A concise approach to chiral chromenes based on levoglucosenone

Article abstract of DOI:10.1016/j.tetlet.2011.04.004

Levoglucosenone, a chiral α,β-unsaturated ketone derived from cellulose, undergoes a stereoselective domino oxa-Michael-aldol reaction with 2-hydroxybenzaldehydes affording optically active pyrano[3,4-b]chromenes. The latter are further converted into 2H-

Full text of DOI:10.1016/j.tetlet.2011.04.004

Tetrahedron Letters 52 (2011) 3026–3028
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A concise approach to chiral chromenes based on levoglucosenone
Alexander V. Samet a, , Dmitriy N. Lutov a, Sergei I. Firgang a, Konstantine A. Lyssenko b, Victor V. Semenov a
⇑
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Pr., 119991 Moscow, Russia
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov St., 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Levoglucosenone, a chiral
a,b-unsaturated ketone derived from cellulose, undergoes a stereoselective
Received 31 January 2011
Revised 22 March 2011
Accepted 1 April 2011
Available online 9 April 2011
domino oxa-Michael–aldol reaction with 2-hydroxybenzaldehydes affording optically active pyr-
ano[3,4-b]chromenes. The latter are further converted into 2H-chromenes via a Beckmann fragmentation
reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Levoglucosenone
2H-Chromenes
Domino reaction
Beckmann fragmentation
A number of biologically active natural compounds contain the
2H-chromene structural motif, and interest in the synthesis of
these compounds is growing rapidly.1 Reaction of 2-hydroxyben-
O
O
X
CHO
OH
R1R2C=CHX
base
-
- H2O
X
R1
zaldehydes with
a,b-unsaturated carbonyl compounds, or other
O
R1
R2
R2
activated alkenes represents a possible synthetic approach to 2H-
chromenes1,2 (Scheme 1).
Scheme 1. Domino oxa-Michael–aldol reaction.
In particular, such reactions with cyclic
a,b-unsaturated car-
bonyl compounds (i.e., cyclohexenones3 or pyranones4) afford
fused chromenes. The use of a chiral catalyst in these transforma-
tions can result in the formation of optically active chromene
derivatives,5 though ee values are not always high. Another possi-
ble approach to the latter compounds requires the use of suitable
chiral substrates. Thus, levoglucosenone (1) [(1S,5R)-6,8-dioxabi-
cyclo[3.2.1]oct-2-ene-4-one], an unsaturated ketone prepared by
acid-catalyzed pyrolysis of cellulose,6 is known to undergo stereo-
selective addition reactions on the C@C bond on the side opposite
to the anhydro bridge,7,8 resulting in its application for the synthe-
sis of optically active compounds.9
R
5
6
CHO
OH
O
O
O
1
3
4
O
H
O
10a
3
4
O
Et3N, EtOH
O
5
9
8
1
6
7
R
2a-d
Scheme 2.
With 2-hydroxybenzaldehydes, levoglucosenone 1 undergoes a
stereoselective domino oxa-Michael–aldol reaction3a,10 (the phe-
nolate-anion attacks from the side opposite to the anhydro
bridge11) (Scheme 2).
In most cases, these reactions proceed smoothly and in high
yields12 (Table 1), however, with 5-nitrosalicylaldehyde the reac-
tion was much slower and the yield was lower (cf. Ref. 3a). This
is probably due to the poor nucleophilicity of the nitrophenolate-
anion.
The reaction of pyranochromene 2a with nucleophiles
(Nu = OMeꢀ, SPhꢀ) in MeOH or EtOH failed to yield the anticipated
adducts A (cf. Ref. 3a), but instead produced a mixture of epimer
11
2a0 and products of an unusual recyclization 3 (Scheme 3).
Most probably, the mechanism involves SN02 substitution with
concomitant chromene ring-opening to yield intermediate B. The
latter could undergo either intramolecular nucleophilic SN02 attack
by the phenolate-anion with ring-closure, resulting in epimer 2a0
[pathway (a)] or SN02 attack by the external nucleophile affording
the recyclization products 3a,b via intermediate C [pathway (b)]
(Scheme 4).
⇑
Corresponding author.
E-mail addresses: sametav@server.ioc.ac.ru, sametav@yahoo.com (A.V. Samet).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.004

A. V. Samet et al. / Tetrahedron Letters 52 (2011) 3026–3028
3027
O
O
O
O
O
O
H
O
OH
H
O
H
Nu
Nu-
O
O
O
+
3a,b
2a
2a'
a:
b:
Nu = OMe (27%)
Nu = SPh (63%)
Nu = OMe (57%)
Nu = SPh (27%)
Nu-
O
O
H
O
O
Nu
A
Scheme 3. Reaction of 2a with nucleophiles.
Figure 1. X-ray structure of product 3b (ORTEP presentation).
Table 1
Yields of products 2 and 4
The structure of product 3b was confirmed by X-ray diffrac-
tion13 (Fig. 1).
R
Yield of 2a (%)
Yield of 4 (%)
The structure of 3a was assigned based on similarities in the
NMR spectra with those of 3b. In particular, the chemical shifts
of C(10a) in the 13C NMR spectra were very close: d 92.60 for 3a
and d 92.32 for 3b.
On reaction with SOCl2, the oximes of pyranochromenes 2 (pre-
pared from 2 and NH2OHꢁHCl) were converted into 3-cyano-2H-
chromenes 4 in good yields14 (Table 1). The reaction proceeds via
the Beckmann fragmentation15 with cleavage of the intermediate
H (a)
84
86
69
67
59
5-Br (b)b
3-MeO (c)b
5-NO2 (d)b
91
36c(52d)
a
Performed at rt for 5 h.
Position of substituents on the 2-hydroxybenzaldehydes is indicated.
Reaction run for 72 h.
b
c
d
Reaction run for 10 days.
O
O
2a'
(a)
-Nu
Nu
(b)
O
2a
Nu
(a)
O
O
Nu
O
O
O-
(b)
OH
O
H
H
-Nu
O
Nu
Nu
B
O-
3a,b
C
Scheme 4. Plausible reaction mechanisms.
R
NOH
R
CN
.
SOCl2, CHCl3
NH2OH HCl
H
2a-c
O
+
O
O
C5H5N
O
O
H
O
H
H
Cl-
D
R
Br
CN
H
CN
H
MeOH
HCl
(R = Br)
OH
OCHO
O
O
H
H
Cl
Cl
5
(91%)
4a-c
Scheme 5. Beckmann fragmentation of the oximes of pyranochromenes 2.

3028
A. V. Samet et al. / Tetrahedron Letters 52 (2011) 3026–3028
1,3-dioxolan-2-ylium cation D by attack of Clꢀ at the least steri-
cally hindered position16,17 (Scheme 5). Acidic hydrolysis of the
formate 4b affords chlorohydrin 5. The structure of 4b was con-
firmed by X-ray crystallographic analysis, the details of which will
be published elsewhere.
In conclusion, the carbohydrate ketone, levoglucosenone (1)
proved to be a suitable template for the stereoselective synthesis
of optically active functionalized 2H-chromenes via a domino
oxa-Michael–aldol reaction followed by transformation of the car-
bohydrate fragment under Beckmann fragmentation conditions.
7. (a) Shafizadeh, F.; Ward, D.; Pang, D. Carbohydr. Res. 1982, 102, 217; (b) Samet,
A. V.; Niyazymbetov, M. E.; Semenov, V. V.; Laikhter, A. L.; Evans, D. H. J. Org.
Chem. 1996, 61, 8786.
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Forsyth, A.; Gould, R.; Paton, R. Tetrahedron 1992, 48, 8053.
9. For reviews, see Ref. 6 and also: (a) Miftakhov, M. S.; Valeev, F. A.; Gaisina, I. N.
Russ. Chem. Rev. 1994, 63, 869; (b) Witczak, Z. J. New Stereoselective
Functionalization of Cellulose-Derived Pyrolysis Derivatives: Levoglucosenone
and Its Dimer. In Materials, Chemicals, and Energy from Forest Biomass; ACS
Symposium Series 954; American Chemical Society: Washington, DC, 2007; pp
332–349; Some recent examples: (c) Nishikawa, T.; Urabe, D.; Isobe, M. Angew.
Chem., Int. Ed. 2004, 43, 4782; (d) Awad, L.; Demange, R.; Zhu, Y.-H.; Vogel, P.
Carbohydr. Res. 2006, 341, 1235; (e) Samet, A. V.; Shestopalov, A. M.; Lutov, D.
N.; Rodinovskaya, L. A.; Shestopalov, A. A.; Semenov, V. V. Tetrahedron:
Asymmetry 2007, 18, 1986; (f) Samet, A. V.; Lutov, D. N.; Konyushkin, L. D.;
Strelenko, Y. A.; Semenov, V. V. Tetrahedron: Asymmetry 2008, 19, 691; (g)
Sarotti, A. M.; Spanevello, R. A.; Suarez, A. G. Tetrahedron 2009, 65, 3502.
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Acknowledgements
This research was supported by a grant from Chemical Block Ltd
(www.chemblock.com).
11. The 1H NMR spectra of compounds 2a and 2a0 (epimers at C-10a) differ mainly
in the coupling constant values J1,10a ꢂ 0 Hz for 2a and J1,10a = 5.2 Hz for 2a0 (cf.
Refs. 7b and 8b).
Supplementary data
12. Preparation of pyrano[3,4-b]chromen-4(3H)-ones 2a–d (general procedure). To a
solution of levoglucosenone (1) (0.63 g, 5 mmol) and the corresponding 2-
hydroxybenzaldehyde (5 mmol) in EtOH (3 ml), was added Et3N (0.10 g,
1 mmol) at rt. After 5 h (72 h for 2d) the resulting suspension was diluted
with H2O (3 ml) and the precipitate filtered and dried.
Supplementary data (experimental procedures for compounds
2a0, 3a,b and characterization data for all new compounds) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.04.004.
13. Crystallographic data for 3b: C19H16O4S, Mr = 340.38, monoclinic, space group
P212121, a = 6.667(2), b = 7.903(3), c = 30.055(9) Å, V = 1583.5(9) Å3, Z = 4,
dcalcd = 1.428 gmꢀ3
,
l
= 2.225 mmꢀ1
,
F(0 0 0) = 712. Intensities of 8099
reflections were measured with a Bruker SMART APEX CCD diffractometer
[k(MoK ) = 0.71072 Å, -scans, h/2h < 56°] and 3784 independent reflections
References and notes
a
x
[Rint = 0.0348] were used for further refinement. The absorption correction was
performed empirically using APEX2 (Bruker, 2005). Analysis of Fourier density
synthesis revealed that the SPh substituent is disordered by two positions with
equal occupancies. The refinement converged to wR2 = 0.0531 and GOF = 1.000
for all independent reflections (R1 = 0.0749 was calculated against F for 3104
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observed reflections with I >2r(I)). The refinement of absolute structure led to
a Flack parameter (Flack, H.D. Acta Crystallogr., Sect. A 1983, 39, 876–881) equal
to 0.00(17). All calculations were performed using SHELXTL PLUS 5.0
(Sheldrick, G.M. Acta Crystallogr., Sect. A 2008, 64, 112–122). CCDC 799240
contains the supplementary crystallographic data for 3b. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: (+44) 1223
336033; or deposit@ccdc.cam.ac.uk.
14. Preparation of chromenes 4a–c (general procedure). A solution of ketone 2a–c
(2 mmol) and NH2OHꢁHCl (2.5 mmol) in pyridine (4 ml) was stirred for 24 h at
rt, the solvent removed in vacuo and the residue triturated with H2O (10 ml).
The resulting oxime precipitate was filtered, dried in vacuo and used in the
next step without further purification. To a solution of the above oxime in dry
CHCl3 (3 ml), a solution of SOCl2 (1.5 ml) in dry CHCl3 (1 ml) was added
dropwise at 0 °C with stirring. The resulting mixture was kept at 0 °C for
40 min and then evaporated to dryness. The residue was chromatographed on
silica gel (eluent: hexane/EtOAc, 5:1) to afford nitriles 4a–c.
15. Gawley, R. E. Org. React. 1988, 35, 1.
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fragmentation under the action of SOCl2 affording 4-chloro-5-
(formyloxy)pent-2-enenitrile (thus, in this case Clꢀ evidently attacks the
more sterically hindered position of the intermediate cation): Valeev, F. A.;
Gorobets, E. V.; Tsypysheva, I. P.; Singizova, G. Sh.; Kalimullina, L. Kh.; Safarov,
M. G.; Shitikova, O. V.; Miftakhov, M. S. Chem. Nat. Compd. 2003, 39, 563.