Asymmetric radical addition of TEMPO to titanium enolates

Article abstract of DOI:10.1021/ol403398u

A mild method for a-hydroxylation of N-acyl oxazolidinones by asymmetric radical addition of the 2,2,6,6-tetramethylpiperidine N-oxy (TEMPO) radical to titanium enolates was developed. The high diastereoselectivity and broad scope of the reaction show synthetic utility for the a-hydroxylation of substrates that are not tolerant to strongly basic conditions.

Full text of DOI:10.1021/ol403398u

Letter
pubs.acs.org/OrgLett
Asymmetric Radical Addition of TEMPO to Titanium Enolates
Phillip J. Mabe and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, United States
S
* Supporting Information
ABSTRACT: A mild method for α-hydroxylation of N-acyl
oxazolidinones by asymmetric radical addition of the 2,2,6,6-
tetramethylpiperidine N-oxy (TEMPO) radical to titanium
enolates was developed. The high diastereoselectivity and
broad scope of the reaction show synthetic utility for the α-
hydroxylation of substrates that are not tolerant to strongly
basic conditions.
Table 1. Optimization of Reaction Time and Temperature
Paramaters
any methods are available for the α-hydroxylation of
a
1
Mcarbonyl compounds.
Among the most commonly
applied is enolate oxidation1,2 by reagents such as MoO5·Py·
HMPA,3 MoO5·Py·DMPU,4 N-sulfonyloxaziridines,5 perox-
ides,6 or hypervalent iodine reagents.7 Stereoselectivity of
enolate oxidations is generally controlled by the approach of
the oxidant to the less sterically hindered face of the enolate
whether the process is catalytic or auxiliary-controlled.1 Highly
stereoselective α-hydroxylations have been reported through
the use of N-acyl oxazolidinones with achiral oxidants8 or,
alternatively, through the use of achiral carbonyl substrates with
chiral oxidants such as (camphorylsulfonyl)oxaziridines.9
However, these methods require the use of strongly basic
reagents such as LDA, or NaN(SiMe3)2, which may be
incompatible with more functionalized substrates.
b
entry
R1, R2, R3
time
temp
dr
conversion, %
1
Bn, Me, Me
30 min
1 min
5 min
15 min
3 h
−78 °C
0 °C
0 °C
0 °C
0 °C
23 °C
23 °C
23 °C
23 °C
23 °C
9:1
5
95
2
20:1
20:1
21:1
17:1
17:1
14:1
7:1
3
100
100
100
98
4
5
6
2 min
30 min
50 min
40 min
40 min
Transition-metal-catalyzed direct asymmetric α-hydroxyla-
tion reactions using chiral titanium,10 ruthenium,9,10 and
palladium11 complexes constitute an important advance in the
field. These reactions are currently limited to β-ketoesters.
Enantioselective organocatalytic oxygenation reactions using
TEMPO have recently been reported.12 However, the scope of
these methods is limited to aldehydes as substrates.
Jahn and co-workers have recently reported an elegant
approach to α-oxygenation of enolates derived from esters,
amides, ketones, nitriles, and carboxylic acids by treatment with
a combination of TEMPO and superstoichiometric amounts of
ferrocenium hexafluorophosphate.2,13 Renaud, Studer and co-
workers recently described the α-oxygenation of enol borinates
using TEMPO.14 Both of these powerful methods provide
access to α-(tetramethylpiperidin-1-yl)oxy carbonyl com-
pounds in excellent yields, although examples of asymmetric
α-aminoxylation reactions in these reports are isolated.
In line with our interest in exploring the radical reactivity of
readily available transition metal enolates,15 we directed our
efforts toward developing a direct asymmetric radical α-
hydroxylation of N-acyl oxazolidinones using TEMPO. Initial
experimentation with 4-benzyl-5,5-dimethyl-N-propionyloxazo-
lidin-2-one 1 (R1 = Bn, R2 = R3 = CH3) immediately revealed
that titanium enolates16 derived from 1 undergo efficient and
facile addition of TEMPO with high diastereocontrol (Table 1).
7
100
100
100
100
8
i-Pr, Me, Me
Ph, Me, H
Bn, H, H
9
5:1
10
4:1
a
Standard conditions: 1 (0.4 mmol), CH2Cl2 (∼0.4 M), TiCl4 (1.05
equiv), 0 or 23 °C, 10 min; Et3N (3.0 equiv), 40 min; TEMPO (2.05
b
equiv), as 1.0 M solution in CH2Cl2 dropwise over 1 min. Conversion
and diastereomeric ratios were determined by 500 or 600 MHz H
1
NMR analysis of the crude mixture of products.
Similar reactivity was observed for enolates generated with
zirconium tetrachloride, although the diastereoselectivity was
notably lower (dr = 4:1). While the rate of the addition was low
at −78 °C (Table 1, entry 1), a rapid addition was observed at
the more experimentally convenient temperatures of 0 °C
(Table 1, entries 2−5) and 23 °C (Table 1, entries 6, 7).
Prolonged reaction times (0 °C, 3 h) result in the erosion of
stereoselectivity (cf. entries 4 and 5).
Replacing the benzyl substituent at the oxazolidinone with an
isopropyl group resulted in a lower diastereoselectivity of 7:1
(Table 1, entry 8). Other oxazolidinones lacking the 5,5-
Received: November 22, 2013
© XXXX American Chemical Society
A
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Organic Letters
Letter
dimethyl substitution also displayed lower diastereocontrol
(Table 1, entries 9, 10).
The scope of the aminoxylation reaction was explored next
(Table 2). While the diastereoselectivity was somewhat lower at
in the titanium enolates. However, these reactions are clean
transformations with unreacted starting material as the major
byproduct, pointing to the lower reactivity of the more
hindered substrates. For 4-benzyl-5,5-dimethyl-N-propionyl-
oxazolidin-2-one (Table 2, 2a), oxazolidinone cleavage (18%)
and oxidative dimerization at the α-position (8%) were
observed at room temperature, in addition to the formation
of the expected α-aminoxylation product.
Table 2. Scope of N-Acyl Oxazolidinones in the α-
a
Aminoxylation Reaction
Substrates with terminal alkene, alkyne, benzyl, and aryl ether
functional groups are well tolerated (Table 2, 2f−2i). The
reduced yield for the reaction of the benzyl ether (Table 2, 2i)
is attributed to TiCl4-mediated debenzylation, resulting in the
formation of the debenzylated byproduct (32%), and a minor
degree of oxazolidinone cleavage (7%). Substrates derived from
arylacetic acids are also suitable starting materials (Table 2, 2j,
2k). Notably, pure products 2j and 2k are somewhat unstable
and have been observed to undergo a spontaneous epimeriza-
tion at the α-position in solution in CDCl3, with a 1:1.7 mixture
of diastereomers formed from a 14:1 mixture after 12 days at
ambient temperature.17
High diastereoselectivity was achieved with both diaster-
eomers of the imide derived from (R)-hydrocitronellic acid
irrespective of the relative configuration at the β-position
(Table 2, 2l and 2m).
Further inquiry probed mechanistic details of the radical
addition of TEMPO to the titanium enolates, first testing the
potential for catalytic turnover of TiCl4.18 Using 0.20 equiv of
TiCl4 and 4-benzyl-5,5-dimethyl-N-propionyloxazolidin-2-one
(1) under the standard reaction conditions (23 °C, 30 min) or
upon heating and prolonged reaction times (40 °C, 17 h)
resulted in ∼20% conversion, indicating no turnover of
titanium tetrachloride. Similar observations were noted when
triethylamine, which may have an inhibitory effect, was replaced
with 1,2,2,6,6-pentamethylpiperidine.14 These results suggest
that the product may be an effective ligand for titanium
tetrachloride, leading to strong product inhibition. Erosion of
stereochemistry in the product upon prolonged reaction times
also indicates that the product remains bound to the Lewis acid
and is subject to a relatively slow but observable enolization.
Two alternative pathways for the radical addition of TEMPO
are envisioned as outlined in Scheme 2. After the initial
generation of Ti enolate ii, pathway A calls for the direct
addition of the TEMPO radical, affording the delocalized open
shell system represented by resonance structures iii and iv.
Subsequent oxidation with the second equivalent of TEMPO
affords the product as a complex with TiCl4, which delivers free
product viii after decomplexation upon quench. In pathway B,
Ti enolate ii is first oxidized by TEMPO to the enol radical
represented by resonance structures vi and vii. The resulting
radical undergoes a radical−radical coupling with TEMPO
giving v and ultimately product viii upon quench. We currently
favor pathway B due to mechanistic similarity with
catecholboron enolate oxidation by TEMPO,19 in addition to
indirect experimental evidence, primarily isolation of the
enolate dimerization byproducts in certain reactions (i.e.,
Tables 2, entry 1).
a
Yields of isolated products as a mixture of diastereomers are reported.
At least two experiments were carried out to confirm reproducibility.
The numbers in parentheses are yields based on recovered starting
material (brsm). Diastereomer ratios were determined by 500 or 600
b
MHz 1H NMR analysis of the crude mixture of products. Formation
of the byproduct (R = H) is attributed to TiCl4-assisted debenzylation.
23 °C, we chose to continue experimentation at this
temperature for operational simplicity. Many N-acyl oxazolidi-
nones can be successfully α-aminoxylated using the general
protocol developed during the course of this investigation.
Unfunctionalized N-acyl oxazolidinones derived from simple
alkanoic acids undergo effective and diastereoselective α-
aminoxylation, with yields decreasing and stereoselectivity
increasing as β-branching of the substrates increases (Table 2,
2a−2e). Diminished yields and improved stereoselectivity with
β-branching are consistent with the increasing steric hindrance
The utility of products described in this study was first
demonstrated by the N−O bond scission to reveal the products
of α-hydroxylation. The N−O bond could be cleaved in high
yield by a reaction with Zn(0) dust (40 equiv) in AcOH/THF
(3/1) at 50 °C for 2 h (Scheme 3).2 We generally observed
high integrity for the stereochemistry at the α-position bearing
the unmasked free hydroxy group.
B
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Organic Letters
Letter
Scheme 2. Mechanistic Overview of Radical α-
Aminoxylation of Titanium Enolates with TEMPO
Scheme 4. Preparation of Enantioenriched Hydroxylated
Building Blocks by Removal of the Chiral Auxiliary via
a
Esterification and Reduction
a
The chiral auxiliary is recovered in nearly quantitative yield for all
reactions
solvolitically while maintaining the integrity of the α-
hydroxylated stereocenter. Further studies into the mechanism
of the reaction and radical reactivity of enolates produced by
soft enolization are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures, characterization data, and
1
copies of H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 3. N−O Bond Cleavage of α-Aminoxylated
Intermediate
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zakarian@chem.ucsb.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a grant from the NSF (CHE-
0836757).
■
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