The use of silyl ketene acetals and enol ethers in the catalytic enantioselective alkylative ring opening of oxa/aza bicyclic alkenes

Article abstract of DOI:10.1002/anie.201400218

Silyl ketene acetals and enol ethers are employed as reactive and functional group tolerant nucleophiles in the enantioselective rhodium-catalyzed alkylative ring opening of a diverse class of oxa/azabicyclic alkenes. This method provides access to enantioenriched dihydronaphthalene and cyclohexene scaffolds, which have the potential to be derivatized toward core motifs of naphthoquinone and sesquiterpene natural products. All purpose strain relief: Employing silyl ketene acetals and enol ethers as a diverse class of nucleophiles enabled the development of a general, mild, and functional group tolerant method for the alkylative asymmetric ring opening of strained and less-strained oxa/azabicyclic alkenes.

Full text of DOI:10.1002/anie.201400218

Angewandte
Chemie
DOI: 10.1002/anie.201400218
Desymmetrization
The Use of Silyl Ketene Acetals and Enol Ethers in the Catalytic
Enantioselective Alkylative Ring Opening of Oxa/Aza Bicyclic
Alkenes**
Lei Zhang, Christine M. Le, and Mark Lautens*
Abstract: Silyl ketene acetals and enol ethers are employed as
reactive and functional group tolerant nucleophiles in the
enantioselective rhodium-catalyzed alkylative ring opening of
a diverse class of oxa/azabicyclic alkenes. This method
provides access to enantioenriched dihydronaphthalene and
cyclohexene scaffolds, which have the potential to be derivat-
ized toward core motifs of naphthoquinone and sesquiterpene
natural products.
T
he catalytic enantioselective ring opening of strained meso
oxa/azabicyclic alkenes enables rapid access to chiral building
blocks.[1] While significant efforts have been invested in the
development of the asymmetric ring opening (ARO) of
benzo-fused, oxabicyclic alkenes, reports on the ARO of the
less-strained non-benzo-fused oxabicyclo-[2.2.1]heptanes[2]
and azabicyclic alkenes[3] remain rare (Scheme 1). Overcom-
ing the lack of reactivity of these challenging bicylic alkenes is
desirable as this would provide access to highly substituted
chiral
cyclohexenes
and
aminodihydronaphthalenes.
Although the alkylative ARO of oxa/azabicylic alkenes has
been demonstrated with hard organometallic reagents,[4] the
enantioselective alkylative ring opening of oxabicyclo-
[2.2.1]heptanes and azabicyclic alkenes has only been ach-
ieved with the use of dimethyl- and diethylzinc.[2a,b,f,3c,d] In
general, the alkylative ARO has been limited in scope due to
the instability and lack of accessibility of the organometallic
reagents. Consequently, only simple alkyl fragments that lack
functional group handles have been reported. While the use
of malonates[2c,e] in the alkylative ARO has been reported,
these nucleophiles are inherently limited in scope and
reactivity by requirement for a,a-disubstitution of electron-
withdrawing groups (Scheme 1). Thus, to effect the addition
of a simple acetate fragment would entail reaction with
malonate followed by decarboxylation. To address these
Scheme 1. Alkylative asymmetric ring opening of bicyclic alkenes.
limitations in the alkylative ARO, we have developed
a general method for the direct addition of a variety of
functionalized alkyl fragments to strained and less-strained
oxa/azabicyclic alkenes.
The need for a reactive yet versatile alkyl nucleophile led
us to the use of silyl ketene acetals and enol ethers. In
comparison to organometallic reagents, these nucleophiles
are stable, can be prepared in a concise manner, react under
much milder conditions, and are more functional group
tolerant.[5] Although Narasaka[6] has reported two examples
of the use of these reagents in reaction with unsymmetrical
oxabicyclic alkenes using a Lewis acid, our work represents
the first catalytic enantioselective variant. In analogy to the
Mukaiyama aldol reaction,[7] the ring opening of oxabicyclic
alkenes with silyl enolates involves a silyl group migration
resulting in an in situ hydroxy protection. The general scope,
functional group tolerance, and in situ hydroxy protection
offer opportunities for further functionalization of the
products such as accessing core motifs of chiral naphthoqui-
none and sesquiterpene lactone natural products (see
Scheme 5).
[*] L. Zhang, C. M. Le, Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
[**] The authors thank Solvias AG and Umicore for the generous
donations of ligands and rhodium catalyst, the Natural Sciences
and Engineering Research Council (NSERC), the University of
Toronto, and Alphora Research Inc for financial support, NSERC/
Merck for an Industrial Research Chair, and the Canada Council for
the Arts for a Killam fellowship. L.Z. thanks Ontario Graduate
Scholarship for funding. C.M.L. thanks NSERC for a CGS-D
Scholarship. We thank Dr. Gavin C. Tsui for helpful discussions.
We began our study on the ARO with a Rh precatalyst,
Josiphos, oxanorbornene 1, and silyl ketene acetal 2 in THFat
708C (Table 1). Screening of Rh catalysts suggested the
importance of cationic [Rh(cod)2OTf] (cod = cyclooctadiene)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400218.
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Table 1: Reaction optimization.[a]
Entry
[Rh]
Solv
Equiv 2
Yield [%]
e.r.
1
2
3
4
[Rh(cod)Cl]2
THF
THF
THF
THF
THF
THF
Dioxane
PhMe
MeCN
1.5
1.5
1.5
1.5
1.5
2.5
2.5
2.5
2.5
0
0
0
77
–
–
–
[Rh(cod)OH]2
[Rh(CO)2Cl]2
[Rh(cod)2OTf]
[Rh(cod)2OTf]
[Rh(cod)2OTf]
[Rh(cod)2OTf]
[Rh(cod)2OTf]
[Rh(cod)2OTf]
>99:1
n.d.
>99:1
n.d.
–
5[b]
6[c,d]
7[c]
8[c]
9[c]
8
95 (90)
47
0
0
–
[a] Representative reaction conditions: [Rh] and Josiphos were added to
a 2 dram vial under Ar atmosphere and 0.5 mL of solvent was added. The
mixture was stirred for 10 min. 1 and 2 were dissolved in 1.5 mL of
solvent and introduced into the vial via syringe. The mixture was stirred
at the described temperature and time. Yields were determined by
1H NMR spectroscopy. [b] [Rh] (2.5 mol%), Josiphos (3 mol%) were
used. [c] Reaction conducted at 508C. [d] Reaction time 3 h. Isolated
yield in parenthesis.
Scheme 2. Silyl nucleophile scope of the opening of oxabicyclic alkene
1. See Table 1 and Supporting Information for details. E.r. based on
silyl deprotection. Absolute stereoconfiguration of 3i determined by
X-ray crystallography.
over neutral RhI precursors for providing the desired
reactivity (entries 1–4). We observed a 77% yield by NMR
with full conversion (entry 4) and silyl group migration. Due
to the nonpolar nature of the ring-opened products, the
enantiomeric ratio of the products were measured after the
cleavage of the silyl protecting group. Excellent e.r. (> 99:1)
was observed. While lowering the temperature of the reaction
to 508C did not affect the reaction, lowering the catalyst
loading had a deleterious effect (entry 5). Optimal reactivity
was observed with 2.5 equiv of the silyl ketene acetal
(entry 6), affording the desired product in 90% yield while
maintaining the enantioselectivity. Deviation from THF as
the solvent gave poorer results.
we observed good to high yields while retaining the excellent
enantioselectivity.
A variety of oxabicyclic alkene substrates reacted favour-
ably with the silyl ketene acetals (Scheme 3). Both electron
poor and rich substrates (3j–3l) were tolerated in the
Having established a high yielding and enantioselective
method, we examined the scope of the reaction with respect
to the nucleophile (Scheme 2). In general, silyl ketene acetals
displayed higher reactivity, affording 3a and 3b. For silyl enol
ethers, we found improved results upon adding Zn(OTf)2 as
a cocatalyst. We suspect that Zn2+ acts either as a Lewis acid
that activates the bridgehead oxygen for the Rh oxidative
insertion,[4a] or it may activate the nucleophile, forming a zinc
enolate intermediate.[8] Various aryl silyl enol ethers under-
went smooth reaction (3c–3 f) and the reaction is amenable to
scale up, at lower catalyst loading and under modified
conditions (3e). An X-ray crystal structure of the enantiomer
of 3i after silyl deprotection revealed the absolute and
relative stereoconfiguration (see Supporting Information).
Although alkyl silyl enol ethers gave lower yields of the ring-
opened products, the enantioselectivity remained excellent.
While the diastereoselectivity remains to be improved (3b),
Scheme 3. Oxabicyclic alkene scope. See Table 1 and Supporting
Information for reaction details. The e.r. values are based on silyl
deprotection. [a] 2 (3 equiv), [Rh(cod)2OTf] (7.5 mol%), (R,S)-PPF-
PtBu2 (9 mol%), 708C, 15 h. [b] The e.r. is based on 8, Scheme 5. [c]
[Rh(cod)2OTf] (3.5 mol%), (R,S)-PPF-PtBu2 (4.5 mol%).
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reaction. The reaction is also amenable to the use of the less
reactive, oxabicyclo[2.2.1]heptanes, though at higher temper-
atures and catalyst loading (Scheme 3, footnote [a]). How-
ever, the catalyst loading can again be reduced when run on
gram scale (3o). Excellent yields and enantioselectivities
were maintained throughout. Direct access to the tetrasub-
stituted cyclohexenes is readily achieved.
We next examined the reaction scope with respect to
azabicyclic alkenes (Scheme 4). Under the optimized con-
ditions, we observed high yields and enantioselectivity
Scheme 4. Azabicyclic alkene scope and derivatization. Absolute
stereoconfiguration of 3q determined by X-ray crystallography. See
Supporting Information for details.
Scheme 5. Further transformations of ARO products. See Supporting
Information for reaction details.
employing the MandyPhos ligand. Similar to previous reports,
the catalyst/ligand ratio is important for achieving the desired
enantioselectivity, possibly by minimizing catalyst/nucleo-
phile interaction prior to the enantiodiscriminating step.[3b]
The sulfonyl aryl nitrogen protecting groups displayed the
best reactivity (3p). N-Boc-azabicyclic alkenes did not
undergo the desired reaction as the Lewis acidic reaction
conditions promoted Boc-cleavage. With the addition of
Zn(OTf)2 as a cocatalyst, silyl enol ethers participated in the
ring opening to afford 3q and 3r. While silyl group migration
was observed in the crude product, the labile N-silylated
product underwent deprotection upon treatment with silica
gel. The ARO product 3pa was hydrogenated to access the 2-
alkyl-1-aminotetralin core 3t with the anti-stereoconfigura-
tion. This approach offers complementary reactivity com-
pared to the asymmetric hydrogenation of tetrasubstituted
cyclic enamides derived from tetralones,[9] which would
provide these cores with the corresponding syn-stereoconfi-
guration.
epoxide 5. These products may provide access to a class of
chiral naphthoquinones such as glycoquinone[10] or avicen-
none G,[11] which are congeners of podophyllotoxins,[12] and
exhibit anti-bacterial and anti-proliferative properties. The
silyl protecting group can also be removed efficiently with
high yields (6). However, keeping the siloxy ether may be
advantageous as saponification and amide coupling can
proceed to afford 8. In addition, lactonization of the ring
opening products can access structural motif 7, found in
sesquiterpene lactones, such as eudesmanolides.[13]
In summary, we have developed the first enantioselective
addition of silyl ketene acetals/enol ethers to a range of oxa/
azabicyclic alkenes. The silyl enolates offer high functional
group tolerance and react under mild conditions. The adducts
of the alkylative ring opening provide access to a variety of
structural motifs. Further investigations on reaction mecha-
nism, scope, and synthesis of the aforementioned natural
products are underway.
We examined a number of modifications of the ring
opening products which allow access to diverse structural
motifs (Scheme 5). For the chiral dihydronaphthalene prod-
ucts, the alkene serves as a useful handle for derivatization.
For example, adduct 3a can be converted to iodolactone 4 or
Received: January 8, 2014
Published online: April 25, 2014
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Keywords: asymmetric catalysis · rhodium · silyl ketene acetals ·
strained molecules
.
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