Unusual enantiopure heterocyclic skeletons by Lewis acid promoted rearrangements of 1,3-dioxolanyl-substituted 1,2-oxazines

Article abstract of DOI:10.1002/ejoc.200800870

Lewis acid promoted rearrangements of different 4-alkoxy-substituted 1,2-oxazines syn-1 are reported. Depending on the nature of this alkoxy group different reaction pathways are possible either providing bicyclic 1,2-oxazinones 2 or the novel tricyclic p

Full text of DOI:10.1002/ejoc.200800870

FULL PAPER
DOI: 10.1002/ejoc.200800870
Unusual Enantiopure Heterocyclic Skeletons by Lewis Acid Promoted
Rearrangements of 1,3-Dioxolanyl-Substituted 1,2-Oxazines
Fabian Pfrengle,[a] Ahmed Al-Harrasi,[a] Irene Brüdgam,[a][‡] and Hans-Ulrich Reißig*[a]
Keywords: Heterocycles / 1,2-Oxazines / Reduction / Furans / Hydrogenation / 1,2-Alkyl shift
Lewis acid promoted rearrangements of different 4-alkoxy-
substituted 1,2-oxazines syn-1 are reported. Depending on
the nature of this alkoxy group different reaction pathways
are possible either providing bicyclic 1,2-oxazinones 2 or the
novel tricyclic products 3–5. A mechanistic rational describ-
ing the role of the 4-alkoxy group is presented. The key step
for formation of tricyclic skeletons 3–5 is a 1,2-alkyl shift. Hy-
drogenation reactions of these tricyclic compounds gave un-
saturated 1,2-oxazines 12 and 13 or tetrahydrofurans 15a–c/
16a–c depending on the time of hydrogenolysis. Tetra-
hydrofuryl-annulated 1,2-oxazine 12 was used for further
transformations into complex substituted tetrahydrofurans.
Reduction with sodium cyanoborohydride and subsequent
cleavage of the N,O-bond by hydrogenation furnished ami-
nofuran derivative 19. Alternatively treatment with a strong
base such as n-butyllithium afforded imidoester 21 via a
Beckmann-type fragmentation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Enantiomerically pure 3,6-dihydro-2H-1,2-oxazines C
are easily accessible via stereocontrolled addition of lithi-
ated alkoxyallenes A to carbohydrate-derived nitrones B
and spontaneous cyclization of the primary allene adducts
(Scheme 1).[1]
Scheme 2. Approach to enantiopure carbohydrate mimetics F via
E by Lewis acid promoted rearrangement of 1,2-oxazines D.
In this report we want to disclose our investigations
towards the Lewis acid promoted rearrangement of related
1,2-oxazines with other 4-alkoxy substituents leading to un-
expected products with tricyclic skeleton and their subse-
quent transformations into new enantiopure heterocycles.[5]
Scheme 1. Synthesis of 3,6-dihydro-2H-1,2-oxazines C from lithi-
ated alkoxyallenes A and nitrones B.
The resulting 1,2-oxazines C have been employed for the
stereoselective synthesis of a variety of highly function-
alized compounds such as polyhydroxylated pyrrolidines
and azetidines, aminopolyols or new carbohydrate deriva-
Results and Discussion
1,3-Dioxolanyl-substituted 1,2-oxazines syn-1 and anti-1
tives.[2] In addition, we recently reported on the Lewis acid with different 4-alkoxy substituents were prepared in a
promoted rearrangement of 4-[2-(trimethylsilyl)ethoxy]- stereodivergent manner by [3+3]-cyclization of lithiated
substituted 1,2-oxazines D into bicyclic compounds E alkoxyallenes and -glycerinaldehyde-derived nitrones.[1b]
which can be further transformed into enantiopure highly When 4-(p-methoxybenzyloxy)-substituted 1,2-oxazine syn-
substituted aminopyrans F (Scheme 2).[3] These carbo- 1a was exposed to tin tetrachloride the expected bicyclic
hydrate mimetics were already converted into uncommon product 2 of type E was obtained in 58% yield[6] whereas
amino acids and conjugates of carbohydrate mimetics.[4]
4-methoxy, 4-benzyloxy, and 4-tBuCH2CH2O groups (syn-
1b–d) led to formation of unexpected products 3–5 with
three annulated heterocycles in reasonable yields
(Scheme 3).
The differing reaction pathways leading to compounds 2
and 3–5 can be rationalized by the following mechanisms
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
[‡] Responsible for X-ray analyses.
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Unusual Enantiopure Heterocyclic Skeletons
Scheme 3. Lewis acid promoted rearrangements of syn-1 with dif-
ferent 4-alkoxy substituents. Reagents and conditions: a) SnCl4,
MeCN, –30 °C to room temp., 6–9 h.
(Scheme 4). Coordination of the Lewis acid to the easier
accessible oxygen of the acetonide in syn-1 leads to ring
opening and formation of a stabilized carbenium ion 6.
This electrophilic species attacks the enol ether moiety sim-
ilar to an aldol or Prins-type reaction to form key interme-
diate 7. The fate of this intermediate strongly depends on
the propensity of group R to undergo a fragmentation. The
TMSE and the PMB group can undergo fast fragmentation
into ethylene and a TMSX species or into the p-meth-
oxybenzyl-cation and thus formation of product 2 is
smoothly achieved. Simple alkyl substituents do not
smoothly undergo a similar fragmentation and therefore
competing pathways are important. The heterocyclic skel-
eton rearranges via a 1,2-alkyl-shift under retention of con-
figuration delivering the more stable carbenium ion 8 which
is stabilized by the nitrogen. A subsequent reaction with the
oxygen of the side chain generates the N,O-acetal and fi-
nally compounds 3–5. The different behaviour of benzyl-
and PMB-substituted 1,2-oxazines syn-1a and syn-1c is
quite remarkably which leads either to compound 2 or to
product 4.
Scheme 4. Proposed reaction pathways leading to rearrangement
products 2 or 3–5 via carbenium ions 6 and 7.
The Lewis acid induced reaction of 4-methoxy-substi-
tuted 1,2-oxazine anti-1 did not lead to similar products.
Instead, the new tricyclic compound 9 was formed in mod-
erate yield. This product can be regarded as an internally
protected form of 1,2-oxazinone derivative 10. Treatment of
9 with 2  HCl actually furnished 10 which was already
Figure 1. X-ray crystal structure of compound 9.[8]
Since rearrangement products 3–5 are surprisingly stable
obtained by the Lewis acid promoted rearrangement of 4- to strong acidic conditions[9] subsequent transformations
TMSEO-substituted 1,2-oxazine anti-1.[3] Alternatively, the were conducted by reductive methods such as hydrogena-
N,O-bond of 9 was cleaved with SmI2 leading to bicyclic tions. We previously reported that debenzylation and N,O-
compound 11 in good yield.[7] The constitution of tricyclic bond cleavage of 2-N-benzyl protected 1,2-oxazines can be
compound 9 was proven by X-ray crystal structure (Fig- induced depending on the time of hydrogenolysis.[10] When
ure 1). Its formation should occur via an intermediate tricyclic compounds 3 and 4 were subjected to hydro-
(Scheme 5) where the cationic centre and Lewis acid coordi- genolytic conditions for 1–1.5 h we observed N-deben-
nated oxygen are sufficiently close to create the new five- zylation and subsequent ring opening of the N,O-acetal
membered ring acetal. In contrast, the diastereomeric inter- moiety leading to unsaturated 1,2-oxazines 12 and 13
mediate 7 of the syn-series does not allow this cyclization (Scheme 6). Acetylation of 12 allowed an X-ray crystal
for simple geometric reasons. Therefore, the discussed 1,2- structure of the resulting 1,2-oxazine 14 (Figure 2). This
shift is the alternative pathway (Scheme 4).
was not only an unambiguous proof of the constitution and
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F. Pfrengle, A. Al-Harrasi, I. Brüdgam, H.-U. Reißig
FULL PAPER
Scheme 6. Short period hydrogenolysis of rearrangement products
3 and 4 leading to compounds 12 and 13. Reagents and conditions:
a) H2, Pd/C, MeOH, room temp., 1–1.5 h; b) Ac2O, pyridine, room
temp., 8 h.
Scheme 5. Lewis acid promoted rearrangements of anti-1 leading
to tricyclic 1,2-oxazine derivative 9 or 1,2-oxazinone 10. Reagents
and conditions: a) SnCl4, MeCN, –30 °C to room temp., 6 h; b) 2
 HCl/dioxane, room temp., 24 h; c) SmI2, THF, room temp., 3 h.
Figure 2. X-ray crystal structure of compound 14.[8]
mary alcohol moieties and one imine unit which can un-
dergo cyclization forming the two regioisomeric N,O-acetals
configuration of 14 but also of its precursor 3. This result 15 or 16.
demonstrates that the 1,2-alkyl shift from intermediate 7 to
8 occurs under retention of configuration (Scheme 4).
When substrate 3 was subjected to typical hydrogenation
conditions for 17 h the respective tetrahydrofuryl-annulated
Hydrogenolysis of compounds 3 and 4 for a longer tetrahydrofurans 15a and 16a were obtained in a ratio of
period of time (17–18 h) furnished the two isomeric tetra- 4:1 (Table 1, entry 1).[11] Out of this mixture pure 15a could
hydrofurans 15 and 16 in moderate to good yields be crystallized giving suitable crystals for an X-ray analysis
(Scheme 7). Here debenzylation and subsequent ring open- (Figure 3). When these crystals were dissolved in chloro-
ing to 1,2-oxazines 12 or 13 is followed by an N,O-bond form the mixture of 15a and 16a was regenerated in the
cleavage. This should provide intermediate 17 with two pri- previously determined ratio. This clearly demonstrates that
Scheme 7. Reductive transformations of rearrangement products 3 and 4 leading to N,O-acetals 15 and 16.
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Unusual Enantiopure Heterocyclic Skeletons
the two isomeric forms are in equilibrium. The same hydro-
genation reaction with in situ Boc protection furnished
analogous products 15b and 16b in a ratio of 7:1 (entry
2). Hydrogenolysis of O-benzyl-substituted 4 for 18 h led in
addition to O-debenzylation giving 15c and 16c in a ratio
of 9:1 after in situ Boc protection (entry 3). The N,O-bond
cleavage can alternatively be conducted by reduction with
SmI2 which does not touch the N-benzyl group. This results
in the formation of products 15d and 16d in a ratio of 4:1
(entry 4).
Scheme 8. Synthesis of tetrahydrofuran derivative 19. Reagents and
conditions: a) Na(CN)BH3, AcOH, room temp., 27 h; b) H2, Pd/
C, Boc2O, MeOH, room temp., 18 h.
In general, reductive methods such as catalytic hydrogen-
ation, SmI2 or Mo(CO)6 treatment and zinc in acetic acid[13]
are used for the cleavage of N,O-bonds. However, alterna-
tive methods have also been explored. Recently we reported
the N,O-bond cleavage of 1,2-oxazines by MeOTf and base
in an internal redox process.[14] Furthermore, oximes and
oxime ethers can be treated by base to give the respective
nitriles, a transformation which is known as Beckmann
fragmentation.[15] A similar reaction was observed when
1,2-oxazine 20 (obtained by TBS protection of 12) was
treated with a strong base (Scheme 9). Two equivalents of
nBuLi were added to compound 20 giving imido ester 21 in
50% yield and by-product 22 in 12% yield.
Table 1. Reductive transformations of products 3 and 4 leading to
isomeric tetrahydrofurans 15 and 16 after N,O-bond cleavage.
Entry Substrate Conditions
Product
R
Ratio
15/16
Yield
RЈ
H2, Pd/C,
Me
H
1
2
3
3
MeOH, 17 h, 15a/16a
room temp.
4:1
7:1
77%
H2, Pd/C,
Boc2O,
Me
15b/16b
Boc
82%
63 %
MeOH, 18 h,
room temp.
H2, Pd/C,
Boc2O,
3
4
4
3
H
Boc
Bn
9:1
4:1
MeOH, 18 h, 15c/16c
room temp.
SmI2, THF,
6 h, room
temp.
Me
15d/16d
43%
Scheme 9. Base-induced cleavage of the N,O-bond of compound 20
leading to 21 and 22. Reagents and conditions: a) TBSOTf, NEt3,
CH2Cl2, room temp., 8 h; b) nBuLi, THF, –40 °C to room temp.,
5 h.
We propose that nBuLi acts as a base and abstracts a
proton at the oxime ether moiety leading to a Beckmann-
type fragmentation. This should lead to a nitrile group
which is attacked by the remaining alkoxide to give imido
ester 21 after subsequent hydrolysis. The reaction pathway
to by-product 22 is so far not certain. However, nBuLi cer-
tainly acts as a nucleophile and either attacks the nitrile or
Figure 3. X-ray crystal structure of compound 15a.[8]
Tetrahydrofuryl-annulated 1,2-oxazines 12–14 are ideal the imido ester moiety at the appropriate stage. The config-
precursors for further conversions into new substituted uration of compound 22 was not proven, but we assume
tetrahydrofuran derivatives. This is demonstrated by the that the nucleophile attacks from the sterically less hindered
synthesis of tetrahydrofuran derivative 19 (Scheme 8). Re- convex site of the precursor.
duction of 14 with sodium cyanoborohydride afforded satu-
In order to further functionalize the N,O-acetals 15a/16a
rated 1,2-oxazine 18, which was still coordinated to we planned to introduce leaving groups such as tosylate.
BH2(CN) after chromatographic purification. Subsequent Unexpectedly, treatment of 15a/16a with 2.5 equiv. of tosyl
hydrogenolytic cleavage of the N,O-bond gave the hexasub- chloride furnished compound 23, which contains three an-
stituted furan derivative 19 in 68% yield. As expected the nulated five-membered rings and is therefore a derivative of
coordinated boron species was removed in this step. Com- 3,6-dioxa-1-azacyclopenta[cd]pentalene (Scheme 10).
pounds like 19 could be interesting as novel furanose mi-
To rationalize this result we assume that tosylations of
the hydroxyl and amino groups of 15a occur in the first
metics.[12]
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F. Pfrengle, A. Al-Harrasi, I. Brüdgam, H.-U. Reißig
FULL PAPER
to literature procedures. Reagents were purchased and were used
as received without further purification unless otherwise stated.
Unless otherwise stated, products were purified by flash
chromatography on silica gel (230–400 mesh, Merck or Fluka) or
HPLC (Nucleosil 50–5). Unless otherwise stated, yields refer to
analytical pure samples. NMR spectra were recorded on Bruker
(AC 500) and JEOL (Eclipse 500) instruments. Chemical shifts are
reported relative to TMS (1H: δ = 0.00 ppm), CDCl3 (13C: δ =
77.0 ppm), or CD3OD (1H: δ = 3.31 ppm, 13C: δ = 49.0 ppm). Inte-
grals are in accordance with assignments; coupling constants are
given in Hz. All 13C-NMR spectra were proton-decoupled. For de-
tailed peak assignments 2D spectra were measured (COSY, HMBC
Scheme 10. Synthesis of tricyclic compound 23. Reagents and con-
ditions: a) pTsCl, DMAP, Et3N, room temp., 19 h.
steps (Scheme 11). The resulting bistosylated species 24
could be isolated in another experiment. In order to allow
cyclization to 23 the configuration at the N,O-acetal centre and HMQC). IR spectra were measured with an FT-IRD spec-
trometer Nicolet 5 SXC. MS and HRMS analyses were performed
with Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT CH7A (ESI-FT
ICRMS) and Agilent 6210 (ESI-TOF) instruments. Elemental
analyses were carried out with CHN-Analyzer 2400 (Perkin–El-
mer). Melting points were measured with a Reichert apparatus
Thermovar and are uncorrected. Single-crystal X-ray data were col-
lected on a Bruker-XPS diffractometer (CCD area detector, Mo-
Kα radiation, λ = 0.71073 Å, graphite monochromator), empirical
absorption correction using symmetry-equivalent reflections (SAD-
ABS), structure solution and refinement by SHELXS-97 and
SHELXL97 in the WINGX System.[19,20] The hydrogen atoms were
located by difference Fourier syntheses.
has to be changed. We propose that this happens via depro-
tonation of the tosylated amino group leading to imine 26
which is in equilibrium with 25 and its C-6 epimer. If the
tosylated amino group is finally correctly oriented, cycliza-
tion to 23 smoothly is feasible.
(3S,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Јyl)-4-(4-meth-
oxybenzyloxy)-3,6-dihydro-2H-1,2-oxazine (syn-1a): To a solution
of (p-methoxybenzyl)oxyallene (300 mg, 1.70 mmol) in THF
(3 mL) was added nBuLi (1.6  in hexane, 1.10 mL, 1.70 mmol) at
–40 °C. After 5 min the resulting solution was cooled to –78 °C and
a solution of (Z)-N-(1-deoxy-2,3-isopropylidene--glycero-1-ylid-
ene)benzylamine N-oxide (200 mg, 0.850 mmol) in THF (1 mL)
was added dropwise over a period of 5 min. After stirring the reac-
tion mixture for 2 h at –78 °C water (10 mL) was added and the
mixture was allowed to come to room temp. Et2O was added, the
phases were separated and the aqueous phase was extracted 3 times
with Et2O. The combined organic phases were dried (Na2SO4) and
the solvent was removed in vacuo. Purification by column
chromatography (silica gel, hexane/EtOAc, 6:1) yielded syn-1a
(210 mg, 60%) as colourless crystals; m.p. 55–56 °C. [α]2D2 = +36.2
(c = 0.80, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 1.34, 1.41 (2s,
3 H each, Me), 3.35 (d, J = 7.6 Hz, 1 H, 3-H), 3.81 (s, 3 H, OMe),
3.93 (mc, 2 H, 5Ј-H), 4.17 (s, 2 H, NCH2), 4.18 (dd, J = 3.5,
14.5 Hz, 1 H, 6-H), 4.44 (dt, J = 1.8, 14.5 Hz, 1 H, 6-H), 4.60 (dt,
J = 6.5, 7.6 Hz, 1 H, 4Ј-H), 4.65, 4.72 (AB system, JAB = 10.8 Hz,
2 H, OCH2), 4.87 (dd, J = 1.8, 3.5 Hz, 1 H, 5-H), 6.90 (mc, 2 H,
Ar), 7.24–7.34 (m, 5 H, Ph), 7.44 (mc, 2 H, Ar) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 26.2, 26.6 (2q, Me), 55.2 (q, OMe), 58.2
Scheme 11. Proposed reaction pathway for the conversion of 15a
into tricyclic compound 23.
Conclusions
In summary, a range of new enantiopure heterocyclic
products was synthesized. High molecular complexity is
created from simple molecules via a Lewis acid promoted
rearrangement of readily available 1,3-dioxolanyl-substi-
tuted 1,2-oxazines. The resulting tricyclic products 3–5 are
good starting points for further transformations. Hydrogen-
ation reactions furnished new 5,6-dihydro-4H-1,2-oxazines
12 and 13 or bicyclic tetrahydrofurans 15/16. These easily
accessible intermediates could be converted into interesting (t, NCH2), 63.5 (d, C-3), 64.4 (t, C-6), 67.0 (t, C-5Ј), 69.0 (t, OCH2),
74.9 (d, C-4Ј), 93.9 (d, C-5), 108.6 (d, Ar), 127.0, 128.1, 128.4,
128.7, 129.3 (3d, 2s, Ph, Ar), 128.7 (d, Ar), 150.6 (s, C-4), 159.5 (s,
compounds such as the tricyclic compound 23 with three
annulated five-membered rings or tetrahydrofuran 19. The
rapid and stereocontrolled accessibility of all these new
enantiopure heterocycles again demonstrates the great syn-
thetic versatility of 1,2-oxazines derivatives.[16]
Ar) ppm. IR (KBr): ν = 3100–3000 (=C–H), 3000–2800 (C–H),
˜
1670 (C=C) cm–1. C24H29NO5 (411.5): calcd. C 70.05, H 7.10, N
3.40; found C 69.91, H 7.08, N 3.45.
Typical Procedure for the SnCl4-Induced Rearrangement of 1,2-Ox-
azines (Method A): To a solution of 1,2-oxazine (1 equiv.) in MeCN
(8 mL/mmol of 1,2-oxazine) is added SnCl4 (3 equiv.) at –30 °C and
the resulting solution is stirred until reaching 0 °C (3 h). After fur-
ther stirring (time is given in the individual procedure) the mixture
is quenched by water (16 mL/mmol of 1,2-oxazine). Addition of
Experimental Section
General Methods: Reactions were generally performed under argon
in flame-dried flasks. Solvents and reagents were added by syringes.
Solvents were dried using standard procedures. Starting materials CH2Cl2 is followed by separation of the phases and the aqueous
(p-methoxybenzyl)oxyallene,[17]
glyceraldehyde nitrone[18] and syn-1b–d[1b] were prepared according
N-benzyl-2,3-isopropylidene--
phase was extracted 3 times with CH2Cl2. The combined organic
phases were dried (Na2SO4) and the solvent was removed in vacuo.
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Unusual Enantiopure Heterocyclic Skeletons
(1S,5R,8S)-2-Benzyl-8-(hydroxymethyl)-6,6-dimethyl-3,7-dioxa-2-aza- dried (Na2SO4) and the solvent was removed in vacuo. Purification
bicyclo[3.3.1]nonan-9-one (2):[3] A solution of 1,2-oxazine syn-1a
(100 mg, 0.24 mmol) in MeCN (2 mL) was treated with SnCl4
(91 µL, 0.72 mmol) according to method A and the resulting solu-
tion was stirred for further 6 h at room temp. after reaching 0 °C.
Purification by column chromatography (silica gel, hexane/EtOAc,
1:1) yielded 2 (40 mg, 58%) as colourless oil.
by column chromatography (silica gel, hexane/EtOAc, 8:1) yielded
5 (137 mg, 69%) as colourless oil. [α]2D2 = +12.6 (c = 0.32, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 0.90 (s, 9 H, tBu), 1.35, 1.40 (2s,
3 H each, Me), 1.48 (mc, 1 H, CH2), 1.50 (mc, 1 H, CH2), 2.15 (dd,
J = 1.2, 5.3 Hz, 1 H, 4a-H), 3.54 (mc, 1 H, CH2O), 3.68 (mc, 1 H,
CH2O), 3.90 (mc, 1 H, 2-H), 3.91 (mc, 1 H, 2-H), 3.97–4.01 (m, 1
H, 5-H), 4.02 (d, J = 13.9 Hz, 1 H, NCH2), 4.10 (dd, J = 5.3,
12.5 Hz, 1 H, 5-H), 4.22 (d, J = 13.9 Hz, 1 H, NCH2), 4.46 (s, 1
H, 7a-H), 4.47 (dd, J = 1.2, 4.6 Hz, 1 H, 2a-H), 7.25–7.39 (m, 5
H, Ph) ppm. 13C NMR (CDCl3, 125 MHz): δ = 24.4, 30.1 (2q,
Me), 29.7 (q, tBu), 43.7 (t, CH2), 48.7 (d, C-4a), 57.5 (t, NCH2),
62.5 (t, CH2O), 67.3 (t, C-5), 70.9 (t, C-2), 85.5 (d, C-2a), 85.9 (s,
C-4), 90.1 (s, C-7b), 93.3 (d, C-7a), 127.1, 128.2, 128.5, 137.1 (3d,
(2aR,4aR,7aS,7bS)-7-Benzyl-7b-methoxy-4,4-dimethylhexahydro-
2H,4H-1,3,6-trioxa-7-azacyclopenta[cd]indene (3): A solution of
1,2-oxazine syn-1b (650 mg, 2.13 mmol) in MeCN (18 mL) was
treated with SnCl4 (780 µL, 6.39 mmol) according to method A
and the resulting solution was stirred for further 5 h at room temp.
after reaching 0 °C. Purification by column chromatography (silica
gel, hexane/EtOAc, 2:1) yielded 3 (440 mg, 68%) as colourless oil.
s, Ph) ppm. IR (film): ν = 3085–3030 (=C–H), 2955–2865 (C–H)
˜
1
[α]2D2 = +4.8 (c = 0.42, CHCl3). H NMR (CDCl3, 500 MHz): δ =
cm–1. MS (EI, 80 eV, 150 °C): m/z (%) = 375 (33) [M+], 360 (5)
[M+ – Me], 244 (100), 91 (57) [C7H7+]. C22H33NO4 (375.5): calcd.
C 70.37, H 8.86, N 3.73; found C 70.11, H 8.81, N 3.50.
1.35, 1.41 (2s, 3 H each, Me), 2.15 (dd, J = 1.1, 5.1 Hz, 1 H, 4a-
H), 3.42 (s, 3 H, OMe), 3.85 (dd, J = 4.6, 10.4 Hz, 1 H, 2-H), 3.99
(dd, J = 1.1, 12.3 Hz, 1 H, 5-H), 4.00 (dd, J = 1.0, 10.4 Hz, 1 H,
2-H), 4.01 (d, J = 14.2 Hz, 1 H, NCH2), 4.08 (dd, J = 5.1, 12.3 Hz, (1S,4S,7R,8R)-9-Benzyl-7-methoxy-2,2-dimethyl-3,6,10-trioxa-9-aza-
1 H, 5-H), 4.22 (d, J = 14.2 Hz, 1 H, NCH2), 4.49 (dd, J = 1.0,
4.6 Hz, 1 H, 2a-H), 4.50 (s, 1 H, 7a-H), 7.24–7.40 (m, 5 H, Ph)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 24.6, 30.2 (2q, Me), 47.8
(d, C-4a), 52.9 (q, OMe), 57.6 (t, NCH2), 67.2 (t, C-5), 71.1 (t, C-
2), 84.8 (d, C-2a), 86.0, 90.5 (2s, C-4, C-7b), 93.4 (d, C-7a), 127.3,
tricyclo[5.4.0.04,8]undecane (9): A solution of 1,2-oxazine anti-1
(500 mg, 1.64 mmol) in MeCN (11 mL) was treated with SnCl4
(599 µL, 4.91 mmol) according to method A and the resulting solu-
tion was stirred for further 3 h at room temp. after reaching 0 °C.
Purification by column chromatography (silica gel, hexane/EtOAc,
2:1) yielded 9 (250 mg, 50 %) as colourless crystals; m.p. 148–
150 °C. [α]2D2 = +148.0 (c = 0.20, CHCl3). 1H NMR (CDCl3,
128.4, 128.6, 137.2 (3d, s, Ph) ppm. IR (film): ν = 3055–3030 (=C–
˜
H), 2970–2870 (C–H) cm–1. MS (EI, 80 eV, 150 °C): m/z (%) = 305
(44) [M+], 244 (100) [M+ – OMe – CH2O], 214 (3) [M+ – C7H7], 500 MHz): δ = 1.38, 1.54 (2s, 3 H each, Me), 1.69 (mc, 1 H, 1-H),
91 (C7H7+, 57). HRMS: calcd. for C17H23NO4 305.16272; found 3.07 (mc, 1 H, 8-H), 3.35 (s, 3 H, OMe), 3.79 (dd, J = 2.3, 9.5 Hz,
305.16366. C17H23NO4 (305.4): calcd. C 66.86, H 7.59, N 4.59;
found C 66.51, H 7.27, N 4.54.
1 H, 5-H), 3.89 (d, J = 9.5 Hz, 1 H, 5-H), 4.03 (d, J = 13.2 Hz, 1
H, NCH2), 4.05 (ddd, J = 1.1, 2.9, 12.0 Hz, 1 H, 11-H), 4.17 (dd,
J = 1.1, 12.0 Hz, 1 H, 11-H), 4.34 (d, J = 13.2 Hz, 1 H, NCH2),
4.64 (t, J = 2.3 Hz, 1 H, 4-H), 7.25–7.40 (m, 5 H, Ph) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 33.2, 34.4 (2q, Me), 49.5 (q, OMe),
52.7 (d, C-1), 62.2 (d, C-8), 63.5 (t, NCH2), 70.7 (t, C-11), 73.8 (t,
C-5), 77.0 (d, C-4), 81.4 (s, C-2), 106.6 (s, C-7), 131.3, 132.2, 132.5,
(2aR,4aR,7aS,7bS)-7-Benzyl-7b-benzyloxy-4,4-dimethylhexahydro-
2H,4H-1,3,6-trioxa-7-azacyclopenta[cd]indene (4): A solution of
1,2-oxazine syn-1c (890 mg, 2.33 mmol) in MeCN (19 mL) was
treated with SnCl4 (880 µL, 6.99 mmol) according to method A
and the resulting solution was stirred for further 6 h at room temp.
after reaching 0 °C. Purification by column chromatography (silica
gel, hexane/EtOAc, 4:1) yielded 4 (486 mg, 55%) as colourless oil.
140.5 (3d, s, Ph) ppm. IR (KBr): ν = 3055–3030 (=C–H), 2970–
˜
2870 (C–H) cm–1. MS (EI, 80 eV, 100 °C): m/z (%) = 305 (100)
[M+], 274 (20) [M+ OMe], 91 (62) [C7H7+]. C17H23NO4 (305.4):
calcd. C 66.86, H 7.59, N 4.59; found C 66.81, H 7.13, N 4.40.
[α]2D2 = +2.0 (c = 0.76, CHCl3). H NMR (CDCl3, 500 MHz): δ =
1
1.43, 1.47 (2s, 3 H each, Me), 2.31 (dd, J = 0.9, 5.2 Hz, 1 H, 4a-
H), 3.94 (dd, J = 4.5, 10.5 Hz, 1 H, 2-H), 4.07 (dd, J = 0.9, 12.4 Hz, (1R,5S,8S)-2-Benzyl-8-(hydroxymethyl)-6,6-dimethyl-3,7-dioxa-2-aza-
1 H, 5-H), 4.07 (d, J = 14.5 Hz, 1 H, NCH2), 4.08 (dd, J = 1.1,
bicyclo[3.3.1]nonan-9-one (10):[3] To a solution of tricyclic com-
10.5 Hz, 1 H, 2-H), 4.20 (dd, J = 5.2, 12.4 Hz, 1 H, 5-H), 4.31 (d, pound 9 (146 mg, 0.480 mmol) in 1,4-dioxane (5 mL) was added
J = 14.5 Hz, 1 H, NCH2), 4.64 (dd, J = 1.1, 4.5 Hz, 1 H, 2a-H), 2  HCl (5 mL). The mixture was stirred at room temp. for 16 h
4.67 (s, 1 H, 7a-H), 4.68 (d, J = 11.7 Hz, 1 H, OCH2), 4.80 (d, J and was subsequently neutralized with 2  NaOH (5 mL). After
= 11.7 Hz, 1 H, OCH2), 7.29–7.48 (m, 10 H, Ph) ppm. 13C NMR addition of CH2Cl2 the phases were separated und the aqueous
(CDCl3, 125 MHz): δ = 24.6, 30.3 (2q, Me), 49.1 (d, C-4a), 57.7 (t, phase was extracted 3 times with CH2Cl2. The combined organic
NCH2), 67.4 (t, C-5), 67.6 (t, OCH2), 71.1 (t, C-2), 85.8 (d, C-2a), phases were dried (Na2SO4) and the solvent was removed in vacuo.
86.2, 90.8 (2s, C-4, C-7b), 93.8 (d, C-7a), 127.3, 127.4, 127.9, 128.4,
Purification by column chromatography (silica gel, hexane/EtOAc,
128.6, 128.7, 137.3, 138.3 (6d, 2s, Ph) ppm. IR (film): ν = 3100– 1:1) yielded 10 (130 mg, 94%) as colourless crystals.
˜
3020 (=C–H), 2980–2850 (C–H) cm–1. MS (EI, 80 eV, 40 °C): m/z
(1S,4S,5R,8R)-(8-Benzylamino-5-methoxy-3,3-dimethyl-2,6-dioxa-
(%) = 381 (39) [M+], 290 (7) [M+ – C7H7], 287 (39), 244 (100),
bicyclo[3.2.1]octan-4-yl)methanol (11): 1,2-Diiodoethane (180 mg,
0.638 mmol) and samarium (105 mg, 0.710 mmol) were transferred
121 (81), 91 (89) [C7H7+], 78 (54). HRMS: calcd. for C23H27NO4
381.19401; found 381.19437. C23H27NO4 (381.5): calcd. C 72.42, H
into a dried flask. THF (8 mL) was added. After the solution
7.13, N 3.67; found C 72.52, H 7.69, N 3.81.
turned blue, the mixture was stirred for further 2 h. Tricyclic com-
(2aR,4aR,7aS,7bS)-7-Benzyl-7b-(3Ј,3Ј-dimethylbutoxy)-4,4-dimeth-
pound 9 (60 mg, 0.197 mmol) in THF (8 mL) was added and the
ylhexahydro-2H,4H-1,3,6-trioxa-7-azacyclopenta[cd]indene (5): A reaction mixture was stirred for 3 h. After addition of sat. NaHCO3
solution of 1,2-oxazine syn-1d (200 mg, 0.533 mmol) in MeCN
(4 mL) was treated with SnCl4 (196 µL, 1.60 mmol) at 0 °C and the
resulting solution was stirred for further 6 h at room temp. Then
the mixture is quenched by water (8 mL). Addition of CH2Cl2 is
followed by separation of the phases and the aqueous phase was
extracted 3 times with CH2Cl2. The combined organic phases were
solution (10 mL) the solution was decanted from the residue and
the solvent was removed in vacuo. Product 11 (47 mg, 79%) was
obtained in analytically pure form as colourless oil. [α]2D2 = –52.9
(c = 0.85, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 1.48, 1.51 (2s,
3 H each, Me), 2.19 (t, J = 3.6 Hz, 1 H, 4-H), 3.03 (dd, J = 0.8,
2.9 Hz, 1 H, 8-H), 3.30 (s, 3 H, OMe), 3.78 (dd, J = 4.3, 11.7 Hz,
Eur. J. Org. Chem. 2009, 282–291
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
287

F. Pfrengle, A. Al-Harrasi, I. Brüdgam, H.-U. Reißig
FULL PAPER
1 H, 4-CH2), 3.86 (d, J = 13.2 Hz, 1 H, NCH2), 3.86 (dd, J = 2.9,
ter addition of CH2Cl2 the phases were separated and the aqueous
9.8 Hz, 1 H, 7-H), 3.89 (dd, J = 3.6, 11.7 Hz, 1 H, 4-CH2), 3.92 (d, phase was extracted 3 times with CH2Cl2. The combined organic
J = 13.2 Hz, 1 H, NCH2), 4.07 (d, J = 9.8 Hz, 1 H, 7-H), 4.20 (t,
phases were dried and the solvent was removed in vacuo. Purifica-
J = 2.9 Hz, 1 H, 1-H), 7.25–7.34 (m, 10 H, Ph) ppm. 13C NMR tion by column chromatography (silica gel, hexane/EtOAc, 2:1)
(CDCl3, 125 MHz): δ = 28.6, 35.1 (2q, Me), 48.9 (q, OMe), 52.6 yielded 14 (472 mg, 84% from 3) as colourless crystals; m.p. 91 °C.
1
(t, NCH2), 54.6 (d, C-4), 55.9 (d, C-8), 59.5 (t, 4-CH2), 68.4 (t, C- [α]2D2 = –85.2 (c = 0.65, CHCl3). H NMR (CDCl3, 500 MHz): δ =
7), 76.0 (d, C-1), 76.1 (s, C-3), 108.9 (s, C-5), 127.5, 128.2, 128.7,
1.21, 1.36 (2s, 3 H each, Me), 2.04 (s, 3 H, Ac), 2.40 (dd, J = 5.5,
138.6 (3d, s, Ph) ppm. IR (film): ν = 3430 (O–H), 3090–3020 (=C– 11.6 Hz, 1 H, 7a-H), 3.22 (s, 3 H, OMe), 3.64 (t, J = 11.6 Hz, 1 H,
˜
H), 2970–2870 (C–H) cm–1. MS (EI, 80 eV, 100 °C): m/z (%) = 307
1-H), 4.11 (dd, J = 5.5, 11.6 Hz, 1 H, 1-H), 4.16–4.19 (m, 2 H, 1Ј-
(0.5) [M+], 292 (0.8) [M+ – CH3], 91 (100) [C7H7+]. HRMS: calcd. H, 5-H), 4.23 (dd, J = 4.6, 5.3 Hz, 1 H, 1Ј-H), 7.12 (s, 1 H, 4-H)
for C17H25NO4 – CH3]: 307.17836; found 307.17771.
ppm. 13C NMR (CDCl3, 125 MHz): δ = 20.8 (q, Ac), 22.7, 26.4
(2q, Me), 42.9 (d, C-7a), 52.4 (q, OMe), 62.8 (t, C-1Ј), 65.7 (t, C-
1), 79.1, 82.1 (2s, C-4a, C-7), 83.5 (d, C-5), 149.4 (d, C-4), 170.5 (s,
Typical Procedure for the Hydrogenation of Tricyclic 1,2-Oxazines
(Method B): A suspension of 10 % palladium on charcoal
(0.25 equiv. Pd) in MeOH (3 mL/mmol of 1,2-oxazine) was satu-
rated with hydrogen for 1 h. After addition of a solution of 1,2-
oxazine (1 equiv.) and if required tert-butyl dicarbonate (1.5 equiv.)
in MeOH (1 mL/mmol of 1,2-oxazine) hydrogen is conducted
through the mixture for 30 min. Subsequently the reaction mixture
is stirred under an atmosphere of hydrogen for the time given in
the individual procedure. The product is filtered through Celite and
the solvent is removed in vacuo.
CO) ppm. IR (KBr): ν = 3040–2830 (C–H), 1745 (C=O), 1660–
˜
1590 (C=N) cm–1. C12H19NO5 (257.3): calcd. C 56.02, H 7.44, N
5.44; found C 56.01, H 7.46, N 5.51.
[(1R,3aR,6S,6aS)-6-Amino-6a-methoxy-3,3-dimethyltetrahydro-
1H,3H-furo[3,4-c]furan-1-yl]methanol (15a) and [(3R,3aS,4R,6aR)-
4-Amino-3a-methoxy-2,2-dimethylhexahydrofuro[3,4-b]furan-3-yl]-
methanol (16a): Tricyclic compound 3 (100 mg, 0.327 mmol) was
hydrogenated for 17 h according to method B. Purification by col-
umn chromatography (silica gel, CH2Cl2/MeOH, 20:1) yielded a
mixture[10] of 15a and 16a (55 mg, 77%) as colourless oil (15a/16a
= 4:1). [α]2D2 = +18.6 (c = 1.53, CHCl3). 15a: 1H NMR (CDCl3,
500 MHz): δ = 1.22, 1.32 (2s, 3 H each, Me), 2.71 (dd, J = 6.0,
9.1 Hz, 1 H, 3a-H), 3.43 (s, 3 H, OMe), 3.68 (dd, J = 6.0, 9.7 Hz,
1 H, 4-H), 3.70 (dd, J = 7.8, 11.9 Hz, 1 H, 1Ј-H), 3.80 (dd, J = 5.5,
11.9 Hz, 1 H, 1Ј-H), 3.97 (dd, J = 9.1, 9.7 Hz, 1 H, 4-H), 4.15 (dd,
J = 5.5, 7.8 Hz, 1 H, 1-H), 4.58 (s, 1 H, 6-H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 24.8, 28.5 (2q, Me), 52.3 (q, OMe), 53.2
(d, C-3a), 61.2 (t, C-1Ј), 65.0 (t, C-4), 73.5 (d, C-1), 79.5 (s, C-3),
86.7 (d, C-6), 93.7 (s, C-6a) ppm. 16a: 1H NMR (CDCl3,
500 MHz): δ = 1.16, 1.31 (2s, 3 H each, Me), 2.59 (dd, J = 5.4,
10.9 Hz, 1 H, 3-H), 3.40 (s, 3 H, OMe), 3.59 (dd, J = 5.4, 12.0 Hz,
1 H, 1Ј-H), 3.72 (dd, J = 1.6, 10.3 Hz, 1 H, 6-H), 3.87 (dd, J =
10.9, 12.0 Hz, 1 H, 1Ј-H), 4.08 (dd, J = 5.0, 10.3 Hz, 1 H, 6-H),
4.46 (dd, J = 1.6, 5.0 Hz, 1 H, 6a-H), 4.95 (s, 1 H, 4-H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 24.7, 30.3 (2q, Me), 48.1 (d, C-3),
51.2 (q, OMe), 59.7 (t, C-1Ј), 70.0 (t, C-6), 77.6 (d, C-6a), 82.5 (s,
[(4aR,5R,7aR)-4a-Methoxy-7,7-dimethyl-4a,5,7,7a-tetrahydro-1H-
furo[3,4-d][1,2]oxazin-5-yl]methanol (12): Tricyclic compound 3
(100 mg, 0.327 mmol) was hydrogenated for 30 min according to
method B. Purification by column chromatography (silica gel, hex-
ane/EtOAc, 1:1) yielded 12 (59 mg, 84%) as colourless oil. [α]2D2
=
1
–32.2 (c = 0.85, CHCl3). H NMR (CDCl3, 500 MHz): δ = 1.20,
1.36 (2s, 3 H each, Me), 2.40 (dd, J = 5.5, 11.1 Hz, 1 H, 7a-H),
3.22 (s, 3 H, OMe), 3.64 (dd, J = 11.1, 11.9 Hz, 1 H, 1-H), 3.69
(ABX system, JAX = 5.5, JAB = 11.7 Hz, 1 H, 1Ј-H), 3.75 (ABX
system, JBX = 4.8, JAB = 11.7 Hz, 1 H, 1Ј-H), 4.06 (ddd, J = 0.5,
5.5, 11.9 Hz, 1 H, 1-H), 4.12 (ABX system, JBX = 4.8, JAX = 5.5 Hz,
1 H, 5-H), 7.22 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 22.8, 26.7 (2q, Me), 43.6 (d, C-7a), 52.5 (q, OMe), 61.6 (t, C-
1Ј), 65.6 (t, C-1), 78.8, 81.9 (2s, C-4a, C-7), 85.8 (d, C-5), 150.2 (d,
C-4) ppm. IR (film): ν = 3600–3200 (O–H), 3000–2820 (C–H),
˜
1670–1600 (C=N) cm–1. C10H17NO4 (215.3): calcd. C 55.80, H
7.96, N 6.51; found C 55.39, H 7.70, N 6.42.
[(4aR,5R,7aR)-4a-Benzyloxy-7,7-dimethyl-4a,5,7,7a-tetrahydro-1H-
furo[3,4-d][1,2]oxazin-5-yl]methanol (13): Tricycle 4 (78 mg,
0.20 mmol) was hydrogenated for 30 min according to method B.
Purification by column chromatography (silica gel, hexane/EtOAc,
1:1) yielded 13 (40 mg, 67%) as colourless oil. [α]2D2 = –37.6 (c =
C-2), 86.8 (d, C-4), 92.9 (s, C-3a) ppm. IR (film): ν = 3400 (O–H),
˜
3320 (N–H), 2955–2855 (C–H) cm–1. MS (FAB): m/z (%) = 240
(55) [M+ + Na], 218 (60) [M+ + H], 154 (100). C10H19NO4 (217.3):
calcd. C 55.28, H 8.81, N 6.45; found C 54.97, H 8.50, N 6.32.
tert-Butyl (1S,3aR,6R,6aS)-6-(Hydroxymethyl)-6a-methoxy-4,4-di-
methylhexahydrofuro[3,4-c]furan-1-yl Carbamate (15b) and tert-Bu-
tyl (3R,3aS,4R,6aR)-3-(Hydroxymethyl)-3a-methoxy-2,2-dimethyl-
hexahydrofuro[3,4-b]furan-4-yl Carbamate (16b): Tricyclic com-
pound 3 (100 mg, 0.327 mmol) was hydrogenated for 18 h in pres-
ence of tert-butyl dicarbonate (214 mg, 0.980 mmol) according to
method B. Purification by column chromatography (silica gel, hex-
ane/EtOAc, 1:1) yielded a mixture of 15b and 16b (86 mg, 82%) as
colourless crystals (15b/16b = 7:1); m.p. 124–126 °C. [α]2D2 = +45.2
(c = 0.86, CHCl3). 15b: 1H NMR (CDCl3, 500 MHz): δ = 1.20,
1.29 (2s, 3 H each, Me), 1.37 (s, 9 H, tBu), 2.56 (dd, J = 4.8, 8.4 Hz,
1 H, 3a-H), 2.70 (br. s, 1 H, OH), 3.31 (s, 3 H, OMe), 3.69 (dd, J
= 4.8, 9.7 Hz, 1 H, 3-H), 3.60–3.64 (m, 2 H, 6Ј-H), 3.87 (dd, J =
8.4, 9.7 Hz, 1 H, 3-H), 4.15 (t, J = 5.8 Hz, 1 H, 6-H), 5.26 (d, J =
8.5 Hz, 1 H, 1-H), 5.59 (d, J = 8.5 Hz, 1 H, NH) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 24.6, 27.6 (2q, Me), 28.1, 80.1 (q, s, tBu),
52.7 (q, OMe), 54.1 (d, C-3a), 58.8 (t, C-6Ј), 65.0 (t, C-3), 77.5 (d,
1
0.42, CHCl3). H NMR (CDCl3, 500 MHz): δ = 1.25, 1.43 (2s, 3
H each, Me), 2.56 (dd, J = 5.6, 11.3 Hz, 1 H, 7a-H), 3.71 (dd, J =
11.3, 11.9 Hz, 1 H, 1-H), 3.76 (ABX system, JAX = 5.0, JAB
=
11.9 Hz, 1 H, 1Ј-H), 3.83 (ABX system, JBX = 4.7, JAB = 11.9 Hz,
1 H, 1Ј-H), 4.15 (dd, J = 5.6, 11.9 Hz, 1 H, 1-H), 4.27 (ABX sys-
tem, JBX = 4.7, JAX = 5.0 Hz, 1 H, 5-H), 4.45 (s, 2 H, OCH2), 7.27–
7.39 (m, 5 H, Ph), 7.31 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 22.7, 26.7 (2q, Me), 44.5 (d, C-7a), 61.4 (t, C-1Ј),
65.6 (t, C-1), 67.2 (t, OCH2), 78.6, 81.9 (2s, C-4a, C-7), 85.8 (d, C-
5), 127.5, 127.7, 128.5, 137.2 (3d, s, Ph), 150.3 (d, C-4) ppm. IR
(film): ν = 3650–3250 cm–1 (O–H), 3100–3020 (=C-H), 3000–2830
˜
(C-H), 1605 (C=N). C16H21NO4 (291.3): calcd. C 65.96, H 7.27, N
4.81; found C 65.59, H 7.10, N 4.71.
[(4aR,5R,7aR)-4a-Methoxy-7,7-dimethyl-4a,5,7,7a-tetrahydro-1H-
furo[3,4-d][1,2]oxazin-5-yl]methyl Acetate (14): To a solution of
crude product 12 (496 mg, max. 2.32 mmol) in pyridine (10 mL)
were added acetic acid anhydride (2.20 mL, 23.0 mmol) and C-6), 79.9 (s, C-4), 82.5 (d, C-1), 92.9 (s, C-6a), 154.6 (s, NCO)
DMAP (40 mg, 0.330 mmol). The resulting solution was stirred for
8 h at room temp. and subsequently water (20 mL) was added. Af-
ppm. 16b: 1H NMR (CDCl3, 500 MHz): δ = 1.24, 1.31 (2s, 3 H
each, Me), 1.37 (s, 9 H, tBu), 2.59 (mc, 1 H, 3-H), 3.32 (s, 3 H,
288
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Eur. J. Org. Chem. 2009, 282–291

Unusual Enantiopure Heterocyclic Skeletons
OMe), 3.62 (mc, 1 H, 3Ј-H), 3.66 (dd, J = 1.0, 10.4 Hz, 1 H, 6-H), C-6a), 127.4, 128.5, 128.6, 138.8 (3d, s, Ph) ppm. 16d: 1H NMR
3.74 (dd, J = 7.1, 11.0 Hz, 1 H, 3Ј-H), 3.91 (dd, J = 4.5, 10.4 Hz,
1 H, 6-H), 4.43 (dd, J = 1.0, 4.5 Hz, 1 H, 6a-H), 5.55 (d, J = 9.0 Hz,
(CDCl3, 500 MHz): δ = 1.09, 1.32 (2s, 3 H each, Me), 2.61 (dd, J
= 5.4, 11.0 Hz, 1 H, 3-H), 3.40 (s, 3 H, OMe), 3.55 (dd, J = 5.4,
1 H, 4-H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 24.2, 31.0 (2q, 12.0 Hz, 1 H, 1Ј-H), 3.70 (dd, J = 11.0, 12.0 Hz, 1 H, 1Ј-H), 3.80
Me), 28.1 (q, tBu), 50.6 (d, C-3), 51.8 (q, OMe), 58.8 (t, C-3Ј), 69.8
(mc, 1 H, 6-H), 3.90 (d, J = 12.7 Hz, 1 H, NCH2), 4.09 (d, J =
(t, C-6), 80.1 (d, C-6a), 83.2 (d, C-4), 92.1 (s, C-3a), 159.7 (s, NCO) 12.7 Hz, 1 H, NCH2), 4.14 (dd, J = 4.9, 10.3 Hz, 1 H, 6-H), 4.47
ppm. Signals of C-2 and the singlet of the tBu group were not
(dd, J = 1.5, 4.9 Hz, 1 H, 6a-H), 4.83 (s, 1 H, 4-H), 7.24–7.29,
detected. IR (KBr): ν = 3550–3300 (O–H, N–H), 2990–2830 (C– 7.30–7.40 (2m, 5 H, Ph) ppm. 13C NMR (CDCl3, 125 MHz): δ =
˜
H), 1720 (C=O) cm–1. C15H27NO6 (317.4): calcd. C 56.77, H 8.57, 24.7, 30.4 (2q, Me), 48.0 (d, C-3), 50.5 (t, NCH2), 51.3 (q, OMe),
N 4.41; found C 56.85, H 8.53, N 4.36.
59.9 (t, C-1Ј), 70.1 (t, C-6), 77.6 (d, C-6a), 82.4 (s, C-2), 90.4 (d,
C-4), 93.3 (s, C-3a), 127.4, 128.5, 128.6, 138.8 (3d, s, Ph) ppm. IR
tert-Butyl (1S,3aR,6R,6aS)-6a-Hydroxy-6-(hydroxymethyl)-4,4-di-
methylhexahydrofuro[3,4-c]furan-1-yl Carbamate (15c) and tert-Bu-
tyl (3R,3aS,4R,6aR)-3a-Hydroxy-3-(hydroxymethyl)-2,2-dimethyl-
hexahydrofuro[3,4-b]furan-4-yl Carbamate (16c): Tricyclic com-
pound 4 (150 mg, 0.393 mmol) was hydrogenated for 18 h in pres-
ence of tert-butyl dicarbonate (129 mg, 0.591 mmol) according to
method B. Purification by column chromatography (silica gel, hex-
ane/EtOAc, 1:4) yielded a mixture of 15c and 16c (75 mg, 63%) as
colourless oil (15c/16c = 9:1). [α]2D2 = +35.7 (c = 0.31, CHCl3) 15c:
1H NMR (CDCl3, 500 MHz): δ = 1.22, 1.36 (2s, 3 H each, Me),
(film): ν = 3365 (N–H), 3300 (O–H), 3085–3030 (=CH), 2955–2855
˜
(C–H), 1600 (C=C) cm–1. MS (FAB): m/z (%) = 308 (45) [M+
+
H], 307 (24) [M+], 264 (17) [M+ + H – 43], 172 (100). HRMS (M+ –
CH3) calcd. for C17H25NO4 292.15488; found 292.15622.
[(4aR,5R,7aR)-5-(Acetoxymethyl)-4a-methoxy-7,7-dimethylhexahy-
dro-1H-furo[3,4-d][1,2]oxazin-3-ium-3-yl] (Cyano)dihydroborate
(18): To a solution of 1,2-oxazine 14 (180 mg, 0.700 mmol) in
AcOH (4 mL) was added NaBH3(CN) (150 mg, 2.34 mmol) and
the resulting solution was stirred at room temp. for 27 h. Sub-
1.43 (s, 9 H, tBu), 2.45 (dd, J = 5.1, 7.7 Hz, 1 H, 3a-H), 3.18 (br. sequently the mixture was poured into sat. NaHCO3 solution
s, 1 H, OH), 3.64 (dd, J = 5.1, 9.4 Hz, 1 H, 3-H), 3.69 (dd, J = 7.7, (23 mL). After addition of CH2Cl2 the phases were separated and
9.4 Hz, 1 H, 3-H), 3.71–3.77 (m, 2 H, 6Ј-H), 4.04 (dd, J = 5.2, the aqueous phase was extracted 3 times with CH2Cl2. The com-
6.6 Hz, 1 H, 6-H), 5.26 (d, J = 8.0 Hz, 1 H, 1-H), 5.84 (d, J = bined organic extracts were dried (Na2SO4) and the solvent was
8.0 Hz, 1 H, NH) ppm. 13C NMR (CDCl3, 125 MHz): δ = 24.3,
removed in vacuo. Purification by column chromatography (silica
28.1 (2q, Me), 28.3 (q, tBu), 60.4 (d, C-3a), 60.5 (t, C-6Ј), 65.1 (t, gel, hexane/EtOAc, 1:4) yielded 18 (152 mg, 73 %) as colourless
C-3), 80.3 (s, C-4), 81.4 (d, C-6), 83.2 (d, C-1), 88.1 (s, C-6a), 155.2
(s, NCO) ppm. The signal for the singlet of the tBu group was not
crystals; m.p. 150–152 °C. [α]2D2 = +48.8 (c = 0.62, CHCl3). 1H
NMR (CDCl3, 500 MHz): δ = 1.34, 1.39 (2s, 3 H each, Me), 2.08
detected. 16c (not all signals detected): 1H NMR (CDCl3, (s, 3 H, Ac), 2.20 (dd, J = 1.1, 3.8 Hz, 1 H, 7a-H), 3.19 (ABX
500 MHz): δ = 1.21, 1.35 (2s, 3 H each, Me), 1.43 (s, 9 H, tBu), system, JAX = 1.9, JAB = 13.8 Hz, 1 H, 4-H), 3.31 (ABX system,
2.59 (dd, J = 5.9, 9.9 Hz, 1 H, 3-H), 3.75 (mc, 1 H, 6-H), 3.91 (mc, JBX = 11.0, JAB = 13.8 Hz, 1 H, 4-H), 3.35 (s, 3 H, OMe), 3.95 (dd,
1 H, 3Ј-H), 4.00 (mc, 1 H, 6-H), 4.25 (mc, 1 H, 3Ј-H), 4.32 (mc, 1 J = 7.2, 12.0 Hz, 1 H, 1Ј-H), 4.08 (dd, J = 1.1, 13.5 Hz, 1 H, 1-H),
H, 6a-H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 28.3 (q, tBu), 4.11 (dd, J = 3.4, 7.2 Hz, 1 H, 5-H), 4.32 (dd, J = 3.4, 12.0 Hz, 1
66.3 (t, C-3Ј), 70.5 (t, C-6), 85.6 (d, C-6a) ppm. IR (film): ν = 3650– H, 1Ј-H), 4.42 (dd, J = 3.8, 13.5 Hz, 1 H, 1-H), 8.12 (ABX system,
˜
3150 (O–H), 2990–2830 (C–H), 1700 (C=O) cm–1. MS (EI, 80 eV, JAX = 1.9, JBX = 11.0 Hz, 1 H, NH) ppm. 13C NMR (CDCl3,
120 °C): m/z (%) = 303 (0.2) [M+], 285 (0.3) [M+ – H2O], 187 (2)
[M+ – NHBoc], 158 (27), 97 (17), 57 (100) [C4H9]+. HRMS: calcd.
for C14H25NO6 303.16818; found 303.16744.
125 MHz): δ = 20.8 (q, Ac), 25.5, 30.6 (2q, Me), 43.5 (d, C-7a),
50.7 (q, OMe), 54.0 (t, C-4), 61.7 (t, C-5Ј), 66.9 (t, C-1), 73.0 (d,
C-5), 79.6 (s, C-7), 99.9 (s, C-4a), 170.7 (s, OCO) ppm. The signal
of the CN group was not detected. IR (KBr): ν = 3650–3260 (N–
˜
[(1R,3aR,6S,6aS)-6-Benzylamino-6a-methoxy-3,3-dimethyltetrahy-
dro-1H,3H-furo[3,4-c]furan-1-yl]methanol (15d) and [(3R,3aS,4-
R,6aR)-4-Benzylamino-3a-methoxy-2,2-dimethylhexahydrofuro-
[3,4-b]furan-3-yl]methanol (16d): 1,2-Diiodoethane (679 mg,
2.41 mmol) and samarium (402 mg, 2.71 mmol) were transferred
into a dried flask. THF (25 mL) was added. After the solution
turned blue, the mixture was stirred for further 2 h. Tricyclic com-
pound 3 (230 mg, 0.750 mmol) in THF (4 mL) was added and the
H), 3060–2840 (C–H), 2420 (B–H), 2215 (CN), 1740 (C=O) cm–1.
MS (FAB): m/z (%) = 321 (44) [M+ + Na], 299 (100) [M+ + H],
282 [M+ + Na – BH2CN], 43 (115) [CH3CO]+. C13H23BN2O5
(298.1): calcd. C 52.37, H 7.78, N 9.40; found C 52.57, H 7.55, N
9.53.
{(2R,3R,4R)-3-[(tert-Butoxycarbonylamino)methyl]-4-(hydroxy-
methyl)-3-methoxy-5,5-dimethyltetrahydrofuran-2-yl}methyl Acetate
reaction mixture was stirred for 3 h. After addition of sat. NaHCO3 (19): 1,2-Oxazine 18 (84 mg, 0.280 mmol) was hydrogenated for
solution (20 mL) the resulting solid was filtered off and CH2Cl2
was added. The phases were separated and the aqueous phase was
extracted 3 times with CH2Cl2. The combined organic phases were
dried (Na2SO4) and the solvent was removed in vacuo. Purification
by column chromatography (silica gel, hexane/EtOAc, 1:1) yielded
a mixture of 15d and 16d (100 mg, 43%) as colourless oil (15d/16d
= 4:1). [α]2D2 = +37.4 (c = 0.31, CHCl3). 15d: 1H NMR (CDCl3,
18 h in presence of tert-butyl dicarbonate (109 mg, 0.500 mmol) ac-
cording to method B. Purification by column chromatography (sil-
ica gel, hexane/EtOAc, 1:2) yielded 19 (69 mg, 68%) as colourless
1
oil. [α]2D2 = +17.6 (c = 0.50, CHCl3). H NMR (CDCl3, 500 MHz):
δ = 1.23, 1.35 (s, 3 H, Me), 1.40 (s, 9 H, tBu), 2.05 (s, 3 H, Ac),
2.21 (br. s, 1 H, OH), 2.43 (t, J = 7.4 Hz, 1 H, 4-H), 3.25 (dd, J =
3.0, 13.4 Hz, 1 H, 3Ј-H), 3.33 (s, 3 H, OMe), 3.47 (dd, J = 6.5,
500 MHz): δ = 1.24, 1.35 (2s, 3 H each, Me), 2.72 (dd, J = 5.9, 13.4 Hz, 1 H, 3Ј-H), 3.66 (dd, J = 7.4, 10.5 Hz, 1 H, 4Ј-H), 3.81
9.3 Hz, 1 H, 3a-H), 3.43 (s, 3 H, OMe), 3.59 (dd, J = 8.4, 11.9 Hz, (dd, J = 7.4, 10.5 Hz, 1 H, 4Ј-H), 3.91 (dd, J = 8.1, 11.7 Hz, 1 H,
1 H, 1Ј-H), 3.72 (dd, J = 5.9, 9.3 Hz, 1 H, 4-H), 3.80 (dd, J = 5.6,
1Ј-H), 4.05 (dd, J = 2.5, 8.1 Hz, 1 H, 2-H), 4.42 (dd, J = 2.5,
11.9 Hz, 1 H, 1Ј-H), 3.90 (d, J = 12.7 Hz, 1 H, NCH2), 4.05 (t, J 11.7 Hz, 1 H, 1Ј-H), 5.08 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3,
= 9.3 Hz, 1 H, 4-H), 4.09 (d, J = 12.7 Hz, 1 H, NCH2), 4.19 (dd, 125 MHz): δ = 20.9 (q, Ac), 24.5, 30.7 (2s, Me), 28.3 (q, tBu), 39.2
J = 5.6, 8.4 Hz, 1 H, 1-H), 4.49 (s, 1 H, 6-H), 7.24–7.29, 7.30–7.40
(t, C-3Ј), 50.7 (q, OMe), 53.6 (d, C-4), 59.1 (t, C-4Ј), 63.4 (t, C-1Ј),
(2m, 5 H, Ph) ppm. 13C NMR (CDCl3, 125 MHz): δ = 24.8, 28.5 76.5 (d, C-2), 79.9, 84.2 (2s, 3-C, 5-C), 155.7 (s, NCO), 170.9 (s,
(2q, Me), 50.4 (t, NCH2), 52.2 (q, OMe), 53.0 (d, C-3a), 61.4 (t, C- OCO) ppm. The signal for the singlet of the tBu group was not
1Ј), 65.2 (t, C-4), 73.1 (d, C-1), 79.5 (s, C-3), 90.5 (d, C-6), 94.2 (s,
detected. IR (film): ν = 3600–3250 (O–H), 2990–2830 (C–H), 1745–
˜
Eur. J. Org. Chem. 2009, 282–291
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
289

F. Pfrengle, A. Al-Harrasi, I. Brüdgam, H.-U. Reißig
FULL PAPER
1685 (C=O) cm–1. MS (FAB): m/z (%) = 384 (46) [M+ + Na], 362
= 7.3 Hz, 3 H, Me), 1.26, 1.37 (2s, 3 H each, Me), 1.32–1.45 (m, 4
(23) [M+ + H], 328 (9) [M+ + Na – C4H8], 328 (20) [M+ + H – H, CH2), 1.60, 1.75 (2 mc, 1 H each, CH2), 2.69 (ABX system I,
C4H8], 57 (100) [C4H9]+, 43 (81) [Ac+]. HRMS (EI, 80 eV, 130 °C): JAX = 6.5, JBX = 9.5 Hz, 1 H, 3a-H), 3.78 (ABX system I, JAX
m/z (%) = (M+ – CH3COOH) calcd. for 301.18892; found 6.5, JAB = 9.5 Hz, 1 H, 3-H), 3.83 (ABX system I, JBX = JAB
=
=
301.18755.
9.5 Hz, 1 H, 3-H), 4.01 (ABX system II, JAX = 5.4, JAB = 11.5 Hz,
1 H, 6Ј-H), 4.06 (ABX system II, JBX = 5.4, JAB = 11.5 Hz, 1 H,
6Ј-H), 4.15 (ABX system II, JAX = JBX = 5.4 Hz, 1 H, 6-H) ppm.
13C NMR (CDCl3, 125 MHz): δ = –5.3, –5.1 (2q, SiMe2), 14.1 (q,
Me), 18.2, 25.9 (q, s, tBu), 23.3, 24.9 (2t, CH2), 24.8, 27.9 (2q, Me),
36.4 (t, CH2), 52.7 (q, OMe), 55.5 (d, C-3a), 62.0 (t, C-6Ј), 63.3 (t,
C-3), 78.9, 96.7 (2s, C-6a, C-4), 82.1 (d, C-6) ppm. The signal for
(4aR,5R,7aR)-5-[(tert-Butyldimethylsiloxy)methyl]-4a-methoxy-7,7-
dimethyl-4a,5,7,7a-tetrahydro-1H-furo[3,4-d][1,2]oxazine (20): To a
solution of crude product 12 (456 mg, max. 2.12 mmol) in CH2Cl2
(5 mL) were added Et3N (890 µL, 6.36 mmol) and TBSOTf
(730 µL, 3.18 mmol) at 0 °C and the resulting solution was stirred
at this temperature for 8 h. Subsequently the mixture was quenched
by addition of sat. NH4Cl solution (10 mL). The phases were sepa-
rated and the aqueous phase was extracted 3 times with CH2Cl2.
The combined organic phases were dried (Na2SO4) and the solvent
was removed in vacuo. Purification by column chromatography (sil-
ica gel, hexane/EtOAc, 2:1) yielded 20 (449 mg, 65% from 3) as
C-1 was not detected. IR (film): ν = 3450–3300 (N–H), 2990–2830
˜
(C–H) cm–1. MS (EI, 80 eV, 50 °C): m/z (%) = 387 (1) [M+], 369
(4) [M+ – H2O], 330 (26) [M+ – C4H9], 313 (59), 197 (100) [M+
–
C4H9 – OTBS – H2O], 137 (45), 73 (99). HRMS: calcd. for
C20H41NO4Si 387.28049; found 387.28084.
colourless oil. [α]2D2 = –81.1 (c = 0.47, CHCl3). H NMR (CDCl3,
1
(2aR,4aR,6aR,6bS)-6b-Methoxy-4,4-dimethyl-1-(tolylsulfonyl)hexa-
500 MHz): δ = 0.03, 0.04 (2s, 3 H each, SiMe2), 0.86 (s, 9 H, tBu),
1.16, 1.35 (2s, 3 H each, Me), 2.37 (dd, J = 5.5, 12.1 Hz, 1 H, 7a-
H), 3.23 (s, 3 H, OMe), 3.59 (t, J = 12.1 Hz, 1 H, 1-H), 3.65 (ABX
system, JAX = 7.3, JAB = 11.0 Hz, 1 H, 5Ј-H), 3.75 (ABX system,
hydro-1H,4H-3,6-dioxa-1-azacyclopenta[cd]pentalene (23): To
a
solution of crude product 15a/16a (211 mg, max. 0.980 mmol) in
CH2Cl2 (8 mL) was added Et3N (170 µL, 1.20 mmol), DMAP
(29 mg, 0.200 mmol) and pTsCl (411 mg, 2.16 mmol) at room temp.
and the resulting solution was stirred for 19 h. Subsequently, the
mixture was quenched by addition of sat. NH4Cl solution (15 mL).
The phases were separated and the aqueous phase was extracted 3
times with CH2Cl2. The combined organic phases were dried
(Na2SO4) and the solvent was removed in vacuo. Purification by
column chromatography (silica gel, hexane/EtOAc, 2:1) yielded 23
(183 mg, 57% from 3) as colourless crystals; m.p. 103–106 °C.
JBX = 3.8, JAB = 11.0 Hz, 1 H, 5Ј-H), 4.08 (ABX system, JBX
=
3.8, JAX = 7.3 Hz, 1 H, 5-H), 4.09 (ddd, J = 0.5, 5.5, 12.1 Hz, 1 H,
1-H), 7.22 (d, J = 0.5 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3,
125 MHz): δ = –5.5 (q, SiMe2), 18.2, 25.8 (s, q, tBu), 22.6, 26.4
(2q, Me), 43.3 (d, C-7a), 52.1 (q, OMe), 62.4 (t, C-5Ј), 65.5 (t, C-
1), 79.8, 81.5 (2s, C-4a, C-7), 86.1 (d, C-5), 150.2 (d, C-4) ppm.
IR (film): ν = 2990–2830 (C–H), 1605 (C=N) cm–1. C H NO Si
˜
16 31
4
[α]2D2 = –66.8 (c = 0.27, CHCl3). H NMR (CDCl3, 500 MHz): δ =
1
(329.5): calcd. C 58.32, H 9.48, N 4.25; found C 58.08, H 9.67, N
4.29.
1.17, 1.28 (2s, 3 H each, Me), 2.42 (s, 3 H, ArMe), 2.65 (dd, J =
8.6, 9.3 Hz, 1 H, 4a-H), 3.29 (s, 3 H, OMe), 3.49 (ABX system,
JAX = 1.1, JAB = 11.0 Hz, 1 H, 2-H), 3.60 (ABX system, JBX = 5.8,
JAB = 11.0 Hz, 1 H, 2-H), 3.77 (t, J = 9.3 Hz, 1 H, 5-H), 4.02 (dd,
(3aR,6R,6aS)-6-[(tert-Butyldimethylsiloxy)methyl]-6a-methoxy-4,4-
dimethyltetrahydrofuro[3,4-c]furan-1(3H)-imine (21) and
(3aR,1R,6R,6aS)-1-Butyl-6-[(tert-butyldimethylsiloxy)methyl]-6a-
methoxy-4,4-dimethylhexahydrofuro[3,4-c]furan-1-amine (22): To a
solution of nBuLi (2.5  in hexane, 240 µL, 0.600 mmol) in THF
(2 mL) is dropped over a period of 5 min a solution of 1,2-oxazine
20 (100 mg, 0.300 mmol) in THF (1 mL) at –40 °C. The mixture
was allowed to reach room temp. and was stirred for 4 h. Sub-
sequently, the reaction mixture was quenched with water (6 mL).
After addition of CH2Cl2 the phases were separated and the aque-
ous phase was extracted 3 times with CH2Cl2. The combined or-
ganic phases were dried (Na2SO4) and the solvent was removed in
vacuo. Purification by column chromatography (silica gel, hexane/
EtOAc, 6:1 Ǟ 1:1) yielded 21 (50 mg, 50%) as colourless crystals
J = 8.6, 9.3 Hz, 1 H, 5-H), 4.39 (ABX system, JAX = 1.1, JBX
=
5.8 Hz, 1 H, 2a-H), 5.65 (s, 1 H, 6a-H), 7.30 (d, J = 8.0 Hz, 2 H,
Ar), 7.78 (d, J = 8.0 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3,
125 MHz): δ = 21.5 (q, ArMe), 23.4, 25.9 (2q, Me), 53.5 (t, C-2),
53.7 (q, OMe), 55.5 (d, C-4a), 68.8 (t, C-5), 81.2 (d, C-2a), 83.0 (s,
C-4), 94.3 (d, C-6a), 108.4 (s, C-6b), 127.6, 129.6, 137.0, 143.6 (2d,
2s, Ar) ppm. IR (KBr): ν = 3090–3030 (=C–H), 2990–2830 (C–H),
˜
1345 (O=S=O), 1165 (C–N) cm–1. MS (EI, 80 eV, 130 °C): m/z (%)
= 353 (7) [M+], 338 (2) [M+ – CH3], 308 (8) [M+ – CH3 – OCH3],
198 (34) [M+ – SO2C7H7], 155 (39) [C7H7SO2]+, 91 (100) [C7H7]+.
HRMS: calcd. for C17H23NO5S 353.12969; found 353.12877.
C17H23NO5S (353.4): calcd. C 57.77, H 6.56, N 3.96, S 9.07; found
C 58.02, H 6.09, N 3.95, S 8.93.
and 22 (12 mg, 12%) as colourless oil. 21: M.p. 52–53 °C. [α]2D2
=
1
+12.5 (c = 0.82, CHCl3). H NMR (CDCl3, 500 MHz): δ = 0.02,
0.03 (2s, 3 H each, SiMe2), 0.86 (s, 9 H, tBu), 1.22, 1.36 (2s, 3 H
each, Me), 2.93 (ABX system I, JAX = JBX = 9.3 Hz, 1 H, 3a-H),
3.72 (ABX system II, JAX = 4.0, JAB = 11.2 Hz, 1 H, 6Ј-H), 3.77
(ABX system II, JBX = 4.0, JAB = 11.2 Hz, 1 H, 6Ј-H), 4.06 (ABX
system II, JAX = JBX = 4.0 Hz, 1 H, 6-H), 4.08 (ABX system I,
Acknowledgments
Support by the Fonds der Chemischen Industrie (PhD fellowship
to F. P.), the Deutscher Akademischer Austausch Dienst (DAAD)
(PhD fellowship for A. A.), the Deutsche Forschungsgemeinschaft
(DFG) and the Bayer Schering Pharma AG is most gratefully ac-
knowledged. We also thank Prof. Dr. D. Lentz for help with the
crystallographic data and Dr. R. Zimmer for discussions and help
during the preparation of the manuscript.
JBX = JAB = 9.3 Hz, 1 H, 3-H), 4.15 (ABX system I, JBX = JAB
=
9.3 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3, 125 MHz): δ = –5.7,
–5.5 (2q, SiMe2), 18.3, 25.8 (s, q, tBu), 23.4, 25.1 (2q, Me), 50.7 (d,
C-3a), 52.6 (q, OMe), 62.0 (t, C-6Ј), 66.6 (t, C-3), 80.5 (s, C-4), 86.8
(d, C-6), 93.0 (s, C-6a), 170.7 (s, C-1) ppm. IR (KBr): ν = 3260
˜
(N–H), 3000–2810 (C–H), 1690 (C=N) cm–1. MS (EI, 80 eV,
40 °C): m/z (%) = 329 (Ͻ 1) [M+], 314 (4) [M+ – CH3], 272 (100)
[M+ – C4H9], 298 (Ͻ 1) [M+ – OCH3], 172 (19), 73 (43).
C16H31NO4Si (329.6): calcd. C 58.32, H 9.48, N 4.25; found C
58.06, H 9.22, N 4.22.
[1] a) W. Schade, H.-U. Reißig, Synlett 1999, 632–643; b) M.
Helms, W. Schade, R. Pulz, T. Watanabe, A. Al-Harrasi, L.
Fisˇera, I. Hlobilová, G. Zahn, H.-U. Reißig, Eur. J. Org. Chem.
2005, 1003–1019.
[2] a) R. Pulz, T. Watanabe, W. Schade, H.-U. Reißig, Synlett 2000,
983–986; b) V. Dekaris, planned dissertation, Freie Universität
1
21: [α]2D2 = +7.3 (c = 0.30, CHCl3). H NMR (CDCl3, 500 MHz):
δ = 0.07, 0.08 (2s, 3 H each, SiMe3), 0.88 (s, 9 H, tBu), 0.92 (t, J
290
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 282–291

Unusual Enantiopure Heterocyclic Skeletons
Berlin, 2009; c) R. Pulz, A. Al-Harrasi, H.-U. Reißig, Synlett
2002, 817–819; d) R. Pulz, A. Al-Harrasi, H.-U. Reißig, Org.
Lett. 2002, 4, 2353–2355; e) B. Bressel, B. Egart, A. Al-Harrasi,
R. Pulz, H.-U. Reißig, I. Brüdgam, Eur. J. Org. Chem. 2008,
467–474.
A. Al-Harrasi, H.-U. Reißig, Angew. Chem. 2005, 117, 6383–
6387; Angew. Chem. Int. Ed. 2005, 44, 6227–6231.
S. Yekta, V. Prisyazhnyuk, H.-U. Reißig, Synlett 2007, 2069–
2072.
For a preliminary communication see: F. Pfrengle, A. Al-Har-
rasi, H.-U. Reißig, Synlett 2006, 3498–3500.
We consider this reaction as a useful alternative to the pre-
viously reported rearrangement (ref. 3) of TMSE-substituted
1,2-oxazine since the preparation of the required p-methoxy-
benzyloxyallene is experimentally easier and less expensive
compared to 2-(trimethylsilyl)ethoxyallene.
For the cleavage of N,O-bond with SmI2 see: a) G. E. Keck,
S. F. McHardy, T. T. Wager, Tetrahedron Lett. 1995, 36, 7419–
7422; b) J. L. Chiara, C. Destabel, P. Gallego, J. Marco-
Contelles, J. Org. Chem. 1996, 61, 359–360; c) J. Revuelta, S.
Cicchi, A. Brandi, Tetrahedron Lett. 2004, 45, 8375–8377; d)
I. S. Young, J. L. Williams, M. A. Kerr, Org. Lett. 2005, 7, 953–
955.
Weinheim, 1998; b) P. Sears, C.-H. Wong, Angew. Chem. 1999,
111, 2446–2471; Angew. Chem. Int. Ed. 1999, 38, 2301–2324.
[13] For Mo(CO)6 cleavage see: a) P. G. Baraldi, A. Barco, S. Be-
netti, S. Manfredini, D. Simoni, Synthesis 1987, 276–278; b) D.
Zhang, C. Süling, M. J. Miller, J. Org. Chem. 1998, 63, 885–
888. For Zn in AcOH see: c) J.-N. Denis, S. Tchertchian, A.
Tomassini, Y. Valle, Tetrahedron Lett. 1997, 38, 5503–5506. For
[3]
[4]
[5]
[6]
SmI2 cleavage see ref.[7]
.
[14] A. Al-Harrasi, H.-U. Reißig, Synlett 2005, 1152–1154.
[15] a) D. Miljkovic, J. Petrovic, J. Org. Chem. 1977, 42, 2101–2102;
b) P. Passacantilli, C. Centone, E. Ciliberti, G. Piancatelli, F.
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[16] Reviews: a) T. L. Gilchrist, Chem. Soc. Rev. 1983, 12, 53–73;
b) P. G. Tsoungas, Heterocycles 2002, 57, 915–953; c) P. G.
Tsoungas, Heterocycles 2002, 57, 1149–1178. For selected re-
cent publications of our group see: d) R. Pulz, A. Al-Harrasi,
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[8] CCDC-701441 (for 9), -701442 (for 14), and -701443 (for 15a)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
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data_request/cif.
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Received: September 8, 2008
Published Online: November 28, 2008
Eur. J. Org. Chem. 2009, 282–291
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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