Diastereoselective synthesis of γ-amino acids and their derivatives from nitroethane via intermediacy of 5,6-dihydro-4H-1,2-oxazines bearing the CH2CH(CO2Me)2 substituent at C3

Article abstract of DOI:10.1055/s-0028-1083360

Stereoselective two-step reduction of available 2-[(5,6- dihydro-4H-1,2-oxazin-3-yl)methyl]malonates provides an efficient route to derivatives of different γ-amino acids. The mechanism and stereochemistry of the first step, reduction of the C=N bond with

Full text of DOI:10.1055/s-0028-1083360

PAPER
741
Diastereoselective Synthesis of g-Amino Acids and Their Derivatives from
Nitroethane via Intermediacy of 5,6-Dihydro-4H-1,2-oxazines Bearing the
CH2CH(CO2Me)2 Substituent at C3
D
iastereoselective
l
Synthe
e
sis of
g
-
Am
x
ino
A
cids an
e
d
T
heir De
y
r
ivatives
f
romNitr
Y
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax +7(499)1355328; E-mail: iof@ioc.ac.ru
Received 14 October 2008
by the limited accessibility of dihydrooxazines 1. Indeed,
Abstract: Stereoselective two-step reduction of available 2-[(5,6-
until recently these heterocycles could be synthesized
dihydro-4H-1,2-oxazin-3-yl)methyl]malonates provides an effi-
only via extremely labile intermediates, nitrosoalkenes A8
cient route to derivatives of different g-amino acids. The mecha-
(Scheme 1). Therefore, special studies were required in
each particular case in order to define the possibility of
this reaction and to optimize the reaction conditions.
However, recently we reported a simple and efficient ap-
proach to the synthesis of diastereomerically pure dihy-
drooxazines 4 and 5 bearing a functionalized group
CH2FG at C3 [Scheme 2, FG = CH(CO2Me)2 4 or CO2Me
5].9
nism and stereochemistry of the first step, reduction of the C=N
bond with sodium cyanoborohydride, is discussed.
Key words: 5,6-dihydro-4H-1,2-oxazines, reduction, g-amino ac-
ids, oxyiminium cations
Catalytic hydrogenation of six-membered cyclic oxime
ethers, 5,6-dihydro-4H-1,2-oxazines 1, is an efficient
method for the synthesis of various types of products such
as pyrrolidines,1 pyrroles,2 1,4-amino alcohols,3 1,4-dike-
tones,4 and furan derivatives.5 Usually, the hydrogenation
process starts with cleavage of the relatively weak en-
docyclic N–O bond and all the above-mentioned products
result from transformations of the initially formed g-hy-
droxy imines B (Scheme 1). The type of final product pri-
marily depends on the presence (or absence) of an alkoxy
substituent at C6 in the dihydrooxazines 1.
In the light of this new approach for the preparation of di-
hydrooxazines, substrates 4 and 5 seem to be attractive
precursors for unnatural g- and b-amino acids 7 and 8, re-
spectively (Scheme 3, route a). However, the catalytic hy-
drogenation of these oxazines resulted in completely
different products [Scheme 3, route b, FG = CH(CO2Me)2].5
Apparently, the reason is that imine intermediates B¢, ini-
tially formed by cleavage of the N–O bond, are not re-
duced further to give the target compounds 7 or 8, but
undergo more rapid processes involving interaction of the
imino group with the FG functionality (for details see ref.
5) to give other products.
If the dihydrooxazine 1 bears an ester function on the ring
(Y or R1 = CO2Me),3,6,7 selective reduction of the oximino
fragment leads to derivatives of unnatural a- and b-amino
acids, respectively (see products 2 and 3 in Scheme 1),
that can have various applications. However, utilization of
this strategy is restricted for several reasons, but mainly
One can consider two possible ways that can direct the re-
duction of dihydrooxazines 4 and 5 to the formation of
amino acids derivatives. Both are based on a two-stage
R3 R2
R1
R1
R3
Br
R2
R4
Y
4
base
Y
R4 R5
5
6
3
Y
R1
2 N
– [baseH]+Br–
1
O
[4+2]-cycloaddition
N
N
R5
O
OH
1
A
R1
R4
HO
R5
R4, R5 = H, Alk
R1
Y
R1
Y = CO2Alk, H
1 = H, CO2Alk
R3
R5
R3
R5
R3
R2
R
R2
R4
Y
R2
R4
Y
[H]
R2, R3 = H, Alk, Ar
R4, R5 = H, Alk, OAlk,
NAlk2, CH2SiMe3
NHX
R1
2
[H]
R2
R4 or R5
OAlk, NAlk2
=
N
NH
O
OH
R3
R4
X = H, Boc
1
Y
B
N
X
3
Scheme 1
SYNTHESIS 2009, No. 5, pp 0741–0754
x
x
.
x
x
.2
0
0
9
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083360; Art ID: P11508SS
© Georg Thieme Verlag Stuttgart · New York

742
A. Yu. Sukhorukov et al.
PAPER
R1
O
R1
O
R1
EtNO2
R2
R2
R2
Me
O
R1CHO
2 steps
TMSBr, Et3N
3
FG
Br
R3
N
N
R2
N
R3
R3
R3
O
R4
R4
R4
R4
R1 = Alk, Ar, OAlk
4, 5
R2, R3 = H, Alk, Ar
FG = CH(CO2Me)2
4
R4 = H, Alk, OAlk, Ar
CO2Me 5
Scheme 2
R1
other products [FG = CH(CO2Me)2]
(b)
(a)
R2
R3
H2, Ra-Ni
or Pd/C
FG
NH
OH
R4
B'
R1
R1
R2
R1
R1
R2
R3
N–O
reduction
R2
R3
R2
R3
FG
NaBH3CN
(c)
FG
or
FG
N
R4
NH2
O
NH
R4
N
H
8
OH
R4
O
FG
R4
4, 5
FG = HC(CO2Me)2
7
R1
C=C and N–O
reduction
R2
R3
AcBr, Ac2O
(d)
FG
NAc
O
R4
Scheme 3
R1
R1
R1
R2
R3
CO2Me
R2
R3
CO2Me
CO2Me
R2
4
methods A, B, C
3
+
CO2Me
N
CO2Me
NX
N
R3
O
O
O
R4
R4
R4
10a–d (method A or B)
O
4a–i
6, X = H (method A)
9, X = Bz (method C)
Scheme 4 Reagents and conditions: Method A: NaBH3CN, AcOH, 2 h;10 Method B: NaBH3CN, AcOH, 24 h; Method C: NaBH3CN, BzCl,
AcOH, 1 h.
Table 1 Reduction of Dihydrooxazines 4a–i with Sodium Cyanoborohydride
Entry
Substrate
R1
R2
H
H
H
H
H
R3
R4
Method
Product
9a
Yield (%)
74
1
2
4a
4b
4c
4c
4d
4e
4f
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
C
C
C
A
C
C
C
C
A
A
9b
90
3
Ana
An
9c
79
4
6c
50b
70
5
4-ClC6H4
An
9d
6
–(CH2)4–
9e
61c
94
7
An
H
H
H
H
Ph
H
9fd
9g
8
4g
4h
4i
An
H
Ph
H
76
9
An
OEt
OMe
6h
82
10
An
Me
6i
81
a An = 4-MeOC6H4.
b The second product is oxazine 10c (30%).
c By conversion of 4e (64%).
d Ratio 9f/9f¢ 1.0:2.5.
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of g-Amino Acids and Their Derivatives from Nitroethane
743
process of oximino fragment reduction that allows the for- ternative method for their generation, by benzoylation of
mation of intermediates B¢ to be avoided. Firstly, there is N2 in the initial dihydrooxazines 4 and subsequent reduc-
a two-stage procedure, including hydride reduction of the tion of the resulting cation, appears to be unlikely, be-
oximino fragment in a six-membered cyclic oxime ether, cause in the model experiment (AcOH, r.t.) no interaction
yielding tetrahydrooxazines in the first step.10 In this par- between dihydrooxazine 4c and benzoyl chloride was ob-
ticular case, in contrast to catalytic hydrogenation, the served. On the other hand, tetrahydrooxazine 6c reacted
process starts with the reduction of the C=N bond smoothly with benzoyl chloride under the same condi-
(Scheme 3, route c). Reduction of the N–O bond in the re- tions to give product 9c.
sulting tetrahydro-2H-oxazines may furnish the target de-
rivatives of amino acids 7 or 8. The second way involves
No reaction was observed when model dihydrooxazine 4c
was treated with sodium cyanoborohydride in the absence
initial migration of the double bond from N2–C3 to C3–
of acetic acid.14
C4 in the ring. Subsequent hydrogenation of the N–O and
Tetrahydrooxazines 6h,i, that possess an alkoxy substitu-
C=C bonds (Scheme 3, route d) can also give the target
ent at C6, underwent cyclization into 10h,i much slower
than products 6a–g. Therefore, these compounds could be
prepared by method A in high yields (Table 1, entries 9
and 10).15 It is noteworthy, that products 6h,i could not be
benzoylated with benzoyl chloride under reduction condi-
tions (NaBH3CN, AcOH); in these experiments complex
inseparable mixtures were obtained. Possibly, this result
amino acids 7 or 8.11
In the present work, two-step reduction of dihydroox-
azines 4 [FG = HC(CO2Me)2] with the use of sodium cy-
anoborohydride in the first step was studied with the aim
of obtaining derivatives of different g-amino acids (see
Scheme 3, route c).
The optimized conditions for the reduction of individual is due to elimination of an alkoxy group from C6 of the di-
stereoisomers of cyclic oxime ethers 4a–i with sodium cy- hydrooxazines 4h,i under the action of benzoyl chloride
anoborohydride in glacial acetic acid are illustrated in and subsequent fragmentation of resulting intermediates
Scheme 4 and Table 1 (Methods A and C). Dihydroox- C (Scheme 5). This assumption is confirmed by the detec-
azines 4a–i bearing various substituents at C4–C6 were tion of conjugated ketoenone 11 among the reduction
examined in the reaction aiming to obtain tetrahydroox- products of dihydrooxazine 4i. (Analogous fragmentation
azines 6. The optimized procedure for this transformation of 6-alkoxydihydro-4H-oxazines was reported recent-
depends on the nature of the substituent at C6 in the start- ly.11) Elimination of an alkoxy group from the axial posi-
ing reagent 4.
tion of C6 is favored by the anomeric effect of the lone
electron pair of the endocyclic oxygen atom.
When oxazines 4a–g, that do not possess an alkoxy group
at C6, were treated with sodium cyanoborohydride ac-
cording to method A,10 the corresponding tetrahydroox-
azines 6a–g could be detected in the reaction mixture after
aqueous workup. However, these products proved to be
unstable under the reaction conditions, undergoing an in-
tramolecular cyclization before the complete conversion
of the starting material was achieved.
An
An
H
CO2Me
CO2Me
CO2Me
Cl
BzCl
+
O
N
N
CO2Me
Ph
O
O–
O
O
Me
Me
Me
Me
4i
– BzOMe
– HCl
The products of this cyclization, bicyclic oxazines 10,
were obtained as mixtures of two stereoisomers differing
in the configuration of the stereocenter bearing the
CO2Me group.12 Increasing the reduction time to 24 hours
(method B) leads to complete conversion of tetrahydroox-
azines 6a–d to corresponding bicyclic compounds 10a–d.
Also the effective transformation of 6c to 10c could be ac-
complished by heating 6c at 100–110 °C in acetic acid for
a short time. Optimized procedures for the preparation of
oxazines 10a–d,h are presented in the experimental part.
For other dihydrooxazines the formation of products 10
was detected by TLC.
CO2Me
CO2Me
An
An
O
CO2Me
CO2Me
+
N
Me
O
N
Me
11
C
products of
An = 4-MeOC6H4
transformations
Scheme 5
The smooth cyclization of 6 to give 10 significantly de-
creases the yields of target tetrahydrooxazines 6 and also
makes their isolation problematic, hence, the introduction
of a protective group to the N–H fragment was required.
It turned out that dihydrooxazines 4a–g could be readily
transformed into corresponding N-benzoyl derivatives
9a–g under the reduction conditions (Table 1, method
C).13 Apparently, derivatives 9a–g are formed in the reac-
tion of tetrahydrooxazines 6 with benzoyl chloride. An al-
Commonly, substituents at C3 and C4 in the resulting tet-
rahydrooxazines 6 and 9 are in the trans position. The ex-
ception is tetrahydrooxazine 9f, where the 3,4-cis-isomer
9f¢ was found to be predominant (see Table 1, entry 7).
Selective catalytic hydrogenation of the N–O bond in tet-
rahydro-2H-oxazines 6 and 9 furnished products 8, 12,
and 13, direct precursors of various types of g-amino acids
(Scheme 6, Table 2).
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

744
A. Yu. Sukhorukov et al.
PAPER
R1
O
R1
O
R2
R3
CO2Me
CO2Me
R2
R3
CO2Me
and
CO2Me
6
6
N
N
X
X
R4
R4
9f'
6h, i
9a–g
method E
method D
method E
for 6h,i
R1
An
R4
R2
An
R3
CO2Me
CO2Me
3
CO2Me
CO2Me
NHBz CO2Me
5
HO
Ph
R4
N
Boc
NHBz CO2Me
13a–e
12a (from 9g,f)
8a,b
for 8a (R4 = H)
or
for 8b (R4 = Me)
An
3,5-cis-8b/3,5-trans-8b = 4.1 : 1.0
An = 4-MeOC6H4
CO2Me
Ph
NHBz CO2Me
12a' (from 9f')
Scheme 6 Reagents and conditions: Method D: H2 (1 bar), Raney nickel (excess), Boc2O, MeOH, r.t., 3 h; Method E: H2 (1 bar), Raney nickel
(excess), MeOH, r.t., 3 h.
The standard procedure for heterogeneous catalytic hy- spective derivative 13. The relative configuration of all
drogenation under hydrogen pressure in an autoclave stereocenters of the initial tetrahydrooxazine remain un-
failed to provide selective cleavage of the N–O bond. For changed during the reduction process (Scheme 6). During
dihydrooxazines 9 reduction of the phenyl group of the the course of the hydrogenation of tetrahydrooxazine 9d
benzoyl fragment takes place to a significant extent. The reduction of the C–Cl bond also occurs (cf. Table 2, en-
desirable process was realized only by barbotation of hy- tries 4 and 6).
drogen through the reaction mixture containing increased
amount of catalyst (for details see the experimental part).
If the phenyl group is attached to C6 of the initial tetrahy-
drooxazine (substrates 9f,f¢,g), a known hydrogenolysis of
the benzylic C–O bond also occurs16 resulting in loss of
Table 2 Catalytic Hydrogenation of Tetrahydro-2H-oxazines 6 and
2-Benzoyltetrahydrooxazines 9 into the Precursors of g-Amino Acids
the stereocenter at C6 (see products 12 in Scheme 6 and
Table 2).
Entry
Initial oxazine
Product
8a
Yield (%)
Hydrogenation of unprotected tetrahydrooxazines 6h,i
bearing an alkoxy substituent at C6 proceeds in a more
complex manner and leads to pyrrolidine derivatives 8a,b
(Scheme 6). Probably, this transformation involves hy-
drogenolysis of the N–O bond, fragmentation of the inter-
mediate semiacetal, followed by the closure of pyrroline
ring and its reduction to pyrrolidine (Scheme 7). As
shown for the example of 8b, in the process the configu-
ration of the stereocenter at C6 is lost (see Scheme 6 and
Table 2, entry 2).
1
2
6h
6i
62
53
75
94
70
69
75
50
69
77
8b
3
9a
9b
9c
9d
9e
9f
13a
13b
13c
4
5
6
13ba
13e
In order to improve the efficiency and selectivity in the
last two cases, it is reasonable to perform hydrogenation
in the presence of tert-butyl dicarbonate to protect the
amino group in the resulting pyrrolidine derivatives 8.
7
8
12a
12a¢
12a
9
9f¢
9g
To transform products 8, 12, and 13 into the correspond-
ing g-amino acids it is necessary to deprotect the amino
and ester groups as well as to decarboxylate the
CH(CO2H)2 fragment. These operations can be performed
in one stage for the synthesis of g-amino acids 14a,b de-
rived from pyrrolidines 8a,b (Scheme 8). A mixture of
diastereomeric pyrrolidines 8b after deprotection and
crystallization gives, almost, an individual diastereomer
10
a After reductive dehalogenation.
The type of resulting g-amino acid precursor strongly de-
pends on the structure of the initial tetrahydrooxazines 6
or 9. If the tetrahydrooxazine does not possess a phenyl or
alkoxy substituent at C6, hydrogenation affords the re-
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

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Diastereoselective Synthesis of g-Amino Acids and Their Derivatives from Nitroethane
745
ously, a special study is required in order to handle this
problem.
An
An
CO2Me
NH2 CO2Me
CO2Me
NH CO2Me
H2, Ra-Ni
Reduction of oxime ethers 4 with sodium cyanoborohy-
dride is the key step in the suggested strategy of the syn-
thesis of unnatural g-amino acids and their derivatives.
The mechanism of this reaction deserves special discus-
sion (Scheme 9).
R3
R4
O
H
R3
O
R4
6h,i
– R3H
As reported previously,10 the reduction starts with revers-
ible protonation of the oximino group to afford iminium
cation D. The later interacts with the [BH3CN]– anion to
give the target tetrahydrooxazine. However, the authors10
did not provide any evidence in favor of this mechanism.
An
O
An
CO2Me
NH2 CO2Me
CO2Me
CO2Me
– H2O
R4
R4
N
H2/Ra-Ni
Boc2O
Herein we present arguments supporting the above-
mentioned mechanism. Thus, salt 15c, which consists of
iminium cation D and a triflate anion, can be reduced with
sodium cyanoborohydride to tetrahydrooxazine 6c (yield:
51%) with the same configuration of stereocenters as the
product 6c obtained from the reduction of dihydrooxazine
4c.18 (Stable salt 15c can be prepared quantitatively by
treatment of initial dihydrooxazine 4c with trifluoro-
methanesulfonic acid. The structure of 15c was supported
by 1H and 13C NMR data.) At the same time in the absence
of acetic acid, when the generation of cation D is impos-
sible, dihydrooxazine 4c does not interact with sodium cy-
anoborohydride.
An = 4-MeOC6H4
R3 = OAlk
An
CO2Me
CO2Me
R4
N
Boc
8a,b
Scheme 7
An
An
CO2Me
CO2Me
method F or G
R4
R4
N
CO2H
N+
Cl–
Boc
H
H
Especial attention should be given to the consideration of
the stereochemical aspects of the reduction of dihydroox-
azines 4 with sodium cyanoborohydride because in most
cases this reduction is highly stereoselective (see
Table 1). Therefore this process can be used for asymmet-
ric synthesis of some unnatural amino acids. (There are
possible ways of inserting chiral auxiliaries into 5,6-dihy-
14a (R4 = H) 80% (ref. 9a)
14b (R4 = Me) 53%
8a,b
R4 = H
4 = Me (cis/trans = 4.1:1.0)
R
An - 4-MeO-C6H4
Scheme 8 Reagents and conditions: Method F: (1) HCl, H2O–
MeOH, reflux, (2) crystallization; Method G: (1) HCl, H2O–MeOH,
r.t., (2) Dowex 50WX2-100, reflux, (3) crystallization.
dro-4H-1,2-oxazines and their N-oxides.19,20
)
of the g-amino acid as its hydrogen chloride salt 14b (de
>90%).
It can be assumed that the relative configuration of stereo-
centers at C4–C6 in the diastereomerically pure initial di-
hydrooxazines 4 is not changed in the reaction with
sodium cyanoborohydride. Therefore only the relative
configuration of the newly formed stereocenters at the ni-
trogen atom and C3 in tetrahydrooxazines 6 should be
considered. Since the stereocenter at the nitrogen atom in
the saturated oxazine ring is flexible under standard con-
ditions due to the rapid inversion of nitrogen,21 the stereo-
However, for N-benzoyl derivatives of amino acids 12
and 13 cleavage of the benzoyl protective group proved to
be a special problem. Standard procedures [HCl, H2O,
reflux;17a KOH, H2O, EtOH, reflux;17b KOH,
HOCH2CH2OH, reflux;17c N2H4·H2O, reflux;17d AlH(i-
Bu)2 in toluene17e] did not result in the successful deben-
zoylation of the amino group in these compounds. Obvi-
[BH3CN]–
AcOH
N+
N
N
O
O
H
O
H
OAc–
D
An
O
An
O
NaBH3CN
3 equiv
CO2Me
NH CO2Me
CO2Me
TfOH
An
O
NH+ CO2Me
CH2Cl2–MeOH
CH2Cl2
Me
Me
CO2Me
OTf–
6c
Me
15c
Me
3 equiv
NaBH3CN
N
CO2Me
An = 4-MeOC6H4
Me
Me
no reaction
CH2Cl2–MeOH
4c
Scheme 9
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

746
A. Yu. Sukhorukov et al.
PAPER
chemical analysis of products 6 reduces to the It is evident that to solve the above-mentioned problems
determination of the relative disposition of the proton (or complicated physicochemical and computational investi-
substituent) at C3 and the proton (or substituent) at any gations are required. However, some preliminary conclu-
other carbon atom of the heterocyclic ring (e.g., at C4). In sions concerning the stereochemical course of the reaction
order to predict the stereochemical outcome of the reduc- 4 with sodium cyanoborohydride can be made using liter-
tion process it is necessary to establish two points: (1) the ature analogies and the data obtained.
true reactive conformation of cation D (D¢ or D¢¢); (2) the
The stereochemistry of C–C coupling of p-nucleophiles
true approach (distal or proximal in relation to C6) of the
with N-siloxy cations generated by silylation of six-mem-
hydride ion to the plane of the reactive conformation of
cation D (Scheme 10).
bered cyclic nitronates was studied in detail recently.23a,b
It was shown, that the above-mentioned cations exist in
dichloromethane as ion pairs with the TfO– anion, and
R3
R2
usually their dominant conformations are the same as the
dominant conformations of the initial nitronates. The C–C
coupling of these cations is diastereoselective and occurs
through a distal (with respect to C6) approach of the p-nu-
cleophiles to the above-mentioned cations. Of course, at
the moment we do not have enough evidence to extend
this conclusion to the process of the reduction of dihy-
drooxazine 4 with sodium cyanoborohydride.24 However
if we assume that the above-mentioned regularities23 are
applied to the reaction of 4 with sodium cyanoborohy-
dride to give 6, we can conclude that the stereoconfigura-
tion of tetrahydrooxazines 6a–d,g–i arises from the distal
attack of the hydride anion to the reactive conformations
D¢ of the iminium cations D (see at the bottom of
Scheme 10). At the same time, for the cation D generated
from the bicyclic dihydrooxazine 4e, conformation D¢¢ is
favored, like its precursor. In this case proximal attack of
the hydride anion is realized due to the sterical effect of
cyclohexane unit (see at the bottom of Scheme 10).25
Hax
R2
R1
Heq
k1
R4
O
6
O
N
4
•
N
•
5
R1
R3
k–1
4'
R4
4''
predominant for 4e,f
predominant for 4a–d,g–i
H+
k3
H+
k–2
k2
k–3
R2
R3
H
O
H
k4
H
R4
O
H
N
•
R2
R1
N
•
D'
R1
R3
k–4
R4
D''
predominant for 15c
(compare with 4c)
distal
[H–]
proximal
[H–]
R3
k6
(R2)
k8
Hax
R2
R1
k4
H
Heq
R4
O
H
O
N
•
k7
N
•
k–4
R1
D''
(R3)
Nonselective reduction of dihydrooxazine 4f might be due
to the presence of two reactive conformations (D¢ and D¢¢)
of the corresponding cationic intermediate or because two
competitive attacks of the hydride anion on one conforma-
tion of cation D are realized.26
k5
D'
R4
[H–]
distal
[H–]
R3
proximal
H
for 4a–d,
g–i
for 4e
R2
R4
O
N
R1
Y
after inversion
of initially formed
boat into chair
H
H
The structures of products 6, 8, 9, 10, 12, 13, and 14b were
established by elemental analysis, NMR (1H, 13C, INEPT,
COSY, HSQC), as well as by chemical transformations il-
lustrated in Schemes 6 and 8. The relative configuration
of substituents attached to C3 and C4 in tetrahydroox-
azines 6h,i is conserved in the products of their hydroge-
nation 8a,b. This fact is confirmed by the presence of
characteristic interactions in 2D-NOESY spectra of pyr-
rolidines 8a,b depicted in Figure 1.
H
6a–e,g–i
• = C-CH2CH(CO2Me)2
Y = CH2CH(CO2Me)2
Scheme 10
In general, the solution to these problems seems to be un-
certain because the same stereochemical outcome of tar-
get tetrahydrooxazines 6 may result from one type of
approach of the nucleophile to the first conformation (for
example, to D¢) as well as from the other approach of the
nucleophile to the second conformation (D¢¢, see at the
bottom of Scheme 10). The true reactive conformation of
cation D depends on thermodynamic and kinetic factors.
The favorability of one or another approach of hydride an-
ion is determined mainly by steric factors. Thus, distal at-
tack must be hampered by the repulsion between the
hydride anion and an axial substituent at C5, while proxi-
mal attack may be blocked by a strongly ‘deviated’ C6
atom22 and especially by an axial substituent attached to
this atom (R3 or R4).
An
CO2Me
CO2Me
Hax
CH2CH(CO2Me)2
Heq
2
3
An
3
5
H
R4
Heq
4
6
N
O
H
N
Boc
8a, b
Hax
Bz
Ph
9f'
R1
R1
H''
H''
H
R2
R3
R2
R3
H
H'
H'
4
4
H
H
5
6
5
6
3
3
CO2Me
CO2Me
N
N
O
O
R4
R4
O
O
10'
10''
Figure 1
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of g-Amino Acids and Their Derivatives from Nitroethane
747
Dimethyl rel-2-{[(4S,6S)-4-(4-Methoxyphenyl)-6-phenyl-5,6-di-
hydro-4H-1,2-oxazin-3-yl]methyl}malonate (4f)
Mp 85–92 °C; Rf = 0.62 (EtOAc–hexane, 1:1).
1H NMR (300 MHz, CDCl3): d = 2.05 (ddd, J = 13.2, 2.2, 2.2 Hz, 1
H, H5eq), 2.34 (ddd, J = 13.2, 11.7, 6.6 Hz, 1 H, H5ax), 2.71 (dd,
J = 16.9, 7.3 Hz, 1 H, H7), 2.94 (dd, J = 16.9, 7.3 Hz, 1 H, H7), 3.52
(dd, J = 6.6, 2.2 Hz, 1 H, H4eq), 3.76 (s, 6 H, 10-CH3, 12-CH3), 3.84
(s, 3 H, 21-CH3), 4.07 (dd, J = 7.3, 7.3 Hz, 1 H, H8), 4.81 (dd,
J = 11.7, 2.2 Hz, 1 H, H6ax), 6.95 (d, J = 8.8 Hz, 2 H, H19), 7.19 (d,
J = 8.8 Hz, 2 H, H18), 7.25–7.37 (m, 5 H, H14, H15, H16).
13C NMR (75 MHz, CDCl3): d = 33.6 and 34.7 (C5, C7), 39.6 (C4),
47.9 (C8), 52.7 (C10, C12), 55.3 (C21), 72.9 (C6), 114.5 (C19),
126.6, 128.1, and 128.4 (C14, C15, C16), 129.4 (C18), 133.3 (C17),
139.4 (C13), 154.0 (C3), 158.9 (C20), 169.4 and 169.6 (C9, C11).
In the products containing a six-membered ring the rela-
tive configuration of the stereocenters at C3 and C4 was
determined for chair-type conformation using Karplus re-
lationships for vicinal coupling constants 3J1H,1H. The rel-
ative configuration of the stereocenters at C4–C6 is not
affected in the course of the reduction of the initial dihy-
drooxazines 4 with sodium cyanoborohydride. The stereo-
chemistry of compound 9f¢ was additionally confirmed by
2D-NOESY experiments (Figure 1). The identical config-
uration of stereocenters at C3 and C4 in tetrahydroox-
azines 9f and 9g is corroborated by the isolation of the
same product 12a in the hydrogenation of both tetrahy-
drooxazines (see Scheme 6).
Anal. Calcd for C23H25NO6: C, 67.14; H, 6.12; N, 3.40. Found: C,
66.99; H, 6.03; N, 3.51.
The trans-configuration of the protons at C3 and C4 in
both isomers of bicyclic oxazines 10 was established with
Karplus relationships for vicinal coupling constants
3J1H,1H. Characteristic correlations in 2D NMR spectra
(see Figure 1) and the absence of correlations between
protons at C3 and C4 were found in 2D-NOESY spectra.
The unambiguous assignment of signals in the NMR spec-
tra of isomer mixtures 10¢ and 10¢¢ was guided by 2D
Dimethyl rel-2-{[(4S,6R)-4-(4-Methoxyphenyl)-6-phenyl-5,6-di-
hydro-4H-1,2-oxazin-3-yl]methyl}malonate (4g)
Mp 95–93 °C; Rf = 0.66 (EtOAc–hexane, 1:1).
1H NMR (300 MHz, CDCl3): d = 2.20 (ddd, J = 13.9, 11.7, 11.0 Hz,
1 H, H5ax), 2.45 (ddd, J = 13.9, 8.1, 1.6 Hz, 1 H, H5eq), 2.58 (dd,
J = 16.9, 7.3 Hz, 1 H, H7), 2.64 (dd, J = 16.9, 7.3 Hz, 1 H, H7), 3.68
NMR experiments COSY, HSQC, NOESY (characteristic (dd, J = 11.0, 8.1 Hz, 1 H, H4ax), 3.72 and 3.73 (2 s, 6 H, 10-CH3,
12-CH3), 3.81 (s, 3 H, 21-CH3), 3.97 (dd, J = 7.3, 7.3 Hz, 1 H, H8),
correlations in 2D-NOESY are illustrated in Figure 1).
4.81 (d, J = 11.7 Hz, 1 H, H6ax), 6.91 (d, J = 8.1 Hz, 2 H, H19), 7.17
(d, J = 8.1 Hz, 2 H, H18), 7.31–7.43 (m, 5 H, H14, H15, H16).
In conclusion, a novel approach to the stereoselective syn-
thesis of several types of g-amino acids and their deriva-
13C NMR (75 MHz, CDCl3): d = 32.3 and 37.9 (C5, C7), 43.2 (C4),
tives starting from nitroethane and other simple molecules
48.1 (C8), 52.6 (C10, C12), 55.3 (C21), 77.9 (C6), 114.6 (C19),
was suggested. The amino acids and their derivatives ob-
tained in this study may have various applications. Specif-
ically, neurotropic27a and antiepileptic27b activity is known
for g-amino acids, derived from pyrrolidine, and anti-HIV
activity for some N-benzoyl g-amino acids.27c
126.6, 128.3, and 129.2 (C14, C15, C16), 131.6 (C18), 131.6 (C17),
139.1 (C13), 157.2 (C3), 159.0 (C20), 169.4 and 169.6 (C9, C11).
Anal. Calcd for C23H25NO6: C, 67.14; H, 6.12; N, 3.40. Found: C,
67.37; H, 6.28; N, 3.42.
Tetrahydrooxazines 6c,h,i; General Procedure Using Method A
NaBH3CN (0.095 g, 1.5 mmol) was added to a stirred soln of ox-
azine 4c, 4i, or 4h (0.5 mmol) in AcOH (2.2 mL) under argon. The
mixture was stirred at r.t. for 2 h and poured into a mixture of EtOAc
(100 mL) and sat. Na2CO3 (100 mL). The aqueous phase was back-
extracted with EtOAc (2 × 50 mL); the combined organic layers
were washed with brine (50 mL) and dried (Na2SO4). The solvent
was evaporated in vacuo and the residue was subjected to column
chromatography (silica gel).
1D and 2D NMR spectra were recorded at room temperature on
Bruker DRX-500 [1H (500.13 MHz), 1H-1H COSY, HSQC (J = 145
Hz), NOESY (mixing time 900 ms)] and Bruker AM-300 (13C 75.13
MHz, INEPT, JMOD, 1H-1H COSY, HSQC, NOESY) NMR spec-
trometers for 0.1–0.2 M solns in CDCl3 or DMSO-d6. For atom-
numbering, see Figure 2 and Figure 3. The chemical shifts (1H and
13C) are given relative to the solvent signal.28 All 1D and 2D NMR
experiments were performed using standard methods and Bruker
NMR technique software. Ratios of stereoisomers were determined
from the relative integral intensity of characteristic signals in the 1H
NMR for the mixtures after workup. Elemental analyses were per-
formed by the Analytical Laboratory of the Institute of Organic
Chemistry and Analytical Laboratory of the Institute of Organoele-
ment Compounds. Melting points (uncorrected) were determined
on a Koffler apparatus. Analytical TLC was performed on Merck
silica gel plates with QF-254. Visualization was accomplished with
UV light or with a soln of ninhydrin in EtOH. Column chromatog-
raphy was performed using Merck Kieselgel 60 230–400 mesh sil-
ica gel. MeOH, hexane, and EtOAc were distilled without drying
agents. Glacial AcOH was recrystallized twice. The following
chemicals were purchased from the indicated sources: NaBH3CN
(Acros), Raney nickel (50% slurry in H2O) (Acros), BzCl (Acros),
Boc2O (Acros), Dowex-50WX2-100 (Sigma-Aldrich).
Dimethyl rel-2-{[(3S,4S)-4-(4-Methoxyphenyl)-6,6-dimethyl-
tetrahydro-2H-1,2-oxazin-3-yl]methyl}malonate (6c)
Yield: 50% (the second product is oxazine 10c, 30% yield); mp
102–108 °C; Rf = 0.58 (EtOAc–hexane, 1:1).
1H NMR (500 MHz, CDCl3): d = 1.20 and 1.33 (2 s, 6 H, 13-CH3,
14-CH3), 1.61 (ddd, J = 15.3, 9.8, 6.5 Hz, 1 H, H7), 1.71 (m, 2 H, 5-
CH2), 1.93 (ddd, J = 15.3, 8.0, 2.8 Hz, 1 H, H7), 2.55 (ddd, J = 10.7,
10.3, 10.3 Hz, 1 H, H4ax), 3.09 (ddd, J = 10.3, 9.8, 2.8 Hz, 1 H,
H3ax), 3.50 (dd, J = 8.0, 6.5 Hz, 1 H, H8), 3.63 and 3.66 (2 s, 6 H,
10-CH3, 12-CH3), 3.77 (s, 3 H, 19-CH3), 4.83 (br, 1 H, 2-NH), 6.82
(d, J = 7.9 Hz, 2 H, H16), 7.06 (d, J = 7.9 Hz, 2 H, H17).
13C NMR (75 MHz, CDCl3): d = 20.0 and 27.8 (C13, C14), 28.0
(C7), 42.1 (C4), 42.9 (C5), 47.1 (C8), 51.0 and 51.1 (C10, C12),
53.7 (C19), 59.0 (C3), 73.1 (C6), 112.7 (C17), 127.0 (C16), 132.6
(C15), 156.9 (C18), 168.0 and 168.7 (C9, C11).
Starting oxazines 4a–e,h,i were prepared from nitroethane accord-
ing to the literature procedure.9a,b Previously undescribed oxazines
4f,g were prepared from the corresponding cyclic nitronates9b using
the same procedure in 25% and 29% yields, respectively.
Anal. Calcd for C19H27NO6: C, 62.45; H, 7.45; N, 3.83. Found: C,
62.90; H, 7.88; N, 3.66.
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

748
A. Yu. Sukhorukov et al.
PAPER
19
OMe
18
19
19
21
OMe
18
OMe
18
OMe
20
17
16
17
16
17
19
16
7
18
17
15
15
4
3
15
4
9
10
9
10
10
9
10
7
7
9
7
4
3
4
CO2Me
3
8
8
8
CO2Me
CO2Me
11 12
3
8
5
6
5
6
CO2Me
5
6
5
6
2
11 12
CO2Me
2
2
12
11
CO2Me
13
11 12
CO2Me
14
1
14
Me
1
NH
1
O
1
NH
6h
Me
NH CO2Me
13
15
16
N2
O
O
O
O
6i
O
13 Me
14 Me
6c
13
14
(the same numeration for
4f and 4g
salt 15c)
20
19
OMe
19 OMe
15
Me
4
18
18
18
9
10
17
17
16
17
16
7
CO2Me
8
3
16
5
6
H'
8
9
11
CO2M1e2
4
3
N2
15
4
CO2Me
15
1
9
10
9
10
H''
12
Me
14
Me
7
7
O
4
5
2
7
CO2Me
11
CO2Me
8
8
CO2Me
16
3
O
3
10 11
6
5
5
1
13Me
12
17
12
CO2Me
11
N
2
2
18
19
6
CO2Me
6
14
14
1
1
O
13
N
N
O
O
Me
O
19
20
Me 13
20
21
13
Me
O
O
9a
Me
14
21
22
20
22
23
15
Me
Me
Me
cis-8b and trans-8b
9b
23
21
9c
24
21
Cl
18
OMe
20
OMe
20
19
18
19
18
17
16
15
17
4
9
10
17
4
10
9
9
10
7
7
7
CO2Me
4
16
5
CO2Me
11
CO2Me
CO2Me
8
8
3
8
3
3
5
6
5
15
14
11 12
CO2Me
12
11 12
CO2Me
2
2
N
2
14
6
14
1
13
1
O
22 O
N
1
O
N
15
16
O
O
6
Me13
Me
O
19
20
22
23
13
23
21
22
24
25
24
25
9d
23
9e
26
26
9f', 9f and 9g
Figure 2
Dimethyl rel-2-{[(3S,4S,6S)-6-Ethoxy-4-(4-methoxyphenyl)tet-
rahydro-2H-1,2-oxazin-3-yl]methyl}malonate (6h)
H, H8), 3.77 (s, 3 H, 19-CH3), 4.65 (br, 1 H, 2-NH), 6.84 (d, J = 8.8
Hz, 2 H, H16), 7.06 (d, J = 8.8 Hz, 2 H, H17).
Yield: 82%; mp 54–60 °C, Rf = 0.54 (EtOAc–hexane, 1:1).
13C NMR (75 MHz, CDCl3): d = 21.6 (C14), 29.5 (C7), 42.7 (C4),
43.0 (C5), 48.5 (C13), 48.6 (C8), 52.4 and 52.5 (C10, C12), 55.2
(C19), 59.4 (C3), 99.2 (C6), 114.2 (C17), 128.4 (C16), 133.9 (C15),
158.5 (C18), 169.5 and 170.2 (C9, C11).
1H NMR (500 MHz, CDCl3): d = 1.25 (t, J = 7.3 Hz, 3 H, 14-CH3),
1.51 (ddd, J = 14.7, 11.0, 5.9 Hz, 1 H, H7), 1.91 (m, 2 H, H5, H7),
1.98 (ddd, J = 13.5, 11.0, 2.8 Hz, 1 H, H5), 2.67 (ddd, J = 11.0,
11.0, 5.2 Hz, 1 H, H4ax), 3.19 (ddd, J = 11.0, 11.0, 2.2 Hz, 1 H,
H3ax), 3.51 (dq, J = 9.6, 7.3 Hz, 1 H, H13), 3.62 (m, 1 H, H8), 3.62
and 3.63 (2 s, 6 H, 10-CH3, 12-CH3), 3.73 (s m, 4 H, 19-CH3, H13),
4.81 (d, 1 H, J = 2.8 Hz, H6), 5.25 (br, 1 H, 2-NH), 6.81 (d, J = 8.7
Hz, 2 H, H16), 7.08 (d, J = 8.7 Hz, 2 H, H17).
13C NMR (75 MHz, CDCl3): d = 15.2 (C14), 29.8 (C7), 37.3 (C5),
41.6 (C4), 48.5 (C8), 52.4 and 52.5 (C10, C12), 55.2 (C19), 60.1
(C3), 63.6 (C13), 98.1 (C6), 114.2 (C17), 128.4 (C16), 133.9 (C15),
158.5 (C18), 169.5 and 170.2 (C9, C11).
Anal. Calcd for C19H27NO7: C, 59.83; H, 7.14; N, 3.67. Found: C,
60.14; H, 7.28; N, 3.72.
Hexahydropyrrolooxazinones 10a–d; General Procedure Using
Method B
NaBH3CN (0.19 g, 3.0 mmol) was added to a stirred soln of oxazine
4a–d (1.0 mmol) in AcOH (4.4 mL) under argon. The mixture was
stirred at r.t. for 24 h and poured into a mixture of EtOAc (100 mL)
and sat. Na2CO3 (100 mL). The aqueous phase was back-extracted
with EtOAc (2 × 50 mL); the combined organic layers were washed
with brine (50 mL) and dried (Na2SO4). The solvent was evaporated
in vacuo and the residue was subjected to a column chromatography
(silica gel) to give oxazines 10.
Anal. Calcd for C19H27NO7: C, 59.83; H, 7.14; N, 3.67. Found: C,
59.37; H, 7.41; N, 3.44.
Dimethyl rel-2-{[(3S,4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-
methyltetrahydro-2H-1,2-oxazin-3-yl]methyl}malonate (6i)
Oil; yield: 81%; Rf = 0.36 (EtOAc–hexane, 1:1).
1H NMR (500 MHz, CDCl3): d = 1.31 (s, 3 H, 14-CH3), 1.53 (ddd,
J = 14.7, 11.0, 5.9 Hz, 1 H, H7), 1.79 (dd, J = 13.2, 12.5 Hz, 1 H,
H5), 1.94 (ddd, J = 14.7, 12.5, 2.9 Hz, 1 H, H7), 1.98 (dd, J = 13.2,
4.4 Hz, 1 H, H5), 2.70 (ddd, J = 12.5, 11.0, 4.4 Hz, 1 H, H4ax), 3.13
(ddd, J = 11.0, 11.0, 2.9 Hz, 1 H, H3ax), 3.29 (s, 3 H, 13-CH3), 3.65
and 3.67 (2 s, 6 H, 10-CH3, 12-CH3), 3.71 (dd, J = 12.5, 5.9 Hz, 1
Methyl 2,2,4-Trimethyl-7-oxohexahydro-2H-pyrrolo[1,2-
b][1,2]oxazine-6-carboxylate (10a)
Yield: 87%; mixture of diastereomers: 10a¢/10a¢¢, 1.7:1.0; mp 81–
85 °C; Rf = 0.16 (EtOAc–hexane, 1:1).
Anal. Calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C,
59.48; H, 8.13; N, 5.91.
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of g-Amino Acids and Their Derivatives from Nitroethane
749
18
OMe
17
Cl
17
17
16
15
16
15
16
15
14Me
14
14
4
14
4
H''
7
H''
7
H''
7
H''
H
H
H
H
4
4
H'
H'
10
H'
H'
5
6
5
6
5
6
11
CO2Me
10
11
5
6
11
CO2Me
10
CO2Me
10
8
8
8
3
3
3
7
3
8
2
2
2
CO2Me
1
13
1
13
Me
1
13
Me
13
Me
1
N
N
N
N
9
9
9
9
2
O
O
O
Me
O
12Me
12Me
12Me
10b' and 10b''
12Me
O
O
O
O
10c' and 10c''
10d' and 10d''
10a' and 10a''
20
18
18
OMe
17
OMe
19
17
18
17
15
Me
16
15
16
9
10
9
10
7
4
7
15
CO2Me
4
CO2Me
11 12
8
16
3
3
8
3
5
6
5
6
8
9
5
6
13
11 12
CO2Me
14
H''
7
12
7
2
2
CO2Me
4
2
14
15
4 H3
CO2Me
14
Me13
14
HN
H'
10 11
O
HN
5
1
O
11
10
8
OH
16
17
Me 13 OH
19
20
CO2Me
2
1
Me 1
HN
O
CO2Me
Me
6
1
21
22
N
18
19
9
21
22
O
O
H
12
23
24
O
13
10h' and 10h''
20
12a and 12a'
13b
13a
23
25
19
OMe
18
21
OMe
20
17
19
15
OMe
14
16
15
18
9
17
4
CO21M0 e
10
9
7
4
7
16
13
8
13
3
2
8
CO2Me
5
5
6
3
H' 11
15
14
11 12
CO2Me
11 12
12
4
3
2
6
14
H''
10
Me
CO2Me
HN
O
1
7
O
NH
O
8
5
2
Me 13 OH
20
21
6
22
23
OH
1
Me
9
N
22
23
24
25
1
OH
H
H
H2O
Cl
14b
13c
13e
24
26
Figure 3
rel-(4R,4aS,6S)-Isomer 10a¢
Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C,
67.16; H, 7.14; N, 4.71.
1H NMR (500 MHz, CDCl3): d = 0.89 (d, J = 6.5 Hz, 3 H, 14-CH3),
1.21 and 1.24 (2 s, 6 H, 12-CH3, 13-CH3), 1.30 (dd, J = 13.0, 12.9
Hz, 1 H, H5), 1.60 (dd, J = 13.6, 3.9 Hz, 1 H, H5), 1.81 (m, 1 H,
H4), 1.99 (m, 1 H, H7¢), 2.42 (ddd, J = 13.0, 9.3, 8.5 Hz, 1 H, H7¢¢),
3.00 (ddd, J = 9.7, 8.5, 7.2 Hz, 1 H, H3), 3.39 (dd, J = 9.3, 8.5 Hz,
1 H, H8), 3.71 (s, 3 H, 11-CH3).
rel-(4S,4aS,6S)-Isomer 10b¢
1H NMR (500 MHz, CDCl3): d = 1.35 and 1.37 (2 s, 6 H, 12-CH3,
13-CH3), 1.79 (dd, J = 13.7, 4.4 Hz, 1 H, H5), 1.90 (m, 1 H, H5),
2.01 (ddd, J = 13.0, 7.5, 6.6 Hz, 1 H, H7¢), 2.19 (m, 1 H, H7¢¢), 2.98
(ddd, J = 12.5, 11.4, 4.4 Hz, 1 H, H4), 3.38 (dd, J = 9.6, 6.6 Hz, 1
H, H8), 3.59 (ddd, J = 11.4, 7.5, 7.5 Hz, 1 H, H3), 3.72 (s, 3 H, 11-
CH3), 7.10–7.30 (m, 5 H, H15, H16, H17).
13C NMR (75 MHz, CDCl3): d = 17.0 (C14), 22.1 and 27.7 (C12,
C13), 25.0 (C7), 33.1 (C4), 43.3 (C5), 45.0 (C8), 52.7 (C11), 58.4
(C3), 81.0 (C6), 162.3 and 170.7 (C9, C10).
13C NMR (75 MHz, CDCl3): d = 21.9 and 27.8 (C12, C13), 24.7
(C7), 42.6 (C5), 44.6 (C4), 44.8 (C8), 52.9 (C11), 57.6 (C3), 81.1
(C6), 127.5, 127.6, and 128.9 (C15, C16, C17), 139.4 (C14), 162.9
and 170.7 (C9, C10).
Characteristic 2D-NOESY correlations: 14-CH3/H3, H3/H7¢¢,
H7¢¢/H8.
rel-(4R,4aS,6R)-Isomer 10a¢¢
1H NMR (500 MHz, CDCl3): d = 0.89 (d, J = 6.5 Hz, 3 H, 14-CH3),
1.21 and 1.24 (2 s, 6 H, 12-CH3, 13-CH3), 1.30 (dd, J = 13.0, 12.9
Hz, 1 H, H5), 1.60 (dd m, J = 13.6, 3.9 Hz, 2 H, H5, H4), 1.81 (m,
1 H, H7¢), 2.51 (m, 1 H, H7¢¢), 3.18 (ddd, J = 9.4, 7.5. 7.3 Hz, 1 H,
H3), 3.31 (m, 1 H, H8), 3.65 (s, 3 H, 11-CH3).
Characteristic 2D-NOESY correlations: H15/H3, H3/H7¢¢, H7¢¢/H8.
rel-(4S,4aS,6R) 10b¢¢
1H NMR (500 MHz, CDCl3): d = 1.35 and 1.37 (2 s, 6 H, 12-CH3,
13-CH3), 1.79 (dd, J = 13.7, 4.4 Hz, 1 H, H5), 1.90 (m, 1 H, H5),
1.95 (m, 1 H, H7¢), 2.29 (m, 1 H, H7¢¢), 2.76 (ddd, J = 11.8, 11.5,
4.4 Hz, 1 H, H4), 3.43 (dd, J = 9.7, 3.5 Hz, 1 H, H8), 3.64 (s, 3 H,
11-CH3), 3.75 (ddd, J = 11.5, 7.4, 7.4 Hz, 1 H, H3), 7.10–7.30 (m,
5 H, H15, H16, H17).
13C NMR (75 MHz, CDCl3): d = 17.0 (C14), 22.2 and 27.7 (C12,
C13), 27.7 (C7), 33.3 (C4), 43.2 (C5), 45.0 (C8), 52.7 (C11), 58.8
(C3), 80.5 (C6), 162.2 and 170.2 (C9, C10).
Characteristic 2D-NOESY correlations: 14-CH3/H3, H3/H7¢¢,
H7¢/H8.
13C NMR (75 MHz, CDCl3): d = 22.1 and 27.8 (C12, C13), 25.4
(C7), 42.6 (C5), 44.7 (C4, C8), 52.8 (C11), 57.9 (C3), 80.8 (C6),
127.5, 127.6 and 128.9 (C15, C16, C17), 139.2 (C14), 162.8 and
170.1 (C9, C10).
Methyl 2,2-Dimethyl-7-oxo-4-phenylhexahydro-2H-pyrro-
lo[1,2-b][1,2]oxazine-6-carboxylate (10b)
Yield: 66%; mixture of diastereomers: 10b¢/10b¢¢, 1.5:1.0; mp 109–
116 °C; Rf = 0.21 (EtOAc–hexane, 1:1).
Characteristic 2D-NOESY correlations: H15/H3, H3/H7¢¢, H7¢/H8.
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

750
A. Yu. Sukhorukov et al.
PAPER
Methyl 4-(4-Methoxyphenyl)-2,2-dimethyl-7-oxohexahydro-
2H-pyrrolo[1,2-b][1,2]oxazine-6-carboxylate (10c)
Oil; yield: 73%; mixture of diastereomers: 10c¢/10c¢¢, 2.0:1.0;
Rf = 0.21 (EtOAc–hexane, 1:1).
(C6), 129.0 and 129.3 (C15, C16), 133.5 and 137.6 (C14, C17),
163.5 and 170.2 (C9, C10).
Characteristic 2D-NOESY correlations: H15/H3, H3/H7¢¢, H7¢/H8.
Anal. Calcd for C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C,
64.43; H, 6.73; N, 4.10.
Transformation of Tetrahydrooxazines 6c,h into Oxazines
10c,h; General Procedure
A soln of tetrahydrooxazine 6c or 6h (0.1 mmol) in AcOH (1.0 mL)
was stirred at 100–110 °C until full conversion of the initial oxazine
(ca. 45 min), then the solvent was evaporated and the residue was
subjected to column chromatography (silica gel) to give oxazines
10c (yield: 94%) or 10h (yield: 95%), respectively.
rel-(4S,4aS,6S)-Isomer 10c¢
1H NMR (500 MHz, CDCl3): d = 1.35 and 1.36 (2 s, 6 H, 12-CH3,
13-CH3), 1.76 (dd, J = 13.2, 4.4 Hz, 1 H, H5), 1.87 (dd, J = 13.2,
12.5 Hz, 1 H, H5), 2.00 (m, 1 H, H7¢), 2.19 (m, 1 H, H7¢¢), 2.92 (ddd,
J = 12.5, 11.0, 4.4 Hz, 1 H, H4), 3.37 (dd, 1 H, J = 10.3, 7.4 Hz, 1
H, H8), 3.53 (ddd, J = 11.0, 7.4, 7.4 Hz, 1 H, H3), 3.72 (s, 6 H, 11-
CH3, 18-CH3), 6.80 (d, J = 8.5 Hz, 2 H, H16), 7.10 (d, J = 8.5 Hz, 2
H, H15).
Methyl 2-Ethoxy-4-(4-methoxyphenyl)-7-oxohexahydro-2H-
pyrrolo[1,2-b][1,2]oxazine-6-carboxylate (10h)
Oil; yield: 94%; mixture of diastereomers: 10h¢/10h¢¢, 1.0:1.0;
Rf = 0.23 (EtOAc–hexane, 1:1).
13C NMR (75 MHz, CDCl3): d = 22.1 and 27.8 (C12, C13), 24.7
(C7), 42.8 (C5), 43.7 (C4), 44.8 (C8), 52.9 (C11), 55.3 (C18), 57.8
(C3), 81.3 (C6), 114.3 (C16), 128.5 (C15), 131.4 (C14), 159.0
(C17), 162.9 and 170.7 (C9, C10).
Anal. Calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C,
61.65; H, 6.64; N, 4.01.
rel-(2S,4S,4aS,6S)-Isomer 10h¢
Characteristic 2D-NOESY correlations: H15/H3, H3/H7¢¢, H7¢¢/H8.
1H NMR (500 MHz, CDCl3, selected signals): d = 1.18 (t, J = 7.2
Hz, 3 H, 13-CH3), 1.99 (dd, J = 13.5, 3.7 Hz, 1 H, H5), 2.10 (dd,
J = 13.5, 13.2 Hz, 1 H, H5), 2.15 (m, 2 H, 7-CH2), 3.20 (ddd,
J = 13.2, 10.1, 3.7 Hz, 1 H, H4), 3.38 (dd, J = 8.9, 7.4 Hz, 1 H, H8),
3.60 (m, 1 H, H12), 3.65 (ddd, J = 13.1, 10.1, 6.6 Hz, 1 H, H3), 3.78
(s, 3 H, 18-CH3), 4.15 (m, 1 H, H12), 5.07 (s, 1 H, H6), 6.85 (d,
J = 7.8 Hz, 2 H, H16), 7.12 (d, J = 7.8 Hz, 2 H, H15).
rel-(4S,4aS,6R)-Isomer 10c¢¢
1H NMR (500 MHz, CDCl3): d = 1.35 and 1.36 (2 s, 6 H, 12-CH3,
13-CH3), 1.76 (dd, J = 13.2, 3.7 Hz, 1 H, H5), 1.87 (dd m, J = 13.2,
12.3 Hz, 2 H, H5, H7¢), 2.30 (ddd, J = 14.0, 11.0, 3.7 Hz, 1 H, H7¢¢),
2.70 (ddd, J = 12.3, 11.8, 3.7 Hz, 1 H, H4), 3.42 (dd, J = 10.3, 3.7
Hz, 1 H, H8), 3.64 (s, 3 H, 11-CH3), 3.70 (m, 1 H, H3), 3.72 (s, 3 H,
18-CH3), 6.80 (d, J = 8.5 Hz, 2 H, H16), 7.08 (d, J = 8.5 Hz, 2 H,
H15).
13C NMR (75 MHz, CDCl3, selected signals): d = 14.8 (C13), 24.6
(C7), 44.7 (C8), 52.9 (C11), 55.3 (C18), 58.2 (C3), 100.5 (C6),
114.4 (C16), 128.7 (C15), 131.6 (C14).
13C NMR (75 MHz, CDCl3): d = 22.0 and 27.8 (C12, C13), 25.4
(C7), 42.8 (C5), 44.0 (C4), 44.8 (C8), 52.8 (C11), 55.3 (C18), 58.2
(C3), 80.9 (C6), 114.3 (C16), 128.5 (C15), 131.2 (C14), 159.0
(C17), 162.8 and 170.1 (C9, C10).
Characteristic 2D-NOESY correlations: H15/H3, H3/7-CH2.
rel-(2S,4S,4aS,6R)-Isomer 10h¢¢
1H NMR (500 MHz, CDCl3, selected signals): d = 1.18 (t, J = 7.2
Hz, 3 H, 13-CH3), 1.92 (ddd, J = 13.7, 9.9, 4.5 Hz, 1 H, H7¢), 1.99
(dd, J = 13.5, 3.5 Hz, 1 H, H5), 2.10 (dd, J = 13.5, 12.3 Hz, 1 H,
H5), 2.34 (ddd, J = 13.7, 7.3, 5.8 Hz, 1 H, H7¢¢), 2.92 (ddd, J = 12.3,
10.9, 3.5 Hz, 1 H, H4), 3.43 (dd, J = 9.9, 5.8 Hz, 1 H, H8), 3.60 (m,
1 H, H12), 3.78 (s, 3 H, 18-CH3), 3.83 (ddd, J = 10.9, 7.3, 4.5 Hz, 1
H, H3), 4.15 (m, 1 H, H12), 5.07 (s, 1 H, H6), 6.85 (d, J = 7.8 Hz, 2
H, H16), 7.09 (d, J = 7.8 Hz, 2 H, H15).
Characteristic 2D-NOESY correlations: H15/H3, H3/H7¢¢, H7¢/H8.
Methyl 4-(4-Chlorophenyl)-2,2-dimethyl-7-oxohexahydro-2H-
pyrrolo[1,2-b][1,2]oxazine-6-carboxylate (10d)
Oil; yield: 85%; mixture of diastereomers: 10d¢/10d¢¢, 1.8:1.0;
Rf = 0.19 (EtOAc–hexane, 1:1).
Anal. Calcd for C17H20ClNO4: C, 60.45; H, 5.97; N, 4.15. Found: C,
60.21; H, 6.28; N, 4.29.
13C NMR (75 MHz, CDCl3, selected signals): d = 14.8 (C13), 24.9
(C7), 44.2 (C8), 52.9 (C11), 55.3 (C18), 57.9 (C3), 100.5 (C6),
114.4 (C16), 128.7 (C15), 131.6 (C14).
rel-(4S,4aS,6S)-Isomer 10d¢
1H NMR (500 MHz, CDCl3): d = 1.40 (s, 6 H, 12-CH3, 13-CH3),
1.82 (dd, J = 14.2, 4.3 Hz, 1 H, H5), 1.92 (dd, J = 14.2, 12.2 Hz, 1
H, H5), 2.04 (m, 1 H, H7¢), 2.28 (ddd, J = 13.5, 9.8, 7.2 Hz, 1 H,
H7¢¢), 2.99 (ddd, J = 12.2, 10.5, 4.3 Hz, 1 H, H4), 3.47 (dd, J = 9.8,
7.9 Hz, 1 H, H8), 3.61 (ddd, J = 10.5, 7.2, 6.7 Hz, 1 H, H3), 3.78 (s,
3 H, 11-CH3), 7.17 and 7.30 (2 d, J = 8.5 Hz, 4 H, H15, H16).
Characteristic 2D-NOESY correlations: H15/H3, H3/H7¢¢, H7¢/H8.
Unassigned signals of both isomers:
1H NMR (500.13 MHz, CDCl3): d = 3.71 and 3.80 (2 s, 3 H, 11-
CH3).
13C NMR (75 MHz, CDCl3): d = 35.8 and 36.1 (C5), 40.6 and 40.7
(C4), 64.8 and 65.1 (C12), 159.1 and 159.3 (C17), 163.0, 163.1 and
171.0 (C9, C10).
13C NMR (75 MHz, CDCl3): d = 22.0 and 27.7 (C12, C13), 24.7
(C7), 42.5 (C5), 44.0 (C4), 44.5 (C8), 53.3 (C11), 57.6 (C3), 81.6
(C6), 129.0 and 129.3 (C15, C16), 133.5 and 137.7 (C14, C17),
163.5 and 170.6 (C9, C10).
Tetrahydrooxazines 9a–g; General Procedure Using Method C
NaBH3CN (0.19 g, 3 mmol) was added to a stirred soln of oxazine
4a–g (1 mmol) and BzCl (0.58 ml, 5 mmol) in AcOH (4.4 mL) un-
der argon. The mixture was stirred at r.t. for 1 h and poured into a
mixture of EtOAc (100 mL) and sat. Na2CO3 (100 mL). The aque-
ous phase was back-extracted with EtOAc (2 × 50 mL); the com-
bined organic layers were washed brine (50 mL) and dried
(Na2SO4). The solvent was evaporated in vacuo and the residue was
subjected to column chromatography (silica gel). Yields of products
are presented in Table 1.
Characteristic 2D-NOESY correlations: H15/H3, H3/H7¢¢, H7¢¢/H8.
rel-(4S,4aS,6R)-Isomer 10d¢¢
1H NMR (500 MHz, CDCl3): d = 1.40 (s, 6 H, 12-CH3, 13-CH3),
1.82 (dd, J = 14.2, 4.3 Hz, 1 H, H5), 1.92 (dd, J = 14.2, 12.5 Hz, 1
H, H5), 1.97 (m, 1 H, H7¢), 2.37 (ddd, J = 13.5, 7.5, 3.2 Hz, 1 H,
H7¢¢), 2.82 (ddd, J = 12.5, 10.5, 4.3 Hz, 1 H, H4), 3.54 (dd, J = 10.5,
3.2 Hz, 1 H, H8), 3.71 (s, 3 H, 11-CH3), 3.75 (ddd, J = 10.5, 7.5, 6.7
Hz, 1 H, H3), 7.16 and 7.30 (2 d, J = 8.5 Hz, 4 H, H15, H16).
13C NMR (75 MHz, CDCl3): d = 22.0 and 27.7 (C12, C13), 25.1
(C7), 42.5 (C5), 44.2 (C4), 44.5 (C8), 53.3 (C11), 58.1 (C3), 81.5
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of g-Amino Acids and Their Derivatives from Nitroethane
751
Dimethyl rel-2-{[(3S,4R)-2-Benzoyl-4,6,6-trimethyltetrahydro-
2H-1,2-oxazin-3-yl]methyl}malonate (9a)
Mp 56–58 °C; Rf = 0.58 (EtOAc–hexane, 1:1).
13C NMR (75 MHz, CDCl3): d = 25.1 and 27.2 (C13, C14), 31.8
(C7), 41.6 (C5), 41.8 (C4), 48.5 (C8), 52.6 (C10, C12), 57.7 (C3),
83.6 (C6), 127.4, 129.0, and 129.4 (C16, C17, C21, C22), 130.7
(C23), 133.0 and 133.7 (C18, C20), 140.6 (C15), 169.1, 169.8, and
170.1 (C9, C11, C19).
1H NMR (500 MHz, CDCl3): d = 0.70 and 1.10 (s, 6 H, 13-CH3, 14-
CH3), 1.10 (d, J = 6.5 Hz, 3 H, 15-CH3), 1.25 (dd, J = 13.5, 12.5 Hz,
1 H, H5), 1.50 (dd, J = 13.5, 3.0 Hz, 1 H, H5), 1.76 (m, 1 H, H4),
2.25 (ddd, J = 14.1, 9.1, 4.5 Hz, 1 H, H7), 2.38 (ddd, J = 14.1, 9.6,
3.0 Hz, 1 H, H7), 3.61 and 3.71 (2 s, 6 H, 10-CH3, 12-CH3), 3.62
(m, 1 H, H8), 4.28 (ddd, J = 9.6, 9.1, 3.0 Hz, 1 H, H3ax), 7.30 (dd,
J = 7.5, 7.5 Hz, 2 H, H19), 7.45 (dd, J = 7.5, 7.5 Hz, 1 H, H20), 7.70
(d, J = 7.5 Hz, 2 H, H18).
Anal. Calcd for C25H28ClNO6: C, 63.35; H, 5.95; N, 2.96. Found: C,
63.70; H, 5.83; N, 2.95.
Dimethyl rel-2-{[(3S,4S,4aR,8aR)-2-Benzoyl-4-(4-methoxyphe-
nyl)octahydro-2H-1,2-benzoxazin-3-yl]methyl}malonate (9e)
Oil; Rf = 0.67 (EtOAc–hexane, 1:1).
13C NMR (75 MHz, CDCl3): d = 18.8 (C15), 25.6 and 27.2 (C13,
C14), 30.1 (C4), 32.0 (C7), 41.0 (C5), 48.6 (C8), 52.6 (C10, C12),
58.4 (C3), 83.3 (C6), 127.5 and 129.2 (C18, C19), 130.4 (C20),
134.0 (C17), 169.5, 169.7, and 170.1 (C9, C11, C16).
1H NMR (300 MHz, CDCl3): d = 1.01–1.26, 1.30–1.44, 1.51–1.75
(3 m, 8 H, 13-CH2, 14-CH2, 15-CH2, 16-CH2), 1.95–2.07 (m, 1 H,
H5), 2.22 (ddd, J = 13.9, 8.8, 2.9 Hz, 1 H, H7), 2.44 (ddd, J = 13.9,
10.3, 5.9 Hz, 1 H, H7), 2.73 (dd, J = 11.0, 7.3 Hz, 1 H, H4ax), 3.57
(dd, J = 8.8, 5.9 Hz, 1 H, H8), 3.64 (s, 6 H, 10-CH3, 12-CH3), 3.80
(s, 3 H, 21-CH3), 3.97 (m, 1 H, H6), 4.87 (ddd, J = 11.0, 10.3, 2.9
Hz, 1 H, H3ax), 6.88 (d, J = 8.8 Hz, 2 H, H19), 7.19 (d, J = 8.8 Hz,
2 H, H18), 7.36–7.48 (m, 3 H, H25, H26), 7.83 (d, J = 7.8 Hz, 2 H,
H24).
13C NMR (75 MHz, CDCl3): d = 20.9, 22.6, 25.5, and 27.0 (C13,
C14, C15, C16), 31.8 (C7), 37.2 (C5), 44.3 (C4), 49.0 (C8), 52.5
(C10, C12), 55.2 (C21), 59.0 (C3), 80.4 (C6), 114.2 (C19), 127.8,
128.8, and 130.8 (C24, C25, C26), 129.4 (C18), 132.7 and 133.8
(C17, C23), 158.6 (C20), 169.1, 169.8, and 171.0 (C9, C11, C22).
Anal. Calcd for C20H27NO6: C, 63.64; H, 7.21; N, 3.71. Found: C,
63.69; H, 7.18; N, 3.78.
Dimethyl rel-2-{[(3S,4S)-2-Benzoyl-6,6-dimethyl-4-phenyltet-
rahydro-2H-1,2-oxazin-3-yl]methyl}malonate (9b)
Mp 71–75 °C; Rf = 0.61 (EtOAc–hexane, 1:1).
1H NMR (500 MHz, CDCl3): d = 0.75 and 1.25 (2 s, 6 H, 13-CH3,
14-CH3), 1.68 (dd, J = 13.8, 3.3 Hz, 1 H, H5), 1.72 (dd, J = 13.8,
13.1 Hz, 1 H, H5), 2.33 (m, 2 H, 7-CH2), 2.86 (ddd, J = 13.1, 9.5,
3.3 Hz, 1 H, H4ax), 3.63 and 3.64 (2 s, 6 H, 10-CH3, 12-CH3), 3.64
(m, 1 H, H8), 4.94 (ddd, J = 9.5, 5.3, 4.6 Hz, 1 H, H3ax), 7.23–7.49
(m, 8 H, H16, H17, H18, H22, H23), 7.82 (d, J = 6.4 Hz, 2 H, H21).
Anal. Calcd for C28H33NO7: C, 67.86; H, 6.71; N, 2.83. Found: C,
67.94; H, 6.81; N, 2.82.
13C NMR (75 MHz, CDCl3): d = 25.2 and 27.3 (C13, C14), 31.8
(C7), 41.8 (C5), 42.4 (C4), 48.7 (C8), 52.6 (C10, C12), 58.0 (C3),
83.6 (C6), 127.3, 127.6, 128.1, 128.9, and 129.5 (C16, C17, C18,
C21, C22), 130.6 (C23), 134.1 (C20), 141.3 (C15), 169.1, 169.8,
and 169.9 (C9, C11, C19).
Dimethyl 2-{[2-Benzoyl-4-(4-methoxyphenyl)-6-phenyltetrahy-
dro-2H-1,2-oxazin-3-yl]methyl}malonate (9f)
Isomers 9f and 9f¢ were obtained as a mixture (ratio 1.0:2.5) after
the reduction of oxazine 4f using Method C and were separated by
column chromatography.
Anal. Calcd for C25H29NO6: C, 68.32; H, 6.65; N, 3.19. Found: C,
68.17; H, 6.55; N, 3.26.
rel-(3R,4S,6S)-Isomer 9f¢
Mp 106–109 °C; Rf = 0.57 (EtOAc–hexane, 1:1).
Dimethyl rel-2-{[(3S,4S)-2-Benzoyl-4-(4-methoxyphenyl)-6,6-
dimethyltetrahydro-2H-1,2-oxazin-3-yl]methyl}malonate (9c)
Oil; Rf = 0.52 (EtOAc–hexane, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.89 (ddd, J = 13.2, 10.6, 1.5 Hz,
1 H, H7), 2.44 (br d, J = 13.9 Hz, 1 H, H5eq), 2.61 (ddd, J = 13.2,
11.5, 4.4 Hz, 1 H, H7), 2.88 (ddd, J = 13.9, 13.9, 6.3 Hz, 1 H, H5ax),
3.48 (dd, J = 10.6, 4.4 Hz, 1 H, H8), 3.62 and 3.68 (2 s, 6 H, 10-CH3,
12-CH3), 3.83 (s, 4 H, H4ax, 21-CH3), 5.10 (ddd, J = 11.5, 4.1, 1.5
Hz, 1 H, H3eq), 5.31 (d, J = 6.3 Hz, 1 H, H6eq), 6.85–6.99 (m, 6 H,
H14, H15, H19), 7.11 (t, J = 7.0 Hz, 1 H, H16), 7.24–7.35 (m, 6 H,
H18, H24, H25), 7.39 (t, J = 7.0 Hz, 1 H, H26).
13C NMR (75 MHz, CDCl3): d = 24.2 (C5), 24.5 (C7), 36.1 (C4),
48.6 (C8), 52.6, 52.7, and 52.8 (C3, C10, C12), 55.2 (C21), 80.0
(C6), 114.2 (C19), 127.3, 127.9, 128.1, 128.3, 128.6, 128.9, and
130.1 (C14, C15, C16, C18, C24, C25, C26), 131.5 and 134.0 (C17,
C23), 136.1 (C13), 158.7 (C20), 168.9, 169.2, and 169.9 (C9, C11,
C22).
1H NMR (500 MHz, CDCl3): d = 0.74 and 1.23 (2 s, 6 H, 13-CH3,
14-CH3), 1.62 (dd, J = 13.8, 4.0 Hz, 1 H, H5), 1.72 (dd, J = 13.8,
12.5 Hz, 1 H, H5), 2.29 (dd, J = 6.6, 6.6 Hz, 2 H, 7-CH2), 2.78 (ddd,
J = 12.5, 9.2, 4.0 Hz, 1 H, H4ax), 3.59 and 3.62 (2 s, 6 H, 10-CH3,
12-CH3), 3.60 (m, 1 H, H8), 3.77 (s, 3 H, 19-CH3), 4.85 (ddd,
J = 9.2, 6.6, 6.6 Hz, 1 H, H3ax), 6.86 (d, J = 8.1 Hz, 2 H, H17), 7.22
(d, J = 8.1 Hz, 2 H, H16), 7.30–7.40 (m, 3 H, H23, H24), 7.78 (d,
J = 7.7 Hz, 2 H, H22).
13C NMR (75 MHz, CDCl3): d = 25.2 and 27.2 (C13, C14), 31.9
(C7), 41.5 (C4), 41.9 (C5), 48.6 (C8), 52.6 (C10, C12), 55.3 (C19),
58.2 (C3), 83.6 (C6), 114.2 (C17), 127.5, 128.9, and 129.4 (C16,
C22, C23), 130.5 (C24), 133.2 and 133.9 (C15, C21), 158.7 (C18),
169.2, 169.8, and 170.0 (C9, C11, C20).
Characteristic 2D-NOESY correlations: H3eq/H4ax, H7/H5ax,
H6eq/H5ax, H6eq/H5eq.
Anal. Calcd for C26H31NO7: C, 66.51; H, 6.55; N, 2.98. Found: C,
66.52; H, 6.59; N, 2.95.
Anal. Calcd for C30H31NO7: C, 69.62; H, 6.04; N, 2.71. Found: C,
69.41; H, 6.02; N, 2.70.
Dimethyl rel-2-{[(3S,4S)-2-Benzoyl-4-(4-chlorophenyl)-6,6-
dimethyltetrahydro-2H-1,2-oxazin-3-yl]methyl}malonate (9d)
Mp 90–98 °C; Rf = 0.57 (EtOAc–hexane, 1:1).
1H NMR (500 MHz, CDCl3): d = 0.72 and 1.22 (s, 6 H, 13-CH3, 14-
CH3), 1.61 (dd, J = 13.7, 2.8 Hz, 1 H, H5), 1.74 (dd, J = 13.7, 12.3
Hz, 1 H, H5), 2.30 (m, 2 H, 7-CH2), 2.82 (ddd, J = 12.3, 9.2, 2.8 Hz,
1 H, H4ax), 3.58 and 3.61 (2 s, 6 H, 10-CH3, 12-CH3), 3.60 (m, 1 H,
H8), 4.86 (ddd, J = 9.2, 7.9, 3.9 Hz, 1 H, H3ax), 7.15–7.40 (m, 7 H,
H16, H17, H22, H23), 7.76 (d, J = 7.5 Hz, 2 H, H21).
rel-(3S,4S,6S)-Isomer 9f
Mp 39–43 °C; Rf = 0.47 (EtOAc–hexane, 1:1).
1H NMR (300 MHz, CDCl3): d = 2.22 (ddd, J = 13.9, 5.1, 3.9 Hz, 1
H, H5eq), 2.41 (ddd, J = 14.0, 10.3, 4.4 Hz, 1 H, H7), 2.50 (ddd,
J = 13.9, 8.8, 4.4 Hz, 1 H, H5ax), 2.71 (ddd, J = 14.0, 11.0, 5.1 Hz,
1 H, H7), 3.18 (ddd, J = 5.1, 4.4, 3.7 Hz, 1 H, H4eq), 3.66 (m, 1 H,
H8), 3.69 and 3.78 (s, 6 H, 10-CH3, 12-CH3), 3.81 (s, 3 H, 21-CH3),
4.85 (dd, J = 8.8, 3.9 Hz, 1 H, H6ax), 5.25 (dd, J = 11.0, 4.4, 3.7 Hz,
1 H, H3eq), 6.92 (d m, J = 8.1 Hz, 3 H, H19, H16), 7.10–7.18 and
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A. Yu. Sukhorukov et al.
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7.27–7.46 (2 m, 9 H, H14, H15, H18, H25, H26), 7.73 (d, J = 7.3
Hz, 2 H, H24).
Dimethyl rel-2-[2-(Benzoylamino)-5-hydroxy-5-methyl-3-phe-
nylhexyl]malonate (13b)
Oil; Rf = 0.20 (EtOAc–hexane, 1:1).
13C NMR (75 MHz, CDCl3): d = 31.4 (C7), 34.2 (C5), 40.0 (C4),
48.7 (C8), 52.7 (C10, C12), 55.2 (C21), 53.3 (C3), 80.1 (C6), 114.2
(C19), 126.3, 127.8, 128.5, 128.6, 129.0, and 130.7 (C14, C15, C16,
C18, C24, C25, C26), 133.7 and 137.0 (C17, C23), 138.2 (C13),
158.4 (C20), 169.2 and 169.7 (C9, C11, C22).
1H NMR (500 MHz, CDCl3): d = 1.10 and 1.15 (2 s, 6 H, 13-CH3,
14-CH3), 1.77 (ddd, J = 14.5, 11.3, 6.6 Hz, 1 H, H7), 1.88 (br, 1 H,
1-OH), 1.94 (dd, J = 14.4, 7.0 Hz, 1 H, H5), 2.03 (dd, J = 14.4, 3.8
Hz, 1 H, H5), 2.17 (ddd, J = 14.5, 9.7, 7.3 Hz, 1 H, H7), 3.10 (m, 1
H, H4), 3.45 and 3.64 [2 s, 7 H, (H8, 10-CH3), 12-CH3], 4.41 (m, 1
H, H3), 6.44 (d, J = 8.6 Hz, 1 H, 2-NH), 7.21–7.36 (m, 5 H, H16,
H17, H18), 7.40 (dd, J = 7.5, 7.5 Hz, 2 H, H22), 7.49 (t, J = 7.5 Hz,
1 H, H23), 7.73 (d, J = 7.5 Hz, 2 H, H21).
13C NMR (75 MHz, CDCl3): d = 29.2 and 31.2 (C13, C14, C7), 45.8
and 46.1 (C4, C5), 49.2 (C8), 52.6 and 52.7 (C10, C12), 53.5 (C3),
71.4 (C6), 127.1, 128.6, and 128.8 (C16, C17, C18, C21, C22),
131.7 (C23), 134.1 (C20), 142.4 (C15), 167.3, 169.6, and 170.6
(C9, C11, C19).
Anal. Calcd for C30H31NO7: C, 69.62; H, 6.04; N, 2.71. Found: C,
69.63; H, 5.86; N, 2.62.
Dimethyl rel-2-{[(3S,4S,6R)-2-Benzoyl-4-(4-methoxyphenyl)-6-
phenyltetrahydro-2H-1,2-oxazin-3-yl]methyl}malonate (9g)
Mp 118–121 °C; Rf = 0.47 (EtOAc–hexane, 1:1).
1H NMR (300 MHz, CDCl3): d = 2.16–2.25 (m, 2 H, H5, H7), 2.36
(ddd, J = 13.2, 12.5, 11.7 Hz, 1 H, H5), 2.76 (ddd, J = 14.7, 11.7,
3.7 Hz, 1 H, H7), 3.22 (ddd, J = 13.2, 11.8, 3.7 Hz, 1 H, H4ax), 3.64
and 3.75 [2 s, 7 H, (H8, 10-CH3), 12-CH3], 3.83 (s, 3 H, 21-CH3),
4.42 (ddd, J = 11.8, 11.0, 3.7 Hz, 1 H, H3ax), 4.83 (dd, J = 11.7, 3.7
Hz, 1 H, H6ax), 6.89 (d, J = 7.3 Hz, 2 H, H14), 6.94 (d, J = 8.8 Hz,
2 H, H19), 7.08–7.18 (m, 3 H, H15, H16), 7.26–7.33 (d m, J = 8.8
Hz, 4 H, H18, H25), 7.39 (t, J = 7.3 Hz, 1 H, H26), 7.66 (d, J = 7.3
Hz, 2 H, H24).
Anal. Calcd for C25H31NO6: C, 68.01; H, 7.08; N, 3.17. Found: C,
67.95; H, 7.34; N, 3.05.
Dimethyl rel-2-[2-(Benzoylamino)-5-hydroxy-3-(4-methoxy-
phenyl)-5-methylhexyl]malonate (13c)
Mp 154–157 °C; Rf = 0.20 (EtOAc–hexane, 1:1).
13C NMR (75 MHz, CDCl3): d = 30.3 (C7), 36.7 (C5), 43.6 (C4),
48.5 (C8), 52.6 (C10, C12), 55.3 (C21), 62.5 (C3), 84.5 (C6), 114.4
(C19), 127.0, 127.6, 128.2, 128.5, 128.7, 129.1, 130.8 (C14, C15,
C16, C19, C24, C25, C26), 133.0 and 134.3 (C17, C23), 137.3
(C13), 158.8 (C20), 169.4 and 169.8 (C9, C11), 173.1 (C22).
1H NMR (500 MHz, CDCl3): d = 1.10 and 1.14 (2 s, 6 H, 13-CH3,
14-CH3), 1.78 (ddd, J = 13.2, 11.0, 5.9 Hz, 1 H, H7), 1.90 (dd,
J = 14.1, 7.4 Hz, 1 H, H5), 2.01 (dd, J = 14.1, 3.5 Hz, 1 H, H5), 2.16
(m, 2 H, H7, 1-OH), 3.06 (m, 1 H, H4), 3.46 and 3.66 [2 s, 7 H, (H8,
10-CH3), 12-CH3], 3.79 (s, 3 H, 19-CH3), 4.37 (m, 1 H, H3), 6.51
(d, J = 8.8 Hz, 1 H, 2-NH), 6.86 (d, J = 7.8 Hz, 2 H, H17), 7.13 (d,
J = 7.8 Hz, 2 H, H16), 7.40 (dd, J = 7.4, 7.4 Hz, 2 H, H23), 7.48 (t,
J = 7.4 Hz, 1 H, H24), 7.73 (d, J = 7.4 Hz, 2 H, H22).
Anal. Calcd for C30H31NO7: C, 69.62; H, 6.04; N, 2.71. Found: C,
69.57; H, 6.07; N, 2.69.
Hydrogenation of Oxazines 9a–g, 6h,i; Methods D and E
Raney Nickel (5 mL, 50% slurry in H2O) was placed in a 2-necked
flack and washed with MeOH (5 × 10 mL), then extra MeOH (4
mL) was added and H2 (from Kipp apparatus) was bubbled through
the mixture for 20 min. A soln of 9 (0.39 mmol, for the preparation
of products 12 and 13, Method E) in MeOH (14 mL) or a soln of 6
(0.39 mmol, for the preparation of products 8, Method D) and
Boc2O (0.255g, 1.17 mmol) in MeOH (14 mL) was added to the cat-
alyst and H2 was bubbled through the mixture with intensive stirring
for 3 h. Then the mixture was filtered [in the case of 12a the catalyst
was additionally washed with hot MeOH (150 mL)], the solvent
was evaporated in vacuo and the residue was subjected to a column
chromatography (silica gel). Yields of products are presented in
Table 2.
13C NMR (75 MHz, CDCl3): d = 29.2 and 31.1 (C13, C14), 31.1
(C7), 45.1 (C4), 45.9 (C5), 49.1 (C8), 52.6 and 52.7 (C10, C12),
53.5 (C3), 55.2 (C19), 71.2 (C6), 114.2 (C17), 127.0, 128.6, and
129.7 (C16, C22, C23), 131.6 (C24), 134.0 and 134.2 (C15, C21),
158.5 (C18), 167.2, 169.5, and 170.6 (C9, C11, C20).
Anal. Calcd for C26H33NO7: C, 66.22; H, 7.05; N, 2.97. Found: C,
66.09; H, 6.91; N, 2.88.
Dimethyl rel-2-{[(2S,3S)-2-(Benzoylamino)-3-[(1R,2R)-2-hy-
droxycyclohexyl]-3-(4-methoxyphenyl]propyl}malonate (13e)
Mp 62–65 °C; Rf = 0.25 (EtOAc–hexane, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.10–1.19 (m, 3 H, H15, 16-CH2),
1.41–1.50 (m, 1 H, H14), 1.52–1.66 (m, 3 H, H13, H14, H15), 1.67
(ddd, J = 13.9, 9.5, 5.9 Hz, 1 H, H7), 1.82–1.92 (m, 1 H, H5), 2.00–
2.08 (m, 1 H, H13), 2.28 (ddd, J = 13.9, 7.3, 2.2 Hz, 1 H, H7), 2.97
(dd, J = 11.7, 2.9 Hz, 1 H, H4), 3.26 (br, 1 H, 1-OH), 3.42 (dd,
J = 7.3, 5.9 Hz, 1 H, H8), 3.56 and 3.74 (2 s, 6 H, 10-CH3, 12-CH3),
3.79 (s, 3 H, 21-CH3), 4.40 (br s, 1 H, H6), 4.60 (dddd, J = 9.5, 8.1,
2.9, 2.2 Hz, 1 H, H3), 6.00 (d, J = 8.1 Hz, 1 H, 2-NH), 6.85 (d,
J = 8.1 Hz, 2 H, H19), 7.01 (d, J = 8.1 Hz, 2 H, H18), 7.42 (t, J = 7.3
Hz, 2 H, H25), 7.50 (t, J = 7.3 Hz, 1 H, H26), 7.70 (d, J = 7.3 Hz, 2
H, H24).
13C NMR (75 MHz, CDCl3): d = 20.1 (C14), 25.5 (C16), 26.1
(C15), 28.8 (C13), 33.4 (C7), 41.5 (C5), 48.2 (C3), 49.1 (C8), 50.8
(C4), 52.7 and 52.8 (C10, C12), 55.2 (C21), 65.9 (C6), 113.9 (C19),
126.9, 128.6, 130.8, and 131.8 (C18, C24, C25, C26), 130.2 and
133.6 (C17, C23), 158.6 (C20), 167.1, 169.5, and 170.3 (C9, C11,
C22).
Dimethyl rel-2-[(2S,3R)-2-(Benzoylamino)-5-hydroxy-3,5-di-
methylhexyl]malonate (13a)
Mp 90–94 °C; Rf = 0.19 (EtOAc–hexane, 1:1).
1H NMR (500 MHz, CDCl3): d = 1.06 (d, J = 7.4 Hz, 3 H, 15-CH3),
1.25 and 1.29 (2 s, 6 H, 13-CH3, 14-CH3), 1.30 (dd, J = 14.2, 5.1 Hz,
1 H, H5), 1.70 (dd, J = 14.2, 4.7 Hz, 1 H, H5), 1.82 (br, 1 H, 1-OH),
2.03 (m, 1 H, H4), 2.09 (ddd, J = 14.7, 11.0, 7.4 Hz, 1 H, H7), 2.35
(ddd, J = 14.7, 6.6, 3.0 Hz, 1 H, H7), 3.56 and 3.73 [2 s, 7 H, (H8,
10-CH3), 12-CH3], 4.12 (m, 1 H, H3), 6.68 (d, J = 8.2 Hz, 1 H, 2-
NH), 7.40 (dd, J = 7.4, 7.4 Hz, 2 H, H19), 7.46 (t, J = 7.4 Hz, 1 H,
H20), 7.78 (d, J = 7.4 Hz, 2 H, H18).
13C NMR (75 MHz, CDCl3): d = 18.6 (C15), 29.2 and 31.0 (C13,
C14), 30.4 (C7), 33.3 (C4), 46.2 (C5), 49.4 (C8), 52.6 and 52.7
(C10, C12), 53.8 (C3), 71.1 (C6), 126.9 and 128.5 (C18, C19),
131.4 (C20), 134.2 (C17), 167.2, 169.7, and 170.8 (C9, C11, C16).
Anal. Calcd for C28H35NO7: C, 67.59; H, 7.09; N, 2.81. Found: C,
67.47; H, 7.06; N, 2.66.
Anal. Calcd for C20H29NO6: C, 63.31; H, 7.70; N, 3.69. Found: C,
63.06; H, 7.80; N, 3.72.
Dimethyl rel-2-[(2R,3S)-2-(Benzoylamino)-3-(4-methoxyphe-
nyl)-5-phenylpentyl]malonate (12a¢)
Mp 119–126 °C; Rf = 0.48 (EtOAc–hexane, 1:1).
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

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Diastereoselective Synthesis of g-Amino Acids and Their Derivatives from Nitroethane
753
1H NMR (300 MHz, CDCl3): d = 1.88 (ddd, J = 6.6, 11.3, 13.9 Hz,
1 H, H6), 1.98–2.17 (m, 2 H, 4-CH2), 2.28 (m, J = 13.9, 6.6, 3.3 Hz,
1 H, H6), 2.44–2.58 (m, 2 H, 5-CH2), 2.83 (ddd, J = 3.9, 5.1, 9.5 Hz,
1 H, H3), 3.44 (dd, J = 6.6, 6.6 Hz, 1 H, H7), 3.46 and 3.73 (2 s, 6
H, 9-CH3, 11-CH3), 3.82 (s, 3 H, 20-CH3), 4.53 (dddd, J = 11.3,
10.3, 3.9, 3.3 Hz, 1 H, H2), 5.72 (d, J = 10.3 Hz, 1 H, 1-NH), 6.92
(d, J = 8.1 Hz, 2 H, H18), 7.05–7.17 and 7.23 (m d, J = 7.3 Hz, 7 H,
H13, H14, H15, H17), 7.40 (t, J = 7.3 Hz, 2 H, H24), 7.48 (t, J = 7.3
Hz, 1 H, H25), 7.63 (d, J = 7.3 Hz, 2 H, H23).
13C NMR (75 MHz, CDCl3): d = 33.3 (C6), 33.5 (C5), 33.9 (C4),
49.0 (C3), 49.2 (C7), 51.5 (C2), 52.5 and 52.7 (C9, C11), 55.3
(C20), 114.2 (C18), 125.8, 126.7, 128.3, 128.5, 129.7, and 131.5
(C13, C14, C15, C16, C17, C23, C24, C25), 134. 1 (C22), 141.8
(C12), 158.7 (C19), 166.8, 169.5, and 170.3 (C8, C10, C21).
Characteristic 2D-NOESY correlations: H17/H4¢, H4¢/12-CH3,
H17/H2, H3/H6.
rel-(2S,3S,5R)-Isomer trans-8b
1H NMR (300 MHz, CDCl3): d = 1.28 (d, J = 6.6 Hz, 3 H, 12-CH3),
1.46 (s, 9 H, 15-CH3), 1.96 (ddd, J = 13.2, 11.7, 4.8 Hz, 1 H, H4¢¢),
2.06 (ddd, J = 13.2, 7.3, 5.9 Hz, 1 H, H4¢), 2.26 (m, 2 H, 6-CH2),
3.07 (ddd, J = 5.9, 5.9, 4.8 Hz, 1 H, H3), 3.62 and 3.67 [(s, m) s, 7
H, H7, 9-CH3, 11-CH3], 3.78 (s, 3 H, 20-CH3), 4.02 (br, 2 H, H2,
H5), 6.81 (d, J = 8.8 Hz, 2 H, H18), 7.04 (d, J = 8.8 Hz, 2 H, H17).
13C NMR (75 MHz, CDCl3): d = 21.8 (C12), 28.4 (C15), 34.7 (C6),
40.4 (C4), 47.7 (C3), 48.7 (C7), 52.4 (C9, C11), 53.7 (C5), 55.2
(C20), 63.1 (C2), 79.5 (C14), 114.1 (C18), 127.9 (C17), 135.1
(C16), 154.0 (C13), 158.3 (C19), 169.7 (C8, C10).
Anal. Calcd for C30H33NO6: C, 71.55; H, 6.60; N, 2.78. Found: C,
72.37; H, 6.59; N, 2.84.
Characteristic 2D-NOESY correlations: H17/H2, H17/H4¢,
H4¢¢/12-CH3.
Dimethyl rel-2-[(2S,3S)-2-(Benzoylamino)-3-(4-methoxyphe-
nyl)-5-phenylpentyl]malonate (12a)
Mp 174–178 °C; Rf = 0.50 (EtOAc–hexane, 1:1).
rel-3-[(2S,3S,5S)-3-(4-Methoxyphenyl)-5-methylpyrrolidin-2-
yl]propanoic Acid Hydrogen Chloride Salt Monohydrate
(14b·H2O) Using Method G
A saturated soln of HCl in H2O (2.0 mL) was added to a soln of pyr-
rolidines 8b (0.158g, 0.36 mmol) in aq MeOH [MeOH (1.5 mL)–
H2O (4.0 mL)] and the mixture was stirred intensively at r.t. for 24
h. The resulting mixture was concentrated in vacuo and the residue
was dissolved in H2O (1.5 mL). Dowex 50WX2-100 (0.1 g) was
added to the soln and the resulting mixture was refluxed for 7 h,
cooled, and filtered [the ion-exchange resin was washed with H2O
(~30 mL)]. The filtrate was washed with CHCl3 (10 mL) and con-
centrated in vacuo. The residue was crystallized (CH2Cl2, –78 °C)
to give 14b (0.061 g, 53%) as a white, hydroscopic solid; mp 72–80
°C. The product contains a small amount (less than 5%) of the cor-
responding 3,5-trans-isomer.
1H NMR (300 MHz, DMSO-d6): d = 1.40 (d, J = 6.2 Hz, 3 H, 10-
CH3), 1.68–1.80 (m, 2 H, H4¢, H6), 1.86–1.94 (m, 1 H, H6), 2.25–
2.38 (m, 3 H, H4¢¢, 7-CH2), 3.06 (ddd, J = 11.0, 6.6, 5.9 Hz, 1 H,
H3), 3.53 (m, 1 H, H2), 3.73 (s m, 4 H, H5, 15-CH3), 6.90 (d, J = 8.2
Hz, 2 H, H13), 7.28 (d, J = 8.2 Hz, 2 H, H12), 9.38 (br, 2 H, 1-NH),
12.2 (br, 1 H, 9-OH).
1H NMR (300 MHz, CDCl3): d = 1.79 (ddd, J = 13.9, 11.7, 6.6 Hz,
1 H, H6), 2.01–2.10 (m, 2 H, 4-CH2), 2.16 (ddd, J = 13.9, 7.3, 2.9
Hz, 1 H, H6), 2.33–2.55 (m, 2 H, 5-CH2), 2.75 (ddd, J = 11.0, 5.1,
2.2 Hz, 1 H, H3), 3.39 (dd, J = 7.3, 6.6 Hz, 1 H, H7), 3.44 and 3.69
(2 s, 6 H, 9-CH3, 11-CH3), 3.83 (s, 3 H, 20-CH3), 4.45 (dddd,
J = 11.7, 9.5, 2.9, 2.2 Hz, 1 H, H2), 5.77 (d, J = 9.5 Hz, 1 H, 1-NH),
6.91 (d, J = 8.8 Hz, 2 H, H18), 7.07 (d, J = 7.3 Hz, 2 H, H13), 7.14
(d and t, J = 8.8, 7.3 Hz, 3 H, H17, H15), 7.21 (t, J = 7.3 Hz, 2 H,
H14), 7.42 (t, J = 7.3 Hz, 2 H, H24), 7.50 (t, J = 7.3 Hz, 1 H, H25),
7.69 (d, J = 7.3 Hz, 2 H, H23).
13C NMR (75 MHz, CDCl3): d = 30.8 (C6), 33.5 (C5), 34.2 (C4),
49.1 (C7), 49.5 (C3), 52.4, 52.5, and 52.7 (C9, C11, C2), 55.2
(C20), 114.2 (C18), 125.8, 126.8, 128.3, 128.4, 128.6, 129.8, and
131.6 (C13, C14, C15, C17, C23, C24, C25), 131.9 and 134.0 (C16,
C22), 141.9 (C12), 158.7 (C19), 166.8, 169.4, and 170.5 (C8, C10,
C21).
Anal. Calcd for C30H33NO6: C, 71.55; H, 6.60; N, 2.78. Found: C,
71.38; H, 6.54; N, 2.79.
13C NMR (75 MHz, DMSO-d6): d = 17.2 (C10), 26.2 (C6), 30.6
(C7), 41.4 (C4), 49.2 (C3), 54.2 (C5), 55.1 (C15), 63.4 (C2), 114.1
(C13), 128.8 (C14), 131.3 (C11), 158.4 (C14), 173.4 (C8).
Dimethyl rel-2-{[1-(tert-Butoxycarbonyl)-3-(4-methoxyphe-
nyl)pyrrolidin-2-yl]methyl}malonate (8a)
All 1H and 13C NMR data for this compound is in good agreement
with previously reported data.9a
Characteristic 2D-NOESY correlations: H2/H12, H5/H4¢¢, H4¢¢/H3.
Anal. Calcd for C15H24ClNO4: C, 56.69; H, 7.61; N, 4.41. Found: C,
56.73; H, 7.59; N, 4.44.
Dimethyl 2-{[1-(tert-Butoxycarbonyl)-3-(4-methoxyphenyl)-5-
methylpyrrolidin-2-yl]methyl}malonate (8b)
Oil; mixture of isomers: cis-8i/trans-8i, 4.1:1.0; Rf = 0.66 (EtOAc–
hexane, 1:1).
rel-3-[3-Methoxy-2-(methoxycarbonyl)-3-oxopropyl]-4-(4-
methoxyphenyl)-6,6-dimethyl-5,6-dihydro-4H-1,2-oxazin-2-
ium Triflate (15c)
Anal. Calcd for C23H33NO7: C, 63.43; H, 7.64; N, 3.22. Found: C,
63.54; H, 7.71; N, 3.19.
TfOH (0.031 mL, 0.35 mmol) was added to a soln of oxazine 4c
(0.128 g, 0.35 mmol) in CH2Cl2 (2 mL) at r.t. After ~5 min the soln
was evaporated to give salt 15c (quant.) as a yellowish oil.
rel-(2S,3S,5S)-Isomer cis-8b
1H NMR (300 MHz, CDCl3): d = 1.47 and 1.48 (2 s, 6 H, 13-CH3,
14-CH3), 2.08 (dd, J = 13.9, 11.2 Hz, 1 H, H5), 2.31 (dd, J = 13.9,
7.1 Hz, 1 H, H5), 2.82 (dd, J = 15.8, 7.7 Hz, 1 H, H7), 3.13 (dd,
J = 15.8, 8.1 Hz, 1 H, H7), 3.70 and 3.71 (2 s, 6 H, 10-CH3,
12-CH3), 3.81 (s, 3 H, 19-CH3), 3.83 (dd, J = 8.1, 7.7 Hz, 1 H, H8),
4.11 (dd, J = 11.2, 7.1 Hz, 1 H, H4), 6.92 (d, J = 8.4 Hz, 2 H, H17),
7.16 (d, J = 8.4 Hz, 2 H, H16), 11.69 (br, 1 H, 2-NH).
13C NMR (75 MHz, HSQC, CDCl3): d = 22.2 and 26.9 (C13, C14),
30.6 and 38.9 (C5, C7), 40.1 (C4), 48.1 (C8), 53.3 and 53.4 (C10,
C12), 55.3 (C19), 84.0 (C6), 115.4 (C17), 120.1 (q, J = 317.4 Hz,
CF3), 126.2 (C15), 129.7 (C16), 160.0 (C18), 167.6 and 167.7 (C9,
C10), 169.6 (C3).
1H NMR (300 MHz, CDCl3): d = 1.17 (d, J = 6.6 Hz, 3 H, 12-CH3),
1.49 (s, 9 H, 15-CH3), 1.66 (ddd, J = 13.2, 11.7, 4.4 Hz, 1 H, H4¢),
2.20 (ddd, J = 13.2, 7.3, 6.6 Hz, 1 H, H6), 2.40 (ddd, J = 13.9, 7.3,
4.4 Hz, 1 H, H6), 2.51 (ddd, J = 13.2, 6.6, 5.1 Hz, 1 H, H4¢¢), 2.98
(ddd, J = 11.7, 6.6, 5.1 Hz, 1 H, H3), 3.52 (m, 1 H, H7), 3.62 and
3.67 (2 s, 6 H, 9-CH3, 11-CH3), 3.78 (s, 3 H, 20-CH3), 3.82 (m, 1 H,
H5), 4.14 (br, 1 H, H2), 6.83 (d, J = 8.4 Hz, 2 H, H18), 7.14 (d,
J = 8.4 Hz, 2 H, H17).
13C NMR (75 MHz, CDCl3): d = 21.1 (C12), 28.5 (C15), 32.8 (C6),
41.0 (C4), 46.4 (C3), 49.0 (C7), 52.4 (C9, C11), 53.6 (C5), 55.2
(C20), 61.8 (C2), 79.5 (C14), 113.9 (C18), 128.2 (C17), 135.1
(C16), 153.6 (C13), 158.3 (C19), 169.7 (C8, C10).
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York

754
A. Yu. Sukhorukov et al.
PAPER
cleaved, because under the applied reduction conditions
tetrahydrooxazines 6 reacted neither with Boc2O nor with
CbzCl.
Acknowledgment
This study was supported by Russian Foundation for Basic
Research (project no. 06-03-32607). Authors also thank Public
Charity Foundation for the Support of National Science for a PhD
studentship.
(14) Attempts to reduce this substrate with Et3SiH in TFA or
TfOH; NaBH4/AcOH; and Zn/AcOH were also
unsuccessful: either no conversion of the starting material
was observed or protonation of oxazine leading to the
corresponding salt occurred (for details see the discussion of
process 4, NaBH3CN, AcOH, Scheme 9).
References
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(12) Our attempts to reduce the N–O bond [H2 (75 bar), Raney
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could not be used in route c (Scheme 3).
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(13) We were unable to obtain derivatives of 6 with carbamate-
type protecting groups (Boc, Cbz), which are more easily
Synthesis 2009, No. 5, 741–754 © Thieme Stuttgart · New York