Catalytic enantioselective three-component hetero-[4+2] cycloaddition/allylboration approach to α-hydroxyalkyl pyrans: Scope, limitations, and mechanistic proposal

Article abstract of DOI:10.1002/chem.200501197

This article describes the design and optimization of a catalytic enantioselective three-component hetero-[4 + 2] cycloaddition/allylboration reaction between 3-boronoacrolein, enol ethers, and aldehydes to afford α-hydroxyalkyl dihydropyrans, The key sub

Full text of DOI:10.1002/chem.200501197

DOI: 10.1002/chem.200501197
Catalytic Enantioselective Three-Component Hetero-[4+2] Cycloaddition/
Allylboration Approach to a-Hydroxyalkyl Pyrans: Scope, Limitations, and
Mechanistic Proposal
Xuri Gao,[a] Dennis G. Hall,*[a] Michael Deligny,[b] Annaick Favre,[b]
FranÅois Carreaux,*[b] and Bertrand Carboni[b]
Abstract: This article describes the
design and optimization of a catalytic
cess were thoroughly examined. The
adduct of 3-boronoacrolein pinacolate
and ethyl vinyl ether was obtained in
high yield and with over 95% enantio-
selectivity. This cyclic a-chiral allylbor-
onate adds to a very wide variety of al-
dehyde substrates, including unsaturat-
ed aldehydes and a-chiral aldehydes to
give diastereomerically pure products.
Acyclic 2-substituted enol ethers can
be employed, in which case the catalyst
promotes a kinetically selective reac-
tion that favors Z enol ethers over the
E isomers. Surprisingly, 3-boronoacro-
lein pinacolate was found to be a supe-
rior heterodiene than ethyl (E)-4-oxo-
butenoate, and a mechanistic interpre-
tation based on a possible [5+2] transi-
tion state is proposed.
enantioselective
three-component
hetero-[4+2] cycloaddition/allylbora-
tion reaction between 3-boronoacro-
lein, enol ethers, and aldehydes to
afford a-hydroxyalkyl dihydropyrans.
The key substrate, 3-boronoacrolein pi-
nacolate (2) was found to be an excep-
tionally reactive heterodiene in the
hetero-[4+2] cycloaddition catalyzed
by Jacobsenꢀs chiral CrIII catalyst 1.
The scope and limitations of this pro-
Keywords: asymmetric catalysis
·
boron · cycloaddition · enol ethers ·
pyrans
Introduction
diverse range of substitution patterns. Consequently, there is
significant interest in the development of new synthetic
methods to access polysubstituted pyran derivatives in opti-
cally pure form.[2] In particular, a-hydroxyalkyl pyrans con-
stitute one of the most common motifs amongst all the dif-
Myriad natural products contain substituted pyran units.[1]
These substances display a broad range of biological proper-
ties, including antibiotic and anticancer activity. The pyran
units embedded within these natural products present a very
[a] X. Gao, Prof. D. G. Hall
Department of Chemistry
Gunning-Lemieux Chemistry Centre
University of Alberta
Edmonton, AB T6G 2G2 (Canada)
Fax : (+1)780-492-8231
E-mail: dennis.hall@ualberta.ca
[b] M. Deligny, A. Favre, Dr. F. Carreaux, Dr. B. Carboni
OrganomØtalliques et Catalyse:
Chimie et Electrochimie MolØculaire
UMR 6509 CNRS-UniversitØ de Rennes 1
Institut de Chimie, Campus de Beaulieu
35042Rennes CEDEX (France)
Fax : (+33)223-236-939
E-mail: francois.carreaux@univ-rennes1.fr
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
ferent structural varieties of pyrans found in nature. Notable
examples include thiomarinol antibiotics[3] and the anti-
cancer agent psymberin.[4]
strategy with diene 2 led to worries that the latter could un-
dergo an undesired “self allylboration” with the intermedi-
ate allylboronate 3, and give product 5 instead of the desired
allylation product 4 from a second aldehyde (Scheme 2,
Here, we report our joint efforts in the development and
optimization of a three-component, catalytic enantioselec-
tive hetero-[4+2] cycloaddition/allylboration method to con-
struct a-hydroxyalkylated dihydropyrans.[5] We envisioned
that 3-boronoacrolein esters could be viable substrates in in-
verse electron demand hetero-[4+2] cycloadditions with
enol ethers (Scheme 1). The known and stable unsaturated
aldehyde 2 represented an ideal model heterodiene to test
Scheme 2.
pin=pinacolate). To circumvent this potential problem, a
fast cycloaddition step that would occur at a lower tempera-
ture than that required for the allylboration step was
needed.
Initial optimization studies focused on both the conver-
sion and enantioselectivity in the formation of cyclic allyl-
boronate 3 by a hetero-Diels–Alder reaction between ethyl
vinyl ether and 3-boronoacrolein pinacolate 2 catalyzed by
chiral complex 1 (Table 1). The enantiomeric excess (ee)
Scheme 1.
this idea.[6] At the outset, the reactivity of 3-boronoacrolein
pinacolate (2) with ethyl vinyl ether was successfully ex-
plored in the presence of [Yb(fod)3] (fod=6,6,7,7,8,8,8-hep-
tafluoro-2,2-dimethyl-3,5-octanedionate.[7] As in the carbo-
cylic variant,[8] the intermediate cyclic allylboronate can be
further reacted with an added aldehyde in a sequential fash-
ion to provide a-hydroxyalkyl dihydropyrans as final prod-
ucts. The asymmetric version of this sequence, performed in
Table 1. Optimization of the hetero-[4+2] reaction of 2 and ethyl vinyl
ether catalyzed by 1.[a]
the
presence
of
Jacobsenꢀs
tridentate
(Schiff
base)chromium(iii) complex 1,[9] would constitute the first
catalytic enantioselective approach to the compelling class
of cyclic a-chiral allylboronates.[10] Furthermore, the realiza-
tion that this three-component sequence could be performed
as an operationally simple one-pot reaction adds significant
value to this strategy. Indeed, multicomponent reactions are
particularly attractive because of their intrinsic advantages
of operational simplicity, step-economy, and high degree of
convergence.[11] Recently, this one-pot three-component re-
action was successfully applied to the enantioselective total
syntheses of a number of natural products, namely, the mos-
quito oviposition pheromone (5R,6S)-6-acetoxy-5-hexadeca-
nolide,[5a] goniodiol,[12] and a thiomarinol antibiotic.[13] This
article presents a thorough study of the scope and limita-
tions of this methodology for use in the synthesis of complex
pyran-containing natural products.
Entry Catalyst loading
[mol%][b]
Additive
BaO
conversion
[%][c]
ee
[%][d]
1[e]
25
3
5
100
<50
BaO
100
95
5
4 Šm.s.
4 Šm.s.
4 Šm.s.
BaO
100
100
100
100
96
96
96
96
4
1
5
6
0.5
0.3
[a] pin=pinacolate, m.s.=molecular sieves. Conditions: distilled 2 (1M,
2mmol, 0.36 g), vinyl ethyl ether (1.9 mL), RT, 14 h. [b] Relative to 2.
[c] Measured by the integration of representative signals by 1H NMR
spectroscopy. [d] Measured by chiral HPLC (Chiralpak AD-RH column).
[e] With nondistilled 2.
was measured for the corresponding secondary alcohol
product 6 following oxidation/hydrolysis of the boronate
substituent with retention of stereochemistry.[14] The ee can
also be determined directly for the cycloadduct by GC anal-
ysis using a chiral stationary phase.
Results and Discussion
Optimization of the hetero-[4+2] cycloaddition: Initially,
our design of the hetero-[4+2] cycloaddition/allylboration
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D. G. Hall, F. Carreaux et al.
We quickly realized that the purity of the key substrate 3-
boronoacrolein pinacolate (2) is crucial. When using hetero-
diene 2 prepared in two steps from 3,3-diethoxy-1-propyne
with our recently described distillation-free procedure,[6]
only a low ee could be obtained under the standard condi-
tions[9] with 5 mol% of catalyst 1 and BaO as the dehydrat-
ing agent for 14 h in neat ethyl vinyl ether (entry 1). Al-
Scheme 4.
1
though the H NMR spectrum of substrate 2 purified by dis-
tillation showed no noticeable difference when compared
with that of a sample obtained as before, the enantioselec-
tivity was drastically improved (entry 2). The ee was equally
high with molecular sieves instead of BaO as the dehydrat-
ing agent (entry 3). The stereoselective formation of product
6 indicates that the endo cycloadduct 3 had been formed as
predicted.[9] We noted that the enantioselectivity was strong-
ly dependent on the reaction temperature and to ensure a
reproducibly high (>95%) enantioselectivity, it was crucial
that the cycloaddition was carried out at or below 238C.
Our next goal was to reduce the catalyst loading (entries 4–
6), and we were glad to observe that both conversion and ee
remained very high with as low as 0.3 mol% of complex 1.
Further reduction of catalyst loading slowed down the cyclo-
addition and allowed competitive formation of significant
amounts of side-product 5 from the allylboration between 3
and 2 (Scheme 2). In comparison with the loading values of
5–10 mol% previously reported for a wide range of a,b-un-
saturated aldehydes,[9] this result suggests that 3-boronoacro-
lein pinacolate (2) is a particularly favorable heterodiene in
this reaction. It is noteworthy to emphasize that it can also
serve as a valuable surrogate for 3-acyloxylacroleins, which
were reported to afford the synthetically useful 4-hydroxy
dihydropyran derivative with lower selectivity (89% ee).[9]
Here, intermediate 6 was isolated in a 81% yield and with
96% ee from the hetero-[4+2] cycloaddition/oxidation reac-
tion of 2. Routine transformations of the hydroxyl group of
6 led to other intermediates (e.g., 7 and 8) that could be
useful in allylic substitution chemistry (Scheme 3, DMAP=
4-dimethylaminopyridine).
3 was not attenuated when using ethyl vinyl ether as the sol-
vent.[15] The addition occurs readily at a relatively low tem-
perature (408C) and affords a-hydroxybenzyl dihydropyran
4a as a single diastereomer. This outcome is consistent with
the expected Zimmerman–Traxler transition structure 9 in-
volving anti coordination of the aldehyde to the boronyl
group, which is positioned in a pseudo-axial orientation with
respect to the pyran ring (Scheme 4). A measurement of the
enantiomeric purity of 4a confirmed that allylboronate 3
suffers no loss of stereochemical integrity in its additions to
aldehydes. On a practical standpoint, we found that it was
not necessary to purify intermediate 3 and eliminate residu-
al catalyst 1 when used only in a 1 mol% loading. Thus, this
hetero-[4+2] cycloaddition/allylboration sequence can be
performed in a “one-pot” procedure from 2 by simple addi-
tion of the aldehyde after completion of the cycloaddition
step. In contrast to recent reports describing the acceleration
of allylborations by certain Lewis acids,[16] our control ex-
periments showed that there is no metal-promoted accelera-
tion nor any retardation effect in the additions of 3 when
using catalyst 1.
Scope of the carbonyl substrate: We first explored the gen-
erality of the allylboration with nonchiral aldehydes. As de-
tailed in Table 2, suitable aldehyde substrates include aro-
matic and a,b-unsaturated aldehydes with different electron-
ic characteristics, and aliphatic aldehydes including function-
alized ones, such as TBDMSOCH2CHO (entry 9, TBDMS=
tert-butyl dimethylsilyl). All these different aldehydes af-
forded dihydropyran products 4a–4p in high yields, and the
adducts were obtained as pure diastereomers according to
1H NMR spectroscopic analysis of crude isolates. The con-
centration of the allylboration reaction has an important
impact. Provided the aldehyde is a liquid, it was found that
unactivated aldehydes afford significantly higher yields with
shorter reaction times when reactions were performed as
neat mixtures. Importantly, reactions with electron-poor a,b-
unsaturated aldehydes required a change of solvent to di-
chloromethane to avoid a competing hetero-[4+2] cycload-
dition of these aldehydes with ethyl vinyl ether (e.g.,
entry 12).
Scheme 3.
Optimization of the three-component process: Following op-
timization of the hetero-Diels–Alder reaction, the second
step in the three-component sequence, the allylboration,
was optimized by using benzaldehyde (Scheme 4, de=dia-
stereomeric excess). To this end, hetero-Diels–Alder adduct
3 was isolated by distillation or by using a short column of
silica gel. Allylboration reactions are usually carried out in
noncoordinating solvents like dichloromethane and toluene.
To our surprise, we found that the reactivity of allylboronate
The possibility of using functionalized a-chiral aldehydes
is particularly attractive in the context of natural product
synthesis. By using both enantiomers of aldehyde 10 as a
model system, and pure isolated allylboronate (S)-3, we
found that the additions are subject to a strong reagent con-
trol effect dominated by the a-chiral allylboronate
3
(Scheme 5, TBDPS=tert-butyl diphenylsilyl). The (S)-enan-
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Dihydropyrans
FULL PAPER
Table 2. Substrate scope for the catalytic enantioselective three-component hetero-[4+2] cycloaddition/allylbo-
tions, the (R)- or (S)-2-(tert-bu-
toxycarbonylamino)-3-phenyl-
propanal, PhCH2-CH(NHBoc)-
CHO, gave only untractable
mixtures of products, probably
due to the low reactivity of
these aldehydes and their ther-
mal decomposition in the allyla-
tion step.
ration reaction.[a]
Entry
Aldehyde [R]
T [8C]
t [h]
Product[b]
Yield [%][c]
1
C6H5
40
2
24
5
4a
24b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
82
92
81
77
75
82
74
81
82
89
78
81
76
88
73
86
24-NO
3
4
5
6
7
8
9
10
2-C6H4
4
4-MeO-C6H4
4-Cl-C6H4
4-F-C6H4
PhCH2
PhCH2CH2
(CH3)2CHCH2
TBDMSOCH2
C10H21
45
40
40
45
45
45
45
45
50
45
50
25
25
40
24
24
24
24
24
24
24
24
18
24
48
24
24
18
Scope of the enol ether: A
number of substituted deriva-
tives were tested as dienophiles.
Enol acetate 13 failed to react,
confirming the need for an
alkoxy substituent, as observed
previously.[9] Likewise, 1-substi-
tuted enol ethers 14 and 15 did
not provide the desired prod-
ucts of hetero-[4+2] cycloaddi-
tion.
11[d]
12[e]
13[d]
14[d]
15[d]
16[d]
(CH3)2CH
(E)-4-NO2-C6H4CH=CH
(E)-CH3CH=(CH3)C
(E)-EtO2CCH=(CH3)C
CH2=CH
CH3(CH2)4CC
One of the main appeals of
this tandem reaction method is
the possibility that 2-substituted
enol ethers, such as cyclic deriv-
atives, can be used. It is known,
however, that 2-substituted enol
[a] pin=pinacolate. Conditions: distilled 2 (1m, 2mmol, 0.36 g), vinyl ethyl ether (1.9 mL), with catalyst
1
(1 mol%), RT, 1.5 h, followed by the addition of the aldehyde (2.0 equiv) and reaction at the indicated temper-
ature and time. [b] Diastereomerically pure. Retention of the absolute stereochemistry in the allylboration of
3 is assumed based on 4a (see Experimental Section). [c] Unoptimized yields of products isolated after flash
chromatography. [d] Ethyl vinyl ether was evaporated after step i), and step ii) was carried out without solvent.
[e] Ethyl vinyl ether was evaporated after step i) and replaced with dichloromethane.
ethers are difficult substrates in inverse electron demand
Diels–Alder (IEDDA) cycloadditions due to the added
steric effect of the 2-substituent.[18] Our preliminary work
with 3 highlighted its exceptional reactivity as a hetero-
diene,[5] which we hoped could overcome the low reactivity
of a 2-substituted enol ether as a dienophilic partner. The
resultant dihydropyrans would integrate a 5-substituent that
would be difficult to install otherwise. In the event, all the
cyclic enol ethers attempted were unsuccessful except for
2,3-dihydrofuran 16. The structure of the resulting adduct 19
was determined by X-ray crystallographic analysis;[19] how-
ever, it was isolated with only about 70% ee (Scheme 6).
Scheme 5.
tiomer of 3 reacted with two equivalents of (R)-10 in tolu-
ene at 708C for 48 h to give the diastereomerically pure
adduct 11 in 78% yield. To decrease the time of the reaction
and the amount of aldehyde, the reaction was also carried
out without solvent. After ten hours at 708C and by using
only one equivalent of 10, compound 11 was obtained in
65% yield. The configurations of the four stereocentres
were determined by X-ray crystallographic analysis, which is
in agreement with Felkin–Anh selectivity.[17] The enantiomer
(S)-10 reacts much slower (36 h, 708C, neat, 55%) to form
the major adduct 12 (90% de) with the same configuration
at the newly formed center. The examples illustrated in
Scheme 5 raise the possibility that an efficient kinetic resolu-
tion of racemic aldehydes could be possible. It is also
worthy to note that, by using the same experimental condi-
Scheme 6.
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D. G. Hall, F. Carreaux et al.
The reaction of acyclic 2-substituted enol ethers was also
examined. These cycloadditions are further complicated by
difficulties in making isomerically pure 2-substituted acyclic
enol ethers. The model Z-configured enol ether 17, synthe-
sized according to a literature method,[20] was studied first in
the [4+2] cycloaddition/allylboration process. The [4+2] cy-
cloaddition reaction was indeed more difficult with such a 2-
substituted enol ether (Scheme 7). Whereas, ethyl vinyl
ture of isomers only afforded products consistent with a ki-
netically selective cycloaddition of the Z isomer. Here, we
have examined the origin of this preference by comparing
the cycloaddition of a 3:1 mixture of (Z)-18 and (E)-18
under catalysis by 1 and a standard achiral catalyst, [Yb-
(fod)3] (Scheme 8). The resulting cycloadducts 24 and 25
were characterized as their separable allylation products 26
and 27 (Scheme 9), and endo/exo stereochemistry was
Scheme 8.
Scheme 7.
ether reacted with 3 in less than 2h with 1 mol% of catalyst
1,[5a] 17 required over 5 h with 3 mol% of 1 (neat, 208C).
Nonetheless, the all-cis endo adduct 20 was cleanly formed
as a single stereoisomer. To our surprise, it was the allylbo-
ration step that proved challenging. Whereas the adduct of
ethyl vinyl ether reacted with various aldehydes at a temper-
ature of 458C, an astonishing 1108C was needed to produce
23 from 20 and aldehyde 21. As a result, the tandem process
could not be performed in “one-pot”, and we found it neces-
sary to remove catalyst 1 with a quick silica filtration to
afford a clean allylboration product. In the putative allylbo-
ration transition state 22 leading to 23, the ring may assume
an unfavorable chair-like conformation (i.e., 22a) with both
pseudo-axial boronate and ethoxy substituents. Alternative-
ly, a stereoelectronically viable boat-like conformation of
type 22b featuring a pseudo-equatorial ethoxy substituent
may also be proposed. In both scenarios, it is possible that
gauche interactions from the n-heptyl chain (R) further in-
crease the barrier for conformational change, thus leading
to a higher reaction temperature. The C4 and C5 stereo-
chemistry can be explained in the same manner as for 3.[5]
A case similar to that of 17 was recently exploited with
success in the total synthesis of a thiomarinol antibiotic.[13]
In the latter work, a (Z)-2-substituted enol ether was found
to be more reactive than its E isomer. Reactions with a mix-
Scheme 9.
proven by NOE experiments. For the enantioselective vari-
ant catalyzed by 1 (Scheme 8), the ee of 96% was measured
by chiral HPLC analysis of derivative 26. As deduced from
the outcome of the [Yb(fod)3]-catalyzed reaction, which
leads to no kinetic selectivity in the formation of adducts 24
and 25, it appears that the huge catalyst 1 (the active cata-
lyst is a water-bridged dimer)[9] provides steric control lead-
ing to
a faster consumption of (Z)-2-substituted enol
ethers.[21] This selectivity is particularly useful in view of the
difficult preparation of isomerically pure, acyclic (Z)-2-sub-
stituted enol ethers.
Preliminary mechanistic investigations: To explore the influ-
ence of the boronate substituent on the reactivity of hetero-
diene 2, a comparison with ethyl (E)-4-oxobutenoate (28)
was conducted (Scheme 10). With both catalyst 1 and [Yb-
(fod)3], the cycloaddition of 2 was significantly faster
(Figure 1, shown for catalyst 1 only).
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Dihydropyrans
FULL PAPER
Conclusion
This article described a useful study of the scope and limita-
tions of the first catalytic enantioselective hetero-[4+2] cy-
cloaddition/allylboration reaction. This multicomponent re-
action process presents several appealing features. From the
key substrate, 3-boronoacrolein pinacolate (2), the one-pot
three-component reaction provides a-hydroxyalkyl dihydro-
pyrans with very high enantio- and diastereoselectivity. The
alkene functionality of these products can be further func-
tionalized to increase the versatility of this tandem hetero-
[4+2]cycloaddition/allylboration reaction. The key cycload-
dition step occurs rapidly and efficiently with as little as 0.3
mol% of the chiral CrIII catalyst. A wide variety of aldehyde
substrates can be employed in the allylboration, including
unsaturated aldehydes and a-chiral aldehydes. Acyclic 2-
substituted enol ethers can be employed, in which case the
catalyst promotes a kinetically selective reaction that favors
Z enol ethers over the E isomers. Further extensions and
applications of this powerful and practical process in the
synthesis of complex natural products are underway.
Scheme 10.
Figure 1. Comparative cycloaddition rates (conversion vs. time) between
3-boronoacrolein pinacolate (2, ) and ethyl (E)-4-oxobutenoate (28, ”)
using catalyst 1 (Scheme 10).
^
As shown for chiral catalyst 1, conversion to product 3 is
significantly faster for 3-boronoacrolein pinacolate (2). An
extrapolation of the data for diene 28 reveals a half-time
conversion value approximately five times longer than that
of 2. It is well known that boronate substituents are much
less electron-withdrawing than carboxyesters. For example,
vinylboronates are much less reactive as dienophiles in
normal electron demand Diels–Alder reactions than acryl-
ates.[22] The electron-stabilizing effect of a boronyl group is
thought to be comparable to that of a phenyl group.[23] The
presence of a two-electron-three-atom center has been
postulated in Singletonꢀs [4+3] transition structure for the
cycloadditions of vinylboranes or the dimerization of 1,3-
dienyl-2-boronic esters.[24,25] The formation of reactant com-
plexes where the nitrone oxygen is bound up to the boron
atom (B··O interactions) has also been proposed in the 1,3-
cycloaddition of nitrones to vinylboranes.[26] The superior re-
activity of heterodiene 2 over 28 may therefore lie in the
presence of a similar interaction between the boronyl group
and the alkenyl moiety of the enol ether, thus suggesting a
[5+2] process (i.e., transition structure 30) rather than a
Experimental Section
General information: Catalyst 1 was prepared according to Jacobsenꢀs
procedure.[9] 3-Boronoacrolein pinacolate 2 was prepared according to
our previously published procedure and purified by Kugelrohr distillation
(<0.5 mm Hg, 94%).[6] Toluene and CH2Cl2 were distilled from CaH2.
Ethyl vinyl ether was stirred over KOH for 30 min before distillation. All
aldehydes were purified by Kugelrohr distillation prior to use. BaO
(Acros) was used as supplied (90% tech powder). Powdered 4 Š molecu-
lar sieves (<5 micron, Aldrich) were dried in a vacuum oven (1388C)
prior to use. Unless otherwise stated, all reagents were purchased from
Aldrich and used as received. Analytical TLC was performed on Merck
Silica Gel 60 F254 plates and were visualized with UV light and 1%
KMnO4 (aq). Deactivated silica-gel refers to silica-gel washed with trie-
thylamine prior to use. NMR spectra were recorded on Varian INOVA-
300, INOVA-400, or INOVA-500 MHz instruments. The residual solvent
protons (1H) or the solvent carbon (13C) were used as internal standards.
1H NMR spectroscopic data are presented as follows: chemical shift in
ppm (d) downfield from tetramethylsilane (multiplicity, coupling con-
stant, integration). The following abbreviations are used in reporting
1H NMR spectroscopic data: s, singlet; brs, broad singlet; d, doublet; t,
triplet; q, quartet; dq, doublet of quartets; dd, doublet of doublets; m,
mutiplet. HRMS were recorded on instruments from the University of
Alberta mass spectrum service laboratory by using either EI or ES ioni-
zation techniques, or by using an MS/MS TOF instrument. IR spectra
were obtained on a Nicolet Magna-IR 750 with frequencies expressed in
cmÀ1. Optical rotations were measured by using a 1 mL cell with a 1 dm
length on a P.E. 241 polarimeter. Melting points were determined in a ca-
pillary tube by using Gallenkamp melting point apparatus and are uncor-
rected. Enantiomeric excesses (ee) of compounds 4d–4g were deter-
mined by gas chromatography by using a Varian CP3380 GC unit equip-
ped with a capillary chiral column Varian WCOT Fused Silica 25”
0.25 mm coated CP Chirasil-dex CB DF=0.25. Other eeꢀs reported were
obtained by chiral HPLC analysis as described in the procedures.
common
[4+2]
Diels–Alder
reaction
mechanism
(Scheme 11). Quantum mechanical calculations will be nec-
essary to rationalize the experimental results and to confirm
(partially or completely) this hypothesis.
Synthesis of (2S,4S)-2-ethoxy-3,4-dihydro-2H-pyran-4-ol (6) (Table 1,
method A): Compound 1 (9.60 mg, 0.020 mmol) and powdered 4 Š mo-
lecular sieves (300 mg) were added to a mixture of 3-boronoacrolein pi-
nacolate
2 (364 mg, 2.00 mmol) and ethyl vinyl ether (1.90 mL,
20.0 mmol) in an oven dried 10 mL round-bottomed flask containing a
Scheme 11.
stirbar. The reaction was stirred for 14 h at ambient temperature (238C)
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D. G. Hall, F. Carreaux et al.
and was then filtered through celite and concentrated in vacuo to give
crude 3. 1H NMR (500 MHz, CDCl3): d=6.22 (dd, J=6.2, 2.1 Hz, 1H),
4.98 (dd, J=3.8, 2.9 Hz, 1H), 4.82 (dd, J=6.2, 4.4 Hz, 1H), 3.82 (dq, J=
9.7, 7.1 Hz, 1H), 3.56 (dq, J=9.7, 7.1 Hz, 1H), 1.96–2.02 (m, 2H), 1.73–
1.79 (m, 1H), 1.16–1.23 ppm (m, 15H).
of 6 (570 mg, 3.95 mmol) in DMF (10 mL). The mixture was stirred at
08C for 30 min and then benzyl bromide (0.570 mL, 4.80 mmol) was
added dropwise. The reaction mixture was slowly warmed to ambient
temperature and stirred overnight. After this time, the mixture was
added to water (25 mL) and ether (50 mL), and the phases were separat-
ed. The aqueous layer was extracted with ether (2”30 mL), and the com-
bined organic layers were washed with an aqueous saturated solution of
NaCl, dried over anhydrous MgSO4, concentrated, and then purified by
flash-column chromatography (deactivated silica-gel, hexanes/ether 95:5)
to provide 8 (878 mg, 95%) as a colorless oil. [a]2D3 =+22.8 (c=1.0 in
The Diels–Alder cycloadduct
3 was dissolved in THF (10 mL) and
cooled to 08C. An aqueous solution of NaOAc (3m, 1.00 mL, 3.00 mmol)
was then added dropwise and the temperature maintained below 58C.
Hydrogen peroxide (0.610 mL, 6.55 mmol) was added and the mixture
was stirred at 08C for 1 h. After this time, water (10 mL) was added and
the aqueous layer was extracted with ether (2”30 mL). The ether layers
were combined, washed with aqueous saturated solutions of NH4Cl
(15 mL) and NaCl (15 mL), then dried over anhydrous MgSO4. Filtration
and concentration in vacuo gave the crude product 6, which was purified
by flash-column chromatography (deactivated silica gel, pentane/ether
4:1) to provide 6 (234 mg, 81%) as a clear oil. [a]2D3 =+136.0 (c=1.0 in
CHCl3); IR (CH2Cl2, cast): n˜ =3064, 2976, 1646, 1229 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=7.10–7.20 (m, 5H), 6.30 (dd, J=6.3, 1.3 Hz, 1H),
4.99 (dd, J=7.7, 2.5 Hz, 1H), 4.92 (ddd, J=6.3, 2.8, 1.0 Hz, 1H), 4.56 (d,
J=1.3 Hz, 2H), 4.15–4.20 (m, 1H), 3.88 (dq, J=9.7, 7.1 Hz, 1H), 3.58
(dq, J=9.7, 7.1 Hz, 1H), 2.22 (dddd, J=13.3, 6.4, 2.5, 1.1 Hz, 1H), 2.05
(ddd, J=13.3, 7.5, 7.5 Hz, 1H), 1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=143.0, 138.6, 128.3, 127.6, 127.5, 102.8, 98.2, 69.7,
67.9, 64.5, 34.3, 15.1 ppm; HRMS (EI): m/z: calcd for C14H18O3:
234.1256; found: 234.1258.
CHCl3); IR (CH2Cl2, cast): n˜ =3553, 3431, 1646, 1297 cmÀ1 1H NMR
;
(500 MHz, CDCl3): d=6.24 (d, J=6.2Hz, 1H), 5.22(dd, J=2.2, 2.2 Hz,
1H), 5.13–5.17 (m, 1H), 3.90- 3.95 (m, 1H), 3.80 (dq, J=9.7, 7.1 Hz,
1H), 3.52(dq, J=9.7, 7.1 Hz, 1H), 3.04 (d, J=11.2 Hz, 1H), 2.21–2.25
(m, 1H), 2.02 (ddd, J=14.5, 5.0, 2.7 Hz, 1H), 1.21 ppm (t, J=7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3): d=140.8, 105.9, 96.6, 64.2, 58.6, 35.0,
15.2ppm; HRMS (EI): m/z: calcd for C7H12O3: 144.0786; found:
144.0783 [M+Na]+; assay of enantiomeric excess: chiral HPLC analysis
(Chiralpak AD-RH, 50% isopropanol/water, 0.300 mLminÀ1, 210.8 nm),
tR(major)=8.60 min; tR(minor)=10.64 min): 96% ee.
General synthesis of compounds 4 (Table 2), exemplified with 4a
(R)-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl](phenyl)methanol
(4a): Compound 1 (9.60 mg, 0.020 mmol) and powdered BaO (400 mg)
were added to a mixture of 3-boronoacrolein pinacolate 2 (364 mg,
2.00 mmol) and ethyl vinyl ether (1.90 mL, 20.0 mmol) in an oven-dried
round-bottomed flask (10 mL) containing a stirbar. After stirring for
1.5 h at ambient temperature (238C), benzaldehyde (424 mg, 4.00 mmol)
was added to the reaction mixture. The reaction mixture was stirred at
408C for 24 h, then diluted with EtOAc and filtered through celite. The
EtOAc solution was stirred for 30 min with an aqueous saturated solution
of NaHCO3. After this time, the organic layer was separated and the
aqueous layer was extracted with EtOAc (2”20 mL). The combined or-
ganic layers were washed with an aqueous saturated solution of NaCl
(20 mL), dried over anhydrous MgSO4, filtered, and concentrated to
afford 4a as a crude product. Purification by flash-column chromatogra-
phy (deactivated silica-gel, hexanes/ether 9:1) led to the pure product 4a
(384 mg, 82%) as a clear oil. [a]2D3 +24.9 (c=1.0 in CHCl3); IR (CH2Cl2,
(2S,4S)-2-Ethoxy-3,4-dihydro-2H-pyran-4-ol (Table 1, method B): Com-
pound 1 (2.90 mg, 0.006 mmol) and powdered BaO (200 mg) were added
to a mixture of 3-boronoacrolein pinacolate 2 (364 mg, 2.00 mmol) and
ethyl vinyl ether (1.90 mL, 20.0 mmol) in an oven-dried round-bottomed
flask (10 mL) containing a stirbar. The reaction was stirred for 14 h at
ambient temperature, then filtered through celite and concentrated in
vacuo to give crude 3. An aqueous solution of NaOAc (3M, 1.00 mL,
3.00 mmol) was then added dropwise to a precooled solution (08C) of
the Diels–Alder cycloadduct 3 in THF (10 mL) and the temperature
maintained below 58C. Hydrogen peroxide (0.610 mL, 6.55 mmol) was
added and the mixture was stirred at 08C for 1 h. After this time, water
(10 mL) was added and the aqueous layer was extracted with ether (2”
30 mL). The ether layers were combined, washed with aqueous saturated
solutions of NH4Cl (15 mL) and NaCl (15.0 mL), then dried over anhy-
drous MgSO4. Filtration and concentration in vacuo gave the crude prod-
uct 6, which was purified by flash-column chromatography (deactivated
silica gel, pentane/ether 4:1) to provide 6 (234 mg, 81%) as a clear oil.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralpak AD-RH,
50% isopropanol/water, 0.300 mLminÀ1, 210.8 nm), tR(major)=8.60 min;
tR(minor)=10.64 min): 96% ee.
cast): n˜ =3451, 3035, 2877, 1640, 1257 cmÀ1 1H NMR (500 MHz, CDCl3):
;
d=7.26–7.40 (m, 5H), 5.75–5.79 (m, 1H), 5.36–5.40 (m, 1H), 4.78 (dd,
J=5.9, 5.9 Hz, 1H), 4.56 (dd, J=7.4, 1.5 Hz, 1H), 4.28–4.32 (m, 1H),
3.96 (dq, J=9.7, 7.1 Hz, 1H), 3.58 (dq, J=9.7, 7.1 Hz, 1H), 3.11 (brs,
1H), 2.10–2.12 (m, 2H), 1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=139.8, 128.3, 128.0, 127.2, 125.4, 124.8, 98.5, 78.7,
76.8, 64.5, 31.1, 15.3 ppm; HRMS (ESI) m/z: calcd for C14H18O3Na:
257.1154; found: 257.1152 [M+Na]+; assay of enantiomeric excess: chiral
HPLC
analysis (chiralpak
AD-RH, 50% isopropanol/water,
0.300 mLminÀ1, 210.8 nm), tR(major)=8.60 min; tR(minor)=10.64 min):
96% ee.
(2S,4S)-2-Ethoxy-3,4-dihydro-2H-pyran-4-yl acetate (7): A solution of 6
(186 mg, 1.29 mmol), 2,6-lutidine (0.200 mL, 1.96 mmol), and DMAP
(15.7 mg, 0.129 mmol) in dry CH2Cl2 (4 mL) was prepared in a round-
bottomed flask (25 mL). The mixture was cooled to 08C and then acetic
anhydride (0.120 mL, 1.29 mmol) was added by a syringe. The reaction
mixture was stirred at 08C for 1 h and then further stirred at ambient
temperature overnight. After this time, water (10 mL) and ether (30 mL)
were added to the solution. The phases were separated and the aqueous
layer was extracted with ether (3”20 mL). The combined organic layers
were washed with an aqueous saturated solution of NaCl, dried over an-
hydrous MgSO4, filtered, concentrated, and purified by flash-column
chromatography (deactivated silica-gel, hexanes/ether 9:1) to provide 7
(233 mg, 96%) as a colorless oil. [a]2D3 =+37.0 (c=1.0 in CHCl3); IR
(R)-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl](4-nitrophenyl)metha-
nol (4b): Same procedure as for 4a, except that the allylboration with 4-
nitrobenzaldehyde (604 mg, 4.00 mmol) took place at ambient tempera-
ture for 24 h. Purification by flash-column chromatography (deactivated
silica-gel, hexanes/ether 9:1) led to the pure product 4b (512mg, 92%)
as a brown solid. M.p. 102–1038C; [a]2D3 =+23.0 (c=1.0 in CHCl3); IR
(CH2Cl2, cast) n˜ =3442, 2977, 1604, 1519, 1431 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d=8.21 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 5.82–5.88
(m, 1H), 5.46–5.50 (m, 1H), 4.79 (dd, J=6.3, 3.9 Hz, 1H), 4.75 (dd, J=
4.9, 4.9 Hz, 1H), 4.35–4.39 (m, 1H), 3.83 (dq, J=9.6, 7.1 Hz, 1H), 3.52
(dq, J=9.6, 7.1 Hz, 1H), 3.39 (d, J=3.9 Hz, 1H), 2.18–2.25 (m, 2H),
1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=147.8,
147.5, 127.8, 125.6, 124.7, 123.4, 98.1, 77.8, 75.6, 64.7, 30.8, 15.3 ppm;
HRMS (EI): m/z: calcd for C14H16O5N: 278.1028 [MÀH]+; found:
278.1027.
1
(CH2Cl2, cast): n˜ =3071, 2929, 1730, 1650, 1244 cmÀ1; H NMR (300 MHz,
CDCl3): d=6.42(dd, J=6.3, 1.0 Hz, 1H), 5.26–5.32 (m, 1H), 5.06 (dd,
J=5.2, 2.9 Hz, 1H), 4.96 (dd, J=6.3, 4.9 Hz, 1H), 3.90 (dq, J=9.7,
7.1 Hz, 1H), 3.58 (dq, J=9.7, 7.1 Hz, 1H), 2.06–2.30 (m, 2H), 2.05 (s,
3H), 1.21 ppm (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=
170.9, 144.2, 100.7, 96.6, 64.5, 62.7, 33.0, 21.3, 15.0 ppm; HRMS (EI):
m/z: calcd for C9H14O4: 186.0892; found: 186.0897.
(R)-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl](4-methoxyphenyl)me-
thanol (4c): Same procedure as for 4a, except that the allylboration with
p-anisaldehyde (544 mg, 4.00 mmol) took place at 458C for 24 h. Purifica-
tion by flash-column chromatography (deactivated silica-gel, hexane/
(2S,4S)-2-Ethoxy-3,4-dihydro-2H-pyran-4-yl benzoate (8): NaH (95%,
ether 9:1) led to the pure product 4c (428 mg, 81%) as a clear oil. [a]D23
=
131 mg, 5.20 mmol) was added to a precooled (ice-water bath) solution
+24.3 (c=1.0 in CHCl3); IR (CH2Cl2, cast): n˜ =3442, 2977, 1604, 1519,
3138
www.chemeurj.org
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Chem. Eur. J. 2006, 12, 3132– 3142

Dihydropyrans
FULL PAPER
1431 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.32(d, J=8.1 Hz, 2H), 6.85
J=5.5, 5.5 Hz, 1H), 4.07–4.11 (m, 1H), 3.96 (dq, J=9.6, 7.1 Hz, 1H),
3.50–3.66 (m, 2H), 2.42 (d, J=5.7 Hz, 1H), 2.18–2.23 (m, 2H), 1.80–1.90
(m, 1H), 1.50–1.60 (m, 1H), 1.22–1.38 (m, 4H), 0.96 (d, J=7.8 Hz, 3H),
0.93 ppm (d, J=7.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=126.6,
124.7, 98.4, 77.7, 71.4, 64.2, 41.9, 31.1, 24.4, 23.6, 21.8, 15.1 ppm; HRMS
(ESI): m/z: calcd for C12H22O3Na: 237.1461; found: 237.1461.
(d, J=8.1 Hz, 2H), 5.72–5.78 (m, 1H), 5.32–5.36 (m, 1H), 4.79 (dd, J=
7.7, 5.3 Hz, 1H), 4.50 (d, J=7.7 Hz, 1H), 4.26–4.30 (m, 1H), 4.01 (dq, J=
9.6, 7.1 Hz, 1H), 3.80 (s, 3H), 3.59 (dq, J=9.6, 7.1 Hz, 1H), 3.18 (brs,
1H), 2.19–2.23 (m, 2H), 1.23 ppm (t, J=7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=159.4, 131.9, 128.5, 125.4, 124.7, 113.7, 98.5, 78.8,
76.4, 64.5, 55.2, 31.1, 15.2 ppm; HRMS (EI) m/z: calcd for C15H20O4:
264.1362; found: 264.1367.
(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-[(2R,6S)-6-ethoxy-5,6-dihydro-
2H-pyran-2-yl]ethanol (4i): Same procedure as for 4a except that the al-
lylboration was carried out with tert-butyl(dimethylsilyloxy)acetaldehyde
(697 mg, 4.00 mmol). Purification by flash-column chromatography (de-
activated silica-gel, hexane/ether 9:1) led to the pure product 4i (496 mg,
82%) as clear oil. [a]2D3 =+34.5 (c=1.0 in CHCl3); IR (CH2Cl2, cast): n˜ =
(R)-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl](4-chlorophenyl)me-
thanol (4d): Same procedure as for 4a, except that the allylboration with
4-chlorobenzaldehyde (280 mg, 2.00 mmol) took place at 408C for 24 h.
Purification by flash-column chromatography (deactivated silica-gel,
hexane/ether 9:1) led to the pure product 4d (206 mg, 77%) as a clear
3324, 3038, 2857, 1317 cmÀ1 1H NMR (300 MHz, CDCl3): d=5.78–5.86
;
oil. [a]2D3 =+48.4 (c=1.0 in CHCl3); H NMR (300 MHz, CDCl3): d=7.34
1
(m, 1H), 5.66–5.70 (m, 1H), 4.76 (dd, J=6.2, 4.7 Hz, 1H), 4.41–4.45 (m,
1H), 3.93 (dq, J=9.6, 7.1 Hz, 1H), 3.60–3.76 (m, 3H), 3.50 (dq, J=9.6,
7.1 Hz, 1H), 2.62 (d, J=5.9 Hz, 1H), 2.18–2.22 (m, 2H), 1.25 (t, J=
7.1 Hz, 3H), 0.86 (s, 9H), 0.02ppm (s, 6H); 13C NMR (125 MHz,
CDCl3): d=126.8, 124.5, 98.4, 73.9, 73.2, 64.4, 63.2, 31.0, 25.9, 18.2, 15.1,
À5.4, À5.5 ppm; HRMS (ESI): m/z: calcd for C15H30O4NaSi: 325.1806;
found: 325.1804.
(s, 4H), 5.78–5.82(m, 1H), 5.40 (dd, J=10.3, 1.8 Hz, 1H), 4.79 (t, J=
5.5 Hz, 1H), 4.61 (d, J=7.0 Hz, 1H), 4.24–4.33 (m, 1H), 3.98 (dq, J=9.6,
7.1 Hz, 1H), 3.58 (dq, J=9.6, 7.1 Hz, 1H), 3.30 (brs, 1H), 2.20–2.27 (m,
2H), 1.26 ppm (t, J=7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3): d=138.6,
133.7, 128.6, 128.5, 125.2, 125.1, 98.4, 78.4, 76.0, 64.5, 30.9; 15.2 ppm; ele-
mental analysis calcd for C14H17ClO3: C 62.57, H 6.38; found: C 62.76, H
6.81.
(1R)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]undecan-1-ol (4j):
Same procedure as for 4a except that the allylboration was carried out
with undecanal (680 mg, 4.00 mmol). Purification by flash-column chro-
matography (deactivated silica-gel, hexane/ether 9:1) led to the pure
product 4j (530 mg, 89%) as a clear oil. [a]2D3 =+54.7 (c=1.0 in CHCl3);
(R)-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl](4-fluorophenyl)me-
thanol (4e): Same procedure as for 4a, except that the allylboration with
4-fluorobenzaldehyde (248 mg, 2.00 mmol) took place at 408C for 24 h.
Purification by flash-column chromatography (deactivated silica-gel,
hexane/ether 9:1) led to the pure product 4e (189 mg, 75%) as a solid.
IR (CH2Cl2, cast): n˜ =3454, 3040, 2854, 1209 cmÀ1 1H NMR (300 MHz,
;
1
M.p. 698C; [a]2D3 =+13.7 (c=1.0 in CHCl3); H NMR (300 MHz, CDCl3):
CDCl3): d=5.80–5.86 (m, 1H), 5.62–5.68 (m, 1H), 4.76 (dd, J=5.5,
5.5 Hz, 1H), 4.12–4.16 (m, 1H), 3.96 (dq, J=9.5, 7.1 Hz, 1H), 3.46–3.62
(m, 2H), 2.42 (d, J=5.7 Hz, 1H), 2.19–2.23 (m, 2H), 1.20–1.60 (m, 21H),
0.88 ppm (t, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=126.7,
124.7, 98.5, 77.2, 73.3, 64.3, 33.0, 31.9, 31.1 29.7, 29.6, 29.6, 29.5, 29.3, 25.6,
22.6, 15.1, 14.0 ppm; HRMS (EI): m/z: calcd for C18H34O3: 298.2508;
found: 298.2504.
d=7.32–7.49 (m, 2H), 7.01–7.22 (m, 2H), 5.72–5.87 (m, 1H), 5.33–5.47
(m, 1H), 4.83 (t, J=5.4 Hz, 1H), 4.65 (dd, J=7.3, 2.2 Hz, 1H), 4.27–4.39
(m, 1H), 4.06 (dq, J=9.5, 7.1 Hz, 1H), 3.67 (dq, J=9.5, 7.1 Hz, 1H), 3.43
(brs, 1H), 2.22–2.32 (m, 2H), 1.30 ppm (t, J=7.1 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d=162.4 (J(C,F)=4.8 Hz), 135.8 (J(C,F)=0.1 Hz),
135.7, 129.0, 128.9, 125.2, 125.1, 115.4, 115.0, 98.5, 78.7, 76.2, 64.6, 31.0;
15.2; elemental analysis calcd for C14H17FO3: C 68.16, H 7.63; found: C
68.16, H 7.81.
Solvent-free procedure for the preparation of 4k and 4m–4p: The cyclo-
addition reaction was carried out by using the same procedure as that for
4a. After the completion of the cycloaddition reaction, the ethyl vinyl
ether was evaporated in vacuo and the aldehyde (4.00 mmol) was added
to the residue. The reaction was stirred at ambient or an elevated temper-
ature for 18–48 h, then diluted with EtOAc and filtered through celite.
The EtOAc solution was stirred for 30 min with an aqueous saturated so-
lution of NaHCO3. The organic layer was separated and the aqueous
layer was extracted with EtOAc (2”20 mL). The combined organic
layers were washed with an aqueous saturated solution of NaCl then
dried over anhydrous MgSO4, filtered, and concentrated to afford 4k or
4m–4p as a crude product. Purification by flash-column chromatography
(deactivated silica-gel, hexanes/ether) led to the pure product 4k or prod-
ucts 4m–4p.
(1R)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]-2-phenylethanol
(4 f): Same procedure as for 4a, except that the allylboration with phe-
nylacetaldehyde (240 mg, 2.00 mmol) took place at 458C for 24 h. Purifi-
cation by flash-column chromatography (deactivated silica-gel, hexane/
ether 9:1) led to the pure product 4 f (204 mg, 82%) as a clear oil. [a]D23
=
+23.7 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3) d=7.25–7.50 (m,
5H), 5.82–5.94 (m, 1H), 5.62–5.70 (m, 1H), 4.80 (t, J=5.4 Hz, 1H), 4.13–
4.21 (m, 1H), 4.09 (dq, J=9.5, 7.1 Hz, 1H), 3.72–3.89 (m, 1H), 3.66 (dq,
J=9.5, 7.1 Hz, 1H), 3.02(d, J=13.5, 6.9 Hz, 1H), 2.92 (d, J=12.5,
7.1 Hz, 1H,), 2.60 (brs, 1H), 2.22–2.29 (m, 2H), 1.25 ppm (t, J=7.1 Hz,
3H); 13C NMR (50 MHz, CDCl3): d=138.9, 129.8, 128.9, 127.3, 126.8,
125.4, 98.9, 75.7, 74.7, 64.9, 40.0, 31.4, 15.7 ppm; HRMS (EI): m/z: calcd
for C13H14O2: 202.0994 [MÀHOC2H5]+; found: 202.0990.
(1R)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]-2-methylpropan-1-
ol (4k): Colorless oil; Yield: 270 mg, 78%; [a]2D3 =À71.0 (c=1.6 in
(1R)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]-3-phenylpropan-1-
ol (4g): Same procedure as for 4a, except that the allylboration with hy-
drocinnamaldehyde (264 mg, 2.00 mmol) took place at 458C for 24 h. Pu-
rification by flash-column chromatography (deactivated silica-gel,
hexane/ether 9:1) led to the pure product 4g (193 mg, 74%) as a clear
oil. [a]2D3 =+70.7 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
7.16–7.34 (m, 5H), 5.80–5.89 (m, 1H), 5.64 (dq, J=10.3, 1.7 Hz, 1H),
4.76 (dd, J=5.4, 6.0 Hz, 1H), 4.15–4.22 (m, 1H), 3.98 (dq, J=9.5, 7.1 Hz,
1H), 3.53–3.65 (m, 2H), 2.84–2.96 (m, 1H), 2.68–2.81 (m, 1H), 2.58 (brd,
J=5.8 Hz, 1H), 2.20–2.28 (m, 2H), 1.82–2.02 (m, 2H), 1.30 ppm (t, J=
7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3): d=142.2, 128.5, 128.4, 126.5,
125.8, 124.9, 98.5, 77.3, 72.6, 64.4, 35.0, 32.0, 31.0, 15.2 ppm; HRMS (EI):
m/z: calcd for C14H16O2: 216.1150 [MÀHOC2H5]+; found: 216.1150.
CHCl3); IR (CH2Cl2, cast): n˜ =3454, 3039, 1471, 1237 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=5.79–5.86 (m, 1H), 5.61–5.66 (m, 1H), 4.75 (dd,
J=6.0, 5.0 Hz, 1H), 4.32–4.37 (m, 1H), 3.96 (dq, J=9.6, 7.1 Hz, 1H),
3.58 (dq, J=9.6, 7.1 Hz, 1H), 3.21 (ddd, J=7.0, 7.0, 3.9 Hz, 1H), 2.32 (d,
J=7.2 Hz, 1H), 2.19–2.25 (m, 2H), 1.91 (octet, J=6.8 Hz, 1H), 1.62–1.66
(m, 6H), 1.25 (t, J=7.1 Hz, 3H), 1.02(d, J=6.8 Hz, 3H), 0.98 ppm (d,
J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=127.4, 124.6, 98.4, 78.1,
75.0, 64.3, 30.9, 30.6, 19.5, 18.1, 15.1 ppm; HRMS (ESI): m/z: calcd for
C11H20O3Na: 223.1305; found: 223.1303.
(1R,2E)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]-2-methylbut-2-
en-1-ol (4m): Colorless oil; Yield: 323 mg, 76%; [a]2D3 =+57.1 (c=1.0 in
CHCl3); IR (CH2Cl2, cast): n˜ =3462, 3041, 1650, 1256 cmÀ1 1H NMR
;
(1R)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]-3-methylbutan-1-ol
(4h): Same procedure as for 4a except that the allylboration was carried
out with isovaleraldehyde (344 mg, 4.00 mmol). Purification by flash-
column chromatography (deactivated silica-gel, hexane/ether 9:1) led to
the pure product 4h (347 mg, 81%) as a clear oil. [a]2D3 =+98.0 (c=1.0 in
(300 MHz, CDCl3): d=5.76–5.82(m, 1H), 5.46–5.62(m, 2H), 4.78 (dd,
J=6.2, 5.0 Hz, 1H), 4.22–4.28 (m, 1H), 3.86–4.02 (m, 2H), 3.58 (dq, J=
9.6, 7.1 Hz, 1H), 2.80 (brs, 1H), 2.19–2.23 (m, 2H), 1.62–1.66 (m, 6H),
1.23 ppm (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=133.8,
126.0, 124.4, 124.2, 98.6, 79.9, 76.0, 63.4, 31.1, 15.2, 13.1, 11.6 ppm; HRMS
(ESI): m/z: calcd for C12H20O3Na: 235.1305; found: 235.1299.
CHCl3); IR (CH2Cl2, cast): n˜ =3446, 3041, 1467, 1293 cmÀ1
(300 MHz, CDCl3): d=5.79–6.05 (m, 1H), 5.62–5.68 (m, 1H), 4.73 (dd,
;
1H NMR
Chem. Eur. J. 2006, 12, 3132– 3142
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3139

D. G. Hall, F. Carreaux et al.
Ethyl-(2E,4R)-4-[(2R,6S)-6-ethoxy-5,6-dihydro-2H-pyran-2-yl]-4-hy-
droxy-3-methylbut-2-enoate (4n): Colorless oil; Yield: 476 mg, 88%;
[a]2D3 =À53.3 (c=1.0 in CHCl3); IR (CH2Cl2, cast): n˜ =3464, 2977, 1714,
7.1 Hz, 3H), 1.02ppm (s, 9H); 13C NMR (50 MHz, CDCl3): d=141.7,
136.5, 136.4, 134.4, 133.7, 129.8, 128.4, 128.2, 127.8, 127.6, 127.9, 124.9,
98.4, 77.3, 76.3, 73.5, 64.6, 31.2, 27.4, 19.8, 15.5 ppm; HRMS (EI): m/z:
calcd for C25H23O3Si: 399.1417 [MÀHOC2H5ÀtBu]+; found: 399.1410.
1652cm À1 1H NMR (500 MHz, CDCl3): d=6.02(s, 1H), 5.82–5.88 (m,
;
1H), 5.58–5.62(m, 1H), 4.73–4.77 (m, 1H), 4.41–4.45 (m, 1H), 4.15 (q,
J=7.1 Hz, 2H), 3.97–4.01 (m, 1H), 3.86 (dq, J=9.6, 7.1 Hz, 1H), 3.52
(dq, J=9.6, 7.1 Hz, 1H), 3.12(d, J=6.3 Hz, 1H), 2.19–2.26 (m, 2H), 2.18
(s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.23 ppm (t, J=7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=166.5, 156.7, 125.8, 124.8, 117.1, 97.7, 77.8, 74.9,
64.4, 59.5, 30.4, 15.2, 15.0, 14.2 ppm; HRMS (ESI): m/z: calcd for
C14H22O5Na: 293.1359; found: 293.1136.
(1S,2S)-2-{[tert-Butyl(diphenyl)silyl]oxy}-1-[(2R,6S)-6-ethoxy-5,6-dihy-
dro-2H-pyran-2-yl]-2-phenylethanol (12): Same procedure as for 11,
except that the allylboration took place at 708C for 36 h, producing the
product (550 mg, 65%) as a clear oil and a mixture of two diastereoiso-
mers (10:1). [a]2D3 =+24.2 (c=0.75 in CHCl3); major diastereoisomer 12:
1H NMR (500 MHz, CDCl3): d=7.70–7.77 (m, 2H), 7.20–7.48 (m, 13H),
5.72–5.78 (m, 1H), 5.57 (dq, J=10.2, 1.6 Hz, 1H), 4.82 (d, J=7.6 Hz,
1H), 4.47 (dd, J=6.1, 7.2Hz, 1H), 3.84–3.90 (m, 1H), 3.75 (ddd, J=1.9,
7.0, 7.6 Hz, 1H), 3.62(dq, J=7.0, 9.5 Hz, 1H), 3.35 (dq, J=7.0, 9.5 Hz,
1H), 2.70 (d, 1H, J=7.0 Hz), 2.02–2.21 (m, 2H), 1.17 (t, J=7.0 Hz, 3H),
1.06 ppm (s, 9H); 13C NMR (50 MHz, CDCl3): d=141.0, 133.8, 133.3,
136.0, 135.8, 129.6, 129.4, 128.0, 127.9, 127.6 127.5, 127.4, 124.4, 98.0, 77.7,
77.3, 72.9, 64.0, 30.7, 27.0, 19.2, 15,2 ppm; HRMS (EI): m/z: calcd for
C25H23O3Si: 399.1416 [MÀtBuÀC2H5OH]+; found: 399.141 [MÀCHOH-
(C5H6O)OC2H5]+; calcd for C23H25OSi: 345.1675; found: 345.1670; minor
(1R)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]prop-2-en-1-ol
(4o): Colorless oil; Yield: 73%; [a]2D3 =+101.95 (c=5.2in CHCl 3); IR
(CH2Cl2, cast): n˜ =3448, 3042, 1648, 1210 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d=5.80–5.98 (m, 2H), 5.63–5.69 (m, 1H), 5.40 (ddd, J=16.3, 1.7,
1.7 Hz, 1H), 5.27 (ddd, J=10.4, 1.7, 1.7 Hz, 1H), 4.78 (dd, J=6.3, 4.3 Hz,
1H), 4.15–4.21 (m, 1H), 4.05 (dd, J=6.2, 6.2 Hz, 1H), 4.02 (dq, J=9.6,
7.1 Hz, 1H), 3.58 (dq, J=9.6, 7.1 Hz, 1H), 2.82 (brs, 1H), 2.30–2.20 (m,
2H), 1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=
136.8, 125.7, 124.7, 117.3, 98.2, 77.1, 74.9, 64.4, 30.9, 15.1 ppm; HRMS
(ESI): m/z: calcd for C10H16O3Na: 207.0992; found: 207.0990.
1
isomer (characteristic signals): H NMR (500 MHz, CDCl3): d=7.65–7.68
(m, 2H), 5.63–5.70 (m, 1H), 4.92 (d, J=4.5 Hz, 1H,), 4.3 (t, J=5.5 Hz,
1H), 3.4.5 (dq, J=7.0, 9.5 Hz, 1H), 3.08–317 ppm (m, 1H).
(1R)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]oct-2-yn-1-ol (4p):
Colorless oil; Yield: 86%; [a]2D3 =+87.16 (c=1.0 in CHCl3); IR (CH2Cl2,
(R)-phenyl[(3aR,6R,7aS)-2,3,3a,7a-tetrahydro-6H-furo [2,3Àb]pyran-6-
yl]methanol (19): Catalyst 1 (48.0 mg, 0.100 mmol) and BaO (400 mg)
were added to a mixture of 3-boronoacrolein pinacolate 2 (182mg,
1.00 mmol) and 2,3-dihydrofuran 16 (700 mg, 10.0 mmol) in an oven-
dried round-bottomed flask(10 mL) containing a stirbar. After 1.5 h of
stirring at ambient temperature (238C), 16 was evaporated in vacuo and
benzaldehyde (212 mg, 2.00 mmol) was added to the residue. The reac-
tion was allowed to stir at room temperature for 24 h, and was then dilut-
ed with EtOAc and filtered through celite. The EtOAc solution was stir-
red for 30 min with an aqueous saturated solution of NaHCO3. The or-
ganic layer was then separated and the aqueous layer extracted with
EtOAc (2”20 mL). The combined organic layers were washed with an
aqueous saturated solution of NaCl, dried over anhydrous MgSO4, fil-
tered, and concentrated to afford 19 as a crude product. Purification by
flash-column chromatography (deactivated silica-gel, hexanes/EtOAc
4:1) led to the pure product 19 (141 mg, 61%) as an oil, which crystal-
lized when stored at À58C. [a]2D3 =À10.2( c=1.23 in CHCl3); IR (CH2Cl2,
cast): n˜ =3441, 3043, 1652, 1210 cmÀ1 1H NMR (500 MHz, CDCl3): d=
;
5.78–5.95 (m, 2H), 4.82 (dd, J=6.4, 4.0 Hz, 1H), 4.22–4.32 (m, 1H), 4.02
(dq, J=9.6, 7.1 Hz, 1H), 3.58 (dq, J=9.6, 7.1 Hz, 1H), 2.92 (d, J=4.0 Hz,
1H), 2.19–2.26 (m, 4H), 1.50–1.58 (m, 2H), 1.30–1.40 (m, 4H), 1.26 (t,
J=7.1 Hz, 3H), 0.88 ppm (t, J=7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=125.5, 124.8, 98.1, 87.0, 77.6, 77.4, 65.4, 64.5, 31.0, 30.8, 28.2,
22.1, 18.7, 15.1, 13.9 ppm; HRMS (ESI): m/z: calcd for C15H24O3Na:
275.1618; found: 275.1619.
(1R,2E)-1-[(2R,6S)-6-Ethoxy-5,6-dihydro-2H-pyran-2-yl]-3-(4-nitrophen-
yl)prop-2-en-1-ol (4l): The cycloaddition reaction was carried out by
using the same procedure as that for 4a. After the completion of cyclo-
addtion, the ethyl vinyl ether was evaporated in vacuo. The residue was
dissolved in CH2Cl2 (1 mL) and 4-nitrocinnamaldehyde (708 mg,
4.00 mmol) was added to the solution. The reaction was stirred at 408C
for 24 h, then diluted with EtOAc and filtered through celite. The EtOAc
solution was stirred for 30 min with an aqueous saturated solution of
NaHCO3. The organic layer was then separated and the aqueous layer
extracted with EtOAc (2”20 mL). The combined organic layers were
washed with an aqueous saturated solution of NaCl, dried over anhy-
drous MgSO4, filtered, and concentrated to afford the title compound as
a crude product. Purification by flash-column chromatography (deacti-
vated silica-gel, hexanes/ether 9:1) led to the pure 4l (495 mg, 81%) as a
brown solid. M.p. 99–1008C; [a]2D3 =+55.0 (c=1.0 in CHCl3); IR
cast): n˜ =3435, 3046, 2877, 1257 cmÀ1 1H NMR (300 MHz, CDCl3): d=
;
5.85 (ddd, J=10.2, 4.4, 2.3 Hz, 1H), 5.56 (ddd, J=10.2, 1.7, 1.7 Hz, 1H),
5.18 (d, J=4.1 Hz, 1H), 4.61 (d, J=7.5 Hz, 1H), 4.28–4.31 (m, 1H), 4.22
(ddd, J=8.2, 8.2, 4.8 Hz, 1H), 3.96 (ddd, J=7.7, 7.7, 7.5 Hz, 1H), 3.42
(brs, 1H), 2.52–2.60 (m, 1H), 2.15–2.22 (m, 1H), 1.73–1.82 ppm (m, 1H);
13C NMR (125 MHz, CDCl3): d=139.9, 128.3, 128.1, 127.3, 127.1, 125.8,
100.6, 77.2, 76.6, 68.2, 38.4, 30.4 ppm; HRMS (ESI) : m/z: calcd for
C14H16O3Na: 255.0992; found: 255.0993.
1
(CH2Cl2, cast): n˜ =3426, 1650, 1596, 1432, 1210 cmÀ1; H NMR (500 MHz,
CDCl3): d=8.18 (d, J=8.7 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 6.80 (d, J=
16.0 Hz, 1H), 6.45 (dd, J=16.0, 5.2Hz, 1H), 5.83–5.88 (m, 1H), 5.66–
5.71 (m, 1H), 4.80 (dd, J=6.4, 3.8 Hz, 1H), 4.25–4.32 (m, 2H), 3.95 (dq,
J=9.6, 7.1 Hz, 1H), 3.57 (dq, J=9.6, 7.1 Hz, 1H), 3.02(brs, 1H), 2.15–
2.35 (m, 2H), 1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d=146.9, 143.1, 133.2, 129.9, 127.0, 125.2, 125.2, 123.9, 98.1, 77.1, 74.3,
64.7, 30.9, 15.2ppm; HRMS (ESI): m/z: calcd for C16H19O5NNa:
328.1161; found: 328.1165.
Ethyl-(2E,4R)-4-[(2R,5R,6S)-6-ethoxy-5-heptyl-5,6-dihydro-2H-pyran-2-
yl]-4-hydroxy-3-methylbut-2-enoate (23): Compound
1
(29.0 mg,
0.060 mmol) and powdered BaO (600 mg) were added to a mixture of 3-
boronoacrolein pinacolate 2 (0.360 g, 2.00 mmol) and (Z)-ethoxy-non-1-
ene 17 (0.510 g, 3.00 mmol) in an oven-dried round-bottomed flask
(10 mL) containing a stirbar. After being stirred for 5 h at 208C, the reac-
tion mixture was diluted with ether (10 mL), filtered through Celite, and
concentrated in vacuo. The catalyst was removed by using a short column
(deactivated silica-gel, hexanes/ether 9:1), and the excess of 17 was partly
recovered by bulb-to-bulb distillation. A mixture of the resulting hetero-
Diels–Alder cycloadduct 20 and ethyl 3-methyl-4-oxocrotonate 21
(0.570 g, 4.00 mmol) was stirred at 1108C for 36 h under argon. After
being cooled to ambient temperature, a saturated aqueous solution of
NaHCO3 (2mL) was added to the reaction mixture, which was stirred
for 30 min. The resulting mixture was then extracted with diethyl ether
(2”10 mL). The ethereal layers were combined, washed with brine
(10 mL), and dried over anhydrous MgSO4. After filtration and concen-
tration in vacuo to evaporate ether, ethyl 3-methyl-4-oxocrotonate was
partly recovered by bulb-to-bulb distillation. The residue was purified by
flash-column chromatography (deactivated silica-gel, hexanes/ether 6:1)
to afford 23 (0.545 g, 74%). [a]2D3 =+3.34 (c=1.0 in CHCl3); IR (CHCl3,
(1S,2R)-2-{[tert-Butyl(diphenyl)silyl]oxy}-1-[(2R,6S)-6-ethoxy-5,6-dihy-
dro-2H-pyran-2-yl]-2-phenylethanol (11): Same procedure as for 4k,
except that, after the hetero Diels–Alder, the cycloadduct was distilled
by using a Kugelrohr apparatus (b.p. 90–958C/0.01 mm Hg). The allylbo-
ration with (R)-[tert-butyldiphenylsilyl)oxy](phenyl)acetaldehyde was car-
ried out at 708C for 10 h. Purification by flash-column chromatography
(deactivated silica-gel, hexane:ether 95:5) led to the pure product 11
(652mg, 65%) as a white solid. [ a]2D3 =+39.3 (c=1.0 in CHCl3); m.p.=
1398C; 1H NMR (300 MHz,CDCl3): d=7.68 (dd, J=7.8, 1.4 Hz, 2H).
7.12–7.50 (m, 13H), 5.73–5.89 (m, 1H), 5.58–5.70 (m, 1H), 4.82 (d, J=
7.6 Hz, 1H), 4.70–4.77 (m, 1H), 4.63 (dd, J=6.1, 4.6 Hz, 1H), 3.78 (td,
J=7.8, 2.6 Hz, 1H), 3.72 (dq, J=9.5, 7.1 Hz, 1H), 3,30 (dq, J=9.5,
7.1 Hz, 1H), 2.47 (d, J=7.9 Hz, 1H), 2.13–2.24 (m, 2H), 1.18 (t, J=
3140
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3132– 3142

Dihydropyrans
FULL PAPER
cast): n˜ =3413, 2926, 1717, 1655 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=
tracted with ether (2”10 mL). The ethereal layers were combined,
washed with brine (10 mL), then dried over anhydrous MgSO4. After fil-
tration and concentration in vacuo to evaporate ether, ethyl 3-methyl-4-
oxocrotonate was partly recovered by bulb-to-bulb distillation. The resi-
due was purified by flash-column chromatography (deactivated silica-gel,
hexanes/ether 6:1) to afford the racemic allylboration product 26
(0.159 g, 56%), for which the spectroscopic data were in full agreement
with the enantioenriched compound, and allylboration product 27
(0.0540 mg, 19%). The relative stereochemistries of 26 and 27 were
partly confirmed by TROESY experiments. IR (CHCl3, cast): n˜ =3472,
6.05 (s, 1H), 5.83 (ddd, J=2.9, 2.9, 10.4 Hz, 1H), 5.62 (ddd, J=2.0, 2,0,
10.4 Hz, 1H), 4.72(d, J=3.7 Hz, 1H), 4.48–4.53 (m, 1H), 4.16 (q, J=
7.2Hz, 2H), 3.97 (dd, J=4.5, 4.5 Hz, 1H), 3.90 (dq, J=11.6, 7.1 Hz, 1H),
3.45–3.53 (m, 2H), 2.22–2.28 (m, 1H), 2.18 (s, 3H), 1.54–1.62 (m, 1H),
1.20–1.42 (m, 17H), 0.89 ppm (t, J=7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=166.6, 157.0, 129.5, 124.8, 116.8, 98.9, 77.8, 74.3, 65.1, 59.6,
38.1, 31.8, 29.8, 29.7, 29.2, 26.8, 22.6, 15.3, 14.8, 14.3, 14.0 ppm; HRMS
(ESI): m/z: calcd for C21H36O5Na: 391.2455; found: 391.2454; assay of en-
antiomeric excess: chiral HPLC analysis (Chiralpak AS, 98% hexane/iso-
propanol, 1.00 mLminÀ1, 210.8 nm, tR (major)=5.384 min; tR (minor)=
4.932min): 96% ee.
1
3034, 1716, 1653 cmÀ1; H NMR (300 MHz, CDCl3): d=6.02(s, 1H), 5.72
(ddd, J=2.4, 2.8, 10.3 Hz, 1H), 5.56 (ddd, J=1.9, 1.9, 10.3 Hz, 1H), 4.37–
4.42(m, 1H), 4.33 (d, J=6.0 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.99 (d,
J=4.5 Hz, 1H), 3.90 (dq, J=9.6, 7.1 Hz, 1H), 3.52(dq, J=9.6, 7.1 Hz,
1H), 3.10 (brs, 1H), 2.22–2.36 (m, 1H), 2.20 (s, 3H), 1.28 (t, J=7.1 Hz,
3H), 1.24 (t, J=7.1 Hz, 3H), 1.02ppm (d, J=7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=166.5, 156.4, 131.7, 124.6, 117.5, 103.5, 78.1, 75.0,
64.9, 59.8, 34.8, 16.8, 15.4, 15.2, 14.4 ppm. HRMS (ESI): m/z: calcd for
C15H24O5Na: 307.1516; found: 307.1514.
Ethyl-(2E,4R)-4-[(2R,5R,6S)-6-ethoxy-5-methyl-5,6-dihydro-2H-pyran-2-
yl]-4-hydroxy-3-methylbut-2-enoate (26) (allylboration product of 24):
Compound 1 (15.0 mg, 0.030 mmol) and powdered BaO (0.300 g) were
added to a mixture of 3-boronoacrolein pinacolate 2 (0.182g, 1.00 mmol)
and ethyl 1-propenyl ether 18 (Z/E 3:1, 0.170 g, 2.00 mmol) in an oven-
dried round-bottomed flask (10 mL) containing a stirbar. After being stir-
red for 14 h at 208C (1H NMR spectroscopy showed that the ratio of
ethyl (Z)-1-propenyl ether and ethyl (E)-1-propenyl ether in the flask
was about 1:1 after completion of the cycloaddition). The reaction mix-
ture was then diluted with ether (5 mL), filtered through Celite, and con-
centrated in vacuo. The catalyst was removed by using a short column
(deactivated silica-gel, hexanes/ether 9:1) to afford the cycloadducts 24
and 25 (1H NMR spectroscopy showed that the ratio of the two cycload-
ducts was about 95:5).
Acknowledgements
For generous financial support of this research we thank the Natural Sci-
ences and Engineering Research Council (NSERC) of Canada (Discov-
ery Grant), the University of Alberta, the Minist›re de l’Education Na-
tionale de la Recherche et de la Technologie (MENRT), the CNRS and
the University of Rennes 1.
A mixture of hetero-Diels–Alder cycloadducts 24 and 25 and ethyl 3-
methyl-4-oxocrotonate 21 (0.280 g, 2.00 mmol) was stirred at 1108C for
36 h under argon. After being cooled to ambient temperature, an aque-
ous saturated NaHCO3 solution (2mL) was added to the reaction mix-
ture, which was stirred for a further 30 min. After this time, the resulting
mixture was extracted with ether (2”10 mL). The ethereal layers were
combined, washed with brine (10 mL), then dried over anhydrous
MgSO4. After filtration and concentration in vacuo to evaporate ether,
ethyl 3-methyl-4-oxocrotonate was partly recovered by bulb-to-bulb dis-
tillation. The residue was purified by flash-column chromatography (de-
activated silica-gel, hexanes/ether 6:1) to afford allylboration product 26
(0.213 g, 75%). [a]2D3 =+19.2( c=2.8 in CHCl3); IR (CHCl3, cast): n˜ =
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3410, 2978, 1716, 1653 cmÀ1 1H NMR (300 MHz, CDCl3): d=6.04 (s,
;
1H), 5.79 (ddd, J=2.5, 3.8, 10.3 Hz, 1H), 5.58 (ddd, J=1.9, 1.9, 10.3 Hz,
1H), 4.69 (d, J=3.6 Hz, 1H), 4.44–4.49 (m, 1H), 4.16 (q, J=7.1 Hz, 2H),
3.94–4.02(m, 1H), 3.90 (dq, J=9.7, 7.1 Hz, 1H), 3.52(dq, J=9.7, 7.1 Hz,
1H), 3.35–3.42 (m, 1H), 2.30–2.43 (m, 1H), 2.20 (s, 3H), 1.28 (t, J=
7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.08 ppm (d, J=7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=166.6, 156.8, 131.2, 124.7, 117.0, 99.4,
77.9, 74.6, 65.0, 59.6, 33.2, 15.3, 14.9, 14.3, 14.3 ppm; HRMS (ESI): m/z:
calcd for C15H24O5Na: 307.1516; found: 307.1513; Assay of enantiomeric
excess: chiral HPLC analysis (Chiralpak AS, 100% hexanes,
1.00 mLminÀ1, 210.8 nm, tR(major)=10.113 min; tR(minor)=9.546 min)
96% ee.
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pyran-2-yl]-4-hydroxy-3-methylbut-2-enoate (27) (allylboration product
of 25): [Yb(fod)3] (106 mg, 0.100 mmol) was added to a mixture of 3-bor-
onoacrolein pinacolate 2 (0.182g, 1.00 mmol) and ethyl 1-propenyl ether
18 (Z/E 3:1) (0.170 g, 2.00 mmol) in an oven-dried round-bottomed flask
(10 mL) containing
a stirbar. After being stirred for 14 h at 208C
(1H NMR spectroscopy showed that the ratio of ethyl (Z)-1-propenyl
ether and ethyl (E)-1-propenyl ether in the flask was about 3:1 after the
completion of the reaction), the reaction mixture was diluted with ether
(5 mL), filtered through Celite, and concentrated in vacuo. The catalyst
was removed by using a short column (deactivated silica-gel, hexanes/
ether 9:1) to afford the cycloadducts 24 and 25 (1H NMR spectroscopy
showed that the ratio of two cycloadducts was about 3:1).
A mixture of hetero-Diels–Alder cycloadducts 24 and 25 and ethyl 3-
methyl-4-oxocrotonate 21 (0.280 g, 2.00 mmol) was stirred at 1108C for
36 h under argon. After being cooled to ambient temperature, an aque-
ous saturated NaHCO3 solution (2mL) was added to the reaction mix-
ture, which was stirred for 30 min. The resulting mixture was then ex-
Chem. Eur. J. 2006, 12, 3132– 3142
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: September 28, 2005
Published online: January 27, 2006
3142
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3132– 3142