Rhodium-Catalyzed Enantioselective Isomerization of Secondary Allylic Alcohols

Article abstract of DOI:10.1021/jacs.7b01096

The first catalytic enantioselective isomerization of secondary allylic alcohols to access ketones with a α-tertiary stereocenter is presented. The racemic allylic alcohol substrates can be converted to the enantioenriched ketone products in a stereoconvergent fashion. The use of commercially available catalysts and mild reaction conditions makes this an attractive method in stereoselective synthesis.

Full text of DOI:10.1021/jacs.7b01096

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Communication
Rhodium-Catalyzed Enantioselective
Isomerization of Secondary Allylic Alcohols
Tang-Lin Liu, Teng Wei Ng, and Yu Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b01096 • Publication Date (Web): 01 Mar 2017
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Rhodium-Catalyzed Enantioselective Isomerization of
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Tang-Lin Liu, Teng Wei Ng, Yu Zhao*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore, 117543
Supporting Information Placeholder
bulky external proton source are typically necessary to
achieve good level of stereoselectivity, which, on the other
hand, inevitably leads to much waste generation (Scheme
1d). Achieving enantioselectivity in the isomerization of
allylic alcohols will be more challenging as modification on
the substrate or proton donor structure is not possible. A
delicate choice of base is also important, which is required to
promote an efficient proton shuffle but should not racemize
the tertiary stereocenter in the product. A catalytic loading of
base will be ideal for the overall economy of the process.
ABSTRACT:
The
first
catalytic
enantioselective
isomerization of secondary allylic alcohols to access ketones
with a α-tertiary stereocenter is presented. The racemic
allylic alcohol substrates can be converted to the
enantioenriched ketone products in a stereo-convergent
fashion. The use of commercially available catalysts and mild
reaction conditions makes this an attractive method in
stereoselective synthesis.
Scheme 1. Catalytic Enantioselective Isomerization of
Allylic Alcohols
The catalytic isomerization of allylic alcohols to the
corresponding carbonyl compounds is an extensively
explored transformation in organic synthesis. This process
has the significant advantage of converting readily available
allylic alcohols to versatile carbonyls in an economical,
redox-neutral fashion.1 Following some pioneering work in
this field,2 various transition-metal complexes based on
rhodium,3 ruthenium,4 iridium,5 palladium,6 iron,7 and
others8 have been successfully developed for the efficient
redox isomerization. For the development of catalytic
enantioselective variant of this process,9 great advancement
has been achieved for the isomerization of β-substituted
primary allylic alcohols from the pioneering work of the Fu
group, the Mazet group and others (Scheme 1a).10 As to the
corresponding secondary allylic alcohols, only kinetic
resolution of racemic alcohols11 or stereospecific
isomerization of enantioenriched substrates to β-substituted
ketones (Scheme 1b)12 were reported in recent years. Herein
we report a Rh-catalyzed stereo-convergent isomerization of
secondary allylic alcohols, and in particular, the first
enantioselective redox-neutral synthesis of ketones with a
α-tertiary stereocenter (Scheme 1c).
We chose allylic alcohol 1a as our model substrate and
optimization was carried out to realize the isomerization
under mild conditions to achieve any stereoselectivity.
Extensive screening of various metal catalysts including
iridium, ruthenium and rhodium complexes proved that the
use of cationic [Rh(COD)2]BF4 led to the most efficient
isomerization reaction, which could be carried out at
ambient temperature to deliver ketone 2a in high yield and
good enantioselectivity (entry 1, Table 1). Test of other anions
on the rhodium complex led to no improvement at all
(results not shown). While further focused screening of
analogous SegPhos ligands proved ineffective (such as entry
2), the screening of more diverse bisphosphine ligands
Our group has focused on the development of catalytic
enantioselective redox-neutral transformations such as
amination of alcohols through borrowing hydrogen
methodology.13 In connection with that, we became
interested in the stereo-convergent isomerization of racemic
secondary allylic alcohols to access ketones with a α-tertiary
stereo-center, a process that requires no external reagent and
is completely atom economical. Such
a
seemingly
possesses
straightforward transformation, however,
significant challenges. In fact, enantioselective protonation
has long been recognized as a difficult task in asymmetric
synthesis.14,15 The use of preformed enolate equivalents and a
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identified (R)-BINAP as the optimal choice (entry 4 vs.
Scheme 2. Catalytic Enantioselective Isomerization of
Acyclic Allylic Alcoholsa
1
2
3
4
5
6
7
8
entries 3, 5-7). The use of other types of ligand such as
P,N-ligands and MonoPhos, on the other hand, turned out to
be completely ineffective. The screening of various reaction
parameters including solvents, concentration, temperature,
etc. led to no improvement either. It is interesting to note
that a catalytic amount of base proved effective (entry 8),
which likely functions as the proton shuffle in this reaction.
The identity of base was also examined at different stages of
optimization. Weak bases such as carbonates or amines
delivered the product in good enantioselectivity (entries
9-11), with silver carbonate still being the optimal. In the
presence of these weak bases, no racemization of 2a was
observed. In contrast, the use of strong bases such as DBU or
KOt-Bu produced 2a in a racemic form, which could be
partially due to product racemization (entries 12-13).
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Table 1. Optimization of Isomerization of 1aa
entry
ligand
(R)-SegPhos
(R)-DTBM-SegPhos
(S)-DifluorPhos
(R)-BINAP
base
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
none
yield (%)b
ee (%)c
80
12
1
2
82
35
50
90
85
86
86
<5
85
83
49
35
90
3
-70
84
84
82
4
5
(R)-T-BINAP
(R)-DM-BINAP
(R)-H8-BINAP
(R)-BINAP
6
7
76
8
\
aSee Table 1 and supporting information for details.
9
10
11
12
13
(R)-BINAP
Li2CO3
Et3N
80
70
(R)-BINAP
Scheme 3. Catalytic Enantioselective Isomerization of
Cyclic Allylic Alcoholsa
(R)-BINAP
pyridine
DBU
76
(R)-BINAP
<2
(R)-BINAP
KOt-Bu
<2
aThe reaction was carried out with 0.2 mmol 1a, 2 mol% [Rh(COD)2]BF4, 5
mol% chiral ligand, 5 mol% base and 50 mg 4 Å MS in 1 mL of solvent.
bIsolated yield. cDetermined by chiral HPLC analysis.
With the optimal conditions in hand, the scope of this
catalytic enantioselective isomerization was examined. For
all substrates the same set of reaction conditions was
adopted. As shown in Scheme 2, a range of racemic acyclic
secondary allylic alcohols bearing aryl substituents
underwent isomerization smoothly to deliver the ketone
products in high yields and good to high level of
enantioselectivity. The electronic variation on the substrates
were well-tolerated and the products were formed with
essentially the same level of efficiency and selectivity (2b, 2d
vs 2a; 2i vs 2j, etc). Heterocyclic substituents could be
tolerated as well (2t). The incorporation of alkyl substituents
at R1, R2 and R3 positions, however, led to reduced
enantioselectivity in general (2e-2f, 2m and 2u-2v). A
1,1,-disubstituted allylic alcohol was also examined, which led
to the formation of 2w in good yield and selectivity (77% ee).
In addition, bicyclic ketone products such as 2x and 2y could
also be accessed in good ee of 81-85% using this system.
aSee Table 1 and supporting information for details. b(R)-BINAP was used and 90%
yield, -76% ee was obtained for 4a.
This catalytic system could also be applied to the enantio
selective isomerization of a range of cyclic allylic alcohols
(Scheme 3). For the isomerization of this series of substrates,
the use of DifluorPhos was identified to be superior to
BINAP. For the model reaction of 3a, the corresponding
cyclic ketone 4a was obtained in a good ee of 82%. In
addition, a range of aryl-substituted five-membered allylic
alcohols could undergo isomerization to yield the
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corresponding cyclopentanones in high yields and good to
high enantioselectivities (4b-4h). Thiophene-substituted 4i
Scheme 5. Mechanistic Insights
1
2
3
4
5
6
7
8
a) Proposed reaction pathway
H
H
O
H
OH
was also obtained in a good ee of 84%. In addition, this
method is not limited to the preparation of cyclopentanones.
Enantioenriched cyclohexanone 4j and cycloheptanone 4k
were also produced by this catalytic system. Overall, this
simple catalytic system using commercially available
catalysts and a simple procedure proved to be highly efficient
for the conversion of a wide range of racemic secondary
R1
R3
R1
R3
R2
R2
1
2
[Rh]
[Rh]
O
H
[Rh]
O
H
R3
R1
R3
B:
R1
B:
R2
HB
R2
HB
E
A
allylic alcohols to enantioenriched ketones bearing
a
9
H
O
[Rh]
H
α-tertiary stereocenter.
[Rh]
O
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R1
R3
O
H
[Rh]
R2
R1
R3
R2
R1
R3
C
R2
B
Scheme 4. Enantioselective Isomerization to Access
D
Ketones with a γ-Stereocenter
b) use of deuterated substrate
HO
(76%)
D
H
O
(80%)
D
Standard Conditions
Ph
Ph
Ph
Ph
Ph
Ph
1a-D
2a-D, 90%
c) cross-over experiment
OH
O
Standard
1-Nap
1-Nap
Conditions
1a-D
+
2a-D
+
OMe
OMe
Full Conv.
As a further demonstration of the scope of this method,
this catalytic system can be extended to the control of
γ-stereocenter to ketones. As shown in Scheme 4,
stereo-convergent desymmetrization of bis-allylic alcohols 5
was achieved under similar conditions to deliver spirocyclic
enones 6 in good to high ee.16 This catalytic system,
therefore, is capable of controlling the selectivity in the
isomerization step as well.
The proposed reaction pathway is shown in Scheme 5a.
Under basic conditions, the generally accepted mechanism
for allylic alcohol isomerization is through an alcohol
dehydrogenation-conjugate reduction sequence.1 Thus,
substrate 1 presumably gets deprotonated and forms the
corresponding rhodium alkoxide intermediate A. β-Hydride
elimination produces intermediate B. A formal conjugate
reduction of the enone then yields the η-1 rhodium complex
C, which should tautomerize through the η-3 tatutomer D to
the key rhodium enolate E. Protonation of E then produces
the product and regenerates the rhodium catalyst. It is
believed that the stereo-convergence in this catalytic system
is realized by a non-selective formation of B (possibly
through dehydrogenation). The chiral rhodium complex then
promotes either enantioselective conjugate reduction to form
6 or enantioselective protonation to generate 2 and 4 in an
overall stereo-convergent fashion.
To shed some light on this reaction pathway,
deuterium-labelled substrate 1a-D was subjected to the
standard reaction conditions (Scheme 5b). As expected, a
clean deuterium labeling on the β-carbon took place and no
scrambling of deuterium to the α-carbon was observed by 1H
as well as 2H NMR. When a cross-over experiment using 1a-D
and 1r were carried out, only 2a-D and 2s were observed as
the products, suggesting that the isomerization is an
intramolecular process (Scheme 5c). This conclusion was
further supported by the attempted transfer hydrogenation
of enone 7 using isopropanol or the reaction of 1a-D in the
presence of enone 8 (Scheme 5d). In both cases, the
proposed [Rh-H] intermediate failed to react in an
intermolecular fashion.
1s
2s
Ph
Ph
<2% deuterium labeling
d) Test of conjugate reduction using an external reductant
O
O
Standard Conditions
OH
Ph
Ph
+
Ph
Ph
O
X
Ph
Ph
2a
7
O
Standard Conditions
2a-D
Full Conv.
+
+
1a-D
Ph
Ph
Ph
Ph
8
>98% recovery
In conclusion, we have developed the first general
catalytic enantioselective redox isomerization of secondary
allylic alcohols to deliver ketones with a α or γ-stereocenter.
By employing commercially available catalysts and a simple
procedure, a range of allylic alcohols could be isomerized in a
stereo-convergent fashion with high yields and good to high
level of enantioselectivity. Current efforts in our laboratory
are focused on the development of other enantioselective
redox isomerization processes.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI:
10.1021/jacs.xxxxxxx.
AUTHOR INFORMATION
Corresponding Author
zhaoyu@nus.edu.sg
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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Mazet, C. J. Am. Chem. Soc. 2014, 136, 16882-16894. (d) Lin, L.;
We are grateful for the generous financial support from
Singapore National Research Foundation (NRF Fellowship
R-143-000-477-281) and the Ministry of Education (MOE) of
Singapore (R-143-000-613-112).
Romano, C.; Mazet, C. J. Am. Chem. Soc. 2016, 138, 10344-10350.
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1998, 1739-1744. (b) Batuecas, M.; Esteruelas, M. A.; García-Yebra, C.;
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Mazet, C. Acc. Chem. Res. 2016, 49, 1232–1241. For selected examples,
see: (b) Ito, M.; Kitahara, S.; Ikariya, T. J. Am. Chem. Soc. 2005, 127,
6172-6173. (c) Li, H.; Mazet, C. Org. Lett. 2013, 15, 6170-6173. (e)
Nelson, D. J.; Fernandez-Salas, J. A.; Truscott, B. J.; Nolan, S. P. Org.
Biomol. Chem. 2014, 12, 6672-6676.
(6) For selected examples, see: (a) Grotjahn, D. B.; Larsen, C. R.;
Gustafson, J. L.; Nair, R.; Sharma, A. J. Am. Chem. Soc. 2007, 129,
9592-9593. (b) Sabitha, G.; Nayak, S.; Bhikshapathi, M.; Yadav, J. S.
Org. Lett. 2011, 13, 382-385. (c) Larionov, E.; Lin, L.; Guénée, L.;
(15) For representative alternative catalytic approaches to deliver
ketones with a α-stereocenter, see: (a) Trost, B. M., Xu, J. J. Am.
Chem. Soc., 2005, 127, 17180–17181. (b) Lou, S., Fu, G. C. J. Am. Chem.
Soc., 2010, 132, 1264–1266. (c) Cherney, A. H., Kadunce, N. T.,
Reisman, S. E. J. Am. Chem. Soc., 2013, 135, 7442–7445.
(16) For an alternative synthesis of 8 using transfer hydrogenation,
see: Naganawa, Y., Kawagishi, M., Ito, J.-i., Nishiyama, H., Angew.
Chem. Int. Ed. 2016, 55, 6873-6876.
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