Metal-catalyzed cycloetherification reactions of β,γ- and γ,δ-allendiols: Chemo-, regio-, and stereocontrol in the synthesis of oxacycles

Article abstract of DOI:10.1002/chem.201001520

Versatile routes that lead to a variety of functionalized enantiopure tetrahydrofurans, dihydropyrans, and tetrahydrooxepines are based on chemo-, regio-, and stereocontrolled metal-catalyzed oxycyclization reactions of β,γ- and γ,δ-allendiols, which were

Full text of DOI:10.1002/chem.201001520

FULL PAPER
DOI: 10.1002/chem.201001520
Metal-Catalyzed Cycloetherification Reactions of b,g- and g,d-Allendiols:
Chemo-, Regio-, and Stereocontrol in the Synthesis of Oxacycles
Benito Alcaide,*[a] Pedro Almendros,*[b] Rocꢀo Carrascosa,[a] and
Teresa Martꢀnez del Campo[a]
Abstract: Versatile routes that lead to
a variety of functionalized enantiopure
tetrahydrofurans, dihydropyrans, and
tetrahydrooxepines are based on
chemo-, regio-, and stereocontrolled
metal-catalyzed oxycyclization reac-
tions of b,g- and g,d-allendiols, which
were readily prepared from (R)-2,3-O-
isopropylideneglyceraldehyde. The ap-
plication of PdII, PtII, AuIII, or LaIII salts
as the catalysts gives controlled access
to differently sized oxacycles in enan-
tiopure form. Usually, chemoselective
cyclization reactions occurred exclu-
sively by attack of the secondary hy-
droxy group (except for the oxybromi-
nation of phenyl b,g-allenic diols 3b
and 3d) to an allenic carbon atom.
Regio- and stereocontrol issues are
mainly influenced by the nature of the
metal catalysts and substituents.
Keywords: allenes
· cyclization ·
gold · palladium · platinum
Introduction
rarely been mentioned because of additional chemoselectivi-
ty problems.[3] Namely, the product distribution must
depend on the chemo- and regioselectivity of the heterocyc-
lization, but in principle, eight different products are possi-
ble.[4] In this context, even if the structure of the substrate
suggests numerous possibilities for reactivity, metal-cata-
lyzed processes can lead to specific control of the transition
state and result in the controlled formation of products with
high selectivity. In continuation of our interest in heterocy-
clic and allene chemistry,[5] we report herein full details of
the chemo- and regioselective palladium-catalyzed cycloe-
therification of b,g- and g,d-allendiols[6] and the extension of
this reaction to precious metals, namely, gold and platinum
salts.
The development of synthetic methods for the preparation
of differently sized oxacycles is important because they are
present in a wide range of natural products and biologically
active molecules.[1] Among the possibilities, the transition-
metal-catalyzed intramolecular addition of oxygen nucleo-
philes across an allene moiety is intriguing from the point of
view of regioselectivity and because it is one of the most
rapid and convenient methods for the preparation of oxacy-
cles.[2] However, metal-catalyzed heterocyclizations of al-
lenes bearing two contiguous nucleophilic centers have
[a] Prof. Dr. B. Alcaide, Dipl.-Chem. R. Carrascosa,
Dr. T. Martꢀnez del Campo
Results and Discussion
Grupo de Lactamas y Heterociclos Bioactivos
Departamento de Quꢀmica Orgꢁnica I
Unidad Asociada al CSIC, Facultad de Quꢀmica
Universidad Complutense de Madrid
28040 Madrid (Spain)
Precursors for the oxacycle formation, enantiopure b,g-al-
lenic diols 3a–d and g,d-allenic diols 4a and 4b, were made
starting from (R)-2,3-O-isopropylideneglyceraldehyde (1)
Fax : (+34)91-3944103
and
(R)-2-(benzyloxy)-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-
E-mail: alcaideb@quim.ucm.es
yl]acetaldehyde (2),[7] respectively, through a regio- and ste-
reocontrolled indium-mediated Barbier-type carbonyl alle-
nylation reaction in aqueous media, followed by protecting-
group manipulation (Schemes 1 and 2). Whereas the alleny-
lation of aldehyde 1 with 1-bromobut-2-yne did take place
with complete diastereoselectivity, thus forming 5a, the car-
bonyl addition reaction of its benzyloxy homologue 2 gave
[b] Dr. P. Almendros
Instituto de Quꢀmica Orgꢁnica General
Consejo Superior de Investigaciones Cientꢀficas, CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-5644853
E-mail: Palmendros@iqog.csic.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem201001520.
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empirical model developed by
Trost et al. through esterifica-
tion with (S)- and (R)-O-meth-
ylmandelic acids.[8] The calculat-
ed differences in the 1H NMR
chemical shifts for the protons
of their acetylmandelates al-
lowed us to tentatively attribute
the S configuration to a-allenol
5a and the R configuration to
a-allenol 7aM.
We decided to investigate the
distinct reactivity of b,g- and
g,d-allenic diols depending on
the nature of the metal catalyst
that initiates electrophilic acti-
vation of the allene moiety. Re-
cently, gold and platinum salts
have emerged as powerful cata-
Scheme 1. Preparation of enantiopure b,g-allenic diols 3a–d. i) 1-Bromobut-2-yne or (3-bromoprop-1-ynyl)ben-
zene, In, THF/NH4Cl (aq. sat.), RT, 5 h. ii) PMPCOCl, Et3N, DMAP, CH2Cl2, RT, 18 h; TPSCl, imidazole,
CH2Cl2, reflux, 24 h; or Me2SO4, NaOH, TBAI, CH2Cl2/H2O, RT, 12 h; iii) BiCl3 (20 mol%), MeCN/H2O, RT,
24 h. DMAP=dimethylaminopyridine, PMP=para-methoxyphenyl, TBAI=tetrabutylammonium iodide,
TPS=tert-butyldiphenylsilyl.
À
lysts for the formation of C C
and C heteroatom bonds.[9]
À
Indeed, in an initial screen with
b,g-allendiol substrates 3, it was
found that AuCl3 was a selec-
tive catalyst to perform the de-
Scheme 2. Preparation of enantiopure g,d-allenic diols 4. i) 1-Bromobut-2-yne or (3-bromoprop-1-ynyl)ben- sired
zene, In, THF/NH4Cl (aq. sat.), RT, 16 h; ii) PMPCOCl, Et3N, DMAP, CH2Cl2, reflux, 8aM: 28 h, 8b: 48 h,
8am: 24 h; iii) BiCl3 (20 mol%), MeCN/H2O, RT, 4aM: 48 h, 4b: 18 h, 4am: 48 h. M=Major isomer; m=
cycloetherification
to
access functionalized dihydro-
pyrans 9 exclusively in reasona-
ble yields (Scheme 3). These re-
sults could be explained
minor isomer.
a-allenols 7a with poor syn/anti stereoselectivity (7aM/
7am=60:40). Fortunately, the diastereomeric a-allenols
7aM and 7am were separated by column chromatography.
In contrast, coupling reactions of aldehydes 1 and 2 with an
organoindium reagent generated in situ from indium and (3-
bromoprop-1-ynyl)benzene were totally diastereoselective,
thus affording a-allenols 5b and 7b as single isomers. The
absolute configurations of the new carbinolic stereocenters
on a-allenols 5a and 7aM were determined according to the
through a 6-endo cycloisomerization by chemo- and regio-
specific attack of the secondary hydroxy group at the termi-
nal allene carbon atom. Worthy of note, in contrast, the
AuCl3-catalyzed cycloisomerization of g,d-allenic diols 4 rep-
resents a selective method to afford tetrahydrofurans 10
Abstract in Spanish: Se han encontrado rutas versꢀtiles que
conducen a tetrahidrooxepinas, dihidropiranos y tetrahidrofu-
ranos funcionalizados enantiopuros, basadas en reacciones
de oxiciclaciꢁn quimio-, regio- y estereocontroladas de b,g- y
g,d-alenildioles catalizadas por metales. Los dioles de partida
se prepararon fꢀcilmente a partir de (R)-2,3-O-isopropiliden-
gliceraldehido. La utilizaciꢁn de sales de PdII, PtII, AuIII
ꢁ
LaIII como catalizadores da lugar a un mꢂtodo de prepara-
ciꢁn controlada de oxaciclos de diferente tamaÇo en forma
enantiopura. Normalmente, las reacciones de ciclaciꢁn qui-
mioselectiva ocurren exclusivamente por ataque del grupo hi-
droxilo secundario (excepto en la oxibromaciꢁn de los fenil
b,g-alenildioles 3b y 3d) a uno de los carbonos alꢂnicos.
Tanto el control regio- como el estereoquꢃmico estꢀn influꢃ-
dos por la naturaleza del metal y los sustituyentes.
Scheme 3. Gold-catalyzed preparation of dihydropyrans 9 and tetrahy-
drofurans 10. i) AuCl3 (5 mol%), CH2Cl2, RT, 9a: 2.5 h, 9b: 2 h, 10a:
16 h, 10b: 16 h, 10c: 25 h.
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Selective Synthesis of Oxacycles
FULL PAPER
bearing a quaternary stereocenter (Scheme 3).[10,11] Thus, re-
gioselectivity can be completely reversed by using a benzyl-
ACHTUNGTRENNUNGoxy allendiol homologue, thus favoring the 5-exo cyclization
of the secondary hydroxy group toward the internal allene
carbon atom over the 6-endo cyclization toward the terminal
allene carbon atom. The reason for the total diastereoselec-
tivity of the 5-exo cyclization toward the internal allene
carbon atom in methyl allendiol 4am, which gave adduct
10c, relative to the moderate diastereoselectivity of methyl
allendiol 4aM, which gave adduct 10a (Scheme 3), may be
related to an increase in ease of access of the incoming
oxygen nucleophile to the allene group from the face trans
to the benzyloxy and para-methoxybenzoyloxy groups. Dif-
ferences in qualitative homonuclear NOE interactions al-
lowed us to assign the stereochemistry at the newly formed
stereocenter of tetrahydrofurans 10. The para-methoxyben-
zoyloxy group comprises a large substituent. Disappointing-
ly, the presence of a large phenyl substituent in the allene
moiety (i.e., 4b) instead of the methyl group (i.e., 4aM) did
affect the reactivity, thus obtaining oxacycle 10b within a
complex reaction mixture.
Scheme 4. Platinum-catalyzed preparation of dihydropyrans 11 and 12
and tetrahydrofurans 10. i) [{PtCl
(10 mol%), CH2Cl2, RT, 2 h; ii) [{PtCl CHTUNGTRENNNUG
(CH2=CH2)}2] (5 mol%), TDMPP
2A(CH2=CH2)}2] (5 mol%), TDMPP
(10 mol%), methyl(triphenylphosphoranylidene)acetate, CH2Cl2, RT, 2 h.
TDMPP=tris(2,6-dimethoxyphenyl)phosphine.
The use of gold catalysis in allene chemistry has already
witnessed spectacular achievements. In contrast, the plati-
num-catalyzed reactions with allenols as substrates are an
almost unexplored field of noble-metal catalysis.[12] It was
nice to observe that upon exposure of the b,g-allenic diol 3a
to platinum catalysis, carbaldehyde 11, the result of a
chemo- and regiospecific cyclization of the secondary hy-
droxy group at the distal allene carbon atom with concur-
rent oxidation,[13] was obtained as the sole product. The fact
that the optimum reaction conditions required the addition
of an equimolecular amount of phosphine ligand for the
platinum center, may suggest that the catalytically active
species could be a platinum(II) monophosphine complex.
Compound 11 was not particularly stable at room tempera-
ture. Thus, the aldehyde must be trapped immediately to
avoid decomposition. The trapping/derivatization was ac-
complished through the use of a stabilized Wittig reagent
during the platinum-catalyzed oxycyclization step, thus
giving rise to a,b-unsaturated ester 12 (Scheme 4). In con-
trast, the cyclization of g,d-allenic diol 4aM was not as re-
warding and tetrahydrofuran 10a was obtained in low yield
(Scheme 4).
Scheme 5. Lanthanide–amide-catalyzed preparation of furan 14. Re-
agents and conditions: i) [La{NACHTUNRGTENNUG(SiMe3)2}3] (5 mol%), toluene, reflux, 13:
4 h, 14: 24 h, 10c: 3 h.
proceed smoothly with complete product selectivity to give
tetrahydrofuran 10c through 5-exo cycloisomerization of the
secondary hydroxy group toward the internal allene carbon
atom. It should be noted that the lanthanum-catalyzed oxy-
cyclization of simple g-allenols afforded six-membered
cyclic ethers.[14]
To screen the reactivity of the allenic diol moiety with dif-
ferent palladium-based catalysts, heterocyclization was ini-
tially explored by the exposure of b,g-allendiol 3a to palladi-
um(0) catalysis. Substrate 2H-pyran 16, which arises from a
totally chemo- and regioselective 6-exo oxycyclization of the
primary hydroxy group at the central allene carbon atom
with concurrent dehydration, was obtained in modest yield
The lanthanide-catalyzed hydroalkoxylation of simple al-
lenols has been recently reported.[14] Our investigations
began with b,g-allenic diols 3a and 3b as model substrates.
Attempts at a cyclization reaction of 3a with [La{N-
ACHTUNGTRENNUNG(SiMe3)2}3] as catalyst failed, thus giving rise to the isomeric
a,b-allenic diol 13 instead. However, the reaction of phenyl
allenic diol 3b by using the lanthanide–amide-catalyzed pro-
tocol afforded furan 14 in good yield. This outcome could
be explained through a selective 5-exo cyclization by attack
of the secondary hydroxy group at the central allene carbon
atom to give the nonisolable dihydrofuran 15, which under
the reaction conditions suffers aromatization to form furan
14 (Scheme 5). Interestingly, the reaction of g,d-allenic diol
4am under identical conditions to those given above could
together with
a
complicated mixture of byproducts
(Scheme 6). Next, 3a was treated with allyl bromide in the
presence of a palladium(II) catalyst. It was nice to observe
that the functionalized dihydropyran 17a was isolated as the
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B. Alcaide, P. Almendros et al.
bly, this outcome is due to steric effects in the transition
state. Thus, for b,g-allendiol 4aM the reaction should take
place more unfavorably for the palladium–tetrahydrofuran
complex than for the palladium–tetrahydrooxepine inter-
mediate as a result of destabilizing steric interactions
around the reactive centers in the former. Differences in the
qualitative homonuclear NOE interactions allowed us to
assign the stereochemistry at the newly formed stereocenter
of tetrahydrofuryl derivative 19b.
It was interesting at this point to test the reactivity of the
allendiol moiety under the conditions for a palladium-cata-
lyzed oxybromination reaction.[15] The treatment of b,g-al-
lenic diols 3a and 3c (bearing a methyl group on the allene
group) with lithium bromide by using a Pd–Cu bimetallic
catalytic system selectively led to bromoetherification prod-
ucts 20 in reasonable yields of the isolated products that
ensued from 6-endo-trig cyclization. We also tested the reac-
tivity of b,g-allendiols 3b and 3d bearing a phenyl rather
than a methyl allene substituent. To our delight, in contrast
to the oxybromination reaction of methyl allendiols 3a and
3c, which led to a bromodihydropyran compound, the reac-
tion of phenyl allendiols 3b and 3d under identical condi-
tions afforded 2-(1-bromovinyl)tetrahydrofurans 21 bearing
a quaternary stereocenter (Scheme 7).[10] Thus, both the
chemo- and the regioselectivity can be completely reversed
Scheme 6. Palladium-catalyzed preparation of dihydropyrans 17, tetrahy-
drooxepines 18, and tetrahydrofuran 19b. i) [Pd(PPh3)4] (5 mol%), PhI,
K2CO3, toluene, 808C, 24 h; ii) allyl bromide, PdCl2 (5 mol%), DMF, RT,
17a: 3 h, 17b: 2 h, 18a: 16 h, 18b: 16 h, 19b: 24 h.
AHCTUNGTRENNUNG
sole isomer in
a reasonable
yield of 65%. Similar behavior
was observed for phenyl deriva-
tive 3b (Scheme 6). This result
could be explained through a 6-
endo cyclization by chemo- and
regiospecific attack of the sec-
ondary hydroxy group at the
terminal allene carbon atom.
The stage was thus set for the
metal-catalyzed cycloetherifica-
tion reaction of g,d-allenic diols
4. Conversion into the corre-
sponding oxacycle could not be
satisfied with palladium(0) pro-
moters. Interestingly, under the
reactions conditions used with
allyl bromide, PdCl2 could be
an excellent catalyst for this
purpose. The cycloetherifica-
Scheme 7. Palladium-catalyzed preparation of dihydropyrans 20 and tetrahydrofurans 21. i) Pd
mol%), LiBr, Cu(OAc)2, K2CO3, MeCN, O2, RT, 2 h.
ACHTUNGTRENNUNG(OAc)2 (7
AHCTUNGTRENNUNG
tion/coupling sequence of g,d-allenic diols 4 was attained;
surprisingly, the regioselectivity was changed by inverting
the configuration of the stereocenter near to the allene
framework (Scheme 6). Thus, we were pleased that g,d-al-
lenic diols 4aM and 4b suffered a 7-endo oxycyclization at
the distal allene carbon atom to give tetrahydrooxepines 18,
whereas g,d-allenic diol 4am followed a 5-exo heterocycliza-
tion pathway at the proximal allene carbon atom to afford
tetrahydrofuran 19b. Therefore, an interesting reversal of
regioselectivity can be achieved by introducing the epimeric
configuration at the allenic contiguous stereocenter. Proba-
by a subtle variation in the substitution pattern of the b,g-al-
lendiol (Ph versus Me). This apparently unusual result can
be explained by the electron-withdrawing capacities of the
phenyl substituent relative to the electron-donating methyl
group. Probably, the presence of a Ph substituent in the
allene moiety strengthened the electrophilicity of the ben-
zylic carbon atom, thus favoring the 5-exo cyclization of the
primary hydroxy group over the 6-endo cyclization of the
secondary hydroxy group. The para-methoxybenzoyloxy
group comprises a large substituent; however, the cis attack,
which would be disfavored with a larger ZO group, increas-
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Selective Synthesis of Oxacycles
FULL PAPER
es with 3b (Z=COPMP) relative to 3d (Z=Me). The
reason for the total diastereoselectivity for 5-exo cyclization
toward the internal allene carbon atom on phenyl allendiol
3d, which gave adduct 21b, relative to the moderate diaste-
reoselectivity of phenyl allendiol 3b, which gave adduct 21a,
in the examples given in Scheme 7 may be related to unfav-
orable steric interactions between the ZO group and Pd
center in the p-allyl–palladium intermediate derived from
3b, thus hampering the required conformation for the trans
attack. Unfortunately, the Pd–Cu bimetallic system could
not induce a clean bromoheterocyclization reaction of g,d-
allenic diols 4 because a complex mixture of products was
formed under the conditions for palladium(II) catalysis.
A possible pathway for the gold-catalyzed preparation of
tetrahydrofurans 10 may initially involve the formation of a
complex 24 through coordination of gold trichloride to the
proximal allenic double bond of g,d-allenic diols 4. Next,
chemo- and regiospecific 5-exo oxyauration forms zwitter-
ionic intermediates 25, which generate neutral species 26
after loss of HCl. Protonolysis of the carbon–gold bond of
26 liberates adduct 10 with concurrent regeneration of the
Scheme 9. Mechanistic explanation for the platinum-catalyzed tandem
oxycyclization/oxidation of b,g-allenic diol 3a. L=ligand.
goldACHTUNGTRENNUNG(III) catalytic species (Scheme 8).
of allenic diol 3a (Scheme 4) in the presence of [{PtACHTUNGTRENNUNG(CH2=
CH2)Cl2}2] and TDMPP in an oxygen atmosphere, thus af-
fording aldehyde 11 in 70% yield.
Scheme 10 comprises a mechanistic rationale for the
[La{NACHTUNGTRNENUG(SiMe3)2}3]-promoted conversion of b,g-allenic diol 3b
into furan 14. First, a lanthanum precatalyst formed the alk-
À
oxide–La complex 30 through protonolysis at the La {N-
(SiMe3)2}3 bond by allendiol 3b. Subsequently, one p bond
of the oxallene–La complex chemo- and regiospecifically
À
adds across the La O functionality of 30 to afford oxacyclic
Scheme 8. Mechanistic explanation for the gold-catalyzed oxycyclization
of g,d-allenic diols 4.
A conceivable mechanism for the formation of dihydro-
pyran 11 may initially involve the formation of p-complex
27 through coordination of the platinum catalyst to the 1,2-
diene moiety of b,g-allenic diol 3a. Next, chemo- and regio-
selective 6-endo oxyplatination to form species 28 followed
by loss of HCl, demetalation, and proton transfer affords
the nonisolable (dihydropyranyl)methanol 9a and regener-
ates the platinum catalyst (Scheme 9). Intermediate 9a is
transformed by aerobic oxidation into (dihydropyranyl)car-
baldehyde 11. To support the proposition that adduct 9a is
an intermediate, we performed the reaction of 9a, which is
the final product from the gold-catalyzed cycloisomerization
Scheme 10. Mechanistic explanation for the lanthanum-catalyzed oxycyc-
lization of b,g-allenic diol 3b.
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13247

B. Alcaide, P. Almendros et al.
intermediate 31 by 5-exo cyclization at the central allene
carbon atom. The intervention of a second molecule of al-
lendiol 3b facilitates the proton-transfer step to afford spe-
cies 33 via transition state 32. Species 33 after complex dis-
sociation delivers dihydrofuran 15, which undergoes aroma-
tization under the reaction conditions to form furan 14, thus
reinitiating the catalytic cycle.
Scheme 11 outlines a mechanistic proposal for the ach-
ievement of tetrahydrooxepines 18. Initial coordination of
the palladium(II) center to the 1,2-diene moiety gave
allene–palladium complex 34, which undergoes a chemo-
and regioselective 7-endo oxycyclization reaction to give the
intermediate palladium–tetrahydrooxepine 35. Treatment of
35 with allyl bromide led, via 36, to the formation of inter-
mediate 37, which after a trans b-heteroatom elimination
generated oxacycles 18 with concurrent regeneration of the
palladium(II) catalyst (Scheme 11).
A likely mechanism for the generation of bromodihydro-
pyrans 20 and tetrahydrofurans 21 should involve the initial
formation of a p-allyl—palladium species. The allene—pal-
ladium complex 38 is formed initially and undergoes nucleo-
philic attack by the bromide ion to produce an s-allyl–palla-
dium species, which rapidly equilibrates to the correspond-
ing p-allyl–palladium intermediate 39. A chemo- and regio-
specific intramolecular cycloetherification reaction by attack
by either the secondary hy-
Scheme 11. Mechanistic explanation for the palladium-catalyzed oxycycli-
zation of g,d-allenic diols 4. X=Cl, Br.
droxy group at the terminal
allene carbon atom or by the
primary hydroxy group at the
internal allene carbon atom
onto the p-allyl–palladium com-
plex must account for the for-
mation of dihydropyrans 20 or
tetrahydrofurans
21
(Scheme 12). Finally, oxidation
of palladium(0) to palladi-
ACHTUNGTRENNUNGum(II) in situ by CuACHUTGNTREN(NGUN OAc)2
completes the catalytic cycle.
Conclusion
In conclusion, the chemo-,
regio-, and stereocontrolled cy-
cloetherification of allenic diols
bearing different substituents
into differently sized oxacycles
has been realized by using vari-
ous metal-based catalysts, such
as PdII, PtII, AuIII, or LaIII salts.
Scheme 12. Mechanistic explanation for the oxybromination reaction of b,g-allendiols 3 under Pd–Cu bimetal-
lic catalysis.
Experimental Section
The scope of these protocols has been investigated and
clearly demonstrates their utility for the selective prepara-
tion of several enantiopure cyclic ethers from structurally re-
lated substrates. At the present time, the application of this
methodology into the selective preparation of other types of
heterocyclic compounds is ongoing in our group.
General methods: 1H and 13C NMR spectra were recorded on Bruker
AMX-500, Bruker Avance-300, Varian VRX-300S, or Bruker AC-200
spectrometers. NMR spectra were recorded in CDCl3, unless otherwise
stated. Chemical shifts are given in ppm relative to trimethylsilane
(TMS; 1H NMR: d=0.0 ppm) or CDCl3 (13C NMR: d=76.9 ppm). Low-
and high-resolution mass spectra were taken on a HP5989A spectrometer
by using electronic impact (EI) or electrospray modes (ES), unless other-
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Selective Synthesis of Oxacycles
FULL PAPER
wise stated. Specific rotation [a]D is given in 10À1 degcm2 gÀ1 at 208C, and
the concentration c is expressed in grams per 100 mL. All commercially
available compounds were used without further purification.
131.9, 128.4, 127.9, 127.8, 122.1, 114.1, 113.8, 84.1, 80.5, 77.2, 75.6, 73.0,
62.5, 55.5, 21.8 ppm; IR (CHCl3): n˜ =3434, 1724 cmÀ1; HRMS (ES): m/z:
calcd for C23H27O6: 399.1808 [M+H]+; found: 399.1804.
General procedure for the Pt-catalyzed cyclization of allenic diols 3 and
General procedure for the Au-catalyzed cyclization of allenic diols 3 and
4: Preparation of tetrahydrofuran 10a and dihydropyrans 11 and 12: [{Pt-
4: Preparation of dihydropyrans
9 and tetrahydrofurans 10: AuCl3
AHCUTNGTER(GNUNN CH2=CH2)Cl2}2] (0.01 mmol) and tris(2,6-dimethoxyphenyl)phosphine
(0.05 mmol) was added to a stirred solution of the corresponding allenic
diol 3 and 4 (1.0 mmol) in dichloromethane (1.0 mL) under argon. The
resulting mixture was stirred at room temperature until disappearance of
the starting material (TLC). The reaction was quenched with brine
(1.0 mL), the mixture was extracted with ethyl acetate (3ꢃ5 mL), and
the combined extracts were washed twice with brine. The organic layer
was dried (MgSO4) and concentrated under reduced pressure. Chroma-
tography of the residue eluted with ethyl acetate/hexane gave analytically
pure adducts 9 and 10.[16]
(0.02 mmol) were added sequentially (methyl(triphenylphosphoranylide-
ne)acetate (1.1 mmol) was also added for the preparation of adduct 12)
to a stirred solution of the corresponding allenic diol 3 and 4 (1.0 mmol)
in dichloromethane (1.0 mL) under argon. The resulting mixture was
stirred at room temperature until disappearance of the starting material
(TLC). The reaction was quenched with brine (1.0 mL), the mixture was
extracted with ethyl acetate (3ꢃ5 mL), and the combined extracts were
washed twice with brine. The organic layer was dried (MgSO4) and con-
centrated under reduced pressure. Chromatography of the residue eluting
with ethyl acetate/hexane mixtures gave analytically pure adducts 10–12.
Dihydropyran (+)-9a: Prepared from b,g-allendiol (À)-3a (75 mg,
0.27 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:1) as the eluent (+)-9a was obtained as a colorless oil (49 mg,
75%). [a]D =+75.1 (c=1.8 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=6.94 and 8.02 (d, each 2H, J=9.0 Hz, Ar), 5.70 (m, 1H), 5.61
(m, 1H), 4.26 (m, 2H), 3.88 (s, 3H), 3.70 (m, 3H), 1.73 ppm (m, 3H);
13C NMR (75 MHz, CDCl3, 258C): d=166.5, 163.8, 132.3, 131.7, 124.4,
121.8, 113.8, 77.6, 67.6, 65.4, 62.4, 55.5, 18.4 ppm; IR (CHCl3): n˜ =3432,
1724 cmÀ1; HRMS (ES): m/z: calcd for C14H16O4: 248.1049 [M+H]+;
found: 248.1045.
Dihydropyran (+)-11: Prepared from b,g-allendiol (À)-3a (50 mg,
0.18 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:2) as the eluent (+)-11 was obtained as a colorless oil (36 mg,
1
62%). [a]D =+3.2 (c=0.6 in CHCl3); H NMR (300 MHz, CDCl3, 258C):
d=10.2 (d, 1H, J=8.1 Hz), 8.06 and 6.95 (d, each 2H, J=9.0 Hz), 6.33
(m, 2H), 5.89 (d, 1H, J=8.1 Hz), 4.38 (m, 2H), 3.88 (s, 3H), 2.09 ppm
(d, 3H, J=1.2 Hz); IR (CHCl3): n˜ =1732, 1725 cmÀ1
.
Dihydropyran (+)-12: Prepared from b,g-allendiol (À)-3a (50 mg,
0.18 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:1) as the eluent (+)-12 was obtained as a colorless oil (32 mg,
Dihydropyran (+)-9b: Prepared from b,g-allendiol (À)-3b (50 mg,
0.14 mmol), and after chromatography of the residue with hexane/ethyl
acetate (2:1) as the eluent (+)-9b was obtained as a colorless oil (21 mg,
55%). [a]D =+32.7 (c=1.3 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.72 and 6.80 (d, each 2H, J=9.0 Hz), 7.26 (m, 5H), 6.24 (m,
2H), 4.48 (t, 2H, J=2.7 Hz), 3.82 (m, 3H), 3.81 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=163.6, 161.0, 137.2, 136.0, 132.3, 131.8, 128.4,
127.5, 126.9, 125.8, 113.6, 77.1, 65.4, 65.2, 62.1, 55.4 ppm; IR (CHCl3): n˜ =
3428, 1722 cmÀ1; HRMS (ES): m/z: calcd for C19H18O4: 310.1205 [M+H]+
; found: 310.1210.
1
54%). [a]D =+3.4 (c=0.8 in CHCl3); H NMR (300 MHz, CDCl3, 258C):
d=8.07 and 6.96 (d, each 2H, J=9.0 Hz, Ar), 7.81 (dd, 1H, J=15.1,
12.0 Hz), 6.94 (m, 1H), 6.07 (m, 2H), 5.85 (d, 1H, J=15.1 Hz), 4.34 (dd,
2H, J=5.6, 1.6 Hz), 3.89 (s, 3H), 3.77 (s, 3H), 2.00 ppm (s ancho, 3H);
13C NMR (75 MHz, CDCl3, 258C): d=163.6, 163.2, 163.0, 141.9, 139.2,
132.6, 132.3, 126.7, 120.0, 113.7, 63.6, 55.5, 53.4, 51.5, 40.9, 21.0 ppm; IR
(CHCl3): n˜ =1724, 1720 cmÀ1; HRMS (ES): m/z: calcd for C19H23O6:
347.1495 [M+H]+; found: 347.1499.
General procedure for the La-catalyzed cyclization of allenic diols 3 and
4: Preparation of tetrahydrofuran 10c, diol 13, and furan 14. [La{N-
AHCTUNGTRENN(GUN SiMe3)2}3] (0.05 mmol) was added to a stirred solution of the corre-
sponding allenic diol 3 and 4 (1.0 mmol) in toluene (10.0 mL) under
argon. The resulting mixture was stirred at reflux until disappearance of
the starting material (TLC). The reaction was filtered through a celite
plug before being concentrated under reduced pressure. Chromatography
of the residue with ethyl acetate/hexane as the elutent gave analytically
pure adducts 10, 13, and 14.
Tetrahydrofuran (+)-10a: Prepared from g,d-allendiol (À)-4aM (66 mg,
0.16 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:1) as the eluent (+)-10a, which contained approximately 20%
of its epimer, was obtained as a colorless oil (34 mg, 51%). The diaste-
reoisomers of 10a are inseparable by column chromatography (1H and
13C NMR data were obtained by analyzing the NMR spectra of the mix-
tures; however, IR and MS spectroscopic data could not be assigned indi-
vidually for them). [a]D =+2.0 (c=2.1 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C): d=8.00 and 6.95 (d, each 0.4H, J=9.0 Hz), 7.94 and 6.92
(d, each 1.6H, J=9.0 Hz), 7. 13 (m, 5H), 6.07 (dd, 0.2H, J=17.3,
10.7 Hz), 5.90 (dd, 0.8H, J=17.3, 10.7 Hz), 5.47 (d, 0.2H, J=2.2 Hz),
5.41 (m, 0.2H), 5.34 (d, 0.8H, J=2.0 Hz), 5.35 (dd, 0.8H, J=17.3,
1.5 Hz), 5.23 (dd, 0.2H, J=10.7, 1.2 Hz), 5.12 (dd, 0.8H, J=11.0, 1.5 Hz),
4.76 and 4.56 (d, each 0.2H, J=17.9 Hz), 4.82 and 4.59 (d, each 0.8H, J=
17.6 Hz), 4.19 (m, 1H), 4.10 (dd, 0.8H, J=5.0, 1.8 Hz), 4.08 (m, 0.2H),
3.88 (s, 0.6H), 3.87 (s, 2.4H), 3.86 (m, 1H), 3.69 (dd, 0.8H, J=11.8,
4.3 Hz), 3.65 (dd, 0.2H, J=12.4, 3.9 Hz), 1.56 (s, 2.4H), 1.55 ppm (s,
0.6H); 13C NMR (75 MHz, CDCl3, 258C): d=165.3 (m), 165.1 (M), 163.7
(m), 163.6 (M), 138.1 (M+ m), 137.6 (M), 137.5 (m), 131.8 (m), 131.7
(M), 128.5 (M), 128.4 (m), 127.8 (M), 127.7 (m), 127.6 (M+m), 122.0
(M), 121.8 (m), 114.8 (M), 114.2 (m), 113.8 (m), 113.7 (M), 84.9 (m), 84.8
(M), 84.7 (M), 84.6 (m), 81.9 (M), 81.3 (m), 77.2 (M +m), 72.3 (M), 72.2
(m), 62.8 (M), 62.7 (m), 55.5 (m), 55.4 (M), 22.9 (M), 22.1 ppm (m); IR
(CHCl): n˜ =3432, 1722 cmÀ1; HRMS (ES): m/z: calcd for C23H27O6:
399.1808 [M+H]+; found: 399.1803.
Diol (+)-13: Prepared from b,g-allendiol (À)-3a (50 mg, 0.18 mmol), and
after chromatography of the residue with hexane/ethyl acetate (3:1) as
the eluent (+)-13 was obtained as a colorless oil (19 mg, 37%). [a]D =+
2.6 (c=1.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=8.02 and
6.93 (d, each 2H, J=9.0 Hz, Ar), 4.86 (m, 2H), 4.52 (d, 2H, J=4.6 Hz),
4.17 (m, 1H), 4.03 (dd, 1H, J=10.2, 4.6 Hz), 2.58 (brs, 2H), 1.80 ppm (t,
3H, J=3.3 Hz); 13C NMR (75 MHz, CDCl3, 258C): d=205.5, 167.0,
163.6, 131.8, 122.1, 113.7, 98.9, 77.5, 72.9, 71.8, 65.7, 55.4, 15.0 ppm; IR
(CHCl3): n˜ =3440, 2990, 1942, 1724 cmÀ1; ES-MS : m/z (%): 279 (100)
[M+H]+, 278 (6) [M]+.
Furan 14: Prepared from b,g-allendiol (À)-3b (50 mg, 0.14 mmol), and
after chromatography of the residue with hexane/ethyl acetate (5:1) as
the eluent 14 was obtained as a colorless oil (24 mg, 88%). 1H NMR
(300 MHz, CDCl3, 258C): d=7.38 (m, 5H, Ar), 6.44 (s, 1H), 4.62 (s, 2H),
3.88 (br s, 1H), 2.46 ppm (s, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
151.6, 148.0, 133.9, 128.6, 127.4, 126.4, 121.6, 109.5, 57.5, 13.1 ppm; IR
(CHCl3): n˜ =3432 cmÀ1; ES-MS: m/z (%): 189 (100) [M+H]+, 188 (19)
[M]+.
Procedure for the Pd0-catalyzed preparation of dihydropyran 16: [Pd-
AHCTUNTGREGUN(NN PPh3)4] (11 mg, 0.0093 mmol) was added to a mixture of b,g-allendiol
(À)-1a (50 mg, 0.18 mmol), iodobenzene (22 mL, 0.19 mmol), and silver
carbonate (99 mg, 0.36 mmol) in DMF (1.5 mL) under argon, and the re-
sulting mixture was heated at 808C until disappearance of the starting
material (TLC, 24 h). The reaction was quenched with brine (1.8 mL)
and the mixture was extracted with ethyl acetate (3ꢃ3 mL). The organic
Tetrahydrofuran (+)-10c: Prepared from g,d-allendiol (À)-4am (48 mg,
0.12 mmol), and after chromatography of the residue with hexane/ethyl
acetate (2:1) as the eluent (+)-10c was obtained as a colorless oil (22 mg,
46%). [a]D =+2.4 (c 1.3 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d=8.07 and 6.94 (d, each 2H, J=9.0 Hz), 7.23 (m, 5H), 5.98 (dd, 1H, J=
17.3, 10.5 Hz), 5.47 (d, 1H, J=4.2 Hz), 5.36 (d, 1H, J=17.3 Hz), 5.16 (d,
1H, J=10.5 Hz), 4.62 and 4.42 (d, each 1H, J=11.5 Hz), 4.16 (m, 2H),
3.88 (s, 3H), 3.85 (m, 1H), 3.64 (dd, 1H, J=12.0, 3.9 Hz), 1.40 ppm (s,
3H); 13C NMR (75 MHz, CDCl3, 258C): d=165.6, 163.7, 142.1, 137.5,
Chem. Eur. J. 2010, 16, 13243 – 13252
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13249

B. Alcaide, P. Almendros et al.
extract was washed with brine, dried (MgSO4), and concentrated under
reduced pressure. Chromatography of the residue with ethyl acetate/
hexane (1:3) as the eluent gave 16 as a colorless oil (16 mg, 35%).
acetate (1:1) as the eluent (+)-19b was obtained as a colorless oil (25 mg,
50%). [a]D =+1.2 (c=0.8 in CHCl3); H NMR (300 MHz, CDCl3, 258C):
1
d=8.08 and 6.96 (d, each 2H, J=9.0 Hz), 7.24 (m, 5H), 5.84 (m, 1H),
5.57 (d, 1H, J=5.0 Hz), 4.58 and 4.42 (d, each 1H, J=11.5 Hz), 4.21 (m,
1H), 4.08 (dd, 1H, J=8.0, 5.0 Hz), 3.89 (s, 3H), 3.87 (dd, 1H, J=12.2,
3.0 Hz), 3.66 (dd, 1H, J=11.9, 5.0 Hz), 2.90 (d, 2H, J=7.0 Hz), 1.44 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=165.6, 163.7, 150.8, 137.5,
136.4, 131.8, 128.3, 127.9, 127.8, 122.1, 116.7, 113.8, 111.3, 86.4, 80.3, 77.3,
1
Dihydropyran 2: H NMR (300 MHz, CDCl3, 258C): d=8.02 and 6.90 (d,
each 2H, J=9.0 Hz), 6.26 (s, 1H), 5.18 (s, 2H), 3.86 (s, 3H), 2.22 (br s,
3H), 1.94 ppm (brs, 3H); IR (CHCl3): n˜ =1725 cmÀ1; ES-MS: m/z (%):
275 (100) [M+H]+, 274 (11) [M]+.
General procedure for the PdII-catalyzed cyclization of allenic diols 3
and 4 in the presence of allyl bromide: Preparation of dihydropyrans 17,
tetrahydrooxepines 18, and tetrahydrofuran (+)-19b. Palladium(II) chlo-
ride (0.005 mmol) was added to a stirred solution of the corresponding al-
lenic diol 3 and 4 (0.10 mmol) and allyl bromide (0.50 mmol) in DMF
(0.6 mL). The reaction was stirred in an argon atmosphere until disap-
pearance of the starting material (TLC). Water (0.5 mL) was added to
the reaction mixture, which was extracted with ethyl acetate (3ꢃ4 mL).
The organic phase was washed with water (2ꢃ2 mL), dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the residue
with hexane/ethyl acetate as the eluent gave analytically pure adducts
17–19.
74.8, 73.0, 62.9, 55.5, 36.2, 22.0 ppm; IR (CHCl3): n˜ =3436, 1724 cmÀ1
;
HRMS (ES): m/z: m/z: calcd for C26H31O6: 439.2121 [M+H]+; found:
439.2118.
General procedure for the PdII-catalyzed cyclization of allenic diols 3 in
the presence of lithium bromide: Preparation of dihydropyrans 20 or tet-
rahydrofurans 21: Palladium(II) acetate (0.01 mmol), lithium bromide
(0.74 mmol), potassium carbonate (0.18 mmol), and copper(II) acetate
(0.32 mmol) were added sequentially to a stirred solution of the corre-
sponding b,g-allendiol 3 (0.15 mmol) in acetonitrile (5 mL). The resulting
suspension was stirred at room temperature in an oxygen atmosphere
until the disappearance of the starting material (TLC). The organic phase
was diluted with brine (2 mL), extracted with ethyl acetate (3ꢃ5 mL),
washed with brine (2 mL), dried (MgSO4), and concentrated under re-
duced pressure. Chromatography of the residue with hexane/ethyl acetate
as the eluent gave analytically pure adducts 20 and 21.
Dihydropyran (+)-17a: Prepared from b,g-allendiol (À)-3a (75 mg,
0.27 mmol), and after chromatography of the residue with hexane/ethyl
acetate (4:1) as the eluent (+)-17a was obtained as a colorless oil (76 mg,
65%). [a]D =+21.9 (c=1.1 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=8.02 and 6.94 (d, each 2H, J=9.0 Hz), 5.74 (m, 1H), 5.61 (d,
1H, J=7.8 Hz), 5.11 (dd, 1H, J=9.3, 1.7 Hz), 5.04 (t, 1H, J=1.8 Hz),
4.16 (m, 2H), 3.88 (s, 3H), 3.68 (m, 3H), 2.87 and 2.68 (dd, each 1H, J=
15.5, 6.0 Hz), 1.67 ppm (brs, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
166.7, 163.2, 134.0, 132.0, 131.9, 125.6, 121.9, 116.0, 113.7, 77.2, 68.3, 67.8,
62.4, 55.5, 33.2, 13.4 ppm; IR (CHCl3): n˜ =3420, 1720 cmÀ1; HRMS (ES):
m/z: calcd for C18H22O5: 318.1467 [M+]; found: 318.1459.
Dihydropyran (+)-20a: Prepared from b,g-allendiol (À)-3a (100 mg,
0.36 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:1) as the eluent (+)-20a was obtained as a colorless oil (68 mg,
1
53%). [a]D =+3.5 (c=1.0 in CHCl3); H NMR (300 MHz, CDCl3, 258C):
d=8.07 and 6.95 (d, each 2H, J=9.0 Hz), 5.71 (m, 1H), 4.34 (m, 2H),
3.89 (s, 3H), 3.72 (m, 3H), 1.84 ppm (d, 3H, J=1.0 Hz); 13C NMR
(75 MHz, CDCl3, 258C): d=163.9, 164.0, 132.3, 132.0, 130.6, 119.7, 113.7,
77.3, 70.3, 68.7, 62.0, 55.5, 17.5 ppm; IR (CHCl3): n˜ =3425, 1716 cmÀ1
;
Dihydropyran (À)-17b: Prepared from b,g-allendiol (À)-3b (50 mg,
0.14 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:1) as the eluent (À)-17b was obtained as a colorless oil
(42 mg, 78%). [a]D =À15.2 (c=1.4 in CHCl3); 1H NMR (CDCl3): d=
7.69 and 6.80 (d, each 2H, J=9.0 Hz), 7.22 (m, 5H), 5.93 (brs, 1H), 5.69
(m, 1H), 5.05 (m, 2H), 4.41 and 4.28 (dd, each 1H, J=16.0, 2.0 Hz), 3.82
(s, 3H), 3.76 (m, 3H), 2.72 ppm (d, 2H, J=6.3 Hz); 13C NMR (CDCl3):
d=166.3, 163.5, 136.8, 134.9, 132.0, 131.6, 128.7, 128.3, 128.1, 127.2, 121.8,
116.6, 113.5, 77.4, 67.7, 67.4, 62.3, 55.4, 34.5 ppm; IR (CHCl3): n˜ =3424,
1715 cmÀ1; ES-MS : m/z (%): 380 (17) [M+], 379 (100) [M+À1].
HRMS (ES): m/z: calcd for C15H17BrO5: 356.0259 [M]+; found: 356.0268.
Dihydropyran (À)-20b: Prepared from b,g-allendiol (+)-3c (75 mg,
0.20 mmol), and after chromatography of the residue with hexane/ethyl
acetate (6:1) as the eluent (À)-20b was obtained as a colorless oil
(47 mg, 51%). [a]D =À22.8 (c=0.5 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C): d=7.72 (m, 4H), 7.32 (m, 6H), 4.14 (m, 3H), 3.72 (td,
1H, J=6.8, 3.1 Hz), 3.46 (dd, 1H, J=7.3, 3.2 Hz), 3.36 (dd, 1H, J=6.8,
5.1 Hz), 1.80 (brs, 3H), 1.06 ppm (s, 9H); 13C NMR (75 MHz, CDCl3,
258C): d=135.9, 135.8, 134.8, 133.3, 132.6, 130.0, 127.8, 127.7, 119.4, 79.5,
70.4, 68.9, 61.9, 27.1, 26.8, 19.8 ppm; IR (CHCl3): n˜ =3429 cmÀ1; EI-MS :
m/z (%): 461 (23) [M+], 443 (100).
Tetrahydrooxepine (À)-18a: Prepared from g,d-allendiol (À)-4aM
(76 mg, 0.19 mmol), and after chromatography of the residue with
hexane/ethyl acetate (1:1) as the eluent (À)-18a was obtained as a color-
Tetrahydrofuran (+)-21a: Prepared from b,g-allendiol (À)-3b (50 mg,
0.14 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:1) as the eluent (+)-21a (33 mg, 57%), which contained ap-
proximately 40% of its epimer as a colorless oil. The diastereoisomers of
21a are inseparable by column chromatography (the 1H and 13C NMR
data were obtained by analyzing the NMR spectra of the mixtures; how-
ever, the IR and MS spectroscopic data could not be assigned individual-
ly for them). [a]D =+5.9 (c=0.8 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=8.11 and 6.98 (d, each 0.8H, J=9.0 Hz), 7.61 (m, 2H), 7.40 (m,
3H), 6.59 and 5.80 (d, each 0.6H, J=2.0 Hz), 6.28 and 5.68 (d, each
0.4H, J=1.7 Hz), 6.12 (d, 0.4H, J=4.6 Hz), 5.29 (m, 0.6H), 4.67 (dd,
0.6H, J=12.4, 3.2 Hz,), 4.07 (m, 2H), 3.89 (s, 1.8H), 3.87 (m, 0.4H),
3.77 ppm (s, 1.2H); 13C NMR (75 MHz, CDCl3, 258C): d=164.0 (m),
163.9 (M), 163.3 (m), 163.2 (M), 150.4 (M+ m), 132.2 (M+ m), 128.5
(m), 128.4 (M+ m), 128.3 (M+ m), 128.2 (M), 127.8 (M+ m), 127.6
(M+ m), 126.3 (M), 126.2 (m), 113.8 (m), 113.3 (M), 88.1 (M+ m), 82.1
(M), 77.5 (m), 71.8 (m), 71.5 (M), 67.1 (m), 63.4 (M), 55.5 (M), 55.2 ppm
1
less oil (49 mg, 59%). [a]D =À1.5 (c=0.1 in CHCl3); H NMR (300 MHz,
CDCl3, 258C): d=8.05 and 6.90 (d, each 2H, J=9.0 Hz), 7.35 (s, 5H),
5.76 (m, 1H), 5.68 (d, 1H, J=3.6 Hz), 5.06 (m, 1H), 4.81 and 4.57 (d,
each 1H, J=11.6 Hz), 4.49 (dd, 1H, J=16.3, 1.9 Hz), 4.19 (dd, 1H, J=
16.3, 1.7 Hz), 3.87 (s, 3H), 3.84 (m, 1H), 3.66 (m, 2H), 3.51 (m, 1H), 2.78
(dd, 1H, J=15.6, 5.6 Hz), 2.62 (dd, 1H, J=15.6, 6.3 Hz), 1.93 ppm (s,
3H); 13C NMR (75 MHz, CDCl3, 258C): d=165.8, 163.4, 137.7, 134.5,
134.2, 131.7, 128.4, 128.1, 127.9, 122.8, 115.9, 113.7, 80.7, 79.3, 74.9, 73.5,
72.7, 63.9, 55.4, 35.3, 20.6 ppm; IR (CHCl3: n˜ =3431, 1728 cmÀ1; HRMS
(ES): m/z: calcd for C26H31O6: 439.2121 [M+H]+; found: 439.2124.
Tetrahydrooxepine (+)-18b: Prepared from g,d-allendiol (+)-4b (28 mg,
0.06 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:1) as the eluent (+)-18b was obtained as a colorless oil
(16 mg, 53%). [a]D =+2.0 (c=0.3 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C): d=7.99 and 6.93 (d, each 2H, J=9.0 Hz), 7.26 (m, 10H),
5.95 (d, 1H, J=2.1 Hz), 5.69 (m, 1H), 5.03 (m, 2H), 4.73 and 4.52 (d,
each 1H, J=11.3 Hz), 4.71 and 4.41 (d, each 1H, J=16.6 Hz), 3.88 (s,
3H), 3.82 (m, 2H), 3.71 and 3.56 (d, each 1H, J=11.9 Hz), 2.69 (dd, 1H,
J=15.0, 6.2 Hz), 2.59 ppm (dd, 1H, J=15.7, 6.5 Hz); 13C NMR (75 MHz,
CDCl3, 258C): d=165.4, 163.4, 142.3, 138.5, 137.5, 135.4, 134.0, 131.8,
128.5, 128.4, 128.3, 128.2, 127.4, 126.9, 116.6, 113.7, 81.0, 79.4, 74.5, 73.3,
72.6, 64.0, 55.5, 36.7 ppm; IR (CHCl3): n˜ =3430, 1725 cmÀ1; HRMS (ES):
m/z: calcd for C31H32NaO6: 523.2097 [M+Na]+; found: 523.2095.
(m); IR (CHCl3): n˜ =3435, 1718 cmÀ1; EI-MS : m/z (%): 420 (98) [M+
2], 418 (100) [M+].
+
Tetrahydrofuran (À)-21b: Prepared from b,g-allendiol (+)-3d (65 mg,
0.30 mmol), and after chromatography of the residue with hexane/ethyl
acetate (3:1) as the eluent (À)-21b was obtained as a colorless oil
(49 mg, 55%). [a]D =À26.3 (c=0.4 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C): d=7.52 (m, 2H), 7.37 (m, 3H), 6.26 and 5.70 (d, each 1H,
J=1.7 Hz), 4.30 (m, 2H), 3.99 (dd, 1H, J=9.5, 6.3 Hz,), 3.85 (dd, 1H, J=
9.5, 4.9 Hz), 3.74 (s, 3H), 3.48 ppm (d, 1H, J=6.8 Hz); 13C NMR
Tetrahydrofuran (+)-19b: Prepared from g,d-allendiol (À)-4am (46 mg,
0.12 mmol), and after chromatography of the residue with hexane/ethyl
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Chem. Eur. J. 2010, 16, 13243 – 13252

Selective Synthesis of Oxacycles
FULL PAPER
(75 MHz, CDCl3, 258C): d=150.7, 128.5, 128.3, 128.1, 126.3, 118.7, 85.8,
77.2, 72.7, 71.2, 61.3 ppm; IR (CHCl3): n˜ =3432 cmÀ1; HRMS (ES): m/z:
calcd for C13H15BrO3: 298.0205 [M]+; found: 298.0212.
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Acknowledgements
Support for this study by the DGI-MICINN (Project CTQ2009-09318),
Comunidad Autꢄnoma de Madrid and Fondo Social Europeo-EU (Proj-
ect S2009/PPQ-1752), and UCM-BSCH (Project GR58/08) are gratefully
acknowledged. T.M.C. and R.C. thank the MEC for predoctoral grants.
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Chem. Eur. J. 2010, 16, 13243 – 13252
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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13251

B. Alcaide, P. Almendros et al.
[16] Experimental procedures and full spectroscopic and analytical data
for compounds not included in the Experimental Section are de-
scribed in the Supporting Information; the characterization data and
experimental procedures for 3a–d, 4aM, 4am, 5a, 5b, 6a–d, 7aM,
(R)-acetylmandelate derivate of 7aM, (S)-acetylmandelate deriva-
tive of 7aM, 7am, 7b, 8aM, and 8am and the NMR spectra of all
the new compounds are given.
Received: June 1, 2010
Published online: September 28, 2010
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Chem. Eur. J. 2010, 16, 13243 – 13252