Ozonolyses of enantiopure 4-alkoxy-3,6-dihydro-2H-1,2-oxazines: An expedient route to functionalized α-amino-β-hydroxy esters

Article abstract of DOI:10.1002/ejoc.200400734

Ozonolysis and subsequent in situ acylation/base treatment converted the enantiopure carbohydrate-derived 1,2-oxazines 1, 5, 8 (either syn- or anti-configured) and anti-11 into the highly functionalized α-amino- β-hydroxy esters 2, 6, 9 and 12 in moderate

Full text of DOI:10.1002/ejoc.200400734

SHORT COMMUNICATION
Ozonolyses of Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines:
An Expedient Route to Functionalized α-Amino-β-hydroxy Esters
Matthias Helms[a] and Hans-Ulrich Reißig*[a]
Keywords: Amino acids / Carbohydrates / 1,2-Oxazines / Ozonolysis
Ozonolysis and subsequent in situ acylation/base treatment
converted the enantiopure carbohydrate-derived 1,2-oxaz-
ines 1, 5, 8 (either syn- or anti-configured) and anti-11 into
the highly functionalized α-amino-β-hydroxy esters 2, 6, 9
and 12 in moderate to good yields. Ketals of 5-hydroxylated
1,2-oxazines (e.g., syn-3) were formed as side products in
most cases; the reactions of precursors syn- and anti-8 even
provided the ketals syn- or anti-10 as major components. The
synthesized functionalized amino esters are valuable inter-
mediates, as demonstrated by the subsequent transformation
of anti-2 into the enantiopure building blocks 13–15. Since
precursor 1,2-oxazines were prepared via lithiated alkoxyall-
enes, the latter species were serving as formyl ester anion
equivalents.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
We required enantiopure functionalized α-amino-β-hy-
droxy esters A in reasonable quantities for stereocontrolled
syntheses of certain polyhydroxylated amines such as sphin-
gosine or polyoxamic acid. Suitable precursors for these
building blocks should be 1,2-oxazine derivatives B,
smoothly available from the lithiated alkoxyallenes and
carbohydrate-derived aldonitrones C (Scheme 1).[1] In this
anticipated overall sequence, lithiated alkoxyallenes were
again expected to serve as formyl ester anion equiva-
lents[2] – a valuable synthetic application that we had al-
ready been able to establish via methoxyallene-amino alde-
hyde adducts, affording α-hydroxy-β-amino acid deriva-
tives.[3] For the transformation B Ǟ A we planned an oxi-
dative cleavage of the enol ether double bond of function-
alized 1,2-oxazines B. A variety of other synthetically very
useful compounds derived from heterocycles B were devel-
oped by our group; all these transformations, however, are
based on reductive or acid-induced hydrolytic conditions.[4]
Scheme 1.
the nitrogen by protonation. These conditions provided un-
satisfactory results, but instead it turned out that the reac-
tion could be performed without any precautions. Ozonoly-
sis of syn-1 and anti-1 at –78 °C in methanol, followed by
in situ treatment with acetic anhydride and triethylamine at
room temperature,[5] furnished the desired esters syn-2 or
anti-2 in 60 % and 68 % yields. Interestingly, considerable
amounts of the 5-hydroxy-substituted 1,2-oxazine ketals 3
were isolated in both reactions (Scheme 2). Formation of
the desired esters 2 proceeds via the expected hydroperox-
ides 4,[6a] which could be isolated and fully characterized
when the second step of our standard procedure was omit-
ted.
Results
Stereodivergent syntheses of the required syn- and anti-
configured 1,2-oxazines 1, 5, 8 and 11 were recently de-
scribed in full detail,[1] and most of the compounds are
smoothly available in useful quantities. Since we assumed
that the nucleophilicity of the benzyl-substituted nitrogen
in the 1,2-oxazines may cause side reactions during ozon-
olysis, we first tried to perform the ozonolysis of anti-1 in
the presence of one equivalent of acid, which should block
The mechanism transforming intermediates 4 into 2 by
O-acylation and elimination−actually an internal redox
process−is straightforward,[5] whereas the formation of 5-
hydroxylated 1,2-oxazines 3 is less easy to explain[6] and will
be discussed in a future full account.[7] At present we have
to state that all attempts to decrease or increase the amount
of these side products by modifying the reaction conditions
had only limited success. Compounds such as syn-3 and
anti-3 should be valuable intermediates for further synthetic
endeavours employing functionalized 1,2-oxazines as
stereodefined functionalized templates.[4]
[a] Institut für Chemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
998
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400734
Eur. J. Org. Chem. 2005, 998–1001

Ozonolyses of Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines
SHORT COMMUNICATION
Scheme 2.
Similar observations were made with d-erythrose-derived 8 and anti-8, both actually derived from d-threose, provided
syn-5 and anti-5, which afforded the expected dia- the 1,2-oxazine ketals syn-10 and anti-10 as major compo-
stereomeric esters syn-6 and anti-6 in moderate yields, to- nent, with the expected amino esters 9 being formed only in
gether with relatively small amounts of 5-hydroxylated 1,2- low yields. The preferred reaction pathway, involving either
oxazines 7 (Scheme 3). Remarkably, the diastereomers syn- conventional fragmentation of the intermediate primary
Scheme 3.
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999

M. Helms, H.-U. Reißig
SHORT COMMUNICATION
ozonide with cleavage of the enol ether double bond or the reactivity is a special feature of many reactions of lithiated
formation of the 5-hydroxylated 1,2-oxazines, is apparently alkoxyallenes and strongly contributes to their synthetic
strongly dependent on the configuration of the precursor value and high versatility.[9] Scheme 5 depicts some initial
compounds.
straightforward transformations of anti-2, showing its syn-
We also introduced the arabinose-derived anti-configured thetic usefulness. Future reports will demonstrate that 5-
1,2-oxazine 11 into the ozonolysis/elimination sequence and hydroxy-substituted 1,2-oxazine derivatives such as syn-10,
gratifyingly obtained the desired functionalized α-amino es- formed during the ozonolyses as minor or even as major
ter 12 in good yield (Scheme 4). No side-product was iso- components, may also be of preparative value. The ozono-
lated in this reaction. All compounds isolated after the oxi- lyses[10] of enantiopure 1,2-oxazine derivatives is therefore a
dative cleavage of the 1,2-oxazine ring still show the relative new and valuable tool for the conversion of these heterocy-
configurations of their starting materials. The amino group cles into new highly functionalized products.
of the resulting amino esters is unusually protected by a
(methoxycarbonyl)methoxy fragment. This hydroxylamine
moiety is of course prone to reductive cleavage as shown
below.
Experimental Section
For general information see ref.[1a] All new compounds displayed
the expected analytical and spectroscopic data.
Typical Procedure for Ozonolysis: Conversion of anti-1 into anti-2
and anti-3: Argon was bubbled through a solution of 1,2-oxazine
anti-1 (1.00 g, 3.27 mmol) in methanol (150 mL) for 5 min with
cooling to –78 °C. Ozone in oxygen was then introduced until the
solution remained blue for 5 min, followed by oxygen for 15 min.
The reaction mixture was allowed to warm to room temperature
over 2 h and the solvent was evaporated at room temperature. The
crude reaction mixture was dissolved in dichloromethane (30 mL),
and acetic anhydride (2.5 mL, 2.67 g, 26.2 mmol) and triethylamine
(0.9 mL, 0.66 g, 6.55 mmol) were added at 0 °C. The reaction mix-
ture was stirred at 0 °C for 30 min and then for 21 h at room tem-
perature. After the addition of methanol (2.5 mL) the mixture was
stirred for further 10 min, diethyl ether (90 mL) was then added,
and the organic layer was extracted twice with sodium hydrogen-
carbonate solution (5 % in water, 40 mL) and once with water
(40 mL). The organic phase was dried with magnesium sulfate and
the solvent was evaporated to yield the crude product (1.30 g) as a
colourless, viscous oil. Column chromatography (silica gel, hexane/
ethyl acetate 3:1) gave anti-2 (817 mg, 68 %) and anti-3 (180 mg,
16 %) as colourless oils.
Scheme 4.
To demonstrate the synthetic value of functionalized and
protected α-amino esters such as anti-2 we disclose a few
representative transformations of these compounds
(Scheme 5). Palladium-catalyzed hydrogenolysis of anti-2 in
the presence of Boc-anhydride furnished the desired pro-
tected α-amino ester 13 in excellent yield. This compound
could be further reduced with lithium aluminium hydride to
produce alcohol 14, which was converted into the selectively
protected enantiopure aminotriol 15 by standard methods.
Compound anti-2: [α]2D2 = +28.1 (c = 0.96, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 1.27, 1.28 (2 × s, each 3 H, Me), 3.63, 3.77
(2 × s, each 3 H, OMe), 3.77–3.85 (mc, 1 H, 2-H), 3.83 (dd, 2J =
8.7, 3J = 5.5 Hz, 1 H, 4-HA), 3.88 (d, 2J = 16.3 Hz, 1 H, 2Ј-HA),
2
3
2
4.00 (dd, J = 8.7, J = 6.3 Hz, 1 H, 4-HB), 4.01 (d, J = 16.3 Hz,
2
1 H, 2Ј-HB), 4.06, 4.15 (2 × d, J = 13.2 Hz, each 1 H, CH Ph),
2
4.49 (mc, 1 H, 3-H), 7.21–7.29 (m, 5 H, Ph). 13C NMR (CDCl3,
126 MHz): δ = 25.3, 26.6 (2 × q, Me), 51.7, 51.8 (2 × q, OMe),
60.0 (t, CH2Ph), 67.2, (t, C-4), 70.0 (d, C-2), 71.9 (t, C-2Ј), 73.8 (d,
C-3), 109.6 (s, CMe2), 127.8, 128.4, 129.8, 136.5 (3 × d, s, Ph),
169.3, 169.9 (2 × s, C=O). IR (film): ν = 3090–3030 (=C-H), 2985–
˜
2840 (C-H), 1755 cm–1 (C=O). MS (EI, 80 eV, 100 °C): m/z (%) =
367 (1) [M]+, 178 (34), 101 (64) [C5H9O2]+, 91 (100) [C7H7]+.
HRMS (EI, 80 eV, 100 °C): calcd. for C18H25NO7 367.16310; found
367.16632. C18H25NO7 (367.4): calcd. C 58.85, H 6.86, N 3.81;
found C 58.70, H 6.86, N 3.61.
(3R,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-hydroxy-
Scheme 5.
4,4-dimethoxy-3,4,5,6-tetrahydro-2H-[1,2]oxazine (anti-3): [α]2D2
=
1
+31.9 (c = 1.59, CHCl3). H NMR (CDCl3, 500 MHz): δ = 1.45,
1.49 (2 × s, each 3 H, Me), 3.12 (s, 3 H, OMe), 3.14–3.16 (m, 1 H,
3-H), 3.34 (s, 3 H, OMe), 3.60 (bd, 3J = 7.9 Hz, 1 H, 5-H), 3.80
Conclusions
2
3
2
(dt, J = 12.0, J = 1.1 Hz, 1 H, 6-HA), 3.96 (d, J = 13.6 Hz, 1 H,
2
3
2
The reactions depicted in Schemes 2–4 reveal that lithi-
ated methoxyallene efficiently serves as the desired formyl
CH Ph), 4.01 (dd, J = 8.0, J = 6.6 Hz, 1 H, 5Ј-HB), 4.22 (dd, J
2
= 12.0, 3J = 2.1 Hz, 1 H, 6-HB), 4.24 (dd, 2J = 8.0, 3J = 9.2 Hz,
ester anion equivalent.[8] The involved formal Umpolung of 1 H, 5Ј-HB), 4.28 (d, 2J = 13.6 Hz, 1 H, CH 2Ph), 4.69 (d, 3J =
1000
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Eur. J. Org. Chem. 2005, 998–1001

Ozonolyses of Enantiopure 4-Alkoxy-3,6-dihydro-2H-1,2-oxazines
SHORT COMMUNICATION
7.9 Hz, 1 H, OH), 4.77 (ddd, 3J = 9.2, 6.6, 1.6 Hz, 1 H, 4Ј-H), 7.24–
7.38 (m, 5 H, Ph). 13C NMR (CDCl3, 126 MHz): δ = 26.0 (q, 2 ×
Me), 47.6, 48.1 (2 × q, OMe), 57.7 (t, CH2Ph), 60.1 (d, C-3), 66.8
(d, C-5), 68.0 (t, C-5Ј), 72.6 (t, C-6), 72.9 (d, C-4Ј), 99.6 (s, C-4),
109.7 (s, CMe2), 127.3, 128.3, 128.6, 137.0 (3 × d, s, Ph). IR (film):
2002, 4, 2353–2355; d) R. Pulz, W. Schade, H.-U. Reißig, Syn-
lett 2003, 405–407; e) R. Pulz, S. Cicchi, A. Brandi, H.-U.
Reißig, Eur. J. Org. Chem. 2003, 1153–1156.
[5] a) S. L. Schreiber, R. E. Claus, J. Reagan, Tetrahedron Lett.
1982, 23, 3867–3870; b) R. E. Claus, S. L. Schreiber, Org.
Synth. Coll. Vol. 7 1990, 168–171.
[6] For a mechanistic discussion of the ozonolysis of enol ethers
see a) P. S. Bailey, Ozonation in Organic Chemistry; Academic
Press: New York, 1978, vol. 1; b) I. J. Borowitz, R. D. Rapp, J.
Org. Chem. 1969, 34, 1370–1373; c) K. Schank, Helv. Chim.
Acta 2004, 87, 2074–2084.
[7] The configurations of syn-3 and anti-3 as depicted in Scheme 2
were confirmed by NOESY experiments and are the result of
ozone attack trans with regard to the dioxolane rings of the
starting materials syn-1 and anti-1.
[8] a) P. Merino, A. Lanaspa, F. L. Merchan, T. Tejero, J. Org.
Chem. 1996, 61, 9028–9032; b) P. Merino, T. Tejero, J. Revuelta,
P. Romero, S. Cicchi, V. Mannucci, A. Brandi, A. Goti, Tetra-
hedron: Asymmetry 2003, 14, 367–379.
[9] 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: Mod-
ern Allene Chemistry (Eds.: N. Krause, A. S. K. Hashmi),
Wiley-VCH, Weinheim, 2004, chapter 8, pp. 425–492. For un-
usual new reactions of lithiated alkoxyallenes see: f) O. Flögel,
H.-U. Reißig, Eur. J. Org. Chem. 2004, 2797–2804; g) O. Flögel,
J. Dash, I. Brüdgam, H. Hartl, H.-U. Reißig, Chem. Eur. J.
2004, 10, 4283–4290.
ν = 3390 (OH), 3085–3030 (=C-H), 2985–2835 (C-H), 1605 cm–1
˜
(C=C). MS (EI, 80 eV, 120 °C): m/z (%) = 353 (1) [M]+, 253 (15),
252 (64) [M – C5H9O2]+, 104 (17), 101 (22) [C5H9O2]+, 91 (100)
[C7H7]+. HRMS (EI, 80 eV, 120 °C): calcd. for M+ (C18H27NO6):
353.18384, found: 353.18567. C18H25NO6 (353.4): calcd. C 61.17,
H 7.70, N 3.96; found C 61.24, H 7.68, N 3.76.
Acknowledgments
The authors thank the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie and Schering AG for generous
support of this research. We thank Dr. R. Zimmer for his assistance
during preparation of this manuscript.
[1] a) M. Helms, W. Schade, R. Pulz, T. Watanabe, A. Al-Harrasi,
L. Fisera, I. Hlobilová, G. Zahn, H.-U. Reißig, Eur. J. Org.
Chem. in press; b) Preliminary report: W. Schade, H.-U. Reißig,
Synlett 1999, 632–634.
[2] For reviews concerning Umpolung of reactivity see: D. See-
bach, Angew. Chem. 1979, 91, 259–278; Angew. Chem. Int. Ed.
Engl. 1979, 18, 239–258; T. A. Hase, Umpoled Synthons, John
Wiley & Sons: New York, Chichester, Brisbane, Toronto, Sin-
gapore, 1987; R. Chinchilla, C. Najera, Chem. Rev. 2000, 100,
1891–1928.
[3] a) S. Hormuth, H.-U. Reißig, D. Dorsch, Liebigs Ann. Chem.
1994, 121–127; b) W. Schade, H.-U. Reißig, J. Prakt. Chem.
1999, 341, 685–686.
[4] a) R. Pulz, T. Watanabe, W. Schade, H.-U. Reißig, Synlett 2000,
983–986; b) R. Pulz, A. Al-Harrasi, H.-U. Reißig, Synlett 2002,
817–819; c) R. Pulz, A. Al-Harrasi, H.-U. Reißig, Org. Lett.
[10] Other methods for oxidative cleavage of the enol ether double
bond of 1,2-oxazines such as anti-1 have not yet been success-
ful; either no reaction occurred or very complex product mix-
tures were obtained; M. Helms, unpublished results.
Received November 18, 2004
Published Online February 15, 2005
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1001