Stereocontrolled oxidation of six-membered cyclic o-silyl nitroso acetals with mCPBA: Umpolung approach to functionalized nitro compounds

Article abstract of DOI:10.1002/ejoc.201101768

Easily available, six-membered cyclic nitroso acetals 2 are smoothly oxidized with meta-chloroperbenzoic acid to δ-nitro alcohols 3 or γ-nitro carbonyl compounds 4 with the retention of their relative configurations of stereocenters (diastereomeric ratio

Full text of DOI:10.1002/ejoc.201101768

FULL PAPER
DOI: 10.1002/ejoc.201101768
Stereocontrolled Oxidation of Six-Membered Cyclic O-Silyl Nitroso Acetals
with mCPBA: Umpolung Approach to Functionalized Nitro Compounds
Anastasia S. Naumova,[a,b] Andrey A. Mikhaylov,*[a,c] Marina I. Struchkova,[a]
Yulia A. Khomutova,[a] Vladimir A. Tartakovsky,[a] and Sema L. Ioffe*[a]
Keywords: Oxidation / Diastereoselectivity / Umpolung / Nitro compounds / Nitroso acetals
Easily available, six-membered cyclic nitroso acetals 2 are
smoothly oxidized with meta-chloroperbenzoic acid to δ-nitro
alcohols 3 or γ-nitro carbonyl compounds 4 with the retention
of their relative configurations of stereocenters (dia-
stereomeric ratio Ͼ 10:1). The reaction sequence – the gener-
ation of diastereomerically pure six-membered cyclic ni-
tronates 1 from simple aliphatic nitro compounds (AN), C–C
coupling of 1 with π-nucleophiles, and the oxidation of the
resulting nitroso acetals 2 – is considered to be a new effec-
tive variant of the umpolung reactivity of AN. An original
approach for the synthesis of alternative diastereomers of ni-
tro derivatives 3 has also been suggested.
amino derivatives. The latter have been used successfully in
the syntheses of a wide range of natural compounds.
The second approach consists of the silylation of 3-alkyl-
substituted 1 into 3-(α-haloalkyl)-5,6-dihydro-4H-1,2-ox-
azines with subsequent modification and reduction.[2] How-
ever, the synthetic significance of nitronates 1 is not exhaus-
ted with the strategies cited above.
Introduction
Six-membered cyclic nitronates 1, which are easily and
stereosectively formed from aliphatic nitro compounds
(AN), aldehydes, and olefins (Scheme 1), have been success-
fully applied in several total-synthesis strategies.[1,2]
Our group has recently suggested yet another possibility
to use nitronates 1.[3] It consists of the C–C coupling of 1
with π-nucleophiles (NuЈ) mediated by silyl Lewis acids,
which leads to nitroso acetals 2 by the reversible formation
of cationic intermediates A+ (Scheme 1). The overall result
could be considered to be a variant of the formal reversion
of the traditional reactivity of AN, because the key stage
includes the generation of an electrophilic center at C-3 in
nitronate 1, which is connected to the NO2 group in the
initial AN. However, the formation of nitroso acetals 2 is
accompanied by the partial reduction of the nitro group of
RCH2NO2. Therefore, the oxidation of intermediates 2 to
highly functionalized nitro compounds 3 or 4 (depending
on the nature of the substituent at C-6) with the cleavage
of the endocyclic N–O bond is required for the completion
of the AN reactivity umpolung. It should be noted that the
nucleophilic addition to nitronate 1 usually proceeds with
high diastereoselectivity[3] to give rise to nitroso acetals 2
with up to four asymmetric centers on ring carbon atoms.
These centers could be retained in the resulting nitro com-
pounds 3 or 4. Furthermore, several approaches for the
preparation of enantiomerically pure nitronates 1 have been
suggested recently,[1,4] which provide the possibility for the
enantioselective synthesis of 3 or 4 based on the strategy
shown in Scheme 1.
Scheme 1. Electrophilic activity of nitronates 1.
Of special note is the tandem [4+2]/[3+2] cycload-
dition.[1] This process provides access to bicyclic nitroso
acetals, which can be reduced to various functionalized
[a] N. D. Zelinsky Institute of Organic Chemistry, Russian Acad-
emy of Sciences,
Leninsky prosp. 47, 119991, Moscow, Russian Federation
Fax: +7-499-1355328
E-mail: iof@ioc.ac.ru
[b] Moscow Chemical Lyceum,
Tamozheniy proezd 4, 111033 Moscow, Russian Federation
[c] Higher Chemical College of the Russian Academy of Sciences,
Miusskaya sq. 9, 125047 Moscow, Russian Federation
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101768.
At present, 3 and 4 are practically unknown. The prod-
ucts 3, which have a secondary alcohol fragment, can be
Eur. J. Org. Chem. 2012, 2219–2224
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A. A. Mikhaylov, S. L. Ioffe et al.
FULL PAPER
obtained by the selective reduction of the carbonyl group Table 1. Oxidation of 2a.
of respective compounds 4. An alternative approach for the
synthesis of 3 with tertiary OH groups can be hardly imag-
ined. In turn, products 4 can be prepared by the Michael
addition of either enolate anions to conjugated nitro ole-
fines[5] or nitronate anions to α,β-unsaturated carbonyl
compounds.[6] However, in spite of the significant progress
recently achieved in this area (e.g. organocatalysis),[7] the
formation of secondary or tertiary nitro compounds with
designated configurations of the stereocenters attached to
the nitro group still remains a complicated problem.[8] The
development of new approaches for the diastereoselective
synthesis of 3 or 4 is an urgent challenge.
Considering the above, the strategy presented in
Scheme 1 could be used in the diastereo- or enantioselective
synthesis of δ-functionalized nitro compounds 3 and 4 from
primary AN and other simple precursors.
Entry Solvent, temperature
t
[h]
Additive
Yield of dr[a]
3a + 3aЈ
[%]
1
2
3
4
5
6
7
CH2Cl2, room temp.
CH2Cl2, room temp.
CH2Cl2, room temp.
CH2Cl2, reflux
CHCl3, reflux
CH3CN, room temp.
CH3CN, reflux
12
12
12
2.5
2.5
12
2
–
76[b]
65[b]
92[c]
85[c]
64[c]
74[b]
82[b]
10:1
6:1
10:1
9:1
9:1
10:1
8:1
K2CO3 (1.5 equiv.)
AcOH (2 equiv.)
–
–
–
NH4F (1.1 equiv.)
[a] Determined by integration of 1H NMR spectra. [b] Determined
1
by H NMR spectroscopy with ClCH=CCl2 as a standard. [c] Iso-
lated yield.
Nitroso acetals can be considered as equivalents of their
respective nitroso compounds.[9] Although the oxidation of
nitroso compounds is well investigated,[10] data on the oxi-
dation of nitroso acetals is scarce. The oxidation of MeO2-
alcohol 3a should be the syn diastereomer. A decrease in the
diastereomeric ratio (dr) in 3a in some experiments could be
connected with the epimerization of the stereocenter at the
NO2 group by a known tautomeric process.[13] Increase of
the temperature or addition of basic reagents significantly
reduced the dr in 3a, which is in good agreement with the
foregoing interpretation. At the same time, the addition of
CCMe2N(OMe)2
with
meta-chloroperbenzoic
acid
(mCPBA) is the only successful example.[11,12]
Results and Discussion
The possibility of the selective oxidation of a nitroso acetic acid almost did not change the dr in 3a (Table 1, En-
acetal fragment was investigated with model compound 2a. tries 1 and 3).
After a series of unsuccessful attempts with various oxidiz-
Optimal reaction conditions for the reaction of 2a
ers [Pb(OAc)4, DDQ, (Me3SiO)2/Me3SiOTf, PhIF2] we oxi- (Table 1, Entry 3), were successfully applied to a series of
dized 2a with mCPBA according to a literature pro- six-membered cyclic nitroso acetals 2. mCPBA oxidized
cedure[11] (Table 1).
most of the tested substrates 2 (Table 2).
The oxidation of 2a to 3a proceeds smoothly with rather
Modification of the substituent at C-6 of 2 resulted in
high diastereoselectivity (Table 1). It is supposed that this different classes of products: δ-nitro alcohols 3 were ob-
process does not change the relative configuration of the tained after the oxidation of 2 if the initial compounds did
stereocenters in 2a. Therefore, the dominant isomer of nitro not contain an alkoxy group at C-6, otherwise γ-nitro carb-
Table 2. Oxidation of 2a–i.
Entry
2
R2/Nu[a]
R1
R2
R3
H
R4
R5
Nu
Product
Yield [%]
dr[b]
1
2
3
a
cis
cis
cis
cis
cis
cis
cis
cis
trans
trans
H
H
Me
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
An
An
An
Me
Me
H
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2C(O)Ph
CH2C(CH3)=CH2
CN
3a (syn)
3b (syn)
3c (syn)
3d (syn)
3e
92
88
86
87
10:1
12:1
b
–(CH2)4–
c
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
Ͼ 20:1
10:1
4
d
[d]
5
e
0[c]
Ͻ 15/61[f,g]
86
–
6[e]
7
f
Me
3f/5
3.0:1
Ͼ 20:1
1.4:1
g
OMe
OEt
H
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CO2Me
4a (syn)
4b/4bЈ (syn/anti)
8[h]
h/hЈ ≈ 1.5:1
95
OEt
H
9
i
OEt
4bЈ (anti)
84
11:1
1
[a] Relative configuration of R2 and Nu. [b] By integration of H NMR spectra. [c] Inseparable mixture of unidentified products. [d] Not
determined. [e] 3.0 equiv. of mCPBA, 2.0 equiv. of AcOH, and 48 h were used instead of the standard conditions. [f] By integration of
the 1H NMR spectra of the crude product. [g] γ-Hydroxyoxime 5 [(E)/(Z) ≈ 1:1] was the main product. [h] Used as a mixture of
stereoisomers.
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Stereocontrolled Oxidation of Cyclic O-Silyl Nitroso Acetals with mCPBA
onyl compounds 4 were formed after protolysis of the acetal phile with a cationic intermediate generated from a cyclic
center at C-6 when R4/5 was an alkoxy group.
nitronate (cf. B+ in Scheme 2 and A+ in Scheme 1). The
The oxidation proceeded with high diastereoselectivity oxidation of 2aЈ to the target anti isomer 3aЈ proceeded
with almost all substrates (the drs vary from 10:1 to Ͼ20:1). smoothly with high diastereoselectivity, although it was ac-
However, the distillation of 3 or 4 led to a significant epi- companied by the formation of some nitronate
merization of the target products (e.g.: 3a: b.p. 150–170 °C/ (Scheme 2).
6
0.08 Torr, dr decreased from 10:1 to 3.5:1 after distillation;
4a: b.p. 158–162 °C/0.112 Torr, dr decreased from Ͼ20:1 to in Scheme 3. This is in good agreement with our experimen-
3.2:1).
tal data as well as that obtained by Rudchenko at al.[11] The
A possible mechanism for the oxidation of 2 is presented
Several structural restrictions that prevent the oxidation formation of 5 during the oxidation of 2f and the blue color
of 2 were found. In particular, the oxidation failed for 2e, of most of the oxidation experiments indicate the intermedi-
which contains a C=C bond (Table 2, Entry 5). The nucleo- acy of the respective nitroso compounds C, which can be
philic C=C bond in 2 is probably oxidized more easily than formally obtained by the protonation of the endocyclic oxy-
the nitroso acetal fragment.
gen atom of 2 in acidic media with subsequent N–O bond
In addition, the oxidation was hindered by the influence cleavage and elimination of the trialkylsilyl moiety [path-
of an electron-withdrawing group at C-3 of 2. The conver- way (a)]. The oxidation of intermediates C leads to the tar-
sion of 2f (Nu = CN, Table 2, Entry 6) was less than 20% get compounds 3 or 4. Another possibility is associated
under the standard conditions. The use of 3 equiv. of oxid- with the protonation of the exocyclic oxygen atom of 2
izer and a prolonged reaction time of 3 d led to the full [pathway (b)] with subsequent elimination of silanol and the
conversion of 2f, but 3f was obtained in low yield (Ͻ15% formation of nitrenium cation D.[18] The oxidation of 2
according to NMR spectroscopy). Its isolation from the re- most likely occurs through pathway (a).[19,20] The only evi-
action mixture was complicated, because the reaction gave dence for the contribution of pathway (b) is the generation
α-oximino cyanide 5 as the main product (yield 61%). The of 6 during the oxidation of 2aЈ. The presence of an elec-
change of mCPBA to the more powerful CF3CO3H (gener- tron-withdrawing group (R = CN) at C-3 leads to a de-
ated from urea·H2O2 and trifluoroacetic anhydride)[14] did crease of the rate of oxidation, and isomerization of nitroso
not increase the yield of 3f.
intermediate C to oxime 5 occurs as a result to give 5 as
By this means, the oxidation of nitroso acetals 2 with cis- the main product (Table 2, Entry 6).
configured R2 and Nu can be considered as a convenient
approach for the controlled synthesis of the syn isomers of
nitro compounds 3 and 4. On the other hand, one cannot
obtain the anti isomers of these nitro derivatives with this
procedure. These isomers can be prepared from available
nitronates 1 only as minor components of the resulting mix-
tures.[15] The exception is the oxidation of 2i with trans-
configured R2 and Nu when the anti isomer 4bЈ was ob-
tained as the major product (Table 2, Entry 9).
Scheme 3. Possible mechanism for the oxidation of 2.
For the directed synthesis of anti isomers 3Ј, a modifica-
The stereoselectivity of the oxidation of 2 is probably
limited by epimerization of the stereocenter ϾCH(NO2) in
the targets 3 or 4, rather than epimerization in the respec-
tive intermediates C. The latter epimerization would have
led to irreversible isomerization to the respective oximes
(similar to 5), which would have been transformed too
slowly into the corresponding AN under the oxidation con-
ditions.
tion of the method that proceeds via nitroso acetals 2Ј with
trans-configured R2 and Nu was developed. This was ac-
complished through the successful synthesis of alcohol 3aЈ
(Scheme 2). For the preparation of 2aЈ, nitronate 6, ob-
tained according to a standard method,[16] was reduced
with Bu3SnH by the stereoselective addition of a hydride
ion to the cationic intermediate B+.[17] The transformation
of 6 to 2aЈ is the first example of the coupling of a σ-nucleo-
The results of this investigation allow one to consider
easily available, six-membered cyclic nitronates 1 as the
chemical equivalents E of functionalized AN with the in-
verted reactivity of the α-carbocation (Scheme 4). This for-
mal umpolung was realized by a two-step procedure [cou-
pling of 1 with silyl enolate (NuЈ) and oxidation of the re-
Scheme 2. Synthesis of 3aЈ. i: TBSOTf, Bu3SnH, CH2Cl2, –78 °C,
72 h, ii: mCPBA, AcOH (2.0 equiv.), CH2Cl2, room temp., 12 h.
Scheme 4. Retrosynthesis of 3 and 4.
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A. A. Mikhaylov, S. L. Ioffe et al.
FULL PAPER
tion mixture was poured into a mixture of Et2O (20 mL)/saturated
aqueous NaHCO3 solution (15 mL) with Na2SO3 (0.3 g). The or-
ganic layer was separated, and the aqueous layer was extracted with
Et2O (2ϫ 7 mL). The combined organic layers were washed suc-
cessively with H2O (15 mL) and brine (15 mL) and dried with
Na2SO4. The solvents were evaporated in vacuo, and the residue
was subjected to column chromatography on silica gel (eluent
EtOAc/hexane, 1:5 Ǟ 1:2) to give pure 3 or 4 (67–95% yield) as a
colorless oil.
sulting nitroso acetal 2] and led to functionalized nitro com-
pounds 3 and 4 with dominantly syn configuration. This
strategy can be considered as new approach to function-
alized nitro-Michael adducts 4. Compounds 3 and 4 are
perspective precursors of amino derivatives,[21,13] and they
can be subjected to other typical AN chemistry transforma-
tions.[21]
Methyl rel-(3S,4R)-6-Hydroxy-6-methyl-3-nitro-4-phenylheptanoate
(3a): Yield: 271 mg (92%). Colorless oil. TLC: Rf = 0.36 (silica gel;
Conclusions
hexane/EtOAc, 1:1; anisaldehyde). IR (CCl film): ν = 3430 (br. w,
˜
A new method for the mild oxidation of six-membered
cyclic nitroso acetals 2 with mCPBA to functionalized nitro
compounds 3 or 4 was developed. The reaction proceeds
with high retention of the configuration of the stereocenter
on C-3 (dr Ͼ 10:1). An extension of this approach to the
other types of nitroso acetals is our task in the near future.
4
νOH), 1739 (s, νC=O), 1552 (vs, νasNO2), 1375 (s, νsNO2) cm–1.
1H NMR (300 K, CDCl3): δ = 1.05 and 1.19 [2 s, 6 H, CH3(1) and
3
2
CH3(2)], 1.75 [br. s, 1 H, OH], 1.98 [dd, J = 3.3, J = 14.3 Hz, 1
H, CHA(4)], 2.14 [dd, J = 8.8, 2J = 14.3 Hz, 1 H, CHB(4)], 2.73
3
3
2
3
2
[dd, J = 3.7, J = 17.6 Hz, 1 H, CHA(7)], 3.09 [dd, J = 10.3, J
= 17.6 Hz, 1 H, CHB(7)], 3.56 [ddd, 3J = 3.3, 3J = 8.8, 3J = 10.3 Hz,
1 H, CH(5)], 3.67 [s, 3 H, CH3(9)], 5.16 [ddd, 3J = 3.7, J = 4.8, J
3
3
3
= 10.3 Hz, 1 H, CH(6)], 7.22 [d, J = 7.7 Hz, 2 H, CH(11)], 7.31–
7.38 [m, 3 H, CH(12) and CH(13)] ppm. 13C NMR (300 K,
CDCl3): δ = 29.3 and 30.1 (C-1 and C-2), 34.4 (C-7), 43.0 (C-4),
44.9 (C-5), 52.3 (C-9), 70.7 (C-3), 88.1 (C-6), 128.1 (C-13), 128.6
and 129.1 (C-11 and C-12), 138.9 (C-10), 170.0 (C-8) ppm. HRMS
(ESI): calcd. for C15H21NO5Na [M + Na]+ 318.1312; found
318.1308.
Experimental Section
General Methods: All reactions, except mCPBA oxidation, were
performed in oven-dried (150 °C) glassware under argon. NMR
spectra were recorded with a Bruker AM-300 (1H: 300.13 MHz;
13C: 75.47 MHz) and referenced to residual solvent peaks. Chemi-
cal shifts (δ) are reported in ppm; multiplicities are indicated by s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br.
(broad). The ratios of stereoisomers were derived from the relative
integral intensities of the characteristic signals in the 1H NMR
spectra. Coupling constants (J) are reported in Hertz. Key NOESY
correlations are shown with arrows in Figure 1. IR spectra were
recorded with a Bruker VEKTOR-22 from 400 to 4000 cm–1 (reso-
lution 2 cm–1) as a thin layer. Melting points were determined with
a Kofler melting-point apparatus. Elemental analyses were per-
formed at the Analytical Laboratory of the N. D. Zelinsky Institute
of Organic Chemistry. HRMS data were recorded with a Bruker
MicroTOFF spectrometer.
Methyl rel-(3S,4R)-4-[(1S,2S)-2-Hydroxycyclohexyl]-3-nitro-4-phen-
ylbutanoate (3b): Yield: 281 mg (88%). White crystals, m.p. 126 °C
(hexane/EtOAc, 5:1); TLC: Rf = 0.48 (hexane/EtOAc, 1:1; anisal-
dehyde). IR (CCl film): ν = 3500 (br. w, νOH), 1738 (s, νC=O),
˜
4
1552 (vs, νasNO2), 1373 (s, νsNO2) cm–1. 1H NMR (300 K, CDCl3):
δ = 1.11–1.40 and 1.44–1.70 [2 m, 3 + 4 H CH2(5), CH2(4), CH2(3)
and CHA(2)], 1.76–1.88 [m, 1 H, CHB(2)], 1.88–2.07 [m, 2 H,
3
2
CH(6), OH], 2.63 [dd, J = 1.4, J = 17.4 Hz, 1 H, CHACHB(9)],
3
2
3.04 [dd, J = 11.9, J = 17.4 Hz, 1 H, CHACHB(9)], 3.68 [s, 3 H,
CH3(11)], 3.70 [dd, J ≈ J = 2.6 Hz, 1 H, CH(7)], 4.07 [br. s, 1 H,
CH(1)], 5.52 [ddd, J = 1.4, J = 5.0, J = 11.9 Hz, 1 H, CH(8)],
3
3
3
3
3
4
3
7.06 [dd, J = 1.8, J = 7.1 Hz, 2 H, 2ϫ CH(13)], 7.23–7.36 [m, 3
H, 2ϫ CH(14) and CH(15)] ppm. 13C NMR (300 K, CDCl3,
INEPT): δ = 19.8, 25.2, 25.6 and 34.0 (C-2, C-3, C-4 and C-5),
32.6 (C-9), 42.3 (C-7), 50.4 (C-6), 52.3 (C-11), 66.7 (C-1), 84.3 (C-
8), 128.0 (C-13 or C-14), 129.0 (C-13 or C-14 and C-15), 136.2 (C-
12), 170.5 (C-10) ppm. C17H24NO5 (322.38): calcd. C 63.54, H 7.21,
N 4.36; found C 63.18, H 6.92, N 4.12.
Methyl rel-(3S,4R)-6-Hydroxy-3,6-dimethyl-3-nitro-4-phenylhept-
anoate (3c): Yield: 266 mg (86%). Colorless oil. TLC: Rf = 0.35
Figure 1. Key NOESY interactions in compounds 3b and 2aЈ.
(hexane/EtOAc, 1:1; anisaldehyde). IR (CCl4 film): ν = 3445 (br.
˜
Analytical TLC was performed with silica gel plates with QF-254
indicator. Visualization was accomplished with UV light and/or an-
isaldehyde/H2SO4. Preparative liquid chromatography was per-
formed on columns with Merck silica (Kieselgel 60, 230–400 mesh).
All solvents for chromatography and extractions were technical
grade and distilled prior to use. The following solvents and reagents
were distilled from the indicated drying agents: CH2Cl2, CHCl3,
Et3N (CaH2); (CF3CO)2O, Ac2O (P2O5); Et2O (Na, benzophenone
ketyl). Commercial reagents: mCPBA (Aldrich), AcOH (Reakhim),
PhCHO (Acros), 1,8-diazabicyclo[5.4.0]undec-7-ene (Acros), 4-(di-
methylamino)pyridine (Aldrich), SnCl4 (Acros), isobutylene (Ald-
rich), Bu3SnH (Merck), 2,6-lutidine (Aldrich), tert-butyldimethyl-
silyl cyanide (TBSCN) (Aldrich).
w, νOH), 1743 (s, νC=O), 1544 (vs, νasNO2), 1363 (s, νsNO2) cm–1.
1H NMR (300 K, CDCl3): δ = 0.96 and 1.11 [2 s, 6 H, CH3(1) and
3
CH3(2)], 1.46 [br. s, 1 H, OH], 1.70 [s, 3 H, CH3(10)], 1.83 [dd, J
≈ 1.0, 2J = 14.2 Hz, 1 H, CHA(4)], 2.10 [dd, 3J = 10.1, 3J = 14.2 Hz,
1 H, CHB(4)], 2.73 [d, 3J = 16.5 Hz, 1 H, CHA(7)], 3.34 [d, 3J =
16.5 Hz, 1 H, CHB(7)], 3.48 [dd, 3J ≈ 1.0 Hz, 3J = 10.1 Hz, 1 H,
CH(5)], 3.68 [s, 3 H, CH3(9)], 7.19–7.37 [m, 5 H, 2ϫ CH(12), 2ϫ
CH(13) and CH(14)] ppm. 13C NMR (300 K, CDCl3): δ = 21.3 (C-
10), 29.5 and 30.6 (C-1 and C-2), 40.3 and 42.8 (C-4 and C-7), 51.1
(C-5), 52.0 (C-9), 70.7 (C-3), 92.4 (C-6), 128.1 (C-14), 128.8 and
129.8 (C-12 and C-13), 138.7 (C-11), 169.8 (C-8) ppm. HRMS
(ESI): calcd. for C16H24NO5 [M + H]+ 310.1652; found 310.1649.
General Procedure: AcOH (114 μL, 120 mg, 2.0 mmol) was added
to a solution of 2 (1.00 mmol) and 70% mCPBA (271 mg,
1.1 mmol) in CH2Cl2 (3 mL). After 12 h at room temp., the reac-
rel-(3S,4R)-6-Hydroxy-6-methyl-3-nitro-1,4-diphenylheptan-1-one
(3d): Yield: 298 mg (87%). White crystals, m.p. 111–112 °C (pent-
ane); TLC: Rf = 0.36 (hexane/EtOAc, 1:1; anisaldehyde). IR
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Stereocontrolled Oxidation of Cyclic O-Silyl Nitroso Acetals with mCPBA
(CHCl3 film): ν = 3470 (br. w, νOH), 1685 (s, νC=O), 1550 (vs,
1.12 mmol) was added. After 3 d at –78 °C, the reaction mixture
νasNO2), 1369 (s, νsNO2) cm–1. 1H NMR (300 K, CDCl3): δ = 1.09 was poured into a mixture of hexane (15 mL) and saturated aque-
and 1.22 [2 s, 6 H, CH3(1) and CH3(2)], 2.07 [dd, 3J = 3.7, 2J =
ous NaHCO3 solution (15 mL). The organic layer was separated,
14.7 Hz, 1 H, CHA(4)], 2.16 [br. s, 1 H, OH], 2.22 [dd, J = 8.8, J and the aqueous layer was extracted with hexane (2ϫ 7 mL). The
˜
3
2
= 14.7 Hz, 1 H, CHB(4)], 3.24 [dd, 3J = 2.9, 2J = 18.3 Hz, 1 H,
CHA(7)], 3.66 [ddd, J = 3.7, J = 4.8, J = 8.8 Hz, 1 H, CH(5)],
combined organic layers were washed successively with H2O
(15 mL) and brine (15 mL), shaken with activated charcoal, and
dried with Na2SO4. The solvents were evaporated in vacuo. The
residue was subjected to column chromatography on silica (eluent
EtOAc/hexane, 1:20 Ǟ 1:10) to give pure 2aЈ (370 mg, 85%, single
isomer) as a colorless oil. Rf = 0.78 (hexane/EtOAc, 1:1; anisal-
dehyde). 1H NMR (300 K, CDCl3): δ = 0.18 and 0.23 [2 s, 6 H,
CH3(14) and CH3(15)], 0.93 [s, 9 H, CH3(17)], 1.34 and 1.47 [2 s,
3
3
3
2
3
3.84 [dd, 3J = 9.5, J = 18.3 Hz, CHB(7)], 5.44 [ddd, 3J = 2.9, J =
3
4.8, J = 9.5 Hz, CH(6)], 7.24–7.40 [m, 5 H, CH(14), CH(15) and
3
3
CH(16)], 7.47 [t, J = 7.3 Hz, 2 H, CH(11)], 7.60 [t, J = 7.3 Hz, 1
H, CH(12)], 7.92 [d, 3J = 7.3 Hz, 2 H, CH(10)] ppm. 13C NMR
(300 K, CDCl3): δ = 29.2 and 31.0 (C-1 and C-2), 38.4 (C-7), 43.4
(C-4), 45.0 (C-5), 70.9 (C-3), 87.5 (C-6), 128.2, 128.7, 128.8, 129.1
(C-10, C-11, C-14, and C15), 128.1 (C-16), 133.9 (C-12), 136.0 (C- 6 H, CH3(2) and CH3(3)], 1.65 [dd, 3J = 4.6, 2J = 13.3 Hz, 1 H,
13), 139.2 (C-9), 195.5 (C-8) ppm. HRMS (ESI): calcd. for
CH2eq(4)], 1.76 [dd, 3J ≈ 2J = 12.8 Hz, 1 H, CH2ax(4)], 2.18–2.38
C20H22NO4 [M +H]+ 340.1543; found 340.1541.
[m, 2 H, CH2(7)], 3.14 [ddd, 3J = 4.6, 3J ≈ 3J = 11.9 Hz, 1 H,
3
3
3
CH(5)], 3.51 [s, 3 H, CH3(9)], 3.65 [ddd, J = 3.7, J = 6.0, J =
10.1 Hz, 1 H, CH(6)], 7.21–7.35 [m, 5 H, CH(11), CH(12) and
CH(13)] ppm. 13C NMR (300 K, CDCl3, JMOD): δ = –4.7 and
–4.0 (C-14 and C-15), 17.6 (C-16), 23.4 and 29.4 (C-2 and C-3),
26.1 (C-17), 35.3 (C-4), 44.1 (C-5), 45.2 (C-7), 51.3 (C-9), 70.7 (C-
6), 76.7 (C-1), 127.0 (C-13), 128.2 and 128.8 (C-11 and C-12), 141.8
(C-10), 171.7 (C-8) ppm. C21H35NO4Si (393.60): calcd. C 64.08, H
8.96, N 3.56; found C 63.85, H 9.08, N 3.32.
Methyl rel-(3S,4R)-3-Nitro-6-oxo-4-phenylheptanoate (4a): Yield:
244 mg (87%). Colorless oil. TLC: Rf = 0.51 (silica gel; hexane/
EtOAc, 1:1; anisaldehyde). IR (CCl4 film): ν = 1739 (vs, νC=O),
˜
1720 (vs, νC=O), 1552 (vs, νasNO2), 1375 (s, νsNO2) cm–1. 1H
NMR (300 K, CDCl3): δ = 2.19 [s, 3 H, CH3(1)], 2.64 [dd, 3J =
2
3
2
3.3, J = 17.6 Hz, 1 H CHA(6)], 2.91 [dd, J = 6.2, J = 18.0 Hz, 1
3
2
H, CHA(3)], 3.00 [dd, J = 10.6, J = 17.6 Hz, 1 H, CHB(6)], 3.23
[dd, 3J = 7.7, 2J = 18.0 Hz, 1 H, CHB(3)], 3.67 [s, 3 H, CH3(8)],
3.75 [ddd, J = 4.8, J ≈ 3 HzJ = 6.5, 1 H, CH(4)], 5.21 [ddd, J ≈
3J = 3.3, 3J = 11.0 Hz, 1 H, CH(5)], 7.10 [d, 3J = 7.1 Hz, 2 H,
CH(10)], 7.28–7.36 [m, 3 H, CH(11) and CH(12)] ppm. 13C NMR
(300 K, CDCl3, JMOD): δ = 30.4 (C-1), 34.0 (C-6), 42.8 (C-4), 44.4
(C-3), 52.0 (C-8), 84.8 (C-5), 127.9 and 128.7 (C-10 and C-11),
128.1 (C-12), 139.4 (C-9), 169.4 (C-7), 205.4 (C-2) ppm. HRMS
(ESI): calcd. for C14H17NO5Na [M + Na]+ 302.0994; found
302.0999.
3
3
3
Methyl rel-(3R,4R)-6-Hydroxy-6-methyl-3-nitro-4-phenylheptanoate
(3aЈ): Compound 3aЈ was obtained according to the general pro-
cedure from 2aЈ in 67% yield (dr Ͼ 20:1, the only isomer according
1
to H NMR spectroscopy). Nitronate 6 was obtained as a byprod-
uct in 12% yield. The IR spectrum and Rf are similar to those of
1
3a. H NMR (300 K, CDCl3): δ = 1.08 and 1.13 [2 s, 6 H, CH3(1)
and CH3(2)], 1.75 [br. s, 1 H, OH], 1.86 [dd, 3J = 4.0, 2J = 14.3 Hz,
3
2
1 H, CHA(4)], 2.08 [dd, J = 8.0, J = 14.3 Hz, 1 H, CHB(4)], 2.49
3
2
3
2
[dd, J = 2.9, J = 17.6 Hz, 1 H, CHA(7)], 2.93 [dd, J = 10.2, J
= 17.6 Hz, 1 H, CHB(7)], 3.58 [m, 1 H, CH(5)], 3.59 [s, 3 H,
CH3(9)], 5.19 [m, 1 H, CH(6)], 7.12–7.37 [m, 5 H, CH(11), CH(12)
and CH(13)] ppm. 13C NMR (300 K, CDCl3): δ = 28.9 and 30.7
(C-1 and C-2), 34.8 (C-7), 44.7 (C-4), 45.2 (C-5), 52.1 (C-9), 70.6
(C-3), 88.1 (C-6), 128.0 (C-13), 128.9 and 129.1 (C-11 and C-12),
138.8 (C-10), 170.1 (C-8) ppm.
Methyl
rel-(3S,4R)-4-(4-Methoxyphenyl)-3-nitro-6-oxohexanoate
(4b) and Methyl rel-(3R,4R)-4-(4-Methoxyphenyl)-3-nitro-6-oxohex-
anoate (4bЈ): Colorless oil. TLC: Rf = 0.37 (silica gel; hexane/
EtOAc, 1:1; anisaldehyde). IR (CCl4 film of the mixture of dia-
stereomers): ν = 1734 (br. vs, νC=O), 1554 (vs, ν NO ), 1377 (s,
˜
as
2
νsNO2) cm–1. 4b: 1H NMR (300 K, CDCl3): δ = 2.64 [dd, J = 3.3,
3
2J = 17.6 Hz, 1 H,CHA(5)], 2.92–3.09 [m, 2 H, CHA(2) and
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the synthesis of the starting com-
pounds, selected spectroscopic data for minor isomers, atom label-
ing (for interpretation of spectra) and NMR spectra for new com-
pounds.
3
2
CHB(5)], 3.16 [dd, J = 6.6, J = 18.3 Hz, 1 H, CH(2)], 3.68 [s, 3
H, CH3(12)], 3,73–3.85 [s and m, 4 H, CH3(7) and CH(3)], 5.17
[ddd, 3J ≈ 3J = 4.0, 3J = 10.3 Hz, 1 H, CH(4)], 6.89 [d, 3J = 8.4 Hz,
2 H, CH(9)], 7.04 [d, 3J = 8.4 Hz, 2 H, CH(10)], 9.72 [s, 1 H, CH(1)]
ppm. 13C NMR (300 K, CDCl3): δ = 34.9 (C-5), 41.4 (C-3), 45.0
(C-2), 52.4 (C-7), 55.4 (C-12), 85.8 (C-4), 114.6 (C-10), 128.1 (C-
8), 129.3 (C-9), 159.7 (C-11), 169.7 (C-6), 199.0 (C-1) ppm. 4bЈ: 1H
NMR (300 K, CDCl3): δ = 2.48 [dd, J = 3.3, J = 17.6 Hz, 1 H,
CHA(5)], 2.82 [dd, J = 4.8, J = 17.6 Hz, 1 H, CHB(5)], 2.92–3.09
[m, 1 H, CHA(2)], 3.16 [dd, J = 6.6, J = 18.3 Hz, 1 H, CHB(2)],
3.62 [s, 3 H, CH3(12)], 3,73–3.85 [s and m, 4 H, CH3(7) and CH(3)],
Acknowledgments
3
2
3
2
This work was supported by grants from the Council of the Presi-
dent of the Russian Federation for Young Scientists and Leading
Scientific Schools (NSh-64800.2010.3 and NSh-412.2012.3) and the
Russian Foundation for Basic Research (Project 12-03-00278a). We
are thankful to Dr. A. D. Dilman for helpful discussions.
3
2
3
3
3
3
5.08 [ddd, J = 2.9, J ≈ J = 10.3 Hz, 1 H, CH(4)], 6.86 [d, J =
8.4 Hz, 2 H, CH(9)], 7.13 [d, J = 8.4 Hz, 2 H, CH(10)], 9.57 [s, 1
3
H, CH(1)] ppm. 13C NMR (300 K, CDCl3): δ = 35.7 (C-5), 42.4
(C-3), 46.4 (C-2), 52.3 (C-7), 55.4 (C-12), 87.3 (C-4), 114.9 (C-10),
128.9 (C-8), 129.3 (C-9), 159.7 (C-11), 169.7 (C-6), 198.3 (C-1)
ppm. HRMS (ESI): mixture of isomers; calcd. for C14H17NO6Na
[M + Na]+ 318.0948; found 318.0948.
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Synthesis of anti Isomer 3aЈ: Methyl {rel-(3R,4R)-2-[(tert-butyldi-
methylsilyl)oxy]-6,6-dimethyl-4-phenyl-1,2-oxazinan-3-yl}acetate (2aЈ):
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Eur. J. Org. Chem. 2012, 2219–2224
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2223

A. A. Mikhaylov, S. L. Ioffe et al.
FULL PAPER
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[6]
[7]
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[19] Reversible proton migration between two oxygen atoms in 2
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bond lengths are 1.422 Å for the endo- and 1.446 Å for the
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(TBAF) into the corresponding nitro compounds with average
Received: December 8, 2011
Published Online: February 22, 2012
2224
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2219–2224