Synthesis and chemical transformations of six/six-membered bicyclic nitroso acetals

Article abstract of DOI:10.1007/s11172-016-1575-9

A synthesis of hitherto unknown bicyclic nitroso acetals possessing two annulated six-membered rings is accomplished. The synthesis comprises formal [3+3] cycloaddition of six-membered cyclic nitronates with donor-acceptor cyclopropanes. Some chemical tra

Full text of DOI:10.1007/s11172-016-1575-9

Russian Chemical Bulletin, International Edition, Vol. 65, No.9, pp. 2243—2259, September, 2016
2243
Synthesis and chemical transformations of
six/sixꢀmembered bicyclic nitroso acetals*
A. A. Tabolin,a E. O. Gorbacheva,a R. A. Novikov,a,b Yu. A. Khoroshutina,a Yu. V. Nelyubina,c and S. L. Ioffea
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499)135 5328. Eꢀmail: tabolin87@mail.ru
bV. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,
32 ul. Vavilova, 119991 Moscow, Russian Federation
cA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation
A synthesis of hitherto unknown bicyclic nitroso acetals possessing two annulated
sixꢀmembered rings is accomplished. The synthesis comprises formal [3+3] cycloaddition of
sixꢀmembered cyclic nitronates with donorꢀacceptor cyclopropanes. Some chemical transꢀ
formations and conformational preferability of the obtained nitroso acetals are discussed.
Key words: nitroso acetals, donorꢀacceptor cyclopropanes, nitronates, cycloaddition.
The [3+2] cycloaddition between nitronic esters (nitrꢀ
onates) 1 and alkenes is known since the 1960s (Scheme 1,
reaction (1)). Cycloadducts, nitroso acetals 2, proved to
serve as useful intermediates for the organic synthesis.1 Of
special note is the tandem [4+2]/[3+2] cycloaddition
(Scheme 1, reaction (2)) thoroughly investigated in the
group of Prof. Denmark aimed at the total synthesis of
nearly two dozens of natural polyhydroxylated alkaloids of
various complexity.1,2 The first step of this sequence is the
[4+2] cycloaddition of nitroalkene 3 with electronꢀrich
olefin leading to sixꢀmembered cyclic alkyl nitronate 4
further subjected to [3+2] cycloaddition with an approꢀ
priate alkene. Thus obtained bicyclic nitroso acetal 5
upon hydrogenation underwent cleavage of both N—O
bonds. Unmasked amino group usually reacts with other
substrate functional groups ultimately leading to the target
molecule core.
One of the possible ways for expanding the described
strategy is the involvement of various dipoles but not only
olefins in cycloaddition with nitronates 4. Particularly,
formal [3+3] cycloaddition can substantially expand the
employment of nitronates 4 in organic synthesis. In the
preliminary communication,3 we disclosed that donorꢀ
acceptor cyclopropanes (DACs)4 6 could be considered as
good reaction partners for nitronates 4 (Scheme 1, reacꢀ
tion (3)). We report herein our full results of this investigaꢀ
tion, namely, the synthesis of nitroso acetals 7, and disꢀ
cuss some transformations of 7.
Results and Discussion
Synthesis of the substrates. Most of nitronates 4 and
DACs 6 were prepared according to the literature proceꢀ
dures. We like to note especially only the synthesis of DAC
6a from styrene and dimethyl malonate (Scheme 2). At
the first step, dimethylsulfonium salt 8 was prepared. At
the second step, salt 8 reacted with dimethyl malonate in
the presence of potassium carbonate. The described proꢀ
cedure led to DAC 6a in moderate yield due to side deꢀ
methylation of intermediate 8A.5 Performing the reaction
in homophasic mixture (acetone—water) enabled the synꢀ
thesis of DAC 6a in 89% yield.
Synthesis of nitroso acetals 7. In most of the cases,
activation of threeꢀmembered ring of DAC requires Lewis
acid. Its coordination to the ester groups leads to polarizaꢀ
tion of the C—C bond of the cyclopropane ring facilitating
the attack of a nucleophile (nitronate 4 in our case). At the
second step, a ring closure occurs via coupling of bisꢀ
(oxy)iminium cation with malonate moiety (Scheme 3).6
By careful choice of Lewis acids for the reaction of model
nitronate 4a and DAC 6a (Scheme 4), it was found that
ytterbium and scandium triflates in the presence of moꢀ
lecular sieves 4Å gave the best results: a complete conꢀ
sumption of substrates was achieved within 3 days in
dichloromethane at ambient temperature giving target
nitroso acetal 7a in high yields. Performing the reaction at
elevated temperature (80 °C) in toluene or 1,2ꢀdichloroꢀ
ethane expectedly accelerated the reaction but decreased
the product yield. This can be explained by acidic degraꢀ
dation of the starting nitronate 4.7 The reaction in nitroꢀ
* Based on the materials of the International Congress on the
Heterocyclic Chemistry "KOSTꢀ2015" (October 17—23, 2015,
Moscow, Russia).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2243—2259, September, 2016.
1066ꢀ5285/16/6509ꢀ2243 © 2016 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Tabolin et al.
Scheme 1
Scheme 2
Reagents and conditions: i. Me2S, Br2; ii. CH2(COOMe)2, K2CO3, acetone, water.
Scheme 3
methane is somewhat faster (reaction time was 24 h) but
this causes a small decrease in the yield of nitroso acetal
7a. Significant increase in the polarity of the reaction
medium (DMSO, ionic liquid [BMIM]OTf (BMIM is
1ꢀbutylꢀ3ꢀmethylimidazolium)) did not lead to a noticeable
conversion of substrates after 24 h. This can be due to
occupation of the coordination sites of Lewis acid by the
polar solvent molecules and/or the existence of a stable
complex between nitronate and Lewis acid withdrawing
the latter from the reaction sphere.8
Optimized conditions were extended to a variety of
substituted nitronates 4 and DACs 6 (Scheme 4, Table 1).
As can be seen form the obtained data, the transformation
is applicable to a wide range of substrates. Nitronates 4
bearing aryl and alkyl substituents as well as annulated
LA is Lewis acid.
with fiveꢀ or sixꢀmembered rings led to nitroso acetals 7 in
good yields. Unfortunately, cyclic nitronates possessing
alkoxy substituent at the C(6) (R3 = OMe, OEt) gave
mixtures of unidentified products due apparently to the
presence of a labile acetal center in the molecule. Monoꢀ

6,6ꢀAnnulated bicyclic nitroso acetals
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2245
Scheme 4*
Donorꢀacceptor cyclopropanes with poor activating subꢀ
stituents (R5 = Pr, H) turned out to be unreactive. Similar
trend was previously observed for the formal [3+3] cycloꢀ
addition of DAC with nitrones. However, more nucleoꢀ
philic nitrones (unlike nitronates) were involved in the
reaction with poorly activated DAC using the increased
catalyst loadings and higher reaction temperatures.10
Structures of the synthesized nitroso acetals 7 were
1
confirmed by H and 13C NMR spectroscopy including
2D NMR techniques (COSY, NOESY, HSQC, and
HMBC), elemental analysis, and highꢀresolution massꢀ
spectrometry. In most examined cases, [3+3] cycloaddiꢀ
tion proceeded with perfect diastereoselectivity producing
only one diastereomer of product 7. Decrease in diastereoꢀ
selectivity was observed for nitronates 4 with bulky subꢀ
stituent R3 (Pr, Ph). The rationale is given in Scheme 5.
At the first step, the equilibrium between nitronate 4, DAC 6,
and their primary adduct, i.e., zwitterꢀion A, is established
(Lewis acid is omitted for clarity). The latter can exists in four
reactive conformations A1—A4, where malonate moiety
approaches the iminium cation from the face opposite to
the bulky substituent R1. For nitronates 4g,h, conformaꢀ
tions A2 and A4 are the dominant due to (pseudo)ꢀ
equatorial position of the substituent R3. Both these conꢀ
formations allow stereoelectronically favored (pseudo)axial
approach of anion to the sixꢀmembered ring to occur. In
such event, conformation A2 leading to products 7 is
more favorable due to equatorial position of R5. For nitroꢀ
nates 4a—f,i, conformations A1 and A3 are preferable with
the substituents R1 and R4 occupying the equatorial posiꢀ
tions. For these conformations, stereoelectronically less
favorable (pseudo)equatorial approach of anion takes
place. Herein, transition state of conformation A1 with
the equatorial substituent R5 can occur, while transition
state of conformation A3 is less favorable due to axial
position of substituent R5 and already mentioned pseudoꢀ
Reagent and conditions: Yb(OTf)3, molecular sieves 4Å, CH2Cl2,
25 °C, 3 days.
* Substituents R1—R5 are given in Table 1.
substituted nitronate 4j (R1 = R2 = R3 = H, R4 = Ph) was
found to be unstable under the reaction
conditions, which is in accord with
the trend of the increasing stability of
nitronates with an increase in the deꢀ
gree of substitution.9 Note that camꢀ
pheneꢀderived nitronate 4k turned out
to be unreactive under the optimized
reaction conditions, which can be asꢀ
cribed to its bulkiness.
Among tested DACs 6, substrates
with strong activating substituents (R5
is aryl, hetaryl, and stiryl) were the
most reactive in [3+3] cycloaddition. For substrate 6f
(R5 = CH=CH2), the lower yield of 7g was observed.
Table 1. Yields of compounds 7 in the reactions of nitronates 4 with DACs 6
Entry Nitronate DAC Product
R1
R2
R3
R4
R5
Yield (%)
dr 7 : 7´
1
2
3
4
4a
4b
4b
4b
4b
4b
4b
4c
4d
4d
4e
4f
6a
6a
6b
6c
6d
6e
6f
6c
6a
6e
6c
6a
6a
6a
6a
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
4ꢀClC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
Ph(CH2)2
4ꢀMeOC6H4
4ꢀMeOC6H4
Ph
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
Ph
Ph
61
91
92
77
70
69
41
75
80
84
92
39
85
67
82
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
2.2 : 1
3.5 : 1
1 : 0
4ꢀClC6H4
4ꢀMeOC6H4
2ꢀThienyl
CH=CHPh
CH=CH2
4ꢀMeOC6H4
Ph
CH=CHPh
4ꢀMeOC6H4
Ph
5
6*
7*
8
9
(CH2)4
(CH2)4
(CH2)3
10
11
12
13
14
15
4ꢀMeOC6H4
4ꢀMeOC6H4
Ph
H
H
H
H
Me
4g
4h
4i
Pr
Ph
H
Ph
Ph
Ph
H
Ph
Ph
* In MeNO2. Reaction time was 24 h.

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Tabolin et al.
Scheme 5
R = CO2Me
(equatorial) approach. Thus, among conformations A1 and
A3 only the former is reactive leading to diastereomers 7.
Investigation of conformation preferability of nitroso
acetals 7. Conformation preferability of nitroso acetals 7
is of special interest. It was determined based on NMR
NOESY data and singleꢀcrystal Xꢀray diffraction analysis.
A priori three possible chair—chair conformations 7A, 7B,
and 7C could be proposed (Scheme 6). They are interconꢀ
nected through processes of inversion of the nitrogen atom
and ring. In conformations 7B and 7C, anomeric effect11
in the O—N—O system can occur thus enhancing the
thermodynamic preferability of these conformations. For
the studied nitroso acetals 7, only conformations 7A and
7B were observed (Table 2). Herewith, in many cases (7a—h,l)
both these conformations were observed by NMR spectroꢀ
scopy. Diastereomeric nitroso acetals 7´ exist in boat—
chair conformation 7D. Reasonably, the Bꢀring impacts
the dominant conformation of products 7 most greatly,
thus in all examined cases a bulky substituent R5 adopted
an equatorial position. For nitroso acetals 7´, this led to
the distortion of the Aꢀring. The preference between conꢀ
formation 7A or 7B for products 7 can be explained by
relative steric hindrance of substituents R1, R3, and R4.
For compounds 7m,n with the bulky substituents R3 (Pr, Ph)
and R4 = H, only conformation 7B was observed in NMR
spectra. In this conformation, the substituent R3 adopted
equatorial position, while the destabilizing 1,3ꢀdiaxial inꢀ
teraction between substituents R1 and R4 is low. Decrease
in the size of substituent R3 (R3 = Me) led to an increase
in the content of conformer 7A (compound 7l). In turn, an
increase in the size of substituent R4 (R4 = Me) increases
the content of conformation 7A (compounds 7a—g).
Conversely, a decrease in the size of substituent R1
(R1 = CH2CH2Ph) with R3 = R4 = Me led to nearly equal
content of conformers (compound 7h). In nitroso acetal 7o,
all bulky aryl substituents (R1 = R4 = R5 = Ph) adopted
equatorial positions in conformation 7A.
Conformers 7A and 7B are diastereomers at nitrogen
atom. Herein, it is interesting that they cannot be separated
Scheme 6
R = CO2Me

6,6ꢀAnnulated bicyclic nitroso acetals
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2247
Table 2. Conformations of compounds 7
Compound
R1
R2
R3
R4
R5
Ratio of
conformations
7A : 7B
7a—g
7h
7i—k
7l
7m,n
7o
Ph, 4ꢀClC6H4, 4ꢀMeOC6H4
Ph(CH2)2
H
H
Me
Me
Me
Me
H
H
H
Ar, CH=CHPh, CH=CH2
4ꢀMeOC6H4
Ph, 4ꢀMeOC6H4, CH=CHPh
>6 : 1
1.2 : 1
1 : 0
1 : 7
0 : 1
4ꢀMeOC6H4, Ph
4ꢀMeOC6H4
4ꢀMeOC6H4, Ph
Ph
(CH2)4, (CH2)3
H
H
H
Me
Pr, Ph
H
Ph
Ph
Ph
Ph
1 : 0
ln(k/T)
by column chromatography although the nitrogen inverꢀ
sion barrier can be high enough for the isomers to be reꢀ
solved.12 In the case of conformers 7A and 7B, a low inꢀ
version barrier is apparently accounted for the bicyclic
structure. The absence of apparent broadening in 1H NMR
spectra as well as presence of the exchange peaks in NOESY
–6.0
–8.0
–10.0
–12.0
1
2
R
R
2 = 0.9855
2 = 0.9936
spectra for the most of nitroso acetals 7 evidenced that
→
conformation change A
B is slow in the NMR timesꢀ
←
cale. Measurements of the barrier using determination of
the rate constants for forward and reverse reactions with
the aid of EXSY NMRꢀspectroscopy13 for nitroso acetal 7b
gave values ΔG≠298(A → B) and ΔG≠298(B → A) equal of 20.9
and 19.2 kcal mol–1, respectively (Fig. 1, Table 3). Thus,
the value of the nitrogen inversion barrier in bicyclic nitroso
acetal 7b is close to those of acyclic bis(alkoxy)amines 9
(ΔG≠298 ≈ 20—24 kcal mol–1) and is substantially lower than
those of monocyclic fiveꢀmembered nitroso acetals, alkoxy
3.15 3.20 3.25 3.30 3.35 3.40 (1/T)•1000
Fig. 1. Dependences ln(k/T)—1/T used for calculation of
→
thermodynamic parameters of conformational change A
for nitroso acetal 7b: 1, process B → A;2, process A → B.
B
←
hydrogenation is accomplished directly after assembly of
the bicyclic nitroso acetal structure although there are
examples of the functional group manipulations remainꢀ
ing the nitroso acetal moiety intact.2d,16 On the basis of
structural similarity of nitroso acetals 5 and 7 their similar
reactivity can be expected. Particularly, the cleavage of
one of the N—O bond should lead to 1,2ꢀoxazine derivaꢀ
tives, which are the useful intermediates for organic synꢀ
thesis and, moreover, are found among the natural comꢀ
pounds (Fig. 2).17 At the same time, unmasking the alcohol
group(s) in the presence of ester groups should lead to
lactone ring closure to give αꢀaminoalkylꢀγꢀbutanolide
moiety also presented in bioactive compounds (see Fig. 2).18
Catalytic hydrogenation of adducts 7 was envisioned
as the most straightforward route to target amino diols.
However, in the most cases attempts of hydrogenation of
model substrate 7b under different conditions (up to
50 atm H2, NiꢀRa, Pd/C, PtO2, etc.) did not lead to its
noticeable conversion. Only hydrogenation over freshly
isoxazolidines 10 (ΔG≠ ≈ 26—29 kcal mol–1).12,14 For
298
analogous sixꢀmembered nitroso acetals, 2ꢀsiloxyꢀ1,2ꢀoxꢀ
azines 11, the inversion barrier was not measured. Howevꢀ
er, the possibility to resolve the diastereomers possessing
nitrogen atom with different configurations suggests that
the barrier is close to those of isoxazolidines 10.15
Chemical transformations of nitroso acetals 7. As it was
mentioned above, reduction is the most investigated transꢀ
formation of nitroso acetals. Their catalytic hydrogenaꢀ
tion releases the amino and alcohol moieties able to react
with other functional groups of substrate. Usually, the
Table 3. Inversion barriers of comformers A and B of compound 7b
Process
Eyring parameters
Arrhenius parameters
ΔH≠/kcal mol–1
ΔS≠/cal mol–1•K–1
Ea/kcal mol–1
lnA
A → B
B → А
25.65 0.92
22.10 1.20
15.99 3.00
19.86 3.92
26.25 0.92
22.70 1.20
38.53 1.51
35.44 1.97

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Tabolin et al.
Fig. 2. Structures of natural and biologically active derivatives of 1,2ꢀoxazine and αꢀaminoalkylꢀγꢀbutyrolactone.
prepared Raney nickel in methanol at elevated temperaꢀ
tures gave the isolable product, amino alcohol 12 (Scheme 7).
A plausible mechanism of formation of 12 involves
a retroꢀMannich reaction (cf. for a plausible mechanism of
the formation of nitroso acetals 7; see Scheme 3) followed
by interception of the iminium cation A by a solvent molꢀ
ecule.19 Thus, hydrogenation involves an intermediate of
type 13 lacking the C—C bond formed during [3+3] anꢀ
nulation. The confirmation of the hypothesis is the appearꢀ
ance of additional signals in the NMR spectra upon reꢀ
fluxing 7b in methanol. Another proof is the stability of
substrate 7b under the hydrogenation conditions using ethyl
acetate or propanꢀ2ꢀol as solvents. Such low reactivity of
nitroso acetal 7b can be accounted for the following facts.
Firstly, a low coordination ability of the O—N—O moiety
possessing three highly electronegative atoms and thus
unable coordinating to metal surface. Secondly, a steric
hindrance around the O—N—O moiety. Thirdly, the abꢀ
sence of any strain in sixꢀmembered ring.*
Among other reduction procedures tried, we should
note the reaction with samarium(II) iodide (Scheme 8).20
Unfortunately, in this case decomposition of carbon backꢀ
bone also occurred producing lactone 1421 as a major prodꢀ
uct (NMR data). This can be ascribed to coordination of
samarium to the ester group followed by electron transfer
to them but not to the N—O bond.
Scheme 7
Another possibility to enable the cleavage of the
nitroso acetals N—O bond is the treatment of 7 with acids.
It is known that under such conditions αꢀCHꢀnitroso aceꢀ
tals are prone to alcohol elimination leading to oxime
ethers.22 Indeed, adduct 7b underwent fast and selective
transformation into oxazinoꢀsubstituted butyrolactone 15
on treatment with strong acids (CF3COOH, camphorsulꢀ
fonic acid, HCl) (Scheme 9). Interestingly, only one of
* Hydrogenation of annulated nitroso acetals possessing fiveꢀ
and sixꢀmembered rings was usually accomplished for two types
of substrates. The first type is the cage structures that are preꢀ
sumably more strained than bis(sixꢀmembered). The second type
is alkoxyꢀsubstituted with the weakened N—O bond.
Ar = 4ꢀMeOC6H4
Reagents and conditions: i. H2 (40 atm.), Raney Ni, Boc2O,
MeOH, 60 °C, 5 h.

6,6ꢀAnnulated bicyclic nitroso acetals
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2249
Scheme 8
Unidentified
products
Ar = 4ꢀMeOC6H4
Reagents and conditions: i. SmI2, THF, 25 °C, 24 h; ii. aqueous workꢀup.
* 1H NMR spectroscopy data.
Scheme 9
Ar = 4ꢀMeOC6H4
two available N—O bonds was broken as well as only one
of two ester groups participated in lactonization. Evidentꢀ
ly, the reaction proceeded through elimination of an alcoꢀ
hol moiety with its concomitant ring closure into ester
group. Partial formation of lactone 15 can be also obꢀ
served after dissolution of nitroso acetal 7b in commercial
(undistilled) deuterochloroform. In weak acetic acid, comꢀ
pound 7b is stable during several days, while a mixture of
15 and its diastereomer 15´ (15 : 15´ = 5 : 1) (Fig. 3) is
formed at elevated temperatures (60—80 °C).
Modification of ester groups of nitroso acetals 7 turned
out to be possible by treatment with lithium aluminum
hydrides leaving nitroso acetal group intact (Scheme 10).
Reduction of both carboxylate moieties occurred on treatꢀ
ment with either LiAlH4 or DIBALꢀH. Selective monoꢀ
reduction of compound 7b was achieved on treatment
with bulky tris(tertꢀbutoxy)aluminum hydride.23 Reasonꢀ
ably, equatorial methoxycarbonyl group underwent reducꢀ
tion, that was proved by the NOESY data. Such transforꢀ
mation is of some generality that is shown on nitroso aceꢀ
tals 7b,h,k,m (see Scheme 10).
Apart from reduction, selective monoꢀsaponification
of the ester group was possible on treatment with sodium
trimethylsilanolate (Scheme 11). Successive acidꢀcataꢀ
lyzed decomposition of nitroso acetals was accompanied
by decarboxylation to furnish oxazine 19.* Compound 19
was subjected to reduction with sodium cyanoborohydride
without additional purification. Thus obtained tetrahyꢀ
* Conversion 7b → 19 without isolation of intermediate nitroso
acetal 18 was challenging. Polar solvent (THF) used for saponiꢀ
fication required substantial excess of TFA (50 equiv.) for decomꢀ
position of nitroso acetal. We accounted it for the increased
basicity of THF relatively to substrate 18.

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Tabolin et al.
C(25)
C(25)
O(6)
C(18)
O(6)
C(22)
C(22)
C(21)
C(20)
O(5)
C(21)
C(23)
C(23)
O(4)
C(17)
C(24)
C(20)
C(19)
C(2)
O(4)
C(19)
C(2)
C(18)
C(7)
C(24)
C(1)
O(3)
C(8)
C(7)
C(16)
C(11)
C(17)
C(3)
C(9)
C(10)
O(2)
O(5)
C(10)
C(15)
N(1)
C(6)
C(4)
O(2)
O(1)
C(9)
C(1)
C(3)
C(4)
C(8)
C(11)
C(14)
C(13)
C(16)
C(14)
C(5)
C(12)
N(1)
C(15)
O(3)
C(12)
O(1)
C(5)
C(6)
C(13)
15
15´
Fig. 3. General view of compounds 15 and 15´ with displacement ellipsoids of nonꢀhydrogen atoms drawn at 50% probability level).
Scheme 10
matography of the crude product we isolated a diastereoꢀ
meric mixture of 19 and 19´ in a 3 : 1 ratio. It is also of
note that treatment of product 19 with either acid (AcOH)
or bases (NEt3, DMAP) did not lead to selective formaꢀ
tion of isomer 19´. On the contrary, appearance of the
additional signals in NMR spectra can be regarded as an
evidence of epimerization of the C(4) oxazine ring stereoꢀ
center. Presumably, epimerization at the αꢀposition of buꢀ
tyrolactone is suppressed due to intermediate formation of
enamine 18A possessing an exoꢀcyclic double bond. Anꢀ
other confirmation is the formation of dihydroꢀ2Hꢀoxꢀ
azine 22 during acylation of substrate 19.24
Ar = 4ꢀMeOC6H4
Dihydrooxazine 19 was converted into polysubstituted
amino alcohol 21 in two steps. Reduction of the C=N
double bond was expectedly stereoselective.17a,25 Reducꢀ
tive cleavage of the N—O bond was accomplished with
samarium diiodide chosen due to its selectivity.19a,26 Inꢀ
deed, the attempts of catalytic hydrogenation of tetraꢀ
hydrooxazine 20 over various catalysts (H2 with Pd/C, H2
with Raney Ni) gave mixtures of unidentified products.
This can be explained by lability of arylꢀsubstituted lactone
also susceptible to hydrogenolysis. No conversion of subꢀ
strate 20 was achieved with such reagents as Mo(CO)6
and Zn.27
Similar transformation sequence was performed for
nitroso acetal 17a (Scheme 12). Here, we should also note
the importance of the correct workꢀup of the reaction
mixture before chromatography of lactone 23. Prelimiꢀ
nary quenching of TFA with sodium hydrogen carbonate
allowed us to selectively prepare the target lactone 23. In
contrast, usual concentrating the reaction mixture led to
Comꢀ
pound
7b, 17a 4ꢀMeOC6H4
7h, 17b Ph(CH2)2
7k, 17c
R1
R2
R3
R4
R5
Ph
Yield of 17
(%)
84
98
74
81
H
H
Me Me
Me Me 4ꢀMeOC6H4
Ph
(CH2)3
H
H
H
4ꢀMeOC6H4
7m, 17d 4ꢀMeOC6H4
Pr
Ph
Reagents and conditions: i. LiAlH4, THF, 6 h; ii. LiAlH(OBut)3,
THF, reflux, 3—8 h.
drooxazine 20 was converted into amino alcohol 21 by
treatment with samarium(II) iodide. It is worthy of note
that additional manipulations with oxazine 19 can lead to
epimerization of stereocenters. Thus, after column chroꢀ

6,6ꢀAnnulated bicyclic nitroso acetals
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2251
Scheme 11*
Ar = 4ꢀMeOC6H4
Reagents and conditions: i. TMSONa, THF, 24 h; ii. CF3COOH, CH2Cl2, 3.5 h; iii. NaBH3CN, AcOH, 18 h; iv. SmI2, THF, 24 h;
v. AcBr, Ac2O, CH2Cl2, 2.5 h.
* Yields of compounds 20 and 22 are given based on nitroso acetal 18.
Scheme 12
Ar = 4ꢀMeOC6H4
Reagents and conditions: i. CF3COOH, CH2Cl2, 1 h; ii. NaBH3CN, AcOH, 18 h; iii. 1) SmI2, THF, 72 h, 2) Boc2O, CH2Cl2, 24 h.
partial epimerization 23 → 23´ (Fig. 4) occurring presumꢀ
(NaBH3CN) and N—O (SmI2) bonds furnished polyfuncꢀ
ably due to increasing acidity. Reduction of the C=N
tional amino diol 25.

2252
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Tabolin et al.
(rel)ꢀ(4S,4aR,7aR)ꢀ4ꢀPhenylꢀ4,4a,5,6,7,7aꢀhexahydrocycloꢀ
penta[e][1,2]oxazine Nꢀoxide (4e). To a solution of [(E)ꢀ2ꢀ
nitroethenyl]benzene35 (1.11 g, 7.4 mmol) in CH2Cl2 (74 mL),
cyclopentene (1.30 mL, 14.8 mmol) and SnCl4 (1.05 mL,
8.9 mmol) were successively added under argon at –78 °C. The
reaction mixture was maintained at –20 °C for 18 h and partiꢀ
tioned between EtOAc (300 mL) and saturated aqueous Na2CO3
(200 mL). The organic layer was successively washed with
Na2CO3 (100 mL), water (100 mL), and brine (2×100 mL), dried
with Na2SO4, and the solvent was removed in vacuo. Crystalliꢀ
zation of the residue from hexane—EtOAc (4 : 1) afforded 1.10 g
(68%) of target Nꢀoxide 4e, white powder, m.p. 77—79 °C;
Rf 0.39 (from hexane—EtOAc, 1 : 1). Found (%): C, 71.70; H, 7.01;
N, 6.41. C13H15NO2. Calculated (%): C, 71.87; H, 6.96; N, 6.45.
1H NMR, δ: 1.52—1.73 (m, 2 H); 1.79—2.04 (m, 4 H); 2.35—2.44
(m, 1 H, 3 H2C, H(5)); 3.48 (dd, 1 H, H(4), J = 6.7 Hz, J = 3.8 Hz);
4.91 (dt, 1 H, H(6), J = 8.1 Hz, J = 4.1 Hz); 6.50 (d, 1 H, H(3),
J = 3.8 Hz); 7.22—7.41 (m, 5 H, Ph). 13C NMR, δ: 22.8, 30.6,
32.1, 45.0, 48.8 (C(4), C(5), C(7), C(8), C(9)); 86.6 (C(6));
117.3 (C(3)); 127.7, 127.9, 129.3 (CHPh); 140.3 (CPh).
C(17)
O(5)
C(23)
C(22)
C(14)
C(24)
O(3)
C(15)
C(16)
C(19)
C(21)
C(20)
C(13)
C(12)
C(7)
C(6)
C(11)
C(3)
O(2)
C(4)
C(8)
C(5)
O(4)
C(2)
C(1)
C(18)
N(1)
O(1)
C(10)
C(9)
(rel)ꢀ(4S,6R)ꢀ4ꢀ(4ꢀMethoxyphenyl)ꢀ6ꢀmethylꢀ5,6ꢀdihydroꢀ
4Hꢀ[1,2]oxazine Nꢀoxide (4f). To a solution of 1ꢀmethoxyꢀ4ꢀ
[(E)ꢀ2ꢀnitroethenyl]benzene35 (0.61 g, 3.4 mmol) in CH2Cl2
(24 mL), SnCl4 (0.44 mL, 3.7 mmol) was added under argon at
–78 °C. Then propene was bubbled through the resultant dark
red solution. Propene was generated by adding PriOH (5 mL) to
P2O5 (14.2 g, 0.1 mol) followed by heating at ∼200 °C; the proꢀ
pene flow was passed through a washing bottle filled with sulfuꢀ
ric acid. The reaction mixture was maintained at –78 °C for 3 days,
partitioned between EtOAc (150 mL), and concentrated aqueꢀ
ous Na2CO3 (150 mL). The organic layer was successively washed
with Na2CO3 (50 mL), water (100 mL), and brine (2×100 mL),
dried with Na2SO4, and the solvent was removed in vacuo. Crysꢀ
tallization of the residue from hexane—EtOAc (4 : 1) afforded
0.44 g (59%) of target Nꢀoxide 4f, white powder, m.p. 74—76 °C.
Rf 0.20 (hexane—EtOAc, 1 : 1). Found (%): C, 64,94; H, 6.95;
N, 6.23. C12H15NO3. Calculated (%): C, 65.14; H, 6.83; N, 6.33.
1H NMR, δ: 1.35 (d, 3 H, Me(6), J = 6.2 Hz); 1.90 (dt, 1 H,
H(5), J = 13.9 Hz, J = 2.4 Hz); 2.09 (ddd, 1 H, H(5), J = 13.9 Hz,
J = 10.5 Hz, J = 7.3 Hz); 3.80 (s, 3 H, OMe); 3.78—3.87
(m, H(4)); 4.52 (dqd, 1 H, HC(6), J = 12.3 Hz, J = 6.2 Hz,
23´
Fig. 4. General view of compound 23´ with displacement ellipꢀ
soids of nonꢀhydrogen atoms drawn at 50% probability level.
In conclusion, the application area for reaction of the
formal [3+3] cycloaddition between nitronates 4 and
DACs 6 was determined. The major regularities of this
transformation were elucidated. Potential for further transꢀ
formations of adducts 7 was demonstrated including apꢀ
plication for the diastereoselective synthesis of polysubstiꢀ
tuted amino alcohols possessing up to four chiral centers.
Experimental
For column chromatography, silica gel Acros 40ꢀ60 μm, 60 Å
was used. NMR spectra were run with Bruker AVꢀ300 (300 MHz)
and Bruker AMXꢀ400 (400 MHz) instruments in CDCl3 (if not
stated overwise). The chemical shifts are given in the δ scale
relative to the residual solvent signal. High resolution mass spectra
were recorded on a Bruker MicroTOF instrument. Elemental
analyses were performed in Analytical Laboratory of N. D. Zelinꢀ
sky Institute of Organic Chemistry of RAS. Melting points were
measured with a Kofler apparatus and are given uncorrected.
Commercially available reagents were used as purchased.
Nitronates 4a,b,3 4c,28 4d,3 4e,3 4h,i,28 and DACs 6b,29 6c,d,30
6e,31 6f32 were synthesized by the known procedures. A solution
of samarium(II) iodide was prepared and titrated prior to use.33
Dimethyl 2ꢀphenylcyclopropaneꢀ1,1ꢀdicarboxylate (6a). To
a stirred solution of K2CO3 (10.8 g, 79 mmol) in water (26 mL),
acetone (26 mL), dimethyl malonate (6.0 mL, 52 mmol), and
dimethylsulfonium salt 85a (8.53 g, 26.2 mmol) were added sucꢀ
cessively. The reaction mixture was stirred for 8 h and partitionꢀ
ed between EtOAc (200 mL) and water (50 mL). The organic layer
was washed with brine (50 mL), dried with Na2SO4, and the
solvent was removed in vacuo. Vacuum distillation of the residue
afforded 5.46 g (89%) of the title product, light yellow oil, b.p.
95—98 °C (0.30 Torr). 1H NMR spectral data of the synthesized
compound 6a are in accord with those published earlier.34
J = 2.0 Hz); 6.45 (d, 1 H, H(3), J = 4.4 Hz); 6.89 (d, 2 H, HCAr
,
J = 8.6 Hz); 7.15 (d, 2 H, HCAr, J = 8.6 Hz). 13C NMR, δ: 18.9
(Me(6)); 34.8 and 37.5 (C(4) and C(5)); 55.4 (OMe); 74.7 (C(6));
113.1 (C(3)); 114.6 (CHAr); 128.8 (CHAr); 133.6 (CAr); 159.2 (CAr).
Synthesis of nitroso acetals 7 (general procedure). Molecular
sieves 4Å were dried under vacuum (0.5 Torr) at 200 °C for 10 min.
A solution of Yb(OTf)3•xH2O (0.05 equiv.) in CH2Cl2 (2 mL
per 1 mmol of nitronate 4) was stirred with molecular sieves 4 Å
(10 mg per 1 mp of Yb(OTf)3) for 20 min under argon. Then
a solution of nitronate 4 (1 equiv.) and DAC 6 (1 equiv.) in CH2Cl2
(3 mL per 1 mmol of nitronate 4) was added. The reaction mixꢀ
ture was stirred at room temperature for 3 days, filtered through
a Celite pad (eluting with MeOBut (40 mL)). The organic layer
was washed with 0.1 M HCl (20 mL), saturated aqueous NaHCO3
(20 mL), brine (2×20 mL), dried with Na2SO4, and the solvent
was removed in vacuo. Purification of the residue by column
chromatography afforded the target nitroso acetals 7. Yields of
nitroso acetals are summarized in Table 1. Physicochemical
properties of compounds 7a—e,i,m,n are in accord with those
published earlier.3

6,6ꢀAnnulated bicyclic nitroso acetals
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2253
Dimethyl (rel)ꢀ(2S,4aR,5S)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ7,7ꢀdiꢀ
methylꢀ2ꢀ((E)ꢀ2ꢀphenylvinyl)hexahydroꢀ4Hꢀ[1,2]oxazino[2,3ꢀb]ꢀ
[1,2]oxazineꢀ4,4ꢀdicarboxylate (7f). Nitroso acetal 7f was synꢀ
thesized following the general procedure with the use of MeNO2
as a solvent, reaction time was 24 h. M.p. 125—127 °C (from
hexane—EtOAc, 20 : 1); Rf 0.26 (hexane—Et2O, 1 : 1). Found (%):
C, 67.99; H, 6.81; N, 2.80. C28H33NO7. Calculated (%): C, 67.86;
H, 6.71; N, 2.83. According to NMR data, nitroso acetal 7f is
a mixture of two diastereomers in a 19 : 1 ratio. 1H NMR (COSY,
NOESY), δ: 1.31, 1.49 (both s, 3 H each, both Me(6)); 1.63 (dd,
1 H, Heq(5), J = 13.3 Hz, J = 4.8 Hz); 1.81 (dd, 1 H, Hax(5),
J = 13.0 Hz, J = 11.8 Hz); 2.10 (dd, 1 H, Hax(8), J = 13.3 Hz,
J = 11.6 Hz); 2.50 (dd, 1 H, Heq(8), J = 13.3 Hz, J = 1.9 Hz); 2.96
(s, 3 H, CO2Me); 3.52 (d, 1 H, H(3), J = 11.3 Hz); 3.78 (s, 3 H,
CO2Me); 3.90 (s, 3 H, OMeAr); 4.50 (td, 1 H, H(4), J = 12.5 Hz,
J = 4.8 Hz); 4.67 (ddd, 1 H, H(9), J = 11.6 Hz, J = 6.3 Hz,
J = 1.9 Hz); 6.16 (dd, 1 H, HC(9)CH=, J = 16.1 Hz, J = 6.3 Hz);
6.66 (d, 1 H, =CHPh, J = 16.1 Hz); 6.83 (d, 2 H, CHAr, J = 8.7 Hz);
7.21—7.37 (m, 7 H, CHAr and Ph). 13C NMR (DEPT, HSQC,
HMBC), δ: 22.9 (CH3(6)); 29.1 (CH3(6)); 38.0 (CH(4)); 40.2
(CH2(8)); 45.8 (CH2(5)); 52.4, 52.5 (CO2Me); 55.3 (OMeAr);
57.2 (C(7)); 74.3 (CH(3)); 76.0 (CH(9)); 77.2 (C(6)); 113.6
(CH(Ar)); 126.0, 126.6, 128.0, 128.6, 130.5 (3 CHPh, CHAr and
C(9)CH=); 132.9 (CAr); 133.0 (=CHPh); 136.4 (CPh); 158.5
(CAr); 169.1, 169.2 (both C=O). Characteristic signals of the
minor conformer in 1H NMR, δ: 5.19—5.27 (m, 1 H, H(9)).
Dimethyl (rel)ꢀ(2S,4aR,5S)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ7,7ꢀdimeꢀ
thylꢀ2ꢀvinylhexahydroꢀ4Hꢀ[1,2]oxazino[2,3ꢀb][1,2]oxazineꢀ4,4ꢀ
dicarboxylate (7g). Nitroso acetal 7g was synthesized following
the general procedure with the use of MeNO2 as a solvent, reacꢀ
tion time was 24 h. Oil, Rf 0.39 (hexane—Et2O, 1 : 1). MS, m/z:
420.2003 [MH]+. C22H29NO7. Calculated for [MH]+: 420.2017.
According to NMR spectral data, nitroso acetal 7g is a mixture
of two conformers in a 6 : 1 ratio. 1H NMR (COSY, NOESY,
acetoneꢀd6), δ: 1.18, 1.38 (s, 3 H, both Me(6)); 1.57 (dd, 1 H,
Heq(5), J = 13.2 Hz, J = 4.8 Hz); 1.72 (dd, 1 H, Hax(5), J = 13.2 Hz,
J = 11.8 Hz); 1.83 (dd, 1 H, Hax(8), J = 13.1 Hz, J = 11.8 Hz);
2.36 (dd, 1 H, Heq(8), J = 13.1 Hz, J = 1.8 Hz); 2.93 (s, 3 H,
CO2Me); 3.33 (d, 1 H, H(3), J = 11.2 Hz); 3.75 (s, 3 H, CO2Me);
3.82 (s, 3 H, OMeAr); 4.36—4.43 (m, 1 H, H(9)); 4.46 (ddd, 1 H,
H(4), J = 11.8 Hz, J = 11.2 Hz, J = 4.8 Hz); 5.17 (d, 1 H,
Hcis(=CH2), J = 10.7 Hz); 5.28 (d, 1 H, Htrans(=CH2), J = 17.4 Hz);
5.80 (ddd, 1 H, H(=CH)), J = 17.4 Hz, J = 10.7 Hz, J = 5.6 Hz);
6.82 (d, 2 H, CHAr, J = 8.6 Hz); 7.23 (d, 2 H, CHAr, J = 8.6 Hz).
13C NMR (DEPT, HSQC, HMBC, acetoneꢀd6), δ: 23.2, 29.3
(both CH3(6)); 40.8 (CH2(8)); 46.3 (CH2(5)); 52.5 (both CO2Me);
55.5 (OMeAr); 57.9 (C(7)); 74.8 (CH(3)); 76.3 (CH(9)); 76.9
(C(6)); 114.2 (CHAr); 117.1 (=CH2); 131.3 (CHAr); 133.8 (CAr);
136.6 (CH=CH2)); 159.4 (CAr); 169.7 and 169.8 (2 C=O)). Charꢀ
acteristic signals of the minor conformer in 1H NMR (acetoneꢀd6),
δ: 2.50 (dd, 1 H, Heq(8), J = 13.6 Hz, J = 2.6 Hz); 3.95—4.09 (m,
2 H, H(3) and H(4)); 4.98—5.04 (m, 1 H, H(9)).
1.81 (dd, 1 H, Heq(5), J = 13.3 Hz, J = 4.7 Hz); 1.82—1.91 (m, 1 H,
HbC—C(4)H); 2.06 (dd, 1 H, Hax(8), J = 11.9 Hz, J = 10.0 Hz);
2.47—2.55 (m, 1 H, HaC—Ph); 2.51 (dd, 1 H, Heq(8), J = 13.4 Hz,
J = 2.1 Hz); 2.62—2.69 (m, 1 H, H(4)); 2.66—2.75 (m, 1 H,
HbC—Ph); 3.34 (d, 1 H, H(3), J = 8.9 Hz); 3.61 (s, 3 H, CO2Me);
3.77 (s, 3 H, OMe); 3.79 (s, 3 H, CO2Me); 5.17 (dd, 1 H, H(9),
J = 11.4 Hz, J = 1.9 Hz); 6.83 (d, 2 H, HCAr, J = 8.7 Hz);
7.15—7.33 (m, 7 H, HCAr and Ph). 13C NMR (DEPT, HSQC,
HMBC), δ: 24.4 (Me); 29.1 (Me); 33.0 (H2C—Ph); 34.2 (C(4));
35.1 (H2C—C(4)H); 39.6 (H2C(5)); 41.4 (H2C(8)); 52.5 and
52.9 (CO2Me); 55.3 (OMe); 57.3 (C(7)); 73.7 (C(3)); 77.3 (C(9));
77.5 (C(6)); 113.8 (HCAr); 125.9, 128.2; 128.3 and 128.4 (CHAr
and Ph); 131.0 (CAr); 142.2 (CPh); 159.7 (COMe); 169.3, 170.9
1
(both C=O). Conformer B. H NMR, δ: 1.11 (s, 3 H, Me(6));
1.35 (dd, 1 H, Heq(5), J = 14.2 Hz, J = 3.7 Hz); 1.44 (s, 3 H,
Me(6)); 1.75 (dd, 1 H, Hax(5), J = 14.2 Hz, J = 7.5 Hz); 1.91
(dd, 1 H, Hax(8), J = 13.5 Hz, J = 11.9 Hz); 1.87—1.97 (m, 1 H,
HaC—C(4)H); 2.23—2.32 (m, 1 H, Hb(4)—C(4)H); 2.56—2.61
(m, 1 H, H(4)); 2.63 (dd, 1 H, Heq(8), J = 13.6 Hz, J = 2.2 Hz);
2.71—2.86 (m, 2 H, H2C—Ph); 3.68 (s, 3 H, CO2Me); 3.78 (s, 3 H,
CO2Me); 3.81 (s, 3 H, OMe); 3.84 (d, 1 H, H(3), J = 1.6 Hz);
5.72 (dd, 1 H, H(9), J = 11.7 Hz, J = 2.1 Hz); 6.86 (d, 2 H,
HCAr, J = 8.8 Hz); 7.15—7.33 (m, 7 H, HCAr and Ph). 13C NMR,
δ: 26.8 (Me); 29.2 (Me); 34.3 (H2C—Ph)); 35.2 (C(4)); 35.9
(H2C(5)); 39.0 (H2C(8)); 39.4 (H2C—C(4)H); 51.6 (C(7)); 52.6
and 52.8 (CO2Me); 55.3 (OMe); 66.6 (C(3)); 69.2 (C(9)); 78.7
(C(6)); 113.9 (HCAr); 125.7, 128.2, 128.4 and 128.5 (CHAr
and Ph); 131.8 (CAr); 142.6 (CPh); 159.6 (COMe); 171.0, 171.3
(both C=O).
Dimethyl (rel)ꢀ(2S,4aR,5S,5aR,9aR)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ
2ꢀ((E)ꢀ2ꢀphenylvinyl)decahydroꢀ4Hꢀ[1,2]oxazino[2,3ꢀb][1,2]ꢀ
benzoxazineꢀ4,4ꢀdicarboxylate (7j). Nitroso acetal 7j was synꢀ
thesized following the general procedure. Oil, Rf 0.31 (hexane—
EtOAc, 3 : 1). MS, m/z: 544.2295 [MNa]+. C30H35NO7. Calcuꢀ
lated for [MNa]+: 544.2306. 1H NMR (COSY, NOESY), δ:
1.15—1.49 and 1.74—1.88 (both m, 6 H and 2 H, 4 H2C); 2.05
(dd, 1 H, Hax(8), J = 13.3 Hz, J = 11.6 Hz); 2.17—2.29 (m, 1 H,
H(5)); 2.49 (dd, 1 H, Heq(8), J = 13.3 Hz, J = 1.7 Hz); 3.00 (s, 3 H,
CO2Me); 3.74 (d, 1 H, H(3), J = 11.7 Hz); 3.79 (s, 3 H, OMe);
3.90 (s, 3 H, CO2Me); 4.21—4.28 (m, 1 H, HC(6)); 4.35 (dd, 1 H,
H(4), J = 11.7 Hz, J = 10.3 Hz); 4.69 (ddd, 1 H, H(9), J = 11.6 Hz,
J = 6.1 Hz, J = 1.7 Hz); 6.14 (dd, 1 H, HC=, J = 15.9 Hz,
J = 6.1 Hz); 6.66 (d, 1 H, HC=, J = 15.9 Hz); 6.79—6.87 (m, 2 H,
HCAr); 7.22—7.38 (m, 7 H, HCAr and Ph). 13C NMR (HSQC,
HMBC), δ: 20.5, 24.4, 26.4 (all 4 H2C); 40.2 (C(4)); 40.3
(H2C(8)); 41.9 (C(5)); 52.4, 52.5 (both CO2Me); 55.2 (OMe);
57.7 (C(7)); 73.8 (C(3)); 76.0 (C(9)); 78.3 (C(6)); 113.8 (br.,
HCAr); 126.0; 126.5; 128.0, 128.7, 131.2; 132.7; 136.3 (CHAr
and =CH); 158.5 (CAr); 169.2 (C=O).
Dimethyl (rel)ꢀ(2S,4aR,5S,5aR,8aR)ꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ
5ꢀphenyloctahydrocyclopenta[e][1,2]oxazino[2,3ꢀb][1,2]oxꢀ
azineꢀ4,4(4aH)ꢀdicarboxylate (7k). Nitroso acetal 7k was synꢀ
thesized following the general procedure. M.p. 75—77 °C (from
petroleum ether—EtOAc, 2 : 1), Rf 0.32 (hexane—EtOAc, 3 : 1).
MS, m/z: 482.2172 [MH]+. C27H31NO7. Calculated for [MH]+:
Dimethyl (rel)ꢀ(2S,4aR,5R)ꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ7,7ꢀdiꢀ
methylꢀ5ꢀ(2ꢀphenylethyl)hexahydroꢀ4Hꢀ[1,2]oxazino[2,3ꢀb]ꢀ
[1,2]oxazineꢀ4,4ꢀdicarboxylate (7h). Nitroso acetal 7h was synꢀ
thesized following the general procedure. Oil, Rf 0.36 (hexane—
EtOAc, 3 : 1). MS, m/z: 498.2495 [MH]+. C28H35NO7. Calcuꢀ
lated for [MH]+: 498.2486. According to NMR spectral data,
nitroso acetal 7h is a mixture of two conformers in a ratio of
A : B = 1.2 : 1. Conformer A. 1H NMR (COSY, NOESY), δ:
1.31 (s, 3 H, Me(6)); 1.35 (s, 3 H, Me(6)); 1.48 (dd, 1 H, Hax(5),
J = 13.2 Hz, J = 10.2 Hz); 1.53—1.59 (m, 1 H, HaC—C(4)H);
1
482.2173. H NMR (COSY, NOESY), δ: 1.24—1.46 (m, 2 H),
1.51—1.59 (m, 1 H); 1.72—1.81, 1.97—2.05 (both m, 2 H each,
3 H2C); 2.22 (dd, 1 H, Hax(8), J = 13.5 Hz, J = 11.9 Hz); 2.40—2.48
(m, 1 H, H(5)); 2.51 (dd, 1 H, Heq(8), J = 13.5 Hz, J = 2.3 Hz);
2.96 (s, 3 H, CO2Me); 3.27 (t, 1 H, H(4), J = 11.3 Hz); 3.80 (s, 3 H,
CO2Me); 3.89 (s, 3 H, OMe); 4.00 (d, 1 H, H(3), J = 11.3 Hz);
5.01 (td, 1 H, H(6), J = 6.5 Hz, J = 2.0 Hz); 5.21 (dd, 1 H, H(9),

2254
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Tabolin et al.
J = 11.9 Hz, J = 2.3 Hz); 6.87 (d, 2 H, HCAr, J = 8.7 Hz); 7.20—7.41
(m, 7 H, HCAr and Ph). 13C NMR, δ: 24.0, 30.6, 32.1, 41.9 and
45.8 (C(4), C(5), C(7), C(8), C(9)); 50.0 and 52.4 (CO2Me); 55.3
(OMe); 59.9 (C(7)); 72.7, 76.9 and 78.8 (C(3), C(6) and C(9));
113.8 (HCAr); 126.9, 127.7, 128.2 and 130.9 (CHAr and Ph);
131.0 (CAr); 138.7 (CPh); 159.6 (CAr); 169.1, 169.2 (both C=O).
Dimethyl (2R,4aS,5R,7S)ꢀ7ꢀmethylꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ
phenylhexahydroꢀ4Hꢀ[1,2]oxazino[2,3ꢀb][1,2]oxazineꢀ4,4ꢀdiꢀ
carboxylate (7l). Nitroso acetal 7l was synthesized following the
general procedure. Oil, Rf 0.16 (hexane—MeOBut, 3 : 1). MS,
m/z: 456.2018 [MH]+. C25H29NO7. Calculated for [MH]+:
456.2017. According to NMR spectral data, nitroso acetal 7l is
71.1 (COH); 114.3, 128.8 (both CHAr); 128.8 (CHAr); 135.9
(CAr); 158.4 (COMe and C=O).
Methyl (3R,5S)ꢀ3ꢀ[(4S)ꢀ6,6ꢀdimethylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ
5,6ꢀdihydroꢀ4Hꢀ1,2ꢀoxazinꢀ3ꢀyl]ꢀ2ꢀoxoꢀ5ꢀphenyltetrahydroꢀ
furanꢀ3ꢀcarboxylate (15). To a solution of nitroso acetal 7b
(301 mg, 0.64 mmol) in CH2Cl2 (3.2 mL), TFA (47 μL, 0.64 mmol)
was added. The reaction mixture was stirred for 2.5 h and partiꢀ
tioned between EtOAc (50 mL) and saturated aqueous NaHCO3
(20 mL). The organic layer was successively washed with water
(20 mL) and brine (20 mL), dried with Na2SO4, and the solvent
was removed in vacio. Crystallization of the residue from hexꢀ
ane—MeOBut (5 : 1) afforded 227 mg (81%) of the target oxꢀ
azine 15, white powder. M.p. 134–136 °C, Rf 0.60 (hexane—
EtOAc, 1 : 1). Found (%): C, 68.59; H, 6.27; N, 3.23. C25H27NO6.
1
a mixture of two conformers in a 7 : 1 ratio. H NMR (COSY,
NOESY), δ: 1.13 (d, 3 H, CH3(6), J = 5.5 Hz); 1.61 (br.d, 1 H,
Heq(5), J = 14.2 Hz); 1.75—1.92 (m, 1 H, Hax(5)); 1.93—2.04
(m, 1 H, Hax(8)); 2.63 (br.d, 1 H, Heq(8), J = 13.5 Hz); 3.70—3.75
(m, 1 H, H(4)); 3.74, 3.90 (both s, 3 H each, CO2Me); 3.79 (s, 3 H,
OMeAr); 4.00 (s, 1 H, H(3)); 4.45—4.64 (m, 1 H, CH(6)); 5.82
(br.d, 1 H, H(9), J = 11.7 Hz); 6.90 (d, 2 H, CHAr, J = 8.1 Hz);
7.26—7.48 (m, 5 H, Ph); 7.56 (d, 2 H, CHAr, J = 8.1 Hz).
13C (DEPT, HSQC, HMBC), δ: 20.5 (CH3(6)), 34.1 (CH2(5)),
38.5 (CH2(8)), 39.8 (CH(4)), 51.5 (C(7)), 52.8 and 53.0
(both CO2Me), 55.3 (OMeAr), 67.4 (CH(3)), 69.5 (C(9)), 73.8
(CH(6)), 113.9 (CHAr), 126.7, 128.2, 128.5 and 129.1 (3 CHPh
and CHAr), 139.4 and 139.5 (CPh and CAr), 158.1 (CAr), 170.9
and 171.1 (2 C=O). Characteristic signals of the minor conꢀ
former in 1H NMR, δ: 5.11 (d, 1 H, H(9), J = 11.6 Hz).
1
Calculated (%): C, 68.63; H, 6.22; N, 3.20. H NMR (COSY,
NOESY), δ: 1.27, 1.38 (both s, 3 H each, both Me(6)); 1.97 (dd,
1 H, Hax(5), J = 13.6 Hz, J = 11.5 Hz); 2.09 (dd, 1 H, Heq(5),
J = 13.6 Hz, J = 8.0 Hz); 2.73—2.90 (m, 2 H, H2C(8)); 3.56
(s, 3 H, CO2Me); 3.80 (s, 3 H, OMeAr); 4.06 (dd, 1 H, H(4),
J = 11.5 Hz, J = 8.0 Hz); 5.26 (dd, 1 H, H(9), J = 10.1 Hz,
J = 6.4 Hz); 6.84 (d, 2 H, HCAr, J = 8.6 Hz); 7.09 (d, 2 H, HCAr
,
J = 8.6 Hz); 7.29—7.37 (m, 5 H, Ph). 13C NMR (DEPT, HSQC,
HMBC), δ: 22.5, 28.2 (both Me(6)); 37.8 (C(4)); 41.8 (C(8));
43.2 (C(5)); 53.4 (CO2Me); 55.3 (OMeAr); 62.5 (C(7)); 75.7
(C(6)); 79.1 (C(9)); 114.1 (CHAr); 126.0, 128.7, 128.8 (CHAr);
129.9 (CAr); 130.8 (CHAr); 138.0 (CPh); 156.5 and 159.1 (C(3)
and CAr); 167.1 and 170.7 (C=O).
Dimethyl (rel)ꢀ(2S,4aR,5S,7R)ꢀ2,5,7ꢀtriphenylhexahydroꢀ
4Hꢀ[1,2]oxazino[2,3ꢀb][1,2]oxazineꢀ4,4ꢀdicarboxylate (7o).
Nitroso acetal 7o was synthesized following the general proceꢀ
dure. M.p. 131—134 °C (from hexane), Rf 0.30 (hexane—EtOAc,
3 : 1). Found (%): C, 71.32; H, 6.07; N, 2.85. C29H29NO6. Calꢀ
Methyl (3S,5S)ꢀ3ꢀ[(4S)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5,6ꢀdimethylꢀ
5,6ꢀdihydroꢀ4Hꢀ1,2ꢀoxazinꢀ3ꢀyl]ꢀ2ꢀoxoꢀ5ꢀphenyltetrahydroꢀ
furanꢀ3ꢀcarboxylate (15´). A solution of nitroso acetal 7b (0.15
g, 0.32 mmol) in AcOH (2 mL) was heated at 80 °C for 7 h and
the volatiles were removed in vacuo. The residue was coꢀevapoꢀ
rated with toluene (5 mL). Column chromatography of the resiꢀ
due (elution with hexane—PriOH (98 : 2)) afforded 10 mg (7%)
of oxazine 15´ and 49 mg (35%) of oxazine 15, colorless oils.
After recrystallization, m.p. 181—183 °C (from hexane—EtOAc,
10 : 1), Rf 0.65 (hexane—EtOAc, 1 : 1). Found (%): C, 68,57;
H, 6.27; N, 3.10. C25H27NO6. Calculated (%): C, 68.63; H, 6.22;
1
culated (%): C, 71.44; H, 6.00; N, 2.87. H (COSY, NOESY),
δ: 2.06—2.22 (m, 2 H, H2C(5)); 2.34 (dd, 1 H, Hax(8), J = 13.5 Hz,
J = 11.7 Hz); 2.64 (dd, 1 H, Heq(8), J = 13.5 Hz, J = 1.9 Hz);
2.92 (s, 3 H, CO2Me); 3.88 (d, 1 H, H(3), J = 11.1 Hz); 3.97
(s, 3 H, CO2Me); 4.63 (td, 1 H, H(4), J = 11.1 Hz, J = 5.4 Hz); 5.05
(dd, 1 H, H(6), J = 10.5 Hz, J = 2.9 Hz); 5.11 (dd, 1 H, H(9),
J = 11.7 Hz, J = 1.9 Hz); 7.22—7.46 (m, 15 H, Ph). 13C NMR
(HSQC, HMBC), δ: 41.1 (C(8)); 41.6 (C(5)); 42.0 (C(4)); 52.3
and 52.7 (CO2Me); 57.6 (C(7)); 73.7 (C(3)); 77.8 (C(9)); 79.4
(C(6)); 126.4, 126.6, 127.1, 128.1, 128.2, 128.3, 128.4 and 129.5
(CHPh); 138.2, 138.8 and 140.4 (CPh); 169.1 (C=O).
1
N, 3.20. H (COSY, NOESY), δ: 1.36, 1.39 (both s, 3 H each,
both Me(6)); 2.14 (dd, 1 H, Ha(5), J = 13.7 Hz, J = 9.3 Hz); 2.25
(dd, 1 H, Hb(5), J = 13.7 Hz, J = 8.4 Hz); 3.04 (dd, 1 H, Ha(8),
J = 13.5 Hz, J = 9.5 Hz); 3.17 (dd, 1 H, Hb(8), J = 13.7 Hz,
J = 6.5 Hz); 3.70 (s, 3 H, CO2Me); 3.79 (s, 3 H, OMeAr); 3.94
(dd, 1 H, H(4), J = 9.6 Hz, J = 8.4 Hz); 4.92 (dd, 1 H, H(9),
J = 9.5 Hz, J = 6.5 Hz); 6.87 (d, 2 H, HCAr, J = 8.6 Hz); 7.17
(d, 2 H, HCAr, J = 8.4 Hz); 7.22—7.35 (m, 5 H, Ph). 13C NMR
(DEPT, HSQC, HMBC), δ: 23.8, 28.6 (both Me(6)); 37.8 (C(4));
40.5 (C(8)); 43.0 (C(5)); 53.5 (CO2Me); 55.3 (OMeAr); 61.7
(C(7)); 76.5 (C(6)); 79.1 (C(9)); 114.4 (CHAr); 125.8, 128.8,
129.9 (CAr); 130.6; 138.0 (CPh); 158.7 and 159.3 (C(3) and CAr);
168.2, 170.6 (both C=O).
(rel)ꢀ(2S,4aR,5S)ꢀ4,4ꢀBis(hydroxymethyl)ꢀ5ꢀ(4ꢀmethoxyꢀ
phenyl)ꢀ7,7ꢀdimethylꢀ2ꢀphenylhexahydroꢀ2Hꢀ[1,2]oxazino[2,3ꢀb]ꢀ
[1,2]oxazine (16). To a solution of nitroso acetal 7b (40 mg,
0.09 mmol) in anhydrous THF (0.84 mL), LiAlH4 (24 mg,
0.63 mmol) was added in two portions. The reaction mixture was
stirred for 6 h, diluted with EtOAc (2 mL) and 15% aqueous
NaOH (2 mL) and partitioned between EtOAc (50 mL) and 15%
aqueous NaOH (20 mL). The aqueous layer was extracted with
EtOAc (20 mL), the combined organics were successively washed
with water (20 mL) and brine (2×30 mL), dried over Na2SO4,
and the solvent was removed in vacuo. Purification of the residue
tertꢀButyl [4ꢀhydroxyꢀ4ꢀmethylꢀ2ꢀ(4ꢀmethoxyphenyl)pentꢀ
yl]carbamate (12). A stirred solution of nitroso acetal 7b (51 mg,
0.11 mmol) and Boc2O (70 mg, 0.32 mmol) in MeOH (1.5 mL)
was hydrogenated with hydrogen (40 atm) over Raney nickel
(∼0.1 g, freshly prepared according36) in a steel autoclave at
60 °C for 5 h. After cooling, the reaction mixture was filtered through
a Celite pad and the filtrate was concentrated in vacuo. Purificaꢀ
tion of the residue by column chromatography (gradient elution
with hexane—EtOAc (3 : 1, 1 : 2)) afforded 15 mg (43%) of target
carbamate 12 (colorless oil) and 9 mg (19%) of the starting
nitroso acetal 7b. Rf 0.09 (hexane—EtOAc, 1 : 1). MS, m/z:
346.1988 [MNa]+. C18H29NO4. Calculated for [MNa]+:
1
346.1989. H NMR, δ: 1.16, 1.17 (both s, 3 H each, both Me);
1.42 (s, 9 H, But); 1.70 (br.s, 1 H, OH); 1.83 (d, 1 H, H2C,
J = 6.3 Hz); 2.93—3.01 (m, 1 H, HCAr); 3.11—3.21 (m, 1 H,
HaCN); 3.34—3.45 (m, 1 H, HbCN); 3.80 (s, 3 H, OMe); 4.46—4.54
(m, 1 H, NH); 6.87 (d, 2 H, HCAr, J = 8.4 Hz); 7.12 (d, 2 H,
HCAr, J = 8.4 Hz). 13C NMR, δ: 28.4 (But); 29.5, 30.5 (both Me);
41.3 (CH); 46.4 (CH2); 47.5 (CH2N); 79.2 (CMe3); 55.2 (OMe);

6,6ꢀAnnulated bicyclic nitroso acetals
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2255
by column chromatography (elution with hexane—EtOAc (1 : 1))
afforded 20 mg (56%) of target nitroso acetal 4a, colorless oil,
Rf 0.44 (hexane—EtOAc, 1 : 1). MS, m/z: 414.2270 [MH]+.
C24H31NO5. Calculated for [MH]+: 414.2275. According to
NMR spectral data, nitroso acetal 16 is a mixture of two conꢀ
formers in a 9 : 1 ratio. 1H NMR (COSY, NOESY), δ: 1.27—1.30
(m, 1 H, OH); 1.29 (s, 3 H, Me(6)); 1.48 (s, 3 H, Me(6)); 1.66
(dd, 1 H, Heq(5), J = 13.5 Hz, J = 4.3 Hz); 1.52 (dd, 1 H, Hax(5),
J = 13.5 Hz, J = 12.5 Hz); 1.84 (dd, 1 H, Hax(8), J = 13.9 Hz,
J = 12.1 Hz); 2.18 (dd, 1 H, Heq(8), J = 13.9 Hz, J = 1.7 Hz); 2.73
(dd, 1 H, HaCOH, J = 10.9 Hz, J = 5.3 Hz); 2.84 (dd, 1 H,
HbCOH, J = 10.9 Hz, J = 4.8 Hz); 2.85—2.87 (m, 1 H, OH);
3.21—3.28 (m, 2 H, HC(3) and H(4)); 3.81 (s, 3 H, OMe); 4.02
(dd, 1 H, HcCOH, J = 10.8 Hz, J = 4.6 Hz); 4.30 (dd, 1 H, HdCOH,
J = 10.8 Hz, J = 4.4 Hz); 5.29 (dd, 1 H, HC(9), J = 12.1 Hz,
oxazino[2,3ꢀb][1,2]oxazineꢀ4ꢀcarboxylate (17b). Nitroso acetal
17b was synthesized in 98% yield similarly to compound 17a.
Reaction time was 8 h. Oil, Rf 0.13 (hexane—EtOAc, 3 : 1). MS,
m/z: 492.2350 [MNa]+. C27H35NO6. Calculated for [MNa]+:
492.2357. According to NMR spectral data, nitroso acetal 17a is
a mixture of two conformers in a ratio of A : B = 1 : 2.3. Conꢀ
former B. 1H NMR (COSY, NOESY), δ: 1.12, 1.43 (both s, 3 H
each, both Me(6)); 1.46 (dd, 1 H, Ha(5), J = 13.8 Hz, J = 7.5 Hz);
1.68—1.77 (m, 2 H, Hb(5), Hax(8)); 1.92—2.07 (m, 3 H,
H2C—C(4)H and OH); 2.50 (dd, 1 H, Heq(8), J = 13.7 Hz,
J = 1.7 Hz); 2.65—2.80 (m, 3 H, H(4), H2C—Ph); 3.13 (d, 1 H,
H(3), J = 2.9 Hz); 3.48 (d, 1 H, HaCOH, J = 10.1 Hz); 3.79,
3.81 (both s, 3 H each, CO2Me, OMeAr); 3.92 (d, 1 H, HbCOH,
J = 10.1 Hz); 5.72 (dd, 1 H, H(9), J = 11.8 Hz, J = 2.1 Hz); 6.89
(d, 2 H, HCAr, J = 8.3 Hz); 7.23—7.37 (m, 7 H, HCAr and Ph).
13C NMR (HSQC, HMBC), δ: 27.5 (both Me); 32.5 (C(4)); 34.0
(H2C—Ph); 36.8, 36.9 (H2C(5), H2C(8)); 39.4 (H2C—C(4)H);
45.9 (C(7)); 52.2 (CO2Me); 55.3 (OMe); 68.0 (C(3)); 68.9
(CH2O); 70.5 (C(9)); 78.1 (C(6)); 113.7 (HCAr); 125.9, 128.0,
128.1 and 128.4 (CHAr and Ph); 132.6 (CAr); 142.0 (CPh); 159.4
(COMe); 174.8 (C=O). Characteristic signals of conformer A in
1H NMR, δ: 1.32, 1.39 (both s, 3 H each, both Me(6)); 2.33 (dd,
1 H, Heq(8), J = 14.1 Hz, J = 2.3 Hz); 3.56 (d, 1 H, HaCOH,
J = 9.7 Hz); 4.09 (d, 1 H, HbCOH, J = 9.7 Hz); 5.41 (dd, 1 H, H(9),
J = 11.6 Hz, J = 2.0 Hz).
J = 1.7 Hz); 6.89 (d, 2 H, HCAr, J = 8.5 Hz); 7.22 (d, 2 H, HCAr
J = 8.5 Hz); 7.25—7.33 (m, 3 H, Ph); 7.42 (d, 2 H, Ph, J = 7.3
Hz). 13C NMR (DEPT, HSQC, HMBC), δ: 22.9, 29.1 (Me(6));
38.6 and 38.7 (CH(4)) and CH2(8)); 44.7 (C(7)); 46.8 (CH2(5));
55.3 (OMe); 65.3 (COH); 68.6 (COH); 73.1 (C(3)); 76.6 (C(6));
77.5 (C(9)); 114.6 (HCAr); 126.6, 128.0, 128.3, 128.6 (CHAr);
134.9 (CAr); 139.7 (CPh); 158.8 (CAr). Characteristic signals of
the minor conformer in 1H NMR, δ: 4.38 (d, 1 H, HdCOH,
J = 10.8 Hz); 5.38 (dd, 1 H, H(9), J = 12.1 Hz, J = 2.0 Hz).
Methyl (rel)ꢀ(2S,4R,4aR,5S)ꢀ4ꢀhydroxymethylꢀ5ꢀ(4ꢀmethꢀ
oxyphenyl)ꢀ7,7ꢀdimethylꢀ2ꢀphenylhexahydroꢀ2Hꢀ[1,2]oxaziꢀ
no[2,3ꢀb][1,2]oxazineꢀ4ꢀcarboxylate (17a). To a solution of
nitroso acetal 7b (300 mg, 0.64 mmol) in THF (3.2 mL), a 0.71 M
solution of LiAlH(OBut)3 in THF (4.5 mL) was added under
argon. The reaction mixture was refluxed for 3 h, cooled to 0 °C,
and carefully treated with water until hydrogen evolution ceased.
The mixture was partitioned between Et2O (50 mL) and saturated
aqueous NaHCO3 (30 mL). The aqueous layer was extracted
with Et2O (2×30 mL). The combined organics were successfully
washed with 15% aqueous NaOH (30 mL) and brine (2×30 mL),
dried with Na2SO4, and the solvent was removed in vacuo. Puriꢀ
fication of the residue by column chromatography (elution with
hexane—EtOAc (3 : 1)) afforded 236 mg (84%) of target nitroso
acetal 17a, colorless oil, Rf 0.15 (hexane—EtOAc, 3 : 1). MS, m/z:
442.2225 [MH]+. C25H31NO6. Calculated for [MH]+: 442.2224.
According to 1H NMR spectral data, nitroso acetal 17a is
,
Methyl (rel)ꢀ(2S,4R,4aR,5S,5aR,8aR)ꢀ4ꢀhydroxymethylꢀ2ꢀ
(4ꢀmethoxyphenyl)ꢀ5ꢀphenyldecahydrocyclopenta[e][1,2]oxꢀ
azino[2,3ꢀb][1,2]oxazineꢀ4ꢀcarboxylate (17c). Nitroso acetal 17c
was synthesized in 74% yield similarly to compound 17a. M.p.
100—103 °C (from MeOH), Rf 0.12 (hexane—EtOAc, 3 : 1).
MS, m/z: 476.2032 [MNa]+. C26H31NO6. Calculated for [MNa]+:
476.2044. According to NMR spectral data, nitroso acetal 17c is
1
a mixture of two conformers in a 4 : 1 ratio. H NMR (COSY,
NOESY), δ: 1.17 (t, 1 H, OH, J = 6.0 Hz); 1.32—1.49 (m, 2 H);
1.54—1.62 (m, 1 H); 1.71—1.82, 1.96—2.04 (both m, 3 H and
1 H, 3 H2C and Hax(8)); 2.28—2.36 (m, 1 H, H(5)); 2.41 (dd, 1 H,
Heq(8), J = 13.7 Hz, J = 2.5 Hz); 2.83—2.86 (m, 2 H, CH2O);
3.06 (dd, 1 H, H(4), J = 11.7 Hz, J = 10.0 Hz); 3.60 (d, 1 H,
H(3), J = 11.7 Hz); 3.80, 3.81 (both d, 3 H each, CO2Me,
OMe); 4.92 (td, 1 H, H(6), J = 6.6 Hz, J = 2.4 Hz); 5.43 (dd, 1 H,
HC(9), J = 11.6 Hz, J = 2.4 Hz); 6.87 (d, 2 H, HCAr, J = 8.6 Hz);
7.28—7.45 (m, 7 H, HCAr and Ph). 13C NMR (DEPT, HSQC,
HMBC), δ: 23.9, 30.3, 30.6 (CH2); 39.9 (C(8)), 45.6 (C(4)); 50.4
(C(5)); 52.0 (CO2Me); 55.3 (OMe); 55.9 (C(7)); 66.1 (CH2O);
73.0 (C(3)); 76.1 (C(6)); 78.7 (C(9)); 113.8 (HCAr); 127.4, 128.1,
128.6 and 129.2 (CHAr and Ph); 131.9 (CAr); 142.2 (CPh); 159.4
(CAr); 173.0 (C=O). Characteristic signals of the minor conꢀ
former in 1H NMR, δ: 2.51 (dd, 1 H, Heq(8), J = 13.9 Hz,
J = 1.9 Hz); 5.69 (dd, 1 H, H(9), J = 11.8 Hz, J = 1.6 Hz).
Methyl (rel)ꢀ(2S,4R,4aR,5S,7aR)ꢀ4ꢀhydroxymethylꢀ2ꢀ(4ꢀ
methoxyphenyl)ꢀ5ꢀphenylꢀ7ꢀpropylhexahydroꢀ2Hꢀ[1,2]oxazinoꢀ
[2,3ꢀb][1,2]oxazineꢀ4ꢀcarboxylate (17d). Nitroso acetal 17d was
synthesized in 81% yield similarly to compound 17a. Oil, Rf 0.53
(hexane—EtOAc, 1 : 1). MS, m/z: 478.2205 [MNa]+. C26H33NO6.
Calculated for [MNa]+: 478.2200. According to NMR spectral
data, nitroso acetal 17d is a mixture of two conformers in a 3 : 1
ratio. 1H NMR (COSY, NOESY), δ: 0.92 (t, 3 H, Me, J = 6.7 Hz);
1.30—1.58 (m, 5 H, CH2CH2, Ha(5)); 1.74—1.90 (m, 2 H,
Hax(8), Hb(5)); 2.10 (br.s, 1 H, OH); 2.62 (dd, 1 H, Heq(8),
J = 13.6 Hz, J = 1.7 Hz); 3.48—3.54 (m, 2 H, H(3), HaCOH);
3.74 (d, 1 H, HC(4), J = 7.0 Hz); 3.82, 3.90 (both s, 3 H each,
OMe and CO2Me); 4.11 (d, 1 H, HbCOH, J = 9.8 Hz); 4.36—4.47
1
a mixture of two conformers in a 4 : 1 ratio. H NMR (COSY,
NOESY), δ: 1.24—1.28 (m, 3 H, Me(6) and OH); 1.46 (s, 3H,
Me(6)); 1.66 (dd, 1 H, Heq(5), J = 13.5 Hz, J = 5.4 Hz); 1.76
(dd, 1 H, Hax(5), J = 13.5 Hz, J = 12.8 Hz); 1.97 (dd, 1 H,
Hax(8), J = 14.1 Hz, J = 11.7 Hz); 2.24 (dd, 1 H, Heq(8), J = 14.1 Hz,
J = 2.3 Hz); 2.86 (dd, 1 H, HaCOH, J = 11.3 Hz, J = 6.9 Hz);
3.10 (dd, 1 H, HbCOH, J = 11.3 Hz, J = 5.8 Hz); 3.21 (d, 1 H,
H(3), J = 11.2 Hz); 3.54 (ddd, 1 H, H(4), J = 12.8 Hz, J = 11.6 Hz,
J = 5.4 Hz); 3.81 (s, 3 H, OMe); 3.88 (s, 3 H, CO2Me); 5.46 (dd,
1 H, HC(9), J = 11.7 Hz, J = 2.3 Hz); 6.88 (d, 2 H, HCAr
,
J = 8.6 Hz); 7.23 (d, 2 H, HCAr, J = 8.6 Hz); 7.26—7.42 (m, 5 H,
Ph). 13C NMR (DEPT, HSQC, HMBC), δ: 22.8, 29.0
(both Me(6)); 39.4 (CH2(8)); 39.6 (C(4)); 46.7 (CH2(5)); 52.0
(CO2Me); 53.5 (C(7)); 55.2 (OMe); 67.0 (CH2OH); 72.0 (C(3)),
76.6 (C(6)); 77.9 (C(9)); 114.3 (HCAr); 126.6, 128.0, 128.2, 129.0
(CHAr and Ph); 134.9 (CAr); 139.5 (CPh); 158.7 (CAr); 173.7
(C=O). Characteristic signals of the minor conformer in 1H NMR,
δ: 2.53 (dd, 1 H, Heq(8), J = 14.0 Hz, J = 2.2 Hz); 5.73 (dd, 1 H,
H(9), J = 11.6 Hz, J = 1.9 Hz).
Methyl (rel)ꢀ(2S,4R,4aR,5R)ꢀ4ꢀhydroxymethylꢀ2ꢀ(4ꢀmethꢀ
oxyphenyl)ꢀ7,7ꢀdimethylꢀ5ꢀ(2ꢀphenylethyl)hexahydroꢀ4Hꢀ[1,2]ꢀ

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Tabolin et al.
(m, 1 H, H(6)); 5.88 (dd, 1 H, H(9), J = 11.8 Hz, J = 1.7 Hz);
6.89 (d, 2 H, HCAr, J = 8.2 Hz); 7.27—7.50 (m, 7 H, Ph and
HCAr). 13C NMR (HSQC, HMBC), δ: 14.2 (Me), 18.5 (CH2),
32.9 (CH2(5)), 36.6 (CH2(8)), 37.2 (CH2), 38.0 (C(4)), 45.7
(C7)), 52.4 (CO2Me), 55.3 (OMe), 67.8 (C(3)), 69.6 (CH2OH),
70.2 (C(9)), 77.2 (C(6)), 113.9 (HCAr), 126.6, 127.9, 128.3, 129.0
(CHAr and Ph), 139.2 and 140.2 (CAr and CPh); 158.1 (CAr);
174.9 (C=O). Characteristic signals of the minor isomer in
1H NMR, δ: 2.98 (dd, 1 H, HaCOH, J = 10.3 Hz, J = 5.2 Hz);
3.20 (dd, 1 H, HbCOH, J = 10.3 Hz, J = 4.0 Hz); 5.47 (dd, 1 H,
HC(9), J = 12.1 Hz, J = 1.4 Hz).
40.8 (C(5)); 44.7 (C(7)); 55.4 (OMe); 75.4 (C(6)); 80.1 (C(9));
114.8 (CHAr); 126.2, 128.7, 128.8 (all CHPh); 129.7 (CHAr);
132.1 (CAr); 138.3 (CPh); 154.4 (C(3)); 159.1 (COMe); 174.8
(C=O). Isomer 19´. 1H NMR (COSY, NOESY), δ: 1.30, 1.39
(both s, 3 H each, both Me(6)); 1.95—2.15 (m, 3 H, H2C(5),
Ha(8)); 3.11 (ddd, 1 H, Hb(5), J = 12.9 Hz, J = 7.2 Hz, J = 4.3 Hz);
3.31—3.36 (m, 1 H, H(7)); 3.80 (s, 3 H, OMe); 3.85 (dd, 1 H,
H(4), J = 11.8 Hz, J = 8.2 Hz); 5.73 (t, 1 H, H(9), J = 7.5 Hz);
6.89 (d, 2 H, HCAr, J = 8.4 Hz); 7.10 (d, 2 H, HCAr, J = 8.4 Hz);
7.25—7.40 (m, 5 H, Ph). 13C NMR (DEPT, HSQC, HMBC), δ:
22.7, 28.4 (both Me(6)); 34.1 (C(8)); 38.8 (C(4)); 40.9 (C(5));
43.5 (C(7)); 55.4 (OMe); 75.6 (C(6)); 81.2 (C(9)); 114.8 (CHAr);
125.4, 128.4, 128.8 (all CHPh); 129.7 (CHAr); 131.7 (CAr); 139.6
(CPh); 155.6 (C(3)); 159.1 (COMe); 174.8 (C=O).
(rel)ꢀ(3R,5S)ꢀ3ꢀ[(3R,4S)ꢀ4ꢀ(4ꢀMethoxyphenyl)ꢀ6,6ꢀdimethꢀ
ylꢀ1,2ꢀoxazinanꢀ3ꢀyl]ꢀ5ꢀphenyldihydrofuranꢀ2(3H)ꢀone (20). To
a solution of nitroso acetal 18 (209 mg, 0.46 mmol) in CH2Cl2
(2.2 mL), TFA (34 μL, 0.46 mmol) was added. The reaction
mixture was stirred at room temperature for 2 h, diluted with
toluene (5 mL), and the volatiles were removed in vacuo. The
residue was dissolved in glacial acetic acid (2.3 mL) and treated
with NaBH3CN (87 mg, 1.4 mmol) with stirring. The reaction
mixture was kept at room temperature for 18 h and partitioned
between EtOAc (50 mL) and saturated aqueous Na2CO3 (30 mL).
The aqueous layer was extracted with EtOAc (20 mL), the comꢀ
bined organics were successively washed with saturated aqueous
Na2CO3 (30 mL), water (20 mL), and brine (2×20 mL), dried
with Na2SO4, and the solvent was removed in vacuo. Purificaꢀ
tion of the residue by column chromatography (elution with
petroleum ether—EtOAc (4 : 1)) afforded 117 mg (67%) of oxꢀ
azinane 20, colorless oil. Rf 0.59 (hexane—EtOAc, 1 : 1). MS,
m/z: 382.2018 [MH]+. C23H27NO4. Calculated for [MH]+:
382.2013. 1H NMR (COSY, NOESY), δ: 1.27, 1.47 (both s, 3 H
each, both Me(6)); 1.86 (d, 2 H, H2C(5), J = 8.3 Hz); 2.38 (ddd,
1 H, HaC(8), J = 12.6 Hz, J = 9.2 Hz, J = 5.0 Hz); 2.43—2.55
(m, 1 H, HbC(8)); 2.79 (ddd, 1 H, HC(7), J = 11.8 Hz, J = 9.2 Hz,
J = 2.3 Hz); 3.26 (dd, 1 H, H(3), J = 10.9 Hz, J = 2.3 Hz); 3.65
(dt, 1 H, H(4), J = 10.9 Hz, J = 8.0 Hz); 3.81 (s, 3 H, OMe);
5.17 (dd, 1 H, H(9), J = 10.7 Hz, J = 6.0 Hz); 5.52 (br.s, 1 H,
(rel)ꢀ(2S,4aR,5S)ꢀ7,7ꢀDimethylꢀ4ꢀmethoxycarbonylꢀ5ꢀ(4ꢀ
methoxyphenyl)ꢀ2ꢀphenylhexahydroꢀ2Hꢀ[1,2]oxazino[2,3ꢀb]ꢀ
[1,2]oxazineꢀ4ꢀcarboxylic acid (18). To a solution of nitroso
acetal 7b (303 mg, 0.65 mmol) in THF (1.3 mL), Me3SiONa
(145 mg, 1.29 mmol) was added. The reaction mixture was stirred
for 24 h and partitioned between EtOAc (50 mL) and water
(30 mL). The organic layer was successively washed with 5 M
aqueous NaHSO4 (20 mL) and brine (2×20 mL), and dried with
Na2SO4. Removal of the solvent in vacuo afforded 302 mg
(∼100%) of pure title product (1H NMR data), white powder.
Recrystallization (petroleum ether— CH2Cl2 (10 : 1)) gave 232
mg (79%) of product 18, white powder. M.p. 176—178 °C, Rf 0.14
(hexane—EtOAc, 1 : 1). Found (%): C, 65.89; H, 6.51; N, 2.99.
C25H29NO7. Calculated (%): C, 65.92; H, 6.42; N, 3.08. 1H NMR
(COSY, NOESY), δ: 1.30, 1.46 (both s, 3 H each, both Me(6));
1.62 (dd, 1 H, Heq(5), J = 13.4 Hz, J = 4.7 Hz); 1.83 (dd, 1 H,
Hax(5), J = 13.4 Hz, J = 12.3 Hz); 2.13 (dd, 1 H, Hax(8), J = 13.5 Hz,
J = 11.9 Hz); 2.67 (dd, 1 H, Heq(8), J = 13.5 Hz, J = 1.7 Hz);
3.33 (s, 3 H, CO2Me); 3.52 (d, 1 H, H(3), J = 13.4 Hz); 3.95
(s, 3 H, OMe); 4.40 (ddd, 1 H, H(4), J = 13.4 Hz, J = 12.3 Hz,
J = 4.7 Hz); 5.04 (dd, 1 H, H(9), J = 11.9 Hz, J = 1.7 Hz); 6.57
(d, 2 H, HCAr, J = 8.7 Hz); 7.16 (d, 2 H, HCAr, J = 8.7 Hz);
7.30—7.44 (m, 5 H, Ph). 13C NMR (DEPT, HSQC, HMBC), δ:
22.9, 29.0 (both Me(6)); 38.1 (C(4)); 41.5 (CH2(8)); 45.1
(CH2(5)); 52.6 (CO2Me); 54.7 (OMe); 57.2 (C(7)); 74.4 (C(3));
77.3 (C(6)); 77.8 (C(9)); 113.0 (HCAr); 126.6, 128.4, 130.7 (CHAr
and Ph); 131.8 (CAr); 138.6 (CPh); 158.6 (CAr); 168.9, 174.7
(both C=O).
(rel)ꢀ(3R,5S)ꢀ3ꢀ[(4S)ꢀ4ꢀ(4ꢀMethoxyphenyl)ꢀ6,6ꢀdimethylꢀ
5,6ꢀdihydroꢀ4Hꢀ1,2ꢀoxazinꢀ3ꢀyl]ꢀ5ꢀphenyldihydrofuranꢀ2(3H)ꢀ
one (19) and (rel)ꢀ(3S,5S)ꢀ3ꢀ[(4S)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ6,6ꢀ
dimethylꢀ5,6ꢀdihydroꢀ4Hꢀ1,2ꢀoxazinꢀ3ꢀyl]ꢀ5ꢀphenyldihydroꢀ
furanꢀ2(3H)ꢀone (19´). To a 0 °C solution of nitroso acetal 18
(265 mg, 0.58 mmol) in CH2Cl2 (1.9 mL), TFA (43 μL, 0.58 mmol)
was added. The reaction mixture was stirred at room temperaꢀ
ture for 3.5 h and the volatiles were removed in vacuo. Purificaꢀ
tion of the residue by column chromatography (elution with
hexane—EtOAc (3 : 1)) afforded 171 mg (77%) of a mixture of
oxazines 19 and 19´ in a ratio of 2.5 : 1 (1H NMR data), colorꢀ
less oil. Rf 0.28 (hexane—EtOAc, 1 : 1). MS, m/z: 402.1676
[MNa]+. C23H25NO4. Calculated for [MNa]+: 402.1668. Isoꢀ
mer 19. 1H NMR (COSY, NOESY), δ: 1.36, 1.38 (both s, 3 H each,
both Me(6)); 1.93 (dd, 1 H, Hax(5), J = 13.7 Hz, J = 11.8 Hz);
2.14 (dd, 1 H, Heq(5), J = 13.7 Hz, J = 8.0 Hz); 2.42 (ddd, 1 H,
HaC(8), J = 13.3 Hz, J = 8.1 Hz, J = 5.6 Hz); 2.94 (ddd, 1 H,
HbC(8), J = 13.3 Hz, J = 12.6 Hz, J = 11.2 Hz); 3.37 (dd, 1 H,
H(7), J = 12.6 Hz, J = 8.1 Hz); 3.83 (s, 3 H, OMe); 4.04 (dd, 1 H,
H(4), J = 11.8 Hz, J = 8.0 Hz); 5.23 (dd, 1 H, H(9), J = 11.2 Hz,
NH); 6.89 (d, 2 H, HCAr, J = 8.6 Hz); 7.20 (d, 2 H, HCAr,
J = 8.6 Hz); 7.27—7.36 (m, 5 H, Ph). 13C NMR (HSQC, HMBC),
δ: 21.5, 29.0 (both Me(6)), 35.1 (C(8)), 39.0 (C(4)), 40.7 (C(7)),
44.0 (C(5)), 55.3 (OMe), 62.1 (C(3)), 75.4 (C(6)), 80.1 (C(9)),
114.4 (CHAr), 126.1, 128.7, 128.8 (all CHAr), 134.2 (CAr), 138.4
(CPh), 158.6 (COMe), 176.2 (C=O).
(rel)ꢀ(3R,5S)ꢀ3ꢀ[(1R,2S)ꢀ1ꢀAminoꢀ4ꢀhydroxyꢀ2ꢀ(4ꢀmethꢀ
oxyphenyl)pentyl]ꢀ4ꢀmethylꢀ5ꢀphenyldihydrofuranꢀ2(3H)ꢀone
(21). To oxazinane 20 (31 mg, 0.08 mmol), a 0.038 M solution of
SmI2 in THF (5.4 mL) was added. The mixture was kept at room
temperature for 24 h without access of air, stirred in air until the
disappearance of the blue color, treated with saturated aqueous
Na2CO3 (5 mL) with stirring (10 min), and partitioned between
EtOAc (50 mL) and saturated aqueous Na2CO3 (30 mL). The
aqueous layer was extracted with EtOAc (20 mL), the combined
organics were washed with brine (2×30 mL), and dried with
Na2SO4. Removal of the solvent in vacuo afforded 26 mg (83%) of
product 21, colorless oil. MS, m/z: 384.2156 [MH]+. C23H29NO4.
Calculated for [MH]+: 384.2169. 1H NMR (COSY), δ: 1.19 (s, 6 H,
2 Me(6)); 1.94 (dd, 1 H, Ha(5), J = 14.5 Hz, J = 7.3 Hz); 2.14
(dd, 1 H, Hb(5), J = 14.5 Hz, J = 5.2 Hz); 2.15 (td, 1 H, Ha(8),
J = 12.4 Hz, J = 10.7 Hz); 2.49 (ddd, 1 H, Hb(8), J = 12.4 Hz,
J = 8.4 Hz, J = 5.8 Hz); 2.70 (ddd, 1 H, H(7), J = 12.4 Hz,
J = 5.6 Hz); 6.91 (d, 2 H, HCAr, J = 8.7 Hz); 7.17 (d, 2 H, HCAr
,
J = 8.7 Hz); 7.24—7.37 (m, 5 H, Ph). 13C NMR (DEPT, HSQC,
HMBC), δ: 22.5, 28.4 (both Me(6)); 33.6 (C(8)); 39.0 (C(4));

6,6ꢀAnnulated bicyclic nitroso acetals
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2257
J = 8.4 Hz, J = 3.5 Hz); 2.84 (dd, 1 H, H(3), J = 9.0 Hz, J = 3.5 Hz);
3.38 (ddd, 1 H, H(4), J = 9.0 Hz, J = 7.3 Hz, J = 5.2 Hz); 3.81
(s, 3 H, OMe); 5.21 (dd, 1 H, H(9), J = 10.7 Hz, J = 5.8 Hz); 6.88
(d, 2 H, HCAr, J = 8.7 Hz); 7.18 (d, 2 H, HCAr, J = 8.7 Hz);
7.30—7.40 (m, 5 H, Ph). 13C NMR (DEPT, HSQC), δ: 29.4,
31.3 (both Me(6)), 36.0 (C(8)), 45.0 (C(7)), 45.1 (C(4)), 47.7
(C(5)), 55.3 (OMe), 57.7 (C(3)), 70.1 (C(6)), 79.3 (C(9)), 114.5
(CHAr), 125.6, 128.6, 128.8, 129.0 (all CHAr), 137.0 (CAr), 139.0
(CPh), 158.4 (COMe), 176.6 (C=O).
[MNa]+. C24H27NO5. Calculated for [MNa]+: 432.1781. 1H NMR
(COSY, NOESY), δ: 1.28, 1.33 (both s, 3 H each, both Me(6));
1.94 (dd, 1 H, Hax(5), J = 13.5 Hz, J = 11.1 Hz); 2.10 (dd, 1 H,
Heq(5), J = 13.5 Hz, J = 8.0 Hz); 2.45 (dd, 1 H, Ha(8), J = 13.2 Hz,
J = 7.4 Hz); 2.54 (dd, 1 H, Hb(8), J = 13.3 Hz, J = 8.9 Hz); 3.11
(br.s, 1 H, OH); 3.60 (dd, 1 H, H(4), J = 11.1 Hz, J = 8.0 Hz);
3.80 (s, 3 H, OMe); 3.86—3.91 (m, 2 H, CH2OH); 5.35 (dd, 1 H,
H(9), J = 8.9 Hz, J = 7.4 Hz); 6.79 (d, 2 H, HCAr, J = 8.6 Hz);
7.00—7.06 (m, 4 H, HCAr); 7.28—7.33 (m, 3 H, HCAr). 13C NMR
(HSQC, HMBC), δ: 22.6, 28.1 (both Me(6)); 37.9 (C(4)); 39.2
(C(8)); 43.1 (C(5)); 55.5 (OMe); 56.7 (C(7)); 64.4 (COH); 75.2
(C(6)); 78.8 (C(9)); 114.6 (CHAr); 125.5, 128.3, 128.4, 130.2
(CHAr); 130.5 (CAr); 139.1 (CPh); 158.1 and 159.0 (C(3) and
COMe); 176.3 (C=O). Isomer 23´. M.p. 160—163 °C (from
Et2O—EtOAc, 5 : 1). Rf 0.50 (hexane—EtOAc, 1 : 1). MS, m/z:
432.1791 [MNa]+. C24H27NO5. Calculated for [MNa]+:
432.1781. 1H NMR (COSY, NOESY), δ: 1.26—1.29 (m, 1 H,
OH); 1.36 (s, 6 H, 2 Me(6)); 1.91—1.99 (m, 1 H, Ha(8));
2.00—2.13 (m, 2 H, H2C(5)); 2.97 (dd, 1 H, Hb(8), J = 13.1 Hz,
J = 6.5 Hz); 3.75 (s, 3 H, OMe); 3.74—3.80 (m, 1 H, HaCOH);
4.06 (dd, 1 H, HC(4), J = 10.8 Hz, J = 8.7 Hz); 4.13 (br.d, 1 H,
HbCOH); 5.32 (dd, 1 H, HC(9), J = 10.5 Hz, J = 6.5 Hz); 6.64
(d, 2 H, Ph, J = 6.7 Hz); 6.78 (d, 2 H, HCAr, J = 8.5 Hz); 7.14
(d, 2 H, HCAr, J = 8.5 Hz); 7.19—7.32 (m, 3 H, Ph). 13C NMR
(DEPT, HSQC, HMBC), δ: 22.1, 28.3 (both Me(6)); 37.5 (C(4));
39.0 (C(8)); 42.4 (C(5)); 55.2 (OMe); 56.4 (C(7)); 65.5 (COH);
75.7 (C(6)); 79.6 (C(9)); 114.6 (CHAr); 125.5, 128.3, 128.4 and
131.5 (CHAr); 129.7 (CAr); 138.1 (CPh); 159.3 and 161.4 (C(3)
and COMe); 175.6 (C=O).
(rel)ꢀ(3R,5S)ꢀ3ꢀHydroxymethylꢀ3ꢀ[(3R,4S)ꢀ4ꢀ(4ꢀmethoxyꢀ
phenyl)ꢀ6,6ꢀdimethylꢀ1,2ꢀoxazinanꢀ3ꢀyl]ꢀ5ꢀphenyldihydrofuranꢀ
2(3H)ꢀone (24). A solution of oxazine 23 (99 mg, 0.24 mmol) in
AcOH (1.2 mL) was treated with NaBH3CN (46 mg, 0.73 mmol).
The reaction mixture was stirred for 18 h and partitioned beꢀ
tween EtOAc (50 mL) and saturated aqueous Na2CO3 (30 mL).
The aqueous layer was extracted with EtOAc (2×20 mL), the
combined organics were successively washed with saturated
aqueous Na2CO3 (30 mL) and brine (2×30 mL), dried with
Na2SO4, and the solvent was removed in vacuo. Purification of
the residue by column chromatography (elution with hexane—
EtOAc (3 : 1)) afforded 82 mg (82%) of oxazine 24, colorless oil.
Rf 0.32 (hexane—EtOAc, 1 : 1). MS, m/z: 412.2118 [MH]+.
C24H29NO5. Calculated for [MNa]+: 412.2118. 1H NMR (COSY,
NOESY), δ: 1.22, 1.40 (both s, 3 H each, both Me(6)); 1.68—1.80
(m, 2 H, H2C(5)); 1.84—1.90 (m, 2 H, H2C(8)); 3.20 (td, 1 H,
H(4), J = 11.4 Hz, J = 4.8 Hz); 3.64 (d, 1 H, H(3), J = 10.4 Hz);
3.76 (s, 3 H, OMe); 3.83 (d, 1 H, HaCOH, J = 11.6 Hz); 4.09
(d, 1 H, HbCOH, J = 11.6 Hz); 5.27 (dd, 1 H, H(9), J = 9.4 Hz,
J = 7.2 Hz); 6.80 (d, 2 H, HCAr, J = 8.7 Hz); 7.10—7.15 (m, 4 H,
HCAr); 7.30—7.35 (m, 3 H, HCAr). Signals of the OH and NH
groups are not visible due to significant widening. 13C NMR
(HSQC, HMBC), δ: 22.5, 28.8 (both Me(6)); 38.9 (C(8)); 39.6
(C(4)); 45.8 (C(5)); 52.5 (C(7)); 55.3 (OMe); 64.5 (COH); 67.0
(C(3)); 74.9 (C(6)); 78.8 (C(9)); 114.2 (CHAr); 125.5, 128.5,
128.7 and 129.3 (CHAr); 133.8 (CAr); 138.9 (CPh); 158.8 (COMe);
177.7 (C=O).
3ꢀ[2ꢀAcetylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ6,6ꢀdimethylꢀ5,6ꢀdihydroꢀ
2Hꢀ1,2ꢀoxazinꢀ3ꢀyl]ꢀ5ꢀphenyldihydrofuranꢀ2(3H)ꢀone (22). To
nitroso acetal 18 (36 mg, 0.08 mmol), a 0.2 M solution of TFA in
CH2Cl2 (0.4 mL) was added. The reaction mixture was stirred at
room temperature for 2 h, diluted with toluene (5 mL), and the
volatiles were removed in vacuo. The residue was dissolved in
CH2Cl2 (0.25 mL) and treated with Ac2O (20 μL, 0.2 mmol) and
AcBr (7 μL, 0.1 mmol) with stirring. The reaction mixture was
kept at room temperature for 2.5 h, filtered through a short silica
gel layer, and the solvent was removed in vacuo. Purification of
the residue by column chromatography (elution with petroleum
ether—EtOAc (1 : 1)) afforded 21 mg (64%) of oxazine 22, colꢀ
orless oil. Rf 0.50 (hexane—EtOAc, 1 : 1). MS, m/z: 444.1770
[MNa]+. C25H27NO5. Calculated for [MNa]+: 444.1781. Ratio
(rel)ꢀ(3R,5S)ꢀ22 : (rel)ꢀ(3S,5S)ꢀ22 = 1.4 : 1. (rel)ꢀ(3R,5S)ꢀ22.
1H NMR (COSY, NOESY), δ: 1.42 (s, 6 H, both Me(6)); 2.25
(s, 3 H, Me(Ac)); 2.25—2.31 (m, 1 H, Ha(5)); 2.37—2.44 (m, 2 H,
H2C(8)); 2.63 (d, 1 H, Hb(5), J = 17.8 Hz); 3.85 (s, 3H, OMe);
3.87—3.96 (m, 1 H, H(7)); 5.18 (dd, 1 H, H(9), J = 9.0 Hz,
J = 8.2 Hz); 6.93 (d, 2 H, CHAr, J = 8.7 Hz); 7.17—7.51 (m, 7 H,
CHAr and Ph). 13C NMR (DEPT, HSQC, HMBC), δ: 22.0
(MeAc), 26.8 (both Me(6)), 36.4 (CH2(8)), 43.3 (CH2(5)), 44.3
(CH(7)), 55.3 (OMe), 79.0 (C(6)), 79.6 (CH(9)), 114.2 (CHAr),
125.9, 127.7 (C(3), C(4)), 126.5, 128.3, 128.5, 129.8 (3 CHPh
and CHAr), 131.3 (CAr), 139.5 (CPh), 159.3 (CAr), 169.4 (CAc),
175.0 (OC=O). (rel)ꢀ(3S,5S)ꢀ22. 1H NMR (COSY, NOESY),
δ: 1.44 (s, 6 H, both Me(6)); 2.07—2.16 (m, 1 H, Ha(8));
2.25—2.31 (m, 1 H, Ha(5)); 2.31 (s, 3 H, MeAc); 2.63 (d, 1 H,
Hb(5), J = 17.8 Hz); 2.81 (dt, 1 H, Hb(8), J = 12.1 Hz, J = 9.9 Hz);
3.82 (s, 3H, OMe); 3.87—3.96 (m, 1 H, H(7)); 5.61 (dd, 1 H,
H(9), J = 9.9 Hz, J = 3.4 Hz); 6.88 (d, 2 H, CHAr, J = 8.6 Hz);
7.17—7.51 (m, 7 H, CHAr and Ph). 13C NMR (DEPT, HSQC,
HMBC), δ: 24.0 (MeAc); 24.1 (both Me(6)); 33.8 (CH2(8)); 41.1
(CH(7)); 43.2 (CH2(5)); 55.3 (OMe); 77.2 (C(6)); 78.2 (CH(9));
114.1 (CHAr); 125.1, 127.8, 128.6, 129.7 (3 CHPh and CHAr);
125.8, 127.7 (C(3), C(4)); 131.1 (CAr); 141.5 (CPh); 159.3 (CAr);
169.9 (CAc); 175.5 (OC=O).
Methyl (rel)ꢀ(3R,5S)ꢀ3ꢀhydroxymethylꢀ3ꢀ[(4S)ꢀ4ꢀ(4ꢀmethꢀ
oxyphenyl)ꢀ6,6ꢀdimethylꢀ5,6ꢀdihydroꢀ4Hꢀ1,2ꢀoxazinꢀ3ꢀyl]ꢀ5ꢀ
phenyldihydrofuranꢀ2(3H)ꢀone (23) and methyl (rel)ꢀ(3R,5S)ꢀ3ꢀ
hydroxymethylꢀ3ꢀ[(4R)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ6,6ꢀdimethylꢀ5,6ꢀ
dihydroꢀ4Hꢀ1,2ꢀoxazinꢀ3ꢀyl]ꢀ5ꢀphenyldihydrofuranꢀ2(3H)ꢀone
(23´). To a solution of nitroso acetal 17a (164 mg, 0.37 mmol) in
CH2Cl2 (1.9 mL), TFA (28 μL, 0.37 mmol) was added. The
mixture was stirred for 1 h and the volatiles were removed
in vacuo. Column chromatography (gradient elution with hexane—
EtOAc (5 : 1, 1 : 2)) afforded 23 mg (15%) of a mixture of oxꢀ
azines in a ratio of 23´ : 23 = 7 : 1 (1H NMR data) and 105 mg
(69%) of a mixture of oxazines in a ratio of 23 : 23´ = 20 : 1
(1H NMR data), colorless oils. When the reaction mixture was
treated with NaHCO3 (35 mg) with stirring for 20 min before the
solvent evaporation, pure isomer 23 was obtained in 85% yield.
Isomer 23. Rf 0.40 (hexane—EtOAc, 1 : 1). MS m/z: 432.1776
tertꢀButyl (rel)ꢀ{(1R,2S)ꢀ4ꢀhydroxyꢀ1ꢀ[(3R,5S)ꢀ3ꢀhydrꢀ
oxymethylꢀ2ꢀoxoꢀ5ꢀphenyltetrahydrofuranꢀ3ꢀyl]ꢀ2ꢀ(4ꢀmethoxyꢀ
phenyl)ꢀ4ꢀmethylpentyl}carbamate (25). To oxazinane 24 (25 mg,
0.06 mmol), a 0.02 M solution of SmI2 in THF (8 mL) was
added. The mixture was kept for 3 days at room temperature
without access of air, then stirred in air until disappearance of

2258
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Tabolin et al.
the blue color, treated with saturated aqueous Na2CO3 (5 mL),
stirred for 10 min, and partitioned between EtOAc (50 mL) and
saturated aqueous Na2CO3 (30 mL). The aqueous layer was exꢀ
tracted with EtOAc (20 mL), the combined organics were washed
with brine NaCl (30 mL), dried with Na2SO4, and the solvent
was removed in vacuo. The residue was dissolved in CH2Cl2
(0.2 mL) and treated with Boc2O (39 mg, 0.18 mmol). After 24 h
stirring at room temperature, the volatiles were removed in vacuo.
Column chromatography of the residue (gradient elution with
hexane—EtOAc (3 : 1, 1 : 1)) afforded 3 mg (12%) of the starting
oxazinane 24 and 11 mg (35%) of target amino alcohol 25, colꢀ
orless oils. Rf 0.21 (hexane—EtOAc, 1 : 1). MS, m/z: 536.2619
[MH]+. C29H39NO7. Calculated for [MNa]+: 536.2609. 1H NMR
(COSY, NOESY), δ: 1.16, 1.18 (both s, 3 H each, both Me(6));
1.44 (s, 9 H, But); 1.61 (dd, 1 H, Ha(5), J = 14.5 Hz, J = 5.3 Hz);
1.93 (br.s, 1 H, OH); 2.09 (dd, 1 H, Hb(5), J = 14.5 Hz, J = 5.3 Hz);
2.20 (br.s, 1 H, OH); 2.42 (dd, 1 H, Ha(8), J = 13.3 Hz, J = 9.8 Hz);
2.61 (dd, 1 H, Hb(8), J = 13.3 Hz, J = 7.4 Hz); 3.51 (td, 1 H,
H(4), J = 9.0 Hz, J = 5.3 Hz); 3.60 (d, 1 H, HaCOH, J = 12.0 Hz);
3.79 (s, 3 H, OMe); 3.83 (d, 1 H, HbCOH, J = 12.0 Hz); 4.18 (t, 1 H,
H(3), J = 9.0 Hz); 5.42 (dd, 1 H, H(9), J = 9.8 Hz, J = 7.4 Hz);
5.98 (d, 1 H, NH, J = 9.9 Hz); 6.82 (d, 2 H, HCAr, J = 8.4 Hz);
7.18 (d, 2 H, HCAr, J = 8.4 Hz); 7.29—7.40 (m, 5 H, Ph). 13C NMR
(HSQC, HMBC), δ: 28.4 (MeBoc); 29.3, 30.9 (both Me(6)); 37.9
(C(8)); 40.7 (C(4)); 47.3 (C(5)); 55.2 (OMe); 56.6 (C(7)); 57.3
(C(3)); 64.9 (CH2OH); 71.0 (C(6)); 78.9 (C(9)); 79.8 (CBoc);
114.5 (CHAr); 125.7, 128.3, 128.6, 129.2 (CHAr); 137.1 (CPh);
139.8 (CAr); 157.2 (C=OBoc); 158.4 (COMe); 178.5 (OC=O).
XꢀRay diffraction studies of compounds 15, 15´, and 23´
were performed with a Bruker APEX2 DUO CCD instrument
(MoKα irradiation, graphite monochromator, ω scan mode).
The structures were solved by direct method and refined by fullꢀ
matrix anisotropic approximation against F2hkl. Positions of the
hydrogen atoms were calculated geometrically and refined by
the riding model. Main crystallographic data and refined paraꢀ
meters are given in Table 4. All calculations were performed
with SHELXTL software.37 The atomic coordinates and full
structures of compounds 15, 15´, and 23´ were deposited with
a Cambridge Crystallographic Data Center (CCDC 1445218,
CCDC 1445217, and CCDC 1445219, respectively).
High resolution mass spectrometry was performed in
Department on Structural Studies of N. D. Zelinsky Instiꢀ
tute of Organic Chemistry of RAS.
This work was financially supported by the Russian
Foundation for Basic Research (Projects Nos. 15ꢀ03ꢀ
05703 and 14ꢀ03ꢀ31560).
Table 4. Principal crystallographic data and refinement paraꢀ
meters for compounds 15, 15´, and 23´
References
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15´
23´
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C25H27NO6 C25H27NO6 C24H27NO5
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Monoclinic
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Orthoꢀ
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P212121
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Received January 20, 2016;
in revised form May 20, 2016