A stereoselective access to dihydroxylated pyrrolidines by reductive ring contraction of 1,2-oxazines

Article abstract of DOI:10.1055/s-2007-983802

Protected dihydroxylated 1,2-oxazine derivatives such as rac-4 were converted into tetrahydro-1,2-oxazines rac-7 by employing BH₃· THF for the stereoselective reduction of the C=N bond. Compound 7a underwent a reductive ring contraction on hydr

Full text of DOI:10.1055/s-2007-983802

PAPER
2681
A Stereoselective Access to Dihydroxylated Pyrrolidines by Reductive Ring
Contraction of 1,2-Oxazines
R
eductive Ring Co
a
ntraction o
n
f
1,2-Oxazin
s
es to
P
yrr
-
olidines Ulrich Reissig,*a Kai Homann,b Florian Hiller,c Reinhold Zimmer*a
a
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
b
c
Institut für Organische Chemie, Technische Universität Darmstadt, 64287 Darmstadt, Germany
Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Received 30 March 2007; revised 22 May 2007
This paper is dedicated with respect to Dr. Maximilian A. Grassberger on the occasion of his 70th birthday.
derivatives and then expanding this methodology to enan-
tiopure heterocycles.
Abstract: Protected dihydroxylated 1,2-oxazine derivatives such
as rac-4 were converted into tetrahydro-1,2-oxazines rac-7 by em-
ploying BH3·THF for the stereoselective reduction of the C=N
bond. Compound 7a underwent a reductive ring contraction on hy-
drogenation in the presence of palladium on charcoal to provide
rac-5 in good yield. Enantiopure 1,2-oxazine derivatives 13 and 14
were prepared using (–)-menthol as chiral auxiliary. Their diastereo-
selective dihydroxylation and BH3·THF reduction furnished enan-
tiopure tetrahydro-2H-1,2-oxazine derivatives 17 and 18 in good
overall yield. Enantiomers (6R)-18 and (6S)-18 were transformed
into the two enantiomeric hydroxylated pyrrolidine derivatives 5 in
moderate yield.
Previously, we have described the synthesis of racemic
acetal-protected 1,2-oxazines rac-4 in a short reaction se-
quence involving a hetero Diels–Alder reaction of 2-bro-
mo enol ether 1 and a-nitrosoalkenes 2 (generated in situ
from the corresponding a-halogen-substituted oximes).2a
The resulting 1,2-oxazines were converted into rac-4 by
diastereoselective cis-dihydroxylation either by treatment
with KMnO4 or with RuCl3/NaIO4 and finally protection
as acetal with 2,2-dimethoxypropane (Scheme 1).5
Key words: cycloaddition, 1,2-oxazines, pyrrolidines, hydrogena-
tion, ring contraction
O
O
Br
R
R
R
ref. 2a
ref. 5
Among the six-membered heterocycles, 1,2-oxazine de-
rivatives are very versatile building blocks since they al-
low stereoselective synthesis of a variety of cyclic or
acyclic nitrogen-containing compounds.1 6H-1,2-Ox-
azines 3 possessing an additional 4,5-C=C bond are
particularly important.2,3 These unsaturated N,O-hetero-
cycles have been used successfully as starting materials
by employing the C=C bond as handle for introduction of
substituents or functional groups, e.g., by addition of nu-
cleophilic and electrophilic agents,4 dihydroxylations,5
epoxidations,6 and 1,3-dipolar cycloadditions.7 All these
transformations furnish a variety of highly functionalized
5,6-dihydro-4H-1,2-oxazines and they generally proceed
with high stereoselectivity, since the 6-alkoxy group leads
to strongly preferred attack of reagents trans to this sub-
stituent. In the last years, we and others have reported nu-
merous applications of 5,6-dihydro-4H-1,2-oxazines as
useful key intermediates for preparation of pyrroles,4d,8
proline derivatives,8c,9 azasugars,10 tetrahydrofurans,11 as
well as acyclic primary and secondary amines.2b,4c,5a,9c,12
Many of these products belong to compound classes with
potential biological activity. In this report, we demon-
strate the viability of this route, by first focusing on the di-
astereoselective synthesis of racemic pyrrolidine
+
N
N
N
EtO
O
EtO
O
EtO
O
2
1
rac-3
rac-4
R = Ph, CO2Et, CF3
Scheme 1 Synthesis of protected 4,5-dihydroxylated 1,2-oxazines
We first examined the reductive ring contraction of 1,2-
oxazines 4 by performing the synthesis of racemic pyrro-
lidines rac-5 and rac-6, respectively (Scheme 2). Hydro-
genation of 1,2-oxazines rac-4 in the presence of Pd/C
produced pyrrolidines rac-5 and rac-6 in good to excel-
lent yields. The hydrogenation of rac-4 with R = CO2Et
was carried out by addition of dilute HCl solution sup-
pressing unidentified side products which were observed
during reduction in the absence of acid.13 Under these
acidic conditions a re-protection of the partially deprotect-
ed hydroxyl groups was necessary.
H2, Pd/C,
MeOH or
EtOH, 2 N HCl
r.t., 24 h
O
O
O
O
R
N
R
(2,2-DMP)
EtO
O
N
H
rac-4
rac-5 (R = Ph)
rac-6 (R = CO2Et)
R = Ph
94% (cis/trans = 33:67)
R = CO2Et 63% (cis/trans = 52:48)
SYNTHESIS 2007, No. 17, pp 2681–2689
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983802; Art ID: T06307SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7
Scheme 2 Hydrogenation of racemic 5,6-dihydro-4H-1,2-oxazines
rac-4 providing pyrrolidine derivatives rac-5 and rac-6

2682
H.-U. Reissig et al.
PAPER
The transformation of 5,6-dihydro-4H-1,2-oxazines into
acyclic amines or pyrrolidines by catalytic hydrogenation
is well investigated. A plausible mechanism of this multi-
step process has already been discussed in previous re-
ports. It involves reductive N–O bond cleavage as the first
step, followed by imine reduction, formation of the pyrro-
lidine ring by cyclization of an acyclic g-amino aldehyde
and final reduction of the intermediate 3,4-dihydro-2H-
pyrrole.9a,12a,14
O
O
O
O
O
O
R
R
Method A or B
CO2Et
NH2
+
N
NH
EtO
O
EtO
O
EtO
O
rac-4
rac-7a–c
8
Method A:
Method B:
a: R = Ph
75% (cis/trans = 89:11)
b: R = CO2Et 21% (cis/trans = 79:21) + 49% of 8
In agreement with this sequence of steps, it is not surpris-
ing that products rac-5 and rac-6 were formed either with
moderate or no diastereoselectivity. Low stereocontrol
can be expected for the reduction of the intermediate acy-
clic imine. To overcome this problem, we decided to pre-
pare the pyrrolidines in an alternative two steps route
inverting the sequence of reductive processes. The stereo-
controlled reduction of the C=N bond should be achieved
at the cyclic stage and then followed by the N–O cleavage
and reductive ring contraction. The borane-tetrahydrofu-
ran complex is a powerful reducing agent for C=N bonds
and has been frequently applied for reductions of oximes
or oxime ethers.15 Reduction of 1,2-oxazines rac-4 with
BH3·THF followed by treatment with aqueous 2 N NaOH
solution furnished the tetrahydro-2H-1,2-oxazines rac-7
in moderate to good yields and with high cis-trans selec-
tivity (Scheme 3). Whereas the reduction of 3-phenyl- and
3-trifluoromethyl-substituted compounds rac-4a and rac-
4c exclusively led to the expected products rac-7a and
rac-7c, the reduction of ethoxycarbonyl-substituted 1,2-
oxazine rac-4b was less chemoselective and led to the un-
expected formation of furan derivative 8 as major product
in 49% yield. As published previously, the reduction of
the C=N unit in rac-4b could be performed more success-
fully by employing sodium cyanoborohydride as reducing
agent,16 which afforded only tetrahydro-2H-1,2-oxazine
rac-7b in 48% yield and with high cis-trans selectivity.17
The reduction of phenyl-substituted precursor rac-4a with
NaBH3CN in acetic acid gave a better yield (77%), but the
diastereoselectivity was only moderate.18 In all examples
c: R = CF3
a: R = Ph
69% (only 1 diastereomer)
77% (cis/trans = 65:35)
b: R = CO2Et 48% (cis/trans = 89:11)17
Scheme 3 Stereoselective conversion of rac-4 into tetrahydro-2H-
1,2-oxazines 7. Reagents and conditions: Method A: (a) BH3·THF,
THF, r.t.; (b) 2 N NaOH, r.t.; Method B: NaBH3CN, AcOH, r.t., 6 h.
presented in Scheme 3, the hydride was delivered to the
sterically better available exo-side of the fairly rigid bicy-
clic compounds 4.
The observed side product 8 is very similar to an interest-
ing class of structurally related furanose derivatives.
These are known precursors of hydantoins, which are
pharmacophores with a wide range of biological activi-
ties.19 The formation of 8 probably starts with a reversible
addition of the Lewis acid borane to the ethoxycarbonyl
group to form intermediate A as illustrated in Scheme 4.
Thereby, activation of the N–O bond resulted in reduction
of this unit to give the acyclic imine C via B. Ring closure
of C to the furan intermediate D followed by hydrolysis
(during workup) affords the isolated compound 8.
The major cis-isomer rac-7a, which is easily separable
from the minor trans-isomer by chromatography, was re-
duced with hydrogen/palladium on charcoal under stan-
dard conditions and furnished the 2-phenyl-substituted
pyrrolidine rac-5 as single cis-cis-diastereomer in good
yield (Equation 1). Thus, the two-step route to pyrro-
OBH3
O
O
O
OBH3
OEt
O
O
O
CO2Et
BH3
BH3
OEt
N
N
NH
EtO
O
EtO
O
EtO
O
BH2
rac-4b
A
B
– BH3
O
O
O
O
O
O
CO2Et
H2O
CO2Et
NH2
CO2Et
NH
EtO
EtO
O
O
EtO
O
NH(BH2)
BH2
D
8
C
Scheme 4 Proposed mechanism for formation of furan derivative 8
Synthesis 2007, No. 17, 2681–2689 © Thieme Stuttgart · New York

PAPER
Reductive Ring Contraction of 1,2-Oxazines to Pyrrolidines
2683
lidines proceeds with significantly higher diastereoselec- (6S)-13 and diastereomerically highly enriched (6R)-13.
tivity than the one-step route.
Similarly, the corresponding 3-ethoxycarbonyl-6H-1,2-
oxazine could be prepared under analogous conditions,
but the yield amounted only to 21%. However, when the
hetero Diels–Alder reaction of 10 and a-nitrosoalkene 2
with R = CO2Et was performed in the absence of solvent
the yield improved to 72% with dr = 56:44. Unfortunate-
ly, separation of both diastereomers of the resulting 3-
ethoxycarbonyl-6H-1,2-oxazine was not possible either
by flash chromatography nor by HPLC.22 The already
described synthesis of 6-menthyloxy-3-phenyl-6H-1,2-
oxazine (14) employs an alternative route in which
(–)-menthol (9) was added to an easily available phenyl-
substituted azapyrylium intermediate.4c The absolute con-
figuration of (6S)-14 at C-6 was unambiguously deter-
mined by an X-ray analysis.23 The assignments of
configuration for (6S)-13 and (6R)-13 are based on com-
parison of the NMR data.
O
O
O
H2, Pd/C, MeOH,
r.t., 48 h
O
Ph
NH
Ph
EtO
O
N
H
81%
rac-7a
rac-5
Equation 1 Reductive ring contraction of tetrahydro-2H-1,2-oxa-
zine rac-7a to cis-cis rac-5
We then focused on the extension of these reductions to
enantiopure 1,2-oxazine derivatives. To this end, conver-
sion of 2-bromo enol ether 1 into the chiral enol ether 10
was performed in two simple steps. Addition of (–)-men-
thol (9) to 1 in the presence of catalytic amounts of tri-
fluoroacetic acid formed an acetal intermediate which was
subsequently treated with trimethylsilyl triflate and trieth-
ylamine analogously to a protocol developed by Dujardin
et al.20 This method afforded menthyloxy-substituted bro-
mo enol ether 10 in good yield as a 85:15 Z/E mixture
(Scheme 5).
All 6-menthyloxy-substituted 6H-1,2-oxazines (6R)-13/
(6S)-13 and (6R)-14/(6S)-14 underwent dihydroxylation
using the typical protocol employing RuCl3/NaIO4 fol-
lowed by standard protection of the 4,5-diol unit with 2,2-
dimethoxypropane (Scheme 7). The reactions again pro-
ceeded with excellent degrees of diastereoselectivity pro-
viding (6S)-15, (6S)-16 and (6R)-16 as single isomers.
The only exception is the case of (6R)-15, where the start-
ing material was contaminated with the minor isomer
(6S)-13.
a) cat. CF3CO2H,
r.t., 5 d
Br
Br
72% (50:50)
+
b) Et3N, TMSOTf,
CH2Cl2, 0 °C
EtO
OH
O
Subsequent treatment of the bicyclic compounds (6R)-15,
(6R)-16 and (6S)-15, (6S)-16 with BH3·THF complex led
to diastereoselective reduction of the C=N bond to give
the expected products (6R)-17, (6R)-18 and (6S)-17, (6S)-
18 in moderate to good yields (Scheme 8). With the ex-
ception of trifluoromethyl-substituted 1,2-oxazine (6R)-
17, all other products were diastereomerically pure (de
>94%). The menthyloxy group thus leads to higher dia-
stereoselectivity compared to the ethoxy compounds
(Scheme 3) although this more bulky substituent is at the
face where the hydride reagent attacks.
79% (Z/E = 85:15)
1
9
10
Scheme 5 Preparation of the chiral bromo enol ether 10
According to the route described above, the chiral enol
ether 10 served as dienophile in the hetero Diels–Alder re-
action with a-nitrosoalkene 12, in situ generated from
11,21 to furnish 6-menthyloxy-substituted 6H-1,2-oxazine
13 in 80% yield as a 1:1 mixture of 6R- and 6S-diastereo-
mers (Scheme 6). Separation of the isomers by flash
chromatography allowed isolation of essentially pure
CF3
Br
N
HO
CF3
11
a
N
R1O
O
(6R)-13
(46%, de = 86%)
Br
CF3
CF3
b
c
R1
=
+
N
N
R1O
O
R1O
+
O
80%
(55:45)
CF3
10
12
13
N
R1O
O
(6S)-13
(39%, de >94%)
Scheme 6 Synthesis and separation of diastereomeric 6H-1,2-oxazines 13. Reagents and conditions: (a) Na2CO3, t-BuOMe, r.t., 6 d; (b)
DBU, r.t., 4 h; (c) separation by flash chromatography.
Synthesis 2007, No. 17, 2681–2689 © Thieme Stuttgart · New York

2684
H.-U. Reissig et al.
PAPER
Hydrogenations of 3-phenyl-substituted tetrahydro-2H-
1,2-oxazines (6R)-18 and (6S)-18 proceeded under stan-
dard conditions and furnished pyrrolidines (2S,3R,4S)-5
and (2R,3S,4R)-5, respectively, in moderate yields
(Scheme 9). We assume that the excellent diastereoselec-
tivity achieved at the level of 18 is completely transferred
to pyrrolidine derivatives 5 which should be essentially
enantiopure (ee >94%). Unfortunately, the corresponding
3-trifluoromethyl-substituted tetrahydro-2H-1,2-oxazines
(6R)-17 and (6S)-17 could not be hydrogenated under
these conditions – even after prolonged reaction times
only starting material was recovered.22
O
R2
R2
O
a,b
N
N
R1O
O
R1O
O
(6R)-13 (R2 = CF3)
(6R)-14 (R2 = Ph)
(6R)-15,16
O
O
R2
R2
a,b
N
N
R1O
O
R1O
O
(6S)-13 (R2 = CF3)
(6S)-14 (R2 = Ph)
(6S)-15,16
O
O
O
O
Ph
a
R1
R2
NH
Ph
(2S,3R,4S)-5
MenthO
O
37% (ee >94%)
N
H
(6R)-16
Ph
69% (de >94%)
(6R)-18
(6R)-15
CF3
61% [containing 7% of (6S)-15]
O
O
O
O
Ph
a
NH
Ph
(2R,3S,4R)-5
MenthO
O
N
(6S)-16
(6S)-15
51% (ee >94%)
Ph 65% (de >94%)
CF3
H
(6S)-18
62% (de >94%)
Scheme 9 Reductive ring contraction of tetrahydro-2H-1,2-oxa-
zines 18 into enantiopure pyrrolidines 5. Reagents and conditions: (a)
H2, Pd/C, MeOH, r.t., 24–48 h.
Scheme 7 Dihydroxylations of diastereomerically pure 6H-1,2-
oxazines 13 and 14. Reagents and conditions: (a) RuCl3·3H2O,
NaIO4, MeCN–(EtOAc)–H2O, 0 ° C, 3–4 min; (b) 2,2-DMP, p-TsOH,
acetone, r.t., 4 h.
In summary, we could demonstrate that the standard re-
ductive ring contractions of 5,6-dihydro-4H-1,2-oxazines
derivatives by directly employing hydrogen/palladium on
charcoal could strongly be improved by development of a
two step sequence. The highly diastereoselective reduc-
tion of 5,6-dihydro-4H-1,2-oxazines by the borane-tet-
rahydrofuran complex was the crucial step in this
sequence. The resulting tetrahydro-1,2-oxazines were
then reductively ring contracted to diastereomerically
pure pyrrolidines. This sequence was applied to the prep-
aration of racemic dihydroxylated pyrrolidines and it
could successfully be extended to the synthesis of enan-
tiopure compounds such as 17, 18 and 5. The dihydroxy-
lated 1,2-oxazines and pyrrolidines are compounds which
should have biological activity since several glycosidase
inhibitors with these structural features are well known.24
O
O
O
O
R
R
a,b
NH
N
MenthO
O
MenthO
O
(6R)-17,18
(6R)-15,16
O
O
O
O
R
R
a,b
NH
N
MenthO
O
MenthO
O
(6S)-17,18
(6S)-15,16
All reactions were performed under argon in flame-dried flasks, and
the components were added by means of syringes. All solvents were
dried by standard methods. IR spectra were measured with a Nicolet
205 FT-IR spectrophotometer. MS spectra were recorded with a
Varian MAT 711 spectrometer. Optical rotations were measured us-
ing a Perkin-Elmer 241 polarimeter at 22 °C. 1H and 13C NMR spec-
tra were recorded on Bruker instruments (AC 200, AC 300 or DXR
500) in CDCl3 solution. The chemical shifts are given relative to the
TMS or to the CDCl3 signal (dH = 7.27, dC = 77.0). Higher order
NMR spectra were approximately interpreted as first-order spectra
if possible. Silica gel 60 (0.04–0.063 mm, Merck-Schuchardt) was
used for column chromatography. Melting points (uncorrected)
were measured with an apparatus from Gallenkamp (MPD 350).
(6R)-18 R = Ph
(6R)-17 R = CF3
(6S)-18 R = Ph
(6S)-17 R = CF3
43% (de >94%)
[a]
68% [containing 9% of (6S)-17]
71% (de >94%)
67% (de >94%)
[a] containing 7% of (6S)-15
Scheme 8 Reduction of 5,6-dihydro-4H-1,2-oxazines with borane-
tetrahydrofuran complex. Reagents and conditions: (a) BH3·THF,
THF, r.t.; (b) 2 N NaOH, r.t.
Synthesis 2007, No. 17, 2681–2689 © Thieme Stuttgart · New York

PAPER
Reductive Ring Contraction of 1,2-Oxazines to Pyrrolidines
2685
Starting materials and reagents 1,25 rac-4a,b,2a,5 and 1121 were pre-
pared by literature procedures. All other chemicals were commer-
cially available and were used as received.
Hz, 1 H, 2-H), 4.22, 4.26 (AB part of ABX3 system, JA,X = JB,X = 7
Hz, JA,B = 11.5 Hz, 2 H, OCH2), 4.70 (mc, 1 H, 4-H), 4.82 (t, J = 5
Hz, 1 H, 3-H).
13C NMR (CDCl3, 75.5 MHz): d = 14.0, 23.9, 25.4 (3 q, 3 × CH3),
51.8 (t, C-5), 60.8 (t, OCH2), 66.2 (d, C-2), 81.5 (d, C-4), 82.3 (d,
C-3), 111.3 (s, CMe2), 168.6 (s, CO2Et).
rac-3,4-O-Isopropylidene-2-phenylpyrrolidine (5)
A suspension of 10% Pd/C (0.290 g) in EtOH (29 mL) was saturated
with H2. 1,2-Oxazine rac-4a (0.804 g, 2.90 mmol) was added and
the mixture was stirred at r.t. under H2 at atmospheric pressure for
24 h. The suspension was then filtered through Celite, eluting with
EtOAc. The filtrate was concentrated in vacuo and the crude prod-
uct was purified by filtration (alumina, t-BuOMe) and Kugelrohr
distillation (110 °C/0.01 mbar) to yield a mixture of cis/trans iso-
mers (33:67) (0.597 g, 94%). The mixture of diastereomers was sep-
arated by chromatography using a chromatotron (hexane–EtOAc,
1:3).
trans-6
Colorless oil.
1H NMR (CDCl3, 300 MHz): d = 1.29 (t, J = 7 Hz, 3 H, CH3), 1.33,
1.49 (2 s, 3 H each, 2 × CH3), 2.57 (br s, 1 H, NH), 2.95 (dd, J = 4,
13 Hz, 1 H, 5-H), 3.14 (d, J = 13 Hz, 1 H, 5-H), 3.84 (s, 1 H, 2-H),
4.19 (q, J = 7 Hz, 2 H, OCH2), 4.72 (mc, 1 H, 4-H), 4.89 (d, J = 5.5
Hz, 1 H, 3-H).
13C NMR (CDCl3, 75.5 MHz): d = 14.0, 23.9, 26.1 (3 q, 3 × CH3),
52.6 (t, C-5), 61.0 (t, OCH2), 67.1 (d, C-2), 81.2 (d, C-4), 83.9 (d,
C-3), 111.3 (s, CMe2), 171.5 (s, CO2Et).
cis-5
Colorless oil.
1H NMR (CDCl3, 300 MHz): d = 1.29, 1.44 (2 s, 3 H each,
2 × CH3), 2.59 (s, 1 H, NH), 2.78 (dd, J = 3, 12.5 Hz, 1 H, 5-H),
3.23 (d, J = 12.5 Hz, 1 H, 5-H), 3.80 (d, J = 3 Hz, 1 H, 2-H), 4.75
(mc, 2 H, 3-H, 4-H), 7.24–7.45 (m, 5 H, C6H5).
Further data obtained from the mixture:
IR (neat): 3320 (N–H), 2990–2870 (C–H), 1740 cm–1 (C=O).
Anal. Calcd for C10H17NO4 (215.3): C, 55.80; H, 7.96; N, 6.51.
Found: C, 55.93; H, 8.05; N, 6.28.
13C NMR (CDCl3, 75.5 MHz): d = 23.9, 25.8 (2 q, 2 × CH3), 53.0 (t,
C-5), 67.3 (d, C-2), 81.8 (d, C-4), 82.3 (d, C-3), 110.7 (s, CMe2),
127.3, 127.5, 128.1, 137.0 (3 d, s, C6H5).
Reduction of 1,2-Oxazines with BH3·THF; General Procedure 1
Under argon, the corresponding 1,2-oxazine dissolved in THF (10
mL/mmol of 1,2-oxazine) was treated with BH3·THF (1 M in THF,
3–4 equiv) at r.t. The solution was stirred for 24–48 h, then aq 2 N
NaOH solution (10 mL/mmol of 1,2-oxazine) was added. After an
additional 2 h at r.t., the phases were separated and the aqueous
phase was extracted with EtOAc (2 × 10 mL/mmol of 1,2-oxazine).
The combined organic phases were dried (Na2SO4) and concentrat-
ed in vacuo. The crude product was purified by column chroma-
tography or by Kugelrohr distillation.
trans-5
Colorless oil.
1H NMR (CDCl3, 300 MHz): d = 1.34, 1.53 (2 s, 3 H each,
2 × CH3), 2.64 (s, 1 H, NH), 2.93 (dd, J = 4, 13.5 Hz, 1 H, 5-H),
3.10 (d, J = 13.5 Hz, 1 H, 5-H), 4.35 (s, 1 H, 2-H), 4.67, 4.82 (2 mc,
1 H each, 3-H, 4-H), 7.23–7.40 (m, 5 H, C6H5).
13C NMR (CDCl3, 75.5 MHz): d = 24.1, 26.4 (2 q, 2 × CH3), 52.7 (t,
C-5), 67.6 (d, C-2), 82.2 (d, C-4), 88.1 (d, C-3), 111.1 (s, CMe2),
126.7, 126.8, 128.4, 139.6 (3 d, s, C6H5).
rac-3,4,5,6-Tetrahydro-4,5-O-isopropylidene-3-phenyl-2H-1,2-
oxazine (7a)
Further data obtained from the mixture:
According to general procedure 1, 1,2-oxazine rac-4a (1.09 g, 3.93
mmol) was treated with BH3·THF (16.0 mL, 16.0 mmol) in THF (40
mL), followed by workup and purification using column chroma-
tography (alumina, hexane–EtOAc, 5:1) to give 7a (0.667 g, 75%;
cis/trans = 89:11) as colorless crystals; mp 131–133.5 °C.
IR (neat): 3340 (N–H), 3090–2860 cm–1 (=C–H, C–H).
Anal. Calcd for C13H17NO2 (219.3): C, 71.21; H, 7.82; N, 6.39.
Found: C, 71.22; H, 7.97; N, 6.28.
1H NMR (CDCl3, 300 MHz): d = 1.28 (t, J = 7 Hz, 3 H, CH3), 1.31,
1.57 (2 s, 3 H each, 2 × CH3), 3.72, 3.97 (AB part of ABX3 system,
JA,X = JB,X = 7 Hz, JA,B = 9.5 Hz, 2 H, OCH2), 4.00, 4.46 (2 mc, 1 H,
2 H, 3-H, 4-H, 5-H), 4.78 (d, J = 7 Hz, 1 H, 6-H), 5.49 (br s, 1 H,
NH), 7.31–7.38, 7.43–7.47 (2 m, 3 H, 2 H, C6H5).
rac-Ethyl 3,4-O-Isopropylidenepyrrolidine-2-carboxylate (6)
A suspension of 10% Pd/C (0.553 g) in EtOH (55 mL) was saturated
with H2. 1,2-Oxazine rac-4b (1.51 g, 5.53 mmol) and aq 2 N HCl (1
mL) were added and the mixture was stirred at r.t. under H2 at atmo-
spheric pressure for 24 h. The suspension was then filtered through
Celite, eluting with EtOAc. After addition of aq sat. NaHCO3 solu-
tion (10 mL), the mixture was concentrated in vacuo. The residue
was extracted with EtOAc (3 × 20 mL) and the combined organic
extracts were dried (Na2SO4), and concentrated in vacuo. The re-
sulting crude product was dissolved in anhyd acetone (10 mL) and
treated with 2,2-dimethoxypropane (2,2-DMP, 2 mL) and a catalyt-
ic amount of p-toluenesulfonic acid for 4 h at r.t. Then an excess of
solid NaHCO3 was added to the mixture, the suspension was fil-
tered, and the volatile components were removed in vacuo. The res-
idue was purified by Kugelrohr distillation (95 °C/0.01 mbar) to
yield a mixture of cis/trans isomers (52:48) (0.746 g, 63%). The
mixture of diastereomers was separated by flash chromatography
(silica gel, t-BuOMe–MeOH, 20:1).
13C NMR (CDCl3, 75.5 MHz): d = 15.3, 26.1, 28.1 (3 q, 3 × CH3),
62.9 (d, C-3), 65.9 (t, OCH2), 75.5, 75.9 (2 d, C-4, C-5), 103.8 (d,
C-6), 110.2 (s, CMe2), 128.3, 128.7, 135.4 (2 d, s, C6H5).
Additional signals assigned to trans-isomer:
1H NMR (CDCl3, 300 MHz): d = 1.10, 1.48 (2 s, 3 H each,
2 × CH3), 1.13 (t, J = 7 Hz, 3 H, CH3), 3.57, 3.95 (AB part of ABX3
system, JA,X = JB,X = 7 Hz, JA,B = 9.5 Hz, 2 H, OCH2), 4.05, 4.13
(2 × mc, 2 H, 1 H, 3-H, 4-H, 5-H), 4.96 (d, J = 6.5 Hz, 1 H, 6-H),
5.14 (br s, 1 H, NH), 7.06–7.16, 7.37–7.39 (2 × m, 3 H, 2 H, C6H5).
13C NMR (CDCl3, 75.5 MHz): d = 14.9, 26.2 (2 q, 2 × CH3), 63.0
(d, C-3), 63.8 (t, OCH2), 73.4, 74.6 (2 d, C-4, C-5), 99.1 (d, C-6),
109.4 (s, CMe2), 137.3 (s, C6H5).
cis-6
cis/trans-7a
IR (Nujol): 3410, 3300 (N–H), 3140–2720 cm–1 (C–H).
Colorless crystals; mp 67–68.5 °C.
1H NMR (CDCl3, 300 MHz): d = 1.27 (t, J = 7 Hz, 3 H, CH3), 1.27,
1.40 (2 s, 3 H each, 2 × CH3), 2.57 (br s, 1 H, NH), 2.64 (dd, J = 3.5,
13.5 Hz, 1 H, 5-H), 3.20 (d, J = 13.5 Hz, 1 H, 5-H), 3.54 (d, J = 5
Anal. Calcd for C15H21NO4 (279.3): C, 64.50; H, 7.58; N, 5.01.
Found: C, 64.51; H, 7.68; N, 4.96.
Synthesis 2007, No. 17, 2681–2689 © Thieme Stuttgart · New York

2686
H.-U. Reissig et al.
PAPER
rac-Ethyl 3,4,5,6-Tetrahydro-4,5-O-isopropylidene-3-phenyl-
2H-1,2-oxazine-3-carboxylate (7b) and rac-Ethyl 4-Amino-6-
ethoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-car-
boxylate (8)
product was purified by filtration (alumina, t-BuOMe) and Kugel-
rohr distillation (110 °C/0.01 mbar) to yield rac-5a as the all cis-
configured diastereomer (0.178 g, 81%).
According to general procedure 1, 1,2-oxazine rac-4b (0.273 g,
1.00 mmol) was treated with BH3·THF (3.3 mL, 3.30 mmol) in THF
(10 mL), followed by workup and filtration (alumina, hexane–
EtOAc, 5:1) to give a mixture of 7b (cis/trans = 79:21) and 8 (0.188
g, 21% of 7b; 49% of 8).
(1S,2R,4R)-2-(2-Bromovinyloxy)-1-isopropyl-4-methylcyclo-
hexane (10)
To a solution of (–)-menthol (9; 39.1 g, 0.25 mol) in 1-bromo-2-
ethoxyethene (1; 37.8 g, 0.25 mol), was added trifluoroacetic acid
(1.0 mL) and the mixture was stirred for 5 d at r.t. The mixture was
diluted with CH2Cl2 (100 mL) and washed once with aq sat.
NaHCO3 solution (30 mL). Separation of the layers, drying of the
organic layer (Na2SO4) and concentration in vacuo gave the bro-
moacetal intermediate (69.5 g). The crude product was purified by
Kugelrohr distillation (120 °C/0.06 mbar) to furnish the bromoace-
tal intermediate (51.1 g, 72%; two diastereomers = 1:1). Under ar-
gon, the bromoacetal (41.5 g, 0.135 mol) and Et3N (19.1 g, 0.189
mol) were dissolved in CH2Cl2 (135 mL) and TMSOTf (33.1 g,
0.149 mmol) was added dropwise at 0 °C. After 16 h at 0 °C, aq 1
N NaOH solution (65 mL) and pentane (65 mL) were added, the
layers were separated and the organic layer was dried (Na2SO4). Re-
moval of the solvent, filtration through alumina (hexane), followed
by Kugelrohr distillation of the crude product led to bromo enol
ether 10 as a colorless oil (26.9 g, 79%; Z/E = 85:15).
The spectroscopic data of 7b are in agreement with those given in
ref. 17.
8
IR (neat): 3420, 3340 (N–H), 3040–2810 (C–H), 1740 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): d = 1.11, 1.32 (2 t, J = 7 Hz, 3 H each,
2 × CH3), 1.37, 1.51 (2 s, 3 H each, 2 × CH3), 2.47 (br s, 2 H, NH2),
3.40, 3.70 (AB part of ABX3 system, JA,X = JB,X = 7 Hz, JA,B = 10
Hz, 2 H, OCH2), 4.21 (mc, 2 H, OCH2), 4.62 (d, J = 6 Hz, 1 H, 4-H),
4.93 (s, 1 H, 5-H), 5.15 (d, J = 6 Hz, 1 H, 3-H).
13C NMR (CDCl3, 75.5 MHz): d = 14.0, 14.7, 24.9, 26.3 (4 q,
4 × CH3), 61.6, 63.2 (2 t, 2 × OCH2), 79.8 (d, C-4), 84.8 (d, C-3),
93.6 (s, C-2), 105.3 (d, C-5), 112.6 (s, CMe2), 169.7 (s, CO2Et).
(Z)-10
MS (EI, 70 eV): m/z = 261 (4), 231 (11), 203 (55), 144 (36), 129
(37), 119 (75), 115 (79), 114 (80), 100 (76), 85 (51), 71 (76), 59
(79), 56 (59), 43 (100), 31 (61).
1H NMR (CDCl3, 200 MHz): d = 0.72–1.74 (m, 16 H, 3-H, 4-H, 5-
H, 6-H, 3 × CH3), 1.94–2.24 (m, 2 H, 2-H, CHMe2), 3.57 (dt,
J = 4.5, 10.5 Hz, 1 H, 1-H), 5.05 (d, J = 4 Hz, 1 H, =CH), 6.65 (d,
J = 4 Hz, 1 H, =CH).
Anal. Calcd for C12H21NO6 (275.3): C, 52.35; H, 7.69; N, 5.09.
Found: C, 52.23; H, 7.64; N, 4.94.
13C NMR (CDCl3, 50.3 MHz): d = 16.45, 20.6, 22.0 (3 q, 3 × CH3),
23.6 (t, C-3), 25.9 (d, CHMe2), 31.6 (d, C-5), 34.23 (t, C-4), 41.5 (t,
C-6), 47.5 (d, C-2), 81.6 (d, C-1), 83.3 (d, =CH), 146.7 (d, =CH).
rac-3,4,5,6-Tetrahydro-4,5-O-isopropylidene-3-trifluorometh-
yl-2H-1,2-oxazine (7c)
According to general procedure 1, 1,2-oxazine rac-4c (0.226 g, 0.84
mmol) was treated with BH3·THF (3.4 mL, 3.40 mmol) in THF (8
mL), followed by workup and purification using Kugelrohr distilla-
tion (85 °C/0.01 mbar) to give 7c (0.157 g, 69%; single diastereo-
mer) as colorless crystals; mp 88–89.5 °C.
Additional signals assigned to (E)-10:
1H NMR (CDCl3, 200 MHz): d = 0.78 (d, J = 7 Hz, 3 H, CH3), 5.47
(d, J = 11.5 Hz, 1 H, =CH), 6.76 (d, J = 11.5 Hz, 1 H, =CH).
13C NMR (CDCl3, 50.3 MHz): d = 16.39, 22.3 (2 q, 2 × CH3), 23.5
(t, C-3), 31.5 (d, C-5), 34.19 (t, C-4), 40.9 (t, C-6), 47.7 (d, C-2),
81.7 (d, C-1), 84.2 (d, =CH), 149.8 (d, =CH).
IR (KBr): 3260 (N–H), 3090–2810 cm–1 (C–H).
1H NMR (CDCl3, 300 MHz): d = 1.23 (t, J = 7 Hz, 3 H, CH3), 1.38,
1.55 (2 s, 3 H each, 2 × CH3), 3.64, 3.91 (AB part of ABX3 system,
JA,X = JB,X = 7 Hz, JA,B = 9.5 Hz, 2 H, OCH2), 3.95 (mc, 1 H, 3-H),
4.02 (dd, J = 5.5, 6 Hz, 1 H, 5-H), 4.48 (dd, J = 3, 5.5 Hz, 1 H, 4-
H), 4.61 (d, J = 6 Hz, 1 H, 6-H), 5.45 (br s, 1 H, NH).
(Z/E)-10
IR (neat): 2960–2870 (C–H), 1640 cm–1 (C=C).
Anal. Calcd for C12H21BrO (261.2): C, 55.18; H, 8.10. Found: C,
55.30; H, 7.86.
13C NMR (CDCl3, 75.5 MHz): d = 15.0, 25.7, 27.5 (3 q, 3 × CH3),
59.3 (dq, JC,F = 29 Hz, C-3), 66.9 (t, OCH2), 69.5 (d, C-5), 74.9 (d,
C-4), 103.0 (d, C-6), 111.3 (s, CMe2), 122.9 (q, JC,F = 281 Hz, CF3).
(6R)- and (6S)-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-
oxy]-3-trifluoromethyl-6H-1,2-oxazine (13)
Anal. Calcd for C10H16F3NO4 (271.2): C, 44.28; H, 5.95; N, 5.16.
Found: C, 44.22; H, 5.81; N, 5.08.
A solution of 2-bromo enol ether 10 (18.3 g, 70.0 mmol; E/Z =
85:15) and oxime 11 (1.44 g, 7.00 mmol) in t-BuOMe (175 mL)
were stirred with freshly ground Na2CO3 (4.45 g, 42.0 mmol). After
stirring at r.t. for 6 d, the suspension was filtered through a pad of
Celite to remove the inorganic salts. To the resulting filtrate was
added DBU (1.07 g, 70.0 mmol) and the solution was stirred at r.t.
for 4 h. The organic layer was washed with H2O (3 × 30 mL) and
dried (Na2SO4). The solvent was removed in vacuo, and the excess
of 10 was distilled off by Kugelrohr distillation (20–60 °C/15
mbar). The residue was filtered through alumina (hexane–EtOAc,
4:1) to furnish 13 (1.71 g, 80%, 6R/6S = 55:45). Separation of 13
(0.870 g) by flash chromatography (silica gel; hexane–EtOAc,
15:1) gave (6S)-13 (0.336 g, 39%, de >94%) as colorless crystals;
mp 64–71 °C, and (6R)-13 (0.403 g, 46%, de = 86%) as a colorless
oil.
Reduction of 1,2-Oxazine 4a with NaBH3CN
1,2-Oxazine 4a (0.205 g, 0.74 mmol) was dissolved in AcOH (7
mL) and NaBH3CN (0.187 g, 2.96 mmol) was added in portions un-
der argon. The solution was stirred mechanically at r.t. for 6 h. After
consumption of the starting material, the solution was slowly added
to an aq sat. Na2CO3 solution (60 mL) and extracted with EtOAc
(3 × 60 mL). The combined organic layers were concentrated in
vacuo, and the crude product (cis:trans = 87:13) was purified by
column chromatography (alumina, hexane–t-BuOMe, 5:1) to give
7a (0.160 g, 77%).
Hydrogenolysis of rac-7a
A suspension of 10% Pd/C (0.100 g) in MeOH (10 mL) was satu-
rated with H2. 1,2-Oxazine rac-7a (0.279 g, 1.00 mmol) was added
and the mixture was stirred at r.t. under H2 at atmospheric pressure
for 48 h. The suspension was then filtered through Celite, eluting
with EtOAc. The filtrate was concentrated in vacuo and the crude
(1¢R,2¢S,5¢R,6S)-13
[a]D +128 (c = 0.47, CHCl3).
IR (KBr): 2980–2820 (C–H), 1630 (C=C), 1570 cm–1 (C=N).
Synthesis 2007, No. 17, 2681–2689 © Thieme Stuttgart · New York

PAPER
Reductive Ring Contraction of 1,2-Oxazines to Pyrrolidines
2687
1H NMR (CDCl3, 200 MHz): d = 0.75–1.72 (m, 16 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 3 × CH3), 1.95–2.27 (m, 2 H, 2¢-H, CHMe2), 3.60 (dt,
J = 4.5, 10.5 Hz, 1 H, 1¢-H), 5.70 (d, J = 4 Hz, 1 H, 6-H), 6.29 (d,
J = 10 Hz, 1 H, 4-H), 6.38 (dd, J = 4, 10 Hz, 1 H, 5-H).
13C NMR (CDCl3, 50.3 MHz): d = 15.8, 20.9, 22.3, 26.0, 27.0 (5 q,
5 × CH3), 23.2 (t, C-3¢), 25.4 (d, CHMe2), 31.3 (d, C-5¢), 34.4 (t, C-
4¢), 39.5 (t, C-6¢), 47.9 (d, C-2¢), 65.6 (d, C-1¢), 72.7 (d, C-4), 75.9
(d, C-5), 94.6 (d, C-6), 110.9 (s, CMe2), 126.6, 128.4, 129.9, 133.7
(3 d, s, C6H5), 157.1 (s, C-3).
13C NMR (CDCl3, 50.3 MHz): d = 16.3, 22.1, 23.2 (3 q, 3 × CH3),
23.2 (t, C-3¢), 25.7 (d, CHMe2), 31.7 (d, C-5¢), 34.2 (t, C-4¢), 42.2 (t,
C-6¢), 48.3 (d, C-2¢), 81.2 (d, C-1¢), 94.0 (d, C-6), 111.9 (d, C-4),
120.3 (q, JC-F = 274 Hz, CF3), 126.2 (d, C-5), 147.1 (q, JC,F = 35 Hz,
C-3).
Anal. Calcd for C23H33NO4 (387.5): C, 71.30; H, 8.58; N, 3.61.
Found: C, 71.40; H, 8.79; N, 3.45.
(4S,5S,6S)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-
4,5-isopropylidene-3-phenyl-5,6-dihydro-4H-1,2-oxazine [(6S)-
16]
(1¢R,2¢S,5¢R,6R)-13
[a]D –174 (c = 0.43, CHCl3).
IR (neat): 2970–2820 (C–H), 1630 (C=C), 1575 cm–1 (C=N).
According to general procedure 2, 1,2-oxazine (6S)-14 (0.313 g,
1.00 mmol) was treated with RuCl3·3H2O (0.018 g, 0.07 mmol) and
NaIO4 (0.321 g, 1.50 mmol), followed by acetalization with 2,2-
DMP (7 mL) in the presence of p-TsOH (0.040 g). Workup and col-
umn chromatography (alumina, hexane–EtOAc, 8:1) afforded (6S)-
16 (0.250 g, 65%, de >94%) as colorless crystals; mp 138–140 °C;
1H NMR (CDCl3, 200 MHz): d = 0.74–1.72 (m, 16 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 3 × CH3), 1.89, 2.08–2.20 (mc, m, 1 H each, 2¢-H, CHMe2),
3.81 (dt, J = 4, 10.5 Hz, 1 H, 1¢-H), 5.81 (d, J = 3.5 Hz, 1 H, 6-H),
6.25 (d, J = 9.5 Hz, 1 H, 4-H), 6.35 (dd, J = 3.5, 9.5 Hz, 1 H, 5-H).
[a]D +28.0 (c = 0.51, CHCl3).
13C NMR (CDCl3, 50.3 MHz): d = 15.7, 20.7, 22.2 (3 q, 3 × CH3),
23.3 (t, C-3¢), 25.3 (d, CHMe2), 31.4 (d, C-5¢), 34.3 (t, C-4¢), 40.1 (t,
C-6¢), 48.0 (d, C-2¢), 75.7 (d, C-1¢), 89.2 (d, C-6), 112.0 (d, C-4),
120.4 (q, JC,F = 274 Hz, CF3), 126.9 (d, C-5), 147.6 (q, JC,F = 35 Hz,
C-3).
IR (KBr): 3100–2750 (=C–H, C–H), 1575 cm–1 (C=N).
1H NMR (CDCl3, 200 MHz): d = 0.75–1.70 (m, 22 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 5 × CH3), 2.09–2.32 (m, 2 H, 2¢-H, CHMe2), 3.56 (dt,
J = 4.5, 10.5 Hz, 1 H, 1¢-H), 4.37 (dd, J = 4.5, 6.5 Hz, 1 H, 5-H),
4.92 (d, J = 4.5 Hz, 1 H, 6-H), 4.95 (d, J = 6.5 Hz, 1 H, 4-H), 7.37–
7.47, 7.80–7.90 (2 m, 3 H, 2 H, C6H5).
Anal. Calcd for C15H22F3NO2 (305.3) from a mixture of (6S)- and
(6R)-13: C, 59.00; H, 7.26; N, 4.59. Found: C, 58.93; H, 7.29; N,
4.95.
13C NMR (CDCl3, 50.3 MHz): d = 16.2, 21.1, 22.1, 26.0, 27.1 (5 q,
5 × CH3), 23.1 (t, C-3¢), 25.4 (d, CHMe2), 31.7 (d, C-5¢), 34.3 (t, C-
4¢), 42.6 (t, C-6¢), 48.8 (d, C-2¢), 66.2 (d, C-1¢), 72.4 (d, C-4), 81.3
(d, C-5), 99.8 (d, C-6), 110.6 (s, CMe2), 126.7, 128.5, 130.0, 133.6
(3 d, s, C6H5), 156.7 (s, C-3).
Dihydroxylation and Acetalization of 1,2-Oxazines, General
Procedure 2
To a vigorously stirred solution of the corresponding 1,2-oxazine in
a mixture of EtOAc and MeCN (18 mL each/mmol of 1,2-oxazine)
at 0 °C, was added a solution of RuCl3·3H2O (0.07 equiv) and
NaIO4 (1.5 equiv) in H2O (5 mL/mmol of 1,2-oxazine). The mixture
was stirred vigorously for 3–4 min and then quenched with aq sat.
Na2S2O3 solution (10 mL/mmol of 1,2-oxazine). The aqueous phase
was separated, extracted with EtOAc (3 × 20 mL/mmol of 1,2-ox-
azine) and the combined organic extracts were dried (MgSO4).
Evaporation of the solvent under reduced pressure gave the 4,5-di-
hydroxylated 1,2-oxazine, which was directly protected without
further purification.
Anal. Calcd for C23H33NO4 (387.5): C, 71.30; H, 8.58; N, 3.61.
Found: C, 71.48; H, 8.82; N, 3.54.
(4R,5R,6R)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-
4,5-isopropylidene-3-trifluoromethyl-5,6-dihydro-4H-1,2-ox-
azine [(6R)-15]
According to general procedure 2, 1,2-oxazine (6R)-13 (0.305 g,
1.00 mmol, de = 86%) was treated with RuCl3·3H2O (0.018 g, 0.07
mmol) and NaIO4 (0.321 g, 1.50 mmol), followed by acetalization
with 2,2-DMP (7 mL) in the presence of p-TsOH (0.040 g). Workup
and column chromatography (alumina, hexane–EtOAc, 15:1) af-
forded (6R)-15 [0.232 g, 61%, de >94%, containing 7% of (6S)-15]
as colorless crystals; mp 90–95 °C; [a]D –203 (c = 0.42, CHCl3).
To a solution of the dried 4,5-dihydroxylated 1,2-oxazine in acetone
(4–20 mL/mmol of 1,2-oxazine) were added 2,2-DMP (1–10 mL/
mmol of 1,2-oxazine) and p-TsOH (40 mg/mmol of 1,2-oxazine).
The mixture was stirred for 4 h at r.t., then an excess of solid
NaHCO3 was added. The suspension was filtered, the solvent was
removed in vacuo, and the resulting crude product was purified by
column chromatography.
IR (KBr): 2960–2870 (=C–H, C–H), 1640 cm–1 (C=N).
1H NMR (CDCl3, 300 MHz): d = 0.68–1.72 (m, 22 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 5 × CH3), 1.88, 2.08–2.15 (mc, m, 1 H each, 2¢-H, CHMe2),
3.64 (dt, J = 4, 10.5 Hz, 1 H, 1¢-H), 4.32 (dd, J = 2.5, 6.5 Hz, 1 H,
5-H), 4.65 (d, J = 6.5 Hz, 1 H, 4-H), 5.37 (d, J = 2.5 Hz, 1 H, 6-H).
(4R,5R,6R)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-
4,5-isopropylidene-3-phenyl-5,6-dihydro-4H-1,2-oxazine [(6R)-
16]
According to general procedure 2, 1,2-oxazine (6R)-14 (0.940 g,
3.00 mmol) was treated with RuCl3·3H2O (0.054 g, 0.21 mmol) and
NaIO4 (0.963 g, 4.50 mmol), followed by acetalization with 2,2-
DMP (20 mL) in the presence of p-TsOH (0.120 g). Workup and
column chromatography (alumina, hexane–EtOAc, 8:1) afforded
(6R)-16 (0.800 g, 69%, de >94%) as colorless crystals; mp 124–
127 °C;
13C NMR (CDCl3, 50.3 MHz): d = 15.5, 20.8, 22.2, 26.1, 26.9 (5 q,
5 × CH3), 23.0 (t, C-3¢), 25.4 (d, CHMe2), 31.2 (d, C-5¢), 34.3 (t, C-
4¢), 39.1 (t, C-6¢), 47.8 (d, C-2¢), 62.2 (d, C-1¢), 71.0 (d, C-4), 76.2
(d, C-5), 93.4 (d, C-6), 112.3 (s, CMe2), 120.1 (q, JC,F = 276 Hz,
CF3), 149.6 (q, JC,F = 33 Hz, C-3).
Anal. Calcd for C18H28F3NO4 (379.4): C, 56.98; H, 7.44; N, 3.69.
Found: C, 57.35; H, 7.79; N, 3.60.
(4S,5S,6S)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-
4,5-isopropylidene-3-trifluoromethyl-5,6-dihydro-4H-1,2-ox-
azine [(6S)-15]
[a]D –72.3 (c = 0.51, CHCl3).
IR (KBr): 3100–2775 (=C–H, C–H), 1580 cm–1 (C=N).
According to general procedure 2, 1,2-oxazine (6S)-13 (0.305 g,
1.00 mmol) was treated with RuCl3·3H2O (0.018 g, 0.07 mmol) and
NaIO4 (0.321 g, 1.50 mmol), followed by acetalization with 2,2-
DMP (7 mL) in the presence of p-TsOH (0.040 g). Workup and col-
umn chromatography (alumina, hexane–EtOAc, 15:1) afforded
1H NMR (CDCl3, 200 MHz): d = 0.68–1.73 (m, 22 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 5 × CH3), 1.93–2.22 (m, 2 H, 2¢-H, CHMe2), 3.71 (dt, J = 4,
10.5 Hz, 1 H, 1¢-H), 4.36 (dd, J = 4, 7 Hz, 1 H, 5-H), 4.94 (d, J = 7
Hz, 1 H, 4-H), 5.16 (d, J = 4 Hz, 1 H, 6-H), 7.36–7.46, 7.78–7.88
(2 m, 3 H, 2 H, C6H5).
Synthesis 2007, No. 17, 2681–2689 © Thieme Stuttgart · New York

2688
H.-U. Reissig et al.
PAPER
(6S)-15 (0.237 g, 62%, de >94%) as colorless crystals; mp 109–
113 °C; [a]D +131 (c = 0.40, CHCl3).
(3R,4R,5R,6R)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-
oxy]-4,5-isopropylidene-3-trifluoromethyl-3,4,5,6-tetrahydro-
2H-1,2-oxazine [(6R)-17]
IR (KBr): 2960–2870 (=C–H, C–H), 1640 cm–1 (C=N).
According to general procedure 1, 1,2-oxazine (6R)-15 [0.189 g,
0.50 mmol, containing 7% of (6S)-15] was treated with BH3·THF
(2.0 mL, 2.00 mmol) in THF (5 mL). Workup and purification using
column chromatography (alumina, hexane–EtOAc, 6:1) afforded
(6R)-17 [0.130 g, 68%, de >94%, containing 9% of (6S)-17] as a
colorless oil; [a]D –89.1 (c = 0.29, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 0.65–1.68 (m, 22 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 5 × CH3), 1.96–2.11 (m, 2 H, 2¢-H, CHMe2), 3.53 (dt,
J = 4.5, 10.5 Hz, 1 H, 1¢-H), 4.34 (dd, J = 3, 6.5 Hz, 1 H, 5-H), 4.64
(d, J = 6.5 Hz, 1 H, 4-H), 5.14 (d, J = 3 Hz, 1 H, 6-H).
13C NMR (CDCl3, 50.3 MHz): d = 16.2, 21.1, 22.0, 26.1, 27.0 (5 q,
5 × CH3), 23.1 (t, C-3¢), 25.6 (d, CHMe2), 31.6 (d, C-5¢), 34.1 (t, C-
4¢), 42.0 (t, C-6¢), 48.6 (d, C-2¢), 62.7 (d, C-1¢), 70.6 (d, C-4), 81.9
(d, C-5), 98.9 (d, C-6), 112.2 (s, CMe2), 120.2 (q, JC,F = 276 Hz,
CF3), 149.9 (q, JC,F = 33 Hz, C-3).
IR (neat): 3250 (N–H), 2970–2870 cm–1 (C–H).
1H NMR (CDCl3, 300 MHz): d = 0.75–1.71 (m, 22 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 5 × CH3), 2.00–2.20 (m, 2 H, 2¢-H, CHMe2), 3.52 (dt,
J = 4.5, 11 Hz, 1 H, 1¢-H), 3.95–4.09 (m, 2 H, 3-H, 5-H), 4.49 (dd,
J = 3, 5.5 Hz, 1 H, 4-H), 4.73 (d, J = 6.5 Hz, 1 H, 6-H), 5.39 (d, J = 9
Hz, 1 H, NH).
Anal. Calcd for C18H28F3NO4 (379.4): C, 56.98; H, 7.44; N, 3.69.
Found: C, 57.15; H, 7.50; N, 3.62.
13C NMR (CDCl3, 75.5 MHz): d = 15.7, 20.9, 22.2, 26.0, 27.7 (5 q,
5 × CH3), 23.1 (t, C-3¢), 25.3 (d, CHMe2), 31.4 (d, C-5¢), 34.3 (t, C-
4¢), 40.1 (t, C-6¢), 47.5 (d, C-2¢), 59.7 (q, JC,F = 29 Hz, C-3), 70.0,
75.3, 77.7 (3 d, C-4, C-5, C-1¢), 100.3 (d, C-6), 111.2 (s, CMe2),
123.0 (q, JC,F = 281 Hz, CF3).
(3S,4R,5R,6R)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-
oxy]-4,5-isopropylidene-3-phenyl-3,4,5,6-tetrahydro-2H-1,2-
oxazine [(6R)-18]
According to general procedure 1, 1,2-oxazine (6R)-16 (0.194 g,
0.50 mmol) was treated with BH3·THF (2.0 mL, 2.00 mmol) in THF
(5 mL). Workup and purification using column chromatography
(alumina, hexane–EtOAc, 6:1) afforded (6R)-18 (0.081 g, 43%; de
>94%) as colorless crystals; mp 42–45 °C; [a]D –40.7 (c = 0.30,
CHCl3).
Anal. Calcd for C18H30F3NO4 (381.4): C, 56.68; H, 7.93; N, 3.67.
Found: C, 56.51; H, 8.19; N, 3.73.
(3S,4S,5S,6S)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-
oxy]-4,5-isopropylidene-3-trifluoromethyl-3,4,5,6-tetrahydro-
2H-1,2-oxazine [(6S)-17]
According to general procedure 1, 1,2-oxazine (6S)-15 (0.172 g,
0.45 mmol) was treated with BH3·THF (1.8 mL, 1.80 mmol) in THF
(5 mL). Workup and purification using column chromatography
(alumina, hexane–EtOAc, 8:1) afforded (6S)-17 (0.165 g, 67%, de
>94%) as colorless crystals; mp 77–80 °C; [a]D –15.2 (c = 0.48,
CHCl3).
IR (KBr): 3440 (N–H), 2985–2870 (=C–H, C–H) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.75–1.70 (m, 22 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 5 × CH3), 2.06–2.32 (m, 2 H, 2¢-H, CHMe2), 3.55 (dt,
J = 4.5, 10.5 Hz, 1 H, 1¢-H), 3.98 (dd, J = 5, 7 Hz, 1 H, 5-H), 4.46
(dd, J = 2.5, 5 Hz, 1 H, 4-H), 4.49 (br s, 1 H, 3-H), 4.88 (d, J = 7 Hz,
1 H, 6-H), 5.43 (br s, 1 H, NH), 7.27–7.38, 7.41–7.49 (2 m, 3 H, 2
H, C6H5).
13C NMR (CDCl3, 75.5 MHz): d = 15.8, 20.9, 22.3, 26.2, 28.1 (5 q,
5 × CH3), 23.2 (t, C-3¢), 25.3 (d, CHMe2), 31.6 (d, C-5¢), 34.4 (t, C-
4¢), 40.3 (t, C-6¢), 47.5 (d, C-2¢), 62.9 (d, C-1¢), 75.6, 76.0, 77.5 (3 d,
C-3, C-4, C-5), 100.7 (d, C-6), 110.1 (s, CMe2), 128.27, 128.31,
128.7, 135.4 (3 d, s, C6H5).
IR (KBr): 3450 (N–H), 2980–2875 cm–1 (C–H).
1H NMR (CDCl3, 300 MHz): d = 0.74–1.68 (m, 22 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 5 × CH3), 2.09–2.18, 2.27 (m, mc, 1 H each, 2¢-H, CHMe2),
3.40 (dt, J = 4.5, 10.5 Hz, 1 H, 1¢-H), 3.92–4.07 (m, 2 H, 3-H, 5-H),
4.47 (dd, J = 2.5, 5.5 Hz, 1 H, 4-H), 4.65 (d, J = 6.5 Hz, 1 H, 6-H),
5.40 (d, J = 9.5 Hz, 1 H, NH).
Anal. Calcd for C23H35NO4 (389.5): C, 70.92; H, 9.06; N, 3.60.
Found: C, 70.86; H, 9.07; N, 3.71.
13C NMR (CDCl3, 75.5 MHz): d = 16.1, 21.0, 22.1, 26.1, 27.7 (5 q,
5 × CH3), 23.1 (t, C-3¢), 25.0 (d, CHMe2), 31.7 (d, C-5¢), 34.2 (t, C-
4¢), 43.5 (t, C-6¢), 48.6 (d, C-2¢), 59.7 (q, JC,F = 29 Hz, C-3), 70.0,
75.5, 82.7 (3 d, C-4, C-5, C-1¢), 105.4 (d, C-6), 111.2 (s, CMe2),
122.9 (q, JC,F = 281 Hz, CF3).
(3R,4S,5S,6S)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-
oxy]-4,5-isopropylidene-3-phenyl-3,4,5,6-tetrahydro-2H-1,2-
oxazine [(6S)-18]
According to general procedure 1, 1,2-oxazine (6S)-16 (0.194 g,
0.50 mmol) was treated with BH3·THF (2.0 mL, 2.00 mmol) in THF
(5 mL). Workup and purification using column chromatography
(alumina, hexane–EtOAc, 6:1) afforded (6S)-18 (0.130 g, 71%; de
>94%) as a colorless resin; [a]D –55.4 (c = 0.57, CHCl3).
Anal. Calcd for C18H30F3NO4 (381.4): C, 56.68; H, 7.93; N, 3.67.
Found: C, 56.83; H, 8.10; N, 3.48.
Hydrogenolysis of (6R)-18
Following the procedure for the hydrogenolysis of rac-4a, 1,2-ox-
azine (6R)-18 (0.097 g, 0.25 mmol) was treated with H2 and 10%
Pd/C (0.025 g) in MeOH (2.5 mL). Removal of (–)-menthol (9) by
Kugelrohr distillation (110 °C/0.01 mbar) and purification of the
residue by column chromatography (alumina, hexane–EtOAc, 1:2)
provided (2S,3R,4S)-5 (0.018 g, 37%, de, ee >94%) as colorless
crystals; mp 49–53 °C; [a]D +138 (c = 0.21, CHCl3).
IR (KBr): 3450 (N–H), 2960–2870 cm–1 (=C–H, C–H).
1H NMR (CDCl3, 300 MHz): d = 0.75–1.70 (m, 22 H, 3-H, 4¢-H, 5¢-
H, 6¢-H, 5 × CH3), 2.12–2.21, 2.38 (m, mc, 1 H each, 2¢-H, CHMe2),
3.45 (dt, J = 4.5, 10.5 Hz, 1 H, 1¢-H), 4.01 (dd, J = 5, 7 Hz, 1 H, 5-
H), 4.43–4.49 (m, 2 H, 3-H, 4-H), 4.82 (d, J = 7 Hz, 1 H, 6-H), 5.45
(br s, 1 H, NH), 7.28–7.38, 7.42–7.50 (2 m, 3 H, 2 H, C6H5).
13C NMR (CDCl3, 75.5 MHz): d = 16.1, 21.1, 23.1, 26.3, 28.1 (5 q,
5 × CH3), 23.1 (t, C-3¢), 24.8 (d, CHMe2), 31.8 (d, C-5¢), 34.3 (t, C-
4¢), 43.8 (t, C-6¢), 48.7 (d, C-2¢), 62.7 (d, C-1¢), 75.5, 76.3, 82.5 (3 d,
C-3, C-4, C-5), 105.6 (d, C-6), 110.1 (s, CMe2), 128.2, 128.3, 128.6,
135.4 (3 d, s, C6H5).
Hydrogenolysis of (6S)-18
Following the procedure for the hydrogenolysis of rac-4a, 1,2-ox-
azine (6S)-18 (0.077 g, 0.20 mmol) was treated with H2 and 10%
Pd/C (0.020 g) in MeOH (2 mL). Removal of (–)-menthol (9) by
Kugelrohr distillation (110 °C/0.01 mbar) and purification by col-
umn chromatography (alumina, hexane–EtOAc, 1:2) provided
(2R,3S,4R)-5 (0.021 g, 51%, de, ee >94%) as colorless crystals; mp
50–54 °C; [a]D –130 (c = 0.30, CHCl3).
Anal. Calcd for C23H35NO4 (389.5): C, 70.92; H, 9.06; N, 3.60.
Found: C, 71.23; H, 9.43; N, 3.42.
Synthesis 2007, No. 17, 2681–2689 © Thieme Stuttgart · New York

PAPER
Reductive Ring Contraction of 1,2-Oxazines to Pyrrolidines
2689
(11) Lee, H. W. Bull. Korean Chem. Soc. 1996, 17, 1106.
Acknowledgment
(12) (a) Hippeli, C.; Reissig, H.-U. Liebigs Ann. Chem. 1990,
475. (b) Arnold, T.; Orschel, B.; Reissig, H.-U. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1033; Angew. Chem. 1992,
104, 1084.
(13) The hydrogenation of ethoxycarbonyl-substituted rac-4 was
carried out in EtOH as solvent. The reaction in MeOH led to
transesterification: see ref. 6a.
Generous support by the Deutsche Forschungsgemeinschaft (Gra-
duiertenkolleg ‘Struktur-Eigenschafts-Beziehungen bei Heterocyc-
len’), the Fonds der Chemischen Industrie, and the Schering AG is
most gratefully acknowledged. We also thank Dr. Robert Pulz for
experimental assistance.
(14) Zimmer, R.; Hoffmann, M.; Reissig, H.-U. Chem. Ber. 1992,
125, 2243.
References
(15) Some selected publications: (a) Jäger, V.; Grund, H.; Buss,
V.; Schwab, W.; Müller, I.; Schohe, R.; Franz, R.; Ehrler, R.
Bull. Soc. Chim. Belg. 1983, 92, 1039. (b) Curran, D. P. J.
Am. Chem. Soc. 1983, 105, 5826. (c) Itsuno, S.; Nakano,
M.; Miyazaki, K.; Masuda, H.; Ito, K. J. Chem. Soc., Perkin
Trans. 1 1985, 2039. (d) Itsuno, S.; Sakurai, Y.; Ito, K.;
Hirao, A.; Nakahama, S. Bull. Chem. Soc. Jpn. 1987, 60,
395. (e) Ghosh, A. K.; McKee, S. P.; Sanders, W. M.
Tetrahedron Lett. 1991, 32, 711.
(1) Reviews: (a) Gilchrist, T. L. Chem. Soc. Rev. 1983, 12, 53.
(b) Tsoungas, P. G. Heterocycles 2002, 57, 915.
(c) Tsoungas, P. G. Heterocycles 2002, 57, 1149.
(d) Reissig, H.-U.; Zimmer, R. Science of Synthesis, Vol. 33;
Molander, G. A., Ed.; Thieme: Stuttgart, 2006, 371.
(2) (a) Homann, K.; Angermann, J.; Collas, M.; Zimmer, R.;
Reissig, H.-U. J. Prakt. Chem. 1998, 340, 649. (b) Zimmer,
R.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1988, 27,
1518; Angew. Chem. 1988, 100, 1576. (c) Chiral 6H-1,2-
oxazines: Zimmer, R.; Orschel, B.; Scherer, S.; Reissig,
H.-U. Synthesis 2002, 1553.
(16) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
Soc. 1971, 93, 2897.
(17) (a) Zimmer, R.; Arnold, T.; Homann, K.; Reissig, H.-U.
Synthesis 1994, 1050. (b) Humphrey, A. J.; Parsons, S. F.;
Smith, M. E. B.; Turner, N. J. Tetrahedron Lett. 2000, 41,
4481. (c) Gallos, J. K.; Sarli, V. C.; Massen, Z. S.; Varvogli,
A. C.; Papadoyanni, C. Z.; Papaspyrou, S. D.; Argyropoulos,
N. G. Tetrahedron 2005, 61, 565.
(18) It should be noted that the reduction of the corresponding
3-trifluoromethyl-substituted 1,2-oxazine rac-4c with
NaBH3CN failed. This may be due to the electron-
withdrawing ability of the trifluoromethyl group which
prevents protonation of the C=N unit.
(19) (a) Burton, J. W.; Son, J. C.; Fairbanks, A. J.; Choi, S. S.;
Taylor, H.; Watkin, D. J.; Winchester, B. G.; Fleet, G. W. J.
Tetrahedron Lett. 1993, 34, 6119. (b) Brandstetter, T. W.;
de la Fuente, C.; Kim, Y.-H.; Johanson, L. N.; Crook, S.; de
Q. Lilley, P. M.; Watkin, D. J.; Tsitsanou, K. E.; Zographos,
S. E.; Chrysina, E. D.; Oikonomakos, N. G.; Fleet, G. W. J.
Tetrahedron 1996, 52, 10721. (c) Estevez, J. C.; Smith, M.
D.; Lane, A. L.; Crook, S.; Watkin, D. J.; Besra, G. S.;
Brennan, P. J.; Nash, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 1996, 7, 387. (d) Gasch, C.; Salameh, B. A. B.;
Pradera, M. A.; Fuentes, J. Tetrahedron Lett. 2001, 42,
8615. (e) Fuentes, J.; Salameh, B. A. B.; Pradera, M. A.; de
Córdoba, F. J. F.; Gasch, C. Tetrahedron 2006, 62, 97.
(20) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett.
1995, 36, 1653.
(21) Zimmer, R.; Reissig, H.-U. J. Org. Chem. 1992, 57, 339.
(22) Hiller, F. Ph.D. Thesis; Technische Universität Dresden:
Germany, 1997.
(23) Jaenicke-Roessler, U.; Zahn, G.; Hiller, F.; Reissig, H.-U. Z.
Kristallogr. NCS 1998, 213, 261.
(24) (a) Iminosugars as Glycosidase Inhibitors; Stütz, A. E., Ed.;
Wiley-VCH: Weinheim, 1999. (b) Håkansson, A. E.; van
Ameijide, J.; Guglielmini, L.; Horne, G.; Nash, R. J.;
Evinson, E. L.; Kato, A.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2007, 18, 282; and references cited therein.
(25) Lau, K. S.; Schlosser, M. J. Org. Chem. 1978, 43, 1595.
(3) For transformations of 6H-1,2-oxazines via azapyrylium
intermediates, see: Zimmer, R.; Reissig, H.-U.; Homann, K.
J. Prakt. Chem. 1995, 337, 521.
(4) (a) Zimmer, R.; Hiller, F.; Reissig, H.-U. Heterocycles 1999,
50, 393. (b) Buchholz, M.; Reissig, H.-U. Synthesis 2002,
1412. (c) Buchholz, M.; Hiller, F.; Reissig, H.-U. Eur. J.
Org. Chem. 2002, 2838. (d) Buchholz, M.; Reissig, H.-U.
Eur. J. Org. Chem. 2003, 3524.
(5) (a) Zimmer, R.; Angermann, J.; Hain, U.; Hiller, F.; Reissig,
H.-U. Synthesis 1997, 1467. (b) Zimmer, R.; Homann, K.;
Angermann, J.; Reissig, H.-U. Synthesis 1999, 1223.
(6) (a) Homann, K. Ph.D. Thesis; Technische Hochschule
Darmstadt: Germany, 1994. (b) Angermann, J. Ph.D.
Thesis; Technische Universität Dresden: Germany, 1997.
(c) Collas, M. Ph.D. Thesis; Technische Universität
Dresden: Germany, 1999.
(7) Schmidt, E.; Reissig, H.-U.; Zimmer, R. Synthesis 2006,
2074.
(8) (a) Chrystal, E. J. T.; Gilchrist, T. L.; Stretch, W. J. Chem.
Res., Synop. 1987, 180. (b) Ellames, G. J.; Hewkin, C. T.;
Jackson, R. F. W.; Smith, D. I.; Standen, S. P. Tetrahedron
Lett. 1989, 30, 3471. (c) Hippeli, C.; Zimmer, R.; Reissig,
H.-U. Liebigs Ann. Chem. 1990, 469. (d) Reissig, H.-U.;
Hippeli, C.; Arnold, T. Chem. Ber. 1990, 123, 2403.
(e) Nakanishi, S.; Otsuji, Y.; Itoh, K.; Hayashi, N. Bull.
Chem. Soc. Jpn. 1990, 63, 3595. (f) Zimmer, R.; Collas, M.;
Roth, M.; Reissig, H.-U. Liebigs Ann. Chem. 1992, 709.
(9) (a) Henning, R.; Lerch, U.; Urbach, H. Synthesis 1989, 265.
(b) Angermann, J.; Homann, K.; Reissig, H.-U.; Zimmer, R.
Synlett 1995, 1014. (c) Paulini, K.; Gerold, A.; Reissig,
H.-U. Liebigs Ann. Chem. 1995, 667. (d) Sifferlen, T.;
Defoin, A.; Streith, J.; Le Nouën, D.; Tarnus, C.; Dosbaâ, I.;
Foglietti, M.-J. Tetrahedron 2000, 56, 971.
(10) Reviews: (a) Streith, J.; Defoin, A. Synthesis 1994, 1107.
(b) Streith, J.; Defoin, A. Synlett 1996, 189. (c) Hultin, P.
G.; Earle, M. A.; Sudharshan, M. Tetrahedron 1997, 53,
14823.
Synthesis 2007, No. 17, 2681–2689 © Thieme Stuttgart · New York