[4+2]/HyBRedOx approach to C-naphthyl glycosides: Failure in the projuglone series and reinvestigation of the HyBRedOx sequence

Article abstract of DOI:10.1002/ejoc.200800655

C-Naphthyl glycosides displaying a 1,5-difunctionality on the naphthalene ring that can undergo oxidation to bromonaphthoquinone are key intermediates in the synthesis of natural C-aryl glycoside analogues. In this area, sugar-modified derivatives are of

Full text of DOI:10.1002/ejoc.200800655

FULL PAPER
DOI: 10.1002/ejoc.200800655
[4+2]/HyBRedOx Approach to C-Naphthyl Glycosides: Failure in the
Projuglone Series and Reinvestigation of the HyBRedOx Sequence
Lucie Maingot,[a,b] Nguyen Quang Vu,[a] Sylvain Collet,[b] André Guingant,[b]
Arnaud Martel,[a] and Gilles Dujardin*[a]
Keywords: Tin / Cycloaddition / Dienophiles / Glycosides / Heterocycles
C-Naphthyl glycosides displaying a 1,5-difunctionality on
the naphthalene ring that can undergo oxidation to bromo-
naphthoquinone are key intermediates in the synthesis of
reactivity towards a range of 4-hetero-substituted (“pro-
sugar”) heterodienes, the expected heteroadducts were ster-
eoselectively obtained in acceptable yields. Application of
natural C-aryl glycoside analogues. In this area, sugar-modi- the hydroboration/reduction/oxidation sequence did not af-
fied derivatives are of specific interest, but their synthesis is
challenging. The de novo access to such compounds has
been investigated through a [4+2] heterocycloaddition route,
previously validated in a model series. For this purpose, two
new dienophiles, conveniently protected at the phenolic po-
sitions, were synthesized. From an extensive study of their
ford the target C-glycosides from the reduced adducts. The
negative effect of the conformational bias of the substrate on
this tandem reaction is discussed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
formation of the B ring. The importance of C-naphthyl-2-
deoxy glycosides 1 has stimulated much effort towards their
synthesis[3] by classical C-glycosylation[4] or organometallic
condensation.[1a,1b] The limitations of these methods led to
the development of new strategies involving the construc-
tion of the naphthalene ring from a C-glycosylfuran.[5]
In the development of biologically active analogues,
Introduction
C-Naphthyl-2-deoxy glycosides 1 are pivotal precursors for
the synthesis of several classes of natural C-aryl glycosides
(Figure 1), for example, angucyclines[1] and medermy-
cines.[2] In these approaches, 1,5-oxy disubstitution of the
naphthalene ring is convenient for delivering the corre-
sponding bromojuglone 2 subsequently involved in the key sugar-modified derivatives of C-naphthyl glycosides 1 are
Figure 1. C-Naphthyl glycosides as key intermediates of biologically active complex C-aryl glycosides.
[a] UCO2M, UMR CNRS 6011, Universite du Maine,
of interest. Owing to the polyfunctionality of 1, modifica-
tions of the sugar unit after C-glycosylation are restricted.[6]
An approach involving modification of glycosyl donors
prior to C-glycosylation has also been reported in the litera-
ture, but failed in some critical cases.[7] De novo approaches
involving the construction of the glycosyl ring have seldom
been reported.[8,9]
72085 Le Mans Cedex 9, France
Fax: +33-2-43833902
E-mail: gilles.dujardin@univ-lemans.fr
[b] CEISAM, UMR CNRS 6230, Universite de Nantes, UFR Sci-
ences et Techniques,
2 rue de la Houssiniere, B. P. 92208, 44322 Nantes Cedex,
France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
412
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 412–422

[4+2]/HyBRedOx Approach to C-Naphthyl Glycosides
Inspired by the pioneering work of Schmidt et al.,[10] we
investigated a [4+2] route towards C-naphthyl glycosides
(Scheme 1, the model series) by a SnCl4-catalyzed heterocy-
cloaddition of α-methoxyvinylnaphthalene with a “pro-
sugar” heterodiene.[11] In a previous report we described the
Results and Discussion
Preparation of the Dienophiles
The naphthalene ring must be suitably 1,5-difunction-
access to β-C-naphthyl glycosides 3 from the reduced dihy- alized in a diprotected form to give access to bromojuglones
dropyran obtained by an unprecedented hydroboration/re- by Grunwell oxidation[13] at a late stage. To equip the dien-
duction/oxidation tandem reaction (HyBRedOx) using the ophile, this double O-protection had to be compatible with
BH3·THF complex as the hydroborating/ketal-reducing the conditions of the heterocycloaddition reaction: The use
agent.[12] The efficiency of this one-pot sequence was found of SnCl4 as catalyst thus excluded acid-sensitive protections
to be highly dependent on the configuration of the substrate such as MOM or benzyl. The choice of acetate protection
because derivatives of endo adducts proved to be less or appeared as the most suitable on account of the well-known
nonreactive. Having validated a stereoselective access to β- ability of 1,5-diacetoxynaphthalene to undergo Grunwell
C-glycosides by this [4+2]/HyBRedOx route, we have fo- oxidation to bromonaphthoquinone.[13] However, with this
cused more recently on the application of this strategy to type of protection we could predict some difficulties relating
the de novo synthesis of C-glycosyl bromojuglones. This re- to the transformation of the heteroadduct into the C-glyco-
quired the use of dienophiles 4, which display a 1,5-dihy- syl unit as both the ester reduction of the adduct and the
droxynaphthalene moiety. In this paper we describe the syn- oxidation of borane at the HyBRedOx stage could not be
thesis of such novel polyfunctionalized dienophiles (Pg = easily conducted in a chemoselective way. For this reason
Ac, Pv) and the study of their reactivity with different “pro- the pivalate group (Pv) was also considered as an alterna-
sugar” heterodienes (X = OR, NR2). In the second part, tive ester-type phenol protection as it is more stable under
the application of the HyBRedOx sequence and its failure basic and reducing conditions than the acetate group.
are discussed.
Moreover, we could expect such protections to be fairly
stable under the conditions of [4+2] activation with SnCl4.
In addition, we had to check the ability of the pivaloyl pro-
tecting groups to allow Grunwell oxidation. For this pur-
pose, the bis-pivalate 9, easily prepared from 6, was treated
with 5 equiv. of NBS in aqueous acetic acid at 70 °C and
led to the expected bromonaphthoquinone 10 in acceptable
yields. This result validates the choice of pivalate as an al-
ternative to acetate protection and thus supported our plan
to prepare the two dienophiles 8 and 12 (Scheme 2).
The diacetylated dienophile 8 was obtained in three steps
starting from 1,5-diacetoxynaphthalene (5). The first step
was the Fries rearrangement described by Uno.[14] 1,5-Di-
acetoxynaphthalene (5) was subjected to solvent-free ther-
mal reaction with BF3·OEt2 followed by saponification of
the residual monoacetate to give ketone 6 with total ortho
regioselectivity in 70% overall yield. The latter was then
treated with methyl orthoformate in an acidic medium to
give the naphthalenediol ketal 7. When submitted to classi-
cal acetylation conditions (acetic anhydride/pyridine), ketal
7 underwent concomitant dehydromethoxylation to give the
desired diacetylated enol ether 8 directly. In this one-pot
process, methanol is efficiently trapped by an excess of ace-
tic anhydride.
Attempts to prepare the corresponding bis-pivalate 12 by
treatment of ketal 7 with pivaloyl chloride in pyridine were
unsuccessful. However, introduction of pivaloyl protection
at an early stage proved to be convenient. Indeed, the bis-
pivaloyloxy ketone 9 underwent ketalization in high yields
with methyl orthoformate under acidic conditions. Gass-
man-type conditions[15] applied to ketal 11 gave poor re-
sults. Interestingly, the conditions applied to ketal 7 (Ac2O,
pyridine, room temp.) were employed with ketal 11 to give
enol ether 12, which was obtained with a low conversion
(20% after 18 h). At 65 °C, the conversion remained low
with acetic anhydride (30%), but full conversion was
Scheme 1. De novo approach to C-naphthyl glycosides.
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G. Dujardin et al.
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Scheme 2. Preparation of dienophiles 8 and 12.
achieved after 18 h by using acetyl chloride. Although stor- heterodiene and the methoxy group delivered by decompo-
able for months at 4 °C, the enol ether 12, obtained in pure sition of enol ether 8. Clearly, the use of methoxy-substi-
form in an overall 70% yield in three steps, proved to have tuted 13b solved this problem of exchange (Entries 2–4).
a high sensitivity towards protic acidic media.[16]
Lowering the reaction temperature to –30 °C restricted the
degradation of the substrates and significantly increased the
yield of cycloadduct 14b. Interestingly, depending on its fi-
nal treatment, this reaction gave very different stereochemi-
cal results. Indeed, when the work-up was carried out at
–30 °C with an aqueous saturated NaHCO3 solution (En-
try 4), poor diastereoselectivity (47/53) in favor of the ad-
duct endo-14b, as a mixture of two separable diastereoiso-
mers, was observed. In contrast, when the same aqueous
treatment was performed at room temperature, the cycload-
dition reaction led exclusively to the adduct exo-14b in 66%
yield[21] as the consequence of a likely rapid epimerization
at the ketal center[22] (Entry 3). This epimerization was ex-
emplified by the following experiment: Treatment of the
pure adduct endo-14b with 15 mol-% of SnCl4 in DCM for
2 h from –30 to 0 °C led to its complete disappearance and
the formation of the epimer exo-14b, together with the
retro-Michael product 9Ј (diacetate analogue of ketone 9,
Scheme 2). Semiempirical AM1 calculations using Spar-
tan®[23] confirmed that exo-14b is approximately 2 kcal/mol
more stable than endo-14b (Table 2).
[4+2] Heterocycloaddition
We selected for this study six heterodienes, all of which
displayed a heterosubstituent able to deliver a hydroxy
(13a,b) or amino (13c–f) group at the C-4’ position of the
target C-glycoside (Figure 2). These “prosugar” heterodi-
enes were prepared according to literature procedures,[17–19]
except for 13d, which was obtained by treatment of 13b with
dibenzylamine.
The SnCl4-catalyzed heterocycloaddition of the dipival-
oyloxy dienophile 12, conducted at –30 °C, displayed the
same features as the acetate series (Entry 5). Again, the re-
sults depended strongly on the experimental conditions.
When warming to room temperature prior to hydrolysis was
too fast, and as a consequence the delay before hydrolysis
Figure 2. Heterodienes 13a–f.
Previous results from model series have demonstrated too short, the reaction led to a 1:1 mixture of diastereoiso-
that the heterocycloaddition reaction promoted by SnCl4 mers endo-14c and exo-14c. In this case, total epimerization
between the heterodiene 13a and α-methoxyvinylnaphtha- to the most stable isomer exo-14c (Table 2) could not be
lene was completely “exo” selective.[20] This “exo” configu- achieved although significant exo selectivity was obtained
ration appeared as the most favorable to give C-naphthyl when aqueous treatment of the reaction mixture was carried
glycosides in good yields and in a stereoselective manner by out after a slow return to room temperature (2 h). Under
the HyBRedOx sequence. On the basis of these promising these conditions, the cycloaddition reaction led mainly to
results, we applied the same conditions to dienophile 8 adduct exo-14c with a 9:1 diastereoselectivity in 62% yield.
using 15 mol-% of SnCl4 at 0 °C (Table 1, Entry 1). With
The two diastereoisomers were easily separable by
heterodiene 13a, “exo” selective heterocycloaddition pro- chromatography on silica gel. Diastereoisomers were iden-
ceeded in acceptable overall yields (46%), however, the tified by comparison with the previously described cycload-
main adduct was 14b (X = OMe, 14b/14a ratio = 2:1) due duct 15 (Table 3).[12] Indeed, the chemical shifts and coup-
to the exchange in situ between the tert-butoxy group of the ling constants of protons 3-H, 4-H, and 5-H are character-
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[4+2]/HyBRedOx Approach to C-Naphthyl Glycosides
Table 1. Heterocycloaddition reactions of dienophiles 8 and 12.
exo/endo
Entry
Diene
X
Dienophile
Catalyst (mol-%)
Conditions
Adduct
% Yield
selectivity[a]
1
2
3
4
5
6
7
8
9
10
13a
13b
13b
13b
13b
13c
13c
13c
13c
13f
OtBu
OMe
OMe
OMe
OMe
NPht
NPht
NPht
NPht
NHBz
8
8
8
SnCl4 (15)
SnCl4 (15)
SnCl4 (15)
SnCl4 (15)
SnCl4 (15)
SnCl4 (15)
SnCl4 (50)
CH2Cl2, 0 °C, 3 h
CH2Cl2, 0 °C, 3 h
14a
14b
14b
14b
14c
14d
14d
–
15[b]
15
66
51
62
Ͼ97:3
Ͼ97:3
Ͼ97:3
47:53
CH2Cl2, –30 °C, 2 h
CH2Cl2, –30 °C, 2 h[c]
CH2Cl2, –30 °C, 3 h
CH2Cl2, –30 °C, 2 h
CH2Cl2, –50 °C, 1 h
THF, –78 °C to room temp. 24 h
toluene, reflux 2d
8
12
12
12
12
12
12
90:10
29
Ͼ97:3[d]
Ͼ97:3[d]
50
[CuII(Ph-Box)] (10)
[Eu(fod)3] (10)
[Eu(fod)3] (10)
0[e]
0[e]
0[e]
–
–
toluene, reflux 2d
1
[a] Diastereoselectivity determined by H NMR analysis. [b] Mixed with 31% of adduct 14b. [c] Work-up at –30 °C. [d] For exo-14d, a
5:1 mixture of two atropoisomers. [e] Complete degradation of the dienophile 12.
Table 2. Relative energies of the cycloadducts endo- and exo-14a–d bearing an N-phthalimido group at the C-4Ј center is
known to display the widest reactivity. Indeed, Tietze[24]
(calculated with semiempirical method AM1).
and Jörgensen and their co-workers[25] obtained very good
Adduct
Eendo – Eexo [kcal/mol]
results with heterodiene 13c in thermal or acid-catalyzed
HDA reactions of vinyl ethers. Thus, we first initiated our
study of the reactions of the aza series of this heterodiene
with dienophile 12 under the conditions previously opti-
mized for the methoxy heterodiene 13b. Under these condi-
tions (0.15 equiv. of SnCl4, –30 °C for 2 h) the adduct 14d
could only be obtained in a modest yield (Table 1, Entry 6).
A better result (Entry 7) was obtained by increasing the
amount of SnCl4 up to 50 mol-% while lowering the tem-
perature to –50 °C. At this low temperature, the kinetics of
the reaction could benefit from an increased quantity of
promoter without increasing the degradation of the dien-
ophile. Under these conditions adduct 14d was readily ob-
tained in 50% yield as a 5:1 mixture of two isomers, iden-
tical to those obtained at –30 °C. Note that in contrast to
14a
14b
14c
14d
1.08
2.11
2.19
3.18
istic of the endo/exo configuration of the cycloadducts. As
examples, we can mention the typical large J4H-5axH coup-
3
ling constant of the pseudoaxial position of 4-H in the exo
form. This specific position of 4-H is also responsible for
the low-field chemical shift of this proton in the exo form
(ca. 4.4 ppm).
From the different aza-substituted heterodienes de-
scribed in inverse-electron demand 1-oxa-Diels–Alder reac-
tions with electron-rich dienophiles, the heterodiene 13c
Table 3. Comparison of the NMR signals of 14b, 14c, and 15.
exo
endo
J [Hz]
δ [ppm]
J [Hz]
δ [ppm]
3-H–4-H 4-H–5eq-H 4-H–5ax-H
4-H
5eq-H
5ax-H
3-H–4-H 4-H–5eq-H 4-H–5ax-H
4-H
5eq-H
5ax-H
[a]
[a]
[a]
[a]
[a]
14b
14c
15
1.8
2.3
2
4.38
4.39
4.41
3.11
3.23
2.63
1.82
1.72
1.77
3.80
3.75
3.80
3.02
2.94
2.58
2.23
2.24
2.13
6.3
6.8
10.6
10.7
4.1
4.1
6.8
6.5
3.5
2.3
[a] Not determinable, due to coalescence at room temp.
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adduct 14c, variation of the experimental conditions (tem- of free rotation around either the C(b)–C(c) bond (Figure 4)
perature and delay before hydrolysis) did not modify the or the C(f)–O(g) bond of the pivaloyloxy group at C-1 of
diastereoisomeric ratio for adduct 14d. Moreover, these dia- the naphthalene ring (Figure 5). To answer this question the
stereomers could not be separated by chromatography on energy profiles of the rotation around these bonds were cal-
silica gel. The three other aza-substituted heterodienes 13d–
f were treated under the new optimized conditions with
SnCl4, but, despite all our efforts, none of them afforded
the desired heteroadduct. The conditions of Jörgensen and
co-workers[25] using the [Ph-Box-CuII] complex as a chiral
catalyst were also investigated with 13c and 12. Unfortu-
nately, these conditions did not lead to the expected adduct:
After aqueous treatment only ketone 9 resulting from the
hydrolysis of the dienophile was isolated (Entry 8). Finally,
the known endo selective catalyst [Eu(fod)3] was tested with
the aim of producing the adduct, from (Z)-heterodiene 13f,
that possesses the appropriate configuration for subsequent
HyBRedOx transformation. However, the formation of cy-
cloadducts starting from 13f (or 13c) was not observed,
even after heating in toluene at reflux for an extended
period of time (Entries 9 and 10).
Concerning the stereochemical outcome of the cycload-
dition catalyzed by SnCl4 between 13c and 12, we had to
assume that both isomers of 14d (in a 5:1 ratio) possess
Figure 4. Energy profile for the rotation around the C(b)–C(c)
bond of 14d.
the same exo relative configuration. Indeed, if significant
differences prevail between the chemical shifts of the
pseudoequatorial proton (5eq-H) of the CH2 group (δ =
3.00 ppm for the major adduct and 2.21 ppm for the minor
adduct), we observed a surprising similarity in the coupling
constants that characterize the signals of all the protons of
the dihydropyran ring. Moreover, comparison between
these coupling constants and those of the adducts 14c sug-
gests that both isomers of 14d possess the same relative con-
figuration, the N-phthalimido group adopting the pseudo-
equatorial position that is characteristic of an exo adduct.
In addition, we did not observe significant differences be-
tween the chemical shifts and coupling constants of the al-
lylic (4-H) protons that differentiate exo and endo isomers.
Considering this body of proof, it seems that the diaste-
reoisomerism observed in the NMR spectra relies on the
presence of two stable atropoisomeric forms of the same
exo adduct 14d (Figure 3). The presence of two atropoiso-
mers indicates that a sufficiently high rotational barrier ex-
ists between these two atropoisomers. The possible explana-
tions for this high rotational barrier might be the restriction of 14d.
Figure 5. Energy profile for the rotation around the C(f)-O(g) bond
Figure 3. Atropoisomerism suggested for exo-14d adduct.
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[4+2]/HyBRedOx Approach to C-Naphthyl Glycosides
1
Figure 6. Temperature effect on the H NMR spectra of exo-14d.
culated by using semiempirical methods (AM1, MNDO) 16a in low yield. Triacetate 16a was contaminated by non-
for 14d. The results of these studies are collected in Fig- identified byproducts. Next, we tested the tandem hydro-
ures 4 and 5. Data were collected at intervals of 5°. The boration/ketal reduction on compound 16a by using
energy barriers calculated are close to 8 kcal/mol for the BH3·THF in THF at room temperature. Unfortunately, de-
rotation around the C(b)–C(c) bond and close to 11 kcal/ spite all our attempts, no product resulting from either hy-
mol for the rotation around the C(f)–O(g) bond. The energy droboration or ketal reduction was observed after treatment
difference is high enough to assume that the restriction of of 16a with BH3·THF and no tetrahydropyran structure
the free rotation around the C–O bond of the pivaloyloxy was identified in the crude product after oxidative treat-
group at C-1 of the naphthalene ring is responsible for the ment.[26] Monitoring of the reaction by TLC showed that
atropoisomerism observed. This perturbation of the free ro- the starting material was still present before oxidation.
tation is caused by the presence of the 8-H proton on one
side and the bulky dihydropyrans on the other side. In fact,
the pivaloyl group adopts an orientation orthogonal to the
naphthalene ring with two energetically close states (Fig-
ure 5). The energy barrier for the rotation (evaluated as
11 kcal/mol) suggests an equilibrium between the two forms
at room temperature that is sufficiently slow to allow obser-
vation of the two atropoisomers by NMR at room tempera-
ture. This assumption is in agreement with the fact that the
stereochemical outcome of the cycloaddition was not affec-
ted by the conditions used. An NMR analysis of 14d at
high temperature confirmed this atropoisomeric phenome-
non. Indeed, increasing the temperature from 25 to 70 °C
produced the expected coalescence of the previously sepa-
rated signals, namely the peaks corresponding to the three
methyl groups of the pivaloyloxy group at the 1-position of
the naphthalene ring (Figure 6).
Scheme 3. Application of HyBRedOx to adduct 14b.
Next we chose to focus on the pivaloyl-protected exo-
Application of the HyBRedOx Sequence to Heteroadducts
14c. This type of protection is known to be more stable
14b,c
under basic and reducing conditions. Application of the
To access the C-glycosides the ester function of the exo- HyBRedOx sequence required the prior chemoselective re-
14b adduct was first reduced to the allylic alcohol by treat- duction of the conjugated ester group and not the pivalate
ment with LiAlH4 (Scheme 3). These conditions led to the groups located on the naphthalene ring. Hence we used di-
deprotection of the acetates on the naphthalenediol. The isobutylaluminium hydride (DIBAL-H) instead of LiAlH4
crude reaction mixture was re-acetylated to afford triacetate to avoid deprotection of the pivaloyl function. Reduction
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G. Dujardin et al.
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of the methyl ester function in exo-14c was efficiently car- could be reduced. On the basis of this result it is reasonable
ried out by using 3 equiv. of DIBAL-H at low temperature to argue that BH3·THF without further assistance could
(Scheme 4). The resulting highly polar primary alcohol was promote the reduction of the ketal function of 18[12] and
acetylated without further purification to give compound that the presence of the naphthalene ring could play a cru-
16b, which displayed only one pivalate group and two ace- cial role in this reduction. Conjugation with the aromatic
tate groups. Further experiments to prevent this unwanted ring most probably acts to stabilize the transition state and
selective reduction of the less hindered pivaloyl ester were favors the boron-assisted abstraction of the ketalic methoxy
unsuccessful or led to partial conversions.
group by a positive overlap with the anti-bonding orbital
of the C–O bond. This overlap would require a specific ori-
entation of the naphthalene ring (Figure 7). However, in the
case of 16b, the presence of the pivaloyloxy group could
disfavor this specific conformation (Figure 7, conforma-
tions A and B).
Scheme 4. Application of HyBRedOx to adduct 14c.
The conditions tested on 16a were applied to 16b
(BH3·THF in THF at room temperature) for the tandem
hydroboration/ketal reduction. Careful TLC monitoring of
the reaction showed that hydroboration of 16 did not occur
under standard conditions (BH3·THF/BH3Me2S). More-
over, oxidative treatment with Me3NO in refluxing di-
glyme[26] led to small quantities of dihydropyranic quinone
as the sole isolated product, thus confirming the failure of
the hydroboration/ketal reduction and the degradative side-
oxidation of the naphthalene ring.
These disappointing results highlight two problems. The
first is the lack of reactivity of the substrate towards borane,
which is clearly related to the presence of functional groups
on the naphthalene core. It was previously assumed that
reduction of the ketal occurred after the hydroboration
step.[12] According to this assumption, the HyBRedOx se-
quence could require a specific orientation of the axial
methoxy group that would assist the approach of the bor-
ane to the double bond. The presence of a bulky substituent
at the C-1 position of the naphthalene core could exclude
Figure 7. Energy profile for rotation around the C(j)–C(k) bond.
A comparison of the energy profiles shows that for com-
this favorable conformation and thus explain the lack of pound 16b, the two conformations corresponding to the
reactivity. previously cited criteria are higher by 1.5–2 kcal/mol than
Another explanation for the lack of reactivity can also those of the corresponding free naphthyl 18. The pivaloyl
be formulated if we consider that, in the HyBRedOx se- group would be responsible for a negative steric interaction
quence, the ketal could be reduced before the hydroboration with the CH2 of the dihydropyran on one side and the oxy-
step. Although to the best of our knowledge, this type of gen of the dihydropyran ring on the other. These interac-
reaction had never been reported in the literature, Brown tions are probably sufficient to prevent reduction of the ke-
and co-workers[27] reported an example of reduction of the tal. Considering the second step, hydroboration is well
ketal function of 2-methoxyflavan promoted by NaBH3CN known to be very sensitive to the bulkiness around the
in an acidic medium. This result suggests that due to the double bond. Thus, the steric decompression created by the
presence of an aromatic ring, even under mild conditions reduction of the ketal function is probably necessary to
and in the absence of a strong Lewis acid, the ketal function achieve the hydroboration.
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[4+2]/HyBRedOx Approach to C-Naphthyl Glycosides
added and the reaction mixture was stirred for 18 h at room tem-
perature. The mixture was neutralized with Et3N (1 mL) before
concentration in vacuo to give a brown oil. Ac2O (1.4 mL, 5 equiv.)
was added to a solution of the crude product in pyridine (20 mL)
at room temperature. The reaction mixture was stirred for 18 h at
room temperature and then quenched with a cold and saturated
NaHCO3 solution. The reaction mixture was then extracted with
EtOAc. The combined organic layers were dried with anhydrous
MgSO4. The residue obtained after concentration in vacuo was
purified by chromatography on silica gel (EtOAc/Cy, 3:7 + 1% of
Et3N) to afford 983 mg of a colorless oil (3.20 mmol, 78%, 2 steps).
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H, Ac), 2.46 (s, 3 H,
The last problem concerns the sensitivity of the 1,5-bis-
(acyloxy)naphthalene core towards oxidative conditions, at-
tested by the (low-yielding) formation of a dihydropyran
byproduct bearing a naphthoquinone moiety together with
a dihydropyran moiety unchanged with respect to 16b. This
propensity to oxidative degradation under the conditions
used[26] (Me3NO, diglyme, 120 °C) was confirmed by a
complementary assay carried out on 1,5-diacetoxynaph-
thalene.
2
Ac), 3.74 (s, 3 H, OMe), 4.45 (d, JH,H = 2.8 Hz, 1 H, 10-H), 4.53
Conclusions
2
4
(d, JH,H = 2.8 Hz, 1 H, 10-H), 7.28 (dd, JH,H = 1.0, J = 7.6 Hz,
In this study we have accessed two new dienophiles of
interest for the synthesis of complex C-aryl glycosides.
These dienophiles were successfully involved in heterocy-
3
3
1 H, 6-H), 7.50 (dd, JH,H = 7.6, JH,H = 8.6 Hz, 1 H, 7-H), 7.60
3
(d, JH,H = 8.6 Hz, 1 H, 3-H), 7.74–7.73 (m, 2 H, 4-H and 8-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.87, 20.94, 55.4, 86.7,
cloaddition reactions with selected heterodienes bearing 118.7, 118.9, 119.5, 126.3, 127.0, 127.8, 128.8 (2 C), 143.9, 146.7,
158.7, 169.0, 169.3 ppm. IR: ν = 1762, 1687 cm–1. HRMS (CI+):
˜
oxygen or nitrogen substituents at the C-4Ј position. To the
best of our knowledge this is the first report of a heterocy-
cloaddition reaction involving a polyfunctionalized vinyl-
naphthalene as the dienophile.
calcd. for C17H17O5 [M + H]+ 301.1076; found 301.1085.
1-(1,5-Dipivaloxynaphthalen-2-yl)ethanone (9): Pivaloyl chloride
(772 µL, 5 equiv.) was added dropwise to a solution of 6 (1.05 g,
5.2 mmol) in pyridine (50 mL) at room temperature. The reaction
This study has demonstrated that the HyBRedOx se-
quence is not compatible with the functionality introduced mixture was stirred at 65 °C for 18 h and then, after being cooled
to room temperature, was quenched with a cold and saturated
NaHCO3 solution. The reaction mixture was extracted with
EtOAc. The organic layers were dried with anhydrous MgSO4. The
residue obtained after concentration in vacuo was purified by
chromatography on silica gel (EtOAc/Cy, 3:7) to afford 1.8 g of a
white solid (4.62 mmol, 89%). 1H NMR (400 MHz, CDCl3): δ =
1.49 (s, 9 H, Pv), 1.52 (s, 9 H, Pv), 2.60 (s, 3 H, Ac), 7.33 (dd, 4JH,H
into the C-naphthyl substrate, which is necessary for subse-
quent oxidative transformation to the ultimate (bromo)-
naphthoquinone. Indeed, the conformation adopted by the
dihydropyran in the reduced adducts 16a,b seems to prevent
the borane reagent from undergoing to the tandem reac-
tion. If this proposed interpretation could be confirmed, a
more convenient case for the application of the
“HyBRedOx” sequence could concern derivatives of the 5-
hydroxynaphthyl series, which may be able to undergo
3
3
3
= 1.5, JH,H = 7.5 Hz, 1 H, 6-H), 7.55 (dd, JH,H = 7.5, JH,H
=
=
4
8.6 Hz, 1 H, 7-H), 7.80 (br. s, 2 H, 3-H, 4-H), 7.87 (dd, JH,H
1.5, 3JH,H = 8.6 Hz, 1 H, 8-H) ppm. 13C NMR (100 MHz, CDCl3):
“HyBRedOx”, as in the model series, and might also be δ = 27.2 (3 C), 27.3 (3 C), 29.6, 39.0 (2 C), 119.0, 120.3, 120.4,
125.4, 126.9, 127.6, 128.9, 129.7, 145.8, 146.8, 176.3, 176.6,
conveniently oxidized to bromonaphthoquinone.
197.8 ppm. IR: ν = 2976, 1750, 1684, 1629, 1599, 1480, 1462 cm–1.
˜
HRMS (CI+): (m/z): calcd. for C22H27O5 [M + H]+ 371.1858;
found 371.1874.
Experimental Section
6-Acetyl-2-bromo-5-pivaloxy-1,4-dihydronaphthalene-1,4-dione (10):
NBS (100 mg, 6 equiv.) in a 1:2 mixture of acetic acid and water
(3 mL) was added dropwise to a solution of 9 (37 mg, 0.1 mmol)
in acetic acid (1 mL) at room temperature. The reaction mixture
was stirred at 70 °C for 1 h and then, after being cooled to room
temperature, quenched with cold water. The reaction mixture was
extracted with CH2Cl2. The combined organic layers were washed
with brine and then dried with anhydrous MgSO4. The residue ob-
tained after concentration in vacuo was purified by chromatog-
raphy on silica gel (EtOAc/Cy, 3:7) to afford 23 mg of an orange
General: Air- and/or moisture-sensitive reactions were carried out
with anhydrous solvents under argon in oven/flame-dried glass-
ware. All anhydrous solvents were distilled prior to use: THF, ben-
zene, toluene, and diethyl ether from Na and benzophenone;
CH2Cl2 from CaH2. Commercial reagents were purchased from Al-
drich, Acros, Fluka and, unless otherwise noted, were used without
purification. Column chromatography was carried out by using sil-
ica gel (60–120 mesh). Nuclear magnetic resonance (NMR) spectra
were acquired with a Bruker Avance 400 spectrometer operating at
1
400 and 100 MHz for H and 13C, respectively; chemical shifts (δ)
solid (0.061 mmol, 61%). 1H NMR (400 MHz, CDCl3): δ = 1.45
are reported in parts per million (ppm) relative to tetramethylsilane,
and coupling constants (J) are reported in Hertz (Hz). The follow-
ing abbreviations are used to designate signal multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m =
multiplet, br. = broad. Infrared spectra were recorded with an FT-
IR Nicolet Avatar 370 DTGS spectrometer (Thermo Electron
Corp.) and reported in cm–1. High-resolution mass spectra
(HRMS) were recorded with a GCT Premier Micromass instru-
ment.
3
(s, 9 H, Pv), 2.58 (s, 3 H, Ac), 7.42 (s, 1 H, 3-H), 7.95 (d, JH,H
=
8.1 Hz, 1 H, 7-H), 8.17 (d, JH,H = 8.1 Hz, 1 H, 8-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 27.4 (3 C), 30.1, 39.0, 125.1, 126.1,
133.8, 133.9, 134.0, 141.9, 142.9, 144.4, 177.0, 177.1, 180.3,
197.4 ppm. HRMS (FI+): calcd. for C17H15O579Br [M]+· 378.0103;
found 378.0119.
3
2-(1-Methoxyvinyl)-1,5-dipivaloxynaphthalene (12): Trimethyl or-
thoformate (5.3 mL, 10 equiv.) was added to a solution of 9 (1.48 g,
4.00 mmol) in methanol (40 mL) at room temperature. One drop
of concd. H2SO4 was added and the reaction mixture was stirred
for 18 h at room temperature. The mixture was neutralized by ad-
dition of Et3N (1 mL) and concentrated in vacuo to give 450 mg
1,5-Diacetoxy-2-(1-methoxyvinyl)naphthalene (8): Trimethyl ortho-
formate (4.56 mL, 10 equiv.) was added to a solution of 1-(1,5-dihy-
droxynaphthalen-2-yl)ethanone (6; 1 g, 4.1 mmol) in methanol
(20 mL) at room temperature. One drop of concd. H2SO4 was
Eur. J. Org. Chem. 2009, 412–422
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
419

G. Dujardin et al.
FULL PAPER
of a red oil. The crude product was dissolved in pyridine (50 mL)
and acetyl chloride (1.4 mL, 5 equiv.) was added at room tempera-
ture. The reaction mixture was stirred for 18 h at 65 °C and then
quenched with a cold and saturated NaHCO3 solution. The reac-
tion mixture was extracted with EtOAc. The combined organic lay-
ers were dried with anhydrous MgSO4. The residue obtained after
concentration in vacuo was purified by chromatography on silica
gel (EtOAc/Cy, 3:7 + 1% of Et3N) to afford 1.33 g of a colorless
oil (3.40 mmol, 85%, 2 steps). 1H NMR (400 MHz, CDCl3: δ =
(374 mg, 1.2 equiv.) in dichloromethane (2 mL) was added to a
solution of dienophile 8 (650 mg, 2.17 mmol) in dry dichlorometh-
ane (10 mL). The reaction mixture was placed in a cooled bath
at –30 °C. A 1  solution of SnCl4 in dichloromethane (0.32 mL,
0.15 equiv.) was added dropwise. After 2 h at –30 °C, the tempera-
ture was slowly increased to room temperature and then the reac-
tion mixture was hydrolyzed by addition of a saturated aqueous
NaHCO3 solution. The aqueous phase was separated and extracted
with EtOAc. The combined organic layers were washed with brine
and then dried with anhydrous MgSO4. The residue obtained after
1.47 (s, 9 H, Pv), 1.48 (s, 9 H, Pv), 3.70 (s, 3 H, OMe), 4.42 (d,
2
2JH,H = 8.5 Hz, 1 H, 10-H), 4.43 (d, JH,H = 8.5 Hz, 1 H, 10-H), concentration in vacuo was purified by chromatography on silica
7.23 (dd, 4JH,H = 1.1 Hz, 3JH,H = 7.5 Hz, 1 H, 6-H), 7.48 (dd, 3JH,H
gel (cyclohexane/EtOAc, 80:20) to afford 635 mg of exo-14b as a
colorless oil (1.43 mmol, 66%). 1H NMR (400 MHz, CDCl3): δ
=1.78–1.86 (m, 1 H, 5ax-H), 2.44 (s, 6 H, 2 OAc), 2.99 (s, 3 H, 6-
3
3
= 7.5 Hz, JH,H = 8.5 Hz, 1 H, 7-H), 7.55 (d, JH,H = 8.8 Hz, 1 H,
3-H), 7.67 (dd, 4JH,H = 1.1 Hz, 3JH,H = 8.5 Hz, 1 H, 8-H), 7.73 (dd,
4JH,H = 1.1 Hz, JH,H = 8.8 Hz, 1 H, 4-H) ppm. 13C NMR
OMe), 3.08–3.14 (m, 1 H, 5eq-H), 3.42 (s, 3 H, 4-OMe), 3.87 (s, 3
3
3
(100 MHz, CDCl3): δ = 27.3 (3 C), 27.4 (3 C), 39.3, 39.5, 55.3, H, CO2Me), 4.34–4.45 (m, 1 H, 4-H), 6.35 (dd, JH,H = 1.8 Hz,
86.7, 118.7, 118.8, 119.5, 126.3, 127.3, 127.7, 128.1, 128.8, 144.1,
4JH,H = 2.1 Hz, 1 H, 3-H), 7.39 (dd, 4JH,H = 1.0 Hz, 3JH,H = 7.6 Hz,
3
3
146.9, 158.7, 176.3, 176.6 ppm. IR: ν = 2974, 1747, 1621, 1604,
1 H, 6Ј-H), 7.57 (dd, JH,H = 7.6 Hz, JH,H = 8.6 Hz, 1 H, 7Ј-H),
7.81–7.86 (m, 3 H, Har) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.0, 21.1, 29.7, 52.4 (2 C), 56.1, 69.3, 102.5, 113.0, 117.0, 119.2,
119.4, 125.8, 126.4, 128.2, 128.6, 129.2, 141.2, 145.1, 147.0, 163.0,
˜
1480, 1460 cm–1. HRMS (CI+): calcd. C23H29O5 [M + H]+
385.2015; found 385.2032.
Methyl (E)-4-(Dibenzylamino)-2-oxo-3-butenoate (13d): Dibenzyl-
amine (187 µL, 1.5 equiv.) was added dropwise to a solution of
heterodiene 13b (100 mg, 0.63 mmol) in THF (2 mL) at room tem-
perature. The reaction mixture was stirred for 2 h. After concentra-
tion in vacuo, the residue obtained was purified by chromatography
on silica gel (EtOAc/Cy, 2:8) to afford 162 mg of a yellow solid
169.2, 169.3 ppm. IR: ν = 2940, 1765, 1731, 1655, 1603, 1563, 1438,
˜
1366, 1165 cm–1. HRMS (FI+): calcd. for C23H24O9 [M]+·
444.1420; found 444.1403.
Methyl (4R*,6R*)-6-(1Ј,5Ј-Diacetoxynaphthalen-2Ј-yl)-5,6-dihydro-
4,6-dimethoxy-4H-pyran-2-carboxylate (endo-14b): Heterodiene 13b
(120 mg, 1.2 equiv.) in dichloromethane (1 mL) was added to a
solution of dienophile 8 (200 mg, 0.66 mmol) in dichloromethane
(7.5 mL). The reaction mixture was placed in a cooled bath at
–30 °C. A 1  solution of SnCl4 in dichloromethane (70 µL,
0.15 equiv.) was added dropwise. After 2 h at –30 °C, the reaction
mixture was hydrolyzed by addition of a saturated aqueous
NaHCO3 solution. The aqueous phase was separated and extracted
with EtOAc. The combined organic layers were washed with brine
and then dried with anhydrous MgSO4. The residue obtained after
concentration in vacuo was purified by chromatography on silica
gel (cyclohexane/EtOAc, 80:20) to afford 80 mg of endo-14b (Rf =
(0.522 mmol, 83%). 1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H,
3
Me), 4.36 (s, 2 H, CH2), 4.46 (s, 2 H, CH2), 6.14 (d, JH,H
=
12.9 Hz, 1 H, 3-H), 7.13–7.20 (m, 4 H, Har), 7.31–7.40 (m, 6 H,
3
Har), 8.20 (d, JH,H = 12.9 Hz, 1 H, 4-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 50.6, 52.3, 59.2, 92.1, 127.2, 127.7 (2 C),
127.9, 128.4, 128.8 (2 C), 128.9 (2 C), 133.9, 134.6, 158.7, 156.0,
164.6, 178.7. IR: ν = 3033, 1719, 1654, 1639, 1548, 1435 cm–1.
˜
HRMS (FI+): calcd. for C19H19NO3 [M]+· 309.1365; found
309.1346.
Methyl (4R*,6R*)-4-tert-Butoxy-6-(1Ј,5Ј-diacetoxynaphthalen-2Ј-
yl)-5,6-dihydro-6-methoxy-4H-pyran-2-carboxylate (exo-14a): Het-
erodiene 13a (144 mg, 1 equiv.) in dichloromethane (1 mL) was
added to a solution of dienophile 8 (216 mg, 0.72 mmol) in dry
dichloromethane (5 mL). The reaction mixture was placed in a co-
oled bath at 0 °C. A 1  solution of SnCl4 in dichloromethane
(0.11 mL, 0.15 equiv.) was added dropwise. After 3 h at 0 °C, the
reaction mixture was hydrolyzed by addition of a saturated aque-
ous NaHCO3 solution. The aqueous phase was separated and ex-
tracted with EtOAc. The combined organic layers were washed
with brine and then dried with anhydrous MgSO4. The residue ob-
tained after concentration in vacuo was purified by chromatog-
raphy on silica gel (cyclohexane/EtOAc, 50:50) to afford 111 mg
of a 1:2 inseparable mixture of exo-14a/exo-14b as a colorless oil
(0.33 mmol, 46%).
0.35, 0.18 mmol, 27%) and 70 mg of exo-14b (Rf
= 0.19,
1
0.16 mmol, 24%) as colorless oils. H NMR (400 MHz, CDCl3): δ
= 2.20–2.27 (m, 1 H, 5ax-H), 2.44 (br. s, 3 H, OAc), 2.47 (s, 3 H,
OAc), 2.95–3.07 (m, 4 H, 6-OMe + 5eq-H), 3.46 (s, 3 H, 4-OMe),
3.77–3.84 (m, 1 H, 4ax-H), 3.88 (s, 3 H, CO2Me), 6.47 (br. s, 1 H,
4
3
3-H), 7.31 (dd, JH,H = 1.0 Hz, JH,H = 7.6 Hz, 1 H, 6Ј-H), 7.52
3
3
3
(dd, JH,H = 7.6 Hz, JH,H = 8.6 Hz, 1 H, 7Ј-H), 7.71 (d, JH,H
8.6 Hz, 1 H, 8Ј-H), 7.79–7.83 (m, 2 H, Har) ppm.
=
Methyl (4R*,6R*)-6-(1Ј,5Ј-Dipivaloxynaphthalen-2Ј-yl)-5,6-dihydro-
4,6-dimethoxy-4H-pyran-2-carboxylate (14c): Heterodiene 13b
(60 mg, 1.2 equiv.) in dichloromethane (1 mL) was added to a solu-
tion of dienophile 12 (300 mg, 0.78 mmol) in dichloromethane
(2 mL). The reaction mixture was placed in a cooled bath at –30 °C.
A 1  solution of SnCl4 in dichloromethane (0.11 mL, 0.15 equiv.)
was added dropwise. After 2 h at –30 °C the temperature was slowly
increased to room temperature and then the reaction mixture was
hydrolyzed by addition of a saturated aqueous NaHCO3 solution.
The aqueous phase was separated and extracted with EtOAc. The
combined organic layers were washed with brine, and then dried
with anhydrous MgSO4. The residue obtained after concentration
in vacuo was purified by chromatography on silica gel (cyclohex-
ane/EtOAc, 80:20) to afford 230 mg of exo-14c (Rf = 0.29,
0.45 mmol, 57%) and 20 mg of endo-14c (Rf = 0.18, 0.04 mmol,
5%).
exo-14a (analytical sample): 1H NMR (400 MHz, CDCl3): δ = 1.26
(s, 9 H, tBu), 1.77–1.83 (m, 1 H, 5ax-H), 2.43 (s, 3 H, OAc), 2.46
(s, 3 H, OAc), 2.93–3.04 (m, 4 H, 6-OMe + 5eq-H), 3.85 (s, 3 H,
3
4
CO2Me), 4.61–4.66 (m, 1 H, 4-H), 6.17 (dd, JH,H = 1.8 Hz, JH,H
4
3
= 2.0 Hz, 1 H, 3-H), 7.30 (dd, JH,H = 1.0 Hz, JH,H = 7.6 Hz, 1
H, 6Ј-H), 7.51 (dd, JH,H = 7.6 Hz, JH,H = 8.6 Hz, 1 H, 7Ј-H),
7.68 (d, JH,H = 8.6 Hz, 1 H, 8Ј-H), 7.85–7.96 (m, 2 H, Har) ppm.
3
3
3
13C NMR (100 MHz, CDCl3): δ = 20.9, 21.2, 28.1 (3 C), 30.2, 52.2,
61.6, 74.6, 102.4, 112.9, 117.0, 119.2, 119.5, 125.8, 126.4, 128.1,
128.6, 129.2, 139.9, 144.7, 146.5, 162.9, 169.3 (2 C) ppm. HRMS
(FI+): calcd. for C26H30O9 [M]+· 486.1890; found 486.1884.
1
Methyl (4R*,6R*)-6-(1Ј,5Ј-Diacetoxynaphthalen-2Ј-yl)-5,6-dihydro-
4,6-dimethoxy-4H-pyran-2-carboxylate (exo-14b): Heterodiene 13b
exo-14c, major isomer: H NMR (400 MHz, CDCl3): δ = 1.49 (s,
3
2
9 H, Pv), 1.51 (s, 9 H, Pv), 1.72 (dd, JH,H = 10.6 Hz, JH,H
=
420
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 412–422

[4+2]/HyBRedOx Approach to C-Naphthyl Glycosides
13.1 Hz, 1 H, 5ax-H), 2.96 (s, 3 H, 6-OMe), 3.23 (ddd, JH,H
4
=
(4S*,6S*)-2-(Acetoxymethyl)-6-(1Ј,5Ј-diacetoxynaphthalen-2Ј-yl)-
5,6-dihydro-4,6-dimethoxy-4H-pyran (16a): LiAlH4 (1.01 mL, 1  in
THF, 3 equiv.) was added dropwise to a solution of adduct exo-14b
3
2
1.7 Hz, JH,H = 6.3 Hz, JH,H = 13.1 Hz, 1 H, 5eq-H), 3.41 (s, 3 H,
3
3
4-OMe), 3.87 (s, 3 H, CO2Me), 4.39 (ddd, JH,H = 2.3 Hz, JH,H
=
3
4
6.3 Hz, JH,H = 10.6 Hz, 1 H, 4ax-H), 6.23 (dd, JH,H = 1.7 Hz, J (150 mg, 0.337 mmol) in dry THF (10 mL) at 0 °C. After 45 min,
= 2.3 Hz, 1 H, 3-H), 7.26 (d, 3JH,H = 7.3 Hz, 1 H, 6Ј-H), 7.47–7.53
the temperature was increased to room temperature and the reac-
tion mixture was stirred for 18 h. The reaction mixture was
quenched by addition of a saturated aqueous NH4Cl solution at
0 °C. After removing THF in vacuo, the aqueous phase was ex-
tracted with EtOAc. The combined organic layers were washed
with brine and then dried with anhydrous MgSO4. The residue ob-
tained after concentration in vacuo was dissolved in pyridine
(5 mL) and then acetic anhydride (320 µL, 10 equiv.) was added.
After 18 h at room temperature, a saturated aqueous NaHCO3
solution was added. The aqueous phase was separated and ex-
tracted with EtOAc. The combined organic layers were washed
with brine and then dried with anhydrous MgSO4. The residue ob-
tained after concentration in vacuo was purified by chromatog-
raphy on silica gel (cyclohexane/EtOAc, 80:20) to afford 41 mg of
16a (0.09 mmol, 27%) as a red oil.1H NMR (400 MHz, CDCl3): δ
= 1.72–1.79 (m, 1 H, 5ax-H), 2.11 (s, 3 H, 1-OAc), 2.46 (s, 3 H, 1Ј-
OAc), 2.47 (s, 3 H, 5Ј-OAc), 2.99 (s, 3 H, 6-OMe), 3.05–3.15 (m, 1
H, 5eq-H), 3.37 (s, 3 H, 4-OMe), 4.25–4.33 (m, 1 H, 4-H), 4.59 (d,
2JH,H = 12.2 Hz, 1 H, 1A-H), 4.74 (m, 1 H, 1B-H), 5.26 (m, 1 H,
3-H), 7.30 (dd, 4JH,H = 1.0, J = 7.6 Hz, 1 H, 6Ј-H), 7.52 (dd, 3JH,H
= 7.6, 3JH,H = 8.6 Hz, 1 H, 7Ј-H), 7.67 (d, 3JH,H = 9.0 Hz, 1 H, 3Ј-
H), 7.79–7.85 (m, 2 H, 4Ј-H , 8Ј-H) ppm. HRMS (CI–): calcd. for
C24H26O9 [M]– 458.1577; found 458.1573.
3
(m, 2 H, 7Ј-H + 8Ј-H), 7.80–7.84 (m, 1 H, 3Ј-H), 8.03 (d, JH,H
=
8.8 Hz, 1 H, 4Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.2 (3
C), 27.4 (3 C), 39.4, 39.4, 51.3, 52.3, 56.7, 69.3, 100.3, 111.9, 118.8,
119.0, 119.3, 119.6, 125.5, 126.3, 128.3, 128.7, 129.3, 141.0, 144.9,
146.9, 163.0, 176.1, 176.7 ppm. IR: ν = 2959, 1720, 1655, 1587,
˜
1550, 1436 cm–1. HRMS (FI+): calcd. for C29H36O9 [M]+ 528.2359;
found 528.2359.
1
endo-14c, major isomer: H NMR (400 MHz, CDCl3): δ = 1.49 (s,
3
3
9 H, Pv), 1.51 (s, 9 H, Pv), 2.24 (dd, JH,H = 6.8, JH,H = 14.8 Hz,
3
3
3
1 H, 5ax-H), 2.94 (ddd, JH,H = 1.8, JH,H = 3.5, JH,H = 14.8 Hz,
1 H, 5eq-H), 3.03 (s, 3 H, 6-OMe), 3.42 (s, 3 H, 4-OMe), 3.75 (ddd,
3
3
3JH,H = 3.5, JH,H = 4.1, JH,H = 6.8 Hz, 1 H, 4eq-H), 3.88 (s, 3 H,
3
3
CO2Me), 6.43 (dd, JH,H = 1.3, JH,H = 4.1 Hz, 1 H, 3-H), 7.26
(dd, JH,H = 1.6, JH,H = 7.3 Hz, 1 H), 7.45–7.60 (m, 2 H), 7.80–
3
3
7.84 (m, 2 H) ppm.
Methyl (4R*,6R*)-6-(1Ј,5Ј-Dipivaloxynaphthalen-2Ј-yl)-5,6-dihydro-
6-methoxy-4-phthalimido-4H-pyran-2-carboxylate (14d): Heterodi-
ene 13c (164 mg, 0.633 mmol) in dichloromethane (1 mL) was
added to a solution of dienophile 12 (364 mg, 1.5 equiv.) in dichlo-
romethane (2 mL). The reaction mixture was placed in a cooled
bath at –30 °C. A 1  solution of SnCl4 in dichloromethane
(0.311 mL, 0.5 equiv.) was added dropwise. After 2 h at –30 °C the
temperature was slowly increased to room temperature and then
the reaction mixture was hydrolyzed by addition of a saturated
aqueous NaHCO3 solution. The aqueous phase was separated and
extracted with EtOAc. The combined organic layers were washed
with brine and then dried with anhydrous MgSO4. The residue ob-
tained after concentration in vacuo was purified by chromatog-
raphy on silica gel (cyclohexane/EtOAc, 90:10) to afford 212 mg of
(4R*,6R*)-2-(Acetoxymethyl)-6-(5Ј-acetoxy-1Ј-pivaloxynaphthalen-
2Ј-yl)-5,6-dihydro-4,6-dimethoxy-4H-pyran (16b): DIBAL-H (1.13
mL, 1  in toluene, 3 equiv.) was added dropwise to a solution of
adduct exo-14c (200 mg, 0.378 mmol) in dry CH2Cl2 (4 mL) at
–78 °C. After 45 min, the temperature was increased to 0 °C and
excess of DIBAL-H was quenched by addition of methanol. A sat-
urated aqueous NH4Cl solution was added. The aqueous phase
was separated and extracted with EtOAc. The combined organic
layers were washed with brine and then dried with anhydrous
MgSO4. The residue obtained after concentration in vacuo was dis-
solved in pyridine (5 mL) and then acetic anhydride (180 µL,
5 equiv.) was added. After 18 h at room temperature, a saturated
aqueous NaHCO3 solution was added. The aqueous phase was sep-
arated and extracted with EtOAc. The combined organic layers
were washed with brine and then dried with anhydrous MgSO4.
The residue obtained after concentration in vacuo was purified by
chromatography on silica gel (cyclohexane/EtOAc, 80:20) to afford
95 mg of 16b (0.192 mmol, 51%) as a colorless oil. 1H NMR
a
5:1 inseparable mixture of two diastereoisomers exo-14d
(0.316 mmol, 50%).
Major isomer: 1H NMR (400 MHz, CDCl3): δ = 1.49 (s, 9 H, Pv),
2
1.52 (s, 9 H, Pv), 2.46 (dd, 3JH,H = 12.4, JH,H = 12.8 Hz, 1 H, 5ax-
4
3
2
H), 3.00 (ddd, JH,H = 1.7, JH,H = 6.3, JH,H = 12.8 Hz, 1 H, 5eq-
3
H), 3.05 (s, 3 H, 6-OMe), 3.85 (s, 3 H, CO2Me), 5.51 (ddd, JH,H
= 2.3, JH,H = 6.3, JH,H = 12.4 Hz, 1 H, 4ax-H), 6.23 (dd, JH,H
1.7, JH,H = 2.3 Hz, 1 H, 3-H), 7.26 (dd, JH,H = 1.3, JH,H
3
3
4
=
=
3
4
3
3
3
7.3 Hz, 1 H, 6Ј-H), 7.47 (dd, JH,H = 7.3, JH,H = 8.3 Hz, 1 H, 7Ј-
H), 7.54 (d, 3JH,H = 8.3 Hz, 1 H, 8Ј-H), 7.67–7.74 (m, 2 H, 2 Phth-
3
3
(400 MHz, CDCl3): δ = 1.51 (s, 9 H, Pv), 1.72 (dd, JH,H = 10.6,
H), 7.80–7.88 (m, 3 H, 2 Phth-H + 3Ј-H), 8.10 (d, JH,H = 9.1 Hz,
3JH,H = 13.3 Hz, 1 H, 5ax-H), 2.11 (s, 3 H, 1-OAc), 2.47 (s, 3 H,
1 H, 4Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.3 (3 C), 27.5
(3 C), 33.4, 39.4, 39.6, 41.7, 51.3, 52.4, 101.3, 112.7, 118.7, 119.2,
119.3, 123.4 (2 C), 125.8, 126.6, 128.2, 128.6, 129.2, 131.8 (2 C),
134.1 (2 C), 141.2, 145.1, 147.0, 162.5, 167.5 (2 C), 176.1,
3
1Ј-OAc), 2.96 (s, 3 H, 6-OMe), 3.21 (ddd, 4JH,H = 1.5, JH,H = 6.3,
2JH,H = 13.3 Hz, 1 H, 5eq-H), 3.37 (s, 3 H, 4-OMe), 4.29 (ddd,
3JH,H = 1.8, 3JH,H = 6.3, 3JH,H = 10.6 Hz, 1 H, 4-H), 4.59 (d, 2JH,H
2
176.8 ppm. IR: ν = 2974, 1748, 1714, 1621, 1604, 1480, 1460 cm–1.
= 12.6 Hz, 1 H, 1A-H), 4.74 (d, JH,H = 12.6 Hz, 1 H, 1B-H), 5.25
˜
4
3
4
HRMS (CI+): calcd. for C36H38NO10 [M + H]+ 644.2496; found
644.2519.
(dd, JH,H = 1.5, JH,H = 1.8 Hz, 1 H, 3-H), 7.30 (dd, JH,H = 1.0,
3
3
J = 7.6 Hz, 1 H, 6Ј-H), 7.50 (dd, JH,H = 7.6, JH,H = 8.7 Hz, 1 H,
7Ј-H), 7.57 (ddd, 4JH,H = 1.0, 5JH,H = 1.1, 3JH,H = 8.7 Hz, 1 H, 8Ј-
H), 7.80 (dd, 5JH,H = 1.1, 3JH,H = 9.0 Hz, 1 H, 4Ј-H), 7.87 (d, 3JH,H
= 9.0 Hz, 1 H, 3Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8,
20.9, 27.4 (3 C), 36.1, 39.2, 50.8, 55.8, 63.4, 70.2, 101.6, 104.2,
118.9, 119.1, 119.5, 125.5, 126.3, 128.1, 129.0, 129.1, 145.0, 146.1,
146.6, 169.2, 170.5, 175.9 ppm. HRMS (CI–): calcd. for C27H32O9
[M]– 500.2046; found 500.2068.
1
Minor isomer: H NMR (400 MHz, CDCl3): δ = 1.49 (s, 9 H, Pv),
4
3
2
1.52 (s, 9 H, Pv), 2.21 (ddd, JH,H = 1.5, JH,H = 6.3, JH,H
=
12.8 Hz, 1 H, 5eq-H), 2.54 (dd, 3JH,H = 12.4, 2JH,H = 12.8 Hz, 1 H,
5ax-H), 3.32 (s, 3 H, 6-OMe), 3.84 (s, 3 H, CO2Me), 5.43 (ddd,
3
3
3JH,H = 2.3, JH,H = 6.3, JH,H = 12.4 Hz, 1 H, 4ax-H), 6.21 (dd,
3
4JH,H = 1.5, JH,H = 2.3 Hz, 1 H, 3-H), 7.26 (m, 1 H, 6Ј-H), 7.49
3
(m, 1 H, 7Ј-H), 7.59 (d, JH,H = 8.6 Hz, 1 H, 8Ј-H), 7.74–7.76 (m,
2 H, 2 Phth-H), 7.84–7.88 (m, 3 H, 2 Phth-H + 3Ј-H), 7.91 (d, Supporting Information (see also the footnote on the first page of
3JH,H = 9.1 Hz, 1 H, 4Ј-H) ppm.
this article): 13C NMR spectra and Spartan® calculations.
Eur. J. Org. Chem. 2009, 412–422
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
421

G. Dujardin et al.
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Received: July 2, 2008
Published Online: December 5, 2008
422
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 412–422