TEMPO-Mediated Oxidative Deformylation of Aldehydes: Applications in the Synthesis of Polyketide Fragments

Article abstract of DOI:10.1002/ejoc.201701349

A TEMPO-mediated oxidative deformylation of aldehydes is reported that yields the TEMPO adducts, which can be further oxidized to the corresponding ketones. The focus of this work was on the optimization of a synthetic protocol for use in natural product

Full text of DOI:10.1002/ejoc.201701349

A Journal of
Accepted Article
Title: TEMPO-mediated oxidative deformylation of aldehydes -
applications in the synthesis of polyketide fragments
Authors: Andreas Kirschning, Andreas Kipke, Kai-Uwe Schoening, and
Mekhman Yusubov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701349
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European Journal of Organic Chemistry
10.1002/ejoc.201701349
FULL PAPER
TEMPO-mediated oxidative deformylation of aldehydes –
applications in the synthesis of polyketide fragments
[
a]
[b]
[c]
[a]
Andreas Kipke , Kai-Uwe Schöning , Mekhman Yusubov , Andreas Kirschning*
Dedication
[
a]
Dr. A. Kipke, Prof. Dr. A. Kirschning
Institute of Organic Chemistry and Center of Biomolecular Drug
Research (BMWZ)
Leibniz Universität Hannover
Schneiderberg 1B, 301267 Hannover, Germany
E-mail: andreas.kirschning@oci.uni-hannover.de
Dr. K.-U. Schöning, BASF Schweiz AG, Klybeckstrasse 141, 4057
Basel, Switzerland
Prof. Dr. M. Yusubov, Department of Technology of Organic
Substances and Polymer Materials, Tomsk Polytechnic
University,30 Lenin Avenue, 634050 Tomsk, Russia
[
[
b]
c]
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European Journal of Organic Chemistry
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Abstract: The TEMPO-mediated oxidative deformylation of
aldehydes is reported that yields the TEMPO adducts which
can be further oxidized to the corresponding ketones. The
focus of this work was on the optimization of a synthetic
protocol for use in natural product synthesis, specifically for
the preparation of chiral backbones with 1,2-oxo
functionalization found in polyketide antibiotics. In addition,
the oxidative deformylation was combined with the oxidation
of the alcohol to the precursor aldehyde in a one-pot protocol.
copper(II).[10] Upon fragmentation of 4, formic acid is liberated as
well as the C-centered radical 5 which is subsequently trapped by
6 to yield the alkoxyamine 2. In that context, these mechanistic
considerations resemble those suggested by Isawa. In their work
on metal-catalyzed deformylation it was thought that homolytic
cleavage of peroxohemiacetal intermediates occur to provide
alkyl radicals.[8]
Indeed, this transformation bears several synthetic opportunities
and this report intends to advance the methodology in several
aspects. These cover the issue of chemoselectivity, stereocontrol
when the -position of the aldehyde bears a stereogenic center
and the application of this method in creating polyketide
backbones with differentiated 1,2-oxy functionalization.
Introduction
Oxidative deformylation reactions are rather rare.[1] Most
commonly it is associated with transition metal chemistry such as
the oxidative decarbonylation of m-terphenyl isocyanide
Results and Discussion
[
2]
complexes of molybdenum and tungsten or alkyl-Heck-type
reactions in which precursor aldehydes are decarbonylated.[3[ In
addition, it was demonstrated that -substituted pyruvic acid
derivatives undergo oxidative decarbonylation using sodium
perborate tetrahydrate to yield the corresponding acetic acid
derivatives.[ Iwasawa and coworkers reported on the catalytic
generation of alkyl radicals from aldehydes using a cobalt-salen
In continuation of the work of Schöning et al.[5b] we here disclose
improved conditions for carrying out oxidative deformylations with
complex aldehydes for application in polyketide synthesis.
Ethanol or THF were found to be the solvents of choice.
Interestingly, also a solvent mixture composed of water and
ethanol provides alkoxyamines of type 2. The ratio of aldehyde 1
and 4-hydroxy-TEMPO 6 could be varied; commonly a 1:2 mixture
gave best yields, while the copper source was employed in
catalytic amount (5 mol%). The amount of hydrogen peroxide can
be raised to 3 equ. without an observable decrease of yield.
4]
.[5] Recently, Maiti et al. disclosed a non
complex with H O
2 2
oxidative palladium-catalyzed deformylation protocol for aromatic
aldehydes.[6,7]
Scheme 1. Tempo-mediated oxidative deformylation of aldehydes and
proposed mechanism.
Catalytic amounts of additives such as Et
tolerated, while the addition of strong Lewis acids such AlCl
3
N, or p-TsOH are
is
3
wreckless. It is also not possible to substitute hydrogen peroxide
by NaOCl or tert-butyl hydroperoxide, respectively.
Scheme 2. Oxidative deformylation of (un)saturated aldehydes 1a-1g and
reductive cleavage of alkoxyamine 2g.
Schöning and coworkers reported on the conversion of aldehydes
to the corresponding N-alkoxyamines using stable nitroxide
radicals (Scheme 1).[8] Important features of this oxidative
deformylation protocol are the presence of a catalytic amount of
copper(I) chloride and stoichiometric amounts of hydrogen
peroxide. Mechanistically, this reaction may be initiated by
nucleophilic addition of hydrogen peroxide to the carbonyl
group.[9] The intermediate hydroxy-hydroperoxide 3 decomposes
under the influence of the copper (I) catalyst, resulting in the
formation of the alkoxy radical 4 and copper(II). As copper(I) is
employed catalytically, a reduction step has to be considered. It
is unclear, whether hydrogen peroxide decomposes under the
influence of copper(II) to oxygen while copper(I) is regenerated.
Likewise, 4-HO-TEMPO 6 could provide the electron for reducing
The transformation of structurally diverse new aldehydes not
reported before[ is summarized in Scheme 2. Besides simple
linear aliphatic aldehydes 1a-1c also citronellal 1d was
deformylated to smoothly yield alkoxyamine 2d. Unsaturated
aldehyde 2e reacted likewise. These two examples are
remarkable because the intermediate C-radical of type 5 (see
8]
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European Journal of Organic Chemistry
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FULL PAPER
Scheme 1) do not cyclize to the cyclopentylmethyl radicals that
would result in the formation of cyclopentane derivatives. Indeed,
Iwasawa and coworkers observed such cyclizations when
creating the corresponding C-radicals by a cobalt-salen-initiated
deformylation. Obviously, the presence of the radical scavenger
HO-TEMPO 6 leads to rapid trapping of the intermediate C-radical
before the cyclization can occur. The chemoselectivity of this
reaction was further demonstrated when using aldehyde 2f that
represents a typical polyketide backbone. For achieving best
results for this complex aldehyde, the reaction conditions were
The oxidative deformylation can also be coupled with the initial
oxidative formation of the starting aldehyde from the
corresponding alcohol. In order to secure the chemoselective
character of the deformylation protocol towards olefinic double
bonds a reagent system was chosen that also relies on 4-hydroxy-
TEMPO 6. Diacetoxyiodo benzene (DAIB), or bisacetoxyiodo
benzene (BAIB) served as possible co-oxidants (Scheme 4). First,
3
-phenylpropan-1-ol 11 was subjected to the oxidation conditions.
Once the transformation to aldehyde 1b had gone to completion
as judged by tlc a second portion of p-HO-TEMPO 6 and H as
2
O
2
slightly modified (6, 2.0 eq., H
2
O
2
(2.0 eq.), EtOH (0.3 M), CuCl (5
well as a catalytic amount of CuCl were added to initiate the
oxidative deformylation and formation of alkoxyamine 2b.
Likewise, unsaturated alkoxyamines 2c and 2d were prepared
from citronellol 12 and 6-nonene-1-ol 13, respectively. Again, no
cyclization products that would originate from an intermediate C-
radical bearing an olefinic double bond were detected.
2
mol%), rt, 16h). Noteworthy, cinnamaldehyde, bearing a sp
center in the -position did not yield any definded product under
te typical reaction conditions.
The alkoxamine 2g obtained from 2-phenypropanal 1g was used
to probe conditions for reductive cleavage of the N,O-bond and
formation of the corresponding alcohol 7. The reagent system
acetic acid and Zn dust allowed to promote reductive cleavage,
while other options such as catalytic hydrogenation with Pd/C or
Scheme 5. Oxidative deformylation of chiral aldehydes 1h and 1i (d.r.
1
determined by H-NMR spectroscopy; relative stereochemistry for single
diastereomers was not determined).
2
SmI did not work. However, it needs to be noted, that the
transformation with Zn/AcOH worked best, when microwave
irradiation served as a source of heat.
Scheme 3. Oxidative deformylation of cyclohexanones 9a,b and proposed
intermediates 10a-9c.
If -branched aldehydes are subjected to the oxidative
deformylation conditions a new stereogenic center will be
generated. In view of developing a method suited for natural
product synthesis, specifically for the synthesis of polyketide
backbones we investigated, whether the configuration of this
newly formed stereogenic center can be controlled by a second
stereogenic center present in the starting aldehyde. Syn-
configured -methyl-oxygenated aldehyde 1h were obtained
by the Evans aldol reaction followed by O-silylation and reductive
removal of the oxazolidinone auxiliary.[11] The resulting primary
alcohol was oxidized to the aldehyde by Dess-Martin oxidation
and subjected to the oxidative deformylation conditions to yield
alkoxyamine 2i in good yield for two steps but as a mixture of
diastereoisomers (Scheme 5).
We also included a brief study on the transformation of ketones
8a,b (Scheme 3). Surprisingly, selective ring opening occurred
which yielded carboxylic acids 9a and 9b, respectively.
Mechanistically, a similar route (10a→10b→10c) as described in
Scheme 1 can be suggested. However, the scope of this oxidative
fragmentation is rather limited, because neither cyclopentanone,
cyloheptanone, nor -unsaturated cyclic ketones yielded
defined product in preparatively relevant yields.
Scheme 4. One-pot oxidation of alcohols 11-13 and oxidative carbonylation of
intermediate aldehydes.
Scheme 6. Oxidative deformylation of chiral aldehyde 1j (configuration of the
newly formed stereogenic center for each diastereomer was not determined;
yield of 2j (resembles ent-2h) is given for two steps: a) Dess-Martin oxidation of
corresponding alcohol and b) oxidative deformylation of resulting crude
aldehyde 1j).
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European Journal of Organic Chemistry
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Such good yield was obtained after slightly modifying the
procedure. Aldehyde 1h was first mixed with hydrogen peroxide
in ethanol and stirred for one hour after which time the copper salt
and 4-hydroxy-TEMPO 6 were added. It has to be noted that
changing the silyl protection in 1h with other silyl groups including
differentiated 1,2-oxy-functionalization may be obtained through
a sequence consisting of oxidative deformylation, mCPBA-
mediated cleavage followed by Paterson-type aldol chemistry.
This is exemplified in the preparation of hydroxyketone 17
(Scheme 8). Starting from aldehyde 1k, also obtained through the
usual Evans syn-aldol chemistry, the oxidative deformylation
yielded alkoxyamine 2k. After oxidative removal of the TEMPO
moiety, the resulting ketone 16 served as enolate component for
Urpi´s variant[13] of the Paterson-aldol reaction with methacroleine
as aldehyde component. The resulting polyketide element 17 was
formed as one diastereoisomer bearing elements with a 1,2- and
a 1,3-oxygen relationship.
3 3 2 3
bulkier ones (Et Si, iPr Si, tBuPh Si, Ph Si) or alternatively to the
MOM group with chelating properties did not lead to principally
other results (yields: 26-54%, d.r.= 1.6:1 to 1:1). Likewise, the
homo derivative 1i gave the same result under the optimized
conditions (Scheme 5).
The initial syn-stereochemistry in aldehydes 1h and 1i may be
responsible for the lack of stereocontrol. Therefore, we also
subjected the -anti-configured aldehyde 1j to the modified
reaction conditions (Scheme 6). This aldehyde was prepared
according to Masamune´s aldol protocol.[12] The oxidative
deformylation proceeded with moderate and with better
diastereoselectivity. Surprisingly, the diastereocontrol was found
to be concentration dependent (0.15 mol/L vs. 0.3 mol/L: >20:1
vs. 4:1).
Conclusion
In conclusion, we reported on the TEMPO-mediated oxidative
deformylation of aldehydes yielding alkoxyamines. In a one-pot
procedure, this oxidation can be combined with the initial
oxidation of alcohols to aldehydes. When defined diastereomers
of -oxygenated -branched aldehydes are employed,
diastereopurity is lost. However, the resulting alkoxyamines can
directly be oxidized to the corresponding ketones with mCPBA.
As a result, -alkoxy-ketones are obtained, that were employed
in the synthesis of polyketide-type fragments. Oxidative
deformylations are very rare reactions in the synthetic chemists`
portfolio so that the current work paves the way for further
synthetic applications in this field.
Scheme 7. Oxidative cleavage of alkoxyamines 2h and 2i.
Next, we pursued to achieve a controlled oxidative cleavage of
alkoxyamines 2, because for diastereomeric mixtures
alkoxyamines 2h and 2i the issue of lack of stereocontrol during
their formation can be resolved. Thus, treatment with mCPBA
smoothly yielded ketones 14 and 15, respectively (Scheme 7).
Experimental Section
General Methods. 1H and 13C NMR spectra were recorded with Bruker DPX-
400, AVANCE-400 and DRX-500 with the residual solvent signal as internal
standard. The choice of solvents are provided with the data of spectra.
Multiplicities are described using the following abbreviations: s= singlet, d=
doublet, t= triplet, q= quartet, o= octet, m= multiplet. 13C NMR spectra are
reported as values in ppm relative to residual solvent signal as internal standard.
The multiplicities refer to the resonances in the off-resonance decoupled
spectra and were elucidated using the distortionless enhancement by
polarisation transfer (DEPT) spectral editing technique, with secondary pulses
at 90° and 135°. Multiplicities are reported using the following abbreviations: q
Scheme 8. Preparation of polyketide fragment 17 bearing
a
1,2-
oxyfunctionalization.
(quaternary carbon), t (tertiary carbon = methyne), s (secondary carbon =
methylene), p = (primary carbon = methyl). High resolution mass spectra were
obtained with a Micromass LCT via loop-mode injection from a Waters (Alliance
2695) HPLC system. Alternatively a Micromass Q-TOF in combination with a
Waters Aquity Ultraperformance LC system was employed. Ionization was
achieved by ESI or APCI. Microwave-assisted heating was carried out in a
Discover S-Class from CEM (max. power 300 W). Analytical thin-layer
chromatography was performed using precoated silica gel 60 F254 plates (Merck,
Darmstadt), and the spots were visualized with UV light at 254 nm or by staining
2 4
with H SO /4-methoxybenzaldehyde in ethanol. Flash column chromatography
was performed on Merck silica gel 60 (230-400 mesh). All reagents were used
as received from the suppliers. THF was dried over sodium wire with
benzophenone as indicator. Specific optical rotations [α] were measured at
2
0 °C with a polarometer type 341 from Perkin-Elmer with a 10 cm cuvette at λ
The oxidative cleavage protocol and liberation of a new carbonyl
group has synthetic potential for preparing polyketide backbones.
For instance, starting from an aldol product bearing the common
=
589.3 mm (sodium-D-line). Reagent 6 and alcohols 7 and 11 and 12 are
commercially available. The preparation of aldehydes 1h, 1i, 1j and 1k is
reported in references.[14] Alkoxyamine 2g is described in ref. . The oxidative
deformylation of aldehydes 1a-1c as well as 1g and the analytic and
1,3-relationship of oxygen functionalities, products with
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European Journal of Organic Chemistry
10.1002/ejoc.201701349
FULL PAPER
spectroscopic data of alkoxamines 2a-2c as well as 2g were reported in
CH
3
); 13C-NMR (100 MHz, CDCl
3
, CDCl
3
= 77.16 ppm): 131.3, 124.9, 81.9,
reference [8].
63.4, 60.2, 48.4, 34.1, 33.3, 33.0, 25.8, 25.7, 21.6, 17.7, 17.5 ppm; HRMS(ESI):
+
m/z: calculated for C18
H
36NO
2
[M+H] :298.2746, found: 298.2755.
General proce8dures for the oxidative deformylation
(
Z)-2,2,6,6-Tetramethyl-1-(oct-5-en-1-yloxy)piperidin-4-ol (2e): 2e was
obtained from aldehyde 1e (21.7 mg, 0.16 mmol, 1 eq.) was subjected to the
general method of oxidative deformylation; purification by column
2 2
Method A (4-hydroxy-TEMPO, CuCl and H O are added together): If the
aldehyde was not commercially available or chemically labile the corresponding
alcohol was oxidized by Dess-Martin oxidation and the crude aldehyde 1 (0.18
mmol, 1 eq.) was directly employed in the oxidative deformylation reaction. It
was dissolved in ethanol (0.6 mL) and treated with 4-hydroxy-TEMPO (6) (46.5
A
chromatography (petroleum ether / ethyl acetate= 3:1); yield 2e (29 mg, 0.1
mmol, 65 %) as a colorless oil.
1H-NMR (200 MHz, CDCl
.02-3.92 (m, 1H, CH-O), 3.73 (t, J = 6.4 Hz, 2H, CH
CH ), 1.84-1.76 (m, 2H, CH ), 1.62-1.40 (m, 6H, CH ), 1.19 (s, 3H, CH
s, 3H, CH ), 0.96 (t, J = 7.4 Hz, 3H, CH , CDCl
); 13C-NMR (100 MHz, CDCl
, CHCl
3
= 7.26 ppm): = 5.31-5.39 (m, 2H, -CH=CH-),
-O), 2.08-1.99 (m, 4H,
), 1.14
3
2 2
mg, 0.27 mmol, 1.5 eq.) CuCl (0.9 mg, 5 mol%) and H O (30%, 30.6 mg, 0.27
4
2
mmol, 1.5 eq.). The solution was stirred for 17 h at rt. The reaction was
terminated by addition of an aqueous solution of ascorbic acid (10%, 10 mL)
and ethyl acetate (10 mL). The phases were separated and the aqueous phase
was washed with ethyl acetate (3x 10 mL). The combined organic extracts were
2
2
2
3
(
3
3
3
3
=
7
7.16 ppm):  131.9 (d), 129.1 (d), 77.5 (t), 63.5 (d), 60.1 (s), 48.4 (t), 33.3 (q),
8.4 (t), 27.2 (t), 26.7 (t), 21.1 (q), 20.6 (t), 14.5 (q) ppm; HRMS(ESI): m/z:
2
washed with an aqueous NaHCO
MgSO ), filtered and concentrated under reduced pressure.
Method B: (premixing of aldehyde with H for 1 h): If the aldehyde was not
3
-solution (saturated), and brine, then dried
+
calculated for C17
H
34NO
2
[M+H] :284.2590, found: 284.2601.
(
4
2 2
O
(2R,5S)-2-(tert.-Butyldimethylsiloxy)-6-(tert.-butyldiphenyl-siloxy)-1-(4-
commercially available or chemically labile the corresponding alcohol was
oxidized by Dess-Martin oxidation and the crude aldehyde 1 (0.18 mmol, 1 eq.)
was directly employed for the oxidative deformylation reaction. It was dissolved
hydroxy-2,2,6,6-tetramethylpiperidinyloxy)-3,5-dimethyl-3-hexen (2f): 2f
was obtained from the corresponding alcohol (20.0 mg, 0.037 mmol, 1 eq) and
the resulting aldehyde 1f was subjected to the general method C of oxidative
deformylation; purification by column chromatography (petroleum ether / ethyl
2 2
in ethanol (0.6 mL), treated with H O (30%, 30.6 mg, 0.27 mmol, 1.5 eq.) and
stirred at rt for one 1h. Then, 4-hydroxy-TEMPO (6) (46.5 mg, 0.27 mmol, 1.5
eq.) and CuCl (0.9 mg, 5 mol%) were added. The solution was stirred for 12 h
at rt. The reaction was terminated by addition of an aqueous solution of ascorbic
acid (10%, 10 mL) and ethyl acetate (10 mL). The phases were separated and
the aqueous phase was washed with ethyl acetate (3x 10 mL). The combined
acetate= 3:1); yield 2f (14 mg, 0.02 mmol, 54 %) as a colorless oil.
] 20
= -11.6 (c = 1.0, MeOH); H-NMR (CDCl
1
[
D
3
, 400 MHz): = 7.67-7.65 (m, 4H,
aromatic H), 7.42-7.35 (m, 6H, aromatic H), 5.27 (d, J = 9.4 Hz, 1H, H-4), 4.06
dd, J = 4.3, 7.0 Hz, 1H, H-2), 3.96-3.91 (m, 1H, H-10), 3.70-3.61 (m, 2H, H-1),
(
3
2
1
.50 (dd, J = 5.6, 9.7 Hz, 1H, H-6), 3.41 (dd, J = 7.3, 9.7 Hz, 1H, H-6’), 2.62-
.55 (m, 1H, H-5), 1.80-1.76 (m, 2H, H-9, H-9’), 1.53 (d, J = 1.3 Hz, 1H, CH C),
.45-1.39 (m, 2H, H-9, H-9’), 1.20 (s, 3H, H-11), 1.15 (s, 3H, H-11’), 1.14 (s, 3H,
), 0.98 (d, J = 6.7 Hz, 3H, H-
), -0.02 (s, 3H, SiCH
); 13C-NMR
, 100 MHz): = 135.8 (q, aromatic C), 135.8 (t, aromatic C), 135.5 (q, C-
), 134.2 (t, aromatic C), 134.2 (t, aromatic C), 129.6 (t, aromatic C), 129.0 (t,
organic extracts were washed with an aqueous NaHCO
3
-solution (saturated),
3
and brine, then dried (MgSO
pressure.
4
), filtered and concentrated under reduced
H-11’’), 1.12 (s, 3H, H-11’’’), 1.05 (s, 9H, SiC(CH
), 0.87 (s, 9H, SiC(CH ), 0.05 (s, 3H, SiCH
CDCl
3 3
)
Method C (2 eq. instead of 1.5 eq. of 4-hydroxy-TEMPO (6) employed): If the
aldehyde was not commercially available or chemically labile the corresponding
alcohol was oxidized by Dess-Martin oxidation and the crude aldehyde 1 (0.04
mmol, 1 eq.) was directly employed for the oxidative deformylation. It was
dissolved in ethanol (0.3 mL) and treated with 4-hydroxy-TEMPO (6) (15.5 mg,
8
)
3 3
3
3
(
3
3
C-4), 127.7 (t, aromatic C), 81.1 (s, C-1), 76.3 (t, C-2), 68.6 (s, C-6), 63.5 (t, C-
0), 60.3 (q, C-12), 60.1 (q, C-12’), 48.5 (C-9 or C-9’), 48.4 (C-9 or C-9’), 35.2
t, C-5), 33.2 (p, C-11), 33.1 (p, C-11), 27.0 (SiC(CH ), 26.0 (SiC(CH ), 21.4
p, C-11), 21.3 (p, C-11), 19.4 (SiC(CH ), 18.4 (SiC(CH ), 17.4 (p, C-8), 13.0
), -4.8 (p, SiCH ); HRMS(ESI): m/z: calculated for
1
0.09 mmol, 2 eq.) CuCl (0.2 mg, 5 mol%) and H
2 2
O (30%, 10.2 mg, 0.09 mmol,
(
(
(
)
3 3
3 3
)
2
eq.). The solution was stirred for 17 h at rt. The reaction was terminated by
3
)
3
3 3
)
addition of an aqueous solution of ascorbic acid (10%, 10 mL) and ethyl acetate
10 mL). The phases were separated and the aqueous phase was washed with
ethyl acetate (3x 10 mL). The combined organic extracts were washed with an
aqueous NaHCO -solution (saturated), and brine, then dried (MgSO ), filtered
and concentrated under reduced pressure.
Method D (one pot procedure starting from the corresponding alcohol): To a
solution of the alcohol (0.17 mmol, 1 eq.) in CH CN (1.0 mL) was added
PhI(OAc) (0.20 mmol, 1.2 eq.) and 4-hydroxy-TEMPO (6) (3.5 mg, 0.02 mmol,
.12 eq.) and the reaction mixture was stirred at r.t. for 3 h. The progress was
monitored by TLC. Then, a second portion of 4-hydroxy-TEMPO (6) (42.4 mg,
p, C-7), -4.6 (p, SiCH
3
3
(
+
C
39
H
66
N
1 4
O Si
1
[M+H ]: 668.4530, found: 668.4521.
3
4
(1S)-1-(tert.-Butyldimethylsiloxy)-2-(4-hydroxy-2,2,6,6-tetramethyl-
piperidinyloxy)-1-phenylpropan (2h): 2h was obtained from the
corresponding alcohol (50.5 mg, 0.18 mmol, 1 eq.) after Dess-Martin oxidation;
crude aldehyde 1h was subjected to the general method B of oxidative
deformylation; purification by column chromatography (petroleum ether / ethyl
acetate= 5:1 to 3:1); yield 2h (50 mg, 0.12 mmol, 65%, d.r.= 1.6:1) as a colorless
oil.
3
2
0
0.25 mmol, 1.5 eq.), CuCl (0.9 -1.4 mg, 5 – 8 mol%) and H
2 2
O (30%, 29-52 mg,
Major diastereoisomer 2h: 1H-NMR (400 MHz, CDCl
, CHCl
.36-7.18 (m, 5H, aromatic H), 4.70 (d, J= 4.2 Hz, 1H, 1-H), 3.99 (m, 1H, 2-H),
.92 (m, 1H, CHOH), 1.80 (m, 1H, HCH), 1.72 (m, 1H, HCH), 1.48-1.38 (m, 2H,
), 1.15, 1.13, 1.09, 1.01 (4s, 12 H, 4x CH ),
)), -0.16 (s, 3H, Si(CH
)); 13C-NMR (100
= 77.16 ppm): = 141.9 (q, C-aromat.), 128.4 (t, C-aromat.), 128.1
3
= 7.26 ppm):=
0.25 – 0.46 mmol, 1.5-2.8 eq.) were added and the solution turned to green after
3
7
3
one hour. After stirring for 8 h at rt the reaction was terminated by addition of an
aqueous solution of ascorbic acid (10%, 10 mL) and ethyl acetate (10 mL). The
phases were separated and the aqueous phase was washed with ethyl acetate
HCH),1.16 (d, J= 6.4 Hz, 3H,CH-CH
3
3
0
.9 (s, 9H, tBu), 0.07 (s, 3H. Si(CH
3
3
(
3x 10 mL). The combined organic extracts were washed with an aqueous
NaHCO -solution (saturated), and brine, then dried (MgSO ), filtered and
concentrated under reduced pressure.
MHz, CDCl
3
3
4
(t, C-aromat.), 127.1 (t, C-aromat.), 77.8 (t, C-2), 65.6 (t, C-1), 63.5 (t, COH),
6
0.1 (q, C-N), 48.9 (s, CH
), 18.2 (C(CH ), 14.3 (p, C-3), -4.5 (p, SiCH
Minor diastereoisomer 2h: 1H-NMR (400 MHz, CDCl
2
), 48.4 (s, CH
2
), 33.2 (p, C(CH
), -5.3 (p, SiCH
, CHCl = 7.26 ppm):=
.36-7.18 (m, 5H, aromatic H), 4.72 (d, J= 6.2 Hz, 1H, 1-H), 3.99 (m, 1H, 2-H),
.92 (m, 1H, CHOH), 1.80 (m, 1H, HCH), 1.72 (m, 1H, HCH), 1.48-1.38 (m, 2H,
), 1.15, 1.13, 1.09, 1.01 (4s, 12 H, 4x CH ),
)), -0.16 (s, 3H, Si(CH
)); 13C-NMR (100
= 77.16 ppm): = 143.4 (q, C-aromat.), 127.8 (t, C-aromat.), 127.0
t, C-aromat.), 126.9 (t, C-aromat.), 83.7 (t, C-2), 77.3 (t, C-1), 63.6 (t, COH),
3
)
2
), 25.8 (p, tBu), 21.0
(C(CH
3
)
2
3
)
2
3
3
).
(
R)-1-((2,6-Dimethylhept-5-en-1-yl)oxy)-2,2,6,6-tetramethyl-piperidin-4-ol
2d): 2d was obtained from aldehyde 1d (23.6 mg, 0.15 mmol; 1 eq.) after
3
3
(
7
3
applying the general method A of oxidative deformylation; purification by column
chromatography (petroleum ether / ethyl acetate= 3:1); yield 2d (34 mg, 0.11
mmol, 76 %) as a colorless oil.
HCH),1.16 (d, J= 6.4 Hz, 3H,CH-CH
0.9 (s, 9H, tBu), 0.07 (s, 3H. Si(CH
MHz, CDCl
3
3
1H-NMR (400 MHz, CDCl
3
3
3
, CHCl
3
= 7.26 ppm):  = 5.10 (t, J = 7.2 Hz, 1H, =CH-),
-O), 3.54 (m, 1H, CH -O), 2.04-2.00 (m,
), 1.68 (s, 3H, CH ), 1.60 (s, 3H, CH ), 1.48-
), 1.19 (s, 6H, CH ), 1.15 (s, 6H, CH ), 0.94 (d, J = 6.8 Hz, 3H,
3
3
2
1
.95 (m, 1H, CH-O), 3.64 (m, 1H, CH
H, CH ), 1.80-1.78 (m, 2H, CH
.42 (m, 4H, CH
2
2
(
2
2
3
3
2 2 3 2
59.5 (q, C-N), 49.0 (s, CH ), 48.7 (s, CH ), 34.8, 34.4 (p, C(CH ) ), 26.1 (p, tBu),
2
3
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701349
FULL PAPER
2
1.4 (C(CH
HRMS (ESI): m/z calculated for
22.3091.
3
)
2
), 18.4 (C(CH
3
)
2
), 14.7 (p, C-3), -4.4 (p, SiCH
3
), -4.7 (p, SiCH
3
);
times with ethyl acetate (3x 10 mL). The combined organic extracts were
C
24
H
44NO
3
Si [M+H]+: 422.3090, found:
2 3 4
washed with an aqueous Na CO -solution (5 %) and brine, then dried (MgSO ),
4
filtered and concentrated under reduced pressure. The crude material was
purified by column chromatography (petroleum ether/ ethyl acetate= 1:1) to yield
the title compound 9a (110 mg, 0.383 mmol; 50%).
(1S)-1-(tert.-Butyldimethylsiloxy)-2-(4-hydroxy-2,2,6,6-tetramethyl-
1H-NMR (400 MHz, CDCl
J = 6.2 Hz, 2H, CH -O); 2.30 (t, J = 7.2 Hz, 2H, CH
.82-1.78 (m, 4H, CH ), 1.68- 1.64 (m, 2H, CH ), 1.57-1.53 (m, 2H, CH
s, 6H, CH ), 1.14, (s, 6H, CH = 77.16 ppm): =
); 13C-NMR (100 MHz, CDCl
, CHCl
3
= 7.26 ppm):= 3.96 (m, 1H, CH-O), 3.73 (t,
); 2.12-2.10 (m, 2H, CH ),
), 1.18
piperidinyloxy)-1-phenylbutan (2i): 2i was obtained from the corresponding
alcohol (53.0 mg, 0.18 mmol, 1 eq.) after Dess-Martin oxidation; intermediate
aldehyde 1h was subjected to the general method B of oxidative deformylation;
purification by column chromatography (petroleum ether / ethyl acetate= 5:1 to
3
2
2
2
1
2
2
2
(
3
3
3
1
80.9. 76.5, 64.4, 59.7, 48.0, 35.9, 32.9, 28.3, 26.1, 25.8, 20.8 ppm; HRMS
3
:1); yield a mixture of diastereoisomers 2i (43 mg, 0.1 mmol, 55%, d.r.= 1.6:1)
+
(ESI): m/z calculated for C15
H
30NO
4
[M+H] : 288.2175, found: 288.2168.
as a colorless oil.
1H-NMR (400 MHz, CDCl
3
3
, CHCl = 7.26 ppm):= 7.43-7.18 (m, 5H, aromatic
6
-((4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)oxy)-4-methylhexanoic
H), 4.80 (d, J= 2.3 Hz, 1H, 1-H), 4.73 (d, J= 3.5 Hz, 1H, 1-H*), 3.91 (m, 1H, 2-
H), 3.92 (m, 1H, CHOH), 1.80 (m, 1H, HCH), 1.72 (m, 1H, HCH), 1.48-1.38 (m,
acid (9b): 4-Methylcyclohexanone 8b (22 mg, 0.197 mmol) was dissolved in
ethanol (0.6 mL) and 4-hydroxy-TEMPO (6) (67.0 mg, 0.39 mmol, 2 eq.) and
CuCl (1.3 mg, 0.013 mmol) were added at room temperature. The colour of the
2
H, HCH),1.16 (d, J= 6.4 Hz, 3H,CH-CH
CH ), 0.9 (s, 9H, tBu), 0.07 (s, 3H. Si(CH
diastereoisomer marked in *; otherwise overlap of signals); 13C-NMR (100 MHz,
CDCl = 77.16 ppm) = 142.5, 142.2 (q, C-aromat.), 128.2, 128.1, 127.8, 127.4,
27.2, 127.0, 126.8, 126.5, (t, C-aromat.), 88.0, 87.6 (t, C-2), 75.9, 74.7 (t, C-1),
3.6, 63.5 (t, C-5), 61.4, 61.0, 59.8, 59.7 (q, C-7), 49.2, 49.1, 49.0, 48.7 (t, C-6),
4.9, 34.8, 34.2, 33.9 (p, C-8), CH ), 34.8, 34.4 (p, C(CH ), 26.0, 25.9 (p, tBu),
2.4, 21.9 (s, C-3), 21.6, 21.4, 21.2, 21.0 (p, C-8), 18.3, 18.2 (q, C(CH ), 11.8,
); HRMS (ESI): m/z calculated for
3
), 1.15, 1.13, 1.09, 1.01 (4s, 12H, 4x
3
3
)), -0.16 (s, 3H, Si(CH )) (minor
3
2 2
solution turned to red. Then, H O (30%, 44.2 mg, 0.39 mmol) was added and
the mixture was stirred over night at r.t. By then, the colour of the solution had
turned to green. The reaction was terminated by addition of ethyl acetate (10
mL) and ascorbic acid (10%, 10 mL). The phases were separated and the
aqueous phase was washed three times with ethyl acetate (3x 10 mL). The
3
1
6
3
2
1
2
3 2
)
combined organic extracts were washed with an aqueous Na
5 %) and brine, then dried (MgSO ), filtered and concentrated under reduced
pressure. The crude material was purified by column chromatography
petroleum ether/ ethyl acetate= 1:1) to yield the title compound 9b (41 mg,
.136 mmol; 69%).
1H-NMR (400 MHz, CDCl
J= 6.8 Hz, 2H, CH ), 2.36-2.32 (m, 2H, CH
m, 2H, CH ), 1.59-1.57 (m, 2H, CH ), 1.56-1.57 (m, 4H, CH
.13 (s, 6H, CH ), 0.92 (d, J = 6.4 Hz, 3H, CH
); 13C-NMR (100 MHz, CDCl
2 3
CO -solution
3 2
)
(
4
1.2 (p, C-4), -4.4, -4.4, -4.8, -5.0 (p, Si(CH
)
3 2
+
C
25
H
3
45NO SiNa [M+Na] : 458.3006, found: 458.3009.
(
0
1
-(((4S)-4-((tert-Butyldimethylsilyl)oxy)-6-phenylhexan-3-yl)oxy)-2,2,6,6-
tetramethylpiperidine (2k): 2k was obtained from the corresponding alcohol
58.0 mg, 0.18 mmol, 1 eq.) after Dess-Martin oxidation; intermediate aldehyde
l was subjected to the general method A of oxidative deformylation; purification
3
, CHCl
3
= 7.26 ppm):= 3.96 (m, 1H, CH-O), 3.77 (t,
), 2.11-2.09 (m, 1H, CH), 1.81-1.78
), 1.19 (s, 6H, CH ),
2
2
(
(
2
2
2
3
1
1
7
1
3
3
3
3
=
by column chromatography (petroleum ether / ethyl acetate= 5:1 to 3:1);
7.16 ppm): = 179.6, 75.1, 64.9, 63.4, 59.9, 48.2, 35.3, 33.1, 32.5, 30.0, 21.0,
9.5 ppm; HRMS (ESI): m/z calculated for C16
02.2343.
diastereomeric mixture of 2k (37 mg, 0.08 mmol, 45%, d.r.= 1.5:1) as a colorless
+
H
32NO
4
[M+H] : 302.2331, found:
oil.
1H-NMR (400 MHz, CDCl
H), 7.21-7.15 (m, 3H, aromatic H), 3.97 (m, 1H, H-7), 3.84 (m, 1H, H-3), 2.82
m, 1H, H-1), 2.58 (m, 1H, H-1´), 2.15 (m, 1H, H-5), 1.98 (m, 1H, H-2), 1.80 (m,
3 3
, CHCl = 7.26 ppm):= 7.30-7.26 (m, 2H, aromatic
Coupling of carbinol oxidation with oxidative deformylation (see also
(
general method D)
3
H, H-2´, H-8), 1.45 (m, 2H, H-8´), 1.38-1.31 (m, 1H, H-5´), 1.25 (s, 3H, H-10),
.23 (s, 3H, H-10´), 1.12 (s, 6H, H-10´´), 0.96-0.92 (m, 12H, H-6, C(CH ), 0.08
); 13C-NMR (100 MHz, CDCl
= 77.16 ppm): = 143.1 (q, C-
1
3
)
3
Preparation of 2c from alcohol 11: A solution of 3-phenylpropan-1-ol 11 (23 mg,
(2s, 6H, Si(CH
3
)
2
3
2
0.169 mmol), PhI(OAc) (65.6 mg, 0.203 mmol) and 4-hydroxy-TEMPO (6) (3.9
aromat.), 128.5 (t, C-aromat.), 128.4 (t, C-aromat.), 125.8 (t, C-aromat.), 87.3 (t,
C-4), 74.4 (t, C-3), 63.5 (t, C-7), 61.3 (q, C-9), 59.9 (q, C-9´), 49.3 (s, C-8), 49.1
mg, 0.023 mmol) in acetonitrile (0.8 mL) was stirred for 3 h at room temperature
thereby monitoring the progress of alcohol oxidation by TLC. Then, a second
portion of 4-hydroxy-TEMPO (6) (42.4 mg, 0.246 mmol) and CuCl (1.4 mg,
(
s, C-8´), 35.0 (s, C-2), 34.8 (p, C-10), 34.4 (p, C-10), 32.7 (s, C-1), 26.2 (p,
TBS), 23.0 (s, C-5), 21.9 (p, C-10), 21.7 (p, C-10), 18.3 (q, C(CH ), 11.9 (p, C-
); HRMS (ESI): m/z calculated for
)
3 2
2 2
0.014 mmol) were added. The colour of the solution turned to red. Then, H O
6
), -3.9 (p, SiCH
3
), -4.2 (p, SiCH
3
(30%, 0.46 mmol, 52.0 mg) was added and the mixture was stirred over night
at r.t. By then, the colour of the solution had turned to green.
+
C
27
H
49NO
3
SiNa [M+Na] : 486.3379, found: 486.3373.
The reaction was terminated by addition of ethyl acetate (10 mL) and ascorbic
acid (10 mL). The phases were separated and the aqueous phase was washed
three times with ethyl acetate (3x 10 mL). The combined organic extracts were
Phenylethan-2-ol (7) from alkoxyamine 2g: To alkoxyamine 2g[8b] (120 mg,
.89 mmol) in acetic acid (15 mL, 50%) was added Zn dust (150 mg) in a
0
2 3 4
washed with an aqueous Na CO -solution (5 %), and brine, then dried (MgSO ),
microwave vial. The suspension was heated by microwave irradiation at 100°C
for 0.5 h. The reaction mixture was cooled to rt, and treated with diethyl ether.
The phases were separated, the aqueous phase was extracted with a second
portion of diethyl ether and the combined organic phases were washed with
filtered and concentrated under reduced pressure. The crude material was
purified by column chromatography (petroleum ether/ ethyl acetate= 3:1) to yield
the title compound 2c (29.5 mg, 0.106 mmol, 63 %) along with the starting
alcohol 11 (4 mg) and aldehyde 1c (5 mg).
4
brine. The organic phase was dried (MgSO ), filtered and diethyl ether was
Under the same conditions (R)-3,7-dimethyloct-6-en-1-ol (12) and (Z)-non-6-en-
removed under mild conditions to yield known phenylethan-2-ol (7) (97 mg, 0.8
1-ol (13) gave products 2d (62%) and 2e (53%), respectively.
mmol, 89%).
(
S)-1-((tert-Butyldimethylsilyl)oxy)-1-phenylpropan-2-one (14): 2h (34 mg,
6
-((4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)oxy)hexanoic acid (9a):
Cyclohexanone 8a (75 mg, 0.765 mmol) was dissolved in ethanol (2.0 mL) and
-hydroxy-TEMPO (6) (194 mg, 1.126 mmol) and CuCl (3.9 mg, 0.039 mmol)
were added at room temperature. The color of the solution turned to red. Then,
(30%, 124.7 mg, 1.1 mmol) was added and the mixture was stirred over
0
.08 mmol, 1 eq.) was dissolved in CH Cl (0.8 mL) and cooled to 0°C. Then,
2
2
mCPBA (70%, 33 mg, 0.13 mmol, 1.5 eq.) was added and the reaction mixture
4
was stirred for 2 h at 0°C. The reaction was terminated by addition of a saturated
solution of Na
2 2 3
S O and stirring was continued for additional 60 min at rt. The
2 2
H O
phases were separated and the aqueous phase was washed three times with
night at r.t. By then, the color of the solution had turned to green. The reaction
was terminated by addition of ethyl acetate (10 mL) and ascorbic acid (10%, 10
mL). The phases were separated and the aqueous phase was washed three
CH
2
Cl
2
followed by ethyl acetate. The combined organic phases were dried
4
), filtered and concentrated under reduced pressure. The crude material
(
MgSO
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701349
FULL PAPER
was purified by column chromatography (silica, petroleum ether / ethyl acetate=
42.1 (s, C-2), 37.0 (s, C-1), 31.6, 25.9 (p, tBu), 19.9 (p, C-9), 18.2 (q, C(CH
9.6 (C-10), -4.6 (p, SiCH ), -4.7 (p, SiCH ); HRMS (ESI): m/z: calculated for [M+
Na]+
SiNa 399.2334; found 399.2331.
3 2
) ),
5
:1) to yield the title compound 14 (17.6 mg, 0.07 mmol; 88%) as a yellowish oil.
3
3
1
[
] 2
D
0= -46.0 (c= 1.2, CDCl
3
); H-NMR (400 MHz, CDCl
3
, CHCl
3
= 7.26 ppm):=
),
)); 13C-NMR (100
= 77.16 ppm): = 209.2 (q, C=O), 138.8 (q, C-aromat.), 128.6 (t, C-
aromat.), 128.2 (t, C-aromat.), 126.0 (t, C-aromat.), 81.4 (t, C-OTBS), 25.9 (p,
t-Bu), 24.1 (p, -(CO)-CH ), 18.4 (q, C(CH ), -4.8 (p, SiCH ), -5.0 (p, SiCH );
HRMS (ESI): m/z: calculated for [M+ Na]+
SiNa 287.1443; found
87.1443.
22 36 3
C H O
7
.46-7.27 (m, 5H, aromatic H), 5.04 (s, 1H, CH-OTBS), 2.11 (s, 3H, (CO)CH
.95 (s, 9H, t-Bu), 0.09 (s, 3H. Si(CH )), -0.0 (s, 3H, Si(CH
3
0
3
3
MHz, CDCl
3
Acknowledgement
3
)
3 2
3
3
15 24 2
C H O
M. Y. thanks the Deutsche Akademische Austauschdienst (DAAD) and the
Russian Science Foundation (RSF-16-13-10081) for financial support.
2
(
S)-1-(tert- Butyldimethylsiloxy)-1-phenyl-2-butanone (15): 2i (143 mg, 0.34
mmol, 1 eq.) was dissolved in CH Cl (3 mL) and cooled to 0°C. Then, mCPBA
70%, 126 mg, 0.52 mmol, 1.5 eq.) was added and the reaction mixture was
stirred for 1 h at 0°C. The reaction was terminated by addition of a saturated
solution of Na and stirring was continued for additional 45 min at 0°C. The
phases were separated and the aqueous phase was washed with CH Cl . The
combined organic phases were dried (MgSO ), filtered and concentrated under
reduced pressure. The crude material was purified by column chromatography
silica, petroleum ether / ethyl acetate= 10:1) to yield the title compound 15 (83
mg, 0.3 mmol; 87%) as a colorless oil.
1H-NMR (400 MHz, CDCl
, CHCl = 7.26 ppm):= 7.43-7.25 (m, 5H, aromatic
H), 5.08 (s, 1H, CH-OTBS), 2.66 and 2.47 (m, 2H, -(CO)CH CH ), 0.95 (s, 9H,
t-Bu), 0.94 (t, J= 7.2 Hz, 3H, -(CO)CH CH ), 0.08 (s, 3H. Si(CH )), -0.01 (s, 3H,
Si(CH = 77.16 ppm): = 211.6 (q, C=O), 139.1 (q,
)); 13C-NMR (100 MHz, CDCl
C-aromat.), 128.6 (t, C-aromat.), 128.0 (t, C-aromat.), 126.0 (t, C-aromat.), 81.2
Keywords: Deformylation • Natural products • Polyketides •
Radical reactions • TEMPO
2
2
(
2
S
O
2 3
[1] Review on deformylation of bulk biomolecules see G. J. S. Dawes, E. L.
2
2
Scott, J. Le Nôtre, J. P. M. Sanders, J. H. Bitter, Green Chem. 2015, 17,
4
3
231-3250.
2] T. B. Ditri, C. E. Moore, A. L. Rheingold and J. S. Figueroa, Inorg. Chem.
011, 50, 10448-10459.
3] Z. Zong, W. Wang, X. Bai, H. Xi, Z. Li, Asian J. Org. Chem. 2015, 4, 622–
25.
[
[
[
(
2
3
3
6
2
3
4] N. Morrow, C. A. Ramsden, B. J. Sargent, C. D. Wallett, Tetrahedron, 1998,
54, 9603-9612.
2
3
3
3
3
[5] E. Watanabe, A. Kaiho, H. Kusama, N. Iwasawa, J. Am. Chem. Soc., 2013,
35, 11744–11747.
6] Reviews: a) T. Patra, S. Manna, D. Maiti, Angew. Chem. Int. Ed. Engl. 2011,
(t, C-OTBS), 29.4 (s, -(CO)CH
2
CH
3
), 25.9 (p, tBu), 18.3 (q, C(CH
3 2
) ), 7.5 (p, -
1
(CO)CH
2
CH
3
), -4.8 (p, SiCH
3
), -5.0 (p, SiCH
3
); RMS(ESI): m/z: calculated for
[
[
[
+
C
16
H
27
O
2
Si [M+H] : 279.1780, found: 279.1783.
5
0, 12140-12142; b) A. Modak, D. Maiti, Org. Biomol. Chem. 2016, 14, 21-
35.
(S)-4-((tert-Butyldimethylsilyl)oxy)-6-phenylhexan-3-one (16): 2k (148 mg,
7] a) A. Modak, S. Rana, A. K. Phukan, D. Maiti, Eur. J. Org. Chem. 2017,
168-4174; A. Modak, A. Deb, T. Patra, S. Rana, S. Maity, D. Maiti, Chem.
0
.34 mmol, 1 eq.) was dissolved in CH Cl (25 mL) and cooled to 0°C. Then,
2
2
4
mCPBA (70%, 128 mg, 0.52 mmol, 1.5 eq.) was added and the reaction mixture
Commun. 2012, 4253-4256.
was stirred for 1 h at 0°C. The reaction was terminated by addition of a saturated
8] a) A. Dichtl, M. Seyfried, K.-U. Schöning, Synlett 2008, 1877-1881; b) K.-
U. Schöning, W. Fischer, S. Hauck, A. Dichtl, M. J. Kuepfert, J. Org. Chem.
2009, 74, 1567–1573.
solution of Na
phases were separated and the aqueous phase was washed with CH
combined organic phases were dried (MgSO ), filtered and concentrated under
reduced pressure. The crude material was purified by column chromatography
silica, petroleum ether / ethyl acetate= 10:1) to yield the title compound 16 (89
2
S
O
2 3
and stirring was continued for additional 20 min at rt. The
2
Cl . The
2
4
[
9] A. Rieche, Ber. Dtsch. Chem. Ges. B 1931, 64, 2328-2335.
10] P- Dussault, Reactions of Hydroperoxides and Peroxides, In Active Oxygen
in Chemistry, Vol. 2, SEARCH Series, Chapman & Hall, London 1995,
chapter 5.
(
[
mg, 0.29 mmol; crude 85%) as a colorless oil. The ketone was directly used for
the next step.
[
11] a) Modern Aldol Reactions, R. Mahrwald (Ed.) Wiley-VCH Weinheim, 2004;
b) J. R. Gage, D. A. Evans, Org. Synth. 1989, 68, 83-91.
12] a) A. Abiko, J. F. Liu, S. Masamune, J. Am. Chem. Soc. 1997, 119, 2586-
2587; b) T. Inoue, J.-F. Liu, D. C. Buske, A. Abiko, J. Org. Chem. 2002, 67,
5250-5256.
(
3S,5R,6R)-3-((tert-Butyldimethylsilyl)oxy)-6-hydroxy-5,7-dimethyl-1-
phenyloct-7-en-4-one (17): Ketone 16 (89 mg, 0.29 mmol, 1 eq.) described
above was dissolved in CH Cl (3 mL) and cooled to 678°C. Then, TiCl (0.34
mL, 1M in CH Cl , 0.34 mmol, 1.2 eq.) was added and the reaction mixture was
[
2
2
4
2
2
stirred for 5 minutes at -78°C. Then, diisopropylethyl amine (DIPEA, 66 L, 0.40
mmol, 1.4 eq.) was added and the solution was stirred for 1.5 h at -78°C.
Methacroleine (71 mL, 0.86 mmol, 3 eq.) was added and the reaction mixture
was stirred for 12 h at -40°C. The reaction was terminated by addition of an
[13] V. Rodríguez-Cisterna, C. Villar, P. Romea, F. Urpí, J. Org. Chem. 2007,
2, 6631–6633.
7
[14] A. Kipke, master thesis 2009 and Ph. D. thesis, 2012, Leibniz Universität
Hannover
aqueous NH
were separated and the aqueous phase was washed three times with CH
The combined organic phases were dried (MgSO ), filtered and concentrated
4
Cl-solution and stirring was continued at rt for 2 h. The phases
2
Cl
2
.
[15] J. E. Babiarz, G. T. Cunkle, A. D. De Bellis, D. Eveland, S. D. Pastor, S. P.
Shum, J. Org. Chem. 2002, 67, 6831-6834.
4
under reduced pressure. The crude material was purified by column
chromatography (silica, petroleum ether / ethyl acetate= 10:1) to yield the title
compound 17 (65 mg, 0.17 mmol; 60%) as a colorless oil.
[
] 2
D
0= +10.7 (c= 1 CHCl
3
); 1H-NMR (400 MHz, CDCl
3
, CHCl = 7.26 ppm):=
3
Graphical Abstract
7
1
2
.31-7.27 (m, 2H, aromatic H), 7.22-7.17 (m, 3H, aromatic H); 5.14 and 4.97 (2s,
H, H-8), 4.34 (t, J= 0.7 Hz, 1H; H-6), 4.21 (t, J= 6.0 Hz, 1H, H-3), 3.23 (dq, J=
.4, 7.2 Hz, 1H, H-5), 2.66 (t, J= 8.2 Hz, 2H, H-1), 2.03-1.96 (m, 2H, H-2), 1.68
(
s, 3H, H-9), 1.07 (d, J= 7.1 Hz, 3H, H-10), 0.96 (s, 9H, t-Bu), 0.1 (s, 3H. Si(CH
3
)),
)); 13C-NMR (100 MHz, CDCl
.08 (s, 3H, Si(CH = 77.16 ppm): = 219.0 (q, C-
3 3
0
4
1
), 143.1 (q, C-7), 141.4 (q, aromat. H), 128.7 (t, C-aromat.), 128.5 (t, C-aromat.),
26.3 (t, C-aromat.), 112.1 (s, C-8), 78.1 (t, C-3), 77.2 (t, C-6), 73.3 (s, C-5),
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701349
FULL PAPER
Key words: aldol reaction, deformylation, oxidation, polyketides,
TEMPO
Supporting Information
The supporting information provides copies of H- and 13C-NMR
1
spectra.
Graphical abstract:
The TEMPO-mediated oxidative deformylation of aldehydes
was further developed for the preparation of chiral
backbones with 1,2-oxo functionalization found in polyketide
antibiotics.
This article is protected by copyright. All rights reserved.