Efficient Access to All-Carbon Quaternary and Tertiary α-Functionalized Homoallyl-type Aldehydes from Ketones

Article abstract of DOI:10.1002/anie.201706236

β,γ-Unsaturated aldehydes with all-carbon quaternary or tertiary α-centers were rapidly assembled from ketones through a unique synthetic operation consisting of 1) C₁ homologation, 2) Lewis acid mediated epoxide–aldehyde isomerization, and 3) electrophilic trapping. The synthetic equivalence of a vinyl oxirane and a β,γ-unsaturated aldehyde is the key concept of this previously undisclosed tactic. Mechanistic studies and labeling experiments suggest that an aldehyde enolate is a crucial intermediate. The homologating carbenoid formation plays a critical role in determining the chemoselectivity.

Full text of DOI:10.1002/anie.201706236

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Accepted Article
Title: Efficient Access to All-Carbon Quaternary and Tertiary α-
Functionalized Homoallyl Aldehydes from Ketones
Authors: VITTORIO PACE, Laura Castoldi, Eugenia Mazzeo, Marta
Rui, Thierry Langer, and Wolfgang Holzer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706236
Angew. Chem. 10.1002/ange.201706236
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10.1002/anie.201706236
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Efficient Access to All-Carbon Quaternary and Tertiary α-
Functionalized Homoallyl Aldehydes from Ketones
Vittorio Pace,* Laura Castoldi, Eugenia Mazzeo, Marta Rui, Thierry Langer and Wolfgang Holzer
Abstract: Widely substituted all-carbon quaternary and tertiary α-
aldehydes are rapidly assembled through unique synthetic
the limitation to access homoallyl or allyl α-quaternary aldehydes
thus, leaving almost undisclosed the access to differently
substituted all-carbon α-quaternary aldehydes. Prior to Evans’
work,[9] the α-derivatization of aldehydes via enolate-type
chemistry – albeit limited to the obtainment of α-tertiary species -
has been achieved by Hodgson[11] via the epoxide-aldehyde
isomerization (Scheme 1 – B1).[12] Accordingly, the treatment of
a mono-substituted epoxide with a lithium amide hindered base
provided a nucleophilic enamine susceptible of alkylation to
finally afford α-substituted alkyl aldehydes. Remarkably, chiral
lithium bases enabled high asymmetric induction.[13]
a
operation from ketones consisting in: 1) C1-homologation; 2)
epoxide-aldehyde Lewis acid mediated isomerization and, 3)
electrophilic trapping. The synthetic equivalence between a vinyl
oxirane and a β,γ-unsaturated aldehyde is the key concept for
introducing such a previously undisclosed tactic. Mechanistic studies
and labeled experiments suggest the intervention of an aldehyde
enolate as the crucial intermediate. Significantly, the homologating
carbenoid formation event (carbenoid precursor and organolithium)
plays a critical role in determining the chemoselectivity.
Analogously almost limited to the synthesis of tertiary α-
aldehydes was the simple – but not fully explored[14]
homologation i.e. direct transformation of a ketone to an
aldehyde (Scheme 1 – B2).[15]
Thus, the isomerization of an epoxide to an aldehyde under
different conditions (i.e. Meinwald-type rearrangement triggered
by a Lewis acid),[16] inspired us to employ the required epoxide
as a naked carbonyl equivalent susceptible of α-functionalization
with a given electrophile. In turn, the key-oxirane could be easily
installed through the C1-homologation of a ketone, as we
recently reported.[17]
–
The all-carbon α-quaternary aldehyde functionality constitutes
an important motif across the chemical sciences.[1] From a
reactivity perspective, the high electrophilicity of the aldehyde
moiety represents an excellent tool for enabling chemistry
juxtaposed to a bulky quaternary center. In this context, the α-
allylation of aldehydes to obtain the corresponding homoallylic
derivatives has been extensively investigated (Scheme 1 – A1).
The introduction by Tamaru in 2001 of Pd-catalyzed chemistry
(Tsuji-Trost) could be considered the breakthrough in the field.[2]
Fine tuning of the reaction conditions put the bases for further
highly enantioselective developments (List[3] and Yoshida[4]),
Herein, we present the versatility of the planned strategy to
target α-quaternary aldehydes through
a single synthetic
which
complemented
previously
known
asymmetric
operation consisting of: 1) ketone homologation; 2) epoxide-
aldehyde isomerization and, 3) α-derivatization.
organocatalytic (Jacobsen)[5] or stereodivergent dual catalytic
(Carreira)[6] approaches. The process also benefited from
switching to Ni-catalysis as disclosed – very recently - by
Sauthier.[7] Interestingly in the case of simple linear aldehydes,
the procedure enabled the development of a tandem aldol
condensation/allylation protocol. The development of these
strategies allowed also to overcome the reluctance of the
conceptually simplest strategy based on the use of aldehyde
enolates as nucleophiles in alkylation chemistry.[8] A major
advancement in the field has been documented in 2016 by P. A.
Evans who developed an enantioselective Rh-catalyzed
allylation of prochiral α,α-disubstituted aldenolates with allyl
benzoate (Scheme 1 – A2).[9] Furthermore, the selective ring
fragmentation of diastereomerically pure and enantioenriched
cyclopropanols represents a versatile tool for accessing acyclic
n-butenals possessing the all-carbon quaternary stereocenters,
as showed in elegant work by Marek (Scheme 1 – A3).[10] In
[*]
Priv. Doz. Dr. Vittorio Pace,* MSc. Laura Castoldi, MSc Eugenia
Mazzeo, Dr. Marta Rui, Prof. Dr. Thierry Langer, Prof. Dr. Wolfgang
Holzer
Department of Pharmaceutical Chemistry
University of Vienna
Althanstrasse, 14, A-1090, Vienna (Austria)
E-mail: vittorio.pace@univie.ac.at
Supporting information for this article is given via a link at the end of
the document.
general, the high efficiency these methods showcase in terms of
enantioselectivity or general applicability is counterbalanced by
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Scheme 1. General context of the presented work.
was generated by employing different organolithium reagents
(RLi) or carbenoid precursors (XCH2Z). Accordingly, by forming
the carbenoid with n-BuLi, PhLi or TMSCH2Li, the reaction
afforded exclusively the β,γ-unsaturated non-substituted
aldehyde 4’ (which isomerized spontaneously to the more stable
α,β-unsaturated one 4).[22] Such a behavior suggested the
electrophilic by-products – less reactive than MeI - obtained
during the carbenoid formation event (n-BuI, PhI, TMSCH2I,
respectively) might be involved in the process (entries 3-5).
At the outset of our investigations – in route to expand the 1,2-
chemoselective addition of lithium carbenoids to α,β-unsaturated
ketones[17a] - we considered the simply increase of temperature
(-78 °C to rt)[18] enough for reaching the highly versatile vinyl
epoxide[19] 2 directly from the enone 1. To our surprise, we
observed the formation of α-methyl aldehyde 3 as the unique
reaction product in 89% isolated yield (Table 1 – entry 1). No
trace of the expected epoxide 2 was evidenced in the 1H-NMR of
the reaction crude.[20]
Furthermore,
generating
the
carbenoid
via
Li/Sn
transmetallation[23] (entry 6) provided, once more, as the unique
product again 4 and, interestingly, the corresponding stannane
by-product
[(n-Bu)3SnMe]
could
be
isolated
after
chromatographic purification. Combining these results, it
seemed likely the source of methyl unit could arise from the
methyl iodide (MeI) delivered during the generation of the
carbenoid (LiCH2X, X = Cl, Br) in the presence of MeLi-LiBr.
One additional point merits mention: the presence of the Lewis
acid (e.g. LiBr)[24] and the increase of temperature from -78 °C to
rt were essential for enabling the α-quaternarization. Performing
the reaction with LiBr-free MeLi gave a 1:0.7 mixture of 3:4
(entry 7), while keeping the reaction – even for prolonged time
(24 h) - at -78 °C afforded the simple halohydrin 5 in 91% yield.
As outlined in Scheme 2, quaternary α-methyl aldehydes
(Scheme 2) were rapidly prepared under the optimized
conditions. The reactions proceeded cleanly, in high chemical
yields regardless the nature [cyclic (6-15) or acyclic (3, 16)] of
the substrates and the substitution pattern across the starting
ketones. We anticipate our method allowed to access important
α-methyl aldehydes (e.g. 8-10) – used as materials for a
plethora of chemical transformations[25] – in just one chemical
operation, without needing to employ multi-steps (four) and
Table 1. Optimization of the reaction
complex procedures routinely employed.[26]
Gratifingly, also
Entry[a]
Carbenoid
precursor
RLi
By-product
generated
Ratio 3:4
Yield (%)
more complex natural products (isophorone and nootkatone)
underwent this novel high-yielding transformation (17-18).
1
ICH2Cl
ICH2Br
MeLi-LiBr
MeLi-LiBr
n-BuLi
MeI
MeI
1:0 (89%)
1:0 (83%)
0:1 (66%)
0:1 (90%)
0:1 (80%)
0:1 (88%)
1:0.7[c]
2
3[a]
4[a]
5[a]
6
ICH2Cl
n-BuI
ICH2Cl
TMSCH2Li
PhLi
TMSCH2I
PhI
ICH2Cl
(n-Bu)3SnCH2Cl
ICH2Cl
MeLi-LiBr
MeLi
(n-Bu)3SnMe[b]
MeI
7[a]
[a] LiBr 1.5 M in THF was added. [b] 82% isolated yield. [c] 3 52% isolated
yield, 4 36% isolated yield. For additional optimization studies, see SI.
In order to fully understand this unusual transformation, the two
separate occurring events (although under Barbier-type
conditions)[21] were investigated (Table 1). The switching to a
different 1,1-dihalomethane carbenoid precursor did not
evidence any alteration in the products’ ratio (entry 2). Two
fundamental observations were deducted when the carbenoid
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Scheme 2. Direct synthesis of quaternary α-methyl aldehydes.
The feasibility of the protocol for the efficient building up of
quaternary α-methyl aldehydes, allowed us to endeavour the
more challenging fully substituted ones, featuring a residue
proceeding from a second – added - electrophile. Based on the
optimization study (Table 1, entry 4), we considered TMSCH2Li-
LiBr the ideal reagent to generate the LiCH2Cl carbenoid. As
shown before, TMSCH2I arising from the carbenoid formation
event is completely unreactive towards the intermediate epoxide.
Pleasingly, by simply adding 3 equiv of an electrophile, the tactic
could be successfully extended for the high yielding,
chemoselective obtainment of all-carbon quaternary α-
functionalized aldehydes (Scheme 3). Benzyl halides proved to
be excellent partners for the reaction without significant
difference in reactivity played by the starting carbonyl species
(19-34). The following points merit mention: 1) the presence of a
potentially
exchangeable
iodine
did
not
alter
the
chemoselectivity (20); 2) the substitution across the aromatic
ring of the benzyl halide is well tolerated (23-25, 28-30 -
noteworthy the presence of a nitro group); 3) no decrease in
reactivity was observed when sterically hindered benzyl halides
were used (23) or when the starting carbonyl featured a
substitution at the α-position (25); 4) a secondary benzyl
bromide could be used for trapping, albeit in lower yield (26); 5)
the bicyclic natural product nootkatone was amenable also for
the α-benzylation (34). Unsaturated functionalities containing
halides (allyl, crotyl, propargyl) served as well as excellent
trapping agents for the transformation for both acyclic (35-39)
and cyclic systems (again without effect of the ring size, 40-45).
Analogously, multielectrophilic partners such as α-bromo esters
did react according to the general scheme, providing interesting
γ-oxo esters (46-49). The trapping with an α-halomethyl sulfide
provided the β-sulfur substituted aldehyde 50 in comparable
chemical yield. The tactic was amenable for extending the
applicability to
a
quaternary α-heteroatom aldehyde as
showcased by the example with a sulfur electrophile [(4-
ClC6H4S)2, 51].
Scheme 3. Synthesis of fully substituted quaternary α-methyl aldehydes.
The mechanism of the transformation could be rationalized as
follows (Scheme 4). The attack of the nucleophilic LiCH2Cl to the
carbonyl compound A produced the O-lithiated halohydrin B,
which upon increase of temperature cyclized to the vinyl epoxide
C. In agreement with Lautens’ work on the amphoteric character
of vinyl oxiranes,[27] the Lewis acid (LiBr) triggered the ring
opening – favored by the formation of the allylic carbocation D –
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to furnish - via 1,2-hydride shift and tautomeric equilibrium - the
enolate F. The latter could then react with an adequate
electrophile yielding the quaternary aldehydes G or, alternatively
upon simple acidic quenching and tautomerization the tertiary
products H.
Scheme 5. Mechanistic proof for elucidating the formation of the enolate
intermediate with deuterated species.
In agreement with the postulated mechanism (Schemes 4-5),
with the aim of taking full advantage of the potentiality of the
methodology, we smoothly accessed α-tertiary aldehydes – i.e.
β-γ unsaturated
- through the one-step homologation –
isomerization procedure (Scheme 6). Significantly, during the
work-up and purification procedure, the β-γ unsaturated
aldehydes spontaneously isomerized to the more stable α,β-
unsaturated ones (4, 56-62). The substrate scope was broad
and, interestingly, an important intermediate (57) for the
synthesis of vitamin D[28] were targeted in a single high-yielding
synthetic operation.
Scheme 4. Plausible mechanism.
In order to gain definitive proof on the enolate-type mechanism,
additional experiments with deuterium labeled carbenoids and/or
methyllithium were conceived (Scheme 5). 1) The use of the
deuterated carbenoid LiCD2Br generated from CD2Br2 and MeLi-
LiBr afforded the aldehyde 52 presenting a α-CH3 group and a
deuterated carbonyl. 2) The employment of CD3Li·LiI and
CH2Br2 – which evidently forms LiCH2Br – gave the H-aldehyde
53 featuring the CD3 group at the α-position. 3) The
homologation with LiCD2Br – formed from CD2Br2 and CD3Li·LiI
– yielded the aldehyde 54 showing deuteration at both sites: the
aldehyde and the α-position. 4) Homologating with LiCD2Br
generated with TMSCH2Li and quenching with an acid, delivered
the deuterated α,β-unsaturated aldehyde 55.
Scheme 6. Synthesis of α,β-unsaturated aldehydes through homologation-
isomerization followed by acidic quenching.
In conclusion, we documented
a rapid and high-yielding
synthesis of all-carbon α-quaternary aldehydes starting from α,β-
unsaturated (acyclic and cyclic) ketones. The single-step
transformation stems on the merging of three concepts, namely
homologation,
epoxide-aldehyde
isomerization
and
functionalization with an added electrophile (carbon or
heteroatom) of the putative aldehyde enolate, whose
intervention was proved through labeled experiments. For the
first time, the effect of the lithium organometallic species
employed for generating a carbenoid and the nature of the
carbenoid precursor were found to be critical for the
chemoselectivity. The protocol showcases an excellent
substrate scope, enabling also the access to α,β-unsaturated
aldehydes whenever no external electrophile was added.
Currently, we are investigating the development of an
asymmetric version of the protocol.
Acknowledgements
The University of Vienna is gratefully acknowledged for financial
support and for a doctoral fellowship to L. C. The Authors thanks
G. B. Missere and M. Miele for help in the experimental work.
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Keywords: Homologation • Enolate • Carbenoid • Isomerization
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