Metal-catalyzed regiodivergent cyclization of γ-allenols: Tetrahydrofurans versus oxepanes

Article abstract of DOI:10.1002/anie.200701611

(Chemical Equation Presented) Ringing the changes: The 5-exo-trig cyclization pathway of γ-allenols can be completely reversed by either changing the metal (Pd instead of Au) or using a (methoxymethyl)oxy protecting group. As a result, the 7-endo-trig alk

Full text of DOI:10.1002/anie.200701611

Communications
DOI: 10.1002/anie.200701611
Synthetic Methods
Metal-Catalyzed Regiodivergent Cyclization of g-Allenols:
Tetrahydrofurans versus Oxepanes**
Benito Alcaide,* Pedro Almendros,* and Teresa Martínez del Campo
Dedicated to Professor Vicente Gotor on the occasion of his 60th birthday
Tetrahydrofuran and oxepane ether rings are ubiquitous
structural units that are extensively encountered in a number
of biologically active natural products and functional mole-
cules. Therefore, the development of synthetic methods for
their construction has attracted much attention.[1] On the
other hand, the allene moiety has developed from almost a
rarity to an established member of the weaponry used in
modern organic synthetic chemistry.[2] In particular, transi-
tion-metal-catalyzed cyclization of functionalized allenes
bearing a nucleophilic center has attracted much attention.[3]
However, regioselectivity problems are significant (endo-trig
versus exo-dig versus exo-trig cyclization). In continuation of
our interest in heterocyclic and allene chemistry,[4] we have
now discovered examples in which, by either changing the
metal or using a protecting group, the 5-exo-trig cyclization
pathway of g-allenols can be completely reversed and 7-endo-
trig alkoxycyclization dominates instead.
Precursors for the formation of tetrahydrofuran and
tetrahydrooxepine, enantiopure g-allenols 3a–d, were readily
prepared in good overall yield beginning from the appropri-
ate carbaldehydes 1a–d by a regiocontrolled, indium-medi-
ated, Barbier-type carbonyl–allenylation reaction in aqueous
media to give a-allenols 2a–d (see Supporting Information,
Table 1),[5] followed by protecting-group manipulation
(Scheme 1).
Scheme 1. Synthesis of enantiopure monocyclic g-allenols 3a–d.
Reagents and conditions: a) In, 1-bromobut-2-yne, THF/NH4Cl (aq.
sat.), RT, 5 h. b) 1. TBSOTf, CH2Cl2, RT, 14 h; or MOMCl, Hünig’s
base, CH2Cl2, reflux, 2 h; 2. NaOMe, MeOH, RT, 08C, 3 h. Z=4-
MeOC6H4CO, Bn=benzyl, E=CO2Me, MOM=MeOCH2, TBS=tert-
butyldimethylsilyl, Tf=trifluoromethanesulfonyl.
=
tive than [PtCl2(CH2 CH2)]2 (60:40 vs. 100:0), it was a more
efficient catalyst that afforded adduct 4a in reasonable yield
(54% vs. 12%). Gratifyingly, we found that AuI or AuIII salts
were effective as 5-exo-selective hydroalkoxylation cata-
lysts.[8] AuCl3 was selected as catalyst of choice because of
its superior performance. No diastereo- or regioisomeric
products were detected, thus giving exclusively the fused five-
membered oxacycles 4 (Scheme 2). Compounds 4 are remark-
We decided to use g-allenol 3a as initial substrate in a
screen to identify regioselective hydroalkoxylation catalysts.
=
Thus, [PtCl2(CH2 CH2)]2 and AgNO3 afforded a rather low
yield or a disappointing diastereomeric mixture of bicyclic
compound 4a.[6,7] Although AgNO3 was less diastereoselec-
[*] Prof. Dr. B. Alcaide, Dipl.-Chem. T. Martínez del Campo
Departamento de Química Orgµnica I
Facultad de Química
Scheme 2. Gold-catalyzed heterocyclization reaction of g-allenol deriva-
tives 3a and 3b. Reaction time: 48 h.
Universidad Complutense de Madrid
28040 Madrid (Spain)
Fax: (+34)91-394-4103
able as they bear a quaternary stereocenter.[9] Qualitative
homonuclear NOE difference spectra allowed us to assign the
stereochemistry at the newly formed stereocenter of tetrahy-
drofurans 4.
One of the challenges of modern synthesis is to create
distinct types of complex molecules from identical starting
materials based solely on catalyst selection. Thus, having
found a solution for the 5-exo-selective hydroalkoxylation, we
next examined the more intricate heterocyclization problem
associated with tuning the regioselectivity of g-allenols.
Notably, the PdII-catalyzed cyclizative coupling reaction of
g-allenols 3a and 3b with allyl halides gave impressive yields
E-mail: alcaideb@quim.ucm.es
Dr. P. Almendros
Instituto de Química Orgµnica General
Consejo Superior de Investigaciones Científicas (CSIC)
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax: (+34)91-564-4853
E-mail: iqoa392@iqog.csic.es
[**] Support for this work by the DGI-MCYT (Project CTQ2006-10292) is
gratefully acknowledged. T.M.C. thanks the MEC for a predoctoral
grant.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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(up to 94%) of the desired seven-membered adducts 5a–d
(Scheme 3), which resulted from a 7-endo oxycyclization.[10]
Having demonstrated the stability of the TBS protecting
group to the AuIII or PdII catalysis conditions, we decided to
a 7-endo oxycyclization. No other isomers or side products
were detected. Although complete conversion of the crude
reaction mixtures was observed by TLC and 1H NMR
analysis, some decomposition of sensitive adducts 4, 6, and 8
was detected during purification by flash chromatography,
which may be responsible for the moderate yields of isolated
products obtained in some cases.
The pathway proposed in Scheme 6 looks valid for the
formation of products 8. It can be presumed that the initially
formed allene–gold complex 9 undergoes an intramolecular
attack (7-endo versus 5-exo oxyauration) by the (methox-
ymethyl)oxy group, which gives rise not to species 10 but to
the tetrahydrooxepine intermediate 11. Protonolysis of the
carbon–gold bond linked to an elimination of methoxyme-
thanol would then liberate the bicyclic compound 8 with
concomitant regeneration of the AuIII species. Probably, the
proton in the last step of the catalytic cycle comes from the
trace amount of water present in the solvent or the catalyst.
To confirm the mechanistic proposal of Scheme 6, we
performed labeling studies with deuterium oxide. Thus, the
Scheme 3. Palladium-promoted preparation of seven-membered oxa-
cycles 5a–d. Reagents and conditions: a) PdCl2 (5 mol%), DMF, RT.
Reaction times: 16, 24, 21, and 24 h for 5a–d, respectively.
DMF=N,N-dimethylformamide.
see if (methoxymethyl)oxy substitution has a bene-
ficial impact on the cyclization reactions. In the event,
MOM cleavage was observed to a small extent during
the reaction of g-allenols 3c and 3d with allyl
bromide in the presence of PdCl2 (Scheme 4). Sur-
prisingly, when g-allenols 3c and 3d were treated with
AuCl3, the 2,5-dihydrofurans 6a and 6b were the sole
products (Scheme 4). This transformation may
involve a chemoselective (5-endo-trig versus 7-endo-
trig) allenol oxycyclization with concomitant MOM
ether deprotection.[11]
Scheme 5. AuIII-catalyzed heterocyclization reaction of MOM-protected g-allenol
derivatives 7a and 7b. Reagents and conditions: a) 4-BrC6H4COCl or PMPCOCl,
Et3N, DMAP, CH2Cl2, reflux, 7a: 6 h; 7b: 8 h. b) AuCl3 (5 mol%), CH2Cl2, RT,
8a: 72 h; 8b: 72 h. DMAP=4-(dimethylamino)pyridine, PMP=4-MeOC6H4.
Scheme 4. Metal-catalyzed heterocyclization reactions of g-allenol
derivatives 3c and 3d. Reagents and conditions: a) 1. PdCl2 (5 mol%),
allyl bromide, DMF, RT, 5e: 5 h; 5 f: 6 h; 2. MOMCl, Hünig’s base,
CH2Cl2, reflux, 2 h. b) AuCl3 (5 mol%), CH2Cl2, RT, 6a: 22 h; 6b: 16 h.
After taking into account the above results, we decide to
test if the AuIII-catalyzed preparation of bicyclic compounds 4
can be directly accomplished from MOM-protected g-allenol
derivatives 7a and 7b. Much to our delight, the 5-exo mode
completely reverted to a 7-endo cyclization to afford bicyclic
compounds 8 in fair yields (Scheme 5). To the best of our
knowledge, this observation is unprecedented. It seems that
the reactivity in this type of AuIII-catalyzed reaction is
determined by the presence or absence of a MOM protecting
group at the g-allenol oxygen atom, as the free g-allenols 3a
and 3b gave 5-exo hydroalkoxylation, whereas MOM-pro-
tected g-allenol derivatives 7a and 7b exclusively underwent
Scheme 6. Mechanistic explanation for the AuIII-catalyzed heterocycli-
zation reaction of MOM-protected g-allenol derivatives 7a and 7b.
addition of two equivalents of D2O to the solution of MOM-
protected g-allenol 7b and AuCl3 in dichloromethane caused
the disappearance of the peak at 6.35 ppm, which is the signal
of the proton H4 on 2-oxa-8-azabicyclo[5.2.0]non-4-en-9-one
(8b). The fact that the AuCl3-catalyzed conversion of allenol
7b into bicyclic compound 8b in the presence of two
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equivalents of D2O afforded [4-D]-8b, as judged by 1H NMR
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spectroscopy (see Supporting Information), suggests that
deuterolysis of the carbon–gold bond in species 11 has
occurred. It may be inferred that different steric effects in
the organometallic species 10 and 11 may be responsible for
the different reactivity preference, by stabilizing one of the
intermediates rather than the other. In the presence of a
MOM group, 5-exo cyclization falters. Probably, 5-exo oxy-
auration via 10 is restricted by the steric hindrance between
the (methoxymethyl)oxy group and the substituents at the
quaternary stereocenter.
Scheme 7 outlines a mechanistic hypothesis for the
achievement of compounds 5. Initial PdII coordination gave
an allene–palladium complex 12. Species 12 underwent an
[2] For general and comprehensive reviews, see: a) S. Ma, Chem.
Rev. 2005, 105, 2829; b) Modern Allene Chemistry (Eds.: N.
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[3] For selected reviews, see: a) R. A. Widenhoefer, X. Han, Eur. J.
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Chem. Int. Ed. 2000, 39, 3590.
[4] See, for instance: a) B. Alcaide, P. Almendros, T. Martꢂnez del
Campo, R. Rodrꢂguez-Acebes, Adv. Synth. Catal. 2007, 349, 749;
b) B. Alcaide, P. Almendros, C. Aragoncillo, M. C. Redondo, J.
Org. Chem. 2007, 72, 1604; c) B. Alcaide, P. Almendros, T.
Martꢂnez del Campo, Angew. Chem. 2006, 118, 4613; Angew.
Chem. Int. Ed. 2006, 45, 4501; d) B. Alcaide, P. Almendros, J. M.
Alonso, Chem. Eur. J. 2006, 12, 2874; e) B. Alcaide, P.
Almendros, M. C. Redondo, Chem. Commun. 2006, 2 616; f) B.
Alcaide, P. Almendros, C. Aragoncillo, M. C. Redondo, M. R.
Torres, Chem. Eur. J. 2006, 12, 1539.
Scheme 7. Mechanistic explanation for the PdII-catalyzed heterocycliza-
tion reaction of g-allenols 3a–d.
[5] 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.
[6] The only available Pt-mediated oxycyclization of a g-allenol is
the 6-exo cyclization of 2,2-diphenylhexa-4,5-dien-1-ol, which
leads 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. Widenhoe-
fer, J. Am. Chem. Soc. 2006, 128, 9066.
intramolecular cycloetherification reaction to give the palla-
datetrahydrooxepine 13. Intermediate 13 reacted with the
appropriate allyl halide to form intermediate 14, which after
dehalopalladation generated tetrahydrooxepine-b-lactams 5
with concomitant regeneration of the PdII species.
[7] For selected examples of Ag-mediated heterocyclizations of a-
allenols, see: a) J. A. Marshall, R. H. Yu, J. F. Perkins, J. Org.
Chem. 1995, 60, 5550; b) O. Flꢁgel, H.-U. Reissig, Eur. J. Org.
Chem. 2004, 2797; c) B. Alcaide, P. Almendros, R. Rodrꢂguez-
Acebes, J. Org. Chem. 2006, 71, 2346.
[8] For a review of gold catalysis, see: a) A. S. K. Hashmi, G. J.
Hutchings, Angew. Chem. 2006, 118, 8064; Angew. Chem. Int.
Ed. 2006, 45, 7896; For gold-catalyzed cyclizations of a- and b-
allenols, see: b) B. Gockel, N. Krause, Org. Lett. 2006, 8, 4485;
c) N. Morita, N. Krause, Eur. J. Org. Chem. 2006, 4634; For
enantioselective gold-catalyzed cycloisomerization of g- and d-
allenols, see: d) Z. Zhang, R. A. Widenhoefer, Angew. Chem.
2007, 119, 287; Angew. Chem. Int. Ed. 2007, 46, 283.
In conclusion, an efficient metal-controlled regiodiver-
gent preparation of tetrahydrofurans and tetrahydrooxepines
starting from enantiopure g-allenols has been developed.[12] In
addition, it has been observed that a (methoxymethyl)oxy
protecting group not only masks a hydroxyl functionality, but
also exerts directing effects as a controlling unit in regiose-
lectivity reversal.
Received: April 12, 2007
Published online: July 30, 2007
Keywords: allenes · gold · heterocycles · palladium ·
.
[9] 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
regioselectivity
À
of a new C C bond at a hindered center. For recent selected
reviews, see: a) QuaternaryStereocenters: Challenges and Sol-
utions for Organic Synthesis (Eds.: J. Christoffers, A. Baro),
[1] For selected reviews, see: a) J. P. Wolfe, M. B. Hay, Tetrahedron
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Chemie
Wiley-VCH, Weinheim, 2005; b) B. M. Trost, C. H. Jiang, Syn-
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[10] As far as we know, the Pd-catalyzed cyclizative coupling reaction
of g-allenols with allyl halides has not yet been reported. For its
pioneering use in a-allenols, see: S. Ma, W. Gao, J. Org. Chem.
2002, 67, 6104.
[11] To the best of our knowledge, no truly catalytic deprotection of
MOM ethers has previously been reported. 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.
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which is the key structural motif in biologically relevant
compounds such as antibiotics and enzyme inhibitors. For
selected reviews, see: a) Chemistryand Biologyof b-Lactam
Antibiotics, Vols. 1–3 (Eds.: R. B. Morin, M. Gorman), Academic
Press, New York, 1982; b) R. Southgate, C. Branch, S. Coulton,
E. Hunt in Recent Progress in the Chemical Synthesis of
Antibiotics and Related Microbial Products, Vol. 2 (Ed.: G.
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