Stereodivergent syntheses of highly substituted enantiopure 4-alkoxy-3,6-dihydro-2H-1,2-oxazines by addition of lithiated alkoxyallenes to carbohydrate-derived aldonitrones

FULL PAPER

Stereodivergent Syntheses of Highly Substituted Enantiopure 4-Alkoxy-3,6-

dihydro-2H-1,2-oxazines by Addition of Lithiated Alkoxyallenes to

Carbohydrate-Derived Aldonitrones

Matthias Helms,^[a]Wolfgang Schade,^[b]Robert Pulz,^[a]Toshiko Watanabe,^[b,c]

[a]

[d]

[a,d]

Gernot Zahn,^[e]and

ˇ

Ahmed Al-Harrasi, Lubor Fisera, Iva Hlobilová,

Hans-Ulrich Reißig*^[a]

Keywords: Allenes / Lithium / Nitrones / Carbohydrates / 1,2-Oxazines

Additions of lithiated alkoxyallenes to

D

-glyceraldehyde-

24 with excellent diastereoselectivity and in good yields. Bis-

nitrone 8 and lithiated methoxyallene furnished a mixture of

six compounds, among which the major componentwas the

C₂-symmetric syn/syn-1,2-oxazine 29. The diastereoselectivi-

ties of these reactions are interpreted on the basis of Don-

doni’s model for reactions between organolithium com-

pounds and nitrones. The mechanisms for formation of 1,2-

oxazines and of side products are discussed. The method in-

troduced here seems to be of broad applicability and an ex-

cellent tool for diastereoselective chain elongation of carbo-

hydrate derivatives, affording stereodefined precursors of

aminopolyols and other highly functionalized compounds.

based nitrones 1 and 2 did not provide the expected hydrox-

ylamine derivatives. Instead, a novel [3+3] cyclization pro-

cess furnished 4-alkoxy-3,6-dihydro-2H-1,2-oxazines 9–14

with excellent syn selectivities and in moderate to good

yields. Through precomplexation of the nitrones the corre-

sponding anti-configured 1,2-oxazines 9, 10 and 13 could be

obtained with high stereoselectivity. The reactions of nitro-

nes 3–6, derived from

D-erythrose or D-threose, generally

proceeded less diastereoselectively, but reasonable yields of

anti-configured 1,2-oxazines such as anti-17 and anti-19

could be obtained under Lewis acid promotion conditions.

This was also the case for reactions of the

D-arabinose-de- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

rived nitrone 7, which provided the anti-1,2-oxazines 23 and

Germany, 2005)

able of undergoing ring-closure to 1,2-oxazine derivatives

D, which are products of an overall [3+3] cyclization

(Scheme 1).

Introduction

During the last decade the addition of organometallic

reagents such as Grignard or organolithium compounds to

nitrones A, affording hydroxylamine derivatives

B

(Scheme 1), has become a very useful synthetic tool.^[1]Al-

though this reaction type has been known for a long time,

recent efforts—in particular by the groups of Dondoni^[2]

and Merino^[3]—have impressively demonstrated that highly

stereoselective reactions are possible, furnishing function-

alized compounds of considerable interest for syntheses of

natural products or their analogues. We expected that lithi-

ated alkoxyallenes^[4]should behave analogously, furnishing

1-alkoxy-1,2-propadienyl-substituted hydroxylamines C cap-

[a] Institut für Chemie, Freie Universität Berlin,

Takustr. 3, 14195 Berlin, Germany

E-mail: hans.reissig@chemie.fu-berlin.de

[b] Institut für Organische Chemie, Technische Universität

Dresden,

01062 Dresden, Germany

[c] Graduate School of Pharmaceutical Sciences, Chiba University,

1-33, Yayoi-cho, Inage, Chiba, 263-8522, Japan

[d] Department of Organic Chemistry, Slovak University of Tech-

nology,

81237 Bratislava, Slovak Republic

[e] Institut für Kristallographie und Festkörperphysik, Technische

Universität Dresden,

01062 Dresden, Germany

Scheme 1.

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DOI: 10.1002/ejoc.200400627

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Alternatively, cyclization to cyclic N-oxides E was also already been executed with 1,2-oxazines prepared from d-

conceivable. These reaction sequences would nicely sup- glyceraldehyde-derived nitrone 1.^[13]

plement earlier investigations with carbonyl compounds^[5]

and imines^[6]as electrophiles, which had provided the ex-

pected primary adducts and, under base or transition metal

catalysis conditions, had given dihydrofuran or dihydropyr-

role derivatives. The formal [3+2] cyclizations of methoxyal-

lene with these two-centre electrophiles were synthetically

very productive and allowed us several natural product syn-

theses^[7]and—possibly more importantly—led to com-

pletely unexpected reaction pathways providing interest-

ingly functionalized compounds^[8]not (easily) available by

alternative methods. We therefore hoped that similarly ver-

satile and surprising chemistry would be possible with

three-centre electrophiles such as nitrones A.

When lithiated alkoxyallenes were combined with nitro-

nes A, we were generally not able, much to our surprise, to

isolate the expected primary adducts C. Instead, the reac-

tion in most cases directly delivered the desired 4-alkoxy-

3,6-dihydro-2H-1,2-oxazines D. Only when sterically de-

manding substituents were present at the nitrone could the

hydroxylamines C be isolated.^[9]These slowly cyclize to give

the expected 1,2-oxazines D—in exceptional cases as mix-

tures with the corresponding cyclic N-oxides E.^[10]Similar

transformations were reported by Dulcère et al., who added

1-lithio-1,2-propadiene to several nitrones and observed

slow isomerization of the expected primary adducts to the

corresponding 1,2-oxazines.^[11]In this paper we present de-

tails of the [3+3] cyclizations of several lithiated alkoxyall-

enes with carbohydrate-derived nitrones. The resulting 4-

alkoxy-3,6-dihydro-2H-1,2-oxazines F are of particular syn-

thetic interest, since they are very versatile functionalized

building blocks employable for stereocontrolled syntheses

of saturated 1,2-oxazines (aza sugars) G, amino sugar deriv-

Results

We investigated the reactions between lithiated alkoxyall-

enes and nitrones 1–8 (Scheme 3), derived from d-glyceral-

dehyde, d-erythrose, d-threose, d-arabinose and d-manni-

tol. Whereas syntheses of nitrones 1–7 have been reported

in the literature,^[14]the preparation of the new C₂-symmetric

bis-nitrone 8 is described here (Scheme 10). The viability of

the use of different alkoxy groups at the allene moiety was

studied, because the benzyloxy and the (trimethylsilyl)-

ethoxy substituents allow transformations and cleavage

conditions not possible with simple alkoxy groups such as

methoxy groups. The known literature synthesis of (tri-

methylsilyl)ethoxyallene^[15]was simplified by performing

the two steps—propargylation of 2-(trimethylsilyl)ethanol

and subsequent base-promoted alkyne–allene isomeriza-

tion—as a one-pot procedure [Equation (1)].

atives

H

or—after recyclization—imino sugars

I

(Scheme 2). All these compounds are of interest because of

their biological activities.^[12]Most of the transformations

outlined in Scheme 2 and other interesting reactions have

Scheme 3.

(1)

The d-glyceraldehyde-derived N-benzyl nitrone 1 was

chosen as a standard substrate to study the addition condi-

tions. Deprotonation of five different alkoxyallenes with n-

butyllithium was performed under standard conditions

(–40 °C in tetrahydrofuran as solvent), and the resulting lithi-

ated species were combined with nitrone 1 at –78 °C. As

mentioned above, aqueous workup directly furnished the 4-

Scheme 2.

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Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines

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alkoxy-3,6-dihydro-2H-1,2-oxazines 9–13, and after brief discussion of their generation as well as the explana-

chromatography these products of a new [3+3] cyclization tion of the diastereoselectivity of the 1,2-oxazine formation

process were isolated in moderate to high yields. In our first is presented below (Schemes 12 and 14).

experiments we employed lithiated methoxyallene in large

Remarkably and very gratifyingly, the stereochemical

excess (up to 20 equivalents), but it turned out that this is outcomes of the additions of lithiated alkoxyallenes to

not a prerequisite to obtain reasonable yields and that 1.2 nitrone 1 could be completely switched to high anti selectiv-

to 3 equiv. are sufficient. Most importantly, the diastereofa- ity. For this purpose the nitrone has to be precomplexed

cial selectivity under the conditions employed is excellent, with the mild Lewis acid diethylaluminium chloride before

giving the syn-configured products exclusively or with very addition of the lithiated allene species. Diethyl ether was

high preference. The ratios of diastereomers given in the solvent of choice, giving better selectivities and yields.

Scheme 4 refer to the crude products, whereas the purified After chromatography, the desired 1,2-oxazines anti-9, anti-

1,2-oxazine derivatives syn-9 to syn-13 were essentially dia- 10 and anti-13 were obtained in diastereomerically pure

stereomerically pure (syn/anti Ͼ 98:2). The determination form and in good yields (Scheme 5). Again, small amounts

of the relative configurations is discussed below. For a sub- (5–10 %) of 1,3-dienes 15 were detected in the crude pro-

sequent product of syn-9 we were able to establish that the duct mixtures, but these were easily removed during purifi-

enantiomeric purity of the nitrone 1 was fully transferred cation. Similar stereodivergent behaviour has been de-

to the 1,2-oxazine.^[13c,13e]

scribed in the seminal report by Dondoni et al.,^[2a]who

treated 1 and related nitrones with organolithium and Grig-

nard compounds. From the experience of this group we just

examined diethylaluminium chloride as Lewis acid with our

lithiated alkoxyallenes, but cannot exclude the possibility

that alternative Lewis acids may be superior for other nitro-

nes.

Scheme 5.

The additions of lithiated methoxyallene to nitrones 3–8

were less diastereoselective, though in certain cases satisfac-

tory levels could be observed. The O-silylated nitrone 3,

derived from d-erythrose, and lithiated methoxyallene

formed the expected 1,2-oxazine 16 in a 62:38 anti/syn ratio,

from which anti-16 and syn-16 could be gained pure in

moderate yields (Scheme 6). Remarkably, addition of an ex-

cess of lithiated methoxyallene to the O-unprotected nitrone

4 furnished a crude product mixture with inverted diaster-

eoselectivity, but the preference for syn-17 was only very

Scheme 4.

The closely related N-methyl nitrone 2 behaves very simi- modest. Purification by chromatography on alumina al-

larly to 1, giving the syn-configured 1,2-oxazine 14 in mod- lowed the isolation of syn-17 in 33 % yield and of anti-17

erate yield and diastereomerically almost pure. The substit- in 15 % yield. In our initial attempts we routinely chromato-

uent at the nitrone nitrogen does not seem to have a crucial graphed the crude product mixtures on silica gel, which

influence on the diastereoselectivity of this overall [3+3] promoted the (acid-induced) addition of the free hydroxy

cyclization. A further interesting feature of these reactions group to the enol ether moiety of the 1,2-oxazine fragment,

is the formation of 1,3-dienes 15 as side products. These thereby providing the two tricyclic compounds 18a and 18b

compounds were observed in amounts of 0 to 20 % (in the in low yields. Fortunately, the relative configurations of

crude product mixtures), the exact portion depending on these compounds could be unequivocally determined by

the substrates, but also on the individual experiment. A NOE experiments. As a consequence, this also established

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the relative configurations of the precursor structures syn- lowed isolation of anti-16, anti-17 and anti-19 in satisfac-

17 and anti-17, as well as those of the related protected tory yields after chromatography, it has to be stated that

derivatives syn-16 and anti-16. The N-methyl-substituted the perfect stereodivergent behaviour of nitrone 1 is not ob-

nitrone 5 and lithiated methoxyallene again showed moder- served with these more complex nitrones. Apparently, the

ate anti selectivity, but the resulting 1,2-oxazines anti-19 and diastereofacial selectivity is dependent on several effects in

syn-19 could be separated only with difficulty; one of the comparison to the reactions in the “simple” case of nitrone

major fractions after the chromatography was still a mix- 1.

ture of diastereomers.

Scheme 7.

The diastereomeric d-threose-derived nitrone 6 accepted

excesses of lithiated methoxyallene and of its trimethylsilyl-

ethoxy analogue with moderate to very good syn selectivi-

ties, furnishing the expected 1,2-oxazines syn-20 and syn-21

as major [3+3] cyclization products (Scheme 8). Precom-

plexation of 6 with diethylaluminium chloride again in-

Scheme 6

duced the distinctly preferred formation of the correspond-

Under standard conditions (in tetrahydrofuran as sol- ing anti-1,2-oxazines. Chromatography allowed the isola-

vent), compounds 3–5 showed a considerably higher ten- tion of pure syn-20 or anti-20. For the trimethylsilylethoxy-

dency than the glyceraldehyde-derived nitrones 1 and 2 to substituted compounds 21 the crude products were not

form anti-configured 1,2-oxazines. It was of interest purified but were directly converted into the O-tert-butyldi-

whether this anti selectivity might be enhanced by diethylal- methylsilyl-protected derivatives syn-22 and anti-22, which

uminium chloride precomplexation of the nitrones, which could be obtained diastereomerically pure after chromatog-

had induced the perfect stereochemical switch of nitrone 1 raphy in good or moderate yield.

as electrophile. Indeed, a remarkable shift in favour of the

Under standard conditions, the d-arabinose-derived

formation of the anti-1,2-oxazines 16, 17 and 19 could be nitrone 7 showed only modest syn selectivity in its reactions

observed under these conditions (Scheme 7), although the with lithiated methoxyallene and the trimethylsilylethoxy

level of anti/syn selectivity here was only in the 85:15 range. analogue, but the Lewis acid-assisted method allowed

Although this modification of the reaction conditions al- highly diastereoselective preparation of the desired anti iso-

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Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines

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Scheme 9.

combined yield. The first three fractions provided the bis-

diene 27 (4 %) and the dienyl-substituted 1,2-oxazines 28

(4 % and 19 %). We assume that the major diastereomer of

28 is syn-configured, as depicted in Scheme 11. Fraction 4

contained the main component of the addition reaction, a

bis-1,2-oxazine 29 in 25 % yield. From its symmetry—

Scheme 8.

mers (Scheme 9). The 1,2-oxazines anti-23 and anti-24, po- clearly expressed by the number of NMR signals ob-

tential precursors for the synthesis of neuraminic acid deriv- served—we assigned its structure as syn/syn-29, which was

atives,^[16]were isolated in moderate yields.

unequivocally confirmed by an X-ray analysis (Figure 1).^[19]

Finally, we prepared the C₂-symmetric bis-nitrone 8 and The smaller fraction 5 afforded the second symmetrically

studied its bidirectional reactions^[17]with lithiated meth- configured bis-1,2-oxazine, which must be anti/anti-29. The

oxyallene. Precursor 25 was prepared from d-mannitol as last fraction contained a bis-1,2-oxazine as major compo-

described,^[18]and oxidative diol cleavage efficiently provided nent; this had more complex NMR spectroscopic data and

the dialdehyde 26, which was directly condensed with N- was assigned as the missing third possible diastereomer syn/

methylhydroxylamine hydrochloride (Scheme 10). This anti-29.^[20]

straightforward two-step procedure afforded a 75 % overall

The diethylaluminium chloride-promoted reaction be-

yield of the desired bis-nitrone 8, which was easily purified tween the bis-nitrone 8 and lithiated methoxyallene pro-

by recrystallization and may be regarded as a derivative of ceeded less cleanly and gave lower yields. However, the ex-

d-tartaric acid.

pected shift to higher anti selectivities was observed: 20 %

Addition of an excess of lithiated methoxyallene to bis- of anti/anti-29, 10 % of syn/anti-29, and roughly equivalent

nitrone 8 under standard conditions not unexpectedly fur- amounts of anti-28 and syn-28 (5 % each) were isolated.

nished a relatively complex mixture consisting of at least These experiments clearly demonstrate that under standard

six different compounds (Scheme 11). Most of them were conditions syn selectivity dominates for the first and the

isolated in pure form after careful chromatography, in 67 % second addition of lithiated methoxyallene to bis-nitrone 8.

Scheme 10.

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Scheme 11

syn configurations. Precomplexation of the nitrone by di-

ethylaluminium chloride apparently gives rise to an alterna-

tive reactive conformation (pathway b), in which attack by

the organolithium compound should generate the anti pro-

duct in excess. It is assumed that the nitrone oxygen and

the β-oxygen of the dioxolane ring provide the chelating

ligands for the Lewis acid.

Figure 1. Structure of 1,2-oxazine syn/syn-29 (ORTEP representa-

tion, hydrogen atoms are shown only at the stereogenic centres)

The Lewis acid-promoted process shows distinct anti selec-

tivity for both steps. However, the inevitable fragmentations

of the primary adducts into bis-dienes 27 and the dienyl-

substituted 1,2-oxazine 28 prevent exact determination of

syn/syn:syn/anti:anti/anti selectivities. The different stereo-

isomers of the intermediate primary double adducts may

undergo fragmentation at differing rates, thus changing the

original ratios of diastereomers.

Scheme 12

The diastereoselectivities observed with nitrones 3–8 are

less pronounced than those seen with nitrones 1 and 2 and

so a discussion in detail is less straightforward and is omit-

ted. The predominance of Felkin–Anh-type conformations

seems to be lower, resulting in weaker syn selectivities; anti

selectivity could generally be induced by diethylaluminium

chloride precomplexation, but even then the perfect syn to

Discussion

The diastereoselectivity of the 1,2-oxazine synthesis by anti shift could not be observed. It is obvious that the pres-

[3+3] cyclizations as reported here is determined during the ence of additional oxygen atoms in the nitrone side chain

first C–C bond-forming step, the addition of the lithiated will increase the possibilities for complexation either with

allene to the nitrone carbon. It therefore appears justifiable the lithium cation or with the added Lewis acids, so any

to employ the model suggested by Dondoni et al.^[2a]for ad- more detailed discussion would be highly speculative. Mod-

ditions of other organolithium compounds or Grignard erate anti-selective additions of other organolithium com-

reagents to d-glyceraldehyde-derived nitrones 1 and 2 as pounds to nitrone 7 have been reported by Dondoni

electrophiles. This group proposed that in the absence of et al.^[2a]

Lewis acid the attack of the organolithium species follows

Our assignments for compounds syn- and anti-9 (and

the stereoelectronically more favourable Felkin–Anh path- their closely related analogues depicted in Schemes 4 and

way, with a preferred conformation of the nitrone as illus- 5) were first based on this analogy to Dondoni’s results, but

trated in Scheme 12 (pathway a), affording products with we were finally able to verify the configuration of anti-9

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Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines

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unambiguously by its conversion into a brominated product may be avoided by proton catalysis resulting in the well sta-

and an X-ray analysis of this compound.^[13d,21]The assign- bilized allylic cation M. This may combine with the hydrox-

ments of configurations for the other 1,2-oxazines reported ylamine oxygen via intermediate N, giving rise after depro-

here are based on analogy and on careful NMR analyses tonation to D. Alternatively, M may also provide E through

of the compounds or their derivatives (e.g., of tricyclic reaction of the hydroxylamine nitrogen.^[22]The report by

products such as 18a and 18b). One significant NMR crite- Dulcère et al.^[11]mentioned above proposes an alkenyl aziri-

rion could be found in the difference of the chemical shifts dine N-oxide O as intermediate for the cyclization, which

for 6-H_Aand 6-H_Bof syn- and anti-configured 1,2-oxazines. should be formed by a reverse Cope elimination and sub-

Whereas for anti compounds the two protons have very sim- sequently undergo a ring expansion to give the 1,2-oxazine.

ilar δ values (ca. 4.3 ppm), the chemical shifts of syn-config- We do not see an unambiguous argument for the involve-

ured products generally show two distinct signals (ca. 4.15 ment of this highly strained intermediate either in their or

and 4.45 ppm) (see Table 1). This criterion was also valid in our systems.

for the bis-1,2-oxazines syn/syn-29 and anti/anti-29, thus

strongly supporting our assignment as depicted in of 1,3-dienes such as 15 (Scheme 4), which were isolated in

Scheme 11. various quantities in almost all addition reactions. In se-

The third mechanistic question concerns the formation

A second intriguing mechanistic question involves the veral experiments with N-benzyl-substituted nitrones we ac-

C–O bond formation during the [3+3] cyclization process. We tually isolated small amounts of benzaldehyde oxime, which

assume that the formation of the 1,2-oxazine ring occurs probably arises through tautomerization of the extruded

only after aqueous workup. An anionic cyclization of pri- benzylnitroso compound. Control reactions with syn-9 and

mary intermediate J before protonation would require as anti-9 showed these 1,2-oxazines to be stable under the re-

intermediate a cyclic alkenyl anion K, which seems energeti- action conditions applied for the addition of lithiated alkoxy-

cally rather unfavourable (Scheme 13). Therefore, after allenes. This suggests the conclusion that 1,2-oxazines D are

quenching with water, the primary addition product J is stable and do not undergo an imaginable retro Diels–Alder

protonated at oxygen, furnishing the hydroxylamine deriva- reaction to give 1,3-diene P and nitroso compound Q, fi-

tive C. In certain cases—mostly with sterically more de- nally resulting in an oxime (Scheme 14). We therefore have

manding substituents at the nitrone carbon or nitrogen— to assume that the fragmentation to P and Q occurs at the

these compounds can be isolated. However, they slowly cy- stage of the intermediate, and not generally isolable, hy-

clize at room temperature to the 1,2-oxazines D, with the droxylamine derivative C. This process may be classified as

cyclic N-oxides E being obtained in certain cases as minor a retro-nitroso-ene reaction.^[23]So far it is not clear which

or major products.^[10]The mechanism of the cyclization structural details of the components or which specific reac-

step to D (or E) is still not trivial: a zwitterionic intermedi- tion conditions promote fragmentation of C into P

ate such as L, again containing an alkenyl anion moiety, and Q.

Scheme 13.

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thylsilyl)-d-erythro-1-ylidene]benzylamine N-oxide (3),^[14c](Z)-N-

(1-deoxy-2,4-O-ethylidene-d-erythro-1-ylidene)benzylamine N-ox-

ide (4),^[14d,14e](Z)-N-(1-deoxy-2,4-O-ethylidene-d-erythro-1-yli-

dene)methylamine N-oxide (5),^[14d,14e](Z)-N-(1-deoxy-2,4-O-ethyli-

dene-d-threo-1-ylidene)benzylamine N-oxide (6),^[14d,14e](Z)-N-(1-

deoxy-2,3:4,5-di-O-isopropylidene-d-arabino-1-ylidene)benzylamine

N-oxide

(7),^[14a]

(4R,5R)-2,2-dimethyl-[1,3]dioxolane-4,5-di-

carbaldehyde (25),^[18]methoxyallene^[26]and propoxyallene^[27]were

prepared by literature procedures. All other chemicals are commer-

cially available and were used without further purification. Tetrahy-

drofuran and diethyl ether were freshly distilled from sodium/

benzophenone under argon for all reactions, dichloromethane was

distilled from calcium hydride and stored over molecular sieves

(4 Å). Products were purified by flash chromatography on silica

gel (230–400 mesh, Merck) or neutral alumina (activity III, Fluka).

Preparative MPLC was performed on a “Büchi 680“ system with

silica gel (Ͼ 400 mesh, Merck) and preparative HPLC was carried

out on a Nucleosil 50–5 column and detected with a Knauer vari-

able UV-detector (λ = 255 nm) and a Knauer refractometer. Unless

otherwise stated, yields refer to analytically pure samples. Isomer

1

ratios were derived from suitable H NMR integrals.

Scheme 14.

¹H [CHCl₃(δ =7.25 ppm) or TMS (δ =0.00 ppm) as internal stan-

dard] and ¹³C NMR spectra [CDCl₃(δ = 77.0 ppm) as internal

standard] were recorded on Bruker AC 200, AC 250, AM 270,

AC 300, DRX 500 or AC 500 or Joel Eclipse 500 instruments in

CDCl₃solution. Missing signals are hidden by signals of the second

compound or could not be unambiguously identified due to low

intensity. Integrals are in accordance with assignments; coupling

constants are given in Hz. IR spectra were measured with an FT-

IR spectrometer Nicolet 5 SXC and 205 (Perkin–Elmer) and gas-

phase IR spectra were measured with an HP 5965B FT-IRD spec-

trometer (Hewlett–Packard). MS and HRMS analyses were per-

formed on Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT 95 (EI,

70 eV), MAT CH7A (EI, 80 eV, 3 kV) and CH5DF (FAB, 80 eV,

3 kV) instruments. The elemental analyses were recorded with “Ele-

mental-Analyzers“ (Perkin–Elmer or Carlo Erba). Melting points

were measured with a Reichert apparatus or after Boëtius on a

Rapido apparatus and are uncorrected. Optical rotations ([α]_D)

were determined with Perkin–Elmer 141 or Perkin–Elmer 241 po-

larimeters at the temperatures given.

Conclusions

We have been able to demonstrate here that carbo-

hydrate-derived nitrones 1–7 react with lithiated alkoxyall-

enes to give highly functionalized dihydro-1,2-oxazine de-

rivatives in moderate to excellent yields. This novel [3+3]

cyclization of nitrones and allenes has no literature prece-

dence, though a very recently described reaction between

nitrones and electron-deficient cyclopropanes to provide

tetrahydro-1,2-oxazines should be mentioned in this con-

text.^[24]Gratifyingly, additions of lithiated alkoxyallenes

with nitrones are highly stereoselective, mostly giving syn-

configured 1,2-oxazines under standard conditions, whereas

anti compounds are produced in excess through precom-

plexation of the nitrones with diethylaluminium chloride.

Since the received 1,2-oxazines can be transformed into a

variety of cyclic and acyclic enantiopure compounds, the

stereodivergent method described here is an excellent tool

for efficient chain-elongations of carbohydrates.

Although the overall yields for C₂-symmetric compounds

such as syn/syn-29 and anti/anti-29 are low, products of this

type should be synthetically particularly valuable. They are

relatively easy to prepare by bidirectional [3+3] cyclization

of smoothly available bis-nitrone 8 and they could serve as

stereodefined polyfunctional building blocks with ten con-

secutive heteroatom-substituted carbon atoms. Synthetic

applications of enantiopure 1,2-oxazines described here will

be reported in due course.^[25]

Benzyloxyallene: Potassium tert-butoxide (5.42 g, 48.4 mmol) was

added to a solution of benzyl propargyl ether (14.5 g, 99.1 mmol)

in toluene (280 mL). The suspension was warmed to 100 °C and

stirred for 1 h. After the mixture had cooled to room temperature,

H₂O (150 mL) was added. The aqueous phase was extracted with

diethyl ether (3 × 150 mL), the combined organic extracts were

dried (MgSO₄), and the solvents were removed. Purification by col-

umn chromatography on alumina (hexane/ethyl acetate 40:1) gave

benzyloxyallene (9.59 g, 68 %) as a yellow oil. ¹H NMR (CDCl₃,

4

250 MHz): δ = 4.70 (s, 2 H, CH₂Ph), 5.59 (d, J = 3.7 Hz, 2 H, 3-

H), 6.95 (t, ⁴J = 3.7 Hz, 1 H, 1-H), 7.40–7.48 ppm (m, 5 H, Ph).

¹³C NMR (CDCl₃, 62.9 MHz): δ = 72.1 (t, CH₂Ph), 90.9 (t, C-3),

121.5 (d, C-1), 126.7, 128.5, 128.9, 137.1 (3 × d, s, Ph), 201.2 ppm

(s, C-2).

One-Pot Synthesis of 2-(Trimethylsilyl)ethoxyallene as Variation of

Experimental Section

Ref.^[15]: 2-(Trimethylsilyl)ethanol (4.12 g, 34.9 mmol) was slowly

General Methods: Reactions were generally performed under argon

in flame-dried flasks, and the components were added by syringe.

The starting materials nitrones (Z)-N-(1-deoxy-2,3-O-isopropylid-

added at 0 °C to a suspension of sodium hydride (1.40 g,

35.0 mmol, 60 % in paraffin oil) in tetrahydrofuran (17 mL). After

stirring for 2 h at room temperature, the suspension was cooled to

ene-d-glycero-1-ylidene)benzylamine N-oxide (1),^[14a](Z)-N-(1-de- 0 °C, and propargyl bromide (4.57 g, 38.9 mmol) was added drop-

oxy-2,3-O-isopropylidene-d-glycero-1-ylidene)methylamine N-ox-

wise. After the system had been stirred for 3 d at room temperature,

potassium tert-butoxide (1.12 g, 10.0 mmol) was added and the re-

ide (2),^[14b](Z)-N-[1-deoxy-2,4-O-ethylidene-O³-(tert-butyldime-

1010

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Eur. J. Org. Chem. 2005, 1003–1019

Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines

FULL PAPER

action mixture was stirred under reflux for 6 h. After removal of

the solvent in vacuo the residue was distilled bulb-to-bulb from a

70 °C bath at 16 mbar to give the product (4.02 g, 74 %) as a

colourless liquid. ¹H NMR (CDCl₃, 500 MHz): δ = 0.01 (s, 9 H,

SiMe₃), 0.99 (t, ³J = 8.5 Hz, 2 H, CH₂Si), 3.63 (t, ³J = 8.5 Hz, 2 H,

OCH₂), 5.40 (d, J = 5.8 Hz, 2 H, 3-H), 6.68 ppm (t, J = 5.8 Hz,

1 H, 1-H). ¹³C NMR (CDCl₃, 126 MHz): δ = –1.4 (q, SiMe₃), 17.8

(t, CH₂Si), 66.3 (t, OCH₂), 90.0 (t, C-3), 121.2 (d, C-1), 201.5 ppm

(s, C-2).

1065 cm^–1(C–O–C). MS (EI, 80 eV): m/z (%) = 305 (2) [M]⁺, 204

(61) [M – C₅H₈O₂]⁺, 91 (100) [C₇H₇]⁺, 43 (24) [C₃H₇]⁺. C₁₇H₂₃NO₄

(305.4): calcd. C 66.86, H 7.59, N 4.59; found C 66.73, H 7.90, N

4.95.

When the reaction was performed with 1.7 equiv. of lithiated meth-

oxyallene only a slight decrease in the yield of the 1,2-oxazine (to

78 %) was observed.

4

(E)- and (Z)-(4S)-4-(2Ј-Methoxy-1Ј,3Ј-butadienyl)-2,2-dimethyl-1,3-

dioxolane (15) (R = Me): (E) isomer: ¹H NMR (CDCl₃, 300 MHz):

δ = 1.42, 1.46 (2 × s, each 3 H, Me), 3.55 (t, ^2,3J = 8.1 Hz, 1 H, 5-

One-Pot Synthesis of 3,3-Dimethylbutoxyallene: 3,3-Dimethylbu-

tan-1-ol (5.00 g, 48.9 mmol) was added slowly at 0 °C to a suspen-

sion of sodium hydride (1.96 g, 49.0 mmol, 60 % in paraffin oil) in

tetrahydrofuran (25 mL). After stirring for 2 h at room tempera-

ture, the suspension was cooled to 0 °C, and propargyl bromide

(6.41 g, 54.5 mmol) was added dropwise. After the system had been

stirred for 3 d at room temperature, potassium tert-butoxide

(1.57 g, 14.0 mmol) was added, and the reaction mixture was

stirred under reflux for 6 h. After removal of the solvent in vacuo,

the residue was distilled bulb-to-bulb (70 °C/10 mbar) to give the

product (4.00 g, 58 %) as a colourless liquid. ¹H NMR (CDCl₃,

500 MHz): δ = 1.34 (s, 9 H, tBu), 1.56 (t, ³J = 7.3 Hz, 2 H,

2

H_A), 3.63 (s, 3 H, OMe), 4.09 (dd, J = 8.1, ³J = 5.8 Hz, 1 H, 5-

H_B), 4.61 (dd, ⁵J = 0.7, ³J = 8.9 Hz, 1 H, 1Ј-H), 4.91 (ddd, ³J =

2

3

5.8, 8.1, 8.9 Hz, 1 H, 4-H), 5.25 (dd, J = 2.0, J = 11.0 Hz, 1 H,

4Ј-H_A), 5.71 (ddd, ²J = 2.0, ³J = 17.1, ⁵J = 0.7 Hz, 1 H, 4Ј-H_B),

6.55 ppm (dd, ³J = 11.0, 17.1 Hz, 1 H, 3Ј-H). (Z) isomer: ¹H NMR

2

3

(CDCl₃, 300 MHz): δ = 5.88 (dd, J = 1.5, J = 10.5 Hz, 1 H, 4Ј-

3

H_A), 6.78 (dd, J = 10.5, 17.5 Hz, 1 H, 3Ј-H); all other signals are

hidden by the signals of the (E) isomer. ¹³C NMR (CDCl₃,

50 MHz): δ = 26.1, 27.0 (2 × q, Me), 54.6 (q, OMe), 70.3 (t, C-5),

72.4 (d, C–4), 98.6 (d, C-1Ј), 108.9 (s, C-2), 127.1 (t, C-4Ј), 127.7

3

4

(d, C-3Ј), 156.1 ppm (s, C-2Ј). IR (gas phase): ν = 2990, 2950, 2880

˜

CH₂tBu), 3.58 (t, J = 7.3 Hz, 2 H, OCH₂), 5.40 (d, J = 5.7 Hz,

2 H, 3-H), 6.68 ppm (t, ⁴J = 5.7 Hz, 1 H, 1-H). ¹³C NMR (CDCl₃,

126 MHz): δ = 23.7, 29.6 (s, q, tBu), 42.3 (t, CH₂tBu), 66.1 (t,

OCH₂), 90.1 (t, C-3), 121.5 (d, C-1), 201.5 ppm (s, C-2). MS (EI,

80 eV, 30 °C): m/z (%) = 141 (10) [M + H]⁺, 85 (97) [C₆H₁₃]⁺, 57

(100) [C₄H₈⁺].

(=C–H, C–H), 1650, 1590 (C=C), 1060 cm^–1(C–O–C). MS (EI,

80 eV): m/z (%) = 184 (20) [M]⁺, 169 (18) [M – CH₃]⁺, 109 (51), 72

(68), 43 (100). C₁₀H₁₆NO₃(184.2): calcd. C 65.19, H 8.38; found

C 65.85, H 8.38.

(3S,4ЈS)-2-Benzyl-4-benzyloxy-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-

yl)-3,6-dihydro-2H-1,2-oxazine (syn-10): Lithiated benzyloxyallene

(3.00 mmol) was treated with nitrone 1 (0.517 g, 2.20 mmol) at

–78 °C in tetrahydrofuran for 2 h as described in GP 1. Column

chromatography of the crude product (syn/anti Ͼ 94:6) on silica gel

(hexane/ethyl acetate 9:1) gave syn-10 (syn/anti 95:5, 0.568 g 68 %)

as colourless crystals and anti-10 (0.005 g, 1 %) as a colourless oil.

The 1,3-butadiene was obtained as a colourless oil (0.067 g, 12 %,

E/Z 86:14). m.p. 108–110 °C. [α]²_D⁰= +38.0 (c = 0.56, CHCl₃). IR

General Procedure 1: Lithiated allene was generated in situunder

an atmosphere of dry argon by treatment of a solution of the allene

in tetrahydrofuran (3 mL per mmol nitrone) at –40 °C with nBuLi

(2.5 m in hexanes). After 5 min, the resulting solution was cooled

to –78 °C, and a solution of the nitrone in tetrahydrofuran (1 mL

per mmol nitrone) was added over a period of 5 min. The mixture

was stirred at –78 °C for the period given in the individual experi-

mental procedures and was then quenched with H₂O. Warming to

room temperature was followed by extraction with diethyl ether

and drying (MgSO₄or Na₂SO₄) of the combined extracts.

(film): ν = 2985–2885 (C–H), 1670 cm^–1(C=C). MS (EI, 80 eV):

˜

m/z (%) = 381 (1) [M]⁺, 366 (2) [M – CH₃]⁺, 280 (52) [M –

C₅H₉O₂]⁺, 91 (100) [C₇H₇]⁺. C₂₃H₂₇NO₄(381.5): calcd. C 72.42, H

7.13, N 3.67; found C 71.74, H 7.30, N 3.48.

General Procedure 2: Under an atmosphere of dry argon, the

nitrone was treated for 10 min at room temperature with Et₂AlCl

(1.0 m in hexanes, 1 equiv.) in diethyl ether (1 mL per mmol

nitrone). Lithiated allene was generated in situin a second flask

under an atmosphere of dry argon by treatment of a solution of

the allene in diethyl ether (3 mL per mmol nitrone) at –40 °C with

nBuLi (2.5 m in hexanes). After 5 min, the resulting solution was

cooled to –78 °C, and the complex of nitrone with Et₂AlCl was

added by syringe over a period of 5 min. The mixture was stirred

at –78 °C for a period given in the individual experimental pro-

ceduresand was then quenched with sodium hydroxide solution

(2 m). Warming to room temperature was followed by extraction

with diethyl ether and drying of the combined extracts.

(3S,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-propoxy-

3,6-dihydro-2H-1,2-oxazine (syn-11): Lithiated propoxyallene

(10.5 mmol) was treated with nitrone 1 (1.93 g, 8.21 mmol) at

–78 °C in tetrahydrofuran for 1.5 h as described in GP 1. After

workup, the crude product (1.05 g) was obtained as a pale yellow

oil (1,2-oxazine/diene 99:1, syn/anti 99:1). Column chromatography

on silica gel (hexane/ethyl acetate 9:1) gave syn-11 (0.881 g, 32 %)

as a colourless oil. [α]²_D²= +13.5 (c = 1.41, CHCl ). IR (KBr): ν =

˜

3

3085–3030 (=C–H), 2980–2840 (C–H), 1670 cm^–1(C=C). MS (EI,

80 eV): m/z (%) = 333 (10) [M]⁺, 318 (3) [M – CH₃]⁺, 232 (100) [M –

C₅H₉O₂]⁺, 91 (94) [C₇H₇]⁺. C₁₉H₂₇NO₄(333.4): calcd. C 68.44, H

8.16, N 4.20; found C 68.61, H 8.23, N 4.20.

1

The H and ¹³C NMR spectroscopic data of 1,2-oxazines derived

from nitrone 1 and 2 are given in Tables 1 and 2.

(3S,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-(3,3-di-

(3S,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-methoxy- methylbutoxy)-3,6-dihydro-2H-1,2-oxazine (syn-12): Lithiated 3,3-

3,6-dihydro-2H-1,2-oxazine (syn-9): Lithiated methoxyallene dimethylbutoxyallene (4.12 mmol) was treated with nitrone 1

(22.8 mmol) was treated with nitrone 1 (0.536 g, 2.28 mmol) at (0.780 g, 3.32 mmol) at –78 °C in tetrahydrofuran for 2 h as de-

–78 °C in tetrahydrofuran for 1 h as described in GP 1. After scribed in GP 1. After workup, the crude product (1.05 g) was ob-

workup a dark yellow oil (0.810 g) was obtained (1,2-oxazine/diene

Ϸ 80:20, syn/anti Ͼ 98:2). Column chromatography on alumina

(hexane/ethyl acetate 6:1) gave syn-9 (0.562 g, 81 %) as a colourless

oil. The 1,3-butadiene 15 (R = Me) was obtained as a colourless

oil (33 mg, 8 %, E/Z 95:5). [α]²_D⁸= +22.6 (c = 2.6, CHCl₃). IR (gas

tained as a pale yellow oil (syn/anti 92:8). Column chromatography

on silica gel (hexane/ethyl acetate 9:1) and HPLC (hexane/ethyl

acetate 9:1) gave syn-12 (0.442 g, 37 %) as colourless crystals. M.p.

65–67 °C. [α]²_D²= +21.4 (c = 0.56, CHCl ). IR (KBr): ν = 3085–

˜

3

3030 (=C–H), 2985–2840 (C–H), 1670 (C=C), 1250 cm^–1(C–O).

phase): ν = 3070–3035 (=C–H), 2990–2850 (C–H), 1670 (C=C), MS (EI, 80 eV): m/z (%) = 375 (6) [M]⁺, 274 (80) [M – C₅H₉O₂]⁺,

˜

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1011

H.-U. Reißig et al.

FULL PAPER

1

Table 1. H NMR data for 1,2-oxazines derived from nitrones 1 and 2

3-H

5-H

6-H

4Ј-H

5Ј-H

R

RЈ

Me

syn-9

3.24 (dd,

4.74 (dd,

4.13 (dd,

4.52 (q,

3.90 (d,

3.55 (s)

4.12 (s)

7.20–7.50

(m)

1.32 (s)

1.38 (s)

³J = 7.0 Hz,

⁴J = 1.4 Hz)

³J = 1.8 Hz,

³J = 3.5 Hz)

²J = 15.0 Hz,

³J = 3.5 Hz)

4.40 (td,

³J = 7.0 Hz)

²J = 15.0 Hz,

³J = 1.8 Hz)

4.17 (dd,

syn-10

syn-11

3.36 (d,

4.86 (m_c)

4.60 (dt,

3.93–3.95 (m) 4.71, 4.77 (2 × d,

²J = 11.6 Hz)

4.16 (s)

7.23–7.43

(m)

1.35 (s)

1.38 (s)

³J = 7.4 Hz)

²J = 14.5 Hz,

³J = 3.3 Hz)

4.43 (d_br,

³J = 6.9 Hz,

³J = 7.4 Hz)

7.23–7.43 (m)

²J Ϸ 14.5 Hz)

4.12 (dd,

3.28 (dd,

4.71 (dd,

4.56 (dt,

3.92 (m_c)

0.97 (t, ³J Ϸ 7.3 Hz,

3ЈЈ-H)

4.15 (s_br

)

1.36 (s)

1.40 (s)

³J = 7.5 Hz,

⁴J = 1.0 Hz)

³J = 1.8 Hz,

³J = 3.4 Hz)

²J = 14.6 Hz,

³J = 3.4 Hz)

4.40 (dd,

³J = 6.4 Hz,

³J = 7.5 Hz)

7.24–7.42

(m)

1.69 (sextet, ³J = 7.3

Hz, 2 H, 2ЈЈ-H)

3.55 (dt, ²J = 9.2 Hz,

³J = 6.6 Hz,

²J = 14.6 Hz,

³J = 1.8 Hz)

1 H, 1ЈЈ-H)

3.68 (dt, ²J = 9.2 Hz,

³J = 6.4 Hz,

1 H, 1ЈЈ-H)

syn-12

3.26

4.73 (dd,

4.14 (dd,

4.55 (dt,

3.91 (m_c)

0.09 (s, 9 H, tBu)

1.58 (ddd, ²J = 13.6 Hz,

³J = 5.4, 8.7 Hz,

1 H, CH₂tBu)

4.15 (s_br

7.22–7.43

(m)

)

1.35 (s)

1.40 (s)

(dd,³J = 7.5 Hz, ³J = 1.8 Hz,

²J = 14.4 Hz,

³J = 3.6 Hz)

4.41 (dd,

³J = 6.3 Hz,

³J = 7.5 Hz)

⁴J = 1.2 Hz)

³J = 3.6 Hz)

²J = 14.4 Hz,

³J = 1.8 Hz)

1.64 (ddd, ²J = 13.6 Hz,

³J = 9.1, 6.3 Hz,

1 H, CH₂tBu)

3.65 (dt, ^2,3J = 9.1 Hz,

³J = 5.4 Hz, 1 H,

OCH₂)

3.77 (dt, ^2,3J = 9.1 Hz,

³J = 6.3 Hz, 1 H,

OCH₂)

syn-13

syn-14

anti-9

3.27 (d,

4.72 (dd,

4.12 (dd,

4.56 (m_c)

3.92 (dd,

0.01 (s, 9 H, SiMe₃)

1.01 (m_c, 2 H, CH₂Si)

3.72, 3.83 (2 × m_c, each 1

H, OCH₂)

4.13 (s)

7.27–7.44

(m)

1.38 (s)

1.43 (s)

³J = 7.3 Hz)

³J = 1.7 Hz,

³J = 3.4 Hz)

²J = 14.7 Hz,

³J = 3.4 Hz)

4.42 (dd,

²J = 8.4 Hz,

³J = 6.0 Hz)

3.96 (t,

²J = 14.7 Hz,

³J = 1.7 Hz)

4.18 (dd,

^2,3J = 8.4 Hz)

3.06 (dd,

4.74 (dd,

4.40 (td,

3.89 (m_c)

3.54 (s)

2.81 (s)

1.39 (s)

1.40 (s)

³J = 7.5 Hz,

⁴J = 1.3 Hz)

³J = 2.2 Hz,

³J = 3.6 Hz)

²J = 15.0 Hz,

³J = 3.6 Hz)

4.46 (td,

³J = 6.2 Hz,

³J = 7.5 Hz)

²J = 15.0 Hz,

³J = 2.2 Hz)

4.23 (m_c)

3.32 (d,

4.81 (t,

4.55 (dt,

3.98–4.16 (m) 3.59 (s)

3.98–4.16

(m)

4.22 (d,

1.35 (s)

1.39 (s)

³J = 5.5 Hz)

³J = 2.9 Hz)

4.33 (ddd,

³J = 5.5 Hz,

³J = 6.5 Hz)

²J = 15.0 Hz,

³J = 2.9 Hz,

⁵J = 1.8 Hz)

²J = 13.6 Hz)

7.25, 7.32,

7.39 (3 × m_c)

4.06 (d,

anti-10

3.26 (d_br,

4.91 (t,

4.24 (dd,

4.61 (dt,

4.05 (dd,

4.82 (s)

7.24–7.40 (m)

1.35 (s)

³J Ϸ 5.6 Hz)

³J = 2.7 Hz)

²J = 14.8 Hz,

³J = 2.7 Hz)

4.35 (ddd,

³J = 5.6 Hz,

³J = 6.3 Hz)

²J = 8.3 Hz,

³J = 6.3 Hz)

4.10 (dd,

²J = 13.7 Hz) 1.38 (s)

4.22 (d,

²J = 13.7 Hz)

7.24–7.40

²J = 14.8 Hz,

³J = 2.7 Hz,

⁵J = 1.7 Hz)

4.25 (m_c)

²J = 8.3 Hz,

³J = 6.3 Hz)

(m)

anti-13

3.35 (d,

4.81 (t,

4.57 (dt,

4.03 (dd,

0.05 (s, 9 H, SiMe₃)

1.07 (m_c, 2 H, CH₂Si)

3.81, 3.86 (2 × m_c, each 1

H, OCH₂)

4.08 (d,

1.38 (s)

³J = 5.0 Hz)

³J = 2.9 Hz)

4.33 (ddd,

³J = 5.0 Hz,

³J = 6.6 Hz)

²J = 8.2 Hz,

³J = 6.6 Hz)

4.16 (dd,

²J = 13.4 Hz) 1.43 (s)

4.30 (d,

²J = 15.0 Hz,

³J = 2.9 Hz,

⁵J = 1.8 Hz)

²J = 13.4 Hz)

7.27, 7.35,

²J = 8.2 Hz,

³J = 6.6 Hz)

7.41 (3 × m_c)

1012

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Eur. J. Org. Chem. 2005, 1003–1019

Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines

Table 2. ¹³C NMR data for 1,2-oxazines derived from nitrones 1 and 2

FULL PAPER

C-3

(d)

C-4

(s)

C-5

(d)

C-6

(t)

C-2Ј (s) C-4Ј

C-5Ј

(t)

R

RЈ

Me

(2 q)

(d)

syn-9

63.4

63.3

63.6

63.7

62.5

151.3 92.7

150.4 94.1

150.6 92.9

150.7 93.0

151.3 92.7

64.3

64.5

64.3

108.6

108.5

108.6

75.0

74.8

74.9

66.7

66.9

66.5

54.1 (q)

58.2 (t, CH₂Ph),

128.7, 128.1, 126.9 (3 d), 137.8

(s)

26.1, 26.6

syn-10

syn-11

syn-12

syn-13

69.2 (t, CH₂Ph)

127.0, 127.5, 128.0, 128.1, 128.5, 128.7 (6 d), 136.2,

137.7 (2 s)

58.2 (t, CH₂Ph)

26.2, 26.6

26.0, 26.3

10.7 (q, C-3ЈЈ)

22.2 (t, C-2ЈЈ)

68.4 (t, C-1ЈЈ)

29.6 (q, tBu)

42.1 (t, CH₂tBu)

64.5 (t, OCH₂)

–2.0 (q, SiMe₃)

16.2 (t, CH₂Si)

62.3 (t, OCH₂)

54.0 (q)

58.3 (t, CH₂Ph),

126.9, 128.1, 128.7 (3 d), 137.9

(s)

58.3 (t, CH₂Ph),

126.9, 128.1, 128.7 (3 d), 137.9

(s)

58.1 (t, CH₂Ph),

126.8, 128.1, 128.1 (3 d), 137.8

(s)

41.9 (q)

60.5 (t, CH₂Ph),

127.1, 128.2, 128.5 (3 d), 137.5

(s)

syn-14

anti-9

65.5

62.3

150.5 92.2

151.4 92.5

62.8

62.5

117.0

108.2

75.3

74.7

66.8

66.4

26.0, 26.6

25.4, 26.4

54.4 (q)

anti-10

anti-13

62.2

62.7

150.2 93.3

150.5 92.4

62.1

64.6

109.2

108.8

76.9

75.1

66.8

66.2

68.9 (t, CH₂Ph)

127.2, 127.3, 127.8, 128.2, 128.4, 128.5 (6 d), 136.7,

137.3 (2 s)

–1.7 (q, SiMe₃)

17.1 (t, CH₂Si)

62.3 (t, OCH₂)

58.3 (t, CH₂Ph)

25.3, 26.5

25.7, 26.5

58.9 (t, CH₂Ph),

127.1, 128.2, 128.9 (3 d), 137.9

(s)

91 (100) [C₇H₇]⁺. C₂₂H₃₃NO₄(375.5): calcd. C 70.37, H 8.86, N obtained (1,2-oxazine/diene 93:7, syn/anti Ͻ 2:98). Column

3.73; found C 70.06, H 8.68, N 3.57.

chromatography of the crude product on silica gel (hexane/ethyl

acetate 4:1) gave anti-9 (2.50 g, 77 %) as colourless crystals. M.p.

(3S,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-[2-(tri-

methylsilyl)ethoxy]-3,6-dihydro-2H-1,2-oxazine (syn-13): Lithiated

(trimethylsilyl)ethoxyallene (6.20 mmol) was treated with nitrone 1

(1.00 g, 4.25 mmol) at –78 °C in tetrahydrofuran for 1.5 h as de-

scribed in GP 1. After workup, the crude product (1.81 g, 1,2-oxa-

zine/diene 96:4, syn/anti 97:3) was obtained. Column chromatog-

raphy on silica gel (hexane/ethyl acetate 9:1) gave syn-13 (1.27 g,

76 %) as colourless crystals. The 1,3-butadiene (60 mg, 5 %) was

49 °C. [α]²_D⁵= –42 (c = 0.6, CHCl ). IR (gas phase): ν = 3070 (=C–

˜

3

H), 2990, 2940, 2850 (C–H), 1670 (C=C), 1065 cm^–1(C–O–C). MS

(EI, 80 eV): m/z (%) = 305 (2) [M]⁺, 204 (98) [M – C₅H₈O₂]⁺, 91

(100) [C₇H₇]⁺, 43 (25) [C₃H₇]⁺. C₁₇H₂₃NO₄(305.4): calcd. C 66.86,

H 7.59, N 4.59; found C 67.16, H 7.31, N 4.66.

(3R,4ЈS)-2-Benzyl-4-benzyloxy-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-

yl)-3,6-dihydro-2H-1,2-oxazine (anti-10): Nitrone 1 (1.00 g,

4.25 mmol) was treated with Et₂AlCl (4.25 mmol) and then with

lithiated benzyloxyallene (5.80 mmol) at –78 °C in diethyl ether for

2 h as described in GP 2. Column chromatography of the crude

product on silica gel (hexane/ethyl acetate 9:1) gave anti-10 (syn/

anti Ͻ 2:98, 1.08 g, 67 %) as a colourless oil and 1,3-butadiene

(0.109 g, 10 %, E:Z 90:10). [α]²_D⁰= –45.1 (c = 0.69, CHCl₃). IR

obtained as a pale yellow oil (E/Z 94:6). M.p. 49–51 °C. [α]²_D²

=

+19.3 (c = 0.37, CHCl ). IR (KBr): ν = 3085–3025 (=C–H), 2985–

˜

3

2845 (C–H), 1675 cm^–1(C=C). MS (EI, 80 eV): m/z (%) = 391 (1)

[M]⁺, 376 (1) [M – CH₃]⁺, 318 (1) [M – SiMe₃]⁺, 91 (100) [C₇H₇]⁺,

73 (54) [SiMe₃]⁺. C₂₁H₃₃NO₄Si (391.6): calcd. C 64.41, H 8.50, N

3.56; found C 64.34, H 8.20, N 3.38.

(film): ν = 2985–2840 (C–H), 1675 cm^–1(C=C). MS (EI, 80 eV):

˜

(3S,4ЈS)-3-(2Ј,2Ј-Dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-meth-oxy-2-

methyl-3,6-dihydro-2H-1,2-oxazine (syn-14): Lithiated methoxyal-

lene (0.753 mmol) was treated with nitrone 2 (0.080 g, 0.502 mmol)

at –78 °C in tetrahydrofuran for 1 h as described in GP 1. After

workup, a dark yellow oil (0.088 g) was obtained (1,2-oxazine/diene

91:9, syn/anti Ͼ 98:2). Column chromatography on alumina (hex-

ane/ethyl acetate 19:1) gave syn-14 (0.061 g, 53 %) as a colourless

m/z (%) = 381 (1) [M]⁺, 366 (2) [M – CH₃]⁺, 280 (36) [M –

C₅H₉O₂]⁺, 91 (100) [C₇H₇]⁺. C₂₃H₂₇NO₄(381.5): calcd. C 72.42, H

7.13, N 3.67; found C 72.45, H 6.81, N 3.38.

(3R,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-[2-(tri-

methylsilyl)ethoxy]-3,6-dihydro-2H-1,2-oxazine (anti-13): Nitrone 1

(1.00 g, 4.25 mmol) was treated with Et₂AlCl (4.25 mmol) and then

with lithiated (trimethylsilyl)ethoxyallene (6.20 mmol) at –78 °C in

diethyl ether for 1.5 h as described in GP 2. After workup a yellow

oil (1.74 g, 1,2-oxazine/diene 95:5, syn/anti 8:92) was obtained. Col-

umn chromatography on silica gel (hexane/ethyl acetate 9:1) gave

anti-13 (1.23 g, 74 %) as colourless crystals. The 1,3-butadiene

(0.060 g, 5 %) was obtained as a yellow oil (E/Z 94:6). M.p. 94–

oil. [α]²_D⁵= +86 (c = 2.4, CHCl ). IR (gas phase): ν = 2990, 2940,

˜

3

2900, 2850 (C–H), 1670 (C=C), 1060 cm^–1(C–O–C). MS (EI,

80 eV): m/z (%) = 229 (6) [M]⁺, 214 (4) [M – CH₃]⁺, 128 (100) [M –

C₅H₈O₂]⁺, 43 (38) [C₃H₇]⁺. C₁₁H₁₉NO₄(229.3): calcd. C 57.63, H

8.35, N 6.11; found C 59.21, H 8.72, N 5.12. Because of the low

quantity of syn-14 no fitting elemental analyses could be obtained.

(3R,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-meth-

oxy-3,6-dihydro-2H-1,2-oxazine (anti-9): Nitrone 1 (2.50 g,

98 °C. [α]²_D²= –18.3 (c = 0.53, CHCl ). IR (KBr):ν = 3085–3025

˜

3

(=C–H), 2985–2845 (C–H), 1675 cm^–1(C=C). MS (EI, 80 eV):

10.6 mmol) was treated with Et₂AlCl (10.6 mmol) and then with m/z (%) = 391 (1) [M]⁺, 376 (1) [M – CH₃]⁺, 318 (1) [M – Me₃Si]⁺,

lithiated methoxyallene (21.2 mmol) at –78 °C in diethyl ether for

1 h as described in GP 2. After workup a brown oil (3.08 g) was

91 (100) [C₇H₇]⁺, 73 (54) [SiMe₃]⁺. C₂₁H₃₃NO₄Si (391.6): calcd. C

64.41, H 8.50, N 3.56; found C 64.70, H 8.46, N 3.44.

Eur. J. Org. Chem. 2005, 1003–1019

www.eurjoc.org

1013

H.-U. Reißig et al.

FULL PAPER

(3R,2ЈR,4ЈS,5ЈR)- and (3S,2ЈR,4ЈS,5ЈR)-2-Benzyl-3-(5Ј-tert-butyldi-

methylsiloxy-2Ј-methyl-1Ј,3Ј-dioxan-4Ј-yl)-4-methoxy-3,6-dihydro-

2H-1,2-oxazine (anti- and syn-16): Lithiated methoxyallene

(4.81 mmol) was treated with nitrone 3 (0.176 g, 0.481 mmol) at

–78 °C in tetrahydrofuran for 2 h as described in GP 1. After

workup the crude product (0.164 g) was obtained (syn/anti 38:62).

Column chromatography on silica gel (hexane/ethyl acetate 9:1)

gave anti-16 (0.053 g, 25 %) as a colourless oil, a mixture of syn-16

and anti-16 (syn/anti 46:54, 0.012 g, 6 %), and syn-16 (0.030 g,

14 %) as a colourless oil. The 1,3-butadiene was obtained as a pale

yellow oil (0.026 g, 16 %, E/Z 96:4).

on alumina (hexane/ethyl acetate 3:2) gave syn-17 (0.171 g, 33 %)

and anti-17 (0.076 g, 15 %) as colourless crystals.

Nitrone 4 (0.251 g, 1.00 mmol) was treated with Et₂AlCl

(2.00 mmol) and then with lithiated methoxyallene (2.00 mmol) at

–78 °C in diethyl ether for 1 h as described in GP 2. After workup

the crude product (0.248 g) was obtained (syn/anti 18:82). Column

chromatography on alumina (hexane/ethyl acetate 1:1) gave anti-17

(0.169 g, 53 %) and syn-17 (0.026 g, 8 %) as colourless crystals.

Compound anti-17: M.p. 86–93 °C. [α]²_D⁰= –83.2 (c = 0.60, CHCl₃).

3

¹H NMR (CDCl₃, 500 MHz): δ = 1.23 (d, J = 5.1 Hz, 3 H, Me),

3

2

3

3.23 (d, J = 6.0 Hz, 1 H, 3-H), 3.35 (dd, J = 10.8, J = 9.6 Hz,

1 H, 6Ј-H_A), 3.54 (s, 3 H, OMe), 3.66 (dt, ³J = 5.3, 9.6 Hz, 1 H, 5Ј-

H), 3.82 (dd, J = 6.0, 9.6 Hz, 1 H, 4Ј-H), 4.01–4.07 (m, 1 H, 6Ј-

H_B), 4.26 (dd, J = 15.1, J = 3.0 Hz, 1 H, 6-H_A), AB system (δ_A

= 4.05, δ_B= 4.10, J_AB= 13.3 Hz, 2 H, CH₂Ph), 4.38 (s_br, 1 H, OH),

4.42 (m_c, 1 H, 6-H_B), 4.58 (q, J = 5.1 Hz, 1 H, 2Ј-H), 4.74 (dd, J

= 2.5, 3.0 Hz, 1 H, 5-H), 7.20–7.30 ppm (m, 5 H, Ph). ¹³C NMR

(CDCl₃, 126 MHz): δ = 20.3 (q, Me), 54.1 (q, OMe), 57.1 (t,

CH₂Ph), 61.6 (t, C-6), 63.4 (d, C-3), 65.4 (d, C-5Ј), 69.9 (t, C-6Ј),

80.7 (d, C-4Ј), 90.5 (d, C-5), 99.0 (d, C-2Ј), 127.6, 128.4, 128.7,

Nitrone 3 (0.110 g, 0.301 mmol) was treated with Et₂AlCl

(0.301 mmol) and then with lithiated methoxyallene (2.74 mmol)

at –78 °C in diethyl ether for 1 h as described in GP 2. After

workup the crude product (0.123 g) was obtained (syn/anti 11:89).

Column chromatography on silica gel (hexane/ethyl acetate 9:1)

gave anti-16 (0.056 g, 43 %) as a colourless oil and a mixture of

anti-16 and syn-16 (anti/syn 47:53,. 0.007 g, 5 %). The 1,3-butadiene

was obtained as a pale yellow oil (0.026 g, 27 %, E/Z 92:8).

3

2

3

Compound anti-16: [α]²_D⁰= +29.0 (c = 0.16, CHCl₃). ¹H NMR

(CDCl₃, 500 MHz): δ = 0.05, 0.09 (2 × s, each 3 H, SiMe), 0.84 (s,

135.8 (3 × d, s, Ph), 151.0 ppm (s, C-4). IR (film): ν = 3380 (OH),

˜

2990–2850 (C–H), 1680 cm^–1(C=C). MS (EI, 80 eV): m/z (%) =

321 (3) [M]⁺, 289 (1) [M – MeOH]⁺, 204 (100) [M – C₅H₉O₃]⁺, 113

(27) [M – C₅H₉O₃– Bn]⁺, 91 (40) [C₇H₇]⁺. C₁₇H₂₃NO₅(321.4):

calcd. C 63.54, H 7.21, N 4.36; found C 63.27, H 6.93, N 4.35.

3

9 H, SitBu), 1.31 (d, J = 5.1 Hz, 3 H, Me), 3.38 (t, ^2,3J = 10.3 Hz,

3

1 H, 6Ј-H_A), 3.43 (m_c, 1 H, 3-H), 3.62 (s, 3 H, OMe), 3.70 (dd, J

2

= 2.7, 9.1 Hz, 1 H, 4Ј-H), 3.85, 4.24 (2 × d, J = 14.6 Hz, each 1

3

H, CH₂Ph), 4.04 (dd, ²J = 15.0, J = 3.5 Hz, 1 H, 6-H_A), 4.13 (dd,

Compound syn-17: M.p. 95–100 °C. [α]²_D⁰= +38.6 (c = 0.22, CHCl₃).

²J = 10.3, ³J = 5.3 Hz, 1 H, 6Ј-H_B), 4.26 (ddd, ³J = 5.3, 9.1,

3

¹H NMR (CDCl₃, 500 MHz): δ = 1.35 (d, J = 5.1 Hz, 3 H, Me),

2

10.3 Hz, 1 H, 5Ј-H), 4.27 (dt, J = 15.0, ^3,5J = 2.0 Hz, 1 H, 6-H_B),

3

5

3.43 (dd, ²J = 11.0, J = 9.9 Hz, 1 H, 6Ј-H_A), 3.49 (dd, J = 2.7, J

= 1.9 Hz, 1 H, 3-H), 3.60 (m_c, 1 H, 5Ј-H), 3.63 (s, 3 H, OMe), 3.86

(dd, ³J = 2.7, 9.1 Hz, 1 H, 4Ј-H), AB system (δ_A= 4.10, δ_B= 4.12,

J_AB= 13.9 Hz, 2 H, CH₂Ph), 4.18 (dd, ²J = 11.0, ³J = 5.3 Hz, 1 H,

3

4.60 (q, J = 5.1 Hz, 1 H, 2Ј-H), 4.85 (dd, J = 2.0, 3.5 Hz, 1 H, 5-

H), 7.23–7.49 ppm (m, 5 H, Ph). ¹³C NMR (CDCl₃, 126 MHz): δ

= –4.7, –3.7 (2 × q, SiMe), 17.8, 25.6 (s, q, SitBu), 20.6 (q, Me),

54.1 (q, OMe), 57.0 (t, CH₂Ph), 59.1 (t, C-6), 60.1 (d, C-3), 62.5

(d, C-5Ј), 71.5 (t, C-6Ј), 80.9 (d, C-4Ј), 92.0 (d, C-5), 99.4 (d, C-2Ј),

126.9, 128.1, 128.3, 137.6 (3 × d, s, Ph), 148.8 ppm (s, C-4). MS (EI,

80 eV): m/z (%) = 435 (11) [M]⁺, 378 (3) [M – tBu]⁺, 204 (100) [M –

2

3

2

6Ј-H_B), 4.23 (dd, J = 14.7, J = 3.4 Hz, 1 H, 6-H_A), 4.46 (dt, J =

14.7, ^3,5J = 1.9 Hz, 1 H, 6-H_B), 4.66 (q, ³J = 5.1 Hz, 1 H, 2Ј-H),

3

4.90 (dd, J = 1.9, 3.4 Hz, 1 H, 5-H), 7.27–7.41 ppm (m, 5 H, Ph).

¹³C NMR (CDCl₃, 126 MHz): δ = 20.6 (q, Me), 54.6 (q, OMe),

58.0 (t, CH₂Ph), 61.8 (d, C-5Ј), 64.2 (t, C-6), 64.4 (d, C-3), 70.2 (t,

C-6Ј), 80.1 (d, C-4Ј), 92.9 (d, C-5), 99.0 (d, C-2Ј), 127.5, 128.4,

128.6, 136.8 (3 × d, s, Ph), 151.0 ppm (s, C-4). Because of the small

amount of material no further characterization was undertaken.

C H O SiMe tBu]⁺, 101 (19), 91 (60) [C H ]⁺. IR (film): ν = 2995–

˜

5

8

3

2

7

2855 (C–H), 1685 cm^–1(C=C). HRMS (EI, 80 eV): calcd. for

C₂₃H₃₇NO₅Si 435.24410; found 435.24621. C₂₃H₃₇NO₅Si (435.6):

calcd. C 63.41, H 8.56, N 3.21; found C 62.05, H 7.92, N 2.96.

Compound syn-16: [α]²_D⁰= –84.6 (c = 1.1, CHCl₃). ¹H NMR

(CDCl₃, 500 MHz): δ = 0.03, 0.04 (2 × s, each 3 H, SiMe), 1.26 (s,

(4aR,5aR,8R,9aS,9bR)-1-Benzyl-4a-methoxy-8-methyl-

3,4,4a,5a,6,8,9a,9b-octahydro-1H-[1,3]dioxino[4Ј,5Ј:4,5]furo-

[3,2-c][1,2]oxazine (18a) and (4aS,5aR,8R,9aS,9bS)-1-Benzyl-4a-

methoxy-8-methyl-3,4,4a,5a,6,8,9a,9b-hexahydro-1H-[1,3]dioxino-

[4Ј,5Ј:4,5]furo[3,2-c][1,2]oxazine (18b): Lithiated methoxyallene

(1.81 mmol) in tetrahydrofuran was treated at –78 °C with nitrone

4 (0.251 g, 1.00 mmol) for 2 h as described in GP 1. After workup

a brown oil (0.248 g) was obtained (syn/anti 56:44). Column

chromatography on silica gel and HPLC (hexane/ethyl acetate 7:3)

gave two tricyclic compounds, with major diastereomer 18a

(0.083 g, 26 %) and minor diastereomer 18b (0.047 g, 15 %) as pale

yellow crystals.

3

2

3

9 H, SitBu), 1.30 (d, J = 5.0 Hz, 3 H, Me), 3.32 (dd, J = 10.3, J

= 9.4 Hz, 1 H, 6Ј-H_A), 3.56 (m_c, 1 H, 3-H), 3.58 (s, 3 H, OMe),

3.85 (d, ²J = 14.3 Hz, 1 H, CH₂Ph), 3.89 (m_c, 1 H, 4Ј-H), 3.96 (dd,

³J = 5.1, 9.4 Hz, 1 H, 5Ј-H), 4.02 (dd, J = 10.3, J = 5.1 Hz, 1 H,

6Ј-H_B), 4.22–4.32 (m, 3 H, 6-H, CH₂Ph), 4.71 (q, ³J = 5.0 Hz, 1 H,

2Ј-H), 4.78 (t, ³J = 2.8 Hz, 1 H, 5-H), 7.23–7.42 ppm (m, 5 H, Ph).

¹³C NMR (CDCl₃, 126 MHz): δ = –4.7, –4.3 (2 × q, SiMe), 14.1,

25.7 (s, q, SitBu), 20.6 (q, Me), 54.2 (q, OMe), 59.0 (t, CH₂Ph),

62.3 (d, C-3), 63.4 (d, C-5Ј), 64.6 (t, C-6), 71.8 (t, C-6Ј), 80.9 (d,

C-4Ј), 92.5 (d, C-5), 98.7 (d, C-2Ј), 126.9, 128.2, 128.3, 138.1 (3 ×

2

3

d, s, Ph), 151.5 ppm (s, C-4). IR (film): ν = 2995–2855 (C–H),

˜

Compound 18a: M.p. 55–59 °C. [α]²_D⁰= –83.8 (c = 0.65, CHCl₃). ¹H

NMR (CDCl₃, 500 MHz): δ = 1.36 (d, ³J = 5.0 Hz, 3 H, Me), 1.85

(ddd, ²J = 13.1, ³J = 6.4, 12.5 Hz, 1 H, 4-H_A), 2.08 (ddd, ²J = 13.1,

³J = 1.2, 2.4 Hz, 1 H, 4-H_B), 3.23 (d, ³J = 4.1 Hz, 1 H, 9b-H), 3.26

1680 cm^–1(C=C). MS (EI, 80 eV): m/z (%) = 435 (35) [M]⁺, 420 (1)

[M – Me]⁺, 378 (3) [M – tBu]⁺, 204 (100) [M – C₅H₈O₃SiMe₂tBu]⁺,

148 (10), 101 (11), 91 (53) [C₇H₇]⁺. C₂₃H₃₇NO₅Si (435.6): calcd. C

63.41, H 8.56, N 3.21; found C 63.40, H 8.30, N 3.19.

2

(s, 3 H, OMe), 3.63, 4.39 (2 × d, J = 14.9 Hz, each 1 H, CH₂Ph),

3

(3R,2ЈR,4ЈS,5ЈR)- and (3S,2ЈR,4ЈS,5ЈR)-2-Benzyl-3-(5Ј-hydroxy-2Ј-

methyl-1Ј,3Ј-dioxan-4Ј-yl)-4-methoxy-3,6-dihydro-2H-1,2-oxazine

(anti- and syn-17): Nitrone 4 (0.401 g, 1.60 mmol) was treated with

lithiated methoxyallene (4.00 mmol) at –78 °C in tetrahydrofuran

for 1 h as described in GP 1. After workup the crude product

(0.480 g) was obtained (syn/anti 43:57). Column chromatography

3.67 (t, ^2,3J = 9.9 Hz, 1 H, 6-H_A), 3.83 (ddd, ²J = 11.8, J = 2.4,

12.5 Hz, 1 H, 3-H_A), 3.89 (dd_br, ²J = 11.8, ³J = 6.4 Hz, 1 H, 3-H_B),

4.13 (dd, ³J = 4.1, 9.9 Hz, 1 H, 9a-H), 4.37–4.41 (m, 1 H, 6-H_B),

3

4.44 (dt, J = 4.3, 9.9 Hz, 1 H, 5a-H), 4.73 (q, J = 5.0 Hz, 1 H, 8-

H), 7.25–7.39 ppm (m, 5 H, Ph). ¹³C NMR (CDCl₃, 126 MHz): δ

= 20.3 (q, Me), 32.2 (t, C-4), 48.2 (q, OMe), 60.9 (t, CH₂Ph), 65.8

1014

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1003–1019

Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines

(t, C-3), 68.9 (d, C-9b), 71.9 (t, C-6), 71.9 (d, C-5a), 81.3 (d, C-9a), 4.9 Hz, 1 H, 2Ј-H), 4.85 ppm (m_c, 1 H, 5-H). ¹³C NMR (CDCl₃,

FULL PAPER

100.7 (d, C-8), 104.8 (s, C-4a), 126.8, 128.0, 128.7, 138.3 ppm (3 ×

126 MHz): δ = 20.5 (q, Me), 41.9 (q, NMe), 54.6 (q, OMe), 61.8

(d, C-5Ј), 63.5 (t, C-6), 66.8 (d, C-3), 70.3 (t, C-6Ј), 80.7 (d, C-4Ј),

d, s, Ph). IR (film): ν = 2990–2860 cm^–1(C–H). MS (EI, 80 eV):

˜

m/z (%) = 321 (14) [M]⁺, 306 (1) [M – Me]⁺, 290 (1) [M – OMe]⁺, 92.9 (d, C-5), 99.0 (d, C-2Ј), 150.8 ppm (s, C-4). IR (KBr): ν = 3460

˜

174 (4) [M – C₅H₈O₃– OMe]⁺, 114 (1) [M – C₅H₈O₃– Bn]⁺, 91 (OH), 2980–2830 (C–H), 1690 cm^–1(C=C). MS (EI, 80 eV):

(100) [C₇H₇]⁺. C₁₇H₂₃NO₅(321.4): calcd. C 63.54, H 7.21, N 4.36;

found C 63.19, H 7.12, N 4.22.

m/z (%) = 245 (6) [M]⁺, 213 (3) [M – MeOH]⁺, 128 (100) [M –

C₅H₉O₃]⁺, 113 (53) [M – C₅H₉O₃– Me]⁺. C₁₁H₁₉NO₅(245.3):

calcd. C 53.87, H 7.81, N 5.71; found C 54.16, H 7.61, N 5.66.

Compound 18b: M.p. 122–125 °C. [α]²_D⁰= +22.0 (c = 0.71, CHCl₃).

3

¹H NMR (CDCl₃, 500 MHz): δ = 1.38 (d, J = 5.0 Hz, 3 H, Me), (3R,2ЈS,4ЈR,5ЈR)- and (3S,2ЈS,4ЈR,5ЈR)-2-Benzyl-3-(5Ј-hydroxy-2Ј-

2

3

2

1.85 (ddd, J = 13.9, J = 8.8, 9.9 Hz, 1 H, 4-H_A), 2.30 (ddd, J =

methyl-1Ј,3Ј-dioxan-4Ј-yl)-4-methoxy-3,6-dihydro-2H-1,2-oxazine

(syn- and anti-20): Lithiated methoxyallene (8.30 mmol) in tetrahy-

drofuran was treated at –78 °C with nitrone 6 (0.717 g, 2.85 mmol)

for 1 h as described in GP 1. After workup the crude product

(0.880 g, syn/anti 72:28) was obtained. Column chromatography on

alumina (hexane/ethyl acetate 2:3) gave syn-20 (0.411 g, 45 %) as

colourless crystals and anti-20 (0.152 g, 17 %) as a colourless oil.

13.9, ³J = 1.6, 7.0 Hz, 1 H, 4-H_B), 3.30 (d, J = 8.3 Hz, 1 H, 9b-

H), 3.35 (s, 3 H, OMe), 3.53 (t, J = 8.3 Hz, 1 H, 9a-H), 3.66–3.77

3

2

(m, 3 H, 5a-H, 6-H_A, 3-H_A), 3.79, 4.07 (2 × d, J = 15.1 Hz, each

1 H, CH₂Ph), 3.96 (ddd, ²J = 9.4, ³J = 1.6, 8.8 Hz, 1 H, 3-H_B),

2

3

4.38 (dd, J = 3.9, J = 9.2 Hz, 1 H, 6-H_B), 4.70 (q, J = 5.0 Hz,

1 H, 8-H), 7.24–7.40 ppm (m, 5 H, Ph). ¹³C NMR (CDCl₃,

126 MHz): δ = 20.2 (q, Me), 32.2 (t, C-4), 49.3 (q, OMe), 60.0 (t,

CH₂Ph), 63.8 (t, C-3), 68.7 (d, C-5a), 70.4 (t, C-6), 74.7 (d, C-9b),

82.2 (d, C-9a), 100.1 (d, C-8), 108.9 (s, C-4a), 127.0, 128.1, 128.2,

Nitrone 6 (0.251 g, 1.00 mmol) was treated with Et₂AlCl

(2.00 mmol) and then with lithiated methoxyallene (2.00 mmol) at

–78 °C in diethyl ether for 1 h as described in GP 2. After workup

the crude product (0.200 g, anti/syn 72:28) was obtained. Column

chromatography on alumina (hexane/ethyl acetate 1:2) gave anti-20

(0.116 g, 36 %) as a colourless oil and syn-20 (0.050 g, 16 %) as

colourless crystals.

137.7 ppm (3 × d, s, Ph). IR (film): ν = 2990–2870 cm^–1(C–H).

˜

MS (EI, 80 eV): m/z (%) = 321 (15) [M]⁺, 290 (2) [M – OMe]⁺, 174

(3) [M – C₅H₈O₃– OMe]⁺, 91 (100) [C₇H₇]⁺. C₁₇H₂₃NO₅(321.4):

calcd. C 63.54, H 7.21, N 4.36; found C 63.19, H 7.09, N 4.31.

(3R,2ЈR,4ЈS,5ЈR)- and (3S,2ЈR,4ЈS,5ЈR)-3-(5Ј-Hydroxy-2Ј-methyl-

1Ј,3Ј-dioxan-4Ј-yl)-4-methoxy-2-methyl-3,6-dihydro-2H-1,2-oxazine

(anti- and syn-19): Lithiated methoxyallene (1.81 mmol) in tetrahy-

drofuran was treated at –78 °C with nitrone 5 (0.175 g, 1.00 mmol)

for 1 h as described in GP 1. After workup the crude product

(0.166 g) was obtained (syn/anti 40:60). Column chromatography

on silica gel (hexane/ethyl acetate 1:1) gave anti-19 (0.071 g, 29 %)

as colourless crystals, a mixture of anti-19 and syn-19 (anti/syn

31:69, 0.045 g, 18 %), and syn-19 (0.030 g, 12 %) as colourless crys-

tals.

Compound anti-20: [α]²_D⁰= –4.8 (c = 0.46, CHCl₃). ¹H NMR

(CDCl₃, 500 MHz): δ = 1.42 (d, ³J = 5.1 Hz, 3 H, Me), 3.57 (s,

2

3

3 H, OMe), 3.76 (m_c, 1 H, 5Ј-H), 3.79 (dd, J = 12.1, J = 1.2 Hz,

2

1 H, 6Ј-H_A), 3.82 (m_c, 1 H, 3-H), 3.92, 4.70 (2 × d, J = 14.1 Hz,

2

3

each 1 H, CH₂Ph), 4.11 (dd, J = 12.1, J = 1.7 Hz, 1 H, 6Ј-H_B),

2

3

5

4.20 (ddd, J = 14.7, J = 4.2, J = 1.5 Hz, 1 H, 6-H_A), 4.23 (dd,

³J = 1.0, 4.2 Hz, 1 H, 4Ј-H), 4.36 (dt, ²J = 14.7, ^3,5J = 1.9 Hz, 1 H,

3

6-H_B), 4.77 (q, J = 5.1 Hz, 1 H, 2Ј-H), 4.95 (dd, J = 1.9, 4.2 Hz,

1 H, 5-H), 5.22 (s_br, 1 H, OH), 7.25–7.42 ppm (m, 5 H, Ph). ¹³C

NMR (CDCl₃, 126 MHz): δ = 21.0 (q, Me), 54.7 (q, OMe), 60.4

(t, CH₂Ph), 63.6 (d, C-5Ј), 64.8 (d, C-3), 65.2 (t, C-6), 71.6 (t, C-

6Ј), 78.2 (d, C-4Ј), 94.3 (d, C-5), 99.9 (d, C-2Ј), 127.2, 128.2, 129.3,

Nitrone 5 (0.175 g, 1.00 mmol) was treated with Et₂AlCl

(2.00 mmol) and then with lithiated methoxyallene (2.00 mmol) at

–78 °C in diethyl ether for 1 h as described in GP 2. After workup 136.9 (3 × d, s, Ph), 150.5 ppm (s, C-4). IR (film): ν = 3315 (OH),

˜

the crude product (0.167 g) was obtained (syn/anti 15:85). Column

chromatography on silica gel (hexane/ethyl acetate 1:1) gave anti-

19 (0.125 g, 51 %) and syn-19 (0.020 g, 8 %) as colourless crystals.

2990–2850 (C–H), 1675 cm^–1(C=C). MS (EI, 80 eV): m/z (%) =

321 (6) [M]⁺, 289 (15) [M – MeOH]⁺, 204 (63) [M – C₅H₉O₃]⁺, 113

(40) [M – C₅H₉O₃– Bn]⁺, 91 (100) [C₇H₇]⁺. C₁₇H₂₃NO₅(321.4):

calcd. C 63.54, H 7.21, N 4.36; found C 63.54, H 6.67, N 4.43.

Compound anti-19: M.p. 68–70 °C. [α]²_D⁰= –123.7 (c = 0.62, CHCl₃).

¹H NMR (CDCl₃, 500 MHz): δ = 1.26 (d, J = 5.0 Hz, 3 H, Me), Compound syn-20: M.p. 163–165 °C. [α]²_D⁰= –0.9 (c = 0.43, CHCl₃).

3

2.75 (s, 3 H, NMe), 3.06 (d, J = 5.8 Hz, 1 H, 3-H), 3.35 (t_br, ^2,3J ¹H NMR (CDCl₃, 500 MHz): δ = 1.43 (d, J = 5.1 Hz, 3 H, Me),

Ϸ 10.5 Hz, 1 H, 6Ј-H_A), 3.52 (s, 3 H, OMe), 3.76 (dd, ³J = 5.8, 3.43–3.45 (m, 1 H, 5Ј-H), 3.48 (d, J = 4.0 Hz, 1 H, OH), 3.51 (dd,

3

5

2

9.3 Hz, 1 H, 4Ј-H), 3.83 (dt, J = 5.0, 9.3 Hz, 1 H, 5Ј-H), 4.05 (dd,

³J = 8.0, J = 1.7 Hz, 1 H, 3-H), 3.64 (s, 3 H, OMe), 3.89 (dd, J

3

2

²J = 10.9, J = 5.0 Hz, 1 H, 6Ј-H_B), 4.17 (s_br, 1 H, OH), 4.25 (dd, = 11.9, J = 1.5 Hz, 1 H, 6Ј-H_A), 4.03, 4.18 (2 × d, J = 14.4 Hz,

3

2

3

²J = 14.8, J = 3.0 Hz, 1 H, 6-H_A), 4.39 (d_br, ²J Ϸ 14.8 Hz, 1 H, 6- each 1 H, CH₂Ph), 4.12 (dd, J = 11.9, J = 1.9 Hz, 1 H, 6Ј-H_B),

H_B), 4.60 (q, ³J = 5.0 Hz, 1 H, 2Ј-H), 4.70 ppm (t, ³J = 3.0 Hz,

1 H, 5-H). ¹³C NMR (CDCl₃, 126 MHz): δ = 20.3 (q, Me), 41.3

(q, NMe), 54.1 (q, OMe), 60.6 (t, C-6), 65.4 (d, C-5Ј), 66.5 (d, C-

4.15 (dd, ²J = 14.7, ³J = 3.3 Hz, 1 H, 6-H_A), 4.27 (d_br, ³J Ϸ 8.0 Hz,

2

1 H, 4Ј-H), 4.42 (dt, J = 14.7, ^3,5J = 1.7 Hz, 1 H, 6-H_B), 4.86 (dd,

3

³J = 1.7, 3.3 Hz, 1 H, 5-H), 4.87 (q, J = 5.1 Hz, 1 H, 2Ј-H), 7.26–

3), 70.0 (t, C-6Ј), 80.6 (d, C-4Ј), 90.4 (d, C-5), 99.2 (d, C-2Ј), 7.40 ppm (m, 5 H, Ph). ¹³C NMR (CDCl₃, 126 MHz): δ = 21.0 (q,

150.8 ppm (s, C-4). IR (KBr): ν = 3280 (OH), 2990–2840 (C–H),

Me), 54.6 (q, OMe), 58.1 (t, CH₂Ph), 62.7 (d, C-3), 64.1 (d, C-5Ј),

64.5 (t, C-6), 71.5 (t, C-6Ј), 77.9 (d, C-4Ј), 94.1 (d, C-5), 99.1 (d,

˜

1680 cm^–1(C=C). MS (EI, 80 eV): m/z (%) = 245 (7) [M]⁺, 213 (3)

[M – MeOH]⁺, 128 (100) [M – C₅H₉O₃]⁺, 113 (25) [M – C₅H₉O₃– C-2Ј), 127.0, 128.2, 128.4, 137.8 (3 × d, s, Ph), 150.4 ppm (s, C-4).

Me]. C₁₁H₁₉NO₅(245.3): calcd. C 53.87, H 7.81, N 5.71; found C

54.26, H 7.62, N 5.63.

IR (KBr): ν = 3520 cm^–1(OH), 2980–2840 (C–H), 1675 cm^–1

˜

(C=C). MS (EI, 80 eV): m/z (%) = 321 (2) [M]⁺, 320 (3) [M – H]⁺,

289 (32) [M – MeOH]⁺, 204 (57) [M – C₅H₉O₃]⁺, 113 (28) [M –

C₅H₉O₃– Bn]⁺, 91 (100) [C₇H₇]⁺. HRMS (EI, 80 eV): calcd. for

Compound syn-19: M.p. 119–123 °C. [α]²_D⁰= +95.7 (c = 0.40,

CHCl₃). ¹H NMR (CDCl₃, 500 MHz): δ = 1.32 (d, ³J = 4.9 Hz,

3 H, Me), 2.79 (s, 3 H, NMe), 3.30 (m_c, 1 H, 3-H), 3.35 (t_br, ^2,3J Ϸ

10.5 Hz, 1 H, 6Ј-H_A), 3.58 (s, 3 H, OMe), 3.60 (dt, ³J = 5.4, 9.8 Hz,

1 H, 5Ј-H), 3.74 (dd, ³J = 3.0, 9.8 Hz, 1 H, 4Ј-H), 4.13 (dd, ²J =

C

₁₇H₂₃NO₅321.15762; found 321.15432. C₁₇H₂₃NO₅(321.4):

calcd. C 63.54, H 7.21, N 4.36; found C 62.68, H 7.04, N 4.21.

(3S,2ЈS,4ЈR,5ЈR)- and (3R,2ЈS,4ЈR,5ЈR)-2-Benzyl-3-(5Ј-hydroxy-2Ј-

10.8, ³J = 5.4 Hz, 1 H, 6Ј-H_B), 4.25 (dd, ²J = 14.8, ³J = 3.2 Hz, methyl-1Ј,3Ј-dioxan-4Ј-yl)-4-[2-(trimethylsilyl)ethoxy]-3,6-dihydro-

1 H, 6-H_A), 4.44 (d_br, ²J Ϸ 14.8 Hz, 1 H, 6-H_B), 4.61 (q, ³J = 2H-1,2-oxazine (anti- and syn-21): Lithiated (trimethylsilyl)ethoxy-

Eur. J. Org. Chem. 2005, 1003–1019

www.eurjoc.org

1015

H.-U. Reißig et al.

FULL PAPER

allene (4.45 mmol) in tetrahydrofuran was treated at –78 °C with

nitrone 6 (0.500 g, 1.99 mmol) for 1.5 h as described in GP 1. After

workup the crude product (1.06 g) was obtained as a yellow oil

(syn/anti 88:12). Filtration through alumina (pentane/ethyl acetate

5:2) gave 21 (0.720 g, 89 %), which was fully characterized after

TBSOTf protection.

3 H, SiMe₂), 0.89 (s, 9 H, SitBu), 1.03 (m_c, 2 H, CH₂Si), 1.40 (d,

3

³J = 5.0 Hz, 3 H, Me), 3.57 (d, J = 9.0 Hz, 1 H, 5Ј-H), 3.71–3.81

(m, 3 H, 3-H, OCH₂), 3.77 (dd, ²J = 12.1, ³J = 7.4 Hz, 1 H, 6Ј-

2

3

H_A), 3.98 (dd, J = 12.1, J = 1.9 Hz, 1 H, 6Ј-H_B), 4.09 (m_c, 1 H,

2

3

4Ј-H), 4.11 (d, J = 14.4 Hz, 1 H, CH₂Ph), 4.21 (dd, J = 14.6, J

= 3.0 Hz, 1 H, 6-H_A), 4.33 (d, ²J = 14.4 Hz, 1 H, CH₂Ph), 4.37 (dt,

²J = 14.6, J = 1.9 Hz, 1 H, 6-H_B), 4.65 (t, J = 2.7 Hz, 1 H, 5-H),

3

Nitrone 6 (0.500 g, 1.99 mmol) was treated at –78 °C with Et₂AlCl

(2.00 mmol) and then with lithiated (trimethylsilyl)ethoxyallene

(5.57 mmol) in diethyl ether for 1.5 h as described in GP 2. After

workup the crude product (1.21 g, syn/anti 16:84) was obtained.

Filtration through alumina (hexane/ethyl acetate 5:2) gave 21

(0.300 g, 37 %), which was fully characterised after TBSOTf protec-

tion.

4.83 (q, J = 5.0 Hz, 1 H, 2Ј-H), 7.20–7.45 ppm (m, 5 H, Ph). ¹³C

3

NMR (CDCl₃, 126 MHz): δ = –4.2 (q, SiMe₂), –1.6 (q, SiMe₃),

17.6 (t, CH₂Si), 18.3, 25.9 (s, q, SitBu), 21.1 (q, Me), 59.0 (t,

NCH₂Ph), 60.8 (t, C-5Ј), 64.1 (t, OCH₂), 64.4 (t, C-6), 65.8 (d, C-

3), 71.5 (d, C-6Ј), 80.3 (d, C-4Ј), 92.1 (d, C-5), 98.9 (d, C-2Ј), 126.7,

128.0, 128.6, 138.7 (s, 3 × d, Ph), 152.3 ppm (s, C-4). IR (KBr): ν

˜

= 3090–3030 (=C–H), 2950–2855 (C–H), 1670 (C=C), 1250 cm^–1

(C–O). MS (EI, 80 eV, 100 °C): m/z (%) = 521 (0.5) [M]⁺, 506 (0.5)

[M – CH₃]⁺, 503 (2) [M – H₂O]⁺, 91 (100) [C₇H₇]⁺, 73 (81)

[Me₃Si]⁺. C₂₇H₄₇NO₅Si₂(521.9): calcd. C 62.14, H 9.08, N 2.68;

found C 61.19, H 8.91, N 2.46.

(3S,2ЈS,4ЈR,5ЈR)-2-Benzyl-3-(5Ј-tert-butyldimethylsilyloxy-2Ј-

methyl-1Ј,3Ј-dioxan-4Ј-yl)-4-[2-(trimethylsilyl)ethoxy]-3,6-dihydro-

2H-1,2-oxazine (anti-22): 1,2-Oxazine anti-21 (0.300 g, 0.730 mmol)

was dissolved in dichloromethane (4 mL) and treated with triethyl-

amine (0.320 g, 2.21 mmol). The solution was cooled to 0 °C, tert-

butyldimethylsilyl triflate (0.320 g, 1.11 mmol) was added, the re-

sulting solution was stirred for 1 h at 0 °C, and satd. NH₄Cl solu-

tion (4 mL) was then added. The two layers were separated and

the aqueous layer was extracted five times with diethyl ether. The

combined organic layers were dried (MgSO₄) and concentrated un-

der vacuum to yield the crude product (0.496 g) as brown crystals,

which were chromatographed on silica gel (pentane/ethyl acetate

7:1) to give anti-22 (0.284 g, 74 %) and syn-22 (0.024 g, 6 %) as

(3R,4ЈS,5ЈR,4ЈЈR)-2-Benzyl-3-(2Ј,2Ј,2ЈЈ,2ЈЈ-tetramethyl-[4Ј,4ЈЈ]bi-

[[1,3]dioxolanyl]-5Ј-yl)-4-methoxy-3,6-dihydro-2H-1,2-oxazine (anti-

23): Nitrone 7 (3.35 g, 10.0 mmol) was treated with Et₂AlCl

(10.0 mmol) and then with lithiated methoxyallene (20.0 mmol) at

–78 °C in diethyl ether for 2 h as described in GP 2, and warmed to

room temp. over 2 h. After workup the crude product (3.89 g, 1,2-

oxazine/diene Ͼ 95:5, anti/syn Ͼ 95:5) was obtained. Column

chromatography on silica gel (hexane/ethyl acetate 5:1) gave anti-

23 (2.82 g, 70 %) as a pale yellow oil. anti-23: [α]²_D²= +61.7 (c =

1.03, CHCl₃). ¹H NMR (CDCl₃, 500 MHz): δ = 1.31, 1.36, 1.38 (3

× s, 3 H, 6 H, 3 H, Me), 3.48 (m, 1 H, 3-H), 3.56 (s, 3 H, OMe),

3.95 (dd, ²J = 8.3, ³J = 6.3 Hz, 1 H, 5ЈЈ-H_A), 4.01–4.06 (m, 2 H,

colourless oils. anti-22: [α]²_D²= +63.9 (c = 0.36, CHCl₃). H NMR

1

(CDCl₃, 500 MHz): δ = 0.05 (s, 9 H, SiMe₃), 0.10, 0.14 (2 × s, each

3 H, SiMe₂), 0.90 (s, 9 H, SitBu), 1.01 (m_c, 2 H, CH₂Si), 1.32 (d,

3

³J = 4.9 Hz, 3 H, Me), 3.42 (d, J = 9.2 Hz, 1 H, 5Ј-H), 3.74 (m_c,

2

5ЈЈ-H_B, CH₂Ph), 4.12–4.17 (m, 2 H, 4ЈЈ-H, CH₂Ph), 4.23 (dd, J =

1 H, 6Ј-H_B), 3.76 (d, ²J = 14.6 Hz, 1 H, CH₂Ph), 3.80 (m_c, 1 H,

3

14.7, J = 3.1 Hz, 1 H, 6-H_A), 4.28 (dd, J = 7.7, 3.0 Hz, 1 H, 4Ј-

2

3

OCH₂), 3.92 (dt, J = 9.6, J = 6.2 Hz, 1 H, OCH₂), 4.03 (dd, J

H), 4.32–4.37 (m, 2 H, 6-H_B, 5Ј-H), 4.80 (dd, J = 2.8 Hz, 1 H, 5-

2

H), 7.22–7.24, 7.28–7.31, 7.38–7.40 ppm (3 × m, 5 H, Ph). ¹³C

NMR (CDCl₃, 126 MHz): δ = 25.3, 26.2, 26.9, 27.1 (4 × q, Me),

53.9 (q, OMe), 58.0 (t, CH₂Ph), 62.2 (d, C-3), 62.5 (t, C-6), 66.2 (t,

C-5ЈЈ), 76.9 (d, C-4ЈЈ), 77.9 (d, C-5Ј), 79.5 (d, C-4Ј), 92.2 (d, C-5),

109.1, 109.2 (2 × s, C-2Ј, C-2ЈЈ), 127.0, 128.0, 128.4, 137.4 (3 × d,

= 1.7, 9.2 Hz, 1 H, 4Ј-H), 4.05 (m_c, 2 H, 6Ј-H_A, 3-H), 4.09 (dd, J

= 15.2, ³J = 3.3 Hz, 1 H, 6-H_B), 4.23 (d, ²J = 14.6 Hz, 1 H,

2

3

CH₂Ph), 4.34 (dt, J = 15.2, ^3,5J = 1.0 Hz, 1 H, 6-H_A), 4.67 (t, J

= 2.5 Hz, 1 H, 5-H), 4.72 (q, ³J = 5.0 Hz, 1 H, 2Ј-H), 7.25–

7.45 ppm (m, 5 H, Ph). ¹³C NMR (CDCl₃, 126 MHz): δ = –4.4,

–4.0 (2 × q, SiMe₂), –1.3 (q, SiMe₃), 17.3 (t, CH₂Si), 18.2, 25.9 (s,

q, SitBu), 21.1 (q, Me), 55.7 (t, NCH₂Ph), 59.4 (t, C-6), 60.5 (t, C-

5Ј), 63.9 (d, C-3), 64.0 (t, OCH₂), 71.7 (d, C-6Ј), 81.3 (d, C-4Ј),

89.8 (d, C-5), 99.2 (d, C-2Ј), 127.1, 128.2, 128.3, 137.4 (3 × d, s,

s, Ph), 150.7 ppm (s, C-3). IR (film): ν = 3085–3030 (=C–H), 2985–

˜

2835 (C–H), 1680 cm^–1(C=C). MS (EI, 80 eV, 100 °C): m/z (%) =

405 (10) [M]⁺, 390 (4) [M – Me]⁺, 204 (100) [M – C₁₀H₁₇O₄]⁺,

91 (57) [C₇H₇]⁺, 43 (23) [C₃H₇]⁺. HRMS (EI, 80 eV): calcd. for

C₂₂H₃₁NO₆405.21515, found 405.21566. C₂₂H₃₁NO₆(405.5):

calcd. C 65.17, H 7.71, N 3.45; found C 64.60, H 7.50, N 2.78.

Ph), 150.9 ppm ( s, C-4). IR (KBr): ν = 3090–3030 (=C–H), 2950–

˜

2855 (C–H), 1670 (C=C), 1250 cm^–1(C–O). MS (EI, 80 eV,

130 °C): m/z (%) = 521 (0.5) [M]⁺, 506 (0.5) [M – CH₃]⁺, 503 (2)

[M – H₂O]⁺, 438 (100), 91 (65) [C₇H₇]⁺, 73 (52) [Me₃Si]⁺.

C₂₇H₄₇NO₅Si₂(521.9): calcd. C 62.14, H 9.08, N 2.68; found C

62.42, H 9.07, N 2.51.

(3S,4ЈS,5ЈR,4ЈЈR)- and (3R,4ЈS,5ЈR,4ЈЈR)-2-Benzyl-3-(2Ј,2Ј,2ЈЈ,2ЈЈ-

tetramethyl-[4Ј,4ЈЈ]bi[[1,3]dioxolanyl]-5Ј-yl)-4-methoxy-3,6-dihydro-

2H-1,2-oxazine (syn- and anti-23): Lithiated methoxyallene

(19.6 mmol) in tetrahydrofuran was treated at –78 °C with nitrone

7 (2.70 g, 8.06 mmol) for 2 h as described in GP 1. After workup

the crude product (3.20 g) was obtained as a pale yellow solid (1,2-

(3R,2ЈS,4ЈR,5ЈR)-2-Benzyl-3-(5Ј-tert-butyldimethylsilyloxy-2Ј-

methyl-1Ј,3Ј-dioxan-4Ј-yl)-4-[2-(trimethylsilyl)ethoxy]-3,6-dihydro-

2H-1,2-oxazine (syn-22): 1,2-Oxazine syn-21 (0.720 g, 1.76 mmol) oxazine/diene 85:15, syn/anti 58:42). Column chromatography on

was dissolved in dichloromethane (8 mL) and treated with triethyl-

amine (0.760 g, 5.27 mmol). The solution was cooled to 0 °C, tert-

butyldimethylsilyl triflate (0.690 g, 2.64 mmol) was added, the re-

sulting solution was stirred for 1 h at 0 °C, and satd. NH₄Cl solu-

tion (5 mL) was then added. The two layers were separated and the

aqueous layer was extracted several times with diethyl ether. The

combined organic layers were dried (MgSO₄) and concentrated un-

der vacuum to yield the crude product (1.21 g) as brown solid,

which were chromatographed on silica gel (pentane/ethyl acetate

7:1) to give syn-22 (0.379 g, 42 %) and anti-22 (0.052 g, 6 %) both

as colourless oils. syn-22: [α]²_D²= –21.7 (c = 0.53, CHCl₃). ¹H NMR

silica gel (hexane/ethyl acetate 6:1) gave a mixture of syn-23 and

anti-23 (syn/anti 76:24, 1.92 g, 59 %) as a colourless oil. syn-23: H

1

NMR (CDCl₃, 500 MHz): δ = 1.32, 1.33, 1.36, 1.40 (4 × s, each 3

3

H, Me), 3.26 (m, dd, J = 6.1, J = 1.3 Hz, 1 H, 3-H), 3.57 (s, 3 H,

OMe), 3.89–3.93, 3.98–4.06, 4.12–4.17, 4.23–4.27, 4.40–4.45 (5 ×

m, 1 H, 3 H, 2 H, 1 H, 2 H, 5ЈЈ-H, CH₂Ph, 4ЈЈ-H, 6-H, 4Ј-H, 6-H_B,

3

5Ј-H), 4.79 (dd, J = 1.7, 3.5 Hz, 1 H, 5-H), 7.20–7.26, 7.28–7.32,

7.38–7.42 ppm (3 × m, 5 H, Ph). ¹³C NMR (CDCl₃, 126 MHz): δ

= 25.4, 26.2, 26.9, 27.4 (4 × q, Me), 53.9 (q, OMe), 57.7 (t, CH₂Ph),

62.9 (d, C-3), 63.1 (t, C-6), 65.3 (t, C-5ЈЈ), 76.1 (d, C-4ЈЈ), 76.7 (d,

C-5Ј), 77.5 (d, C-4Ј), 92.8 (d, C-5), 109.0, 109.4 (2 × s, C-2Ј, C-2ЈЈ),

(CDCl₃, 500 MHz): δ = 0.04 (s, 9 H, SiMe₃), 0.09, 0.10 (2 × s, each 127.1, 128.1, 128.7, 137.4 (3 × d, s, Ph), 150.2 (s, C-3) ppm.

Eur. J. Org. Chem. 2005, 1003–1019

Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines

(3S,4ЈS,5ЈR,4ЈЈR)- and (3R,4ЈS,5ЈR,4ЈЈR)-2-Benzyl-3-(2Ј,2Ј,2ЈЈ,2ЈЈ- 8.88 mmol) was added at 0 °C to a solution of 3,4-O-isopropylid-

FULL PAPER

tetramethyl-[4Ј,4ЈЈ]bi[[1,3]dioxolanyl]-5Ј-yl)-4-[2-(trimethylsilyl)-

ethoxy]-3,6-dihydro-2H-1,2-oxazine (syn-and anti-24): Lithiated (tri-

methylsilyl)ethoxyallene (2.44 mmol) in tetrahydrofuran was

treated at –78 °C with nitrone 7 (0.780 g, 2.33 mmol) for 2 h as

described in GP 1. After workup the crude product (1.06 g) was

obtained as a pale yellow solid (1,2-oxazine/diene 89:11, syn/anti

65:35). Column chromatography on silica gel (hexane/ethyl acetate

9:1) and HPLC (hexane/ethyl acetate 9:1) gave syn-24 (0.346 g,

30 %) as a colourless oil and anti-24 (0.221 g, 19 %) as colourless

crystals.

ene-d-mannitol (25, 0.658 g, 2.96 mmol) in MeOH (40 mL) and

phosphate buffer (pH 7.13, 50 mL). The mixture was stirred at

room temperature for 1 h. Workup by the reported method gave

dialdehyde 26 as a colourless syrup (0.529 g). N-Methylhydroxyl-

amine hydrochloride (0.621 g, 7.44 mmol) and NaHCO₃(0.625 g,

7.44 mmol) were added to a solution of the crude aldehyde 26 in

EtOH (15 mL), and the suspension was then stirred at room tem-

perature for 1 h. MgSO₄(0.900 g, 7.54 mmol) was added to this

mixture, which was stirred at room temperature for 22 h. The pre-

cipitates were filtered off and washed with CH₂Cl₂(100 mL) and

MeOH (20 mL). The organic layer was washed with brine (2 ×

50 mL), dried over MgSO₄and evaporated to give dinitrone 8 as

yellow crystals (0.480 g, 75 % from 25, pure according to NMR),

which were recrystallized from iPrOH/Et₂O to afford colourless

prisms. m.p.: 115–117 °C (dec.). [α]²_D⁰= –68.3 (c = 0.5, CHCl₃). ¹H

NMR (CDCl₃, 300 MHz): δ = 1.46 (s, 6 H, Me), 3.71 (s, 6 H,

Nitrone 7 (3.32 g, 9.89 mmol) was treated with Et₂AlCl

(9.89 mmol) and then with lithiated (trimethylsilyl)ethoxyallene

(10.4 mmol) at –78 °C in diethyl ether for 2 h as described in GP 2.

After workup the crude product (1.74 g, 1,2-oxazine/diene 95:5,

anti/syn 92:8) was obtained. Column chromatography on silica gel

(hexane/ethyl acetate 5:1) and HPLC (hexane/ethyl acetate 6:1)

gave anti-24 (2.37 g, 49 %) as colourless crystals.

3

NMe), 5.07 (d, J = 5.5 Hz, 2 H, 2-H), 6.96 ppm (d, J = 5.5 Hz,

2 H, 1-H). ¹³C NMR (CDCl₃, 76 MHz): δ = 26.4 (q, Me), 52.7 (q,

NMe), 73.3 (d, C-2), 110.7 (s, CMe), 135.9 ppm (d, C-1). IR (KBr):

Compound syn-24: [α]²_D²= –8.9 (c = 0.95, CHCl₃). ¹H NMR

(CDCl₃, 500 MHz): δ = 0.03 (s, 9 H, SiMe₃), 1.08 (m_c, 2 H, 2ЈЈЈ-

ν = 3150–2910 (=C–H, C–H), 1595 cm^–1(C=N). C₉H₁₆N₂O₄

˜

3

H), 1.31, 1.32, 1.36, 1.39 (4 × s, each 3 H, Me), 3.24 (dd, J = 6.1,

(216.2): calcd. C 49.99, H 7.46, N 12.95; found C 49.90, H 7.67, N

12.70.

⁴J = 0.9 Hz, 1 H, 3-H), 3.73, 3.82 (2 × m_c, each 1 H, 1ЈЈЈ-H), 3.87–

3.93 (m, 1 H, 5ЈЈ-H_A), 3.94–4.01 (m, 3 H, 4ЈЈ-H, 5ЈЈ-H_B, CH₂Ph),

3

4.13 (dd, ²J = 14.7, J = 3.4 Hz, 1 H, 6-H_A), 4.16 (d, ²J = 13.8 Hz,

Reaction of Bis-nitrone 8: Lithiated methoxyallene (8.07 mmol) in

tetrahydrofuran was added at –78 °C to nitrone 8 (0.471 g,

2.18 mmol) and allowed to react at –40 °C for 1 h as described in

GP 1. After workup the crude product (0.596 g) was obtained as a

pale yellow oil. Column chromatography on silica gel (hexane/ethyl

acetate 20:1 to 2:1) gave six fractions.

3

2

1 H, CH₂Ph), 4.22 (dd, J = 7.5, 6.1 Hz, 1 H, 4Ј-H), 4.42 (dt, J =

3

14.7, J = 1.4 Hz, 1 H, 6-H_B), 4.50 (dd, J = 7.5, 3.7 Hz, 1 H, 5Ј-

H), 4.74 (dd, ³J = 1.4, 3.4 Hz, 1 H, 5-H), 7.20–7.24, 7.26–7.31,

7.38–7.41 ppm (3 × m, 5 H, Ph). ¹³C NMR (CDCl₃, 126 MHz): δ

= –1.4 (q, SiMe₃), 17.3 (t, C-2ЈЈЈ), 25.5, 26.3, 27.0, 27.4 (4 × q,

Me), 57.9 (t, CH₂Ph), 63.2 (t, C-6), 63.4 (d, C-3), 64.3 (t, C-1ЈЈЈ),

65.1 (t, C-5ЈЈ), 75.9 (d, C-4ЈЈ), 76.5 (d, C-5Ј), 77.3 (d, C-4Ј), 93.0

(d, C-5), 108.9, 109.4 (2 × s, C-2Ј, C-2ЈЈ), 127.1, 128.2, 128.8, 137.6

Fraction 1: (E,E)-(5R,6R)-5,6-Isopropylidenedioxy-3,8-dimethoxy-

1,3,7,9-decatetraene (27): 25.3 mg (4 %), colourless prisms. M.p.

44–45 °C. [α]²_D⁰= +10.6 (c = 0.5, CHCl₃). ¹H NMR (CDCl₃,

300 MHz): δ = 1.47 (s, 6 H, Me), 3.62 (s, 6 H, OMe), 4.46–4.58 (m,

4 H, 4-H, 5-H, 6-H, 7-H), 5.22 (ddd, ²J = 1.8, ³J = 11.0, ⁵J =

(3 × d, s, Ph), 149.4 ppm (s, C-4). IR (film): ν = 3085–3030 (=C–

˜

H), 2985–2840 (C–H), 1670 cm^–1(C=C). MS (EI, 80 eV, 130 °C):

m/z (%) = 491 (2) [M]⁺, 476 (8) [M – Me]⁺, 409 (19), 408 (62) [M –

Me₃Si]⁺, 290 (14) [M – Me₃Si – C₅H₈O₂]⁺, 263 (14), 262 (42), 143

(12), 101 (14) [C₅H₉O₂]⁺, 91 (100) [C₇H₇]⁺, 73 (65) [SiMe₃]⁺.

C₂₆H₄₁NO₆Si (491.6): calcd. C 63.51, H 8.40, N 2.85; found C

63.57, H 8.28, N 2.64.

2

3

1.4 Hz, 2 H, 1-H_A, 10-H_A), 5.68 (dd, J = 1.8, J = 17.0 Hz, 2 H,

1-H_B, 10-H_B), 6.51 ppm (dd, ³J = 11.0, 17.0 Hz, 2 H, 2-H, 9-H).

¹³C NMR (CDCl₃, 76 MHz): δ = 27.4 (q, Me), 54.6 (q, OMe), 78.1

(d, C-5, C-6), 96.9 (d, C-4, C-7), 108.2 (s, CMe₂), 117.0 (t, C-1, C-

10), 128.0 (d, C-2, C-9), 156.9 ppm (s, C-3, C-8). IR (KBr): ν =

˜

Compound anti-24: M.p. 49–51 °C. [α]²_D⁰= +51.6 (c = 1.57, CHCl₃).

¹H NMR (CDCl₃, 500 MHz): δ = 0.03 (s, 9 H, SiMe₃), 0.93–1.08

(m, 2 H, 2ЈЈЈ-H), 1.30, 1.35, 1.37 (3 × s, 3 H, 6 H, 3 H, Me), 3.44

3050–2820 (=C–H, C–H), 1655, 1595 cm^–1(C=C). C₁₅H₂₂O₄

(266.3): calcd. C 67.65, H 8.33; found C 68.01, H 8.81.

3

(m_c, 1 H, 3-H), 3.72–3.83 (m, 2 H, 1ЈЈЈ-H), 3.93 (dd, ²J = 8.2, J =

Fraction 2: (E)-(3S,4ЈR,5ЈR)-2-Methyl-3-[5Ј-(2-methoxy-1,3-butadi-

enyl)-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl]-4-methoxy-3,6-dihydro-

2

3

6.5 Hz, 1 H, 5ЈЈ-H_A), 4.02 (dd, J = 8.2, J = 6.3 Hz, 1 H, 5ЈЈ-H_B),

4.05 (d, ²J = 13.9 Hz, 1 H, CH₂Ph), 4.13 (ddd, ³J = 6.5, 6.3, 5.9 Hz,

1 H, 4ЈЈ-H), 4.15 (d, ²J = 13.9 Hz, 1 H, CH₂Ph), 4.21 (dd, ²J =

2H-1,2-oxazine (anti-28): 29.5 mg (4 %), colourless oil. [α]²_D⁰

=

+88.2 (c = 0.5, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ = 1.42,

3

1.43 (2 × s, each 3 H, Me), 2.83 (s, 3 H, NMe), 3.35 (dd, J = 2.3,

14.7, J = 2.9 Hz, 1 H, 6-H_A), 4.26 (dd, J = 7.6, 3.2 Hz, 1 H, 4Ј-

H), 4.32 (dd, ²J = 14.7, ³J = 2.9 Hz, 1 H, 6-H_B), 4.38 (dd, ³J = 7.6,

5.9 Hz, 1 H, 5Ј-H), 4.77 (t, ³J = 2.9 Hz, 1 H, 5-H), 7.21–7.25, 7.28–

7.30, 7.37–7.40 ppm (3 × m, 5 H, Ph). ¹³C NMR (CDCl₃,

126 MHz): δ = –1.4 (q, SiMe₃), 17.4 (t, C-2ЈЈЈ), 25.5, 26.3, 27.1,

27.2 (4 × q, Me), 58.1 (t, CH₂Ph), 62.3 (d, C-3), 62.6 (t, C-6), 64.3

(t, C-1ЈЈЈ), 66.2 (t, C-5ЈЈ), 76.9 (d, C-4ЈЈ), 78.0 (d, C-5Ј), 79.6 (d, C-

4Ј), 92.5 (d, C-5), 109.3, 109.4 (2 × s, C-2Ј, C-2ЈЈ), 127.1, 128.2,

⁵J = 1.9 Hz, 1 H, 3-H), 3.46 (s, 3 H, 4-OMe), 3.59 (s, 3 H, 2ЈЈ-

3

2

OMe), 4.14 (dd, J = 2.3, 8.5 Hz, 1 H, 4Ј-H), 4.20 (ddd, J = 14.5,

³J = 2.9, ⁵J = 1.9 Hz, 1 H, 6-H_A), 4.26 (d, ²J = 14.5 Hz, 1 H, 6-

3

H_B), 4.48 (d, J = 9.5 Hz, 1 H, 1ЈЈ-H), 4.68 (t, J = 2.9 Hz, 1 H, 5-

H), 5.13 (t, ³J Ϸ 9.0 Hz, 1 H, 5Ј-H), 5.17 (dd, ²J = 1.9, ³J =

11.0 Hz, 1 H, 4ЈЈ-H_A), 5.63 (dd, ²J = 1.9, ³J = 17.0 Hz, 1 H, 4ЈЈ-

H_B), 6.61 ppm (dd, ³J = 11.0, 17.0 Hz, 1 H, 3ЈЈ-H). ¹³C NMR

(CDCl₃, 76 MHz): δ = 26.9, 27.3 (2 × q, Me), 44.3 (q, NMe), 54.0

(q, 4-OMe), 54.4 (q, 2ЈЈ-OMe), 63.1 (t, C-6), 63.3 (d, C-3), 72.8 (d,

C-5Ј), 80.8 (d, C-4Ј), 93.3 (d, C-5), 98.8 (d, C-1ЈЈ), 107.9 (s, C-2Ј),

116.0 (t, C-4ЈЈ), 128.4 (d, C-3ЈЈ), 150.1 (s, C-4), 155.9 ppm (s, C-2ЈЈ).

128.5, 137.5 (3 × d, s, Ph), 149.7 ppm (s, C-4). IR (film): ν = 3085–

˜

3030 (=C–H), 2985–2840 (C–H), 1675 cm^–1(C=C). MS (EI, 80 eV,

130 °C): m/z (%) = 491 (1) [M]⁺, 476 (6) [M – Me]⁺, 409 (17), 408

(59) [M – Me₃Si]⁺, 290 (10) [M – Me₃Si – C₅H₈O₂]⁺, 263 (12),

262 (39), 101 (14) [C₅H₉O₂]⁺, 91 (100) [C₇H₇]⁺, 73 (62) [SiMe₃]⁺.

C₂₆H₄₁NO₆Si (491.6): calcd. C 63.51, H 8.40, N 2.85; found C

63.48, H 8.27, N 2.87.

IR (KBr): ν = 3030–2800 (=C–H, C–H), 1680, 1595 cm^–1(C=C).

˜

C₁₆H₂₅NO₅(311.4): calcd. C 61.72, H 8.09, N 4.50; found C 61.95,

H 8.55, N 4.70.

(Z),(Z)-(2R,3R)-N,NЈ-(2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bu-

tylidene)bis(methylamine) N,NЈ-Dioxide (8): NaIO₄(1.90 g,

Fraction 3: (E)-(3R,4ЈR,5ЈR)-2-Methyl-3-[5Ј-(2-methoxy-1,3-butadi-

enyl)-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl]-4-methoxy-3,6-dihydro-

Eur. J. Org. Chem. 2005, 1003–1019

www.eurjoc.org

1017

H.-U. Reißig et al.

FULL PAPER

2H-1,2-oxazine (syn-28): 126 mg (19 %), pale yellow oil. [α]²_D⁰

=

3.56 (s, OMe), 4.19 (dd, ²J = 14.9, ³J = 3.4 Hz, 6-H_Aor 6Ј-H_A),

–99.6 (c = 0.5, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ = 1.41, 1.42 4.30–4.35 (m), 4.40–4.50 (m), 4.75–4.83 ppm (m, 5-H or 5Ј-H).

(2 × s, each 3 H, Me), 2.76 (s, 3 H, NMe), 3.05 (d, ³J = 6.7 Hz,

3

1 H, 3-H), 3.29 (s, 3 H, 4-OMe), 3.58 (s, 3 H, 2ЈЈ-OMe), 4.10 (t, J

3

Acknowledgments

Ϸ 7.4 Hz, 1 H, 4Ј-H), 4.13 (dd, ²J = 14.9, J = 3.3 Hz, 1 H, 6-H_A),

2

3

5

3

4.45 (ddd, J = 14.9, J = 1.8, J = 1.6 Hz, 1 H, 6-H_B), 4.48 (d, J

3

The authors thank the Deutsche Forschungsgemeinschaft, the

Deutscher Akademischer Austauschdienst (fellowship for A. H.),

the Fonds der Chemischen Industrie and Schering AG for financial

support of this research. We are grateful to L. Schefzig for experi-

mental assistance and to W. Münch for numerous HPLC separa-

tions. Finally we thank Dr. R. Zimmer for his assistance during

preparation of this manuscript.

= 9.1 Hz, 1 H, 1ЈЈ-H), 4.59 (dd, J = 1.8, 3.3 Hz, 1 H, 5-H), 4.83

3

2

3

(t, J Ϸ 8.8 Hz, 1 H, 5Ј-H), 5.22 (dd, J = 1.9, J = 11.0 Hz, 1 H,

4ЈЈ-H_A), 5.68 (dd, J = 1.9, ³J = 17.1 Hz, 1 H, 4ЈЈ-H_B), 6.59 ppm

2

(dd, J = 11.0, 17.1 Hz, 1 H, 3ЈЈ-H). ¹³C NMR (CDCl₃, 76 MHz):

3

δ = 27.1, 27.4 (2 × q, Me), 41.4 (q, NMe), 54.0 (q, 4-OMe), 54.5

(q, 2ЈЈ-OMe), 62.2 (t, C-6), 64.9 (d, C-3), 73.2 (d, C-5Ј), 79.8 (d, C-

4Ј), 91.8 (d, C-5), 97.7 (d, C-1ЈЈ), 107.8 (s, C-2Ј), 116.6 (t, C-4ЈЈ),

128.3 (d, C-3ЈЈ), 159.3 (s, C-4), 156.8 ppm (s, C-2ЈЈ). IR (KBr): ν

˜

= 3120–2800 (=C–H, C–H), 1675, 1595 cm^–1(C=C). C₁₆H₂₅NO₅

(311.4): calcd. C 61.72, H 8.09, N 4.50; found C 61.54, H 8.30, N

4.79.

[1] Recent review: M. Lombardo, C. Trombini, Synlett 2000, 759–

774.

[2] a) A. Dondoni, S. Franco, F. Junquera, F. L. Merchán, P. Me-

rino, T. Tejero, V. Bertolasi, Chem. Eur. J. 1995, 1, 505–520;

b) A. Dondoni, Pure Appl. Chem. 2000, 72, 1577–1588; c) A.

Dondoni, D. Perrone, Tetrahedron 2003, 59, 4261–4273.

[3] P. Merino, S. Franco, F. L. Merchán, T. Tejero, Synlett 2000,

442–454.

Fraction 4: (3R,3ЈR,4ЈЈR,5ЈЈR)-3-(2ЈЈ,2ЈЈ-Dimethyl-1ЈЈ,3ЈЈ-dioxolan-

4ЈЈ,5ЈЈ-yl)bis(4-methoxy-2-methyl-3,6-dihydro-2H-1,2-oxazine) (syn/

syn-29): 195 mg (25 %), colourless crystals. M.p. 114–115 °C. [α]²_D⁰

1

= –145.1 (c = 0.5, CHCl₃). H NMR (CDCl₃, 300 MHz): δ = 1.42

[4] Reviews: a) R. Zimmer, Synthesis 1993, 165–178; b) H.-U.

Reißig, S. Hormuth, W. Schade, G. M. Okala Amombo, T. Wa-

tanabe, R. Pulz, A. Hausherr, R. Zimmer, Lectures in Heterocy-

clic Chemistry Vol. XVI, in: J. Heterocycl. Chem. 2000, 37, 597–

606; c) H.-U. Reißig, GIT Labor-Fachzeitschrift 2000, 44, 254–

256; d) H.-U. Reißig, W. Schade, G. M. Okala Amombo, R.

Pulz, A. Hausherr, Pure Appl. Chem. 2002, 74, 175–180; e) R.

Zimmer, H.-U. Reißig, Donor-Substituted Allenes, in: Modern

Allene Chemistry (Eds.: N. Krause, A. S. K. Hashmi), Wiley-

VCH, Weinheim, 2004, chapter 8, pp. 425–492.

[5] a) S. Hoff, L. Brandsma, J. F. Arens, Recl. Trav. Chim. Pays-

Bas 1968, 87, 916–924; b) S. Hoff, L. Brandsma, J. F. Arens,

Recl. Trav. Chim. Pays-Bas 1968, 87, 1179–1184; c) S. Hoff, L.

Brandsma, J. F. Arens, Recl. Trav. Chim. Pays-Bas 1969, 88,

609–619; d) S. Hormuth, H.-U. Reißig, J. Org. Chem. 1994, 59,

67–73; e) S. Hormuth, W. Schade, H.-U. Reißig, Liebigs Ann.

1996, 2001–2006.

[6] a) G. M. Okala Amombo, A. Hausherr, H.-U. Reißig, Synlett

1999, 1871–1874; b) O. Flögel, H.-U. Reißig, Synlett 2004, 895–

897; c) For related reactions of lithiated methoxyallene with

chiral hydrazones derived from SAMP or RAMP see: V. Breuil-

Desvergnes, P. Compain, J.-M. Vatéle, J. Goré, Tetrahedron

Lett. 1999, 40, 5009–5012. V. Breuil-Desvergnes, J. Goré, Tetra-

hedron 2001, 57, 1939–1950; V. Breuil-Desvergnes, J. Goré, Tet-

rahedron 2001, 57, 1951–1960.

[7] Synthesis of (–)-detoxinine: O. Flögel, G. M. Okala Amombo,

H.-U. Reißig, G. Zahn, I. Brüdgam, H. Hartl, Chem. Eur. J.

2003, 9, 1405–1415. Synthesis of (–)-preussin: A. Hausherr,

Dissertation, Freie Universität Berlin (Germany), 2001. Syn-

thesis of (+)-anisomycin: S. Kaden, M. Kratzert, H.-U. Reißig,

Helv. Chim. Acta, submitted.

(s, 6 H, Me), 2.74 (s, 6 H, NMe), 2.92 (s_br, 2 H, 3-H, 3Ј-H), 3.51 (s,

6 H, OMe), 4.12 (dd, ²J = 15.0, ³J = 3.6 Hz, 2 H, 6-H_A, 6Ј-H_A),

4.46 (ddd, ²J = 15.0, ³J = 1.8, ⁵J = 1.6 Hz, 2 H, 6-H_B, 6Ј-H_B), 4.63–

4.68 (m, 2 H, 4ЈЈ-H, 5ЈЈ-H), 4.71 ppm (dd, ³J = 1.8, 3.6 Hz, 2 H, 5-

H, 5Ј-H). ¹³C NMR (CDCl₃, 76 MHz): δ = 27.2 (q, Me), 41.7 (q,

NMe), 53.7 (q, OMe), 61.0 (t, C-6, C-6Ј), 64.5 (d, C-3, C-3Ј), 75.7

(d, C-4ЈЈ, C-5ЈЈ), 91.6 (d, C-5, C-5Ј), 108.8 (s, C-2ЈЈ), 149.9 ppm (t,

C-4, C-4Ј). IR (KBr): ν = 3000–2820 (=C–H, C–H), 1680 cm^–1

˜

(C=C). C₁₇H₂₈N₂O₆(356.4): calcd. C 57.29, H 7.92, N 7.86; found

C 57.53, H 8.11, N 7.77.

Crystals of syn/syn-29 suitable for X-ray analysis were obtained by

recrystallization from hexane/diethyl ether. C₁₇H₂₈N₂O₆, M_r=

356.4; T = 301 (2) K; crystal size: 0.80 × 0.70 × 0.50 mm; ortho-

rhombic, space group P2₁2₁2₁, a = 8.8000(4), b = 14.6592(7), c =

14.7210(7) Å; V = 1899.02(15) Å³; Z = 4; ρ_calcd.= 1.247 Mg m^–3;

F(000) 768; µ(Mo_Kα) = 0.71073 mm^–1. Φ range for data collection;

1.96–27.99°; index ranges: 0 Յ h Յ 11, 0 Յ k Յ 19, 0 Յ l Յ 19;

reflections collected/unique: 5043/4592 (R_int= 0.0130); goodness-

of-fit on F²= 1.037; final R [I Ͼ 2σ(I)]: R₁= 0.0450, wR₂= 0.1051;

R (all data): R₁= 0.0616, wR₂= 0.1180.

For the structure solution and refinement the programs

SHELXS97 and SHELXL97 were used.^[28]

Fraction 5: (3S,3ЈS,4ЈЈR,5ЈЈR)-3-(2ЈЈ,2ЈЈ-Dimethyl-1ЈЈ,3ЈЈ-dioxolan-

4ЈЈ,5ЈЈ-yl)bis(4-methoxy-2-methyl-3,6-dihydro-2H-1,2-oxazine) (anti/

anti-29): 27.7 mg (4 %), pale yellow oil. [α]²_D⁰= +79.4 (c = 0.5,

1

CHCl₃). H NMR (CDCl₃, 300 MHz): δ = 1.35 (s, 6 H, Me), 2.75

(s, 6 H, NMe), 3.21 (s, 2 H, 3-H, 3Ј-H), 3.52 (s, 6 H, OMe), 4.24–

4.33 (m, 4 H, 6-H, 6Ј-H), 4.62 (s, 2 H, 4ЈЈ-H, 5ЈЈ-H), 4.76 ppm (t,

³J = 2.9 Hz, 2 H, 5-H, 5Ј-H). ¹³C NMR (CDCl₃, 76 MHz): δ =

27.1 (q, Me), 42.9 (q, NMe), 54.1 (q, OMe), 63.1 (t, C-6, C-6Ј),

64.7 (d, C-3, C-3Ј), 76.7 (d, C-4ЈЈ, C-5ЈЈ), 92.6 (d, C-5, C-5Ј), 108.5

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[9] For a preliminary communication, see: W. Schade, H.-U.

Reißig, Synlett 1999, 632–634.

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Chem.1999, 111, 794–815; Angew. Chem. Int. Ed. 1999, 38,

(s, C-2ЈЈ), 151.3 ppm (t, C-4, C-4Ј). IR (KBr): ν = 3020–2800 (=C–

˜

H, C–H), 1680 cm^–1(C=C). C₁₇H₂₈N₂O₆(356.4): calcd. C 57.29,

H 7.92, N 7.86; found C 57.61, H 8.04, N 7.44.

Fraction 6: Mixture of 3-(2ЈЈ,2ЈЈ-Dimethyl-1ЈЈ,3ЈЈ-dioxolan-4ЈЈ,5ЈЈ-

yl)bis(4-methoxy-2-methyl-3,6-dihydro-2H-1,2-oxazine) (syn/anti-

29) and (anti/anti-29): Ratio according to NMR 2.5:1. 83.5 mg

(11 %), yellow oil. Signals assigned to syn/anti-29. ¹H NMR

(CDCl₃, 300 MHz): δ = 1.39, 1.42 (2 × s, Me), 2.77, 2.79 (2 × s,

NMe), 3.07 (d, ³J = 4.4 Hz, 3-H or 3Ј-H), 3.14 (s, 3-H or 3Ј-H),

1018

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1003–1019

Highly Substituted Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines

FULL PAPER

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ated water. Very surprisingly, no deuterium was incorporated

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Scheme 13, position 5 in compound 9 should be deuterated. At

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Received September 2, 2004

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[19] CCDC-252498 (syn/syn-29) contains the supplementary crys-

tallographic data for this paper. These data can be obtained

free of charge from The Cambridge Crystallographic Data

Centre via www.ccdc.cam.ac.uk/data_request/cif.

[20] The bis-nitrone analogous to 8, but bearing an N-benzyl group,

behaved very similarly, but we were unable to separate the re-

Eur. J. Org. Chem. 2005, 1003–1019

www.eurjoc.org

1019

Article Doi

Stereodivergent syntheses of highly substituted enantiopure 4-alkoxy-3,6-dihydro-2H-1,2-oxazines by addition of lithiated alkoxyallenes to carbohydrate-derived aldonitrones

DOI: 10.1002/ejoc.200400627

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