Three-step assembly of 4-aminotetrahydropyran-2-ones from isoxazoline-2-oxides

Article abstract of DOI:10.1039/c3ra47309k

Tetrahydropyran-2-ones with a 4-amino function connected to a tertiary carbon atom-a widely naturally occurring fragment-are constructed by a three step protocol from easily available isoxazoline 2-oxides. In the first stage, the carbon skeleton of the target product is formed upon a C,C-coupling of a silyl ketene acetal with a nitronate function, under silyl triflate catalysis. The key step of the assembly consists of the oxidative cleavage of an endocyclic N-O bond of intermediate cyclic nitroso acetals with mCPBA, accompanied with lactone ring closure, and gives rise to β-nitro-δ-lactones in 63-85% yields. The latter are reduced with amalgamated aluminium, to furnish the target scaffold.

Full text of DOI:10.1039/c3ra47309k

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Three-step assembly of 4-aminotetrahydropyran-
2-ones from isoxazoline-2-oxides†
Cite this: RSC Adv., 2014, 4, 12467
A. S. Naumova,ab A. A. Mikhaylov, a Yu. A. Khomutova,a R. A. Novikov,a D. E. Arkhipov,c
*
c
a
*
A. A. Korlyukov and S. L. Ioffe
Tetrahydropyran-2-ones with a 4-amino function connected to a tertiary carbon atom – a widely naturally
occurring fragment – are constructed by a three step protocol from easily available isoxazoline 2-oxides. In
the first stage, the carbon skeleton of the target product is formed upon a C,C-coupling of a silyl ketene
acetal with a nitronate function, under silyl triflate catalysis. The key step of the assembly consists of the
oxidative cleavage of an endocyclic N–O bond of intermediate cyclic nitroso acetals with mCPBA,
accompanied with lactone ring closure, and gives rise to b-nitro-d-lactones in 63–85% yields. The latter
are reduced with amalgamated aluminium, to furnish the target scaffold.
Received 4th December 2013
Accepted 7th January 2014
DOI: 10.1039/c3ra47309k
www.rsc.org/advances
A common retrosynthetic analysis for the b-amino acid
moiety in lactones 1 employs a Mannich-type disconnection
Introduction
with the g-imino alcohol cations A as key precursors for the
generation of amines 1 (Scheme 1). However, this type of
reaction is not generally applied, due to the complexity of the
Mannich reaction with ketimines,12 although the approach
could provide the fast and simple assembly of the target
molecule 1.
Our recent results in the area of ve-membered cyclic
nitronates chemistry13 suggest that the easily available ve-
membered nitronates 2 (isoxazoline 2-oxides)11 can serve as
The 4-aminosubstituted six-membered lactone scaffold
(marked as structure 1 in Fig. 1), derived from b-amino
acids, occurs in different classes of natural products, like
stephadiamine,1 kopsihainin D2 and the tetrodotoxin (TTX)
family3,4 (Fig. 1), exhibiting various biological activities. In
particular, TTX and its congeners constitute the key
components of the puffer sh fugu poison5 and due to their
complex structure are considered as classical objects for
total synthesis.6 However, few syntheses of these compounds
have succeeded.7–10 Difficulties usually arise from the
construction of the stereogenic quaternary carbon center
connected with an amine (further guanidine) function. For
this purpose, non-trivial or indirect methods such as Beck-
mann7b and Overman8 rearrangements, asymmetric trans-
ferring Strecker synthesis9 or chiral Rh-catalyzed C–H
nitrene insertion10 have to be employed. Therefore, the
development of simple, direct methods for the construction
of lactones 1 is an urgent task.
useful synthetic equivalents for ketiminium cations
A
(Scheme 1) in the reaction with a silyl ketene acetal, but this
approach requires an additional step for the reduction of both
of the N–O bonds and the cyclization of the resulting products
In this manuscript
a convenient strategy for the
synthesis of the scaffold 1 is suggested, which is based on a
detailed investigation of the transformations of cyclic
nitronates.11
aN. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow,
Russian Federation. E-mail: iof@ioc.ac.ru; Fax: +7-499-1355328
bHigher Chemical College of the Russian Academy of Sciences, Miusskaya sq. 9,
125047, Moscow, Russian Federation
cA. N. Nesmeyanov Institute of Organoelement Compounds, Vavilova str. 28, 119991
Moscow, Russian Federation
† Electronic supplementary information (ESI) available: Copies of 1H, 13C and
two-dimensional NMR spectra for all novel compounds. CCDC 959160 and
959161. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3ra47309k
Fig.
1 Selected natural products containing b-alkyl-b-amino-d-
valerolactone moiety 1.
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Thus, the suggested strategy starts with the coupling of
nitronates 2 with silyl ketene acetals. This transformation, like
other Mukaiyama–Mannich reactions, requires a Lewis acid
catalyst – tert-butyldimethylsilyl triate (TBSOTf), in particular
– for the production of nitroso acetals 3 (Scheme 2) in a rather
highly diastereoselective fashion.13,14 The products 3 contain
the complete carbon skeleton of the target amines 1 and for
their transformation into lactones 1, only the transformations
of the functional groups is required. However, the direct
reduction of compounds 3 into amines 1 with both N–O bonds
cleavage and lactone ring closure, within a one step protocol
turned out to be ineffective.13 A more convenient approach
seems to employ two steps (Scheme 2): (1) lactone cycle
Scheme 1 Retrosynthesis via Mannich-disconnection of scaffold 1.
formation via oxidation of isoxazolidines
3 into nitro
compounds 4; (2) selective nitro group reduction in lactones 4.
This modied scheme is supported with our recent research on
the six-membered analogues of nitroso acetals 3 which are
effectively oxidized with mCPBA into the corresponding nitro
compounds with the retention of the relative conguration of
all the stereocenters.15,16
Scheme 2 Three-step protocol for synthesis of the target amines 1 via
intermediacy of nitro lactones 4.
A nitro group connected to a tertiary carbon in lactones 4
can be a priori regarded as a latent amine function, due its
inertness to common reagents.17 Therefore, in this manu-
script, the main accent was on the preparation of the
nitroso acetals 3 (step 2 / 3) and their oxidation to nitro
lactones 4.
Table 1 Silyl ketene acetal addition to five-membered cyclic nitro-
nates 2a
Results and discussion
Starting from the available nitronates 2 (ref. 11), a repre-
sentative series of functionalized nitroso acetals 3a–h
was obtained via silyl ketene acetal addition, according
to a well-known protocol,13 or its modied version (Table 1,
see the Experimental section for details). Only three of
these: compounds trans-3a, 3g (inseparable mixture of
isomers trans/cis 5.5 : 1) and trans-3d (containing 8% of the
cis-isomer) have been obtained previously.13 The synthesis
of the derivatives trans-3b and cis-3b proceeded in a
rather similar way, although for 3e the trans-selectivity
was apparently decreased in comparison with the
analogous 3d.
To the best of our knowledge, no 4-substituted nitronates
2 were introduced in this type of reaction beforehand.
These compounds were found to exhibit nearly a 100% trans-
selectivity in coupling with the silyl ketene acetal, but
required prolonged reaction times. The synthesis of the 4-
phenyl-substituted trans-3c was completed in only 24 h
with 0.2 equivalents of TBSOTf. The synthesis of the even
more bulky bicyclic trans-3f required a full equivalent of
the promoter within 8 h exposure at ꢀ78 ꢁC. The trans-
position of the substituent at C-4 and the introduced ketene
acetal residue was proved by NOE NMR experiments
(see Fig. 3).
a
Conditions i: CH2Cl2 (0.2 M), TBSOTf (0.1–1.0 eq.), 2,6-
dimethylpyridine (0.25 eq.), ꢀ78 ꢁC, 1–24 h; see Experimental section
for details. b Isolated yield of pure isomer.
into lactones 1 (Scheme 2). It should be noted that this method
employs reagents with their usual polarities, with the congu-
ration of the C-4 stereocenter of the target product being set at
the stage of the C–C bond forming reaction.
The electrophilic activity of the nitronate 2h, containing a
halomethyl group at C-3, might appear in two different fashions
– nucleophile addition at the C]N bond, or its halogenation.18
Fortunately, the nitronate 2h (R0 ¼ Br) reacted with the silyl
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only a 55% yield, along with the nitrous acid elimination product
5a (8%) and a mixture of unidentied linear by-products. The best
result (Scheme 3), conditions (ii), achieved with sole mCPBA
utilization and prolongation of the reaction time up to 3 days,
accomplished the lactone ring-closure step. With the latter process
in hand, this increased the isolated yield of the nitro lactone 4a
to 85%.
The optimized oxidation conditions were applied to the
whole nitroso acetal 3 series. The individual diastereomers of
the 5- or 4-aryl substituted nitroso acetals trans-3a–c and cis-
3b were smoothly oxidized to give the desired lactones 4a–c
and 4b0 in moderate to high yields with the retention of
conguration of all the stereocenters (Table 2, entries 1–4).
The R0CH2-substituted at C-3 nitroso acetals 3f–h (R0 ¼ Ph, Br,
entries 7–9), that were usually used as diastereomeric
mixtures, also gave the target nitro lactones 4f–h, but a longer
reaction time was required. When the nitroso acetals 3d,e,
with the electron-withdrawing CO2Me group at C-5 were
employed (entries 5–6), only the formation of acyclic g-nitro
alcohols 6d,e – the proposed precursors of lactones 4 – was
observed, reasonably due to the lower nucleophilicity of the
alcohol function in these substrates. Even more acidic
conditions (Amberlyst-15®), did not manage to achieve the
cyclization of 6d and 6e into the corresponding lactones, 4d
and 4e.
Fig. 2 Molecular structures of 4b and 4h presented in thermal ellip-
soids at 50% probability. Hydrogen atoms are omitted for clarity.
The congurations of compounds 4b and 4h were supported
by X-ray diffraction analysis (Fig. 2). The stereochemistry of the
other nitro lactones 4 was assigned by the similarity of their
coupling constants with those of 4b and 4h in the 1H NMR
spectra. The nitro group formation in all of the compounds 4
was proven by 14N NMR.
The last step of the lactones 1 preparation – selective
reduction of the nitro group – despite many precedents in
the literature for tertiary nitro compounds17,19 – turned out
to be rather capricious. The standard hydrogenation condi-
tions, like Pd/C in MeOH performed on 4a gave only the
acyclic product 7 in almost a quantitative yield as the result
of the hydrogenolysis of the CH(Ph)–OC(O) fragment
(Scheme 4). The other screened reagents (NaBH4/NiCl2,20 Fe/
AcOH,19 Fe/NH4Cl19 and even H2/NiRa17,19) gave mainly the
“HNO2” elimination product 5a, along with by-products, of
unknown structures. [A more convenient protocol for the
synthesis of enones 5 from lactones 4 was developed with the
utilization t-BuOK in THF. It furnished compounds 5a and
5c with 94% and 95% yields, within 15–30 minutes, respec-
tively (Scheme 4)].
Fig. 3 Key NOE correlations for trans-3c and trans-3f.
In these circumstances, we managed to reduce the nitro
group with the rarely used amalgamated aluminium.21 The
most complicated intermediates – nitro compounds 4a and 4b
with the benzyl carboxylate function – gave the protected
Scheme 3 Optimization of nitroso acetal 3 oxidation.
ketene acetal in a usual fashion, to give the respective nitroso derivatives Boc-1a and Boc-1b of target amines in 52 and 57%
yields, respectively (Scheme 4). For the extremely sterically
acetal 3h (trans/cis ¼ 8 : 1).
For the elaboration of the second stage of the suggested hindered lactone 4c, a slightly modied procedure was applied,
protocol (Scheme 2, 3 / 4) the oxidation was optimized on the when the reduction and protection were divided into two
model nitroso acetal 3a. When the conditions, previously reported technical steps. By this methodology and the utilization of a
for 6-membered cyclic analogues of 3,15 were applied to 3a catalytic amount of DMAP for the Boc2O activation, the desired
(Scheme 3), protocol (i), the target nitro lactone 4a was obtained in product Boc-1c was obtained in a 79% yield.
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Table 2 Oxidation of nitroso acetals 3 series
#
1
2
3
4
5
6
7
8
9
Nitroso acetal 3 (substituents)
Reaction time, days
Product, yield, % (trans/cis dra)
4a, 85
trans-3a
3
3
3
2
1
1
7
5
5
(R ¼ 5-Ph, R0 ¼ H)
trans-3b
4b, 79
(R ¼ 5-(4-BrC6H4), R0 ¼ H)
cis-3b
4b0, 63
(R ¼ 5-(4-BrC6H4), R0 ¼ H)
trans-3c
4c, 76
(R ¼ 4-Ph, R0 ¼ H)
3d, trans/cis, 11/1
(R ¼ 5-CO2Me, R0 ¼ H)
3e, trans/cis, 5.2/1
(R ¼ 5-CO2Me and 5-Me, R0 ¼ H)
trans-3f
6d/6d0, 95 (15 : 1)
6e/6e0, 92 (6.3 : 1)
4f, 64
(R ¼ cis-4,5-(CH2)3-, R0 ¼ Ph)
3g, trans/cis, 5.5/1
(R ¼ 5-Ph, R0 ¼ Ph)
3h, trans/cis, 8/1
(R ¼ 5-Ph, R0 ¼ Br)
4g/4g0, 79 (6.5 : 1)
4h, 85 (>20 : 1)
a
Determined by 1H NMR spectra.
group). This procedure was applied to the synthesis of scaffolds
1 for the rst time. In our opinion, there are no obstacles for the
accomplishment of this strategy in an asymmetric manner.
Experimental section
General remarks
ꢁ
Reactions with TBSOTf were performed in oven-dried (150 C)
glassware under an argon atmosphere. The NMR spectra were
recorded on a Bruker AM-300 (1H: 300.13 MHz, 13C: 75.47 MHz,
14N: 21.69 MHz, 29Si: 59.63 MHz) and Bruker AMX-400 (1H:
400.1 MHz, 13C: 100.6 MHz) and referenced to a residual solvent
peak. The chemical shis are reported in ppm (d); multiplicities
are indicated by s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet) and br (broad). The ratios of the stereoisomers were
derived from the relative integral intensities of the character-
1
istic signals in the H NMR spectra. Coupling constants, J, are
Scheme 4 Reduction and accompanying reactions of nitro lactones
4a–c.
reported in Hertz. Key NOESY correlations are shown with
arrows (Fig. 2). The IR spectra were recorded on a Bruker
VEKTOR-22 in the range 400–4000 cmꢀ1 (resolution 2 cmꢀ1) as a
thin layer. The melting points were determined on Koer
melting point apparatus and are uncorrected. The elemental
Conclusions
In summary, we have demonstrated that the target b-amino-d- analyses were performed by the Analytical Laboratory of the N.
lactones 1, or more precisely, their N-Boc derivatives, can be D. Zelinsky Institute of Organic Chemistry. The HR mass
obtained from the ve-membered cyclic nitronates 2, according spectra were recorded on a Bruker MicroTOFF spectrometer
to the suggested three-step protocol. The novelty of the with electrospray ionization (ES-I).
approach consists of the combination of three transformations
The X-ray diffraction measurements were carried out using
(C,C-coupling, oxidation and selective reduction of the NO2 SMART 1000 CCD and Smart APEX II diffractometers at 100 K.
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The frames were integrated and corrected for absorption by the
APEX 2 program package [APEX2 Soware Package, Bruker AXS
Inc., 5465, East Cheryl Parkway, Madison, WI 5317, 2005]. The
details of crystallographic data and experimental conditions are
given in Table SI1 in the ESI.† The structures were solved by a
direct method and rened by the full-matrix least-squares
technique against F2 in the anisotropic–isotropic approxima-
tion. The hydrogen atoms were located from the difference
Fourier maps and rened in a rigid body model. All the calcu-
lations were performed using the APEX 2 program package
[APEX2 Soware Package, Bruker AXS Inc., 5465, East Cheryl
Parkway, Madison, WI 5317, 2005].
The analytical thin-layer chromatography was performed on
silica gel plates, with the QF-254 indicator. The visualization of
the TLC plates was accomplished with a UV light and/or ani-
saldehyde/H2SO4. The preparative liquid chromatography was
performed on columns with “Merck”-silica (Kieselgel 60, 230–
400 mesh). All the solvents for the chromatography and
extractions were of technical grade and distilled prior to use.
The following solvents and reagents were distilled from the
indicated drying agents: CH2Cl2, CHCl3, Et3N (CaH2), MeOH
(Mg), THF, dioxane (LiAlH4).
Methyl rel-((2R,3S,5R)-5-(4-bromophenyl)-(2-tert-butyldime-
thylsilyloxy)-3-methylisoxazolidin-3-yl)acetate cis-2b. Mp
¼
1
ꢁ
46 C (pentane), TLC: Rf ¼ 0.51 (hexane–EtOAc, 3/1); H NMR
(300.13 MHz, 323 K, CDCl3): d ¼ 0.17 and 0.19 [2s, 6H, Si(CH3)2],
0.91 [s, 9H, t-Bu], 1.34 [s, 3H, Me], 2.52 [t, 2J z 3J ¼ 12.0 Hz, 1H,
CHAHB], 2.59–2.68 [m, 2H, CHAHB and CHCHD(CO2Me)], 2.90 [d,
2J ¼ 14.9 Hz, 1H, CHCHD(CO2Me)], 3.70 [s, 3H, CO2Me], 5.25 [dd,
3J z 3J ¼ 7.8 Hz, 1H, CH], 7.36 [d, 3J ¼ 8.3 Hz, 2H, CHo-Ar] and
7.44 [d, 3J ¼ 8.3 Hz, 2H, CHm-Ar] ppm; 13C NMR (75.47 MHz, 323
K, CDCl3): d ¼ ꢀ4.9 and ꢀ4.6 [Si(CH3)2], 17.8 [C(CH3)3], 21.9
[CH3], 26.0 [C(CH3)3], 41.5 [CH2CO2Me], 43.7 [CH2], 51.4
[OCH3], 74.6 [CNO2], 84.6 [CH], 121.4 [Ci-Ph], 129.1 and 131.1
[CHo-Ph and CHm-Ph], 135.5 [CBr], 171.3 [OC ¼ O] ppm; 29Si NMR
(300 K, CDCl3): d ¼ 25.4 ppm.
C19H30NO4BrSi (444.44): calcd C, 51.35; H, 6.80; N, 3.15;
found C, 51.66; H, 7.05; N, 3.38%.
Methyl
rel-((2S,3R,5R)-(2-tert-butyldimethylsilyloxy)-3-
methyl-4-phenylisoxazolidin-3-yl)acetate trans-3c. Obtained by
the same procedure as 3b. The reaction was performed on 2.0
mmol scale with 24 h exposure. Yield 681 mg (93%); dr > 20:1;
1
ꢁ
mp ¼ 26 C (pentane); TLC: Rf ¼ 0.49 (hexane–EtOAc, 5/1); H
NMR (400.1 MHz, 305 K, CDCl3): d ¼ 0.15 and 0.23 [2s, 6H,
2
Si(CH3)2], 0.95 [s, 9H, t-Bu], 1.09 [s, 3H, Me], 2.56 [d, J ¼ 14.9
Hz, 1H, CHAHB(CO2Me)], 2.77 [d, 2J ¼ 14.9 Hz, 1H, CHAHB-
(CO2Me)], 3.55 [s, 3H, CO2Me], 4.07 [dd, 3J ¼ 9.9, 3J ¼ 7.9 Hz, 1H,
Synthesis of nitroso acetals 3 (rst step, see Scheme 3)
Nitroso acetals trans-3b and ꢁcis-3b. TBSOTf (150 mL, 173 mg, CH], 4.26 [t, 2J z 3J ¼ 7.9 Hz, 1H, CHCHD], 4.59 [dd, 3J ¼ 9.9, 2J ¼
0.65 mmol) was added at ꢀ78 C to a stirred solution of 5-(4- 7.9 Hz, 1H, CHCHD], 7.27–7.35 [m, 5H, Ph] ppm; 13C NMR (100.6
bromophenyl)-3-methyl-isoxazoline-2-oxide 2b (837 mg, 3.27 MHz, 305 K, CDCl3): d ¼ ꢀ5.1 and ꢀ4.7 [Si(CH3)2], 18.1
mmol), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (0.93 [C(CH3)3], 20.4 [CH3], 26.0 [C(CH3)3], 40.3 [CH2CO2Me], 51.2
mL, 788 mg, 3.92 mmol) and 2,6-lutidine (95 mL, 87 mg, 0.82 [OCH3], 52.1 [CH], 73.0 [OCH2], 76.6 [CN], 127.3 [CHp-Ph], 128.4
mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at and 129.3 [CHPh], 136.7 [Ci-Ph], 170.7 [OC ¼ O] ppm; 29Si NMR
the same temperature for 1 hour, then quenched with MeOH (300 K, CDCl3): d ¼ 26.1 ppm. C19H31NO4Si (365.54): calcd C,
(33 mL, 26 mg, 0.82 mmol) and poured into a mixture of water 62.43; H, 8.55; N, 3.83; found C, 62.53; H, 8.38; N, 3.84%.
(10 mL) and hexane (20 mL). The aqueous layer was separated
Methyl 2-(((tert-butyldimethylsilyl)oxy)-3-methoxycarbonyl-
out and back-extracted with hexane (2 ꢂ 5 mL). Combined 3,5-dimethylisoxazolidine-5-carboxylate) 3e. Obtained by the
organic layers were washed successively with sat. NaHCO3 same procedure as 3b on a 2.0 mmol scale. Yield 691 mg (96%),
solution (7 mL) and brine (15 mL) and dried over Na2SO4. The dr 5.2 : 1 (inseparable mixture), colorless oil; TLC: Rf ¼ 0.66
1
residue was subjected to column chromatography (eluent (hexane–EtOAc, 1/1); H NMR (400.1 MHz, 305 K, CDCl3): rel-
EtOAc–hexane 1/40 / 1/20 / 1/10) to give the separated dia- 2S,3R,5R-isomer, trans-3e (major): d ¼ 0.11 and 0.20 [2s, 6H,
stereomers, trans-3b (852 mg, 59%) and cis-3c (233 mg, 16%) Si(CH3)2], 0.89 [s, 9H, t-Bu], 1.13 [s, 3H, NCCH3], 1.69 [s, 3H,
each as a slowly crystallizing colorless oil (dr 3.5 : 1).
OCCH3], 2.50 [d, 2J ¼ 14.7 Hz, 1H, CHAHB], 2.51 [d, 2J ¼ 12.8 Hz,
Methyl rel-((2S,3R,5R)-5-(4-bromophenyl)-(2-tert-butyldime- 1H, CHCHD(CO2Me)], 2.82 [d, 2J ¼ 14.7 Hz, 1H, CHAHB], 2.85 [d,
thylsilyloxy)-3-methylisoxazolidin-3-yl)acetate trans-3b. Mp ¼ 2J ¼ 12.8 Hz, 1H, CHCHD(CO2Me)], 3.66 [s, 3H, CO2CH3], 3.73 [s,
42–43 ꢁC (pentane), TLC: Rf ¼ 0.58 (hexane–EtOAc, 3/1); 1H NMR 3H, CH2CO2CH3]; rel-2R,3S,5R-isomer, cis-3e (minor): d ¼ 0.08
(300.13 MHz, 299 K, CDCl3): d ¼ 0.17 and 0.22 [2s, 6H, Si(CH3)2], and 0.17 [2s, 6H, Si(CH3)2], 0.84 [s, 9H, t-Bu], 1.27 [s, 3H,
0.94 [s, 9H, t-Bu], 1.28 [s, 3H, Me], 2.10 [dd, 2J ¼ 12.3, 3J ¼ 5.6 Hz, NCCH3], 1.53 [s, 3H, OCCH3], 2.50 [d, 2J ¼ 14.7 Hz, 1H, CHAHB],
1H, CHAHB], 2.58 [d, 2J ¼ 15.1 Hz, 1H, CHAHB(CO2Me)], 2.52–2.67 2.51 [d, 2J ¼ 12.8 Hz, 1H, CHCHD(CO2Me)], 2.82 [d, 2J ¼ 14.7 Hz,
[m, 2H, CHAHB and CHAHB(CO2Me)], 3.69 [s, 3H, CO2Me], 5.54 1H, CHAHB], 2.85 [d, 2J ¼ 12.8 Hz, 1H, CHCHD(CO2Me)], 3.66 [s,
3
3
3
[dd, J ¼ 9.6, J ¼ 5.6 Hz, 1H, CH], 7.25 [d, J ¼ 8.7 Hz, CHo-Ar
]
3H, CH2CO2CH3], 3.68 [s, 3H, CO2CH3] ppm; 13C NMR (100.6
and 7.48 [d, 3J ¼ 8.7 Hz, CHm-Ar] ppm; 13C NMR (75.47 MHz, 299 MHz, 305 K, CDCl3): rel-2S,3R,5R-isomer, trans-3e (major): d ¼
K, CDCl3): d ¼ ꢀ5.0 and ꢀ4.8 [Si(CH3)2], 18.0 [C(CH3)3], 25.5 ꢀ5.0 and ꢀ4.4 [Si(CH3)2], 17.8 [C(CH3)3], 22.8 [NCCH3], 26.8
[CH3], 25.9 [C(CH3)3], 42.0 [CH2CO2Me], 43.7 [CH2], 51.6 [OCH3], [C(CH3)3], 28.5 [OCCH3], 42.1 [CH2CO2Me], 46.5 [CH2], 51.7
74.4 [CNO], 80.3 [CH], 121.3 [Ci-Ph], 128.1 and 131.5 [CHo-Ph and [CH2CO2CH3], 52.6 [CO2CH3], 74.4 [N–C], 88.6 [N–O–C], 171.4
CHm-Ph], 139.5 [CBr], 171.6 [OC ¼ O] ppm; 29Si NMR (300 K, [CH2CO2Me], 174.0 [CO2Me]; rel-2R,3S,5R-isomer, cis-3e
CDCl3): d ¼ 25.9 ppm. C19H30NO4BrSi (444.44): calcd C, 51.35; H, (minor): d ¼ ꢀ4.9 and ꢀ4.4 [Si(CH3)2], 17.9 [C(CH3)3], 24.3
6.80; N, 3.15; found: C, 51.57; H, 6.88; N, 3.16%.
[NCCH3], 25.2 [C(CH3)3], 25.8 [OCCH3], 42.3 [CH2CO2Me], 44.1
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[CH2], 51.7 [CH2CO2CH3], 52.3 [CO2CH3], 74.8 [N–C], 86.4 [N–O– mL) were kept, with occasional shaking, at room temperature
C], 171.5 [CH2CO2Me], 175.1 [CO2Me] ppm. 29Si NMR (305 K, for 1–7 days (a green or blue color of reaction mixture aer
CDCl3, INEPT): rel-2S,3R,5R-isomer, trans-3e (major): d ¼ 26.0; mCPBA addition was observed in several cases, due to the
rel-2R,3S,5R-isomer, cis-3e (minor): d ¼ 26.2 ppm. HRMS (ES-I) intermediacy of nitroso compounds). The reaction mixture was
calcd for C16H31NO6SiH [M + H]+ 362.1993; found 362.1990.
poured into a mixture of EtOAc (15 mL)/NaHCO3 (12 mL,
Methyl
2-(rel-(2S,3S,3aS,6aS)-3-benzyl-(2-tert-butyldime- saturated aqueous solution). The aqueous layer was back-
thylsilyloxy)-hexahydro-2H-cyclopenta[d]isoxazol-3-yl)acetate
extracted with EtOAc (2 ꢂ 5 mL). The combined organic phase
trans-3f. Obtained by the same procedure as 3b with 1.0 eq. of was washed with H2O (10 mL), brine (10 mL) and dried over
TBSOTf and 8 h exposure. Performed on a 1.20 mmol scale. Na2SO4. The solvents were evaporated in vacuo. The residue was
Yield 307 mg (64%), dr > 20 : 1, slightly greenish oil, TLC: Rf ¼ subjected to column chromatography (eluent EtOAc–hexane 1/5
0.85 (hexane–EtOAc, 1/1); 1H NMR (300.13 MHz, 300 K, CDCl3): / 1/3 / 1/2), or to recrystallization from CHCl3–hexane or
d ¼ ꢀ0.21 and 0.09 [2s, 6H, Si(CH3)2], 0.87 [s, 9H, t-Bu], 1.66– Et2O to give the nitro compound 4 or 6 as colorless crystals.
1.80 [m, 4H, CH2Cyc.], 1.90–2.00 and 2.11–2.21 [2m, 2H, CH2Cyc.
]
rel-(4R,6R)-4-Methyl-4-nitro-6-phenyltetrahydro-2H-pyran-2-
2
2.27 [d, 2J ¼ 16.3 Hz, 1H, CHAHB], 2.73 [d, J ¼ 16.3 Hz, 1H, one, 4a. Yield 199 mg (85%), mp ¼ 92–95 C (Et2O), TLC: Rf ¼
CHAHB], 2.83 [d, 2J ¼ 13.7 Hz, 1H, CHCHDPh], 3.02 [d, 2J ¼ 13.7 0.43 (hexane–EtOAc, 1/1). IR (thin layer from CCl4): 1753 (br vs.,
Hz, 1H, CHCHDPh], 3.06 [t, 3J z 3J ¼ 7.3 Hz, 1H, CH], 3.71 [s, 3H, nC]O), 1547 (vs., nasNO2), 1354 (s, nsNO2); 1H NMR (300.13
CO2Me], 5.16 [dd, 3J ¼ 6.4, 3J ¼ 5.3 Hz, 1H, OCH], 7.16–7.31 [m, MHz, 299 K, CDCl3): d ¼ 1.87 [s, 3H, CH3], 2.56 [dd, 2J ¼ 15.5, 3J
ꢁ
5H, Ph] ppm. 13C NMR (75.47 MHz, 300 K, CDCl3): d ¼ ꢀ5.2 and ¼ 3.7 Hz, 1H, CHAHB], 2.63 [dd, 2J ¼ 15.5, J ¼ 11.4 Hz, 1H,
3
ꢀ5.0 [Si(CH3)2], 17.8 [C(CH3)3], 25.9 [C(CH3)3], 26.6, 27.9, 30.6, CHAHB], 2.98 [d, 2J ¼ 16.9 Hz, 1H, CHCHD], 3.35 [d, 2J ¼ 16.9 Hz,
37.4 and 38.9 [CH2], 51.4 [OCH3], 53.3 [CH], 79.0 [C–N], 87.4 1H, CHCHD)], 5.32 [dd, 3J ¼ 11.4, 3J ¼ 3.7 Hz, 1H, CH], 7.33–7.45
[OCH], 126.2 [CHp-Ph], 127.5 and 128.5 [CHo-Ph and CHm-Ph], [m, 5H, Ph] ppm; 13C NMR (75.47 MHz, 299 K, CDCl3): d ¼ 25.8
137.9 [Ci-Ph], 172.0 [OC ¼ O] ppm; 29Si NMR (300 K, CDCl3): d ¼ [CH3], 40.0 [CH2], 42.0 [CH2C]O], 77.2 [CH], 84.4 [CNO2], 126.0
25.1 ppm; HRMS (ES-I) calcd for C22H35NO4SiNa [M + Na]+ and 128.6 [CHo-Ph and m-Ph], 129.1[(CHp-Ph], 137.2 [Ci-Ph], 167.6
428.2228; found 428.2208.
[OC]O] ppm; 14N NMR (299 K, CDCl3): d ¼ 16 (n1/2 z 100 Hz)
Methyl 3-bromomethyl-5-phenyl-(2-tert-butyldimethylsily- ppm. C12H13NO4 (235.24): calcd C, 61.27; H, 5.57; N, 5.95; found
loxy)-isoxazolidin-3-ylacetate 3h. Obtained by the same procedure C, 61.36; H, 5.72; N, 5.85%.
as 3b except with a 3 h exposure. The reaction was performed on a
rel-(4R,6R)-6-(4-Bromophenyl)-4-methyl-4-nitrotetrahydro-
1.50 mmol scale; yield 570 mg (86%), dr 8.0 : 1 (inseparable 2H-pyran-2-one 4b. Yield 249 mg (79%), mp ¼ 162–165 ꢁC
mixture), TLC: Rf ¼ 0.76 (hexane–EtOAc, 1/1); 1H NMR (300.13 (Et2O), TLC: Rf ¼ 0.33 (hexane–EtOAc, 1/1); 1H NMR (300.13
MHz, 302 K, CDCl3): rel-2S,3R,5R-isomer, trans-3h (major): d ¼ 0.22 MHz, 312 K, CDCl3): d ¼ 1.88 [s, 3H, CH3], 2.55–2.64 [m, 2H,
and 0.26 [2s, 6H, Si(CH3)2], 0.97 [s, 9H, t-Bu], 2.65 [dd, 2J ¼ 13.2, 3J ¼ CH2], 2.97 [d, 2J ¼ 17.2 Hz, 1H, CHAHB], 3.35 [d, 2J ¼ 17.2 Hz, 1H,
10.2 Hz, 1H, CHAHB], 2.92 [dd, 2J ¼ 13.2, 3J ¼ 8.8 Hz, 1H, CHAHB], CHAHB], 5.29 [dd, 3J ¼ 10.5, 3J ¼ 3.5 Hz, 1H, CH], 7.25 [d, 3J ¼ 8.0
3
3.00 [d, 2J ¼ 16.9 Hz, 1H, CHCHD(CO2Me)], 3.12 [d, 2J ¼ 16.9 Hz, 1H, Hz, 2H, CHAr], 7.56 [d, J ¼ 8.0 Hz, 2H, CHAr] ppm; 13C NMR
CHCHD(CO2Me)], 3.64 [d, 2J ¼ 11.0 Hz, 1H, CHEHFBr], 3.72 [s, 3H, (75.47 MHz, 312 K, CDCl3): d ¼ 25.7 [CH3], 40.1 [CH2], 41.6
CO2Me], 3.78 [d, 2J ¼ 11.0 Hz, 1H, CHEHFBr], 5.63 [dd, 3J ¼ 8.8, 3J ¼ [CH2], 76.5 [CH], 83.9 [CNO2], 123.2 [CBr], 127.5 [CAr], 132.2 and
6.6, 1H, CH], 7.28–7.48 [m, 5H, Ph]; rel-2R,3S,5R-isomer, cis-3h 136.3 [CHAr], 166.6 [OC]O] ppm; 14N NMR (312 K, CDCl3): d ¼
(minor): d ¼ 0.04 and 0.20 [2s, 6H, Si(CH3)2], 0.90 [s, 9H, t-Bu], 2.32 13 (n1/2 z 150 Hz) ppm; C12H12BrNO4 (314.13): calcd C, 45.88;
[dd, 2J ¼ 13.2, 3J ¼ 6.6 Hz, 1H, CHAHB], 2.87–3.01 [m, 2H, CHAHB H, 3.85; N, 4.46; found C, 45.62; H, 3.77; N, 4.21%.
and CHCHD(CO2Me), overlaps with major isomer], 3.14 [d, 2J ¼ 16.9
rel-(4S,6R)-6-(4-Bromophenyl)-4-methyl-4-nitrotetrahydro-
Hz, 1H, CHCHD(CO2Me)], 3.67 [d, 2J ¼ 17.6 Hz, 1H, CHEHFBr], 3.72 2H-pyran-2-one 4b0. Yield 198 mg (63%), mp ¼ 111–112 ꢁC
[s, 3H, CO2Me], 3.78 [d, 2J ¼ 17.6 Hz, 1H, CHEHFBr], 5.63 [dd, 3J ¼ (Et2O), TLC: Rf ¼ 0.57 (hexane/EtOAc, 1/1). 1H NMR (300.13
3
10.2, J ¼ 8.1 Hz, 1H, CH], 7.28–7.48 [m, 5H, Ph] ppm; 13C NMR MHz, 323 K, CDCl3): d ¼ 1.77 [s, 3H, CH3], 2.08 [dd, 2J ¼ 14.5, 3J
(75.47 MHz, 302 K, CDCl3): rel-2S,3R,5R-isomer, trans-3h (major): d ¼ 11.7 Hz, 1H, CHAHB], 2.79 [d, 2J ¼ 17.7 Hz, 1H, CHCHD], 2.86
¼ ꢀ5.2 and ꢀ4.8 [Si(CH3)2], 18.0 [C(CH3)3], 25.9 [C(CH3)3], 37.8 and [dd, 2J ¼ 14.5, 3J ¼ 1.7 Hz, 1H, CHAHB], 3.63 [d, 2J ¼ 17.7 Hz, 1H,
37.9 [CH2CO2Me and CH2Br], 42.3 [CH2], 51.7 [OCH3], 77.3 [C–N], CHCHD], 5.27 [dd, 3J ¼ 11.7, 3J ¼ 1.7 Hz, 1H, CH], 7.25 [d,3J ¼ 8.1
80.3 [OCH], 126.4 [CHp-Ph], 128.0 and 128.7 [CHo-Ph and CHm-Ph], Hz, 2H, CHAr], 7.54 [d, J ¼ 8.1 Hz, 2H, CHAr] ppm; 13C NMR
3
139.1 [Ci-Ph], 171.0 [OC ¼ O]; rel-2R,3S,5R-isomer, cis-3h (minor): d ¼ (75.47 MHz, 323 K, CDCl3): d ¼ 27.1 [CH3], 39.6 [CH2], 41.7
ꢀ4.9 and ꢀ4.5 [Si(CH3)2], 17.8 [C(CH3)3], 25.7 [C(CH3)3], 35.1 [CH2], 76.7 [CH], 85.3 [CNO2], 123.0 [CBr], 127.3 [CAr], 132.0 and
[CH2Br], 37.4 [CH2CO2Me], 41.8 [CH2], 51.7 [OCH3], 76.5 [C–N], 84.7 136.5 [CAr], 166.2 [OC ¼ O] ppm. 14N NMR (323 K, CDCl3): d ¼ 13
[OCH], 127.3, 127.7 and 128.2 [CHPh], 140.1 [Ci-Ph], 170.8 [OC ¼ O] (n1/2 z 150 Hz) ppm; C12H12BrNO4 (314.13): calcd C, 45.88; H,
ppm; HRMS (ES-I) calcd for C19H30BrNO4SiNa [M + Na]+ 466.1020 3.85; N, 4.46; found C, 45.91; H, 3.62; N, 4.48%.
and 466.1000; found 466.1023 and 466.1002.
rel-(4S,5S)-4-Methyl-4-nitro-5-phenyltetrahydro-2H-pyran-2-
ꢁ
one 4c. Yield 179 mg (76%), mp ¼ 122–124 C (CHCl3–hexane,
1
2/1), TLC: Rf ¼ 0.36 (hexane–EtOAc, 1/1); H NMR (400.1 MHz,
Nitro lactone 4 formation (second step, see Scheme 3)
2
305 K, CDCl3): d ¼ 1.59 [s, 3H, CH3], 2.80 [d, J ¼ 17.8 Hz, 1H,
General procedure. The nitroso acetal 3 (1.00 mmol) and CHAHB], 3.35 [d, 2J ¼ 17.8 Hz, 1H, CHAHB], 3.38 [dd, 3J ¼ 11.0, 3J
mCPBA (70%, 271 mg, 1.10 mmol) as a solution in CH2Cl2 (3.0 ¼ 5.3 Hz, 1H, CH], 4.51 [dd, 2J ¼ 12.1, 3J ¼ 5.3 Hz, 1H, CHAHB],
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4.78 [t, 2J z 3J ¼ 11.7 Hz, 1H, CHAHB], 7.04 [d, 3J ¼ 7.7 Hz, 2H, (300.13 MHz, CDCl3): rel-4R,6R-isomer 4g (major): d ¼ 2.65 [dd,
CHo-Ph], 7.30–7.42 [m, 3H, CHm-Ph and CHp-Ph] ppm; 13C NMR 2J ¼ 15.4, 3J ¼ 11.7 Hz, 1H, CHAHB], 2.78 [dd, 2J ¼ 15.4, 3J ¼ 3.7
(100.6 MHz, 305 K, CDCl3): d ¼ 24.4 [CH3], 40.9 [CH2C]O], 48.4 Hz, 1H, CHAHB], 3.07 [d, 2J ¼ 16.9 Hz, 1H, CHCHD], 3.26 [d, 2J ¼
[CH], 68.5 [OCH2], 87.7 [CNO2], 128.5 and 129.2 [CHo-Ph and 16.9 Hz, 1H, CHCHD], 3.41 [d, 2J ¼ 14.0 Hz, 1H, CHEHF], 3.52 [d,
3
3
CHm-Ph], 129.4 [CHp-Ph], 132.4 [Ci-Ph], 166.7 [OC]O] ppm; 14N 2J ¼ 14.0 Hz, 1H, CHEHF], 5.12 [dd, J ¼ 11.7, J ¼ 3.7 Hz, 1H,
NMR (28.9 MHz, 299 K, CDCl3): d ¼ 7 (n1/2 z 100 Hz) ppm; CH], 7.11–7.19 [m, 2H, CHPh], 7.25–7.44 [m, 8H, Ph]; rel-4S,6R-
2
C
12H13NO4 (235.24): calcd C, 61.27; H, 5.57; N, 5.95; found C, isomer 4g0 (minor): d (selected signals) ¼ 2.86 [d, J ¼ 14.0 Hz,
2
3
60.99; H, 5.56; N, 5.96%.
1H, CHCHD], 3.50 [d, J ¼ 14.0 Hz, 1H, CHEHF], 5.22 [dd, J ¼
Dimethyl rel-(2R,4R)-2-hydroxy-4-methyl-4-nitrohexanediolate 12.5, J ¼ 2.0 Hz, 1H, CH] ppm; 13C NMR (75.47 MHz, CDCl3):
6d. Yield 237 mg (95%), oil, TLC: Rf ¼ 0.30 (hexane–EtOAc, 1/1); rel-4R,6R-isomer 4g (major): d ¼ 37.6, 40.3, 44.8, [3 CH2], 77.0
1H NMR (300.13 MHz, 299 K, CDCl3): d ¼ 1.75 [s, 3H, CH3], 2.43 [CH], 87.9 [CNO2], 125.8, 128.6, 129.0, 129.1, 129.2 and 129.9
[dd, 2J ¼ 14.7, 3J ¼ 10.4 Hz, 1H, CHAHB], 2.58 [dd, 2J ¼ 14.7, 3J ¼ [CHPh], 132.4 and 137.5 [Ci-Ph], 167.4 [OC ¼ O], rel-4S,6R-isomer
2.6 Hz, 1H, CHAHB], 3.09–3.24 [m, 3H, CH2 and OH], 3.67 [s, 3H, 4g0 (minor): d ¼ 37.1, 40.4 and 45.8 [3 CH2], 77.3 [CH], 87.9
CO2Me], 3.79 [s, 3H, CO2Me], 4.27 [dd, 3J ¼ 10.4, 3J ¼ 2.4 Hz, 1H, [CNO2], 126.0, 127.3, 128.4, 128.9, 129.0 and 129.9 [CHPh], 132.0
CH] ppm; 13C NMR (75.47 MHz, 299 K, CDCl3): d ¼ 24.1 [CH3], and 138.1 [Ci-Ph], 166.7 [OC]O] ppm; 14N NMR (299 K, CDCl3): d
41.7 and 41.8 [CH2], 52.0 and 53.1 [OCH3], 67.3 [CH], 87.1 [CNO2], ¼ 15 (n 1/2, ca. 200 Hz) ppm; HRMS (ES-I) calcd for C18H17NO4Na
169.7 and 174.3 [OC]O] ppm; 14N NMR (299 K, CDCl3): d ¼ 14 [M + Na]+ 334.1050; found 334.1050.
3
(n1/2 z 200 Hz) ppm; HRMS (ES-I) calcd for C9H15NO7Na [M +
rel-(4R,6R)-4-Bromomethyl-4-nitro-6-phenyltetrahydro-2H-
Na]+ 272.0741; found 272.0747.
pyran-2-one 4h. Yield 85%, dr > 20 : 1, mp ¼ 92–95 C (Et2O),
ꢁ
Dimethyl 2-hydroxy-2,4-dimethyl-4-nitrohexanediolate 6e/ TLC: Rf ¼ 0.43 (hexane–EtOAc, 1/1); 1H NMR (300.13 MHz, 299
6e0. Yield 235 mg (89%), dr 6.3 : 1 (inseparable mixture), oil, K, CDCl3): d ¼ 2.70–2.84 [m, 2H, CH2], 3.20 [d, 2J ¼ 16.9 Hz, 1H,
TLC: Rf ¼ 0.32 (hexane–EtOAc, 1/1); 1H NMR (300.13 MHz, 299 CHAHB], 3.41 [d, J ¼ 16.9 Hz, 1H, CHAHB], 3.95–4.09 [m, 2H,
2
3
3
K, CDCl3): rel-2R,4R-isomer 6e (major): d ¼ 1.41 [s, 3H, CH3], CH2Br], 5.32 [dd, J ¼ 9.5, J ¼ 5.2 Hz, 1H, CH], 7.32–7.49 [m,
1.68 [s, 3H, CH3], 2.67 [s, 2H, CH2], 2.95 [d, J ¼ 16.4 Hz, 1H, 5H, Ph] ppm; 13C NMR (75.47 MHz, 299 K, CDCl3): d ¼ 35.2
2
CHAHB], 3.09 [d, 2J ¼ 16.4 Hz, 1H, CHAHB], 3.20 [br s, 1H, OH], [CH2Br], 37.2 and 40.1 [CH2 and CH2C]O], 77.1 [CH], 86.4
3.68 [s, 3H, CO2Me], 3.79 [s, 3H, CO2Me]; rel-4S,6R-isomer 6e0 [CNO2], 125.9 and 129.0 [CHo-Ph and CHm-Ph], 129.3 [CHp-Ph],
(minor): d ¼ 1.42 [s, 3H, CH3], 1.64 [s, 3H, CH3], 2.64 [d, 2J ¼ 15.2 136.4 [Ci-Ph], 168.6 [OC]O] ppm; 14N NMR (21.69 MHz, 299 K,
Hz, 1H, CHCHD], 2.74 [d, 2J ¼ 15.2 Hz, 1H, CHCHD], 3.12 [d, 2J ¼ CDCl3): d ¼ 6 (n1/2, ca. 170 Hz) ppm; C12H12BrNO4 (314.13): calcd
17.2 Hz, 1H, CHAHB], 3.20 [br s, 1H, OH], 3.25 [d, 2J ¼ 17.2 Hz, C, 45.88; H, 3.85; N, 4.46; found: C, 46.00; H, 3.87; N, 4.27%.
1H, CHAHB], 3.68 [s, 3H, CO2Me], 3.80 [s, 3H, CO2Me] ppm; 13
C
NMR (75.47 MHz, 299 K, CDCl3): rel-4R,6R-isomer 6e (major): d
¼ 23.0 and 29.7 [CH3], 43.1 and 45.8 [CH2], 52.0 and 53.2
[OCH3], 73.0 [C], 86.6 [CNO2], 169.4 and 176.9 [OC]O]; rel-
4S,6R-isomer 6e0 (minor): d ¼ 23.9 and 29.6 [CH3], 41.9 and 45.3
Reduction of nitro lactones 4 into carbamates Boc-1 (third
step, see Scheme 3)
General procedure. Aluminum foil was cut into strips (8
[CH2], 51.9 and 53.2 [OCH3], 72.9 [C], 87.4 [CNO2], 169.9 and pieces, 20 ꢂ 5 mm, 120 mg, 5.2 mmol, 20 eq.). The clean meal
176.9 [OC]O] ppm; 14N NMR (299 K, CDCl3): d ¼ 19 (n1/2, ca. surface was washed with hexane and Et2O. Aer that, it was
200 Hz) ppm; HRMS (ES-I) calcd for C10H17NO7Na [M + Na]+ poured into a 2% HgCl2 solution in water (10 mL) for 15 s, then
286.0897; found 286.0900.
washed with MeOH, and Et2O without drying. Aer all these
rel-(4R,4aS,7aS)-4-Benzyl-4-nitrohexahydrocyclapenta[b]- preliminary preparations22 the foil was added to nitro lactone 4a
pyran-2(3H)-one 4f. Yield 178 mg (64%), mp ¼ 105–107 ꢁC or b (0.26 mmol, 1.0 eq.) as a solution in THF/H2O (9/1, 5 mL)
1
(hexane–EtOAc, 10/1), TLC: Rf ¼ 0.66 (hexane–EtOAc, 1/1); H with water bath cooling (Caution! exothermic reaction and
NMR (300.13 MHz, 301 K, CDCl3): d ¼ 1.52 [ddd, 2J ¼ 17.7, 3J ¼ hydrogen evaluation). The reaction mixture was stirred for 1
12.3, 2J ¼ 7.4 Hz, 1H, CHAHB(1)], 1.73–1.97 [m, 3H, CH2(2), hour and Boc2O (40 mg, 0.18 mmol, 1.5 eq.) was added. Aer an
CHAHB(1)], 2.03–2.16 [m, 2H, CH2(3)], 2.94 [dt, 3J ¼ 9.1, 3J z 3J ¼ additional 18 hours, the reaction mixture was poured into a
5.7, Hz 1H, CH], 2.99 [s, 2H, CH2Ph], 3.10 [d, 2J ¼ 14.3 Hz, 1H, EtOAc (15 mL)/H2O (10 mL) mixture. The water layer was back-
CHCHDCO], 3.10 [d, 2J ¼ 14.3 Hz, 1H, CHCHDCO], 5.00 [dd, 3J ¼ extracted with EtOAc (2 ꢂ 3 mL). The combined organic layers
3
3
4
7.3, J ¼ 4.9 Hz, 1H, OCH], 7.03 [dd, J ¼ 6.5, J ¼ 2.9 Hz, 2H, were washed with H2O (7 mL), brine (10 mL) and dried over
CHo-Ph], 7.29–7.37 [m, 3H, CHm-Ph, CHp-Ph] ppm; 13C NMR (75.47 Na2SO4. The solvents were evaporated in vacuo. The residue was
MHz, 301 K, CDCl3): d ¼ 22.2 [CH2-2], 26.2 [CH2-1], 32.7 subjected to column chromatography (eluent EtOAc–hexane,
[CH2Ph], 34.3 [CH2-3], 44.9 [CH2CO], 45.6 [CH], 82.3 [OCH], 90.0 1/5 / 1/3 / 1/1), to give the protected amine Boc-1a or 1b, as a
[CNO2], 128.3 [CHp-Ph], 129.1 and 130.1 [CHm-Ph and CHo-Ph], colorless solid.
132.2 [Ci-Ph], 167.3 [OC]O] ppm; 14N NMR (299 K, CDCl3): d ¼ 8
tert-Butyl
[rel-(2R,4R)-4-methyl-6-oxo-2-phenyltetrahydro-
(n z 230 Hz) ppm; HRMS (ES-I) calcd for C15H17NO4Na [M + 2H-pyran-4-yl]carbamate Boc-1a. Yield: 41.3 mg (52%); mp ¼
½
Na]+ 298.1050; found 298.1050.
99–101 ꢁC (CDCl3); TLC: Rf ¼ 0.35 (hexane–EtOAc, 1/1); 1H NMR
4-Benzyl-4-nitro-6-phenyltetrahydro-2H-pyran-2-one 4g/4g0. (400 MHz, 305 K, CDCl3): d ¼ 1.44 [s, 9H, C(CH3)3], 1.54 [s, 3H,
Yield 245 mg (79%), dr 6.5 : 1 (inseparable mixture), mp ¼ 129– CH3], 2.21 [dd, 2J ¼ 15.6, 3J ¼ 3.4 Hz, 1H, CHAHB], 2.48 [t, 2J z 3J
135 ꢁC (Et2O), TLC: Rf ¼ 0.47 (hexane–EtOAc, 1/1); 1H NMR ¼ 14.0 Hz, 1H, CHAHB], 2.72 [d, 2J ¼ 16.9 Hz, 1H, CHCHD], 3.08
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1
[d, 2J ¼ 16.9 Hz, 1H, CHCHD], 4.61 [br s, 1H, NH], 5.29 [dd, 3J ¼ (hexane–EtOAc, 1/1); H NMR (400.1 MHz, 305 K, CDCl3): d ¼
2
12.1, 3J ¼ 3.4 Hz, 1H, CH], 7.26–7.42 [m, 5H, Ph] ppm; 13C NMR 1.36 [s, 3H, CH3], 1.42 [s, 9H, t-Bu], 2.29 [d, J ¼ 17.2 Hz, 1H,
(75.47 MHz, 305 K, CDCl3): d ¼ 26.6 [CH3], 28.5 [C(CH3)3], 42.5 CHAHB], 2.80 [d, 2J ¼ 17.2 Hz, 1H, CHAHB], 3.24 [t, 3J z 3J ¼ 6.8 Hz,
[CH2], 42.8 [CH2], 77.1 and 77.3 [C–N and C(CH3)3], 78.4 [OCH], 1H, CH], 4.48 [dd, 2J ¼ 11.2, 3J ¼ 7.8 Hz, 1H, CHCHD], 4.57 [dd, 3J ¼
126.0 and 128.8 [CHm-Ph and CHo-Ph], 128.6 [CHp-Ph], 139.0 11.2, 3J ¼ 6.7 Hz, 1H, CHCHD], 6.52 [br s, 1H, NH], 7.23 [dd, 3J ¼
[Ci-Ph], 154.2 [C]OBoc], 170.3 [OC ¼ O] ppm; HRMS (ES-I) calcd 7.8, 4J ¼ 1.4 Hz, 2H, CHo-Ph], 7.28–7.34 [m, 3H, CHm-Ph and CHp-Ph
]
for C17H23NO4Na [M + Na]+ 328.1519; found 328.1513.
ppm. 13C NMR (100.6 MHz, 305 K, CDCl3): d ¼ 21.8 [CH3],
tert-Butyl [rel-(2R,4R)-2-(4-bromophenyl)-4-methyl-6-oxo-tet- 27.8 [t-Bu], 41.5 [CH2C ¼ O], 50.8 [CH], 69.7 [OCH2], 69.7 [C–N],
rahydro-2H-pyran-4-yl]carbamate Boc-1b. Yield 55 mg (55%); 82.7 [C–O], 128.2 [CHp-Ph], 129.0 and 129.2 [CHo-Ph
m-Ph],
and
ꢁ
mp ¼ 172–173 C (hexane–Et2O, 1/1),TLC: Rf ¼ 0.39 (hexane– 136.8 [Ci-Ph], 153.2 [C]OBoc], 176.9 [OC]O] ppm; HRMS (ES-I)
1
EtOAc, 1/1); H NMR (300.13 MHz, 300 K, CDCl3): d ¼ 1.43 [s, calcd for C17H23NO4Na [M + Na]+ 328.1519; found 328.1523.
9H, C(CH3)3], 1.53 [s, 3H, CH3], 2.20 [dd, 2J ¼ 14.0, 3J ¼ 2.5 Hz,
1H, CHAHB], 2.49 [t, 2J z 3J ¼ 14.0 Hz, 1H, CHAHB], 2.71 [d, 2J ¼
16.9 Hz, 1H, CHCHD], 3.10 [d, 2J ¼ 16.9 Hz, 1H, CHCHD], 4.63 [br
Other transformations of nitro lactones 4
s, 1H, NH], 5.27 [dd, 3J ¼ 12.0, 3J ¼ 2.5 Hz, 1H, CH], 7.27 [d, 3J ¼
3-Methyl-3-nitro-5-phenylpentanoic acid 7. A solution of
8.4 Hz, 2H, CHAr], 7.53 [d, 3J ¼ 8.4 Hz, 2H, CHAr] ppm; 13C NMR nitro compound 4a (94 mg, 0.4 mmol) and suspended 5% Pd/
(75.47 MHz, 300 K, CDCl3): d ¼ 26.6 [CH3], 28.3 [C(CH3)3], 37.0 C (15 mg) in MeOH (2.0 mL) was stirred in a H2 atmosphere
[CH2], 42.3 [CH2], 77.5 [OCH], 78.2 and 80.2 [C–N and C(CH3)3] (from a balloon) for 8 hours. Aer that, the catalyst was
122.4 [CBr], 125.9 [CAr], 127.5 and 131.8 [CHAr], 154.1 [C]OBoc], separated out on a lter paper, washed 5 times with MeOH
169.7 [OC]O] ppm; HRMS (ES-I) calcd for C17H22BrNO4Na [M + (5 ꢂ 2 mL). The solvents were evaporated in vacuo. The residue
Na]+ 406.0624; found 406.0619.
was subjected to column chromatography (eluent MeOH–
Reduction of nitro lactone 4c. Aluminum foil was cut into CHCl3, 1/25) to give 92 mg (97%) of the nitro acid 7 as
ꢁ
strips (8 pieces, 20 ꢂ 5 mm, 120 mg, 4.4 mmol). The clean meal colorless prisms; mp ¼ 76–77 C (hexane–EtOAc, 1/20), TLC:
surface was washed with hexane and Et2O. Aer that, it was Rf ¼ 0.38 (CHCl3/CH3OH, 25/1); 1H NMR (300.13 MHz, 299 K,
poured into a 2% HgCl2 solution in water (10 mL) for 15 s, then CDCl3): d ¼ 1.81 [s, 3H, CH3], 2.19–2.37 [m, 2H, CH2], 2.63–
2
washed with MeOH, and Et2O without drying. Aer all these 2.69 [m, 2H, CH2], 2.94 [d, J ¼ 16.9 Hz, 1H, CHAHB], 3.30 [d,
preliminary preparations22 the foil was added to dioxane (4.5 2J ¼ 16.9 Hz, 1H, CHAHB], 6.00–7.10 [br s, 1H, COOH], 7.13–
mL). Then, the nitro lactone 4c (69 mg, 0.29 mmol) and water 7.35 [m, 5H, Ph] ppm; 13C NMR (75.47 MHz, 299 K, CDCl3): d ¼
(0.5 mL) were added successively with water bath cooling 22.9 [CH3], 30.2, 41.8 and 41.9 [3 CH2], 81.78 [CNO2], 126.5,
(Caution! exothermic reaction and hydrogen evaluation). The 128.3 and 128.7 [CHPh], 139.7 [Ci-Ph], 174.0 [COOH] ppm;
reaction mixture was stirred for 1 hour and additional water (0.5
C12H15NO4 (237.25): calcd C, 60.75; H, 5.90; N, 6.37; found C,
mL) was added. Aer an additional 18 hours, the reaction 60.88; H, 5.92; N, 6.33.
mixture was ltered through Celite® and washed with MeOH (3
4-Methyl-6-phenyl-5,6-dihydropyran-2-oneꢁ5a. tBuOK (21 mg,
ꢂ 7 mL). The solvents were evaporated in vacuo. The residue was 0.187 mmol) was added to a precooled to 0 C solution of the
dissolved in CHCl3 (5 mL) and poured into a mixture of brine (5 nitro lactone 4a (40 mg, 0.170 mmol) in THF (1.0 mL). The
mL) and CHCl3 (5 mL). The organic layer was separated and the reaction mixture was stirred for 15 min and poured into a Et2O
aqueous phase was extracted with CHCl3 (2 ꢂ 5 mL). The (5 mL)/H2O (4 mL) mixture. The water layer was back-extracted
combined organic phase was dried over Na2SO4, and the with Et2O (2 ꢂ 2 mL). The combined organic layers were washed
solvents were evaporated, to give the crude amine 1c (ꢃ60 mg), with H2O (4 mL), brine (4 mL) and dried over Na2SO4. The
which was dissolved in CH2Cl2 (2.0 mL).
solvents were evaporated in vacuo. The residue was subjected to
rel-(4S,5S)-4-Amino-4-methyl-5-phenyltetrahydro-2H-pyran- column chromatography (eluent EtOAc–hexane, 1/3) to give 30.1
1
2-one 1c. TLC: Rf ¼ 0.19 (hexane–EtOAc, 1/1); H NMR (300.1 mg (94%) of the enone 5a23 as a colorless solid; mp ¼ 58–60 ꢁC
MHz, 300 K, CDCl3): d ¼ 1.25 [br s, 2H, NH2], 1.40 [s, 3H, CH3], (Et2O), TLC: Rf ¼ 0.29 (hexane–EtOAc, 1/1); 1H NMR (300.13
2
2.32 [d, 2J ¼ 17.3 Hz, 1H, CHAHB], 2.79 [d, J ¼ 17.3 Hz, 1H, MHz, 299 K, CDCl3): d ¼ 2.03 [s, 3H, CH3], 2.46 [dd, 2J ¼ 17.9, 3J
3
3
2
3
CHAHB], 3.13 [dd, J ¼ 8.2, J ¼ 5.5 Hz, 1H, CH], 3.96 [dd, J ¼ ¼ 3.8 Hz, 1H, CHAHB], 2.65 [dd, 2J ¼ 17.9, J ¼ 12.1 Hz, 1H,
3
2
3
3
3
11.1, J ¼ 5.5 Hz, 1H, CHCHD], 4.24 [dd, J ¼ 11.1, J ¼ 8.2 Hz, CHAHB], 5.41 [dd, J ¼ 12.1, J ¼ 3.8 Hz, 1H, CH], 5.92 [s, 1H,
1H, CHCHD], 7.20 [dd, J ¼ 8.8, J ¼ 1.5 Hz, 2H, CHo-Ph], 7.19– ¼CH], 7.27–7.55 [m, 5H, Ph] ppm; 13C NMR (75.47 MHz, 299 K,
3
4
7.40 [m, 3H, CHm-Ph and CHp-Ph] ppm.
CDCl3): d ¼ 22.9 [CH3], 36.9 [CH2], 78.6 [OCH], 116.8 []CH],
tert-Butyl rel-(4S,5S)-4-methyl-2-oxo-5-phenyltetrahydro-2H- 126.1, 128.6 and 128.7 [CHPh], 138.7 [Ci-Ph], 157.0 []C], 164.9
pyran-4-ylcarbamate Boc-1c. To furnish the protected amine, [OC]O] ppm.
Boc2O (59 mg, 0.31 mmol) along with DMAP (2 mg, cat.) was
4-Methyl-5-phenyl-5,6-dihydropyran-2-one 5c. Obtained by
added to the 1c solution and the reaction mixture was stirred for the same procedure as 5a; yield 30.5 mg (95%), mp ¼ 49–50 ꢁC
2.5 hours. The solvents were evaporated in vacuo. The residue (Et2O), TLC: Rf ¼ 0.38 (hexane–EtOAc, 1/1); 1H NMR (400.1 MHz,
was subjected to preparative thin layer chromatography (eluent 305 K, CDCl3): d ¼ 1.85 [d, 4J ¼ 0.6 Hz, 3H, CH3], 3.49 [t, 3J z 3J ¼
hexane–EtOAc, 1/1) chromatography to give 70 mg (79%) of pure 4.8 Hz, 1H, CHPh], 4.38 [dd, 2J ¼ 11.2, 3J ¼ 4.8 Hz, 1H, CHAHB],
Boc-1c as a colorless oil, crystallized from a CH2Cl2–pentane 4.58 [dd, 2J ¼ 11.2, 3J ¼ 4.8 Hz, 1H, CHAHB], 5.98 [q, 4J ¼ 0.6 Hz,
mixture. Mp ¼ 106–107 C (pentane–Et2O, 2/1), TLC: Rf ¼ 0.31 1H, ¼CH], 7.19 [dd, 3J ¼ 7.9, 4J ¼ 1.5 Hz, 2H, CHo-Ph], 7.26–7.36
ꢁ
12474 | RSC Adv., 2014, 4, 12467–12475
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[m, 3H, Ph] ppm; 13C NMR (100.3 MHz, 305 K, CDCl3): d ¼ 21.7
[CH3], 45.1 [CH], 78.6 [OCH2], 117.7 []CH], 128.0 [CHp-Ph],
(b) T. Umezawa, T. Shinada and Y. Ohfune, Chem. Lett.,
2010, 39, 1281–1282.
128.1 and 129.1 [CHPh], 137.1 [Ci-Ph], 159.2 []C], 164.2 [OC]O]; 10 A. Hinman and J. Du Bois, J. Am. Chem. Soc., 2003, 125,
HRMS (ES-I) calcd for C12H12O2 [M + Na]+ 211.0730; found
211.0731.
11510–11511.
11 S. L. Ioffe, in Nitrile Oxides, Nitrones and Nitronates in Organic
Synthesis, ed. H. Feuer, John Wiley & Sons, Chichester,
United Kingdom, 2nd edn, 2008, pp. 435–748.
X-Ray data
12 S. Saaby, K. Nakama, M. A. Lie, R. G. Hazell and
K. A. Jørgensen, Chem.–Eur. J., 2003, 9, 6145–6154.
Single crystals, suitable for X-ray diffraction analysis, were
obtained by the slow cooling and slow evaporation of CHCl3
solutions of 4b, 4h, saturated at reux.
13 V. O. Smirnov, A. S. Sidorenkov, Yu. A. Khomutova, S. L. Ioffe
and V. A. Tartakovsky, Eur. J. Org. Chem., 2009, 3066–3074.
14 About C-C- and C-N-coupling of other nitronate types with
various nucleophiles, see (a) V. O. Smirnov, S. L. Ioffe,
A. A. Tishkov, Yu. A. Khomutova, I. D. Nesterov,
M. Y. Antipin, W. A. Smit and V. A. Tartakovsky, J. Org.
Chem., 2004, 69, 8485–8488; (b) Yu. A. Khomutova,
V. O. Smirnov, H. Mayr and S. L. Ioffe, J. Org. Chem., 2007,
72, 9134–9140; (c) V. O. Smirnov, Yu. A. Khomutova,
V. A. Tartakovsky and S. L. Ioffe, Eur. J. Org. Chem., 2012,
3377–3384; (d) A. A. Mikhaylov, A. D. Dilman,
Yu. A. Khomutova, D. E. Arkhipov, A. A. Korlyukov and
S. L. Ioffe, Eur. J. Org. Chem., 2013, 5670–5677.
Acknowledgements
This work was performed with the nancial support of the
Russian Foundation for Basic Research (Grant # 12-03-00278-a)
and the President of Russian Federation Program for support-
ing young scientists and leading scientic schools (Grant NSh-
412.2012.3).
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