture): 1H NMR (500 MHz,
CDCl3): δ = 1.92 (s, 3 H), 2.87 (dd, J = 13.5, 8.9 Hz, 1 H), 2.99
(dd, J = 13.5, 4.0 Hz, 1 H), 3.34 (d, J = 11.0 Hz, 1 H), 3.48 (td, J
= 8.8, 4.4 Hz, 1 H), 3.55 (d, J = 11.2 Hz, 1 H), 3.82 (dd, J = 8.8,
4.9 Hz, 1 H), 5.73 (s, 1 H) ppm.
Data for Isomer 50b-B: Rf = 0.30 (40% EtOAc/CH2Cl2). [α]2D0
=
–20.3 (c = 0.33, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.20 (d,
J = 6.1 Hz, 3 H), 1.22–1.38 (m, 2 H), 1.53–1.86 (m, 10 H), 2.36
(m, 2 H), 3.39 (d, J = 11.2 Hz, 1 H), 3.46 (app. dt, J = 8.3, 6.0 Hz,
1 H), 3.59 (d, J = 11.0 Hz, 1 H), 3.86 (dd, J = 9.0, 4.9 Hz, 1 H),
3.98 (m, 1 H), 4.13 (d, J = 4.6 Hz, 1 H), 5.11–5.18 (m, 2 H), 5.93
(ddt, J = 17.5, 10.2, 7.1 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 23.5, 23.6, 24.0, 35.5, 37.9, 41.1, 41.9, 64.9, 69.6, 70.3,
Ethyl (–)-(E)-4-{(3aS,4S,7R,7aS)-7-Hydroxy-7-[(4R,5S,E)-4-
methyl-5-(triethylsilyloxy)hex-2-enyl]tetrahydro-3aH-spiro[[1,3]diox-
olo[4,5-c]pyran-2,1Ј-cyclohexan]-4-yl}-3-methylbut-2-enoate (58):
From 57 (3 mg, 0.008 mmol, 1 equiv.), 54 (3 mg, 0.016 mmol), and
Grubbs catalyst (0.3 mg, 0.0004 mmol, 0.05 equiv.), according to
the general procedure described in the Supporting Information, 58
was obtained. Purification by chromatography (5–30% EtOAc/hex-
ane) afforded 58 (3 mg, 0.005 mmol, 66%) as a colorless oil. (The
spectral data was assigned following the pseudomonic acid num-
bering.) Rf = 0.33 (20% EtOAc/hexane.) [α]2D0 = –9.7 (c = 0.35,
75.5, 76.3, 77.3, 110.7, 119.2, 132.1 ppm. IR (film): ν = 3429, 2934,
˜
2860, 1641, 1451, 1368, 1276, 1161, 1110, 1037, 726 cm–1. MS (ES):
m/z (%) = 335 (100) [M + Na]+.
(–)-1-[(3aS,4S,7R,7aS)-7-Allyl-7-hydroxytetrahydro-3aH-spiro-
[[1,3]dioxolo[4,5-c]pyran-2,1Ј-cyclohexan]-4-yl]propan-2-one (52b):
From alcohol 50b (21 mg, 0.067 mmol), PCC (29 mg, 0.134 mmol,
2 equiv.), and 4 Å molecular sieves (201 mg, 3 g/mmol), according
to the general procedure described in the Supporting Information
(2 h 30 min), ketone 52b was obtained. Purification by chromatog-
raphy (0–20% EtOAc/CH2Cl2) afforded 52b (18 mg, 0.058 mmol,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.56 (q, J = 8.0 Hz, 6
H), 0.93 (t, J = 7.8 Hz, 9 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.03 (d, J
= 6.1 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.35 (m, 2 H), 1.54–1.73
(m, 8 H), 2.17 (d, J = 1.0 Hz, 3 H), 2.14–2.24 (m, 2 H), 2.29 (m, 2
H), 2.47 (d, J = 14.4 Hz, 1 H), 3.35 (d, J = 11.3 Hz, 1 H), 3.41 (td,
J = 9.3, 2.9 Hz, 1 H), 3.55 (d, J = 11.3 Hz, 1 H), 3.70 (dd, J = 9.3,
4.7 Hz, 1 H), 3.71 (app. d, J = 4.3 Hz, 1 H), 4.09 (d, J = 3.9 Hz, 1
H), 4.12 (q, J = 7.1 Hz, 2 H), 5.50 (m, 2 H, 10-H), 5.71 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 5.0 (3 C), 6.9 (3 C),
14.3, 15.5, 19.1, 20.5, 23.6, 24.0, 24.9, 31.9, 35.5, 38.1, 40.1, 44.2,
59.5, 69.7, 70.6, 71.6, 75.5, 76.1, 76.4, 110.5, 117.7, 123.2, 137.7,
86%) as a colorless oil. Rf = 0.33 (20% EtOAc/CH2Cl2). [α]2D0
=
–1.8 (c = 1.32, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.31–
1.44 (m, 2 H), 1.52–1.78 (m, 8 H), 2.17 (s, 3 H), 2.36 (m, 3 H), 2.54
(dd, J = 15.9, 8.5 Hz, 1 H), 2.67 (dd, J = 15.8, 3.0 Hz, 1 H), 3.40
(d, J = 11.2 Hz, 1 H), 3.56 (d, J = 11.2 Hz, 1 H), 3.69 (td, J = 9.0,
3.2 Hz, 1 H), 3.77 (dd, J = 9.3, 4.6 Hz, 1 H), 4.11 (d, J = 4.4 Hz,
1 H), 5.09–5.17 (m, 2 H), 5.92 (ddt, J = 17.5, 10.4, 7.3 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.6, 24.0, 24.9, 30.8,
35.5, 37.9, 41.0, 46.6, 69.6, 70.4, 74.6, 74.9, 77.3, 110.8, 119.1,
132.2, 206.3 ppm. IR (film): ν = 3456, 2936, 2862, 1718, 1641, 1450,
˜
156.1, 166.6 (C-1) ppm. IR (film): ν = 3446, 2927, 2855, 1713, 1650,
˜
1432, 1366, 1275, 1231, 1164, 1110, 1051, 927, 851, 757 cm–1. MS
(ES): m/z (%) = 643 [2M + Na]+, 333 (100) [M + Na]+, 311 [M +
1]+. C17H26O5 (310.39): calcd. C 65.78, H 8.44; found C 65.53, H
8.19.
1451, 1368, 1263, 1217, 1150, 1108, 1039, 928, 759, 667 cm–1. MS
(ES): m/z (%) = 589 (100) [M + Na]+, 567 [M + 1]+.
Ethyl (+)-(E)-3-Methyl-4-{(2S,3R,4S,5R)-3,4,5-trihydroxy-5-
[(4R,5S,E)-5-hydroxy-4-methylhex-2-enyl]tetrahydro-2H-pyran-2-
yl}but-2-enoate (30): From 58 (3 mg, 0.005 mmol) and DOWEX
resin (3 mg, 0.5 g/mmol), according to the general procedure B de-
scribed in the Supporting Information (5 d), alcohol 30 was ob-
tained. Purification by chromatography (80–100% EtOAc/CH2Cl2)
afforded 30 (2 mg, 0.004 mmol, 80%) as a colorless oil. (The spec-
tral data was assigned following the pseudomonic acid numbering.)
Rf = 0.18 (EtOAc). [α]2D0 = +7.2 (c = 0.18, CHCl3). 1H NMR
(400 MHz, CDCl3, COSY): δ = 1.00 (d, J = 6.8 Hz, 3 H, 15-H),
1.17 (d, J = 6.2 Hz, 3 H, 14-H), 1.25 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 1.53–1.65 (m, 3 H, 3 OH), 2.12 (q, J = 6.8 Hz, 1 H,
12-H), 2.19 (s, 3 H, 17-H), 2.26 (dd, J = 15.0, 9.3 Hz, 1 H, 4-H),
2.35 (app. d, J = 6.9 Hz, 2 H, 9-H), 2.62 (d, J = 15.0 Hz, 1 H, 4-
H), 3.38 (d, J = 11.2 Hz, 1 H, 16-H), 3.39 (m, 1 H, 6-H), 3.46 (d,
J = 10.8 Hz, 1 H, 16-H), 3.53 (qui, J = 6.3 Hz, 1 H, 13-H), 3.62
(app. t, J = 6.7 Hz, 2 H, 5-H, OH), 3.81 (br. s, 1 H, 7-H), 4.12 (q,
J = 7.1 Hz, 2 H, CH3CH2O), 5.49 (dd, J = 15.5, 7.0 Hz, 1 H), 5.55
(dd, J = 15.5, 6.3 Hz, 1 H), 5.74 (s, 1 H, 2-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.3, 16.7, 20.7, 24.3, 31.9, 38.3, 44.9, 59.6,
68.8, 70.0, 71.2, 71.4, 72.5, 74.4, 117.7, 124.6, 138.4, 156.5, 166.6
Ethyl (–)-(E)-4-[(3aS,4S,7R,7aS)-7-Allyl-7-hydroxytetrahydro-3aH-
spiro[[1,3]dioxolo[4,5-c]pyran-2,1Ј-cyclohexan]-4-yl]-3-methylbut-2-
enoate (57): A solution of triethyl phosphonoacetate (42 µL,
0.211 mmol, 6.6 equiv.) in THF (0.1 mL) was added dropwise to a
cold suspension (0 °C) of NaH (5 mg, 0.192 mmol, 6 equiv.) in
THF (0.2 mL) and the mixture was stirred at room temp. for
30 min. The reaction was cooled to –70 °C, a solution of ketone
52b (10 mg, 0.032 mmol, 1 equiv.) in THF (0.1 mL) was added, and
the reaction was stirred from –70 °C to room temp. until no change
was observed (TLC, 3 d). The reaction was quenched by the ad-
dition of H2O and the layers were separated. The aqueous layer was
extracted with EtOAc (3ϫ4 mL/mmol) and the combined organic
layers were washed with brine, dried with MgSO4, filtered, and
evaporated under reduced pressure. The crude product was purified
by column chromatography on silica gel (5–20% EtOAc/hexane) to
afford an 80:20 mixture of (E/Z)-57 (4 mg, 0.011 mmol, 34%) as a
colorless oil along with impure recovered starting material (6 mg,
0.019 mmol, 60%).
Data for (E)-57 (from the Mixture): Rf = 0.23 (20% EtOAc/hexane).
1
[α]2D0 = –13.0 (c = 0.71, CHCl3). H NMR (500 MHz, CDCl3): δ =
(C-1) ppm. IR (film): ν = 3405, 2925, 2854, 1713, 1647, 1463, 1378,
˜
1.25 (t, J = 7.1 Hz, 3 H), 1.29–1.40 (m, 2 H), 1.54–1.74 (m, 8 H),
2.17 (s, 3 H), 2.19 (dd, J = 14.7, 9.3 Hz, 1 H), 2.32–2.41 (m, 3 H),
1262, 1217, 1151, 1099, 1045, 759 cm–1. MS (ES): m/z (%) = 395
(100) [M + Na]+.
Eur. J. Org. Chem. 2009, 2312–2322
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2321

R. Fernández de la Pradilla, N. Lwoff, A. Viso
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Acknowledgments
This research was supported by the Dirección General de Investiga-
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04522/BQU) and the Comunidad de Madrid (S-SAL-0249-2006).
We thank JANSSEN-CILAG for additional generous support and
the Ministerio de Educación y Ciencia (MEC) for a doctoral fel-
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[24] As our synthetic plan included the oxidation of the secondary
alcohol of the C-5 side-chain, the isomers were not separated
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diastereoisomers before oxidation.
[25] The scale of the preparation of fragment 54 proved to be criti-
cal. No methylation of ethyl (S)-3-hydroxybutyrate was ob-
served on a small scale or in the absence of DMPU.
Received: November 14, 2008
Published Online: March 19, 2009
2322
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2312–2322