Thieme Chemistry Journal Awardees - Where are they now? An asymmetric organocatalytic sequence towards 4a-methyl tetrahydroxanthones: Formal synthesis of 4-dehydroxydiversonol

Article abstract of DOI:10.1055/s-0028-1087927

Tricyclic systems generated by an asymmetric vinylogous aldol-oxa-Michael reaction of salicylaldehydes with senecialdehyde were further elaborated using a strategy developed by Tietze et al. to generate 4a-methyl tetrahydroxanthones. Georg Thieme Verlag S

Full text of DOI:10.1055/s-0028-1087927

550
LETTER
Thieme Chemistry Journal Awardees– Where are They Now?
An Asymmetric Organocatalytic Sequence towards 4a-Methyl
Tetrahydroxanthones: Formal Synthesis of 4-Dehydroxydiversonol
S
ynthesis of 4-Deh
i
ydroxy
c
diversonolole Volz,a Manuel C. Bröhmer,a Martin Nieger,b Stefan Bräse*a
a
Institut für Organische Chemie, Universität Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: braese@ioc.uka.de
Laboratory of Inorganic Chemistry, University of Helsinki, 00014 Helsinki, Finland
b
Received 30 September 2008
Abstract: Tricyclic systems generated by an asymmetric vinylo-
gous aldol–oxa-Michael reaction of salicylaldehydes with seneci-
aldehyde were further elaborated using a strategy developed by
Tietze et al. to generate 4a-methyl tetrahydroxanthones.
Key words: domino vinylogous aldol–oxa-Michael reaction,
Wittig reaction, natural products
Organocatalytic domino reactions have recently attracted
much attention due to the mild and straightforward access
to complex structures that they provide.1 The domino
reaction of salicylaldehydes 1 with a,b-unsaturated alde-
hydes 2 has been recently investigated in light of their use
in total synthesis of natural products.
Stefan Bräse was born in Kiel, Germany in 1967. After he studied in
Göttingen, Bangor (UK) and Marseille, he received his Ph.D. in 1995,
after working with Armin de Meijere in Göttingen. After post-docto-
ral appointments at Uppsala University (Jan E. Bäckvall) and The
Scripps Research Institute, La Jolla (K. C. Nicolaou), he began his in-
dependent research career at the RWTH Aachen (Germany) in 1997
(associated to Dieter Enders). In 2001, he finished his Habilitation
Depending on the reaction conditions, in most cases an
oxa-Michael–aldol reaction occurs to give chromenes 3.
However, under a yet different set of conditions, we and and moved to the University of Bonn as Professor for Organic
Chemistry. Since 2003, he is full professor at the University of Karls-
ruhe, Germany. He is recipient (among other awards) of the OrChem
award of the GDCh and the Lilly award. His research interests include
methods in drug-discovery (including drug-delivery), combinatorial
others have discovered that rigid tricyclic systems 4 are
formed by a vinylogous aldol–oxa-Michael reaction
(Scheme 1).2
chemistry towards the synthesis of biologically active compounds, to-
tal synthesis of natural products and nanotechnology.
Recently, the Woggon group elaborated an organocatalyt-
ic procedure which at the end culminated in an elegant to-
tal synthesis of a-tocopherol (6).3
firmed by X-ray crystallography (CCDC-717754, Figure 1)8.
Using Jørgensen’s proline-derived organocatalyst3,9 – (S)-bis-
[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanoltri-
methylsilyl ether – we were able to obtain the tricycle 4a
in 66% yield with an ee value of 98%.
In the meantime, the Tietze group developed a yet differ-
ent approach for the synthesis of chromanes which was
based on an asymmetric Wacker–Heck reaction. They
were able to convert these building blocks into
tocopherols4 and, very recently, into tetrahydroxanthones
like 4-dehydroxydiversonol (5).5–7
In this paper we explore the chemistry of the tricycles 4 to
show the compatibility of both approaches.
The required salicylaldehydes are mostly commercially
available. Salicylic aldehyde 1b can be derived from orci-
nol over three steps in an overall yield of 70% according
to a literature procedure.6a
The reaction of salicylaldehydes 1 with senecialdehyde
(2a) gave the tricycles 4 in good to very good yields. The
wide scope of this type of reaction is shown in Table 1.
It is interesting to note that under yet similar conditions, salicyl-
aldehyde 1b gave the best yield. The structure of 4b was con-
SYNLETT 2009, No. 4, pp 0550–0553
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
Figure 1 Molecular Structure of 4b. Displacement parameters are
DOI: 10.1055/s-0028-1087927; Art ID: S09908ST
drawn at 50% probability level
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 4-Dehydroxydiversonol
551
Table 1 Scope of the Oxa-Michael–Aldol and Vinylogous Aldol-
oxa-Michael Reaction of Salicylaldehydes 1 with Senecialdehyde
(2a, R5 = Me)a
R4
R3
R2
CHO
OH
Entryb
Salicylaldehyde (1)
Cond.a Yield (%)
1
R1
1
R1
H
R2
R3
R4
H
3
4
oxa-Michael–
aldol
vinylogous aldol–
oxa-Michael
1
1a
1a
1b
1b
1c
1d
1e
1f
H
H
A
B
A
B
A
A
A
A
A
A
A
A
A
A
A
19
0
46
66
79
74
46
61
36
44
46
10
57
51
47
61
44
CHO
R5
2
H
H
H
H
R4
R4
O
OH
R3
R3
R2
CHO
R5
2
3
H
Me
Me
HO
C5H11
H
H
MeO
MeO
H
0
4
H
H
0
R2
O
O
R5
R1
R1
4
5
H
H
37
0
3
Woggon
ref. 3
6
H
H
MeO
H
OH
O
OH
HO
OH
7
MeO
H
H
13
4
8
MeO
H
H
H
O
2
O
9
1g
1h
1i
H
MeO
H
H
36
0
4-dehydroxydiversonol (5)
tocopherol (6)
10
11
12
13
14
15
H
Et2N
H
H
Tietze
ref. 4,5
MeO
Br
H
Br
Cl
O2N
H
H
10
17
0
Wacker–Heck
(Tietze)
1j
H
H
CO2Me
1k
1l
H
H
CO2Me
O
R
OH
R
7
8
Allyl
Ph
H
H
19
23
Scheme 1 Strategies for the synthesis of chromenes based on a,b-
unsaturated aldehydes 2
1m
H
H
H
a Conditions A: senecialdehyde (1.0 equiv), Et3N (0.5 equiv), 55 °C,
2.5 d; conditions B: senecialdehyde (1.0 equiv), benzoic acid
(0.3 equiv), (S)-a,a-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrro-
lidinemethanoltrimethylsilyl ether (0.3 equiv), r.t., 3.5 d.
b For entries 7–15, see ref. 2a. The ee was determined by HPLC anal-
ysis using chiral stationary phases (Daicel Chiralpak AS 0.46 ¥ 25
cm).
CHO
R4
R4
O
OH
Ph3P=CHCO2Et
CHO
OH
2a
see text
R2
O
R2
1a (R2 = H, R4 = H)
4a (66%, 98% ee)
4b (79%, 87% ee)
The absolute configuration was determined by correlation
with the results of Woggon et al.3
1b (R2 = Me, R4 = OMe)
R4
OH
R4
Reaction of tricycles 4 with stabilized ylides produced the
alcohols 9 as a mixture of the two double-bond isomers
(E/Z ratio between 5:1 and 5:3). Exhaustive concomitant
reduction of the double bond and the secondary alcohol10
led to chromanes 10 in excellent yields.11 Chromanes 10
were used before by Tietze et al. yielding xanthones 13
through chromanones 12 via a Dieckmann condensa-
tion.5,12 We obtained chromanones 12 by oxidation of the
alcohols 9 (Dess–Martin periodinane, DMP) and subse-
quent hydrogenation. The heterocycles 12 were then cy-
clized to give xanthones 13 in the presence of titanium
tetrachloride (Scheme 2).5
H2, PtO2
R2
O
R2
O
CO2Et
CO2Et
10a (99%)
10b (90%)
9a (75%)
9b (quant)
DMP
R4
O
R2
O
ref. 5
CO2Et
11a (79%)
11b (83%)
H2, PtO2
Tietze et al. previously converted compound 13b (which
was synthesized starting from orcinol in 12 steps and an
overall yield of 14%) into 4-dehydroxydiversonol
(Scheme 3).5
R4
O
O
OH
R4
O
TiCl4, Et3N
R2
O
R2
Starting from orcinol we have shown in this paper that the
synthesis of xanthone 13b could be improved to an eight-
step synthesis with an overall yield of 25%.
CO2Et
13a (32%)
13b (64%)
12a (95%)
12b (92%)
Scheme 2 Conversion of salicylaldehydes 1 into xanthones 1310
Synlett 2009, No. 4, 550–553 © Thieme Stuttgart · New York

552
N. Volz et al.
LETTER
difference electron density determination and refined using
a ‘riding’ model (H(O)) free).
In conclusion, we have shown that tetrahydroxanthones
can be formed from tricycles generated by a vinylogous
aldol–oxa-Michael reaction. Furthermore the formal syn-
thesis of 4-dehydroxydiversonol was accomplished.
4b: Colorless crystals, C14H18O4, M = 250.28, crystal size
0.50 x 0.45 x 0.40 mm, triclinic, space group P-1 (No.2): a =
5.9907(2) Å, b = 8.5207(3) Å, c = 12.4965(5) Å, a =
97.603(2)º, β = 95.458(2)º, γ = 97.465(2)º, V = 622.81(4) Å3,
Z = 2, ρ(calcd) = 1.335 Mg m-3, F(000) = 268, µ = 0.097
OH
O
OH
OH
1) DMDO (74%)
2) NaBH4 (71%)
3) BBr3 (85%)
OMe
O
OH
mm-1, 5344 reflections (2θmax = 55°), 2715 unique (Rint
=
0.025), 168 parameters, 1 restraint, R1 (I > 2σ(I)) = 0.036,
wR2 (all data) = 0.104, GooF = 1.07, largest diff. peak and
hole 0.264 and –0.228 e Å-3. Crystallographic data
(excluding structure factors) for the structure reported in this
work have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC 717754 (4b). These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
O
O
13b
5
Scheme 3 Completion of the synthesis of 4-dehydroxydiversonol
(5) according to Tietze et al.5
Acknowledgment
(9) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 18296.
Financial support has been provided by the DFG (SPP 1179) and the
University of Karlsruhe (TH).
(10) For the hydrogenation of benzylic alcohols, see: (a) Suzuki,
M.; Kimura, Y.; Terashima, S. Bull. Chem. Soc. Jpn. 1986,
59, 3559. (b) Orsini, F.; Sello, G.; Travaini, E.; Di Gennaro,
P. Tetrahedron: Asymmetry 2002, 13, 253. (c) Couche, E.;
Fkyerat, A.; Tabacchi, R. Helv. Chim. Acta 2003, 86, 210.
(d) Kolarovic, A.; Berkes, D.; Baran, P.; Povazanec, F.
Tetrahedron Lett. 2005, 46, 975.
References and Notes
(1) For organocatalytic domino reactions: (a) Enders, D.;
Grondal, C.; Hüttl, M. M. Angew. Chem. Int. Ed. 2007, 46,
1570; Angew. Chem. 2007, 119, 1590. (b) For
organocatalytic conjugate addition reactions, see: Almasi,
D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007,
18, 299. (c) The use of salicylaldehyde in domino oxa-
Michael reactions for the synthesis of chromenes,
coumarins, and related heterocycles has already been
reviewed: Shi, Y.-L.; Shi, M. Org. Biomol. Chem. 2007, 5,
1499.
(11) Selected NMR Data
Compound 4b: 1H NMR (400 MHz, CDCl3): d = 1.42 (s,
3 H), 1.57 (dd, J = 13.5, 9.8 Hz, 1 H), 1.67 (td, J = 13.5 Hz,
1 H), 2.06–2.14 (m, 2 H), 2.28 (s, 3 H), 3.70 (s, 3 H), 3.86–
3.90 (m, 1 H), 4.89 (mc, 1 H), 5.25 (mc, 1 H), 6.13 (s, 1 H),
6.24 (s, 1 H). 13C NMR (100 MHz, CDCl3): d = 21.9, 28.6,
34.7, 45.5, 55.4, 61.9, 73.9, 89.9, 102.9, 105.9, 108.5, 140.3,
156.2, 157.1.
(2) (a) Lesch, B.; Toräng, J.; Vanderheiden, S.; Bräse, S. Adv.
Synth. Catal. 2005, 347, 555. (b) Gérard, E. M. C.; Sahin,
H.; Encinas, A.; Bräse, S. Synlett 2008, 2702. (c) Rao,
T. V.; Rele, D. N.; Trivedi, G. K. J. Chem. Res. 1987, 196.
(d) Lesch, B.; Toräng, J.; Nieger, M.; Bräse, S. Synthesis
2005, 1888. (e) Nising, C. F.; Bräse, S. Chem. Soc. Rev.
2008, 37, 1218.
(3) Liu, K.; Chougnet, A.; Woggon, W.-D. Angew. Chem. Int.
Ed. 2008, 47, 5827; Angew. Chem. 2008, 120, 5911.
(4) Tietze, L. F.; Stecker, F.; Zinngrebe, J.; Sommer, K. M.
Chem. Eur. J. 2006, 12, 8770.
Compound 9b: 1H NMR (400 MHz, CDCl3): d = 1.21–1.30
(m, 2 H), 1.28 (t, J = 7.3 Hz, 3 H), 2.04 (s, 3 H), 2.28 (s,
3 H), 2.59 (ddd, J = 14.1, 8.0, 1.3 Hz, 1 H), 2.72 (ddd,
J = 14.1, 7.3, 1.3 Hz, 1 H), 3.26 (br s, 1 H), 3.86 (s, 3 H), 4.18
(q, J = 7.3 Hz, 2 H), 4.97 (dd, J = 5.8, 5.3 Hz, 1 H), 5.87
(ddd, J = 15.5, 1.3, 1.3 Hz, 1 H), 6.29 (s, 1 H), 6.35 (s, 1 H),
7.02 (ddd, J = 15.5, 7.8, 7.8 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 14.2, 21.7, 25.3, 38.7, 41.4, 55.4, 60.1, 60.2,
75.5, 103.3, 109.9, 111.0, 139.7, 144.4, 153.0, 158.2, 166.3.
Compound 10b: 1H NMR (400 MHz, CDCl3): d = 1.25 (t,
J = 7.1 Hz, 3 H), 1.27 (s, 3 H), 1.53–1.67 (m, 2 H), 1.68–1.85
(m, 4 H), 2.27 (s, 3 H), 2.28–2.34 (m, 2 H), 2.55–2.64 (m, 2
H), 3.80 (s, 3 H), 4.12 (q, J = 7.1 Hz, 2 H), 6.22 (s, 1 H), 6.28
(s, 1 H). 13C NMR (100 MHz, CDCl3): d = 14.2, 16.4, 19.2,
21.6, 23.8, 30.4, 34.5, 38.8, 55.3, 60.2, 75.4, 102.4, 107.0,
110.3, 136.9, 154.1, 157.6, 173.5.
(5) Tietze, L. F.; Spiegl, D. A.; Stecker, F.; Major, J.; Raith, C.;
Große, C. Chem. Eur. J. 2008, 14, 8956.
(6) For a different approach to diversonol, see: (a) Nising,
C. F.; Ohnemüller, U. K.; Bräse, S. Angew. Chem. Int. Ed.
2006, 45, 307; Angew. Chem. 2006, 118, 313. (b) Nicolaou,
K. C.; Li, A. Angew. Chem. Int. Ed. 2008, 47, 6579; Angew.
Chem. 2008, 120, 6681.
(7) The Trost group used also an asymmetric catalytic approach
towards chromanes. The key step is a palladium-catalyzed
etherification of phenols with allylic substrates to yield a
tetrasubstituted stereogenic center and subsequent ring
closure: (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc.
1998, 120, 9074. (b) Trost, B. M.; Shen, H. C.; Dong, L.;
Surivet, J.-P. J. Am. Chem. Soc. 2003, 125, 9276. (c) Trost,
B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.; Sylvain, C.
J. Am. Chem. Soc. 2004, 126, 11966.
Compound trans-11b: 1H NMR (400 MHz, CDCl3):
d = 1.28 (t, J = 7.1 Hz, 3 H), 1.39 (s, 3 H), 2.30 (s, 3 H),
2.50–2.74 (m, 4 H), 3.88 (s, 3 H), 4.18 (q, J = 7.1 Hz, 2 H),
5.87 (d, J = 15.5 Hz, 1 H), 6.30 (s, 1 H), 6.37 (s, 1 H), 6.95
(ddd, J = 15.5, 7.6, 7.6 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 14.2, 22.4, 23.9, 41.9, 48.5, 56.0, 60.4, 79.5,
104.7, 108.4, 110.8, 125.4, 142.1, 147.7, 160.2, 160.8,
165.9, 190.0.
Compound cis-11b: 1H NMR (400 MHz, CDCl3): d = 1.27
(t, J = 7.2 Hz, 3 H), 1.39 (s, 3 H), 2.30 (s, 3 H), 2.59 (d,
J = 16.0 Hz, 1 H), 2.77 (d, J = 16.0 Hz, 1 H), 3.13 (mc, 2 H),
3.88 (s, 3 H), 4.15 (q, J = 7.2 Hz, 2 H), 5.94 (d, J = 11.7 Hz,
1 H), 6.29 (s, 1 H), 6.32–6.40 (m, 2 H). 13C NMR (100 MHz,
CDCl3): d = 14.2, 22.4, 23.7, 38.3, 48.5, 56.0, 60.0, 79.9,
104.6, 108.5, 110.7, 122.7, 143.0, 147.6, 160.2, 161.0,
166.1, 190.4.
(8) Crystal Structure Study of 4b
Single-crystal X-ray diffraction studies were carried out on
a Nonius KappaCCD diffractometer at 123(2) K using
MoKα radiation (λ = 0.71073 Å). The structures were solved
by Direct Methods (SHELXS-9713) and refinement were
carried out using SHELXL-9713 (full-matrix least-squares
refinement on F2). The hydrogen atoms were localized by
Synlett 2009, No. 4, 550–553 © Thieme Stuttgart · New York

LETTER
Compound 12b: 1H NMR (400 MHz, CDCl3): d = 1.22 (t,
Synthesis of 4-Dehydroxydiversonol
553
(ddd, J = 18.7, 11.6, 6.8 Hz, 1 H), 3.92 (s, 3 H), 6.34 (s, 1 H),
6.35 (s, 1 H), 15.98 (s, 1 H). 13C NMR (125 MHz, CDCl3):
d = 18.3, 22.4, 25.5, 30.2, 35.9, 56.1, 78.2, 105.4, 108.2,
108.7, 111.2, 147.1, 160.2, 160.6, 180.3, 182.0.
J = 7.1 Hz, 3 H), 1.36 (s, 3 H), 1.60–1.80 (m, 4 H), 2.25–2.30
(m, 2 H), 2.28 (s, 3 H), 2.56 (d, J = 15.8 Hz, 1 H), 2.70 (d,
J = 15.8 Hz, 1 H), 3.86 (s, 3 H), 4.09 (q, J = 7.1 Hz, 2 H),
6.26 (s, 1 H), 6.33 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 14.1, 19.0, 22.3, 23.5, 34.1, 38.5, 48.6, 56.0, 60.3, 80.0,
104.3, 108.4, 110.7, 147.4, 160.1, 161.2, 173.1, 190.7.
Compound 13b: 1H NMR (500 MHz, CDCl3): d = 1.44 (s,
3 H), 1.70–1.82 (m, 1 H), 1.91–2.00 (m, 1 H), 2.00–2.08 (m,
2 H), 2.31 (s, 3 H), 2.37 (dd, J = 18.7, 5.9 Hz, 1 H), 2.48
(12) Other Dieckmann condensations generating a 6-6 ring
system: (a) Fu, X.; Pechacek, J. T.; Smith, D. L.; Wheeler,
D. M. S. Nat. Prod. Lett. 1992, 1, 213. (b) Hill, C. L.;
McGrath, M.; Hunt, T.; Grogan, G. Synlett 2006, 309.
(c) Stetter, H.; Heidel, H. Chem. Ber. 1966, 99, 2172.
(13) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.
Synlett 2009, No. 4, 550–553 © Thieme Stuttgart · New York

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