Regioselectivity control in the metal-catalyzed O-C functionalization of γ-allenols, part 1: Experimental study

Article abstract of DOI:10.1002/chem.200802034

We describe versatile regiocontrolled metal-catalyzed heterocyclization reactions of γ-allenol derivatives leading to a variety of fused enantiopure tetrahydrofurans, dihydropyrans, and tetrahydrooxepines. Regioselectivity control in the O-C functionaliza

Full text of DOI:10.1002/chem.200802034

FULL PAPER
DOI: 10.1002/chem.200802034
ꢀ
Regioselectivity Control in the Metal-Catalyzed O C Functionalization of g-
Allenols, Part 1: Experimental Study#
Benito Alcaide,*[a] Pedro Almendros,*[b] Teresa Martꢀnez del Campo,[a]
Elena Soriano,[b] and Josꢁ L. Marco-Contelles[b]
Dedicated to Professor Franco Fernꢀndez on the occasion of his 65th birthday
Abstract: We describe versatile regio-
controlled metal-catalyzed heterocycli-
zation reactions of g-allenol derivatives
leading to a variety of fused enantio-
pure tetrahydrofurans, dihydropyrans,
and tetrahydrooxepines. Regioselectivi-
served that for the Au-catalyzed cycloi-
somerization, the presence of a me-
thoxymethyl protecting group not only
masks a hydroxy functionality, but also
exerts directing effects as a controlling
unit in a regioselectivity reversal (7-
endo versus 5-exo cyclization). In addi-
tion, the regioselectivity of the La-cata-
lyzed cycloetherification can be tuned
(5-exo versus 7-endo) simply through a
subtle variation in the substitution pat-
tern of the allene component (Ph
versus Me). Thus, for the first time the
regiocontrolled heterocyclization of g-
allenol derivatives is both catalyst- and
substrate-directable. These metal-cata-
lyzed heterocyclization reactions have
been developed experimentally (Part 1,
this paper), and their mechanisms have
additionally been investigated by a the-
oretical study (Part 2, accompanying
paper).
ꢀ
ty control in the O C functionalization
of g-allenols can be achieved through
the choice of catalyst: use of AuCl3 ex-
clusively affords tetrahydrofurans, use
of La[NACHTUNGTRENNUNG(SiMe3)2]3 usually favors the
formation of dihydropyrans, whereas
use of PdCl2 solely gives tetrahydroox-
epines. In addition, it has been ob-
Keywords: allenes
· cyclization ·
gold · heterocycles · palladium
Introduction
with the use of these products as starting materials in the
preparation of a- and b-amino acids, alkaloids, heterocycles,
taxoids, and other types of compounds of biological and me-
dicinal interest,[4] provide the motivation to explore new
methodologies for the synthesis of substances based on the
b-lactam core.
In addition, tetrahydrofuran, dihydropyran, and oxepane
ether rings are ubiquitous structural units extensively en-
countered in a number of biologically active natural prod-
ucts and functional molecules, and their stereocontrolled
synthesis therefore remains an intensively investigated re-
search area.[5]
b-Lactams are among the most important pharmacophores
for treatment of diseases caused by bacterial infections.[1]
Additionally, there are many important non-antibiotic uses
of azetidin-2-ones in fields ranging from enzyme inhibition[2]
to gene activation.[3] These biological activities, combined
[a] Prof. Dr. B. Alcaide, T. Martꢀnez del Campo
Departamento de Quꢀmica Orgꢁnica I
Facultad de Quꢀmica
Universidad Complutense de Madrid
28040 Madrid (Spain)
On the other hand, allene chemistry has attracted consid-
erable attention in recent years.[6] In particular, the transi-
tion-metal-catalyzed cyclization of allene derivatives bearing
nucleophilic substituents—such as hydroxy, carbonyl, car-
boxy, thio, and amino groups—has led to many synthetically
useful transformations.[7] Regioselectivity problems (endo-
trig versus exo-dig versus exo-trig cyclization) are significant,
however. In a preliminary study,[8] the metal-catalyzed regio-
controlled cyclization of azetidin-2-one-tethered methyl-g-
allenols to give tetrahydrofurans and tetrahydrooxepines
Fax : (+34) 91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros, Dr. E. Soriano, Prof. Dr. J. L. Marco-Contelles
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
[#] For Part 2, see ref. [10].
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802034.
Chem. Eur. J. 2009, 15, 1901 – 1908
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1901

Table 1. Preparation of a-allenic alcohols 2.
was accomplished. The regioselectivities observed in these
reactions were substantially different, when applicable, from
those reported for related simple reactants and suggested
that the regioselectivity was strongly modulated both by the
nature of the metal (gold versus palladium) and by the
status of the hydroxy group (i.e., free or protected) in the
methyl-g-allenol. In continuation of our investigations into
heterocyclic and allene chemistry,[9] here we report a system-
atic study of the metal-catalyzed (Au, Ag, Pt, Pd, and La)
heterocyclization reactions of methyl- and phenyl-g-allenols,
which fully confirms and extends our earlier conclusions and
establishes versatile and regiocontrolled routes to a variety
of enantiopure fused tetrahydrofuran-, dihydropyran-, and
tetrahydrooxepine-b-lactams. In addition, the mechanisms
of these metal-catalyzed cycloetherification reactions have
also been investigated theoretically (Part 2, accompanying
paper, see ref. [10]).
Aldehyde
a-Allenol
Yield
[%][a]
68
61
65
Results and Discussion
Precursors for the formation of five-, six-, and seven-mem-
bered oxacycles—the enantiopure g-allenols 4a–g—were
readily prepared in good overall yield from the appropriate
starting carbaldehydes 1a–d through regiocontrolled
indium-mediated Barbier-type carbonyl-allenylation reac-
tions in aqueous media to give a-allenols 2a–g (Table 1),[11]
followed by protecting group manipulation. a-Allenols 2
were protected as the corresponding ethers (methoxymethyl
and tert-butyldimethylsilyl) or esters (acetate and benzoate)
3a–j, which were easily converted into g-allenols 4a–g
(Table 2). Because of steric hindrance, phenyl-a-allenols 2e–
63
74
55
60
Abstract in Spanish: La reacciꢁn de heterociclaciꢁn de g-ale-
noles catalizada por metales es un proceso regiocontrolado
que da lugar a una amplia variedad de tetrahidrofuranos, te-
trahidropiranos y tetrahidrooxepinas fusionadas enantiopu-
ꢀ
ras. La regioselectividad en la funcionalizaciꢁn O C se
puede controlar y dirigir con la elecciꢁn del catalizador: la
utilizaciꢁn de AuCl3 exclusivamente da lugar a tetrahidrofu-
[a] Yield of pure, isolated product with correct analytical and spectral
data. a-Allenols 2 were obtained as single isomers (de >95%), except in
the case of compound 2b (de 70%). PMP=4-MeOC6H4, MOM=
MeOCH2.
ranos, La[NACHTUNGTRENNUNG(SiMe3)2]3 normalmente genera dihidropiranos,
mientras que PdCl2 favorece la formaciꢁn de tetrahidrooxe-
pinas. Ademꢀs, se ha observado que un grupo protector me-
toximetil no sꢁlo enmascara una funcionalidad hidroxilo,
sino que tambiꢂn controla un cambio regioquꢃmico (ciclaciꢁn
7-endo frente a 5-exo). Por otra parte, la regioselectividad de
la cicloeterificaciꢁn catalizada por La se puede revertir (5-
exo frente a 7-endo) con un simple cambio en la sustituciꢁn
del aleno (Ph frente a Me). Asꢃ, por primera vez la heteroci-
claciꢁn regiocontrolada de derivados de g-alenol se puede
modular tanto por el catalizador como por el sustrato. Estas
heterociclaciones catalizadas por metales se han desarrollado
experimentalmente (Parte 1, este artꢃculo) y ademꢀs sus meca-
nismos han sido investigados teꢁricamente en detalle (Parte 2,
artꢃculo siguiente).
g could not be protected as their corresponding tert-butyldi-
methylsilyl ethers.
Firstly, the general reactivity of g-allenols toward the re-
gioselective hydroalkoxylation reaction was tested with sub-
strate 4a in the presence of [PtCl
AuCl, and AuCl3 as catalysts (Table 3). [PtCl CTHUNGTRENNUNG
(CH2=CH2)]2, AgNO3,
2A(CH2=CH2)]2
and AgNO3 afforded rather low yields or disappointing dia-
stereomeric mixtures of bicycle 5a.[12,13] Although AgNO3
was less diastereoselective than [PtCl2ACHTNUGTRNE(UGN CH2=CH2)]2 (60:40 vs
100:0), it was a more efficient catalyst, affording adduct 5a
in reasonable yield. Gratifyingly, we found that Au salts
were effective as 5-exo-selective hydroalkoxylation cata-
lysts.[14] AuCl3 was selected as catalyst of choice because of
1902
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1901 – 1908

g-Allenols
FULL PAPER
Table 2. Preparation of protected g-allenols 3 and free g-allenols 4.
its superior performance. No
regioisomeric products were de-
tected, the fused five-mem-
bered oxacycle being obtained
exclusively. Compounds 5 are
remarkable because they each
bear a quaternary stereocen-
ter.[15] Qualitative homonuclear
NOE difference spectra al-
lowed us to assign the stereo-
chemistry at the newly formed
stereocenters of tetrahydrofur-
ans 5.
One of the challenges for
modern synthesis is to create
distinct types of complex mole-
cules from identical starting
materials solely through selec-
tion of catalyst. Thus, having
found a solution for the 5-exo-
selective hydroalkoxylation, we
next examined the more intri-
cate heterocyclizative problem
associated with tuning of the re-
gioselectivities of g-allenols.
Specifically, subjection of the g-
allenol 4a to the lanthanide
amide-catalyzed protocol did
Substrate
Protected g-allenol
Yield [%][a]
g-Allenol
Yield [%][a]
quant.
70
conditions A
conditions B
conditions A
conditions D
conditions D
conditions D
79
71
61
60
60
quant.
quant.
quant.
conditions B
conditions C
conditions C
conditions D
afford
dihydropyran
6a
(Scheme 1), with the nucleo-
philic attack taking place at the
central allene carbon through a
6-endo cyclization.[16] In addi-
tion, partial epimerization was
observed through the isolation
of epi-6a. Notably, the PdII-cat-
alyzed cyclizative coupling reac-
tions between g-allenols 4a, 4c,
and 4g and allyl halides gave
impressive yields (up to 94%)
of the desired seven-membered
adducts 7a–e (Scheme 2), the
results of 7-endo oxycyclization,
as the sole products.[17] Particu-
larly, judicious choice of cata-
lyst (Au, La, or Pd) allows the
ring size (five, six, or seven) of
the fused oxacycle to be modu-
lated.
77
56
77
quant.
quant.
60
conditions B
conditions D
conditions B
conditions C
conditions D
conditions E
Having demonstrated the sta-
bilities of the benzoate and
TBS protecting groups to the
AuIII- or PdII-catalyzed condi-
tions, we decided to see wheth-
er methoxymethyl substitution
would have a beneficial impact
on the cyclization reactions. In
Chem. Eur. J. 2009, 15, 1901 – 1908
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1903

B. Alcaide, P. Almendros et al.
prisingly, though, the PdCl2-cat-
alyzed reactions between allyl
bromide and phenyl-g-allenols
4e and 4 f afforded the dihydro-
furans 9a and 9b, correspond-
ing to the heterocyclizative cou-
pling of the MOM-deprotected
a-allenols (Scheme 3). Interest-
ingly, when the two methyl-g-al-
lenols 4b and 4d and the
Table 2. (Continued)
Substrate
Protected g-allenol
Yield [%][a]
g-Allenol
Yield [%][a]
71
conditions C
[a] Yield of pure, isolated product with correct analytical and spectral data; PMP=4-MeOC6H4, PBrP=4-
BrC6H4, MOM=MeOCH2, TBS=tert-butyldimethylsilyl.
Scheme 1. Lanthanum-promoted preparation of six-membered oxacycles
6a and epi-6a. a) 5 mol% La[NACHTNUTRGNEUNG(SiMe3)2]3, toluene, reflux; TBS=tert-bu-
tyldimethylsilyl.
Scheme 3. Palladium-catalyzed heterocyclization reactions of g-allenol
derivatives 4b and 4d–f. a) PdCl2 (5 mol%), allyl bromide, DMF, RT;
MOM=MeOCH2, E=CO2Me.
phenyl-g-allenol 4e were treated with AuCl3 the 2,5-dihy-
drofurans 10a–c were the sole products (Scheme 4). These
transformations may involve a chemoselective (5-endo-trig
versus 7-endo-trig) allenol oxycyclization with concomitant
MOM ether removal.[18]
In view of the above results, we decide to examine wheth-
er the metal-catalyzed preparation of bicycles 5 and 7 could
be directly accomplished from MOM-protected g-allenol de-
rivatives 3. In the event, MOM ethers 3e, 3 f, 3i, and 3j re-
mained unchanged in the presence of PdCl2 and allyl bro-
mide. Much to our delight though, when allenic MOM
ethers 3e, 3 f, 3i, and 3j were treated with AuCl3, the 5-exo
mode was completely abolished and replaced by a 7-endo
Scheme 2. Palladium-promoted preparation of seven-membered oxacy-
cles 7a–e. a) PdCl2 (5 mol%), DMF, RT; PMP=4-MeOC6H4.
the event, appreciable extents of MOM cleavage were ob-
served during the reactions of methyl-g-allenols 4b and 4d
with allyl bromide in the presence of PdCl2 (Scheme 3). Sur-
Table 3. Heterocyclization of g-allenol derivatives 4 under modified metal-catalyzed hydroalkoxylation conditions.[a]
Allenol
R1
R2
PG
Catalyst
[Pt][c]
AgNO3
AuCl
Bicycle
dr
Yield [%][b]
(ꢀ)-4a
(ꢀ)-4a
(ꢀ)-4a
(ꢀ)-4a
(ꢀ)-4b
(+)-4c
(+)-4g
Bn
Bn
Bn
Bn
Bn
allyl
Bn
Me
Me
Me
Me
Me
Me
Ph
TBS
TBS
TBS
TBS
MOM
TBS
COPMP
(+)-5a
(+)-5a
(+)-5a
(+)-5a
(+)-5b
(+)-5c
(+)-5d
100:0
60:40
100:0
100:0
100:0
100:0
100:0
12
54
37
57
47
58
50
[d]
AuCl3
AgNO3
AuCl3
AuCl3
[d]
[a] Reactions were conducted in CH2Cl2 at room temperature, except when otherwise stated. [b] Yield of pure, isolated product with correct analytical
and spectral data. [c] [Pt]=[PtCl2A(CH2=CH2)]2. [d] Reactions were conducted in acetone/H2O 4:1 at reflux temperature; PMP=4-MeOC6H4, MOM=
MeOCH2, TBS=tert-butyldimethylsilyl.
CTHUNGTRENNUNG
1904
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1901 – 1908

g-Allenols
FULL PAPER
Scheme 4. Gold-catalyzed heterocyclization of g-allenol derivatives 4b,
4d, and 4e. a) AuCl3 (5 mol%), CH2Cl2, RT; E=CO2Me.
cyclization to afford bicycles 11a–c and 12 in fair yields
(Scheme 5). To the best of our knowledge, this observation
is unprecedented. It seems that the reactivity in these classes
of AuIII-catalyzed reactions is determined by the presence or
absence of a methoxymethyl protecting group at the g-alle-
nol oxygen atom, because the free g-allenols 4a–c and 4g
gave 5-exo hydroalkoxylation, while the MOM-protected g-
allenol derivatives 3e, 3 f, 3i, and 3j exclusively underwent
7-endo oxycyclization. We have thus demonstrated that re-
Scheme 6. LaIII-catalyzed heterocyclization reactions of g-allenol deriva-
tives 4b and 4e. a) La[NACHTUNGTRNEUG(N SiMe3)2]3 (5 mol%), toluene, reflux.
which from the above results with Au and Pd was anticipat-
ed not to change the electronic properties of the propa-1,2-
dienyl moiety significantly. Much to our delight, however,
the reaction proceeded smoothly to afford the strained tricy-
cle 14 in a remarkably high isolated yield of 77%; addition-
ally, a small amount (7% yield) of the dihydropyran 6b was
observed (Scheme 6). Thus, through a subtle variation in the
substitution pattern of the allene component (Ph versus Me)
the preference for La-catalyzed formation of the seven-
membered regioisomer can be reversed.
ꢀ
gioselectivity control in the metal-catalyzed O C functional-
ization of g-allenols can be achieved both through the
choice of catalyst (Au versus La versus Pd) and also through
the nature of the g-allenol (free versus protected).[19] This
appears to be the first time that such an effect has been re-
ported.
It should be noted that some of the metal-based cata-
lysts—such as AgNO3, AuCl3, or PdCl2—are not dependent
on the use of absolute solvents, whereas others such as
La[NACTHNUGRTNEUNG(SiMe3)2]3 often do need absolute solvents.
To understand the highly regio- and diastereoselective na-
tures of these metal-catalyzed transformations, a computa-
tional study on the ring-closure steps of free and protected
g-allenols 3 and 4 was undertaken (Part 2, accompanying
paper).
Scheme 5. AuIII-catalyzed heterocyclization reaction of MOM-protected
g-allenol derivatives 3e, 3 f, 3i, and 3j. a) AuCl3 (5 mol%), CH2Cl2, RT.
Conclusion
In conclusion, efficient metal-controlled regiodivergent
preparations of bicyclic tetrahydrofurans, dihydropyrans,
and tetrahydrooxepines also incorporating b-lactam moiet-
ies—key structural motifs in biologically relevant com-
pounds such as antibiotics and enzyme inhibitors—from
starting enantiopure g-allenols have been developed. In ad-
dition, it has been observed that the presence of a methoxy-
methyl protecting group not only masks a hydroxy function-
ality, but also exerts directing effects as a controlling unit in
a regioselectivity reversal. In addition, the regioselectivity of
the La-catalyzed cycloetherification can be tuned (5-exo
versus 7-endo) simply through subtle variation in the substi-
tution pattern of the allene component (Ph versus Me). Re-
giocontrolled heterocyclization reactions of g-allenol deriva-
tives are thus for the first time both catalyst- and substrate-
directable. The mechanisms of these metal-catalyzed hetero-
cyclization reactions were also analyzed by calculation-
based methods (Part 2, accompanying paper).[10]
From the Au- and Pd-catalyzed results, the heterocycliza-
tion reaction is very sensitive to the presence of the MOM
ether functionality. To expand the utility of the metal-cata-
lyzed cycloetherification further, allenes incorporating me-
thoxymethyl groups were studied with the lanthanide amide
methodology. Accordingly, the La-catalyzed reactions of
MOM-protected g-allenols 3e, 4b, and 4e were investigated.
When compound 3e was subjected to the lanthanide amide
conditions, the starting material still remained unaltered
even after 2 days of reaction time. Fortuitously, however,
when the reaction of methylallene 4b was conducted in the
presence of a catalytic amount of La[NACHTNUGTRNE(UNG SiMe3)2]3, the
MOM-free seven-membered adduct 13 was obtained exclu-
sively (Scheme 6).[20] Intrigued by this unusual outcome, we
set out to investigate the lanthanum-catalyzed reaction of
phenylallene 4e, in which the C-methyl group on allene was
replaced by a sterically more demanding C-phenyl group,
Chem. Eur. J. 2009, 15, 1901 – 1908
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1905

B. Alcaide, P. Almendros et al.
General Procedure for PdII-catalyzed coupling of g-allenols 4 with allyl
bromides—preparation of fused tetrahydrooxepines 7: PdCl2
(0.005 mmol) was added to a stirred solution of the corresponding g-alle-
nol 4 (0.10 mmol) and the appropriate allyl bromide (0.50 mmol) in N,N-
dimethylformamide (0.6 mL). The reaction mixture was stirred under
argon until disappearance of the starting material (TLC). Water (0.5 mL)
was added before extraction with ethyl acetate (3ꢃ4 mL). The organic
phase was washed with water (2ꢃ2 mL), dried (MgSO4), and concentrat-
ed under reduced pressure. Chromatography of the residue with elution
with hexanes/ethyl acetate mixtures gave analytically pure fused tetrahy-
drooxepines 7.
Experimental Section
General methods: 1H NMR and 13C NMR spectra were recorded with
Bruker Avance 300, Varian VRX 300S, or Bruker AC 200 instruments.
NMR spectra were recorded in CDCl3 solutions, except when otherwise
stated. Chemical shifts are given in ppm relative to TMS (1H, 0.0 ppm) or
CDCl3 (13C, 76.9 ppm). Low- and high-resolution mass spectra were
taken with a HP 5989 A spectrometer in electronic impact (EI) or elec-
trospray (ES) modes unless otherwise stated. Specific rotations ([a]D) are
given in 10ꢀ1 degcm2 gꢀ1 at 208C, and concentrations (c) are expressed in
g per 100 mL. All commercially available compounds were used without
further purification.
General Procedure for the AuIII-catalyzed cyclizations of g-allenols (ꢀ)-
4a, (+)-4c, and (+)-4g—preparation of fused tetrahydrofurans 5: AuCl3
(0.05 mmol) was added under argon to a stirred solution of the corre-
sponding g-allenol 4 (1.0 mmol) in dichloromethane (1.0 mL). The result-
ing mixture was stirred at room temperature until disappearance of the
starting material (TLC). The reaction was then 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 with elution with ethyl acetate/hexanes mixtures
gave analytically pure tetrahydrofuran adducts 5. Spectroscopic and ana-
lytical data for a representative compound of type 5 follow.[21]
Fused tetrahydrooxepine (+)-7d: g-Allenic alcohol (+)-4c (20 mg,
0.06 mmol), after chromatography of the residue with hexanes/ethyl ace-
tate 3:1, gave the tetrahydrooxepine (+)-7d (22 mg, 94%) as a colorless
oil. [a]D =+5.2 (c=2.3 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d=5.74 (m, 2H), 5.17 (m, 2H), 5.08 (m, 2H), 5.04 (m, 1H), 4.53 (d, J=
4.4 Hz, 1H), 4.52 (m, 1H), 4.25 (dt, J=5.1, 1.5 Hz, 1H), 3.96 (dt, J=16.3,
1.7 Hz, 1H), 3.63 (dd, J=9.3, 4.4 Hz, 1H), 3.62 (m, 1H), 2.66 and 2.48
(dd, J=16.0, 6.0 Hz, each 1H), 1.69 (s, 3H), 0.96 (s, 9H), 0.12 and
0.07 ppm (s, each 3H); 13C NMR (75 MHz, CDCl3, 258C): d=166.1,
134.2, 131.5, 131.3, 126.3, 118.3, 115.2, 81.3, 74.0, 72.5, 61.8, 44.3, 34.2,
25.7, 18.0, 14.1, ꢀ4.8, ꢀ4.9 ppm; IR (CHCl3): n˜ =1744 cmꢀ1; MS (ES):
m/z (%): 364 (100) [M+H]+, 363 (17) [M]+; elemental analysis calcd
(%) for C20H33NO3Si (363.6): C 66.07, H 9.15, N 3.85; found: C 66.20, H
9.10, N 3.82.
Fused tetrahydrofuran (+)-5c: g-Allenic alcohol (+)-4c (50 mg,
0.15 mmol), after chromatography of the residue with hexanes/ethyl ace-
tate 4:1, gave the tetrahydrofuran (+)-5c (28 mg, 58%) as a colorless oil.
[a]D =+68.6 (c=0.5 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=
5.96 (dd, J=17.6, 11.0 Hz, 1H), 5.76 (m, 1H), 5.29 (m, 1H), 5.23 (m,
2H), 5.16 (d, J=3.7 Hz, 1H), 5.08 (dd, J=11.0, 0.7 Hz, 1H), 4.11 (s, 1H),
3.93 (d, J=3.7 Hz, 1H), 3.90 and 3.54 (m, each 1H), 1.31 (s, 3H), 0.92 (s,
9H), 0.11 ppm (s, 6H); 13C NMR (75 MHz, CDCl3, 258C): d=162.1,
142.2, 131.6, 119.5, 113.4, 91.7, 86.6, 75.2, 66.1, 43.6, 25.8, 25.7, 24.0, ꢀ4.8,
ꢀ5.0 ppm; IR (CHCl3): n˜ =1746 cmꢀ1; MS (ES): m/z (%): 324 (100)
[M+H]+, 323 (10) [M]+; elemental analysis calcd (%) for C17H29NO3Si
(323.5): C 63.12, H 9.04, N 4.33; found: C 63.00, H 8.99, N 4.36.
Fused tetrahydrooxepine (+)-7e: g-Allenic alcohol (+)-4g (34 mg,
0.07 mmol), after chromatography of the residue with hexanes/ethyl ace-
tate 2:1, gave the tetrahydrooxepine (+)-7e (23 mg, 66%) as a colorless
oil. [a]D =+39.0 (c=1.3 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d=7.39 and 6.73 (d, J=8.5 Hz, each 2H), 7.07 (m, 10H), 6.62 (d, J=
9.8 Hz, 1H), 5.53 (m, 1H), 4.89 (m, 3H), 4.84 (d, J=4.4 Hz, 1H), 4.66
and 3.96 (d, J=15.4 Hz, each 1H), 4.20 (m, 1H), 4.11 (dd, J=9.8, 4.4 Hz,
1H), 3.83 (s, 3H), 2.40 ppm (d, J=6.6 Hz, 2H); 13C NMR (75 MHz,
CDCl3, 258C): d=165.2, 164.7, 163.3, 137.5, 135.3, 135.0, 134.9, 132.9
(2C), 131.3 (2C), 129.0, 128.6 (2C), 128.0 (2C), 127.6 (2C), 126.8 (2C),
121.8, 116.4, 113.1 (2C), 113.0, 82.6, 73.8, 73.5, 61.6, 55.3, 45.2, 35.8 ppm;
IR (CHCl3): n˜ =1745, 1730 cmꢀ1; MS (ES): m/z (%): 496 (100) [M+H]+,
495 (15) [M]+; elemental analysis calcd (%) for C31H29NO5 (495.6): C
75.13, H 5.90, N 2.83; found: C 75.27, H 5.85, N 2.80.
General procedure for the LaIII-catalyzed cyclization of g-allenols 4:
La[NACHTUNGTRENUNG(SiMe3)2]3 (0.05 mmol) was added under argon to a stirred solution
of the corresponding g-allenol 4 (1.0 mmol) in toluene (10.0 mL). The re-
sulting mixture was stirred at reflux temperature until disappearance of
the starting material (TLC). The reaction was then filtered through a
celite plug before being concentrated under reduced pressure. Chroma-
tography of the residue with elution with ethyl acetate/hexanes mixtures
gave analytically pure adducts 6, 13, and 14.
LaIII-catalyzed cyclization of g-allenol (ꢀ)-4a—preparation of fused dihy-
dropyrans (+)-6a and (+)-epi-6a: g-Allenic alcohol (ꢀ)-4a (99 mg,
0.31 mmol), after chromatography of the residue with hexanes/ethyl ace-
tate 4:1, afforded the less polar compound (+)-6a (52 mg, 44%) and the
more polar compound epi-6a (5 mg, 4%).
General Procedure for the AuIII-catalyzed cyclization of (methoxymethyl)-
oxy allenes 3—preparation of fused tetrahydrooxepines 11: AuCl3
(0.025 mmol) was added under argon to a stirred solution of the corre-
sponding methoxymethyl-substituted allene 3 (0.5 mmol) in dichlorome-
thane (0.5 mL). The resulting mixture was stirred at room temperature
until disappearance of the starting material (TLC). The reaction was then
quenched with brine (0.5 mL), the mixture was extracted with ethyl ace-
tate (3ꢃ3 mL), and the combined extracts were washed twice with brine.
The organic layer was dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue with elution with ethyl acetate/
hexanes mixtures gave analytically pure tetrahydrooxepine adducts 11.
Fused dihydropyran (+)-6a: Colorless oil; [a]D =+33.2 (c=0.5 in
CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=7.31 (m, 5H), 5.05 (d,
J=5.0 Hz, 1H), 4.47 and 4.31 (d, J=15.0 Hz, each 1H), 3.83 (dd, J=5.0,
1.5 Hz, 1H), 3.75 (d, J=1.5 Hz, 1H), 1.80 and 1.44 (d, J=0.9 Hz, each
3H), 0.81 (s, 9H), ꢀ0.06 and ꢀ0.08 ppm (s, each 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=165.9, 146.8, 135.7, 129.0 (2C), 128.4 (2C),
128.1, 106.8, 78.1, 67.1, 61.3, 44.8, 25.9, 25.7, 18.0, 16.9, ꢀ4.6, ꢀ4.8 ppm;
IR (CHCl3): n˜ =1746 cmꢀ1; MS (ES): m/z (%): 374 (100) [M+H]+, 373
(11) [M]+; elemental analysis calcd (%) for C21H31NO3Si (373.6): C
67.52, H 8.36, N 3.75; found: C 67.65, H 8.31, N 3.79.
Fused tetrahydrooxepine (+)-11b: Methoxymethyl-substituted allene
(ꢀ)-3 f (55 mg, 0.11 mmol), after chromatography of the residue with
hexanes/ethyl acetate 2:1, gave the tetrahydrooxepine (+)-11b (27 mg,
58%) as
a
colorless oil. [a]D =+26.3 (c=0.6 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.80 and 7.60 (d, J=8.5 Hz, each 2H), 7.20
(m, 3H), 7.04 (m, 2H), 6.33 (d, J=9.8 Hz, 1H), 5.27 (m, 1H), 4.76 (d, J=
4.4 Hz, 1H), 4.62 and 4.13 (d, J=15.4 Hz, each 1H), 4.64 and 4.12 (m,
each 1H), 3.99 (dd, J=9.5, 4.4 Hz, 1H), 1.60 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=164.6, 162.2, 135.3, 132.2, 131.7, 131.8 (2C),
131.3 (2C), 128.7 (2C), 127.9, 127.7, 127.6 (2C), 122.7, 82.5, 75.1, 70.9,
61.3, 45.3, 20.3 ppm; IR (CHCl3): n˜ =1744, 1728 cmꢀ1; MS (ES): m/z (%):
443 (100) [M+2+H]+, 441 (11) [M+H]+; elemental analysis calcd (%)
for C22H20BrNO4 (442.3): C 59.74, H 4.56, N 3.17; found: C 59.62, H 4.53,
N 3.20.
Fused dihydropyran (+)-epi-6a: Colorless oil; [a]D =+14.6 (c=0.2 in
CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=7.28 (m, 5H), 4.94 (d,
J=5.0 Hz, 1H), 4.78 and 4.33 (d, J=15.5 Hz, each 1H), 4.48 (m, 1H),
4.12 (dd, J=5.0, 3.8 Hz, 1H), 1.84 (m, 3H), 1.63 (t, J=1.2 Hz, 3H), 0.90
(s, 9H), 0.07 and ꢀ0.01 ppm (s, each 3H); IR (CHCl3): n˜ =1746 cmꢀ1
;
Fused tetrahydrooxepine (+)-11c: Methoxymethyl-substituted allene
(+)-3i (40 mg, 0.08 mmol), after chromatography of the residue with hex-
anes/ethyl acetate 3:1, gave the tetrahydrooxepine (+)-11c (23 mg, 62%)
as a colorless oil. [a]D =+27.5 (c=0.7 in CHCl3); 1H NMR (300 MHz,
MS (ES): m/z (%): 374 (100) [M+H]+, 373 (9) [M]+; elemental analysis
calcd (%) for C21H31NO3Si (373.6): C 67.52, H 8.36, N 3.75; found: C
67.66, H 8.42, N 3.70.
1906
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1901 – 1908

g-Allenols
FULL PAPER
CDCl3, 258C): d=7.63 and 6.80 (d, J=9.0 Hz, each 2H), 7.23 (m, 5H),
7.10 (m, 5H), 6.58 (d, J=9.3 Hz, 1H), 5.52 (dd, J=4.5, 2.8 Hz, 1H), 4.89
(d, J=4.4 Hz, 1H), 4.83 and 4.35 (m, each 1H), 4.71 and 4.02 (d, J=
15.1 Hz, each 1H), 4.18 (dd, J=9.0, 4.4 Hz, 1H), 3.85 ppm (s, 3H);
13C NMR (75 MHz, CDCl3, 258C): d=165.4, 164.7, 163.4, 139.3, 138.4,
131.6 (2C), 128.7 (2C), 128.1 (2C), 128.0 (2C), 127.8, 127.7 (2C), 127.5,
127.1, 121.6, 113.4 (2C), 83.2, 77.2, 73.1, 70.9, 61.6, 55.4, 45.3 ppm; IR
(CHCl3): n˜ =1746, 1731 cmꢀ1; MS (ES): m/z (%): 456 (100) [M+H]+, 455
(9) [M]+; elemental analysis calcd (%) for C28H25NO5 (455.2): C 73.83, H
5.53, N 3.08; found: C 73.70, H 5.49, N 3.11.
LaIII-catalyzed cyclization of g-allenol (+)-4e—preparation of fused dihy-
dropyran (+)-6b and tricycle (+)-14: g-Allenic alcohol (+)-4e (30 mg,
0.07 mmol), after treatment by the General Procedure for the LaIII-cata-
lyzed cyclization of g-allenols 4 and chromatography of the residue with
hexanes/ethyl acetate 3:1, afforded the less polar compound (+)-6b
(2 mg, 7%) and the more polar compound (+)-14 (17 mg, 77%).
D. E. Bergles, L. Jin, M. D. Hoberg, S. Vidensky, D. S. Chung, S. V.
Toan, L. I. Bruijn, Z.-Z. Su, P. Gupta, P. B. Fisher, Nature 2005, 433,
73.
[4] For selected reviews, see: a) B. Alcaide, P. Almendros, C. Aragoncil-
lo, Chem. Rev. 2007, 107, 4437; b) B. Alcaide, P. Almendros, Curr.
Med. Chem. 2004, 11, 1921; c) A. R. A. S. Deshmukh, B. M. Bhawal,
D. Krishnaswamy, V. V. Govande, B. A. Shinkre, A. Jayanthi, Curr.
Med. Chem. 2004, 11, 1889; d) B. Alcaide, P. Almendros, Synlett
2002, 381; e) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide,
Synlett 2001, 1813; f) B. Alcaide, P. Almendros, Chem. Soc. Rev.
2001, 30, 226; g) I. Ojima, F. Delaloge, Chem. Soc. Rev. 1997, 26,
377; h) M. S. Manhas, D. R. Wagle, J. Chiang, A. K. Bose, Heterocy-
cles 1988, 27, 1755.
[5] For selected reviews, see: a) I. Larrosa, P. Romea, F. Urpꢀ, Tetrahe-
dron 2008, 64, 2683; b) J. P. Wolfe, M. B. Hay, Tetrahedron 2007, 63,
261; c) P. A. Clarke, S. Santos, Eur. J. Org. Chem. 2006, 2405;
d) N. L. Snyder, H. M. Haines, M. W. Peczuh, Tetrahedron 2006, 62,
9301; e) X.-L. Hou, Z. Yang, K.-S. Yeung, H. N. C. Wong in Progress
in Heterocyclic Chemistry, Vol. 17 (Eds.: G. W. Gribble, J. A. Joule),
Elsevier, Oxford, 2005, pp. 142–171; f) X.-L. Hou, Z. Yang, K.-S.
Yeung, H. N. C. Wong in Progress in Heterocyclic Chemistry, Vol. 16
(Eds.: G. W. Gribble, J. A. Joule), Elsevier, Oxford, 2004, pp. 156–
197; g) The Chemistry of Heterocycles: Structure, Reactions, Synthe-
ses, and Applications (Eds.: T. Eicher, J. S. Hauptmann), Wiley-
VCH, Weinheim, 2003; h) Special issue: Tetrahedron 2002, 58,
1779–2040; i) G. Rousseau, F. Homsi, Chem. Soc. Rev. 1997, 26,
453–461; j) H. Heaney, J. S. Ahn in Comprehensive Heterocyclic
Chemistry II, Vol. 2 (Ed.: C. W. Bird), Elsevier, Amsterdam, 1995,
Chapter 2.06, pp. 297–350; k) U. Koert, Synthesis 1995, 115; l) J.-C.
Harmange, B. Figadꢅre, Tetrahedron: Asymmetry 1993, 4, 1711;
m) B. M. Fraga, Nat. Prod. Rep. 1992, 9, 217; n) A. T. Merritt, S. V.
Ley, Nat. Prod. Rep. 1992, 9, 243; o) F. M. Dean in Advances in Het-
erocyclic Chemistry, Vol. 30 (Ed.: A. R. Katritzky), Academic Press,
New York, 1982, pp. 167–238.
Fused dihydropyran (+)-6b: Colorless oil; [a]D =+96.7 (c=0.3 in
CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=7.27 (m, 8H), 7.05 (m,
2H), 5.18 (d, J=4.9 Hz, 1H), 4.57 (dd, J=14.9, 7.1 Hz, 2H), 4.49 and
4.33 (d, J=14.9 Hz, each 1H), 4.19 (d, J=4.9 Hz, 1H), 4.18 (m, 1H),
3.23 (s, 3H), 1.92 ppm (s, 3H); IR (CHCl3): n˜ =1746 cmꢀ1; MS (ES): m/z
(%): 374 (100) [M+H]+, 373 (11) [M]+; elemental analysis calcd (%) for
C22H23NO4 (365.4): C 72.31, H 6.34, N 3.83; found: C 72.44, H 6.29, N
3.87.
Tricycle (+)-14: Colorless oil; [a]D =+58.3 (c=0.3 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.33 (m, 8H), 7.06 (m, 2H), 5.76 (ddd, J=
4.5, 1.7, 0.7 Hz, 1H), 5.29 (d, J=5.1 Hz, 1H), 4.97 (t, J=1.6 Hz, 1H),
4.47 (s, 2H), 4.43 (t, J=0.6 Hz, 1H), 4.17 ppm (dd, J=5.1, 4.5 Hz, 1H);
13C NMR (75 MHz, CDCl3, 258C): d=167.5, 152.7, 138.7, 135.6, 129.0,
128.8 (2C), 128.5 (2C), 128.3, 128.1 (2C), 127.4 (2C), 122.2, 101.1, 78.7,
66.1, 49.1, 45.2 ppm; IR (CHCl3): n˜ =1751 cmꢀ1; MS (ES): m/z (%): 320
(100) [M+H]+, 319 (11) [M]+; elemental analysis calcd (%) for
C20H17NO3 (319.3): C 75.22, H 5.37, N 4.39; found: C 75.08, H 5.32, N
4.43.
[6] For general and comprehensive reviews, see: a) S. Ma, Chem. Rev.
2005, 105, 2829; b) Modern Allene Chemistry (Eds.: N. Krause,
A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004; c) R. Zimmer, C. U.
Dinesh, E. Nandanan, F. A. Khan, Chem. Rev. 2000, 100, 3067.
[7] For selected reviews, see: a) R. A. Widenhoefer, Chem. Eur. J. 2008,
14, 5382; b) N. Bongers, N. Krause, Angew. Chem. 2008, 120, 2208;
Angew. Chem. Int. Ed. 2008, 47, 2178; c) R. A. Widenhoefer, X.
Han, Eur. J. Org. Chem. 2006, 4555; d) A. Hoffmann-Rçder, N.
Krause, Org. Biomol. Chem. 2005, 3, 387; e) S. Ma, Acc. Chem. Res.
2003, 36, 701; f) R. W. Bates, V. Satcharoen, Chem. Soc. Rev. 2002,
31, 12; g) A. S. K. Hashmi, Angew. Chem. 2000, 112, 3737; Angew.
Chem. Int. Ed. 2000, 39, 3590.
Acknowledgement
Support for this work from the DGI-MEC (CTQ2006-10292), the Comu-
nidad Autꢄnoma de Madrid (CCG-07-UCM/PPQ-2308), and the Univer-
sidad Complutense de Madrid (Grant GR74/07) is gratefully acknowl-
edged. T.M.C. thanks the MEC for a predoctoral grant.
[8] B. Alcaide, P. Almendros, T. Martꢀnez del Campo, Angew. Chem.
2007, 119, 6804; Angew. Chem. Int. Ed. 2007, 46, 6684.
[1] See, for example: a) D. Niccolai, L. Tarsi, R. J. Thomas, Chem.
Commun. 1997, 2333; b) R. Southgate, Contemp. Org. Synth. 1994,
1, 417; c) R. Southgate, C. Branch, S. Coulton, E. Hunt in Recent
Progress in the Chemical Synthesis of Antibiotics and Related Micro-
bial Products Vol. 2 (Ed.: G. Lukacs), Springer, Berlin, 1993, p. 621;
d) The Chemistry of b-Lactams (Ed.: M. I. Page), Chapman and
Hall, London, 1992; e) Chemistry and Biology of b-Lactam Antibiot-
ics Vols. 1–3 (Eds.: R. B. Morin, M. Gorman), Academic Press, New
York, 1982.
[9] See, for instance: a) B. Alcaide, P. Almendros, T. Martꢀnez del Cam-
po, Chem. Eur. J. 2008, 14, 7756; b) B. Alcaide, P. Almendros, R.
Carrascosa, M. C. Redondo, Chem. Eur. J. 2008, 14, 637; c) B. Al-
caide, P. Almendros, T. Martꢀnez del Campo, R. Rodrꢀguez-Acebes,
Adv. Synth. Catal. 2007, 349, 749; d) B. Alcaide, P. Almendros, T.
Martꢀnez del Campo, Angew. Chem. 2006, 118, 4613; Angew. Chem.
Int. Ed. 2006, 45, 4501.
[10] See following paper: B. Alcaide, P. Almendros, T. Martꢀnez del Cam-
po, E. Soriano, J. L. Marco-Contelles, Chem. Eur. J. 2009, 15, 1901–
1908.
[11] a) B. Alcaide, P. Almendros, C. Aragoncillo, M. C. Redondo, Eur. J.
Org. Chem. 2005, 98; b) B. Alcaide, P. Almendros, C. Aragoncillo,
Chem. Eur. J. 2002, 8, 1719.
[12] The only available Pt-mediated oxycyclization of a g-allenol is the 6-
endo cyclization of 2,2-diphenyl-hexa-4,5-dien-1-ol leading to 6-
methyl-3,3-diphenyl-3,4-dihydro-2H-pyran. See: Z. Zhang, C. Liu,
R. E. Kinder, X. Han, H. Qian, R. A. Widenhoefer, J. Am. Chem.
Soc. 2006, 128, 9066.
[2] Some of the more notable advances concern the development of
mechanism-based serine protease inhibitors of elastase, cytomegalo-
virus protease, thrombin, prostate specific antigen, and cell metasta-
sis and as inhibitors of acyl-CoA cholesterol acyl transferase. For a
review, see: a) G. Veinberg, M. Vorona, I. Shestakova, I. Kanepe, E.
Lukevics, Curr. Med. Chem. 2003, 10, 1741. For recent selected ex-
amples, see: b) P. C. Hogan, E. J. Corey, J. Am. Chem. Soc. 2005,
127, 15386; c) J. W. Clader, J. Med. Chem. 2004, 47, 1; d) L. Kværno,
T. Ritter, M. Werder, H. Hauser, E. M. Carreira, Angew. Chem.
2004, 116, 4753; Angew. Chem. Int. Ed. 2004, 43, 4653; e) D. A. Bur-
nett, Curr. Med. Chem. 2004, 11, 1873.
[13] For selected examples of Ag-mediated heterocyclizations of a-alle-
nols, see: a) J. A. Marshall, R. H. Yu, J. F. Perkins, J. Org. Chem.
1995, 60, 5550; b) O. Flçgel, H.-U. Reissig, Eur. J. Org. Chem. 2004,
[3] It has been reported that b-lactams act to modulate the expression
of glutamate neurotransmitter transporters via gene activation. See:
J. D. Rothstein, S. Patel, M. R. Regan, C. Haenggeli, Y. H. Huang,
Chem. Eur. J. 2009, 15, 1901 – 1908
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1907

B. Alcaide, P. Almendros et al.
2797; c) B. Alcaide, P. Almendros, R. Rodrꢀguez- Acebes, J. Org.
Chem. 2006, 71, 2346.
[16] For the sole report on lanthanide-catalyzed hydroalkoxylations of al-
lenols, see: X. Yu, S. Seo, T. J. Marks, J. Am. Chem. Soc. 2007, 129,
7244.
[17] As far as we known, the Pd-catalyzed cyclizative coupling reaction
of g-allenols with allyl halides has not yet been reported. For its pio-
neered used in a-allenols, see: S. Ma, W. Gao, J. Org. Chem. 2002,
67, 6104.
[18] To the best of our knowledge, no catalytic deprotection of MOM
ethers has previously been reported. This unprecedented gold- and
palladium-catalyzed MOM ether cleavage is extremely mild and se-
lective. For comprehensive reviews, see: a) P. G. M. Wutz, T. W.
Greene, Protective Groups in Organic Synthesis, 4th ed., Wiley, New
York, 2006; b) P. J. Kocienski, Protecting Groups, 3rd ed., Thieme,
Stuttgart, 2003.
[19] Substrate-directable reactions are an important class of selective or-
ganic transformations, and understanding their mechanism of direc-
tion is paramount to their utility. For a review, see: A. H. Hoveyda,
D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307.
[20] The preferential regioselective 7-endo cyclization here differs mark-
edly from that of the only reported La-mediated oxycyclization of a
g-allenol, namely the 6-endo/6-exo cyclization of hexa-4,5-dien-1-ol
leading to 6-methyl-3,4-dihydro-2H-pyran and 2-methylenetetrahy-
dro-2H-pyran as a 4:1 mixture. See reference [15].
[21] Experimental procedures as well as full spectroscopic and analytical
data for compounds not included in this Experimental Section are
described in the Supporting Information. It contains as well copies
of NMR spectra for all new compounds.
[14] For recent reviews on gold catalysis, see: a) J. Muzart, Tetrahedron
2008, 64, 5815; b) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180;
c) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. 2006, 118, 8064;
Angew. Chem. Int. Ed. 2006, 45, 7896; d) L. Zhang, J. Sun, S. A.
Kozmin, Adv. Synth. Catal. 2006, 348, 2271; e) A. Fꢆrstner, P. W.
Davies, Angew. Chem. 2007, 119, 3478; Angew. Chem. Int. Ed. 2007,
46, 3410. For gold-catalyzed cyclizations of a- and b-allenols, see:
f) B. Gockel, N. Krause, Org. Lett. 2006, 8, 4485; g) N. Morita, N.
Krause, Eur. J. Org. Chem. 2006, 4634; h) R. Zriba, V. Gandon, C.
Aubert, L. Fensterbank, M. Malacria, Chem. Eur. J. 2008, 14, 1482;
i) ꢇ. Akssn, N. Krause, Adv. Synth. Catal. 2008, 350, 1106. For gold-
catalyzed cyclizations of g- and d-allenols, see: j) Z. Zhang, R. A.
Widenhoefer, Angew. Chem. 2007, 119, 287; Angew. Chem. Int. Ed.
2007, 46, 283.
[15] The formation of all carbon quaternary centers in an asymmetric
manner is one of the most difficult problems in organic chemistry,
ꢀ
not least because the process requires the creation of a new C C
bond at a hindered center. For recent selected reviews, see: a) P. G.
Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007, 5969;
b) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH, Weinheim,
2005; c) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347, 1473;
d) Y. Ohfune, T. Shinada, Eur. J. Org. Chem. 2005, 5127; e) B. M.
Trost, C. H. Jiang, Synthesis 2006, 369. The total diastereoselectivity
for tetrahydrofurans 5 could be explained by attack of the hydroxyl
group to the allene–metal complex from the less hindered face.
Received: October 2, 2008
Published online: January 8, 2009
1908
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1901 – 1908