Synthesis of new enantiopure poly(hydroxy)aminooxepanes as building blocks for multivalent carbohydrate mimetics

Article abstract of DOI:10.3762/bjoc.10.17

New compounds with carbohydrate-similar structure (carbohydrate mimetics) are presented in this article. Starting from enantiopure nitrones and lithiated TMSE-allene we prepared three 1,2-oxazine derivatives which underwent a highly stereoselective Lewis

Full text of DOI:10.3762/bjoc.10.17

Synthesis of new enantiopure
poly(hydroxy)aminooxepanes as building blocks for
multivalent carbohydrate mimetics
Léa Bouché, Maja Kandziora and Hans-Ulrich Reissig*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 213–223.
Freie Universität Berlin, Institut für Chemie und Biochemie,
Takustrasse 3, D-14195 Berlin, Germany
doi:10.3762/bjoc.10.17
Received: 24 August 2013
Accepted: 01 December 2013
Published: 20 January 2014
Email:
Hans-Ulrich Reissig* - hans.reissig@chemie.fu-berlin.de
* Corresponding author
Associate Editor: J. N. Johnston
Keywords:
© 2014 Bouché et al; licensee Beilstein-Institut.
License and terms: see end of document.
aminooxepanes; carbohydrate mimetics; hydrogenolyses; Lewis
acid-induced; lithiated allenes; nitrones; 1,2-oxazines;
rearrangements; reductions
Abstract
New compounds with carbohydrate-similar structure (carbohydrate mimetics) are presented in this article. Starting from enan-
tiopure nitrones and lithiated TMSE-allene we prepared three 1,2-oxazine derivatives which underwent a highly stereoselective
Lewis acid-induced rearrangement to give bicyclic products in good yield. Subsequent reductive transformations delivered a library
of new poly(hydroxy)aminooxepane derivatives. The crucial final palladium-catalyzed hydrogenolysis of the 1,2-oxazine moiety
was optimized resulting in a reasonably efficient approach to a series of new seven-membered carbohydrate mimetics.
Introduction
Since carbohydrates play a crucial role in biochemistry, com- ing an anomeric center) [8] as well as compounds without an
pounds mimicking their structure and/or function (carbohydrate acetal moiety. Known methods for the construction of the
mimetics) have attracted great attention in academic research seven-membered polyhydroxylated oxacycle, are for instance
and in drug development [1-3]. These mimetics should not have cycloaddition [9-11] or cyclodehydration of commercially
the drawbacks of carbohydrates such as low binding affinity or available alcohols [12-14]. The disadvantages of these methods
instability [4,5]. Many carbohydrates and their mimetics contain are the lack of selectivity as well as of stereocontrol and hence
pyran rings, however, the corresponding ring-expanded com- other routes are needed. One interesting option is the pathway
pounds, oxepanes, have been investigated only in a limited via oxepines [15-18] and the subsequent dihydroxylation or
number of studies. Several oxepane units can be found in direct reduction of their C=C double bond to give the corres-
natural products, in particular as toxins in marine organisms or ponding oxepane derivatives [19,20]. Alternatively, oxepanes
plants [6,7]. A few reports in the literature deal with seven- were also synthesized by the ring enlargement of their six-mem-
membered polyhydroxylated ethers like septanosides (contain- bered homologues [21,22]. Disappointingly, these methods
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Beilstein J. Org. Chem. 2014, 10, 213–223.
often involve long reaction sequences and display sometimes
restricted flexibility. A search for new stereoselective ap-
proaches is therefore highly desirable.
During the last years our group systematically studied a new ap-
proach to carbohydrate mimetics D [23-28]. The general
approach is shown in Scheme 1: the chiral pool-derived nitrones
A [29,30] undergo a [3 + 3]-cyclization with lithiated
[2-(trimethylsilyl)ethoxy]allene (TMSE-allene) [31] as C-3
building block [32] to form the 3,6-dihydro-2H-1,2-oxazines B;
subsequent Lewis acid-promoted reactions [23] lead to the
highly functionalized bicyclic 1,2-oxazinones C which can be
regarded as protected aminopolyol precursors offering the
option for plenty of selective transformations [27,28]; after
reductive steps the polyhydroxylated cyclic ethers D are
obtained. The advantages of this route are the stereocontrol and
the flexibility concerning the chain length. In 2005, Al-Harrasi
synthesized the first tert-butyldimethylsilyl (TBS)-protected
aminopyrans (n = 0) and aminooxepanes (n = 1) via this reac-
tion route [23]. Several of the poly(hydroxy)aminopyrans [24]
were connected to gold nanoparticles and the resulting multiva-
lent conjugates showed extremely high binding to P- and
L-selectine [33,34]. For the planned biological testing of the
Scheme 1: General approach to enantiopure the poly(hydroxy)amino-
pyrans D (n = 0) and the aminooxepanes D (n = 1) by [3 + 3]-cycliza-
tion of the (Z)-nitrones A with lithiated TMSE-allene followed by Lewis
acid-induced rearrangement of 3,6-dihydro-2H-1,2-oxazines B. [TBS =
tert-butyldimethylsilyl, TMSE = 2-(trimethylsilyl)ethyl]
corresponding aminooxepanes as components of multivalent 1 employing p-bromobenzaldehyde dimethylacetal, the ring
conjugates, we required the fully deprotected compounds. double bond was oxidatively cleaved to give the sodium
Moreover, it was desirable to have additional derivatives with carboxylate which was directly transformed into the corres-
different configurations or functional groups. In this article, we ponding ethyl ester [36]. Protection with a TBS-group
therefore describe the full details of our route to a series of new proceeded quantitatively to gain 2 in very good overall efficacy.
enantiopure poly(hydroxy)aminooxepanes with variations at the Final transformation into the desired nitrone 3 was achieved in
2-, 5- and 7-position of the seven-membered cyclic ether D.
83% yield (over two steps) by reduction of the ester using
DIBAL-H at low temperature, followed by condensation with
N-benzylhydroxylamine according to a Dondoni protocol [29].
Results and Discussion
The enantiopure (Z)-nitrones 3, 6 and 8 were synthesized This route allows the synthesis of enantiopure nitrone 3 in
essentially following known pathways [35] (Scheme 2 and multi-gram scale.
Scheme 3). The new D-erythrose-derived nitrone 3 containing a
p-bromophenyl moiety in the dioxolane ring was obtained in a The enantiopure (Z)-configured nitrones 6, 8 and 3 were treated
straightforward manner (Scheme 2). Commercially available with in situ lithiated TMSE-allene at −78 °C furnishing the
D-isoascorbic acid (1) was smoothly transformed in four steps expected 1,2-oxazines syn-7 [37], syn-9 and syn-10 in high
into the ethyl ester 2. After protection of the free 1,2-diol unit of yields and with excellent diastereoselectivities (Scheme 3). The
Scheme 2: Synthesis of (Z)-nitrone 3. Conditions: a) 1. p-Bromobenzaldehyde dimethylacetal, TFA, DMF, rt, 5 d; 2. 30% H2O2, K2CO3, H2O,
0 → 20 °C, 16 h; 3. EtI, MeCN, reflux, 20 h; b) TBSCl, imidazole, DMAP, CH2Cl2, 3 d, rt; c) 1. DIBAL-H, CH2Cl2, −78 °C, 3.5 h; 2. N-benzylhydroxyl-
amine, MgSO4, CH2Cl2, rt, 16 h. [TFA = trifluoroacetic acid, DMAP = 4-(N,N-dimethylamino)pyridine, DIBAL-H = diisobutylaluminium hydride]
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Beilstein J. Org. Chem. 2014, 10, 213–223.
Scheme 3: Synthesis of 1,2-oxazines syn-7, syn-9 and syn-10. Conditions: a) n-BuLi, THF, −40 °C, 15 min; b) 1. THF, −78 °C, 1.5 to 3 h; 2. H2O,
1 h, −78 °C → rt. The syn:anti ratios were determined by 1H NMR spectroscopic analysis of the crude products and are all >95:5 (see Supporting
Information File 2).
nitrone 3 was used as a 96:4 mixture (with respect to the stereo- β-carbon (1,3-induction) has no or negligible influence. A few
genic center of the 1,3-dioxolane ring) and it could therefore syn-selective additions of other nucleophiles to nitrones with
provide four diasteromers of 1,2-oxazine syn-10 (two major two stereogenic centers similar to 6 or 8 were reported in the
syn- and two minor anti-diasteromeres), but only a single syn- literature [38,39]. A preferred transition structure as depicted in
stereoisomer (with respect to C-3 of the 1,2-oxazine ring) was Figure 1 plausibly explains our results. The silyloxy group at
isolated after column chromatography. A product derived from the α-carbon occupies an orthogonal position, the substituent R
the minor isomer of nitrone 3 was not detected and was appar- is close to the nitrone hydrogen substituent and the lithiated
ently lost during the reaction or the purification. Since the allene attacks from the Re-side of the nitrone (Felkin–Anh
stereogenic center of the 1,3-dioxolane ring is converted into an model for nitrones as proposed by Dondoni et al. [30]). An ad-
sp2-hybridized carbon during the Lewis acid-induced ring ditional coordination of the lithium cation to the nitrone oxygen
opening, the configuration of syn-10 was not assigned at this is possible.
center.
We discussed the mechanism of this [3 + 3]-cyclization in detail
including possible side-reactions in an earlier report [31]. The
observed high syn-diastereoselectivities are in accordance with
our previously published results and were supported by an
X-ray analysis of syn-7 [37]. We conclude from our observa-
tions that the formation of 1,2-oxazines from nitrones 3, 6 and 8
Figure 1: Proposed transition structure for the addition of lithiated
TMSE-allene 5 to chiral nitrones 3, 6 and 8.
is mainly steered by the stereogenicity at the α-carbon (1,2-
induction) [30,31], whereas the stereogenic center at the
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Beilstein J. Org. Chem. 2014, 10, 213–223.
The Lewis acid-induced rearrangements of 1,2-oxazines syn-7, 13 (for other Lewis acid-mediated formations of seven mem-
syn-9 and syn-10 were achieved in moderate to good yields bered oxacycles, see references [40,41]).
using TMSOTf as promoter (Scheme 4). A higher yield of 73%
was achieved for the p-bromophenyl derivative 13 (isolated as a The relative configuration of the newly formed stereogenic
single diastereomer) which may be due to the stabilized car- center at the C-2 position of 13 was successfully determined by
benium ion formed at the benzylic position.
NOE experiments. By irradiation of the 2-H proton (Figure 2)
several dipolar couplings with 1-H, 4-H and with one proton of
the p-bromophenyl group were observed. For this reason, it is
assumed that the 2-H proton of 13 is cis-orientated to the 1-H
and 4-H protons and consequently shows an (R)-configuration.
Ketones 11, 12 and 13 were subsequently smoothly reduced
with sodium borohydride in ethanol. In all cases, only one
diastereomer (hydroxy group at C-10 with an S-configuration)
was isolated (Scheme 6). These results are in accordance with
previous observations obtained for the corresponding TBS-pro-
tected derivatives [42] suggesting that a preferred conformation
of the seven-membered ring favors the hydride attack only from
the Re-side. The Si-side (back-side) attack is probably hindered
by the bulky OTBS group (also see Scheme 5). The configura-
tional assignments are in accordance with NOE experiments
performed with the alcohol derived from ketone 13 (precursor
of 16), where dipolar couplings have been observed between the
10-H and 9-H protons (CH2 next to the N–O bond). Finally, the
TBS-groups were removed under standard conditions furnishing
triols 14, 15 and 16 in high yields.
The free primary hydroxy group of bicyclic ketone 11 was
propargylated in 71% yield employing propargylic bromide
under standard conditions (Scheme 7). After reduction of the
carbonyl group [43] and TBS cleavage, propargylic ether 18
was obtained (88% yield over two steps) [44]. The alkyne
Scheme 4: Synthesis of ketones 11, 12 and 13 with a bicyclic 1,2-
oxazine skeleton by Lewis acid-induced rearrangement. Conditions: a)
1. TMSOTf, CH2Cl2, −5 °C, 5 to 6 h; 2. aq NH3, rt, 10 min. [TMSOTf =
trimethylsilyl trifluoromethanesulfonate]
This rearrangement presents a relatively rare example of an moiety provides options for further transformations, e.g. Sono-
intramolecular aldol-like reaction of an enol ether with an acti- gashira reactions, Glaser couplings or 1,3-dipolar cycloaddi-
vated acetal (which may also be regarded as a special case of a tions (click reactions) [45].
Prins reaction) forming a seven-membered ring. We propose a
Zimmerman–Traxler-type transition state (Scheme 5), placing We were also interested in the preparation of the bicyclic azide
the aryl group R2 (R1 = H) in the sterically more favorable 24 and hence the primary hydroxy group of 11 was converted
pseudo-equatorial position in the reaction leading to compound into mesylate 19 followed by a reduction of the carbonyl group
Scheme 5: Proposed extended chair-like conformation with Zimmerman–Traxler-type transition state.
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Beilstein J. Org. Chem. 2014, 10, 213–223.
Figure 2: GOESY–NMR spectrum (CDCl3, 500 MHz) of bicyclic 1,2-oxazine 13: irradiation of the 2-H proton. [GOESY = gradient enhanced nuclear
Overhauser effect spectroscopy]
come the formation of this side product, the introduction of the
azido group was directly performed with mesylate 19. Since the
nucleophilic substitution of 19 into 23 gave only moderate
yields with low reproducibility (from 39–67%), this step was
optimized using Mitsunobu conditions with diphenylphos-
phoryl azide according to a protocol by Bose [46]. The desired
bicyclic azide 23 was now isolated in 79% yield and its subse-
quent reduction and deprotection with TBAF gave compound
24 in essentially quantitative yield (over two steps). After
protection of the two hydroxy substituents of 24 with TBS-
groups, a Staudinger reaction was performed, which furnished
bicyclic 1,2-oxazine derivative 25 with a primary amino group
in 80% yield (over two steps).
Next we wanted to synthesize the unexpectedly formed unique
tricyclic 1,2-oxazine 20 with higher efficacy. After reduction of
19 with sodium borohydride the intermediate alcohol was
heated with triethylamine (to avoid the deprotection of the TBS-
group) and compound 20 was obtained in 75% yield (over three
steps).
Scheme 6: Synthesis of triols 14, 15 and 16 by reduction of the car-
The previously isolated unprotected triols 14, 15 and 20 were
subjected to standard hydrogenolysis conditions using palla-
dium on charcoal in order to remove the N-benzyl group and to
cleave the N–O bond [47,48] in one step. This process is often
bonyl group and deprotection. Conditions: a) NaBH4, EtOH, 0 °C,
40 min to 16 h; b) TBAF (1 M THF), THF, 0 °C, 10 min to 3.5 h. [TBAF
= tetra-n-butylammonium fluoride]
(Scheme 8). The attempted nucleophilic substitution by sodium challenging due to the difficult control of the various reaction
azide gave a mixture of two products: the desired TBS-pro- parameters and also because of the high polarity of the newly
tected azide 21 and an unexpected side product 22. To over- formed compounds. According to the experience of our group
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Beilstein J. Org. Chem. 2014, 10, 213–223.
Scheme 7: Synthesis of propargylic ether 18. Conditions: a) propargyl bromide, NaOH, TBAI, H2O/CH2Cl2, −20 °C → rt, 7 d; b) NaBH4, EtOH, 0 °C,
4 h; c) TBAF (1 M THF), THF, 0 °C → rt, 3 d. [TBAI = tetra-n-butylammonium iodide]
Scheme 8: Synthesis of tricyclic compound 20, bicyclic azide 24 and bicyclic amine 25. Conditions: a) MsCl, Et3N, CH2Cl2, 0 °C → rt, 5 h; b) NaBH4,
EtOH, 0 °C, 6 to 16 h; c) NaN3, DMF, reflux, 16 to 46 h; d) Et3N, DMF, reflux, 16 h; e) TBAF (1 M THF), THF, 0 °C → rt, 1 h; f) TPP, DIAD, DPPA,
THF, −20 °C → rt, 2 d; g) TBSOTf, Et3N, CH2Cl2, 0 °C → rt, 3.5 h; h) TPP, THF/H2O, rt, 16 h. [Ms = methanesulfonate, TPP = triphenylphosphane,
DIAD = diisopropyl azodicarboxylate, DPPA = diphenylphosphoryl azide]
this step often leads to irreproducible results in particular in the The irreproducible results with 14 and 15 are probably due to
case of the oxepane derivatives. This was confirmed by reduc- the formation of side products such as 29 and 30 isolated in low
tions performed with 14 and 15. In Scheme 9, we present the quantities (proposed structures are presented in Figure 3). The
best results obtained under these “standard conditions”. 1H NMR spectra of all observed side products show signals at
The aminooxepanes 26 and 27 [49] were isolated in 63% and ca. 4.5 ppm, typically appearing as two symmetric doublets
88% yield, respectively. Gratifyingly, the unique tricyclic 1,2- (AX system) with a coupling constant of 5.7 Hz. These observa-
oxazine 20 was very efficiently converted into bicyclic amino- tions suggest the presence of a methylene bridge at the amino-
oxepane derivative 28 (96% yield) without formation of side oxepane skeleton. The position of the methylene bridge was
products.
only determined for side product 27 using HMBC NMR spec-
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Beilstein J. Org. Chem. 2014, 10, 213–223.
reduction processes of amines [54]. Acetic acid in methanol
(1:5) was a good medium for our reductions and substrate 14
was now smoothly reduced under hydrogen atmosphere with
palladium on charcoal. After filtration through a pad of acidic
DOWEX® resin followed by elution with aqueous ammonia
the clean poly(hydroxy)aminooxepane 26 was obtained
in 90% yield (Scheme 10). Under these optimized reaction
conditions other hydrogenolyses were studied. p-Bromophenyl-
substituted triol 16 was transformed into the corresponding
poly(hydroxy)aminooxepane derivative 31 in 73% yield. As
expected, the bromo substituent of the aryl group was also
reductively removed delivering a phenyl group in product 31.
Propargylic ether 18 was converted in quantitative yield into
n-propyl ether 32. Remarkably, the hydrogenolysis of bicyclic
azide 24 smoothly furnished the diaminooxepane 33 in 72%
yield. The results obtained using these new conditions are
promising for other N–O cleavages of polar 1,2-oxazine deriva-
tives. Furthermore, due to the newly formed amino group the
prepared poly(hydroxy)aminooxepanes offer the option to
Scheme 9: Hydrogenolyses of bicyclic and tricyclic 1,2-oxazines 14,
15 and 20 to aminooxepanes 26, 27 and 28. Conditions: a) H2, Pd/C,
MeOH, rt, 18 h.
Figure 3: Proposed structures of the observed side products 29 and
30 during the hydrogenolyses of 14 and 15.
troscopy which shows a small coupling between one proton of
the methylene bridge and C-3 (position of the alcohol). We
assume that they are formed by in situ generated formaldehyde
(dehydrogenation of methanol) [50-53] and subsequent aminal
formation with aminooxepanes 26 and 27. The aminoalcohol 28
seems not to form the corresponding compounds. We suppose
that bicyclic compound 28 is more strained and hence the for-
mation of a third ring may be unfavorable.
In order to avoid this side-reaction we performed hydrogenoly-
sis experiments in alternative solvents, e.g. with ethanol or
isopropanol, but small amounts of the corresponding side prod-
ucts were also observed in these experiments. Unpolar solvents
were not suitable for the hydrogenolysis, probably due to the
low solubility and conversion of the fairly polar starting ma-
terials or intermediates. After these problems we tried to
diminish the nucleophilicity of the amino group by addition of
acid since this protocol has proved to be advantageous in other
Scheme 10: Hydrogenolyses of bicyclic 1,2-oxazines to amino-
oxepanes 26, 31 and 32 and to diaminooxepane 33 under optimized
conditions. Conditions: a) 1. H2, Pd/C, MeOH/AcOH = 5:1, rt, 17 h;
2. DOWEX® H+; 3. aq NH3.
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Beilstein J. Org. Chem. 2014, 10, 213–223.
selectively perform reductive aminations or Schotten–Baumann 1.00, 1.09 (AB part of ABXY system, JAX = 5.2 Hz,
reactions. All these processes can lead to new carbohydrate JBY = 6.7 Hz, JAY = 10.2 Hz, JBX = 10.8 Hz, JAB = 14.0 Hz,
mimetics, also in a multivalent fashion.
1H each, 2’’’-H), 1.28, 1.34 (2 s, 3H each, Me), 2.78 (mc, 1H,
3-H), 3.12, 3.19 (AB part of ABX-system, JAX = 6.6 Hz,
JBX ≈ JAB = 7.8 Hz, 1H each, 5’’-H), 3.78, 3.83 (XY part of
Conclusion
In summary, the presented route employs the following key ABXY system, JAX = 5.2 Hz, JBY = 6.7 Hz, JXY = 8.5 Hz,
steps: Dondoni protocol for nitrone synthesis, [3 + 3]-cycliza- JAY = 10.2 Hz, JBX = 10.8 Hz, 1H each, 1’’’-H), 3.86 (d,
tion with lithiated TMSE-protected allene, Lewis acid-induced J = 12.5 Hz, 1H, NCH2), 3.87 (dd, J = 3.5, 8.0 Hz, 1H, 1’-H),
rearrangement and reductive processes including a final hydro- 4.14* (d, J = 12.5 Hz, 1H, NCH2), 4.14* (dd, J = 3.5, 15.1 Hz,
genolysis. The new highly functionalized poly(hydroxy)amino- 1H, 6-H), 4.25 (dt, J ≈ 6.6, 8.0 Hz, 1H, 4’’-H), 4.46 (td, J ≈ 2.0,
oxepanes were thereby successfully synthesized in a highly 15.1 Hz, 1H, 6-H), 4.81 (dd, J = 2.0, 3.5 Hz, 1H, 5-H), 7.28,
stereocontrolled manner. The obtained compounds are potential 7.33, 7.38 (3 mc, 1H, 2H, 2H, Ph) ppm, * overlapping signals;
carbohydrate mimetics and supplement the already studied six- ESI–TOF (m/z): [M + H]+ calcd for C28H50NO5Si2, 536.3222;
membered homologues [33,34]. The introduction of new func- found, 536.3289. The analytical data are in accordance
tional groups such as alkynyl or azido substituents at the with literature [23,37]. Characteristic signals of anti-7: 1H NMR
bicyclic skeleton will also allow further transformations such as (700 MHz, CDCl3): δ 1.33, 1.36 (2 s, 3H each), 4.08
click reactions or palladium-catalyzed couplings. We expect (t, J ≈ 6.3 Hz, 1H, 6-H), 4.29 (mc, 1H, 4’’-H), 4.76 (mc, 1H,
that the newly prepared aminooxepanes or their multivalent 5-H) ppm.
conjugates will have interesting properties and possibly bio-
Typical procedure for the Lewis acid-induced
rearrangement (procedure 2)
logical activities, e.g. as selectine inhibitors, which is currently
investigated.
(1R,4S,5S,6S)-7-Benzyl-5-(tert-butyldimethylsiloxy)-4-
(hydroxymethyl)-2,2-dimethyl-3,8-dioxa-7-azabicyclo-
[4.3.1]decan-10-one (11): Analogous to literature [23,37],
under argon atmosphere 1,2-oxazine syn-7 (2.00 g, 3.73 mmol,
syn:anti 94:6) was dissolved in dry CH2Cl2 (32 mL). The solu-
tion was cooled to −5 °C and TMSOTf (1.35 mL, 7.46 mmol)
was slowly added. After 5.5 h stirring at 0 °C, the dark red mix-
ture was quenched with a solution of aq ammonia (5%) turning
yellow. Work-up was performed with CH2Cl2 (3 × 30 mL). The
combined organic layers were washed with brine, dried with
Na2SO4, filtered through cotton and the solvent was removed in
vacuo. The crude material (orange oil, 2.05 g) was purified by
column chromatography (silica gel, hexanes/EtOAc 5:1 to 4:1)
to yield 11 (851 mg, 53%, lit. [23] 55%) as a pale-yellow oil;
TLC (silica gel, hexanes/EtOAc 2:1) Rf 0.48; 1H NMR
(500 MHz, CDCl3) δ −0.09, −0.02 (2 s, 3H each, SiMe), 0.86
(s, 9H, Sit-Bu), 1.37, 1.38 (2 s, 3H each, Me), 1.72 (bs, 1H,
OH), 2.57 (mc, 1H, 1-H), 3.37 (mc, 1H, 6-H), 3.56, 3.67 (AB
part of ABX system, JAX = 4.5 Hz, JBX = 8.1 Hz,
JAB = 10.9 Hz, 1H each, 4-CH2), 3.94 (A part of AB system,
JAB = 13.4 Hz, 1H, NCH2), 4.11–4.13 (m, 4H, 5-H, 9-H,
NCH2), 4.58 (dd, J = 4.5, 8.1 Hz, 1H, 4-H), 7.26–7.29 (m, 5H,
Ph) ppm; ESI-TOF (m/z): [M + H]+ calcd for C23H38NO5Si,
436.2514; found, 436.2553. The analytical data are in accor-
dance with literature [23,37].
Experimental
General methods: See Supporting Information File 1
Typical procedure for the preparation of syn-
1,2-oxazines by addition of lithiated TMSE-
allene to chiral nitrones (procedure 1)
(3S,1’S,4’’S)-2-Benzyl-1’-[(tert-butyldimethylsiloxy)-(2’’,2’’-
dimethyl-1’’,3’’-dioxolan-4’’-yl)methyl]-4-[2’’’-
(trimethylsilyl)ethoxy]-3,6-dihydro-2H-1,2-oxazine (syn-7):
Analogous to literature [31], under argon atmosphere TMSE-
allene 4 (5.00 g, 32.0 mmol) was dissolved in dry THF (60 mL).
The slightly yellow solution was cooled to −40 °C and n-BuLi
(2.5 M in hexanes; 10.2 mL, 25.6 mmol) was slowly added.
After 15 min, the resulting strong-yellow mixture was cooled to
−78 °C, and a solution of nitrone 6 (4.00 g, 10.5 mmol) in dry
THF (60 mL) was added dropwise. The reaction mixture turned
pink, then orange and later dark red. After stirring at this
temperature for 2.5 h, the reaction mixture was quenched with
water (40 mL) and left to warm to rt and then extracted with
Et2O (3 × 65 mL). The combined organic layers were washed
with brine, dried with Na2SO4, filtered through cotton and the
solvent was removed in vacuo. Crude material [orange solid,
4.00 g; syn:anti-7 >95:5 and corresponding diene (see
Supporting Information File 1) <2%] was purified by column
chromatography (silica gel, hexanes/EtOAc 17:0.5) to yield
syn-7 (3.69 g, 65%, lit. [23,37] 71%, syn:anti-7 94:6) as a pale-
yellow solid; mp 102–105 °C; TLC (silica gel, hexanes/EtOAc
8:1) Rf 0.34; 1H NMR (700 MHz, CDCl3) δ 0.02 (s, 3H, SiMe),
0.06 (s, 9H, SiMe3), 0.08 (s, 3H, SiMe), 0.87 (s, 9H, Sit-Bu),
Typical procedure for ketone reduction with
NaBH4 (procedure 3)
(1S,4S,5S,6R,10S)-7-Benzyl-5-(tert-butyldimethylsiloxy)-4-
(hydroxymethyl)-2,2-dimethyl-3,8-dioxa-7-azabicyclo-
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Beilstein J. Org. Chem. 2014, 10, 213–223.
[4.3.1]decan-10-ol: Under argon atmosphere ketone 11 6-H), 3.63, 3.71 (AB part of ABX system, JAX = 3.5 Hz,
(703 mg, 1.61 mmol) was dissolved in dry EtOH (26 mL). The JBX = 6.5 Hz, JAB = 11.0 Hz, 1H each, 4-CH2), 3.74 (dd,
solution was cooled to 0 °C and NaBH4 (119 mg, 3.15 mmol) J = 3.0, 12.8 Hz, 1H, 9-H), 3.91 (d, J = 14.1 Hz, 1H, NCH2),
was added in portions. After stirring at 0 °C for 4 h, the solvent 3.96 (d, J = 12.8 Hz, 1H, 9-H), 4.12 (d, J = 14.1 Hz, 1H,
was removed in vacuo. The crude material was dissolved in NCH2), 4.44–4.47 (m, 3H, 4-H, 5-H, 10-H), 7.22, 7.29, 7.35
CH2Cl2 (20 mL) and then extracted with CH2Cl2 (3 × 25 mL). (3 mc, 1H, 2H, 2H, Ph) ppm; 13C NMR (175 MHz, CD3OD)
The combined organic layers were washed with brine, dried δ 24.6, 34.5 (2 q, Me), 48.7 (d, C-1), 49.9 (d, C-5), 59.4 (t,
with Na2SO4, filtered through cotton and the solvent was NCH2), 63.6 (t, 4-CH2), 65.9 (t, C-9), 70.0 (d, C-4), 74.7 (d,
removed in vacuo to yield the corresponding alcohol (704 mg, C-6), 76.3 (d, C-10), 79.1 (s, C-2), 128.1, 129.2, 129.4, 139.2
quant.) as a colorless solid; melting range 132–137 °C; (3 d, s, Ph) ppm; IR (ATR) : 3360 (OH), 3085–3030 (=C-H),
[α]D22 −61.1 (c 0.63, CHCl3); TLC (silica gel, hexanes/EtOAc 2970–2860 (C-H), 1215 (C-O), 1060 (C-O-C) cm−1; ESI–TOF
2:1) Rf 0.58; 1H NMR (700 MHz, CDCl3) δ −0.09, −0.04 (2 s, (m/z): [M + Na]+ calcd for C17H25NO5Na, 346.1630; found,
3H each, SiMe), 0.88 (s, 9H, Sit-Bu), 1.32, 1.53 (2 s, 3H each, 346.1622; anal. calcd for C17H25NO5 (323.4): C, 63.14; H,
Me), 1.75 (bs, 1H, 4-OH), 2.17 (mc, 1H, 1-H), 3.29 (dd, J = 2.5, 7.79; N, 4.33; found: C, 63.20; H, 7.83; N, 4.31.
4.8 Hz, 1H, 6-H), 3.56 (mc, 1H, 4-CH2), 3.70 (B part of ABX
system, JAX = 8.5 Hz, JAB = 10.7 Hz, 1H, 4-CH2), 3.81 (A part Synthesis of (1R,4S,5S,6S)-4-(azidomethyl)-7-benzyl-5-(tert-
of ABX-system, JAX = 3.0 Hz, JAB = 12.0 Hz, 1H, 9-H), 3.87 butyldimethylsiloxy)-2,2-dimethyl-3,8-dioxa-7-azabicyclo-
(d, J = 13.9 Hz, 1H, NCH2), 3.93 (B part of ABX system, [4.3.1]decan-10-one (23): Under argon atmosphere TPP
JAB = 12.0 Hz, 1H, 9-H)*, 3.94 (d, J = 11.4 Hz, 1H, 10-OH), (99 mg, 0.38 mmol) was dissolved in dry THF (1.5 mL) and the
4.17 (d, J = 13.9 Hz, 1H, NCH2), 4.33 (dt, J ≈ 1.0, 2.5 Hz, 1H, solution was cooled to −20 °C. DIAD (76.5 mg, 0.378 mmol)
5-H), 4.40-4.44 (m, 2H, 4-H, 10-H), 7.27–7.28, 7.32–7.36 (2 m, was added and the reaction mixture became milky white. After
5H, Ph) ppm, *no BX coupling present; 13C NMR (175 MHz, 10 min stirring at that temperature, alcohol 11 (150 mg,
CDCl3) δ −4.9, −4.4 (2 q, SiMe), 18.1 (s, SiCMe3), 24.9 (q, 0.344 mmol in 0.6 mL of dry THF) was slowly added and the
Me), 25.9 (q, SiCMe3), 34.6 (q, Me), 47.4 (d, C-1), 58.4 (t, mixture was stirred for further 30 min at −20 °C. The now
NCH2), 63.6 (t, 4-CH2), 64.5 (d, C-5), 68.6 (t, C-9), 71.1 (d, milky-yellow solution was progressively warmed to 0 °C and
C-6), 72.8 (d, C-10), 75.7 (d, C-4), 78.3 (s, C-2), 127.6, 128.3, DPPA (89.0 μL, 0.413 mmol) was added. After stirring for 6 h
128.6, 137.3 (3 d, s, Ph) ppm; IR (ATR) : 3570, 3435 (OH), at 0 °C and 1 d at rt, the reaction mixture was quenched with
3085–3030 (=C-H), 2990–2855 (C-H), 1250, 1215 (C-O), 1060, water (2 mL) and extracted with EtOAc (3 × 5 mL). The
1040 (C-O-C) cm−1; ESI–TOF (m/z): [M + H]+ calcd for combined organic layers were washed with brine, dried with
C23H40NO5Si, 438.2670; found, 438.2702; anal. calcd for Na2SO4, filtered through cotton and the solvent was removed in
C23H39NO5Si (437.6): C, 63.12; H, 8.98; N, 3.20; found: C, vacuo. Crude material (yellow oil, 479 mg) was purified by
62.68; H, 8.96; N, 3.09.
column chromatography (silica gel, hexanes to hexanes/EtOAc
8:1) to yield azide 23 (125 mg, 79%) as a colorless solid; mp
117–121 °C; [α]D22 +22.7 (c 1.01, CHCl3); TLC (silica gel,
hexanes/EtOAc 3:1) Rf 0.73; 1H NMR (500 MHz, CDCl3)
Typical procedure for deprotection using
TBAF (procedure 4)
(1S,4S,5S,6R,10S)-7-Benzyl-4-(hydroxymethyl)-2,2- δ −0.11, −0.03 (2 s, 3H each, SiMe), 0.86 (s, 9H, Sit-Bu), 1.37,
dimethyl-3,8-dioxa-7-azabicyclo[4.3.1]decan-5,10-diol (14): 1.42 (2 s, 3H each, Me), 2.55 (t, J ≈ 2.8 Hz, 1H, 1-H), 3.05 (dd,
The TBS-protected alcohol (200 mg, 0.457 mmol) was J = 4.3, 12.3 Hz, 1H, 4-CH2), 3.36 (dd, J = 1.1, 2.8 Hz, 1H,
dissolved in THF (11 mL) and the solution was cooled to 0 °C. 6-H), 3.45 (dd, J = 8.7, 12.3 Hz, 1H, 4-CH2), 3.95 (A part of
After addition of TBAF (1 M in THF; 0.9 mL, 0.90 mmol), the AB system, JAB = 13.5 Hz, 1H, NCH2), 4.05 (mc, 1H, 5-H),
reaction mixture was stirred at this temperature for 10 min. 4.14 (B part of AB system, JAB = 13.5 Hz, 1H, NCH2), 4.18
Then the mixture was quenched with water (5 mL) and (mc, 2H, 9-H), 4.61 (ddd, J = 0.8, 4.3, 8.7 Hz, 1H, 4-H),
extracted with EtOAc (3 × 20 mL). The combined organic 7.27-7.35 (m, 5H, Ph) ppm; 13C NMR (125 MHz, CDCl3)
layers were washed with brine, dried with Na2SO4, filtered δ −4.8, −4.6 (2 q, SiMe), 18.2 (s, SiCMe3), 22.4 (q, Me), 25.8
through cotton and the solvent was removed in vacuo. The (q, SiCMe3), 31.6 (q, Me), 53.2 (t, 4-CH2), 58.1 (d, C-1), 58.7
crude material (yellow oil, 224 mg) was purified by column (t, NCH2), 67.9 (t, C-9), 69.4 (d, C-5), 74.2 (d, C-4), 75.0 (s,
chromatography (silica gel, hexanes/EtOAc 1:2 to pure EtOAc) C-2), 75.1 (d, C-6), 127.9, 128.66, 128.71, 136.2 (3 d, s, Ph),
to yield 14 (135 mg, 91%) as a colorless solid; mp 50–53 °C; 199.8 (s, C-10) ppm; IR (ATR) : 3090–3030 (=C-H),
[α]D22 −52.5 (c 0.6, MeOH); TLC (silica gel, hexanes/EtOAc 2855–2995 (C-H), 2095 (N3), 1710 (C=O), 1495 (C=C), 1295,
1:3): Rf 0.27; 1H NMR (700 MHz, CD3OD) δ 1.31, 1.49 (2 s, 1255 (C-O), 1190–1075 (C-O-C) cm−1; ESI–TOF (m/z):
3H each, Me), 2.13 (mc, 1H, 1-H), 3.34 (dd, J = 3.0, 5.0 Hz, 1H, [M + H]+ calcd for C23H37N4O4Si, 461.2579; found, 461.2607.
221

Beilstein J. Org. Chem. 2014, 10, 213–223.
Typical procedure for hydrogenolysis with
Pd/C in AcOH/MeOH (procedure 5)
Selter for experimental assistance. We acknowledge valuable
discussions and help during preparation of the manuscript by
(2S,3S,4R,5S,6S)-4-Amino-2,6-bis(hydroxymethyl)-7,7- Dr. R. Zimmer and J. Salta.
dimethyloxepan-3,5-diol (26): Bicyclic compound 14 (100 mg,
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This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
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(http://www.beilstein-journals.org/bjoc)
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43.We assume that the hydride reagent also attacks the Re-side, as in the
previous reductions (see Scheme 4 and Scheme 5). NMR data of the
corresponding alcohol are in accordance with this assignment.
44.Conditions used were analogous to procedures in ref [24].
223