Synthesis of enantiopure (S)-7-hydroxy-3-amino-3,4-dihydro-2H-1-benzopyran en route to (+)-scyphostatin

Article abstract of DOI:10.1016/j.tetlet.2007.01.006

(S)-7-Hydroxy-3-amino-3,4-dihydro-2H-1-benzopyran, a key synthetic intermediate towards the total synthesis of (+)-scyphostatin, has been prepared in >98% ee. Key synthetic steps were (i) the oxidative dearomatization of an l-tyrosine derived phenol, (ii)

Full text of DOI:10.1016/j.tetlet.2007.01.006

Tetrahedron Letters 48 (2007) 1523–1526
Synthesis of enantiopure (S)-7-hydroxy-3-amino-3,4-
dihydro-2H-1-benzopyran en route to (+)-scyphostatin
Emmanuel N. Pitsinos,* Vassilios I. Moutsos and Olga Vageli
Natural Product Synthesis and Bioorganic Chemistry Laboratory, Institute of Physical Chemistry,
NCSR ‘Demokritos’, PO Box 60228, GR 153 10 Ag. Paraskevi, Greece
Received 11 December 2006; revised 21 December 2006; accepted 4 January 2007
Available online 7 January 2007
Abstract—(S)-7-Hydroxy-3-amino-3,4-dihydro-2H-1-benzopyran, a key synthetic intermediate towards the total synthesis of (+)-
scyphostatin, has been prepared in >98% ee. Key synthetic steps were (i) the oxidative dearomatization of an L-tyrosine derived
phenol, (ii) the transformation of the resulting p-quinol acetate to the corresponding resorcinol upon exposure to Thiele reaction
conditions and, (iii) the direct formation of the benzopyran ring upon treatment of an N-Boc protected 4-(2-acetoxybenzyl)oxazol-
idin-2-one with sodium methoxide.
Ó 2007 Elsevier Ltd. All rights reserved.
3-Aminochroman derivatives are medicinally interesting
compounds as potential pharmacological tools for
studying the serotonin (5-HT) receptor.1 In addition,
we have recently demonstrated that racemic 7-hydr-
oxy-3-amino-3,4-dihydro-2H-1-benzopyran (2, Scheme
1) is the key synthetic intermediate in a diastereoselec-
tive route towards the pharmacophoric polar core of
the natural product scyphostatin (1).2 Preparation of
this aminochroman derivative in an optically pure form
should lead to the total synthesis of the natural product
upon coupling with the corresponding optically active,
fatty acid side chain.
Although the resolution of 3-aminochroman derivatives
has been described,1c–e only the racemic synthesis of 7-
alkoxy-3-amino-3,4-dihydro-2H-1-benzopyran has been
reported to date.1b,2a Furthermore, the available syn-
thetic methodology for the preparation of enantiomeri-
cally pure 3-aminochromans3 is not suited for the
preparation of this particular derivative. Thus, an enan-
tiocontrolled synthesis of this compound was required
and we report our results herein.
The close structural similarity of (S)-7-hydroxy-3-
amino-3,4-dihydro-2H-1-benzopyran (2) with L-tyrosine
Scheme 1. Retrosynthetic plan for (+)-scyphostatin.
(4) led us to investigate this readily available amino acid
Keywords: [Bis(trifluoroacetoxy)iodo]benzene; p-Quinol; Amino-
chroman.
as a starting material. The recent report by Kita et al.4 of
*
a direct synthesis of 7-methoxy-3,4-dihydro-2H-1-benzo-
pyran (10, Scheme 2) by PIFA-mediated cyclization of
Corresponding author. Tel.: +30 210 6503789; fax: +30 210
6511766; e-mail: pitsinos@chem.demokritos.gr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.006

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E. N. Pitsinos et al. / Tetrahedron Letters 48 (2007) 1523–1526
Scheme 2. Exploration of path A. PIFA = [bis(trifluoroacetoxy)-
iodo]benzene; MK-10 = Montmorillonite K10.
3-(4-methoxyphenyl)propan-1-ol (8) indicated that the
direct conversion of a suitable tyrosinol derivative (3)
to the desired 3-aminochroman might be feasible (Path
A, Scheme 1). The reaction mechanism suggested by
the authors for this transformation involved the
formation of spiro-intermediate 9 and subsequent
rearrangement via C–O bond migration to yield 10.
Unfortunately, in our hands, 3-(4-methoxyphenyl)pro-
pan-1-ol (8) failed to provide any 7-methoxy-3,4-dihy-
dro-2H-1-benzopyran (10)5 employing the published
experimental procedure.4 Instead, the known6 isomeric
Scheme 4. Synthesis of (S)-7-hydroxy-3-amino-3,4-dihydro-2H-1-benzo-
pyran.
6-methoxy-3,4-dihydro-2H-1-benzopyran
(11)
was
obtained in a 40% yield presumably via formation of
spiro-intermediate 9 and subsequent rearrangement via
C–C bond migration, as it is usually observed upon
treatment of such oxaspirodienones with acids.7
yield. Direct oxidative dearomatization of 16 towards
p-quinol acetate 18 by treatment with [bis(acet-
oxy)iodo]benzene (PIDA) in glacial acetic acid proved
to be problematic furnishing the product in only a mod-
erate yield (35–40%) contaminated with varying
amounts of the corresponding p-quinol 17. On the other
hand, the two-step procedure of oxidizing 16 with PIFA
in wet acetonitrile to obtain p-quinol 17 followed by
acetylation with Ac2O in pyridine was more efficient
and reproducible, yielding quinol acetate 18 in a 79%
overall yield.
On the other hand, successful alkoxylation meta to the
hydroxyl group of L-tyrosine by refluxing a solution of
dienone lactone 12 in methanol in the presence of
BF3ÆEt2O has been reported (Scheme 3).8 However, the
optical purity of the product 13 was compromised
(88% ee) under the reaction conditions, presumably
due to the sensitivity of the a-amino acid moiety. In
an effort to overcome this drawback, p-quinol acetate
6 (Path B, Scheme 1) was targeted with the hope that
the tertiary acetoxy group will retain the observed pref-
erence of spirolactone 12 to aromatize via C–O bond
scission while incorporation of the amino function in
an oxazolidinone ring will protect it from racemization.
Thus, the stage was set for the crucial meta-functional-
ization of the phenol ring. Gratifyingly, rearrangement
of 18 under the conditions of the Thiele reaction,10 ace-
tic anhydride in the presence of sulfuric acid, furnished
resorcinol 19 in a good yield (82%). At this point it
should be noted that, subjecting the free quinol 17 to
the same conditions resulted in poorer yields (31%) of
the desired product.
Therefore, to access p-quinol acetate 6, tyrosinol deriva-
tive 14 was prepared as previously described9 in >99%
ee. Treatment of 14 with NaH in THF at room temper-
ature resulted in intramolecular cyclization of the result-
ing alkoxide onto the N-Boc-protecting group to form
the oxazolidinone anion, which was trapped in situ by
the addition of Ac2O (Scheme 4).
With all the required functionality present in 19 we
turned our attention to the formation of the benzopyran
ring. For this transformation we planned to exploit the
oxazolidinone moiety as a leaving group in an intra-
molecular nucleophilic attack by the neighbouring
phenol.11,12 For this feat to be accomplished it was
deemed necessary to activate the oxazolidinone by
replacing the acetyl with a tert-butoxycarbonyl protect-
ing group. Thus, methanolysis of the acetyl protecting
groups, followed by selective reacetylation of the phe-
nols and N-tert-butoxycarbonyl protection of the oxazo-
lidinone furnished 20 in a good overall yield (79%).
Treatment with K2CO3 in a 1:1 mixture of methanol/
THF afforded the free resorcinol 21. Upon treatment
of 21 with 2 equiv of NaH in THF at 60 °C we observed
the formation of benzopyran 22 in a very good overall
yield (83%). Alternatively, the direct treatment of 20
with sodium methoxide in THF at 60 °C for 3 h
Thus, oxazolidinone 15 was obtained in one step and in
95% yield. Subsequent hydrogenolysis of the benzyl pro-
tecting group furnished phenol 16 in a quantitative
Scheme 3. Reported meta alkoxylation of L-tyrosine.

E. N. Pitsinos et al. / Tetrahedron Letters 48 (2007) 1523–1526
1525
Supplementary data
Spectroscopic data and experimental procedures for
compounds 15–20 and 22. Copies of the 1H NMR,
HSQC and HMBC spectra of 11. Copies of the 1H
NMR and 13C NMR spectra of compounds 15–20 and
22, 23 and 25. HPLC chromatograms of compounds
23 and 25. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2007.01.006.
References and notes
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furnished (S)-7-hydroxy-3-amino-3,4-dihydro-2H-1-benzo-
pyran 22 in one step and in an excellent yield (96%).
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Acknowledgements
Professor A. Giannis and Dr. V. Sarli are gratefully
acknowledged for their assistance in obtaining HRMS
spectra for the compounds synthesized. The authors
are grateful to Professor H. Katerinopoulos and Profes-
sor P. Magriotis for helpful comments during the prep-
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