Enantioselective titanium(III)-catalyzed reductive cyclization of ketonitriles

Article abstract of DOI:10.1002/anie.201204469

Reduction, please! The title reaction affords ?-hydroxyketones, a common structural motif in biologically active natural products, in good yields and high enantioselectivities at room temperature. The commercially available ansa-titanocene 1 was found to be an efficient catalyst for this process, which presumably proceeds by addition of a ketyl radical to a nitrile.

Full text of DOI:10.1002/anie.201204469

Angewandte
Chemie
DOI: 10.1002/anie.201204469
Radical Cyclizations
Enantioselective Titanium(III)-Catalyzed Reductive Cyclization of
Ketonitriles**
Jan Streuff,* Markus Feurer, Plamen Bichovski, Georg Frey, and Urs Gellrich
Table 1: Catalyst optimization and additive effects.[a]
Samarium(II)-mediated reductive cyclizations are standard
tools in organic chemistry and have found broad application
in the synthesis of natural products and drugs.[1] Of these
reactions, the reductive cyclization of w-ketonitriles[2] is of
particular interest because the resulting a-hydroxyketone
(acyloin) fragment is present in over 1500 known natural
products. Examples include barbacenic acid, cortistatin D,
dragmacidin F, sieboldine A, and sphaerococcenol A, which
all contain a ketone with a tetrasubstituted, oxygenated a-
carbon.[3] In addition to SmI2, a number of other stoichio-
metric reagents were successfully employed for the cycliza-
tion of ketonitriles and related reactions.[2c,d,f,4] However,
asymmetric variants of such radical cyclizations are scarce and
usually require stoichiometric chiral additives.[1c,5] A transi-
tion-metal catalyst in combination with an inexpensive
terminal reductant instead would represent a significant
advance and also enable the asymmetric cyclization.[6]
Based on our recent work on the TiIII-catalyzed synthesis of
ketonitriles,[7] and previous reports by others that have
Entry Cat. (mol%)
Additive
(equiv)
T [8C] t [h] Yield[b] [%] ee[c] [%]
already demonstrated the versatility of titanium catalysis in
related radical reactions,[8] we reasoned that a chiral titanium-
based catalyst could facilitate the desired transformation.
Hence, a mild and highly enantioselective titanium(III)-
catalyzed reductive ketonitrile cyclization was developed
[Eq. (1)].
1
2
3a (5)
3b (5)
3c (5)
3d (5)
3e (5)
3 f (5)
3g (5)
3a (5)
3a (5)
3a (10)
Coll·HCl (1.3)
Coll·HCl (1.3)
Coll·HCl (1.3)
Coll·HCl (1.3)
Coll·HCl (1.3)
Coll·HCl (1.3)
Coll·HCl (1.3)
none
40
40
40
40
40
40
40
40
18
18
18
18
18
18
18
18
18
24
67
77
26
58
0
0
0
45
72
88
80
25
À20
À55
–
–
–
54
83
3
4
5
6
7
8
9
10
Et3N·HCl (1.3) 40
Et3N·HCl (2.0) 23
91[d]
[a] Conditions: 1a (0.2 mmol), catalyst 3 (5–10 mol%), zinc dust
(2.0 equiv), TMSCl (3.0 equiv), additive, THF (c=0.4m), 18 h; workup:
TBAF, aq. NaHCO3, followed by flash chromatography. [b] Yield of
isolated product. [c] Determined by GC on a chiral stationary phase.
[d] Workup by acid–base extraction. Coll=collidine.
Our investigations started with 1,5-ketonitrile 1a and we
found that product 2a formed only in the presence of the
titanocene catalysts 3a–d (Table 1, entries 1–4).[9] In detail,
only Brintzingerꢀs commercially available ansa-titanocene 3a
provided the product with high enantioselectivity (80% ee)
and reasonable yield (67%) after workup with tetra-n-
butylammonium fluoride (TBAF).[9a] Other catalysts such as
the TADDOL- or Salen-based complexes 3e–g, which
previously showed high selectivities in pinacol coupling
reactions, did not mediate this cyclization (Table 1,
entries 5–7).[10] After a second screening of a variety of
additives, triethylamine hydrochloride was identified to be
superior and it was found that the yield and enantioselectivity
of the reaction strongly depend on this hydrochloride additive
(Table 1, entries 8 and 9).[11] Importantly, no reaction was
observed under these conditions in the absence of catalyst and
addition of radical scavengers such as BHT shut down the
reaction completely.[12] Under the final optimized reaction
conditions the product was obtained in 88% yield and 91% ee
after a reaction time of 24 h at room temperature (Table 1,
entry 10). The yield and enantiomeric ratio remained con-
[*] Dr. J. Streuff, M. Feurer, P. Bichovski, G. Frey, U. Gellrich
Institut fꢀr Organische Chemie und Biochemie
Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
E-mail: jan.streuff@ocbc.uni-freiburg.de
Homepage: http://portal.uni-freiburg.de/streuff
[**] Financial support for this work was provided by the Fonds der
Chemischen Industrie and the Deutsche Forschungsgemeinschaft
(DFG, STR 1150/3-1).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204469.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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sistent for reactions carried out on scales between 0.2–
3.0 mmol.
We then submitted a number of w-ketonitriles to the
optimized conditions and observed that the R,R catalyst
produced the S-configured product and vice versa
(Table 2).[13] A range of functional groups were tolerated on
tivity at room temperature.[13] It is known that the intra-
molecular reaction of a ketyl radical with a nitrile to form
a six-membered ring is significantly slower than that forming
a five-membered ring.[2b] Still, cyclohexanone 2m and piper-
idinone 2n were synthesized in moderate yields with only
slightly diminished enantioselectivities.[14] In the case of 2n
a single crystallization afforded nearly enantiomerically pure
material. Finally, the challenging formation of a-hydroxytetr-
alone 2o, which itself can be easily reduced by the catalyst,
was successful. The product was obtained in 55% yield and
82% ee when zinc dust was added in two portions. Here,
hydrolysis of the crude imine with HCl in THF/H2O afforded
the desired product. During our initial experiments we found
that the product can be isolated conveniently by simple acid–
base extraction and chromatographic purification can be
avoided. Of all the products in Table 2, only 2k and 2n
required chromatographic purification.
Table 2: Scope of the titanium-catalyzed reductive cyclization.[a]
In a plausible mechanistic scenario, the low-valent tita-
nium catalyst formed in situ first coordinates the substrate 1a
at the carbonyl group and then performs a one-electron
reduction (Scheme 1). The resulting donor-stabilized radical
[a] Yields of isolated products. Conditions: 1 (0.2–1.0 mmol, 1 equiv), 3a
(0.1 equiv), Zn (2.0 equiv), TMSCl (3.0 equiv), HCl·NEt3 (2.0 equiv), THF
(c=0.4m), 238C, 24 h; then 1n HCl, neutralization, extraction with
CH2Cl2. [b] Average of three experiments. [c] (S,S)-3a was used instead.
[d] 48 h reaction time. [e] Product purified by chromatography. [f] 96 h
reaction time. [g] 72 h reaction time. [h] Workup with TBAF instead.
[i] After crystallization from 2-propanol. [j] The corresponding imine
required hydrolysis with HCl in THF/H2O (55% overall yield). [k] Zn was
added in two portions of 1.0 equiv, one portion initially and one after
7.5 h.
Scheme 1. Proposed catalytic cycle.
attacks the nitrile in an enantiodiscriminating 5-exo cycliza-
tion.[15] The newly formed N-centered radical is quickly
reduced and the resulting titanium(IV) alcoholate quenched
by TMSCl to liberate the a-oxygenated imine 4, which is then
converted into the desired product during workup. The low-
valent catalyst is regenerated by Zn as the terminal reductant.
A possible transition state (see box) explains the stereose-
lectivity of this reaction. The formation of the opposite
enantiomer instead would require the phenyl group to point
backwards, leading to stronger interactions with the ligand.
In addition to the aforementioned results, the still TMS-
protected a-hydroxyketone 5 was isolated from the reaction
mixture in 71% yield and 91% ee (Scheme 2). Furthermore,
this titanium(III) catalysis makes it possible to synthesize
vicinal amino alcohols and diols with high syn and anti
selectivity, respectively. For example, when the reaction
mixture was directly added to sodium cyanoborohydride in
methanol, the corresponding TMS-protected syn-amino alco-
hol 6 was obtained in high diastereomeric ratio (7:1 d.r.). This
the aromatic moiety. Substrates bearing either electron-rich
or electron-poor para substituents (2b–f) provided the
respective products in high yield (88–99%) and high enan-
tiomeric excess (86–93% ee) after 24 h reaction time.
Cyclic tertiary alcohols 2g and 2h with a 2-naphthyl and
a m-tolyl group, respectively, were obtained with similar
results. A heteroaromatic group, such as 3-furyl was tolerated
and product 2i was isolated in good yield and moderate
enantioselectivity.[14] Importantly, the aryl substituent was not
required for the reaction to proceed. Instead, different alkyl
substituents were successfully installed and the desired
products 2j–l formed in good yields and high enantioselec-
2
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Chemie
methane (3 ꢁ 10 mL). The dichloromethane layer was dried (Na2SO4),
filtered, and concentrated to yield the analytically pure product 2a in
88% yield and 91% ee.
Received: June 8, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · cyclization · radical reactions ·
.
reduction · titanium
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also proves that the postulated imine 4 is indeed the primary
product of the catalysis. Along these lines, a-hydroxyketone
2a was transformed with perfect diastereoselectivity into
trans-diol 7 by sequential reduction with L-selectride.[16]
Again, no chromatographic separation was required in the
synthesis of 7 starting from 1a.
In summary, we have developed a titanium(III)-catalyzed
asymmetric reductive coupling of ketones with nitriles. The
cyclic a-hydroxyketone products were formed in good yield
and high enantioselectivity and a number of aromatic and
aliphatic substitution patterns, heterocyclic groups, and annu-
lated rings were tolerated. The reaction was applied to the
stereoselective synthesis of tertiary syn-amino alcohols and
trans-diols. In most cases the isolation of analytically pure
product was possible by a simple and practical extraction
procedure. Our ongoing investigations now focus on the
elucidation of the reaction mechanism and the development
of related cyclizations.
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Experimental Section
Representative procedure: A 10 mL Schlenk tube closed with
a rubber septum and containing a magnetic stir bar was evacuated,
heated with a heat gun for one minute, and backfilled with argon.
Triethylamine hydrochloride (55 mg, 0.4 mmol, 2.0 equiv) was added,
followed by zinc dust (26.2 mg, 0.4 mmol, 2.0 equiv) and catalyst 3a
(7.7 mg, 0.02 mmol, 10 mol%). Stirring was started and the tube was
evacuated again for one minute and backfilled with argon. Degassed
THF (0.5 mL, tolerated water content: 10–300 ppm) was added and
the mixture stirred until the color of the mixture changed (ca. 1–
2 min) from red to green (depending on the water content). Substrate
1a (34.6 mg, 0.2 mmol) was quickly added followed by chlorotrime-
thylsilane (76 mL, 0.6 mmol, 3.0 equiv). The septum was replaced by
a greased glass stopper and a metal clip and the mixture was stirred
for 24 h at room temperature (238C). Dichloromethane (1 mL) was
added to the reaction and the mixture was transferred to a separatory
funnel containing 15 mL of ice-cold aq. 1n HCl and 40 mL of ice-cold
diethyl ether. The reaction vessel was rinsed with an additional 2 mL
of cold diethyl ether. The mixture was briefly shaken and the aqueous
layer quickly separated and collected. This aqueous extraction was
repeated six times. The collected aqueous layers were stirred until the
deprotection was complete by TLC (about 5–10 min) then carefully
neutralized to pH 8 (sat. aq. NaHCO3) and extracted with dichloro-
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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[12] The cyclization can take place in the abscence of a Ti catalyst,
but harsher conditions (20 equiv Zn, 6 equiv TMSCl, lutidine,
reflux in THF) are required (see Ref. [2f]).
[13] The absolute configuration was determined for (S)-2a and (S)-
2m by asymmetric dihydroxylation and subsequent oxidation of
1-phenylcyclopentene and 1-phenylcyclohexene, respectively. In
addition, the specific optical rotations matched literature reports
(see Ref. [6d]). The absolute configuration of 2j was assigned by
CD spectroscopy (see the Supporting Information).
[14] In general, the size of the a-substituent and the newly formed
ring appear to influence the coordination of the substrate to the
catalyst and thus the enantioselectivity. In the case of 2n,
hydrogen bonding might have an additional effect.
[15] Additional activation of the nitrile by the catalyst is also
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L. M. Burꢆn, R. R. Clemente, R. R. Gonzꢅlez, J. Org. Chem.
2007, 72, 9973 – 9982.
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For detailed information on the screening of additives, see the
Supporting Information.
[16] The relative configuration of 6 was confirmed by a NOESY
experiment. Product 7 and the corresponding syn-diol were
independently synthesized to assign the relative configuration
(see the Supporting Information).
4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Angewandte
Chemie
Communications
Radical Cyclizations
J. Streuff,* M. Feurer, P. Bichovski,
G. Frey, U. Gellrich
&&&& — &&&&
Enantioselective Titanium(III)-Catalyzed
Reductive Cyclization of Ketonitriles
Reduction, please! The title reaction
affords a-hydroxyketones, a common
structural motif in biologically active
natural products, in good yields and high
enantioselectivities at room temperature.
The commercially available ansa-titano-
cene 1 was found to be an efficient
catalyst for this process, which presum-
ably proceeds by addition of a ketyl
radical to a nitrile.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!