Tandem reactions with chiral enolates: Preparation of allylic alcohols via trapping with vinyl oxiranes

Article abstract of DOI:10.1021/ol9027682

[Chemical equation presented] An opening of vinyl oxiranes has been accomplished with Zn and Al enolates resulting from asymmetric conjugate addition reactions on cyclic enones. This novel tandem procedure affords the adducts In moderate to good yields, enantioselectivities up to 98%, and moderate to good cis/trans selectivities. This provides potentially useful synthetic substrates to prepare complex bicyclic compounds.

Full text of DOI:10.1021/ol9027682

ORGANIC
LETTERS
2010
Vol. 12, No. 3
576-579
Tandem Reactions with Chiral Enolates:
Preparation of Allylic Alcohols via
Trapping with Vinyl Oxiranes
Matthias Welker,† Simon Woodward,*,† and Alexandre Alexakis*,‡
Department of Organic Chemistry, UniVersity of GeneVa, 30, quai Ernest Ansermet,
CH-1211 GeneVa 4, Switzerland, and School of Chemistry, UniVersity of Nottingham,
UniVersity Park, NG7 2RD Nottingham, United Kingdom
alexandre.alexakis@chiorg.unige.ch; simon.woodward@nottingham.ac.uk
Received December 1, 2009
ABSTRACT
An opening of vinyl oxiranes has been accomplished with Zn and Al enolates resulting from asymmetric conjugate addition reactions on
cyclic enones. This novel tandem procedure affords the adducts in moderate to good yields, enantioselectivities up to 98%, and moderate to
good cis/trans selectivities. This provides potentially useful synthetic substrates to prepare complex bicyclic compounds.
Vinyl oxiranes are powerful synthetic substrates to provide
allylic alcohols. They have been known to open Via nucleo-
philic substitutions. Reports on the use of nonstabilized
nucleophiles to perform nucleophilic additions on vinyl
oxiranes under Pd0 catalysis are quite rare, as this transfor-
mation usually requires more stabilized nucleophiles. How-
ever, Trost et al.1 noticed that a simple ketone (cyclopen-
tenone) can participate in this reaction despite a low yield.
Interestingly, Tsuji et al.2 described the addition of silyl enol
ethers to vinyl oxiranes, however without giving any details.
More recently Malacria et al.3 showed that ester lithium
enolates are also suitable reagents to perform those addition
reactions.
improved the interest of investigating the reactivity of the
enolates formed in situ. As a consequence, various examples
of novel tandem reactions, leading to the formation of
complex products containing several stereogenic centers with
high enantio- and diastereoselectivities, have appeared in the
literature over the past few years.5
This includes for example the use of Zn enolates as
nucleophiles for aldol reactions,6-8 Mannich reactions,9
N-nitroso aldol10 Dieckmann condensations,11 alkylation,12
sillylation,13 or allylation reactions.14-17 The use of alumi-
num enolates is far less developed so far; however, they can
(4) For a recent review in Cu-catalyzed conjugate addition reactions,
see: Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M.
Chem. ReV. 2008, 108, 2796–2823.
On another note, advances in Cu-catalyzed asymmetric
conjugate addition to enones now enables the preparation
of 1,4-addition adducts with ee values up to 99%.4 This has
(5) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354–366.
(6) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries,
A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620–2623
(7) Howell, G. P.; Fletcher, S. P.; Geurts, K.; ter Horst, B.; Feringa,
B. L. J. Am. Chem. Soc. 2006, 128, 14977–14985
(8) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc.
2001, 123, 4358–4359
(9) Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. Tetrahedron Lett. 2008,
49, 2343–2447. Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. J. Org. Chem.
2009, 74, 2547–2553.
.
† University of Nottingham.
‡ University of Geneva.
.
(1) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103, 5969–
5972.
.
(2) Tsuji, J. Pure Appl. Chem. 1986, 58, 869–878.
(3) Elliott, M. R.; Dimhane, A. L.; Malacria, M. Tetrahedron Lett. 1998,
39, 8849.
10.1021/ol9027682  2010 American Chemical Society
Published on Web 01/08/2010

react with acetic anhydride to provide the corresponding
acetates.18
Increasing the excess of vinyl oxirane leads to an increase
of the yield, which could be explained by competing Me
transfer from the Zn alkoxide to the vinyl oxirane, although
this product could not be isolated.
More interestingly, aluminum enolates also proved to be
effective, albeit in slighlty lower yield. Magnesium enolates
led to a complex mixture from which not even traces of
product were obtained.
This led us to consider the possibility of combining the
asymmetric conjugate addition (ACA) of dialkylzinc reagents
to enones with enolate trapping with isoprene monoxide in
a one pot procedure, as shown in Scheme 1. Pd should
enhance the reactivity of the vinyl oxirane through the
formation of a π-allyl-Pd complex.
However, despite excellent enantioselectivities on the ACA
reaction, the reaction lead to an approximately trans/cis 2:1
mixture of diastereomers which cannot be driven to the trans
product through epimerization with DBU. This result is however
consistent with results obtained by Caine et al.19 on 2-allyl-
3methylcyclohexanone who found out the thermodynamic
mixture is composed of 65% of trans and 35% of cis isomers.
The reaction also showed moderate E/Z selectivity with 4:1
ratios. Interestingly a Swern oxidation of alcohol 2 led to a 2:1
mixture of cis/trans aldehyde and only one geometric isomer.
This could also serve as a potentially useful synthon for further
functionnalisation (Scheme 2).
Scheme 1. Tandem ACA/Vinyl Oxirane Opening
Early optimization results are outlined in Table 1. We were
pleased to notice that Zn enolate reacted with isoprene
monoxide even in the absence of Pd0 catalyst, albeit in low
yield. The addition of Pd(PPh3)4 seemed to have a positive
effect on the reaction, leading to improved yields (entry 3).
Scheme 2. Oxidation of the Allylic Alcohol
Table 1. Conditions Optimization
Vinyl oxiranes are readily available materials which can
be obtained either by epoxidation of diene precursors or by
olefination of the corresponding aldehydes.20 Cyclic vinyl
oxiranes are available in two steps from the corresponding
cyclic enones.21,22
We therefore decided to prepare some of these substrates
(Scheme 3) and investigate the scope of the reaction by
changing the Michael acceptors and the R,ꢀ-unsaturated
oxiranes (Table 2).
The zinc enolates resulting from the highly stereoselective
methyl additions were treated with various oxirane electro-
philes. Not suprisingly, butadiene and isoprene monoxide
gave the best results. However, although no noticeable
amount of the branched addition adduct was isolated, the
trans/cis
nucl.
(equiv)
equiv
E+
ratiob;
entry
catalyst
/
yield
E:Z (eec)
1
2
3
4
5
6
7
ZnMe2 (1.2)
ZnMe2 (1.2)
ZnMe2 (1.2)
ZnMe2 (1.2)
ZnMe2 (1.2)
AlMe3 (1.2)
MeMgBr (1.2)
1.5
30% 2/1; 4:1 (96%)
1.5 Ni(OAc)2 5% 33%a 2.5/1; n.d.
1.1 Pd(PPh3)4 5% 61% 2/1; 4:1
1.5 Pd(PPh3)4 5% 55%d 2/1; 4:1 (98%)
1.5 Pd(PPh3)4 5% 74% 2/1; 4:1
1.5 Pd(PPh3)4 5% 40% 2/1; 4:1. (91%)
5
Pd(PPh3)4 5%
/
/
a All yields presented in the table are isolated yield after column
chromatography; b Determined by 1H NMR; c Determined by GC. d Reaction
performed in Et2O.
(15) Dijk, E. W.; Panella, L.; Pinho, P.; Naasz, R.; Meetsma, A.;
Minnaard, A. J.; Feringa, B. L. Tetrahedron 2004, 60, 9687–9693.
(16) Rathgeb, X.; March, S.; Alexakis, A. J. Org. Chem. 2006, 71, 5737–
5742.
Although Et2O gave also an acceptable yield (entry 4,
55%), we noticed that toluene gave slightly superior results.
(17) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron Lett.
1996, 37, 5141–5144.
(18) Vuagnoux-d’Augustin, M.; Alexakis, A. Tetrahedron Lett. 2007,
48, 7408–7412.
(10) Xu, Y.-J.; Liu, Q.-Z.; Dong, L. Synlett 2007, 2, 273–277.
(11) Agapiou, K.; Cauble, D. F; Krische, M. J. J. Am. Chem. Soc. 2004,
126, 4528–4529.
(19) Caine, D.; Chao, S. T.; Smith, H. A. Organic Syntheses 1977, 56,
52.
(12) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755–756.
(20) Olofsson, B; Somfai, P. Vinylepoxides in organic synthesis. In
Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-
VCH: Weinheim, Germany, 2006; pp 315-347.
(13) Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835–3837.
(14) Naasz, R.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Chem.
Commun. 2001, 735–736.
(21) Felix, D.; Wintner, C.; Eschenmoser, A. Org. Synth. 1988, 6, 679.
(22) Tanis, S. P.; Herrinton, P. M. J. Org. Chem. 1985, 50, 3988–96.
Org. Lett., Vol. 12, No. 3, 2010
577

Scheme 3. Preparation of R,ꢀ-Unsaturated Oxiranes
Table 2. Scope of the Reaction
reaction proceeded in moderate E:Z and trans/cis selectivi-
ties. Cyclic oxiranes were also reactive leading to a similar
mixture of trans and cis isomers. An enantiomerically pure
oxirane derived from cinnamaldehyde (entries 4, 13) reacted
with no loss of diastereoselectivity and an improved E/Z
selectivity.
Interestingly the enolate derived from ACA of ZnPh2
proved also to be efficient, and led to what appeared to
be an improved trans/cis mixture of isomers. Aluminum
enolates (entries 7-8) proved to be reactive as well, albeit
in lower yields. It is also noticeable that the use of
2-cycloheptenone as Michael acceptor led to increased
trans/cis selectivities (entries 11-15), although the prod-
ucts were isolated in slightly lower yields. Cyclic oxiranes
used in large excess (entries 3, 14), lead to a mixture of
epimers at the newly created C-OH chiral center with
an excess of one epimer.
Finally, propargylic oxiranes (entry 10) are known to
react with high selectivity with ZnMe2 under CuI cataly-
Scheme 4. Application to Synthesis
a Isolated yield as a mixture of isomers. b Estimated by 1H NMR.
c Estimated by 13C NMR. d Performed with 2 equiv of electophile.
e Performed with 3 equiv of electrophile. f Performed with 5 equiv of
electrophile. g Ratio of epimer at the newly formed C-OH position could
not be determined. h Determined by chiral GC.
sis,23 but in this case we could not observe the expected
allene. Nonterminal R,ꢀ-unsaturated oxiranes proved to
be unreactive with Zn enolates (entry 9).
(23) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.;
Feringa, B. L. Tetrahedron Lett. 1999, 40, 4893–4896.
578
Org. Lett., Vol. 12, No. 3, 2010

This tandem reaction was applied to the synthesis of
complex [6,7]-bicyclic homoallylic alcohol 25 (Scheme
4). Cyclohexanone was sujected to the described ACA/
vinyl oxiranes trapping to provide 2 in acceptable yield,
as a mixture of cis/trans and E/Z isomers. Acetylation
provide 22 which is then subjected to Pd catalyzed
hydrogenolysis which provide 23, as a mixture of trans
and cis isomers. Coumpound 23b is a known precursor12
in the synthesis of anticancer agent ClaVularin B. Notice-
ably, this is also to the best of our knowledge only the
second exemple of the introduction of an homoallyl group
using Zn enolates.12 Precedents14 persuaded us that a
Grignard addition should proceed to give selectively the
adduct with a trans relationship between the homoallyl
and the newly introduced methallyl groups, but in our
hands it led to a 3/2.4/1 mixture of 3 isomers. The
selectivity was improved to 5.7/3.2/1.1 using the more
sterically hindered methallyl zinc iodide. Cyclisation with
Grubbs second generation catalyst afforded the bicyclic
homoallylic alcohol 25 as a ca.2:1 separable mixture of
diastereomers.
In conclusion,we successfully developed a novel reactivity
for zinc and aluminum enolates through a tandem reaction
involving highly enantioselective ACA reactions. Moderate
diastereoselectivity was achieved for the trapping of enolates
with various vinyl oxiranes, and the resulting allylic alcohols
were then used in the synthesis of [6,7]-bicyclic adducts and in
a formal synthesis of claVularin B.
Acknowledgment. We thank the Marie Curie EST Program
INDAC-Chem (MEST-CT-2005-019780) for financial support.
Supporting Information Available: Experimental pro-
1
cedures, H and 13C spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL9027682
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