Enantiomerically pure decalinic structures from carbohydrates using intramolecular Diels-Alder and Ferrier carbocyclization

Article abstract of DOI:10.1139/v00-057

The synthesis of enantiomerically pure decalinic structures, advanced intermediates for the synthesis of the hexahvdronaphtalen part of mevinic acids, is described. The key steps are the intramolecular Diels-Alder cycloaddition of a suitably substituted sugar enone obtained via the Ferrier rearrangement of tri-O-acetyl-D-glucal with the appropriate alcohol representing the diene part of the system. Chemical manipulation of the resulting. diastereomerically pure, cycloadduct led to a 5,6-unsaturated carbohydrate which was submitted to the Ferrier carbocylization. This reaction proved difficult likely because of the embedding of the aglycon in a cycle, the hydration product of the double bond being the main product. This compound was in turn transformed into the decalinic structures by treatment in basic medium. The inverse strategy. Ferrier carbocyclization followed by IMDA of an enone and a diene linked via an ester bond was unsuccessful.

Full text of DOI:10.1139/v00-057

708
Enantiomerically pure decalinic structures from
carbohydrates using intramolecular Diels–Alder
and Ferrier carbocyclization
Claude Taillefumier and Yves Chapleur
Abstract: The synthesis of enantiomerically pure decalinic structures, advanced intermediates for the synthesis of the
hexahydronaphtalen part of mevinic acids, is described. The key steps are the intramolecular Diels–Alder cycloaddition
of a suitably substituted sugar enone obtained via the Ferrier rearrangement of tri-O-acetyl-D-glucal with the appropri-
ate alcohol representing the diene part of the system. Chemical manipulation of the resulting, diastereomerically pure,
cycloadduct led to a 5,6-unsaturated carbohydrate which was submitted to the Ferrier carbocylization. This reaction
proved difficult likely because of the embedding of the aglycon in a cycle, the hydration product of the double bond
being the main product. This compound was in turn transformed into the decalinic structures by treatment in basic
medium. The inverse strategy, Ferrier carbocyclization followed by IMDA of an enone and a diene linked via an ester
bond was unsuccessful.
Key words: Intramolecular Diels–Alder reaction, enantiomerically pure decalin, Ferrier carbocyclization, carbohydrates.
Résumé : La synthèse de structures décaliniques énantiomériquement pures, intermédiaires avancés dans la synthèse de
la partie hexahydronaphtalene des acides méviniques est décrite. Les étapes clés sont une cycloaddition de Diels–Alder
sur une énone dérivée d’un sucre obtenu par réarrangement de Ferrier du tri-O-acetyl-D-glucal avec un alcool
représentant la partie diènique du système. Le cycloadduit obtenu, diastéréoisomériquement pur, est ensuite transformé
en sucre 5,6 insaturé pouvant subir une carbocyclisation de Ferrier. Cette réaction donne, outre les décalones attendues,
les produits d’hydratation de la double liaison, très probablement à cause de l’inclusion de l’aglycone dans un cycle.
Un des produits d’hydratation a été carbocyclisé en milieu basique, sans l’aide de sels mercuriques, pour conduire aux
structures décaliniques recherchées. La stratégie inverse, carbocyclisation de Ferrier suivie d’une cycloaddition
intramoléculaire de l’énone résultante avec un diène lié par un pont ester s’est révèlée improductive.
Mots clés : Réaction de Diels–Alder intramoléculaire, décaline énantiomériquement pure, carbocyclisation de Ferrier,
hydrates de carbone. Taillefumier and Chapleur 722
Introduction
this useful reaction (IMDA) (3–6) also led to major achieve-
ments in the field of mevinic acids synthesis (7). This reac-
tion is also well precedented in carbohydrate chemistry (8).
Many naturally occuring compounds consist of a basic
decalinic structure decorated with substituents and (or) func-
tional groups. Among them, compounds such as mevinic ac-
ids mevinolin, pravastatin, and congeners (1) or diterpenoids
like forskolin and representatives of the labdane series (2)
are of interest as pharmaceuticals. Accordingly much syn-
thetic work, devoted to the preparation of suitable
functionalized decalinic structures, has been published in
connection with the search for new drugs. The Diels–Alder
cycloaddition played a prominent role in the synthesis of
cyclohexane ring systems and the intramolecular version of
In connection with a synthetic program originally dealing
with the synthesis of the hexahydronaphthalene ring of
mevinic acids using the Chiron approach (9), we have inves-
tigated the synthetic possibilities of two six-membered ring
forming reactions namely IMDA and the Ferrier carbocycli-
zation (10) This mercury-catalyzed intramolecular aldol re-
action is a major breakthrough in carbohydrate chemistry
which transforms a 5,6-unsaturated pyranoside into a chiral
cyclohexanone. The high diastereoselection of the process
led to numerous studies for the synthesis of highly
functionalized cyclohexanes such as inositol (11), condur-
itols (12), and other natural products (13, 14). An elegant
variant, using a 6-substituted 5,6-unsaturated pyranoside, al-
lowed the synthesis of α -substituted cyclohexanone (15). In
addition other conditions, which do not rely on a mercury
catalysis, have led to interesting developments of this sugar
to carbocycle transformation (16). However, if numerous ex-
amples of this basic transformation to form isolated cyclo-
hexane rings are available, application of this reaction on
annelated pyranose is very limited.
Received November 22, 1999. Published on the NRC
Research Press website on May 19, 2000.
Warmly dedicated to Professor Stephen Hanessian in
recognition of his visions and pioneering work in
carbohydrate chemistry.
C. Taillefumier and Y. Chapleur.1 Groupe SUCRES, Unité
Mixte de Recherche 7565, CNRS-Université Henri Poincaré-
Nancy I, BP 239, F-54506 Nancy-Vandoeuvre, France.
1Author to whom correspondence may be addressed. Fax:
+33 383 91 24 79. e-mail: yves.chapleur@meseb.uhp-nancy.fr
We have investigated such an approach with some success
by combining an intramolecular Diels–Alder on a suitably
Can. J. Chem. 78: 708–722 (2000)
© 2000 NRC Canada

Taillefumier and Chapleur
709
Scheme 1. Two strategies for the synthesis of cis decalinic structures.
functionalized sugar followed by the Ferrier carbo-
cyclization of the resulting annulated pyranoside. We have
reported our preliminary results along this line (17). This pa-
per describes the full details of our investigations together
with another approach combining the Ferrier carbocycli-
zation followed by IMDA on the resulting cyclohexenone
which proved unsuccessful.
The dihydroxylated decalinic structure 1 seemed a partic-
ularly interesting target and the two retrosynthetic strategies
toward this compound are depicted in Scheme 1. In the first
approach (Route (a)) the IMDA was planned at the end of
the synthesis. A chiral cyclohexenone would be the dieno-
phile and the electron-rich diene was tethered to this first
cyclohexane ring by an ester linkage on an hydroxyl group
of the cyclohexenone 2. The absolute configuration of the
carbon bearing the tether was chosen to secure the required
absolute stereochemistry of the ring junction by forcing the
diene to interact preferentially with one face of the dieno-
phile. The synthesis of cyclohexenone 2 was based on the
Ferrier carbocyclization of an appropriate deoxy sugar 4 giv-
ing the aldol product 3 (10b). The starting sugar 5, a pre-
Results
First approach
Two routes to the key intermediate 4 were explored, the
first one involving selective protection at C-2 of the known
mono-benzylidene derivative of D-mannose (10) (19). As-
suming that subsequent deoxygenation should reasonably be
carried out using a radical reaction, we attempted to intro-
duce a phenylthionocarbonate group at C-3 by selective
alkylation with phenylthionocarbonyl chloride (PTCCl) (20)
using the stannylene approach as described by Nashed (21)
for the synthesis of the 3-O-para-methoxybenzyl derivative
of 10. Thus treatment of 10 with dibutyltin oxide in
refluxing methanol led to the intermediate stannylene which
was treated with PTCCl in dimethylformamide at 100°C for
30 min. However, only the known cyclic thionocarbonate 11
was isolated (22). Gratifyingly the treatment of 10 with
PTCCl, (1 molar equiv.) under standard conditions led to the
expected monophenylthionocarbonate 12 in 54% yield and
to the thionocarbonate 11 in 36% yield after chromatogra-
phy on silica gel. Treatment of 12 with 1.3 equiv. of
tris(trimethylsilyl)-silane (23, 24) and a catalytic amount of
AIBN in refluxing toluene gave the deoxy-derivative 13 in
68% yield. The low overall yield of this sequence, prompted
us to use a more efficient route from the known epoxide 20
(25) which was transformed into the alcohol 13 upon treat-
ment with LiAlH4.(26)
The next problem to address was the introduction of a
leaving group at C-6 and to differentiate the two secondary
hydroxyl groups at C-2 and C-4. We tried to take advantage
of the presence of the benzylidene protecting group.
Hanessian–Hullar opening of this acetal using our modified
conditions (27), gave the corresponding 6-bromo derivative
21 but all attempts to eliminate hydrobromic acid using sil-
ver fluoride in hot pyridine led only to the unexpected
2,6-anhydro structure 22. All other conditions, (AgF,
pyridine, rt; DBU, rt) left the starting material unchanged.
cursor of the key intermediate
4
of the Ferrier
carbocyclization, should be prepared from D-mannose by
deoxygenation at C-3 (carbohydrate numbering) or from D-
glucose by the same procedure and further inversion of con-
figuration at C-2.
In the second approach (Route (b)) the Ferrier carbocycli-
zation was now planned at the end of the synthesis on the
annulated pyranoside 6. The IMDA reaction could be also
performed on a suitably activated double bond, i.e., the enone
function of 7. The advantage of this strategy relies on the
fact that the tether between the diene and the dienophile
does not have to be a detachable link because the Ferrier
carbocyclization would cleave the glycosidic link. The trienic
system 8 could came from the Ferrier rearrangement of tri-
O-acetyl-D-glucal (9)with the corresponding dienic alcohol
(18).
© 2000 NRC Canada

710
Can. J. Chem. Vol. 78, 2000
Scheme 2. Reagents: (i) Phenyl thionocarbonyl chloride 1.1 equiv.; CH2Cl2–acetone–pyr 2 h, 54%; (ii) tris(trimethylsilyl) silane, 1.2
equiv.; AIBN, degassed toluene reflux, 68%; (iii) TsCl 1.4 equiv.; NaOH 5%; Bu4NHSO4, CH2Cl2, 93%; (iv) MeONa, MeOH reflux,
quant.; (v) LiAlH4, THF, 50°C, 100%; (vii) HCl 12 N; EtOH–H2O (10:1), reflux, 67%; (viii) PPh3, imidazole, I2, toluene, 55°C, 82%;
(ix) NaH, MOMCl; (x) NBS, 1.1 equiv.; CaCO3, CCl4, reflux, 98%; (xi) AgF, pyridine, 80°C.
Hydrogenolysis of the benzylidene according to the Liptak
procedure was also explored (28), but probably because of
Fig. 1. Approximate geometry of an exo transition state for the
IMDA of 28.
the absence of a chelating oxygen at C-3, a mixture of 4-O-
benzyl and 6-O-benzyl derivatives in a 1:1 ratio was ob-
tained. A multi-step sequence was then carried out which
consisted first in the protection of the hydroxyl group at C-2
as a benzoate followed by acid hydrolysis of the benzylidene
ring to give the diol 15 in 67% overall yield. This diol was
treated with triphenylphosphine, imidazole, and I2 to provide
the iodo-derivative 16 in 82% yield. Treatment of 16 with
silver fluoride in pyridine at room temperature gave the 5,6-
rect geometrical arrangement in the transition state. Another
unsaturated compound 23 (52%), which was treated with
more likely reason is that the lone pair of the ester oxygen is
MOMCl to provide the fully protected derivative 24 in 85%
almost perpendicular to the π orbital of the carbonyl in the
yield. Alternately the alcohol 16 could be protected as the
transition state as shown on the approximate geometry of the
MOM ether 17 (71%) and subsequent elimination of
transition state depicted on Fig. 1. Thus the absence of or-
iodohydric acid led to 24 in the same overall yield. Treat-
bital overlap should destabilize the transition state of the
ment of 24 with ammonia in methanol gave quantitatively
cyclization. Such an explanation has already been invoked to
the alcohol 25 which was esterified with the dienic acid 31.
explain the more drastic conditions needed to achieve
The latter was prepared through a three-step sequence in-
intramolecular Diels–Alder reaction involving an ester junc-
volving Wittig olefination of 2-methyl butenal (29) with
tion (31).
carbethoxymethyl triphenylphosphorane followed by
saponification of the resulting ester to provide 30. Treatment
Second approach
with a base and trapping the kinetic enolate (29) gave the
The first crucial step of this second approach was the
expected carboxylic acid 31. Esterification of alcohol 25 us-
glycoside formation using Ferrier rearrangement of tri-O-
ing DCC activation gave the key intermediate 26 in 89%
acetyl-D-glucal with the dienic alcohol 33. This homoallylic
yield. In spite of the number of olefinic bonds and the pres-
alcohol 33 was prepared in two steps from commercially
ence of the MOM acetal, Ferrier carbocyclization catalyzed
available ocimen (32) by ozonolysis – sodium borohydride re-
by mercuric sulfate proceeded uneventfully to give 27 and
duction according to patent literature (32). This alcohol was
treatment of this compound with triflic anhydride at –10°C
gave the expected enone 28 in modest yield.
reacted with tri-O-acetyl-D-glucal (9) in the presence of boron
trifluoride–etherate as the catalyst under carefully controlled
Treatment of enone 28 in degassed toluene in the presence
of hydroquinone failed to give any cyclized product. The
only observable reaction was the splitting of the MOM pro-
tecting group. No reaction was observed using Lewis acid
catalyst such as diethyl aluminium chloride which has been
reported to have beneficial effects (30).
The presence of the ester function in the tether of the
diene and the dienophile was likely responsible for the fail-
ure of this IMDA cyclization. One explanation should be
that the preferred transoid form of the ester impedes the cor-
conditions because compound 33 was prone to degradation in
the presence of this catalyst. The unsaturated glycoside 34
was prepared in 84% as a α and β (80:20) mixture.
Saponification of the acetates under standard conditions
led to the corresponding diols from which compound 35 was
obtained as a pure product by column chromatography. Se-
lective protection by selective pivaloylation was troublesome
due to the high reactivity of the secondary allylic alcohol
and gave 36 and the diester 37 as a 7:3 mixture. However
the diester 37 could be recycled to the diol 35 by LiAlH4 re-
© 2000 NRC Canada

Taillefumier and Chapleur
711
Scheme 3. Reagents: (i) AgF, pyr. rt, 52%; (ii) MOMCl, iPr2NEt, CH2Cl2, 85%; (iii) NH3, MeOH, quant; (iv) V, DCC, CCl4, DMAP,
CH2Cl2, 89%; (v) (Ph)3PCHCOOEt, THF reflux, 80%; (vi) NaOH 1 N, MeOH reflux; (vii) LDA, 2.2 equiv., –78°C then AcOH, 65%;
(viii) HgSO4 0.02 equiv.;, H2SO4 5 mM; 1,4-dioxane, 50°C; (ix) Tf2O, CH2Cl2–Pyr (10:1), –10°C, 30%, 2 steps.
duction. Oxidation of the alcohol 36 with pyridinium dichro-
mate yielded the ketone 38 in 50–55% yield, and freshly
prepared manganese dioxide cleanly oxidized the allylic al-
cohol in up to 90% yield. Ketone 38 proved very unstable
and underwent decomposition, maybe by β-elimination of
the ester group upon concentration, and was kept in solution.
amounts was achieved by sodium borohydride reduction of
41 in 88% yield.
The next problem to address was the chemical manipula-
tion of the annulated pyranoside 40 to secure the formation
of the 5,6-unsaturation required for the Ferrier carbocycli-
zation. Selective mesylation of the primary alcohol of the 42
and 43 mixture gave the mesylates 44 and 45 respectively,
easily separated by column chromatography. Substitution of
the mesylate group by iodide was carried out separately on
each compound giving 46 and 47 in 60 and 82% yield, re-
spectively. If elimination of iodohydric acid can be per-
formed cleanly on alcohol 46, the same sequence cannot be
applied to 47 without formation of an oxetane by intramole-
cular substitution of iodine by the hydroxyl group at C-4.
Protection of the hydroxyl group of 46 and 47 was achieved
and formation of the methoxy methyl ether proceeded in
60% yield to provide 48 and 49 respectively. Once again,
treatment of each iodo-derivative with silver fluoride in pyridine
cleanly gave 50 and 51 in 72% and 87% yield, respectively.
Only a few examples of the Ferrier carbocyclization on
annulated pyranose have been reported in the literature (33).
In addition, our substrates 50 and 51 bear two electron-rich
double bonds which are susceptible to reaction with the mer-
cury catalyst. Ferrier carbocyclization was investigated on
these two key intermediates. A large panel of different cata-
lysts and reaction conditions have been proposed in the liter-
ature for this reaction (10b). Mercuric trifluoroacetate, a
catalyst we have introduced in 1984 for the carbocyclization
of amino sugars (34), and which is efficient in a number of
cases (35, 13), proved disappointing in our reaction. The cat-
alytic method based on the use of mercury sulfate, intro-
duced by Machado et al. (36), was more efficient. Thus,
treatment of the unsaturated pyranoside 50 gave a mixture of
three compounds 52, 54, and 56 in a 1:1:6 ratio in 95%
overall yield. If compounds 52 and 54 where the expected
The intramolecular Diels–Alder reaction proceeded un-
eventfully by simple treatment of 38 in degassed toluene at
155°C in a sealed tube in the presence of hydroquinone. The
cycloadduct 40 was obtained in 75% overall yield. As seen
from careful examination of the NMR spectrum, a single
isomer was formed and the observed coupling constants J1,2
2.0 Hz and J2,3 3.5 Hz were in favour of an all cis arrange-
ment of these three protons. This was in agreement with an
attack of the enone double bond from the α face as expected.
Determination of the configuration at C-3 (see Scheme 4),
which reflects the attack from one face of the diene (i.e.,
endo–exo transition state) could not be determined on the
basis of coupling constants due to signal overlaps. It was an-
ticipated that an exo transition state would be favoured over
the endo one to minimize steric interactions between the
diene and the sugar ring.
Reduction of the keto group of 40 was achieved by lith-
ium aluminium hydride, conditions which also removed the
pivaloyl group. Low diastereoselection was observed for the
ketone reduction and a 1.7:1 mixture of diols 42 and 43 was
obtained.
In the meantime, a shorter route to these compounds was
sought which would avoid the formation of the bis-protected
derivative 37. Thus, selective oxidation of the allylic alcohol
of the diol 35 by manganese dioxide was carried out to af-
ford the ketone 39 in 83% yield. This unstable ketone was
immediately engaged in the IMDA under our standard con-
ditions to provide the adduct 41 in 66% yield as a single iso-
mer. Formation of the diols 42 and 43 in almost equal
© 2000 NRC Canada

712
Can. J. Chem. Vol. 78, 2000
Scheme 4. Reagents: (i) O3, MeOH, –50°C then NaBH4, H2O, 59%; (ii) BF3–Et2O, CH2Cl2, 84%; (iii) MeONa, MeOH; (iv) Pivaloyl
chloride, CH2Cl2, Pyr, –5°C, AI 63%, AH 27%; (v) PDC, CH2Cl2, 55% from AI; MnO2, CCl4 90% from AI, 83% from AG; (vi) tolu-
ene, hydroquinone, 155°C, 75% from AJ, 66% from JA; (vii) LiAlH4, THF, 87% from AK; (viii) NaBH4, MeOH, 88%; (ix) MsCl,
Pyr, 95%; (x) NaI, butanone reflux; (xi) MOMCl, iPr2NEt, THF, 55°C, 62%; (xii) AgF, Pyr, 87%.
Scheme 5. Reagents: (i) Hg++, H2O see text; (ii) Na2CO3 1.8 equiv; DBU, THF–MEOH, rt, 50%.
cyclohexanones, compound 56 was clearly the result of the
hydroxy-mercuration of the 5,6-double bond. Suspecting an
interruption of the catalytic cycle of mercury, we used a
stoichiometric amount of mercury sulfate but 56 was still the
major product of this reaction. The same results were ob-
tained from olefin 51. Three compounds 53, 55, and 57 were
formed in a 1:1:2 ratio in 84% yield. The hydration product
57 again predominated. It should be emphasized that
carbocyclization occurred without notable diastereoselection
in contrast with other reported cases where one isomer is
formed preferentially and even exclusively.
The formation of hydration products 56 and 57, which are
rarely observed in the Ferrier carbocyclization, may be due
to the involvement of the aglycon into a tricyclic ring system.
This arrangement should preclude the formation of the free
aldehyde group needed for carbocyclization. The reaction is
then considerably slowed down so that the intermediate
mercury species did cyclize but was hydrolysed to the
© 2000 NRC Canada

Taillefumier and Chapleur
713
Fig. 3. Possible transition states for the Ferrier carbocyclization
Fig. 2. Transition states of the IMDA cyclization of 38 and 39.
of 51.
hydration products. Such hydration products have been ob-
served by Blattner et al. (37) in the carbocyclization of 5,6-
unsaturated pyranose having a benzoate group at the
anomeric position. Hydration was believed to proceed by
hydrolysis of the postulated intermediate 6-mercuriated spe-
cies. This difficulty was overcome by using a stoichiometric
amount of mercuric acetate to catalyse the carbocyclization.
These conditions were tested on compounds 51 and a mix-
ture of 53, 55, and 57 in a 2.5:1:1.7 ratio was obtained. It is
worthy of note that the main product 53 has a “3,5-trans”
(cyclohexanone numbering) relative stereochemistry which
prevails in most of the reported Ferrier carbocyclizations
(38).
Examination of the structure of compounds 56 and 57
shows that all requirements needed to perform an intramole-
cular aldol reaction, i.e., the keto group at C-5 and aldehyde
at C-1, were present. We thus examined the possibility of
going from compound 57 to carbocycles 53 or 55 without
the use of mercury catalysis. After some experiments, we
found that basic conditions in a protic medium, Na2CO3,
DBU in THF/MeOH were well suited to transform com-
pound 57 into aldol 53 as a single isomer in 50% yield and
50% recovered starting material. No attempt was made at
this time for the cyclization of 56. The structure of com-
pound 53 was firmly established by single crystal X-ray dif-
fraction (17). The absolute configurations at C-1, C-4, C-5,
C-5a, and C-8a (See Scheme 5) which were tentatively as-
signed by NMR were thus confirmed. The complete
stereocontrol of the IMDA reaction which occurred in the
exo mode with attack of the diene from the bottom face of
the dienophile was confirmed by the configuration of C-5.
Moreover, this configuration was that of the mevinic acids
(see Fig. 2).
erentially (38). On the other hand, it has been shown that the
stereochemistry at C-5 of the formed cyclohexanone can be
correlated with the conformation of the starting sugar (36).
Several mechanistic explanations for this phenomenon have
been proposed. One explanation is based on a chelation by a
mercury atom of the oxygen atoms of both the aldehyde and
the ketone groups involved in this aldol-type reaction (39,
40). A chair transition state in which these carbonyl groups
occupy two axial positions (see TS1, Fig. 3) should be fa-
voured over a twisted transition state in which the two car-
bonyl groups are pseudo-equatorial. Another explanation
involves a chelation between the mercury atom linked to C-
6 and the substituent at C-3 (carbohydrate numbering) lead-
ing to a boat transition state in which the two carbonyl
groups are located on the opposite side of the C-3
substituent. This explanation is supported by the absence of
stereoselectivity in the Ferrier carbocyclization of 3-deoxy
sugars (38).
The C-2—C-3 and C-8—C-9 bonds in compounds 51 or
50 are in a trans relationship which forces these groups to be
only in equatorial orientations. Thus, the conformation of
the unsaturated pyranose ring is more or less fixed and
1
should adopt only the C4 conformation or the 2,5B confor-
mation. In compound 51, the chair conformation places the
C-4 OMOM substituent in an equatorial orientation and
should be favoured over the boat conformation. This is con-
It is worthy of note that the conformation of the decalone
ring of 53 in the solid state as shown by X-ray crystal struc-
ture (17) is opposite to that determined on the basis of the
1H NMR spectrum. The OH group was found to be in an
1
firmed by the coupling constant value in the H NMR spec-
trum of 51 (J3,4 = 10.5 Hz). On this basis, according to
Machado et al. (36), it could be predicted that the major
isomer would be compound 53. The boat transition state
involving chelation of the substituent at C-3 cannot be in-
voked in our case because of the absence of such a chelating
group and because of the conformational bias. The transition
state TS1 leading to 53 should be a chair having the two ox-
ygen chelated by mercury in an axial orientation.
To explain the substantial amount of the other isomer 55,
two possibilities can be envisioned. In the first one, the
conformation of the intermediate resulting from the opening
of the acetal function changes so that the orientation of the
carbonyl groups are reversed and thus the aldehyde is then
attacked from the other face via transition state TS3 (Fig. 3).
Another, maybe better, explanation takes into account the
equatorial orientation in solution as shown by the large J2,3
=
10.3 Hz and J3,4 = 9.5 Hz in benzene solution, which are
typical of trans diaxial arrangement of these protons. The
smaller values of these coupling constants in DMSO sug-
gested that, in this solvent, a conformational equilibrium
should take place. Molecular mechanics calculations per-
formed on the two conformers have shown that the energy
difference between these two conformers was less than
1.5 kcal/mol.
Formation of a single isomer in the carbocyclization of 57
to 53 deserves comments. Usually Ferrier carbocyclization
gives high diastereoselection, the product having a 3,5 trans
arrangement (cyclohexanone numbering) being formed pref-
© 2000 NRC Canada

714
Can. J. Chem. Vol. 78, 2000
Fig. 4. Possible transitions states for the ring closure of 57.
yielded compound 11 (1,59 g, 0.51 mmol, 85%) as a white
solid; mp 140–142°C (lit. (22) = 144–145°C). Rf 0.50 (hex-
22
ane/EtOAc, 7:3). [α]D –89.7° (c 1.0, CHCl3) (lit. (22) =
22
1
value [α]D –85.7° (c 0.6, CHCl3). H NMR (CDCl3) δ:
3.43 (s, 3 H, OCH3), 3.72–3.90 (m, 3 H, H-4, H-6 and H-6′),
4.36 (m, 1 H, H-5), 4.78 (d, 1 H, J2,3 7.0 Hz, H-2), 5.07 (m,
1H, H-3), 5.10 (s, 1 H, H-1), 5.60 (s, 1 H, PhCH), 7.33–
7.53 (m, 5 H, Ph). 13C NMR (CDCl3) δ: 55.75 (OCH3),
59.52, 69.04, 77.97, 79.54, and 80.42 (C-2, C-3, C-4, C-5,
and C-6), 96.62 (C-1), 102.11 (OCHPhO), 126.39 (Ph),
128.62 (Ph), 129.66 (Ph), 136.67 (Ph), 189.69 (C=S). Anal.
calcd. for C15H16O6S: C 55.54, H 4.97, S 9.88; found: C
55.71, H 5.05, S 9.77.
presence of the hydroxyl group at C-7 which can be in-
volved in a chelation with the aldehyde group and mercury
so that again the Si face of the aldehyde is presented to the
attacking carbon atom in TS2 leading to 55. In both hypoth-
eses the presence of the bicyclic system or the hydroxyl
group are responsible for the absence of selectivity. Support
of this assumption is given by the fact that the aldol reaction
conducted in basic medium in the absence of mercury is
highly selective and probably involves a transition state in
which the steric interactions rather than chelation govern the
stereochemical course. As shown on Fig. 4, two transition
states should be devised leading to both isomers but TS4, in
which the carbonyl group points upwards is likely favoured
over TS5 in which strong 1,3-diaxial interactions between
the carbonyl and the methylene groups may exist.
Methyl-4,6-O-phenylmethylene-3-O-phenylthionocar-
bonyl-α-D-mannopyranoside (12)
Methyl-4,6-O-phenylmethylene-α-D-mannopyranoside
(980 g, 3.5 mmol) was dissolved in an anhydrous CH2Cl2–
acetone–pyridine (4:2:1) mixture (35 mL) under nitrogen. To
this solution cooled to 0°C was added dropwise phenyl
chlorothionoformate (0.50 mL, 3.85 mmol, 1.1 equiv.). After
being stirred for 2 h the reaction mixture was quenched with
ethanol and solvents were evaporated under reduced pres-
sure. The residue was diluted with CH2Cl2, washed with wa-
ter until neutral, dried over Na2SO4, and concentrated in
vacuo. At this stage, TLC revealed the presence of a single
product (Rf 0.22 (hexane–EtOAc, 7:3)). The crude product
was chromatographed on silica gel to afford the expected
compound 12 (800 mg, 1.91 mmol, 54%) accompanied with
the cyclic thionocarbonate 11 (400 mg, 1.28 mmol, 36%),
the latter being formed during purification. Rf 0.22 (hexane–
EtOAc, 7:3). 1H NMR (CDCl3) δ: 2.60 (br s, 1 H, OH), 3.43
(s, 3 H, OCH3), 3.41–3.80 (m, 2 H, H-5 and H-6), 4.27–4.39
(m, 2 H, J4,5 9.5 Hz, H-4 and H-6′), 4.47 (br s, 1 H, H-2),
4.81 (d, 1 H, J1,2 1.5 Hz, H-1), 5.61 (s, 1 H, PhCH), 5.79
(dd, 1 H, J2e,3a 3.0; J3a,4a 10.0 Hz, H-3), 7.05–7.54 (m, 10 H,
Ph).
Experimental
All reactions were performed under nitrogen atmosphere.
Melting points are uncorrected and recorded with a Büchi
capillary tube melting-point apparatus. Optical rotations were
measured on a Perkin Elmer 141 polarimeter in a 1 dm cell
at 20°C. FTIR spectra were recorded on a Perkin–Elmer
Spectrum 1000 on NaCl windows or KBr pellets. Unless
1
otherwise stated H NMR and 13C spectra were recorded on
a Bruker AC 250 spectrometer at 250 MHz and 62.5 MHz
respectively. 400 MHz 1H NMR were recorded on a Bruker
AC 400 spectrometer. Chemical shifts are reported in ppm
using the residual of chloroform as internal standard
(7.27 ppm and 77.0 ppm respectively). Attribution of 13C
signals are based on the J-modulated spin-echo sequence.
Analytical thin-layer chromatography were performed on Merck
60F254 precoated silica gel glass plates. Compounds were
visualized on developed plates by UV light followed by
charring with 10% H2SO4 in methanol. Preparative chroma-
tography was performed on silica gel 60 (230–40 mesh ASTM)
using ethyl acetate and hexane mixtures or by high pressure
liquid chromatography using Merck silica gel 60H (45µM).
Methyl 3-deoxy-4,6-O-phenylmethylene-α-D-arabino-
hexopyranoside (13)
(i) By radical deoxygenation of 12: To a solution of
phenylthionocarbonate (12) (400 mg, 0.95 mmol) in de-
gassed toluene (20 mL) under nitrogen was added in one
portion AIBN (200 mg, 1.21 mmol, 1.2 equiv.). To the re-
sulting mixture was added dropwise tris(trimethylsilyl)silane
(0.38 mL, 1.23 mmol, 1.26 equiv.). The solution was then
heated to reflux and after 40 min, TLC (hexane–EtOAc, 7:3)
indicated complete reduction of the starting material. The
solution was cooled and concentrated under reduced pres-
sure. The residue was chromatographed on silica gel to give
pure deoxy-compound 13 (170 mg, 0.64 mmol, 68%) as a
white solid.
(ii) By epoxide opening: To 180 mg (4.7 mmol, 3.5 equiv.)
of LiAlH4 suspended in dry THF (20 mL) was added drop-
wise a solution of epoxide 20 (350 mg, 1.32 mmol) in dry
THF. The resulting mixture was stirred for 18 h at 50°C and
then treated successively with water (0.18 mL), aqueous 30%
NaOH (0.54 mL), and water (0.54 mL). The salts were fil-
tered off through a pad of Celite, washed with hot THF. The
solvent was removed and the residue was chromatographed
on silica gel with hexane/EtOAc (1:1) as eluent to give 13 in
Methyl-4,6-O-phenylmethylene-2,3-thionocarbonyl-α-D-
mannopyranoside (11)
To a solution of methyl-4,6-O-phenylmethylene-α-D-man-
nopyranoside (1,69 g, 6 mmol) in anhydrous methanol (200 mL)
was added dibutyltin oxide (4.2 g, 16.8 mmol, 2.8 equiv.).
The solution was heated at reflux for 4 h. Methanol was re-
moved under vacuum, the residue was diluted with DMF
(40 mL) and PTCCl (2.5 mL, 18 mmol, 3 equiv.) was added.
The mixture was stirred at 100°C for 0.5 h then quenched
with methanol and concentrated in vacuo. The residue was
diluted with CH2Cl2, washed successively with 3 N aqueous
NaOH, brine, dried over Na2SO4 and concentrated in vacuo.
Chromatography on silica gel with n-hexane–EtOAc (9:1)
© 2000 NRC Canada

Taillefumier and Chapleur
715
nearly quantitative yield, mp 109°C (lit. (26) mp 111–
(hexane–EtOAc, 4:1). [α]D22 +70.8 (c 0.70, CHCl3). IR (cm–1):
1722. H NMR (250 MHz, CDCl3) δ: 2.07 (ddd, 1 H, Jgem
22
1
112°C. Rf 0.31 (hexane–EtOAc, 3:2). [α]D +95.5 (c
22
0.81, CHCl3) (lit. (26) [α]D +107.3° (c 0.94, CHCl3)). IR
13.5, J2,3a 3.0, J3a,4 11.0 Hz; H-3a), 2.35 (ddd, 1 H, J2,3e 3.5,
J3e,4 4.5 Hz, H-3e), 3.28 (s, 3 H, CH2OCH3), 3.41 (dd, 1 H,
Jgem 10.0, J5,6 6.5 Hz, H-6), 3.48 (s, 3 H, OCH3), 3.52 (m, 1
H, H-5), 3.61 (dd, 1 H, J5,6′ 2.5 Hz, H-6′), 3.80 (ddd, 1 H,
J4,5 9.5 Hz, H-4), 4.69 (m, 2 H, Jgem 7.0 Hz, CH2OCH3),
4.72 (br s, 1 H, H-1), 5.15 (ddd, 1 H, J1,2 2.0 Hz, H-2),
7.40–8.12 (m, 5 H, Ph). 13C NMR (CDCl3) δ: 7.88 (C-6),
30.05 (C-3), 55.18, and 55.76 (2 × OCH3) 70.05, 70.45,
72.43 (C-2, C-4, and C-5), 95.65, 97.59 (C-1 and
OCH2OCH3), 128.37 (Ph), 129.79 (Ph), 133.20 (Ph), 165.46
(C=O). EIMS: 405 (M-OCH3), 309 (M-I) 233 (100%), 221.
Anal. calcd. for C16H21IO6: C 44.05, H 4.85, I 29.06; found:
C 44.36, H 4.95, I 28.54.
1
(cm–1): 3452 (OH). H NMR (CDCl3) δ: 1.99–2.18 (m, 2 H,
2 × H-3), 3.41 (s, 3 H, OCH3), 3.73–4.04 (m, 4 H, H-2, H-5,
and 2 × H-6), 4.25 (m, 1 H, H-4), 4.55 (s, 1 H, H-1), 5.58 (s,
1 H, PhCH), 7.31–7.52 (m, 5 H, Ph).
Methyl 2-O-benzoyl-3-deoxy-α-D-arabino-hexopyranoside (15)
To a solution of alcohol 13 (413 mg,1.55 mmol) in dry
pyridine (15 mL) under argon was added dropwise benzoyl
chloride (1.86 mmol, 1.2 equiv.). After being stirred over-
night, pyridine was evaporated and the residue was
codistillated three times with toluene to provide the expected
crude benzoate as a crystalline solid. It was dissolved in a
mixture of ethanol–water (10:1, 55 mL) and three drops of
12 N HCl were added. After 3 h at reflux the reaction was
over. The pH was adjusted to 7 with aqueous 3 N NaOH, the
solvent was evaporated under reduced pressure and the resi-
due was taken up in CH2Cl2. The organic layer was washed
with saturated aqueous NaHCO3 and water, dried over
Na2SO4, and concentrated in vacuo. Chromatography on sil-
ica gel with hexane–EtOAc as eluent yielded diol 15
(294 mg, 1.04 mmol 67%)as a white solid, mp 105°C (lit.
Methyl 4-O-benzoyl-6-bromo-3,6-dideoxy-α-D-arabino-
hexopyranoside (21)
Compound 13 (350 mg, 1.31 mmol) was dissolved in dry
CCl4 (20 mL) under argon and N-bromosuccinimide
(250 mg, 1.44 mmol, 1.1 equiv.) and calcium carbonate
(140 mg, 1.44 mmol, 1.1 equiv.) were added successively.
The mixture was refluxed for a few minutes. The resulting
orange mixture was diluted with CH2Cl2, washed succes-
sively with aqueous 10% NaHSO3 and water, dried over
MgSO4, and concentrated in vacuo. Chromatography on sil-
ica gel eluting with hexane–EtOAc (7:3) gave compound 21
(447 mg, 1.29 mmol, 98%) as a gum. Rf 0.47 (hexane–
22
(41) mp 109°C). Rf 0.39 (hexane–EtOAc, 1:4). [α]D +49.4
(c 0.37, CHCl3) (lit. (41)value [α]D22 +52.2° (c 1.1, CHCl3)).
1H NMR (CDCl3) δ: 2.05 (ddd, 1 H, Jgem 14.0, J2,3a 3.0, J3a,4
11.5 Hz, H-3a), 2.26 (ddd, 1 H, J2,3e 3.5, J3e,4 5.0 Hz, H-3e),
2.40–2.90 (m, 2 H, 2 × OH), 3.43 (s, 3 H, OCH3), 3.67
(ddd, 1 H, J4,5 10.0, J5,6 4.5, J5,6 ′5.0 Hz, H-5), 3.83–3.97 (m,
2 H, H-6 and H-6′), 4.10 (ddd, 1 H, H-4), 4.71 (br s, 1 H, H-
1), 5.16 (m, 1 H, J1,2 1.5 Hz, H-2), 7.40–8.12 (m, 5 H, Ph).
22
EtOAc, 3:2). [α]D +87.6 (c 0.59, CHCl3). IR (cm–1): 3462
1
(OH), 1720 (C=O), 1601. H NMR (CDCl3) δ: 2.04 (ddd, 1
H, Jgem 13.0, J2,3a 3.0, J3a,4 12.0 Hz, H-3a), 2.33 (ddd, 1 H,
J2,3e 4.0, J3e,4 4.5 Hz, H-3e), 3.40–3.54 (m, 4 H, J5,6 7.5 Hz,
H-6 and OCH3), 3.58 (dd, 1 H, Jgem 11.0, J5,6′ 2.5 Hz, H-6′),
3.94 (m, 1 H, J1,2 2.0 Hz, H-2), 4.10 (m, 1 H, H-5), 4.67
(br s, 1 H, H-1), 5.26 (ddd, 1 H, J4,5 10.5 Hz, H-4), 7.40–
8.10 (m, 5 H, Ph). Anal. calcd. for C14H17BrO5: C 48.71, H
4.96, Br 23.14; found: C 48.92, H 5.03, Br 22.84.
Methyl 2-O-benzoyl-3,6-dideoxy-6-iodo-α-D-arabino-
hexopyranoside (16)
A mixture of diol 15 (483 mg, 1.71 mmol), triphenyl-
phosphine (0.61 g, 2.32 mmol, 1.5 equiv.), imidazole (0.31 g,
4.65 mmol, 3 equiv.), and iodine (0.47 g, 1.86 mmol, 12 equiv.)
in dry toluene (30 mL) was vigorously stirred at 55°C for 4 h.
Toluene was evaporated and the residue was taken up in
CH2Cl2, washed successively with aqueous 0.5 N HCl, aque-
ous 1 N NaHCO3, and water. The organic layer was dried over
MgSO4 and concentrated in vacuo. Chromatography on silica
gel eluting with hexane–EtOAc (4:1) gave the iodo-derivative
16 (503 mg, 1.28 mmol, 82%). Rf 0.27 (hexane–EtOAc, 4:1). [
Methyl 2,6-anhydro-4-O-benzoyl-3-deoxy-α-D-arabino-
hexopyranoside (22)
Compound 21 (370 mg, 1.07 mmol) was suspended in dry
pyridine (20 mL) with AgF (227 mg, 1.78 mmol, 1.7 equiv.)
and the mixture was stirred overnight in the dark without any
evolution. An additional amount of AgF (200 mg, 1.57 mmol)
was added and the suspension was stirred at 80°C for 4 h. The
mixture was then diluted with EtOAc, filtered off through
Celite, and the solvent was evaporated. Chromatography of the
brown residue with hexane–EtOAc (4:1) as eluent yielded 22
(80 mg, 0.30 mmol, 28%), mp 57–58°C, and starting material
(129 mg, 0.37 mmol, 36%). Rf 0.54 (hexane–EtOAc, 3:2).
22
1
α]D +77.5 (c 0.85, CHCl3). IR (cm–1): 3466, 1720. H NMR
(CDCl3) δ: 2.06 (ddd, 1 H, Jgem 13.5, J2,3a 3.0, J3a,4 11.5 Hz H-
3a), 2.25 (ddd, 1 H, J2,3e 4.0, J3e,4 5.0 Hz, H-3e), 3.37–3.55 (m,
5 H, OCH3, H-5, H-6 and H-6′), 3.88 (m, 1 H, H-4), 4.73
(br s, 1 H, H-1), 5.15 (m, 1 H, H-2), 7.22–7.65 and 8.01–8.12
(m, 5 H, Ph). 13C NMR (CDCl3) δ: 8.06 (C-6), 32.51 (C-3),
55.30 (OCH3), 66.75, 70.75, 72.36 (C-2, C-4 and C-5), 97.65
(C-1), 128.54 (Ph), 129.84 (Ph), 133.47 (Ph), 165.79 (C=O).
Anal. calcd. for C14H17O5I: C 42.87, H 4.36, I 32.35; found: C
42.36, H 4.43, I 32.52.
22
[α]D +20.0° (c 0.24, CHCl3). IR (cm–1): 1715 (C=O), 1602.
1H NMR (CDCl3) δ: 2.26 (m, 1 H, H-3e), 2.45 (ddd, 1 H, Jgem
14.5, J2,3a 3.5, J3a,4 10.0 Hz, H-3a), 3.51 (s, 3 H, OCH3), 3.79–
3.89 (m, 2 H, 2 × H-6), 4.07 (m, 1 H, J5,6 10.0, J4,5 3.0 Hz, H-
5), 4.20 (m, 1 H, H-2), 5.06 (br d, 1 H, J1,2 3.0 Hz, H-1), 5.10
(ddd, 1 H, J3e,4 2.5 Hz, H-4), 7.40–7.43 and 8.06–8.15 (m, 5H,
Ph). 13C NMR (CDCl3) δ: 28.57 (C-3), 54.93 (OCH3), 65.33,
65.99, 67.31, 69.00 (C-2, C-4, C-5, and C-6), 99.76 (C-1),
128.41 (Ph), 129.79 (Ph), 130.25 (Ph), 133.12 (Ph), 166.27
(C=O). EIMS: 263 (M-H), 246, 233 (M-OCH3), 204, 175, 142,
Methyl 2-O-benzoyl-3,6-dideoxy-6-iodo-4-O-
methoxymethyl-α-D-arabino-hexopyranoside (17)
The alcohol 16 (4.0 g, 10.20 mmol) was protected as the
methoxymethylether according to the procedure described
for the preparation of 24 (3.16 g, 7.25 mmol, 71%). Rf 0.59
© 2000 NRC Canada

716
Can. J. Chem. Vol. 78, 2000
105. Anal. calcd. for C14H16O5: C 63.62, H 6.10; found: C
63.51, H 6.15.
butenal (3.78 mL, 39.13 mmol) in dry THF (225 mL) under
argon was refluxed for 24 h. The solvent was evaporated
and the residue was chromatographed with hexane–EtOAc
(10:0.3) to afford the expected diene (4.77 g, 30.93 mmol,
80%) as an oil. Saponification of the ester function of the
latter was carried out using one equiv. of aqueous 1 N
NaOH in reflux methanol. The mixture was concentrated
and the residue was acidified with 3 N aqueous HCl. The
expected carboxylic acid was extracted with ether and then
transformed into its carboxylate sodium salt with 1 N
NaOH. The aqueous layer was acidified with 3 N HCl and
extracted with ether. The organic layer was dried over
MgSO4 and concentrated in vacuo to provide the carboxylic
acid 30 (3.11 g, 24.74 mmol, 80%) which was used in the
next step without further purification.
Methyl 2-O-benzoyl-3,6-dideoxy-α-D-threo-hex-5-
enopyranoside (23)
Silver fluoride (0.45 g, 3.59 mmol, 1.5 equiv.) was sus-
pended in dry pyridine (25 mL) containing the iodo-
derivative 16 (940 mg, 2.39 mmol). Stirring was maintained
overnight, in the dark and the mixture was poured in EtOAc
(200 mL). After filtration of the salts, the solvent was evapo-
rated and the brown residue was chromatographed with hex-
ane–EtOAc (7:3) to yield derivative 23 (332 mg, 1.25 mmol,
1
52%). Rf 0.27 (hexane–EtOAc, 7:3). H NMR (CDCl3) δ:
2.13 (ddd, 1 H, Jgem 13.5, J2,3a 3.0, J3a,4 11.0 Hz, H-3a), 2.30
(ddd, 1 H, J2,3e 3.5, J3e,4 6.0 Hz, H-3e), 3.50 (s, 3 H, OCH3),
4.55 (m, 1 H, H-4), 4.72 (br s, 1 H, H-1), 4.80 (br s, 1 H,
H-6), 4.82 (br s, 1 H, H-6′), 5.24 (m, 1 H, J1,2 2.5 Hz, H-2),
7.40–8.12 (m, 5 H, Ph).
4-Methyl-3,5-hexadienoic acid (31)
A solution of lithium diisopropylamide (2.2 equiv.) in THF
was prepared by the slow addition of n-BuLi (46.80 mmol in
hexane) to a solution of diisopropylamine (6.60 mL,
46.80 mmol) in dry THF (30 mL) under N2. The solution
was cooled to –80°C and dry hexamethyl phosphoramide
(8.15 mL, 46.80 mmol) was added dropwise and the mixture
allowed to stir for 0.5 h. Diene 30 (3.28 g, 21.28 mmol) was
added to the cooled solution over 1h. Stirring was main-
tained an additional hour at –80°C and the mixture was
transferred into a rapidly stirred solution of acetic acid
(6.5 g) in water (130 mL). The resulting solution was ad-
justed to pH 1 with 3 N HCl and extracted with Et2O. The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. Chromatography on silica gel with hex-
ane–EtOAc (9:1) as eluent yielded compound 31 (2.13 g,
Methyl 2-O-benzoyl-3,6-dideoxy-4-O-methoxymethyl-α-
D-threo-hex-5-enopyranoside (24)
To a solution of 23 (330 mg, 1.25 mmol) in anhydrous
CH2Cl2 (15 mL) was added successively diisopropyl-
ethylamine (0.87 mL, 5 mmol, 4 equiv.) and MOMCl
(0.19 mL, 2.5 mmol, 2 equiv.). The stirring was maintained
for 12 h under argon and the mixture was diluted with
CH2Cl2. The organic layer was washed with aqueous 3 N
HCl, dried over MgSO4, and concentrated in vacuo. Chro-
matography on silica gel gave 24 (328 mg, 1.06 mmol, 85%)
as a gum. Rf 0.66 (hexane–EtOAc, 7:3). [α]D22 –24.5 (c 0.36,
1
CHCl3). IR (cm–1): 1722, 1662. H NMR (CDCl3) δ: 2.20–
2.29 (m, 2 H, 2 × H-3), 3.40 (s, 3 H, CH2OCH3), 3.50 (s, 3
H, OCH3), 4.45 (br dd, 1 H, H-4), 4.68–4.82 (m, 5 H, H-1, 2
× H-6 and CH2OCH3), 5.26 (br dd, 1 H, H-2), 7.40–8.12 (m,
5 H, Ph). 13C NMR (CDCl3) δ: 31.59 (C-3), 55.27, and
55.60 (2 × OCH3), 68.44, 69.99 (C-2 and C-4), 95.40, 95.45,
99.67 (C-1, OCH2O, and C-6), 128.39 (Ph), 129.75 (Ph),
133.27 (Ph), 155.63 (C-5), 165.47 (C=O). EIMS: 277
(M-OCH3), 247, 233, 221, 215, 105 (100%), 77.
1
13.83 mmol, 65%) as an oil. H NMR (CDCl3) δ: 1.77 (s, 3
H, CH3), 3.24 (d, 2 H, J2,3 7.5 Hz, 2 × H-2), 5.03 (d, 1 H,
J
cis 10.5 Hz, H-6), 5.18 (d, 1 H, Jtrans 17.5 Hz, H-6′), 5.64 (t,
1 H, H-3), 6.41 (dd, 1 H, H-5), 10–11 (br s, 1 H, COOH).
Methyl-3,6-dideoxy-2-O-[4′-methyl-3′,5′-hexadienoyl]-4-
O-methoxymethyl-α-D-threo-hex-5-enopyranoside (26)
To a solution of alcohol 25 (200 mg, 0.98 mmol) in dry
CH2Cl2 were added successively under argon, the carboxylic
acid 31 (285 mg, 2.26 mmol, 2.3 equiv.), a catalytic amount
of DMAP, and DCC (300 mg, 1.5 mmol, 1.5 equiv.) in solu-
tion in CCl4. The mixture was stirred for 1 h and the salts
were filtered off. After evaporation of the solvent, the brown
residue was chromatographed on silica gel eluting with
hexane–EtOAc (20:1) to give compound 26 (273 mg,
Methyl-3,6-dideoxy-4-O-methoxymethyl-α-D-threo-hex-5-
enopyranoside (25)
Ammonia was bubbled through a solution of 24 (328 mg,
1.06 mmol) in MeOH (20 mL) for 5 h. The solvent was
evaporated and the residue was chromatographed on silica
gel with hexane–EtOAc (7:3) to give the alcohol 25 in quan-
22
titative yield. Rf 0.18 (hexane–EtOAc, 7:3). [α]D +44.6 (c
22
1
1.82, CHCl3). IR (cm–1): 3436, 1660. H NMR (CDCl3) δ:
0.87 mmol, 89%). Rf 0.66 (hexane–EtOAc, 7:3). [α]D –9.5
1
(c 1.09, CHCl3). H NMR (CDCl3) δ: 1.77 (s, 3 H, CH3 vi-
1.90 (ddd, 1 H, Jgem 13.5, J2,3 8.0, J3,4 4.5 Hz, H-3), 2.16
(ddd, 1 H, J2,3′ 4.0, J3′,4 6.5 Hz, H-3′), 2.35 (br d, 1 H, OH),
3.37 (s, 3 H, CH2OCH3), 3.53 (s, 3 H, OCH3), 3.94 (ddd, 1
H, H-2), 4.28 (dd, 1 H, H-4), 4.39 (d, 1 H, J1,2 5.5 Hz, H-1),
4.56–4.62 (m, 2 H, Jgem 7.0, H-6 and CHHOCH3), 4.70–4.76
(m, 2 H, H-6′ and CHHOCH3). 13C NMR (CDCl3) δ: 34.36
(C-3), 55.49 and 56.23 (OCH3 and OCH2OCH3), 66.63
(C-2), 68.92 (C-4), 94.00 (OCH2OCH3), 97.65 (C-6), 105.08
(C-1), 155.02 (C-5).
nyl), 2.06–2.14 (m, 2 H, J3,4 = J3′,4 8.0, H-3 and H-3′), 3.24
(m, 2 H, H-8 and H-8′), 3.39 (s, 3 H, CH2OCH3), 3.45 (s, 3
H, OCH3), 4.33 (br dd, 1 H, 4-H), 4.64 (d, 1 H, J1,2 2.5 Hz,
H-1), 4.65–4.76 (m, 4 H, H-6, H-6′ and CH2OCH3), 4.97–
5.05 (m, 2 H, H-2 and H-12), 5.17 (d, 1 H, J11,12′ 17.5 Hz,
H-12′), 5.65 (dd, 1 H, J8,9 7.0, J8′,9 7.5 Hz, H-9), 6.40 (dd, 1
H, J11,12 10.5 Hz, H-11).
(4S, 6S)-4-(4′-Methyl-3′,5′-hexadienoyl)oxy-6-methoxy-
methoxy-cycohex-2-enone (28)
4-Methyl-2,4-hexadienoic acid (30)
A mixture of carbethoxymethyl triphenylphosphorane
(16.36 g, 46.95 mmol, 1.2 equiv.) and (trans) 2-methyl-2-
To a solution of 26 (273 mg, 0.87 mmol) in dioxane
(10 mL) was added HgSO4 (5 mg, 0.017 mmol, 0.02 equiv.)
© 2000 NRC Canada

Taillefumier and Chapleur
717
and 5 mM H2SO4 (2.6 mL). The mixture was stirred at 50°C
for 4 h. The mixture was then cooled to room temperature,
diluted with CH2Cl2, and washed with water until neutral.
The organic layer was dried over MgSO4, concentrated in
vacuo to afford crude 27. To a solution of the latter in
CH2Cl2–pyridine (10:1, 11 mL) mixture under argon at
–10°C was added triflic anhydride (0.15 mL, 0.97 mmol, 1.5
equiv.). The cooled mixture was stirred for 20 min and more
triflic anhydride (0.15 mL) was added. The stirring was con-
tinued for 15 min and the mixture was diluted with CH2Cl2,
washed with aqueous saturated NaHCO3 and brine. The or-
ganic layer was dried over MgSO4, concentrated in vacuo,
and the residue was chromatographed on silica gel eluting
with hexane–EtOAc (4:1) to afford 28 (69 mg, 0.25 mmol,
COCH3), 28.78 (C-2′), 62.96 (C-6), 65.24 (C-4), 66.92
(C-5), 68.05 (C-1′), 94.37 (C-1), 111.13 (C-6′), 127.79 (C-2
or C-3), 128.18 (C-3′), 129.05 (C-2 or C-3), 135.85 (C-4′),
141.12 (C-5′), 170.21 and 170.59 (2 × COCH3).
(E)-(4′-Methyl-3′,5′-hexadien)yl 2,3-dideoxy-α-D-erythro-
hex-2-enopyranoside (35)
Saponification of the acetates of 34 (5.77 g, 17.8 mmol, α
and β mixture (4:1)) was achieved under Zemplen procedure
to give the α-anomer 35 (3.53 g, 14.7 mmol, 82%) separated
from its β-anomer (0.79 g, 3.30 mmol, 18%) by column
chromatography over silica gel using hexane–EtOAc (1:1) as
22
eluent. Rf 0.18 (hexane–EtOAc, 1:1). [α]D +6.1 (c 0.47,
1
CHCl3). IR (cm–1): 3350, 1719, 1601. H NMR (CDCl3) δ:
22
30%) as a gum. Rf 0.76 (hexane–EtOAc, 3:2). [α]D –239.1
1.74 (s, 3 H, CH3 vinyl), 2.10–2.14 (m, 2 H, 2 × OH), 2.45
(m, 2 H, 2 × H-2′), 3.53 (ddd, 1 H, Jgem 9.5, J = J′ 7.0 Hz,
H-1′a), 3.70 (ddd, 1 H, J4,5 9.0, J5,6 = J5,6′ 4.5 Hz, H-5),
3.74–3.92 (m, 3 H, H-6, H-6′ and H-1′b), 4.21 (dd, 1 H, J2,4
1.0 Hz, H-4), 4.90–5.01 (m, 2 H, H-1 and H-6′a), 5.10 (d, 1 H,
Jtrans 17.5 Hz, H-6′b), 5.48 (dd, 1 H, J 7.5, J′ 8.0 Hz, H-3′),
5.74 (ddd, 1 H, J2,3 10.0, J3,4 2.5, J1,3 2.0 Hz, H-3), 5.95 (br
1
(c 0.32, CHCl3). H NMR (CDCl3) δ: 1.79 (s, 3 H, CH3 vi-
nyl), 2.31 (ddd, 1 H, Jgem 13.5, J4,5 5.5, J5,6 5.0 Hz, H-5),
2.45 (ddd, 1 H, J4,5′ 4.5, J5′,6 8.5 Hz, H-5′), 3.24 (m, 2 H, H-2′a
and H-2′b), 3.39 (s, 3 H, CH2OCH3), 4.36 (dd, 1 H, H-6),
4.71 (d, 1 H, Jgem 7.0 Hz, CHHOCH3), 4.80 (d, 1 H,
CHHOCH3), 5.03 (d, 1 H, Jcis 10.5 Hz, H-6a′), 5.18 (d, 1 H,
Jtrans 17.5 Hz, H-6′b), 5.58–5.73 (m, 2 H, H-4 and H-3′),
6.07 (br d, 1 H, J2,3 10.5 Hz, H-2), 6.40 (dd, 1 H, H-5′),
6.84 (dd, 1 H, J3,4 4.0 Hz, H-3). Anal. calcd. for C15H20O5:
C 64.27, H 7.19; found: C 64.15, H 7.04.
d, 1 H, J1,2 1.5 Hz, H-2), 6.36 (dd, 1 H, Jcis 11.0 Hz, H-5′). 13
C
NMR (CDCl3) δ: 11.79 (CH3 vinyl), 28.86 (C-2′), 62.27 (C-
6), 63.70 (C-4), 67.96 (C-1′), 71.52 (C-5), 94.34 (C-1),
111.26 (C-6′), 125.93 (C-3), 128.30 (C-3′), 133.41 (C-2),
135.89 (C-4′), 141.14 (C-5′).
Thermal cycloaddition of 28: A solution of enone 28
(69 mg, 0.25 mmol) and hydroquinone (10 mg, 0.09 mmol,
0.37 equiv.) in degassed toluene (10 mL) was placed in a
sealed tube and heated at 135°C for 6 h, 165°C for 12 h, and
220°C for 12 h. At the end of each period of heating, the
(E)-(4′-Methyl-3′,5′-hexadien)yl 2,3-dideoxy-6-(2,2-
dimethylpropionyl)-α-D-erythro-hex-2-enopyranoside (36)
To a stirred solution of diol 35 (3.5 g, 14.5 mmol) in a
CH2Cl2–pyridine (1:1.5, 25 mL) mixture was added
dropwise, under argon at –5°C pivaloyl chloride (1.79 mL,
17.4 mmol, 1.2 equiv.). The solution was stirred for 1.30 h
and a further amount of pivaloyl chloride (0.35 mL,
2.9 mmol, 0.2 equiv.) was added. Stirring for 2 additional h
was followed by quenching with water and extractive work-
up (CH2Cl2). The organic layer was dried over Na2SO4, con-
centrated in vacuo, and chromatographed with hexane–
EtOAc (4:1) to give the ester 36 (2.96 g, 2.13 mmol, 63%)
1
crude mixture was analyzed by H NMR spectroscopy, but
no cycloadduct compound was detected. After concentration
in vacuo, the residue was chromatographed on silica gel
eluting with hexane–EtOAc (85:15) to afford the starting
material (20 mg, 0.075 mmol, 30%) and a more polar prod-
uct resulting from the splitting of the MOM protecting group
(25 mg, 0.10 mmol, 44%).
(E)-(4′-Methyl-3′,5′-hexadien)yl 2,3-dideoxy-4,6-di-O-
acetyl-α-D-erythro-hex-2-enopyranoside (34)
22
as a gum. Rf 0.25 (hexane–EtOAc, 4:1). [α]D +3.5 (c 1.09,
CHCl3). IR (cm–1): 3455, 1733, 1713, 1600. 1H NMR
(CDCl3) δ: 1.25 (s, 9 H, CO(CH3)3), 1.75 (s, 3 H, CH3 vi-
nyl), 2.45 (m, 2 H, 2 × H-2′), 3.53 (ddd, 1 H, Jgem 14.0, J =
J′ 7.0 Hz, H-1′a), 3.75–3.87 (m, 2 H, H-5 and H-1′b), 3.98
(m, 1 H, J4,5 9.5 Hz, H-4), 4.25 (dd, 1 H, J5,6 2.0, Jgem
12.5 Hz, H-6), 4.45 (dd, 1 H, J5,6′ 5.0, H-6′), 4.92 –5.01 (m,
2 H, H-1 and H-6′a), 5.11 (d, 1 H, Jtrans 17.5, H-6′b), 5.48
(t, 1 H, J 7.0 Hz, H-3′), 5.74 (m, 1 H, J2,3 10.0, J3,4 2.5 Hz,
H-3), 5.95 (m, 1 H, H-2), 6.36 (dd, 1 H, Jcis 11.0 Hz, H-5′).
To a stirred solution of tri-O-acetyl-D-glucal (5.71 g,
21 mmol) and homoallylic alcohol 33 (2.7 g, 24 mmol, 1.15
equiv.) in anhydrous CH2Cl2 (200 mL) was added under ar-
gon boron trifluoride ethyl etherate (21 drops) over a period
of 3.30 h. At the end of the addition the resulting brown
mixture was quenched with pyridine (1 mL) and washed
successively with aqueous saturated NaHCO3 and brine. The
organic layer was dried over MgSO4, concentrated in vacuo,
and chromatographed with hexane–EtOAc (4:1) to give an
unseparable mixture of α and β-glycosides (34) in a 4:1 ra-
tio (5.77 g, 17.8 mmol, 84%). Rf 0.35 (hexane–EtOAc, 4:1).
[2R-[2α ,6 β(E)]] 2,2-Dimethyl-[3,6-dihydro-6-[(4′-
methyl-3′,5′-hexadienyl)oxy]-3-oxo-2H-pyran-2-
yl]methyl ester propanoic acid (38)
22
[α]D +69.6 (c 3.0, CHCl3). IR (cm–1): 1744, 1643, 1606,
1
1234. α anomer: H NMR (CDCl3) δ: 1.75 (s, 3 H, CH3
vinyl), 2.07 (s, 6 H, 2 × COCH3), 2.44 (t, 1 H, J 7.0, H-2′a),
2.47 (dd, 1 H, J 7.0, H-2′b), 3.55 (ddd, 1 H, J 9.5 Hz, H-1′a),
3.78 (ddd, 1 H, J 9.5 Hz, H-1′b), 4.10 (m, 1 H, H-5), 4.17–
4.30 (m, 2 H, 2 × H-6), 4.96 (d, 1 H, Jcis 10.5 Hz, H-6′a),
5.11 (d, 1 H, Jtrans 17.5 Hz, H-6′b), 5.03 (br s, 1 H, H-1),
5.31 (dd, 1 H, J4,5 10.0, J3,4 1,5 Hz, H-4), 5.50 (dd, 1 H, H-3′),
5.77–5.98 (m, 2 H, H-2 and H-3), 6.37 (dd, 1 H, H-5′). 13C
NMR (CDCl3) δ: 14.05 (CH3 vinyl), 20.69 and 20.75 (2 ×
(i) PDC oxidation: Freshly prepared pyridinium dichro-
mate (1.57 g, 4.2 mmol, 1.38 equiv.) was suspended in dry
CH2Cl2 (1.5 mL) containing the alcohol 36 (1.0 g, 3.08 mmol).
The mixture was stirred for 20 h, a further amount of PDC
(300 mg, 0.80 mmol, 0.26 equiv.) was added, and stirring
was still maintained for 12 h. The mixture was diluted with
hexane and the salts were filtered off through Celite, washed
with a mixture of CH2Cl2 and hexane. After concentration of
© 2000 NRC Canada

718
Can. J. Chem. Vol. 78, 2000
the filtrate, the residue was chromatographed on silica gel
eluting with hexane–EtOAc (9:1) to give the expected
ketone 38 (545 mg, 1.69 mmol, 55%) as a gum.
purification on silica gel eluting with hexane–EtOAc (3:1).
Rf 0.29 (hexane–EtOAc, 1:1). IR (cm–1): 3424, 1720. 1H
NMR (CDCl3) δ: 1.42 (m, 1 H, J6a,7 12.5 Hz, H-7), 1.61 (s,
3 H, CH3 vinyl), 1.94 (m, 1 H, Jgem 13 Hz, H-7′), 2.08 (m, 1
H, H-4), 1.18–2.30 (m, 2 H, H-6a and H-9b), 2.80 (m, 1 H,
Jgem 18.5 Hz, H-4′), 2.91 (m, 1 H, J3a,9b 3.5 Hz, H-3a), 3.80
(ddd, 1 H, J7,8′ 4.5, J7′,8′ 1.5 Hz, H-8′), 4.05 (ddd, 1H, Jgem
11.5, J7,8 11.5, J7′,8 3.5 Hz, H-8).
Compound 42 and 43: To a suspension of LiAlH4
(430 mg, 11.3 mmol, 1.45 equiv.) in dry THF (90 mL) at
0°C under argon was added dropwise 40 (2.55 g,
7.75 mmol) in THF (2 mL). After the completion of the ad-
dition, the mixture was allowed to warm-up to room temper-
ature and the stirring was continued for 4 h. To this mixture
was then added at 0°C, water (0.45 mL), 30% aqueous
NaOH (1.35 mL), and water (1.35 mL). Filtration over a pad
of celite and washing the cake of salts with hot THF fol-
lowed by concentration and purification on silica gel gave
the diastereomeric mixture of 42 and 43 in a 1.7:1 ratio
(1.62 g, 6.74 mmol, 87%). An analytical sample of this mix-
ture was purified by preparative HPLC to separate the two
diastereoisomers.
(ii) Activated MnO2 oxidation: Freshly prepared manga-
nese dioxide (25 g) was suspended in dry carbon tetrachlo-
ride (350 mL) containing the alcohol 36 (3.0 g, 9.25 mmol).
The resulting mixture was vigorously stirred for 3 h. Filtra-
tion over a pad of Celite and evaporation of the filtrate gave
a residue which was chromatographed on silica gel eluting
with hexane–EtOAc (9:1) to afford 38 (2.68 g, 8.32 mmol,
22
90%) as a gum. Rf 0.51 (hexane–EtOAc, 4:1). [α]D –131.6
(c 0.58, CHCl3). 1H NMR (CDCl3) δ: 1.17 (s, 9 H,
CO(CH3)3), 1.75 (s, 3 H, CH3 vinyl), 2.48 (m, 2 H, 2 × H-
2′), 3.63 (ddd, 1 H, Jgem 9.5, J 6.5, J′ 7.0, H-1′a), 3.86 (ddd,
1 H, J = J′ 7.0 Hz, H-1′b), 4.42 (dd, 1 H, Jgem 12.0, J
5.5 Hz, CHHOCO(CH3)3), 4.52 (dd, 1 H, J 2.5 Hz,
CHHOCO(CH3)3), 4.65 (dd, 1 H, H-2), 4.96 (d, 1 H, Jcis
11.0 Hz, H-6′a), 5.11 (d, 1 H, Jtrans 17.5 Hz, H-6′b), 5.25 (d,
1 H, J5,6 3.5 Hz, H-6), 5.46 (m, 1 H, H-3′), 6.11 (d, 1 H, J4,5
10.5 Hz, H-4), 6.35 (dd, 1 H, H-5′), 6.87 (dd, 1 H, H-5).
[2R-[2α ,6β(E)]] [3,6-Dihydro-6-[(4′-methyl-3′,5′-
hexadienyl)oxy]-3-oxo-2H-pyran-2-yl]methanol (39)
Compound 39 was obtained in 83% yield from diol 35 ac-
cording to the above mentioned procedure. Rf 0.29 (hexane–
[2R-(2α , 3α , 3aα , 6aβ, 9aα , 9bα )] 3, 3a, 4, 6a, 7, 8,
9a, 9b-Octahydro-3-hydroxy-6-methyl-2H-pyrano[4, 3,
2-ij][2]benzopyran-2-methanol (42)
1
EtOAc, 1:1). H NMR (CDCl3) δ: 1.75 (s, 3 H, CH3 vinyl),
22
2.30 (m, 1 H, J2 ′a,3′ 7.0, Jgem 14.0 Hz, H-2′a), 2.50 (m, 1 H,
J2 ′ b,3′ 7.5 Hz, H-2′b), 3.63 (ddd, 1 H, Jgem 13.0, J 6.5, J′ 7.0,
H-1′a), 3.80 (ddd, 1 H, J = J′ 7.0 Hz, H-1′b), 3.90 (dd, 1 H,
Jgem 12.0, J 4.5 Hz, CHHOH), 4.52 (dd, 1 H, J 2.5 Hz,
CHHOH), 4.55 (dd, 1 H, H-2), 4.96 (d, 1 H, Jcis 11.0 Hz, H-
6′a), 5.11 (d, 1 H, Jtrans 17.5 Hz, H-6′b), 5.25 (d, 1 H, J5,6
3.5 Hz, H-6), 5.36 (m, 1 H, H-3′), 6.11 (d, 1 H, J4,5 10.5 Hz,
H-4), 6.35 (dd, 1 H, H-5′), 6.87 (dd, 1 H, H-5).
Rf 0.15 (hexane–EtOAc, 3:7); mp 168°C. [α]D –91.0 (c
1
0.10, CH3OH). H NMR (400 MHz; CD3OD) δ: 1.36 (m, 1
H, J6a,7 12.5, J7, 8 12.5 Hz, H-7), 1.65–1.77 (m, 4 H, H-9b
and CH3 vinyl), 1.97 (m, 1 H, Jgem 12.5 Hz, H-7′), 2.17 (m,
1 H, Jgem 18.5 Hz, H-4), 2.23 (m, 1 H, H-3a), 2.50 (m, 1 H,
H-4′), 3.10 (m, 1 H, H-6a), 3.69 (d, 1 H, J3, 3a 3.5 Hz, H-3),
3.72 (dd, 1 H, J 6.5 Hz, CHHOH), 3.85 (ddd, 1 H, J7′, 8′ 1.5,
J7, 8′ 4.5, Jgem 11.5 Hz, H-8′), 3.88 (dd, 1 H, J ′ 7.0, Jgem
11.5 Hz, CHHOH), 4.05–4.20 (m, 2 H, H-2, H-8), 5.14 (d, 1
H, J9a, 9b 2.5 Hz, H-9a), 5.43 (m, 1H, H-5).
[2R-(2α , 3aα , 6aβ, 9aα , 9bα )] 2,2-Dimethyl-(3, 3a, 4, 6a,
7, 8, 9a, 9b-octahydro-6-methyl-3-oxo-2H-pyrano[4, 3,
2-ij][2]benzopyran-2-yl)methyl ester propanoic acid (40)
A solution of enone 38 (2.5 g, 7.76 mmol) and
hydroquinone (0.14 g, 1.39 mmol, 0.18 equiv.) in degassed
toluene (150 mL) was placed in a sealed tube and heated at
155°C for 14 h. The resulting mixture was then cooled to
room temperature, concentrated in vacuo, and purified by
column chromatography with hexane–EtOAc (9:1) to pro-
vide the single cycloadduct 40 (1.87 g, 5.82 mmol, 75%) as
[2R-(2α , 3β, 3aα , 6aβ, 9aα , 9bα )] 3, 3a, 4, 6a, 7, 8,
9a, 9b-Octahydro-3-hydroxy-6-methyl-2H-pyrano[4, 3,
2-ij][2]benzopyran-2-methanol (43)
22
Rf 0.21 (hexane–EtOAc, 3:7); mp 128°C. [α]D –6.3 (c
1
0.11, CH3OH). H NMR (CD3OD) δ: 1.33 (m, 1 H, J6a,7
12.5, J7,8 12.5 Hz, H-7), 1.65 (s, 3 H, CH3 vinyl), 1.77 (ddd,
1 H, J9a,9b 2.0, J6a,9b 11.5, J3a,9b 4.0 Hz, H-9b), 1.91 (m, 1 H,
Jgem 12.5 Hz, H-7′), 2.02 (m, 1 H, H-3a), 2.13 (m, 1 H, H-4),
2.30 (m, 1 H, J4,4′ 18.0 Hz, H-4′), 2.58 (m, 1 H, H-6a), 3.76
(ddd, 1 H, J7′,8′ 1.5, J7,8′ 4.0, Jgem 11.5 Hz, H-8′), 3.81 (dd, 1
H, Jgem 10.5 Hz, CHHOH), 3.85–4.05 (m, 3 H, H-3,
CHHOH and H-8), 4.15 (ddd, 1 H, J 3.5, J′ 9.0, J2,3 6.0 Hz,
H-2), 5.07 (d, 1 H, J9a,9b 2.0 Hz, H-9a), 5.21 (m, 1 H, H-5).
Anal. calcd. for C13H20O4: C 64.98, H 8.39; found: C 64.94,
H 8.51.
Compounds 44 and 45: To a solution of diols 42 and 43
(2.82 g, 11.7 mmol) in dry pyridine (120 mL) was added
dropwise at 0°C under argon methanesulfonyl chloride
(1.81 mL, 23.4 mmol, 1.2 equiv.). After the completion of
the addition, the mixture was stirred for 5 h at room temper-
ature, pyridine was removed in vacuo, and the resulting resi-
due was diluted with methylene chloride. The solution was
washed successively with 3 N aqueous HCl, water, 3 N
aqueous NaOH, and water. The organic layer was dried over
22
a gum. Rf 0.44 (hexane–EtOAc, 1:1); [α]D –343.4 (c 0.29,
1
CHCl3). IR (cm–1): 1730. H NMR (400 MHz; CDCl3) δ:
1.20 (br s, 9 H, CO(CH3)3), 1.42 (m, 1 H, J7,6a 12.0 Hz, H-7),
1.61 (s, 3 H, CH3 vinyl), 1.94 (m, 1 H, Jgem 13.0 Hz, H-7′),
2.08 (m, 1 H, H-4), 1.18–2.30 (m, 2 H, H-6a and H-9b),
2.80 (m, 1 H, J4,4′ 18.5 Hz, H-4′), 2.91 (m, 1 H, J3a, 9b
3.5 Hz, H-3a), 3.83 (ddd, 1 H, J7, 8′ 5.0, J7′, 8′ 2.0 Hz, H-8′),
4.05 (ddd, 1 H, J8, 8′ 11.5, J7, 8 11.5, J7′, 8 3.5 Hz, H-8), 4.35
(m, 2 H, CH2OCO), 4.46 (t, 1 H, J = J′ 4.0 Hz, H-2), 5.31
(m, 1 H, H-5), 5.64 (d, 1 H, J9a, 9b 2.0 Hz, H-9a).
[2R-(2α , 3aα , 6aβ, 9aα , 9bα )] (3, 3a, 4, 6a, 7, 8, 9a,
9b-Octahydro-6-methyl-3-oxo-2H-pyrano[4, 3, 2-
ij][2]benzopyran-2-yl)methanol (41)
Adduct 41 was obtained as a gum in 66% yield from
ketone 39 according to the above mentioned procedure and
© 2000 NRC Canada

Taillefumier and Chapleur
719
Na2SO4 and concentrated in vacuo. Purification by column
chromatography on silica gel gave the mesylates 44 (2.22 g,
7.02 mmol, 60%) as a solid and 45 (1.31 g, 4.09 mmol,
35%) as a foam.
[2S-(2α , 3β, 3aα , 6aβ, 9aα , 9bα )] 3, 3a, 4, 6a, 7, 8,
9a, 9b-Octahydro-2-(iodomethyl)-6-methyl-2H-pyrano[4,
3, 2-ij][2]benzopyran-3-ol (47)
Compound 47 was prepared from 45 (1.59 g, 5.0 mmol)
according to the above mentioned procedure (1.44 g,
4.1 mmol, 82%); mp 152–153°C. Rf 0.73 (hexane–EtOAc,
[2R-(2α , 3α , 3aα , 6aβ, 9aα , 9bα )] 3, 3a, 4, 6a, 7, 8,
9a, 9b-Octahydro-3-hydroxy-6-methyl-2H-pyrano[4, 3,
2-ij][2]benzopyran-2-methanol α-methanesulfonate (44)
Rf 0.75 (EtOAc); mp 138°C. [α]D22 –100.0 (c 0.11, CHCl3).
22
1
1:1). [α]D +9.7 (c 0.41, CHCl3). H NMR (CD3OD) δ:
1.41 (m, 1 H, J6a,7 12.5, J7,8 12.5 Hz, H-7), 1.73 (s, 3 H, CH3
vinyl), 1.86 (ddd, 1 H, J6a,9b 11.5, J3a,9b 4.5 Hz, H-9b), 2.01
(m, 1 H, Jgem 12.5 Hz, H-7′), 2.05–2.50 (m, 3 H, H-3a, H-4
and H-4′), 2.66 (m, 1 H, H-6a), 3.66 (dd, 1 H, J 4.0 Hz,
CHHI), 3.76 (dd, 1 H, J 11.5, Jgem 11.5 Hz, CHHI), 3.86
(ddd, 1 H, J7′,8′ 1.5, J7,8′ 4.5 Hz, H-8′), 3.91 (dd, 1 H, J3,3a
12.5, J2,3 6.5 Hz, 4-H), 4.06 (ddd, 1 H, Jgem 11.5, J7′,8
2.5 Hz, H-8), 4.27 (ddd, 1 H, H-2), 5.11 (d, 1 H, J9a,9b
2.0 Hz, H-9a), 5.44 (m, 1 H, H-5). Anal. calcd. for
C13H19O3I: C 44.59, H 5.47, I 36.24; found: C 44.67, H
5.50, I 36.31.
1
IR (KBr) (cm–1): 3450, 1730, 1637. H NMR (CDCl3) δ:
1.35 (m, 1 H, J6a,7 12.5, J7,8 12.5, J7,8′ 4.5 Hz, H-7), 1.67 (s,
3 H, CH3 vinyl), 1.73 (ddd, 1 H, J6a,9b 11.0, J3a,9b 4.5 Hz, H-
9b), 1.90 (m, 1 H, Jgem 12.5, J6a,7′ 4.0 Hz, H-7′), 2.0–2.2 (m,
2 H, H-3a and H-4), 2.22 (d, 1 H, J3,OH 2.0 Hz, OH), 2.54
(m, 1 H, Jgem 19.0 Hz, H-4′), 3.00 (m, 1 H, H-6a), 3.10 (s, 3
H, CH2OSO2CH3), 3.71 (br d, 1 H, J3,3a 3.5 Hz, H-3), 3.86
(ddd, 1 H, J7′,8′ 2.0, J7,8′ 4.0 Hz, H-8′), 4.06 (ddd, 1 H, Jgem
11.5, J7′,8 2.5, J7,8 13.0 Hz, H-8), 4.28 (dd, 1 H, J 5.0 Hz,
CHHOSO2CH3), 4.40 (dd, 1 H, H-2), 4.51 (dd, 1 H, J 7.5,
Jgem 10.0 Hz, CHHOSO2CH3), 5.10 (d, 1 H, J9a,9b 2.5 Hz, H-
9a), 5.50 (m, 1 H, H-5). Anal. calcd. for C14H22O6S: C
52.81, H 6.96 ; found: C 52.70, H 6.89.
[2S-(2α , 3β, 3aα , 6aβ, 9aα , 9bα )] 3, 3a, 4, 6a, 7, 8,
9a, 9b-Octahydro-2-(iodomethyl)-3-(methoxymethoxy)-6-
methyl-2H-pyrano[4, 3, 2-ij][2]benzopyran (49)
To a solution of compound 47 (686 mg, 1.96 mmol) in dry
CH2Cl2 (20 mL) was added dropwise at room temperature
diisopropylethylamine (3.41 mL, 19.6 mmol, 10 equiv.) and
chloromethylmethyl ether (1.2 mL, 15.7 mmol, 8 equiv.). The
solution was stirred at 55°C for 12 h and further amounts of
diisopropylethylamine (3.40 mL) and chloromethylmethyl
ether (1.2 mL) were added. Stirring was maintained for 24 h
and the solvents were evaporated. The residue was washed
with water, 1 N aqueous HCl and brine. The organic layer
was dried over MgSO4 and concentrated in vacuo. Chroma-
tography on silica gel eluting with hexane–EtOAc (20:1.5) af-
forded compound 49 (481 mg, 1.21 mmol, 62%). Rf 0.63
[2R-(2α , 3β, 3aα , 6aβ, 9aα , 9bα )] 3, 3a, 4, 6a, 7, 8,
9a, 9b-Octahydro-3-hydroxy-6-methyl-2H-pyrano[4, 3,
2-ij][2]benzopyran-2-methanol α-methanesulfonate (45)
22
1
Rf 0.82 (EtOAc). [α]D –17.2 (c 0.25, CHCl3). H NMR
(CDCl3) δ: 1.38 (m, 1 H, J6a,7 12.5, Jgem 12.5, H-7), 1.66 (s,
3 H, CH3 vinyl), 1.84 (ddd, 1 H, J6a,9b 11.0, J3a,9b 4.5 Hz, H-
9b), 1.89 (m, 1 H, H-7′), 1.92–2.28 (m, 3 H, H-3a, H-4 and
H-4′), 2.51 (m, 1 H, H-6a), 3.11 (s, 3 H, CH2OSO2CH3),
3.82 (ddd, 1 H, J7′,8′ 1.5, J7,8′ 4.5, H-8′), 3.97 (ddd, 1 H, Jgem
11.5, J7′,8 2.5, J7,8 12.5 Hz, H-8), 4.04 (dd, 1 H, J3,3a
11.5 Hz, H-3), 4.44 (ddd, 1 H, J2,3 6.5 Hz, H-2), 4.57 (dd, 1
H, J 3.0 Hz, CHHOSO2CH3), 4.74 (dd, 1 H, J 8.5, Jgem
11.5 Hz, CHHOSO2CH3), 5.24 (d, 1 H, J9a,9b 2.0 Hz, H-9a),
5.33 (m, 1 H, H-5).
22
(hexane–EtOAc, 7:3). [α]D +10.3 (c 1.76, CHCl3). 1H NMR
(CDCl3) δ: 1.36 (m, 1 H, J6a,7 12.5, J7,8 12.5 Hz, H-7), 1.64
(s, 3 H, CH3 vinyl), 1.81 (ddd, 1 H, J6a,9b 11.0, J3a,9b 3.5 Hz,
H-9b), 1.87 (m, 1 H, Jgem 12.5 Hz, H-7′), 2.00–2.20 (m, 3 H,
H-3a, H-4 and H-4′), 2.55 (m, 1 H, H-6a), 3.39 (3 H, s,
CH2OCH3), 3.45–3.60 (m, 2 H, CH2I), 3.75 (dd, 1 H, J3,3a
11.5, J2,3 6.0 Hz, H-3), 3.81 (ddd, 1 H, J7′,8′ 1.5, J7,8′ 4.0 Hz,
H-8′), 4.00 (ddd, 1 H, Jgem 11.5, J7′,8 2.5 Hz, H-8), 4.38 (m, 1
H, H-2), 4.50–4.70 (m, 2 H, CH2OCH3), 4.97 (d, 1 H, J9a,9b
2.0 Hz, H-9a), 5.30 (m, 1 H, H-5).
[2S-(2α , 3α , 3aα , 6aβ, 9aα , 9bα )] 3, 3a, 4, 6a, 7, 8,
9a, 9b-Octahydro-2-(iodomethyl)-6-methyl-2H-pyrano[4,
3, 2-ij][2]benzopyran-3-ol (46)
To a solution of 44 (770 mg, 2.41 mmol) in butanone
(100 mL) was added sodium iodide (10 g, 66.7 mmol, 27
equiv.) and the mixture was stirred at reflux for 36 h. Buta-
none was evaporated, the residue was diluted with CH2Cl2
and washed successively with water, 3 N aqueous NaOH,
and brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was chromatographed on
silica gel to give 46 (506 mg, 1.44 mmol, 60%) as a white
[3R-(3α , 3aα , 6aβ, 9aα , 9bα )] 3, 3a, 4, 6a, 7, 8, 9a,
9b-Octahydro-3-(methoxymethoxy)-6-methyl-2-
methylene-2H-pyrano[4, 3, 2-ij][2]benzopyran (51)
To a solution of compound 49 (481 mg, 1.22 mmol) in
dry pyridine (60 mL) was added AgF (450 mg, 3.5 mmol,
2.90 equiv.) and the resulting mixture was stirred at 85°C for
1 h in the dark and then poured into EtOAc (200 mL). After
filtration of the salts, solvents were evaporated and the
brown residue was chromatographed on silica gel eluting
with hexane–EtOAc (9:1) to give compound 51 (284 mg,
22
solid; mp 137–138°C. Rf 0.72 (hexane–EtOAc, 1:1). [α]D
1
–76.0 (c 0.25, CHCl3). H NMR (CDCl3) δ: 1.34 (m, 1 H,
J6a,7 12.5, Jgem 12.5 Hz, H-7), 1.62–1.73 (m, 4 H, H-9b and
CH3 vinyl), 1.89 (m, 1 H, H-7′), 1.58 (m, 1 H, OH), 2.00–
2.20 (m, 2 H, H-3a and H-4), 2.55 (m, 1 H, H-4′), 2.98 (m,
1 H, H-6a), 3.22 (dd, 1 H, J 8.5 Hz, CHHI), 3.42 (dd, 1 H, J
7.0, Jgem 10.5, CHHI), 3.87 (ddd, 1 H, J7′,8′ 1.5, J7,8′ 4.0, Jgem
11.5 Hz, H-8′), 3.94 (d, 1 H, J3,3a 3.5 Hz, H-3), 4.08 (ddd, 1
H, J7,8 12.5, J7′,8 2.5 Hz, H-8), 4.32 (dd, 1 H, H-2), 5.01 (d, 1
H, J9a,9b 2.5 Hz, H-9a), 5.43 (1 m, 1 H, H-5). Anal. calcd.
for C13H19O3I: C 44.58, H 5.46, I 36.23; found: C 44.39, H
5.41, I 35.53.
22
1.06 mmol, 87%). Rf 0.71 (hexane–EtOAc, 7:3). [α]D
+54.1 (c 0.61, CHCl3). 1H NMR (CDCl3) δ: 1.42 (m, 1 H, H-
7), 1.65 (s, 3 H, CH3 vinyl), 1.80–2.35 (m, 5 H, J6a,9b
11.0 Hz, H-3a, H-4, H-4′, H-7′ and H-9b), 2.54 (m, 1 H, H-
6a), 3.41 (s, 3 H, CH2OCH3), 3.88 (1 H, ddd, J7′,8′ 1.5, J7,8′
4.0, Jgem 11.5 Hz, H-8′), 3.92–4.07 (m, 2 H, J7′,8 2.5, J7,8
© 2000 NRC Canada

720
Can. J. Chem. Vol. 78, 2000
12.5, J3,3a 10.5 Hz, H-3 and H-8), 4.56 (d, 1 H, Jgem 1.0 Hz,
C=CHH), 4.65 (d, 1 H, Jgem 7.0 Hz CHHOCH3), 4.72 (d, 1
H, C=CHH), 4.74 (d, 1 H, CHHOCH3), 5.01 (d, 1 H, J9a,9b
2.0 Hz, H-9a), 5.36 (m, 1 H, H-5). Anal. calcd. for
C15H22O4: C 67.65, H 8.33; found: C 67.74, H 8.43.
14.3 Hz, CHHCH2OH), 1.84 (m, 1 H, H-4a), 1.90 (m, 1H,
J4a,5 9.5 Hz, H-5), 1.96 (dd, 1 H, Jgem 14.0, J3,4 3.9 Hz, H-3),
2.20–2.41 (m, 2 H, H-8 and H-8′), 2.50–2.64 (m, 2 H, J3′,4
2.5 Hz, H-3′ and H-8a), 3.27 (s, 3 H, CH2OCH3), 3.31 (m, 2
H, CH2CH2OH), 3.93 (m, 1 H, H-4), 4.31 (d, 1 H, J1,8a
6.2 Hz, H-1), 4.71 (d, 1 H, Jgem 6.7 Hz, CHHOCH3), 4.92
(d, 1 H, CHHOCH3), 5.32 (m, 1 H, H-7). Anal. calcd. for
C15H24O5: C 63.36, H 8.51; found: C 64.01, H 8.50.
[3S-(3α , 3a β, 6aα , 9a β , 9b β )] 3, 3a, 4, 6a, 7, 8, 9a,
9b-Octahydro-3-(methoxy methoxy)- 6-methyl-2-
methylene-2H-pyrano[4, 3, 2-ij][2]benzopyran (50)
Compound 50 was prepared from 48 (154 mg,
0.39 mmol) according to the above mentioned procedure
(75 mg, 0.28 mmol, 72%); mp 60°C. Rf 0.69 (hexane–
[2S-(2α , 3α , 3aα , 6aβ, 9aα , 9bα )]- and [2R-(2α , 3β,
3aβ, 6aα , 9aβ, 9bβ)]-3, 3a, 4, 6a, 7, 8, 9a, 9b-
Octahydro-3-(methoxymethoxy)-2,6-dimethyl-2H-
pyrano[4, 3, 2-ij][2]benzopyran-2-ol (56)
22
EtOAc, 7:3). [α]D –113.1 (c 0.32, CHCl3). 1H, NMR
(CDCl3) δ: 1.38 (m, 1 H, J6a,7 12.5, Jgem 12.5 Hz, H-7), 1.66
(s, 3 H, CH3 vinyl), 1.70 (ddd, 1 H, J6a,9b 11.5, J3a,9b 4.5 Hz,
H-9b), 1,89 (m, 1 H, J6a,7′ 5.0 Hz, H-7′), 2.08 (m, 1 H, H-4),
2.15 (m, 1 H, H-3a), 2.40 (m, 1 H, H-4′), 2.95 (m, 1H, H-
6a), 3.34 (s, 3 H, CH2OCH3), 3.86–3.96 (m, 2 H, J3,3a 4.5,
J7′,8′ 1.5, J7,8′ 4.0 Hz, H-3 and, H-8′), 4.06 (ddd, 1 H, Jgem
12.0, J7′,8 2.5, J7,8 11.5 Hz, H-8), 4.45 (s, 1 H, C=CHH), 4.47
(d, 1 H, Jgem 6.5 Hz, CHHOCH3), 4.75 (d, 1 H, CHHOCH3),
4.78 (s, 1 H, C=CHH), 4.93 (d, 1 H, J9a,9b 2.5 Hz, H-9a),
5.35 (m, 1 H, H-5). Anal. calcd. for C15H22O4: C 67.65, H
8.33; found: C 67.85, H 8.40.
C-2 epimers mixture (1:1):. mp 92°C. Rf 0.15 (hexane–
EtOAc, 7:3). [α]D of the mixture –73.7° (c 1.23, CHCl3).
Anal. calcd. for C15H24O5: C 63.36, H 8.51; found: C 63.95,
H 8.42.
22
Ferrier carbocyclization of 51 using Lukacs methodology
Using the above mentioned procedure, compound 51
(100 mg, 0.37 mmol) was converted into cyclohexanones 53
and 55 and the hydration product 57 (1:1:2) in 84% overall
yield.
[1R-(1α ,4α ,4aα ,5α ,8aα )] 3,4,4a,5,8,8a-Hexahydro-4-
hydroxy-5-(2-hydroxyethyl)-1-(methoxymethoxy)-6-
methyl-2(1H)-naphtalenone (53)
Ferrier carbocyclization of 50 using Lukacs method
Compound 50 (100 mg, 0.37 mmol) was dissolved in 1,4-
dioxane (10 mL) and HgSO4 (6 mg, 0.02 mmol, 0.05 equiv.)
and 5 mM aqueous H2SO4 (1.1 mL) were added succes-
sively. This mixture was then heated at 50°C for 1 h. At the
end of this period TLC (hexane–EtOAc, 7:3) showed no
more starting material and the formation of three products.
The mixture was cooled to room temperature and diluted
with CH2Cl2 (100 mL). The organic layer was washed with
water and brine, dried over Na2SO4, and concentrated in
vacuo. The residue was chromatographed on silica gel
eluting with hexane–EtOAc (1:4) to give 52 (11.5 mg,
0.04 mmol, 12%), 54 (12 mg, 0.04 mmol, 12%), and 56
(76 mg, 0.26 mmol, 71%).
22
Rf 0.51 (CH2Cl2–MeOH, 9:1); mp 91°C. [α]D +33.6° (c
0.12, CHCl3). IR (cm–1): 3416, 1711, 1661. 1H NMR
(400 MHz, C6D6) δ: 1.44 (m, 1 H, CHHCH2OH), 1.58 (m, 1
H, H-8), 1.71 (m, 1 H, H-8′), 1.73 (s, 3 H, CH3 vinyl), 1.83
(m, 1 H, CHHCH2OH), 2.38 (m, 2 H, H-4a and H-8a), 2.54
(m, 1 H, H-5), 2.61 (dd, 1 H, J3,4 4.8 Hz, H-3), 2.93 (dd, 1
H, J3′,4 10.2, Jgem 12.7 Hz, H-3′), 3.19 (s, 3 H, CH2OCH3),
3.54 (ddd, 1 H, J4,4a 9.0 Hz, H-4), 3.61 (m, 1 H,
CH2CHHOH), 3.70 (m, 1 H, CH2CHHOH), 3.78 (d, 1 H,
J1,8a 3.0 Hz, H-1), 4.50 (d, 1 H, Jgem 6.7 Hz, CHHOCH3),
1
4.60 (d, 1 H, CHHOCH3), 5.22 (m, 1 H, H-7). H NMR
(400 MHz, DMSO)δ: 1.47 (m, 1 H, CHHCH2OH), 1.52–1.75
(m, 5 H, CH3, H-8 and CHHCH2OH), 1.87 (m, 1 H, H-8′),
2.01 (ddd, 1 H, J4,4a 7.6, J4a,8a 4.0, J4a,5 4.0 Hz, H-4a), 2.29
(m, 2 H, H-5 and H-8a), 2,54 (m, 2 H, J3,4 8.0, J3′,4 4.0 Hz,
H-3 and H-3′), 3.25 (s, 3 H, CH2OCH3), 3.44 (m, 2 H,
CH2CH2OH), 3.64 (m, 1 H, H-4), 3.68 (d, 1 H, J1,8a 5.9 Hz,
H-1), 4.42 (t, 1 H, J = J′ 4.9 Hz, CH2CH2OH), 4.58 (m, 2 H,
Jgem 6.7 Hz, CH2OCH3), 4.98 (d, 1 H, J4,OH 5.3 Hz, OH),
5.26 (m, 1 H, H-7). Anal. calcd. for C15H24O5: C 63.36, H
8.51; found: C 63.62, H 8.42.
[1S-(1α,4α ,4aβ,5β,8aβ)] 3,4,4a,5,8,8a-Hexahydro-4-
hydroxy-5-(2-hydroxyethyl)-1-(methoxymethoxy)-6-methyl-
2(1H)-naphtalenone (52) (see numbering in Scheme 5)
22
Rf 0.49 (CH2Cl2–MeOH, 9:1). [α]D + 4.6° (c 0.21,
1
CHCl3). H NMR (CDCl3) δ: 1.35–1.65 (m, 2 H, H-8 and
CHHCH2OH), 1.72 (s, 3 H, CH3 vinyl), 1.94 (m, 1 H, Jgem
14.0 Hz, CHHCH2OH), 2.06 (m, 1 H, J4a,5 10.5 Hz, H-4a),
2.14 (m, 1 H, Jgem .18.5 Hz, H-8′), 2.40–2.60 (m, 3-H, H-2,
H-5 and H-8a), 2.80 (dd, 1 H, J3′,4 5.5, Jgem 13.5 Hz, H-3′),
3.39 (s, 3 H, CH2OCH3), 3.74–3.87 (m, 3 H, H-4 and
CH2CH2OH), 4.40 (d, 1 H, J1,8a 5.5 Hz, H-1), 4.71 (d, 1 H,
Jgem 6.5 Hz, CHHOCH3), 4.92 (d, 1 H, CHHOCH3), 5.35
(m, 1 H, H-7). Anal. calcd. for C15H24O5: C 63.36, H 8.51;
found: C 63.12, H 8.47.
[1R-(1α ,4β,4aα ,5α ,8aα )] 3,4,4a,5,8,8a-Hexahydro-4-
hydroxy-5-(2-hydroxyethyl)-1-(methoxymethoxy)-6-
methyl-2(1H)-naphtalenone (55)
22
Rf 0.54 (CH2Cl2–MeOH, 9:1). [α]D +40.3° (c 0.33,
CHCl3). 1H NMR (CDCl3) 1.68–1.84 (m, 3 H, CHHCH2OH,
CH3 vinyl), 1.92 (m, 1 H, CHHCH2OH), 2.03–2.14 (m, 2 H,
H-8 and H-8′), 2.20–2.34 (m, 2 H, H-5 and H-8a), 2.48
(ddd, 1 H, J4,4a 3.0, J4a,8a 5.0, J4a,5 6.0 Hz, H-4a), 2.57 (dd, 1
H, J3,4 6.5 Hz, H-3), 2.92 (dd, 1 H, Jgem 14.0, J3′,4 4.5 Hz, H-
3′), 3.35 (s, 3 H, CH2OCH3), 3.72–3.83 (m, 2 H,
CH2CH2OH), 3.88 (d, 1 H, J1,8a 6.5 Hz, H-1), 4.26 (ddd, 1
[1S-(1α ,4β,4aβ,5β,8aβ)] 3,4,4a,5,8,8a-Hexahydro-4-
hydroxy-5-(2-hydroxyethyl)-1-(methoxymethoxy)-6-
methyl-2(1H)-naphtalenone (54)
22
Rf 0.47 (CH2Cl2–MeOH, 9:1). [α]D + 20.2° (c 0.45,
CHCl3). 1H NMR (400 MHz, C6D6) δ: 1.22 (m, 1 H,
CHHCH2OH), 1.50 (s, 3 H, CH3 vinyl), 1.59 (m, 1 H, Jgem
© 2000 NRC Canada

Taillefumier and Chapleur
721
H, H-4), 4.63 (d, 1 H, Jgem 13.5 Hz, CHHOCH3), 4.66 (d, 1
H, CHHOCH3), 5.49 (m, 1 H, H-7).
References
1. Y. Chapleur. The chemistry and total synthesis of mevinic ac-
ids. In Recent progress in the chemistry of antibiotics. Vol. 2.
Edited by G. Lucaks and S. Ueno. Springer, New York. 1993.
pp. 829–937.
2. M.I. Colombo, J. Zinezuk, and E.A. Ruveda. Tetrahedron, 48,
963 (1992).
[2S-(2α , 3α , 3aα , 6aβ, 9aα , 9bα )] and [2R-(2α , 3β,
3aβ, 6aα , 9aβ, 9bβ)] 3, 3a, 4, 6a, 7, 8, 9a, 9b-
Octahydro-3-(methoxymethoxy)-2,6-dimethyl-2H-
pyrano[4, 3, 2-ij][2]benzopyran-2-ol (57)
C-2 epimers mixture (7:1): Rf 0.17 (hexane–EtOAc, 7:3).
22
[α]D +3.8 (c 0.28, CHCl3). Major isomer: 1H NMR
3. E. Ciganek. Org. React. (N.Y.) 32, 1 (1984).
(CDCl3) δ: 1.36 (m, 1 H, J7,8 12.5, J7,8′ 4.5, Jgem 12.5 Hz, H-
7), 1.51 (s, 3 H, CH3 vinyl), 1.64 (s, 3 H, C(OH)CH3), 1.80
(ddd, 1 H, J6a,9b 11.5, J9a,9b 3.5, J3a,9b 4.0 Hz, H-9b), 1.86
(m, 1 H, H-7′), 2.13–2.34 (m, 3 H, H-3a, H-4 and H-4′),
2.42 (m, 1 H, H-6a), 2.71 (s, 1 H, OH), 3.40 (d, 1 H, J3,3a
10.5 Hz, H-3), 3.42 (s, 3 H, CH2OCH3), 3.83 (ddd, 1 H, J7′,8′
1.5, J7,8′ 5.0, Jgem 11.5 Hz, H-8′), 3.95 (ddd, 1 H, J7′,8 2.5 Hz,
H-8), 4.67 (d, 1 H, Jgem 7.0 Hz, CHHOCH3), 4.73 (d, 1 H,
CHHOCH3), 5.30–5.40 (m, 2 H, H-5 and H-9a). 13C NMR
(CDCl3) δ: 20.04 (C(OH)CH3), 25.09 (C-4), 27.30 (CH3 vi-
nyl), 29.09 (C-7), 30.65 (C-6a), 32.32 (C-3a), 41.72 (C-9b),
56.42 (CH2OCH3), 63.22 (C-8), 79.49 (C-3), 93.03 (C-9a),
98.13 (C-2 or C-6), 98.91 (CH2OCH3), 120.18 (C-5), 133.96
(C-2 or C-6).
4. W.R. Roush. Intramolecular Diels–Alder reactions. In Com-
prehensive organic synthesis. Vol. 5. Edited by B.M. Trost and
I. Fleming. Pergamon Press, Oxford. 1991. p. 513.
5. D. Craig. Chem. Soc. Rev. 16, 187 (1987).
6. A.G. Fallis. Acc. Chem. Res. 32, 464 (1999).
7. (a) E.A. Deutsch and B.B. Snider. J. Org. Chem. 47, 2682
(1982); (b) G.E. Keck and D.F. Kachensky. J. Org. Chem. 51,
2487 (1986); (c) K. Narasaka, M. Saito, and N. Iwasawa. Tet-
rahedron: Assymmetry. 2, 1305 (1991); (d) S. Hanessian, P.J.
Roy, M. Petrini, P.J. Hodges, R. Di Fabio, and G. Garganico. J.
Org. Chem. 55, 5766 (1990); (e) R.L. Funk and W.E. Zeller. J.
Org. Chem. 47, 180 (1982); (f) P.A. Grieco, R. Lis, R.E. Zelle,
and J. Finn. J. Am. Chem. Soc. 108, 5908 (1986); (g) A.H.
Davidson, A.J. Jones, C.D. Floyd, C. Lewis, and P.L. Meyers.
J. Chem. Soc. Chem. Commun. 1786 (1987); (h) J.S. Prasad,
D.L.J. Clive, and G.V.J. da Silva. J. Org. Chem. 51, 2717
(1986).
Ferrier carbocyclization of 51 using a stoichiometric
amount of mercuric acetate
8. (a) R.M. Giuliano. Cycloaddition reactions in carbohydrate
chemistry — an overview. Cycloaddition reactions in carbohy-
drate chemistry. Vol. 494. 1992. pp. 1–23; (b) J.C. Lopez,
A.M. Gomez, and B. Fraser-Reid. J. Chem. Soc. Chem.
Commun. 762 (1993); (c) R.V. Bonnert and P. Jenkins. J.
Chem. Soc. Perkin Trans. 1, 413 (1989); (d) R.M. Giuliano,
A.D. Jordan, A.D. Gauthier, and K. Hoogsteen. J. Org. Chem.
58, 4979 (1993); (e) A.A. Ghini, C. Burnouf, J.C. Lopez, A.
Olesker, and G. Lukacs. Tetrahedron Lett. 31, 2301 (1990);
(f) I. Hanna, J.-Y. Lallemand, and P. Wlodyka. Tetrahedron
Lett. 35, 6685 (1994); (g) J. Herscovici, S. Delatre, and K.
Antonakis. Tetrahedron Lett. 32, 1183 (1991); (h) R. Tsang
and B. Fraser-Reid. J. Org. Chem. 57, 1065 (1992); (i) S. Woo,
S. Legoupy, S. Parra, and A.G. Fallis. Org. Lett. 1, 1013
(1999); (j) J. Herscovici, S. Delatre, L. Boumaiza, and K.
Antonakis. J. Org. Chem. 58, 3928 (1993); (k) I. Hanna and P.
Wlodyka. J. Org. Chem. 62, 6985 (1997).
To a solution of 51 (78 mg, 0.29 mmol) in a mixture of
acetone (12 mL) and water (5 mL) was added Hg(OAc)2
(160 mg, 0.52 mmol, 1.8 equiv.) and acetic acid (0.17 mL).
The mixture was stirred at reflux for 12 h, solvents were
evaporated under reduced pressure, and the residue was
taken up with CH2Cl2. The organic layer was washed with
saturated aqueous NaHCO3, water, dried over MgSO4, and
concentrated in vacuo. Column chromatography on silica gel
eluting with hexane–EtOAc afforded the cyclohexanones 53
(23 mg, 0.08 mmol, 28%) and 55 (9 mg, 0.03 mmol, 11%)
and the hydration product 57 (14.5 mg, 0.05 mmol, 18%)
[53:55:57 (2.5:1:1.7)].
Conclusions
This work allowed the preparation of the bicyclic struc-
tures 55 and 54 which can be regarded as key compounds
for the synthesis of the hexahydro-naphthalene ring of
mevinic acids such as pravastatin and mevinolin, the keto
group at C-1 being amenable to reduction or Wittig
methylenation. This strategy is applicable for the synthesis
of other complex decalinic structures present in a number of
natural products. The IMDA reaction of cyclohexenone as
the dienophile failed likely because of the ester link used in
the tether. Other links like mixed acetals should be devised.
This type of link was efficient in the IMDA of a sugar enone
to provide bis-annulated pyranosides. However it is worth
noting that the Ferrier carbocyclization on these bis-
annulated pyranosides is less efficient than in the pyranoside
series in terms of stereoselectivity and of yield. But one in-
teresting consequence of this limitation was also the direct
carbocyclization of 57 without mercury catalysis. It is likely
that direct hydration of the double bond of 51 or 50 followed
by base-catalyzed carbocyclization would be a good alterna-
tive and a good improvement of our synthetic sequence.
9. S. Hanessian. Total synthesis of natural products: the chiron
approach. Edited by J.E. Baldwin. Pergamon Press, Oxford.
1983.
10. (a) R.J. Ferrier. J. Chem. Soc. Perkin Trans. 1, 1455 (1979);
(b) R.J. Ferrier and S. Middleton. Chem. Rev. 93, 2779 (1993).
11. (a) D.J. Jenkins, D. Dubreuil, and B.V.L. Potter. J. Chem. Soc.
Perkin Trans. 1, 1365 (1996); (b) S. Augy-Dorey, D.H.R.
Barton, S.D. Gero, B. Quiclet-Sire, and I. Sagnard. J. Chem.
Soc. Chem. Commun. 960 (1993); (c) H.B. Mereyala and S.
Guntha. J. Chem. Soc. Perkin Trans. 1, 841 (1993); (d) C.
Jaramillo, J.-L. Chiara, and M. Martin-Lomas. J. Org. Chem.
59, 3135 (1994); (e) E. Poirot, H. Bourdon, F. Chrétien, Y.
Chapleur, B. Berton, M. Hilly, J.-P. Mauger, and G. Guillon.
Biorg. Med. Chem. Lett. 5, 569 (1995); (f) K. Sato, S. Sakuma,
S. Muramatsu, and M. Bokura. Chem. Lett. 1473 (1991).
12. F. Chrétien, R. Wolf, and Y. Chapleur. Nat. Prod. Lett. 2, 69
(1993).
13. (a) N. Chida, M. Ohtsuka, K. Nakazawa, and S. Ogawa. J.
Org. Chem. 56, 2976 (1991); (b) N. Chida, M. Ohtsuka, and S.
Ogawa. J. Org. Chem. 58, 4441 (1993).
© 2000 NRC Canada

722
Can. J. Chem. Vol. 78, 2000
14. F. Chrétien, S. Ibn Ahmed, A. Masion, and Y. Chapleur. Tetra-
hedron, 49, 7463 (1993).
27. F. Chrétien, M. Khaldi, and Y. Chapleur. Synth. Commun. 20,
1589 (1990).
15. (a) Z.J. Jia, L. Olsson, and B. Fraser-Reid. J. Chem. Soc.
Perkin Trans. 1, 631 (1998); (b) V.A. Estevez and G.D.
Prestwich. J. Am. Chem. Soc. 113, 9885 (1991); (c) S.L.
Bender and R.J. Budhu. J. Am. Chem. Soc. 113, 9883 (1991);
(d) O. Thum, J. Chen, and G.D. Prestwich. Tetrahedron Lett.
37, 9017 (1996); (e) G. Dorman, J. Chen, and G.D. Prestwich.
Tetrahedron Lett. 36, 8719 (1995); (f) J. Chen, G. Dorman,
and G.D. Prestwich. J. Org. Chem. 61, 393 (1996).
16. (a) S.K. Das, J.M. Mallet, and P. Sinaÿ. Angew. Chem. Int. Ed.
Engl. 36, 493 (1997); (b) M. Sollogoub, J.M. Mallet, and P.
Sinaÿ. Tetrahedron Lett. 39, 3471 (1998); (c) P.I. Dalko and P.
Sinaÿ. Angew. Chem. Int. Ed. Engl. 38, 773 (1999).
17. C. Taillefumier, Y. Chapleur, D. Bayeul, and A. Aubry. J.
Chem. Soc. Chem. Commun. 937 (1995).
28. A. Liptak, P. Fügedi, and P. Nanasi. Carbohydr. Res. 68, 151
(1979).
29. R.V. Stevens, R.E. Cherpeck, B.L. Harrison, J. Lai, and R.
Lapalme. J. Am. Chem. Soc. 98, 6317 (1976).
30. W.R. Roush, H.R. Gillis, and A.I. Ko. J. Am. Chem. Soc. 104,
2269 (1982).
31. R.K. Boeckman, Jr. and D.M. Demko. J. Org. Chem. 47, 1789
(1982).
32 E. Bertele and P. Schudel. FR 1572831, 1969.
33. I. Dyong, H.W. Hagedorn, and J. Thiem. Liebigs Ann. Chem.
551 (1986).
34. F. Chrétien and Y. Chapleur. J. Chem. Soc. Chem. Commun.
1268 (1984).
35. N. Chida, M. Ohtsuka, K. Ogura, and S. Ogawa. Bull. Chem.
Soc. Jpn. 64, 2118 (1991).
36. A.S. Machado, A. Olesker, and G. Lukacs. Carbohydr. Res.
135, 231 (1985).
37. R. Blattner, R.J. Ferrier, and S.R. Haines. J. Chem. Soc. Perkin
Trans. 1, 2413 (1985).
18. R.J. Ferrier and N. Prasad. J. Chem. Soc. Perkin Trans. 1, 570
(1969).
19. J.G. Buchanan and J.C.P. Schwarz. J. Chem. Soc. 4470 (1962).
20. M.J. Robins, J.S. Wilson, and F. Hansske. J. Am. Chem. Soc.
105, 4059 (1983).
21. N.A. Nashed. Carbohydr. Res. 60, 200 (1978).
22. K. Neumann. Acta Chem. Scand. 46, 913 (1992).
23. C. Chatgilialoglu. Acc. Chem. Res. 25, 188 (1992).
24. M. Ballestri, C. Chatgilialoglu, K.B. Clark, D. Griller, B.
Giese, and B. Kopping. J. Org. Chem. 56, 678 (1991).
25. H.R. Bollinger and D.A. Prins. Helv. Chim. Acta, 28, 465
(1945).
38. P. Laszlo, I.F. Pelyvas, and F. Sztaricskai. Carbohydr. Chem.
175, 227 (1988).
39. A.S. Machado, D. Dubreuil, J. Cleophax, S.D. Gero, and N.F.
Thomas. Carbohydr. Res. 233, C5-C8 (1992).
40. T. Iimori, H. Takahashi, and S. Ikegami. Tetrahedron Lett. 37,
649 (1996).
41. G. Rembarz. Chem. Ber. 95, 825 (1962).
26. D.A. Prins. J. Am. Chem. Soc. 70, 3955 (1948).
© 2000 NRC Canada