A unified strategy for the asymmetric total syntheses of diversonol and lachnone C

Article abstract of DOI:10.1002/chem.201102192

A unified synthetic strategy for the asymmetric syntheses of the natural products diversonol and lachnone C was developed by using the domino vinylogous aldol-oxa-Michael reaction as the enantioselective key step. Further transformations include dihydroxylation, lactol-opening by a Wittig-reaction, and lactonization. The obtained chromone lactones, a class of mycotoxins, can further be converted to tetrahydroxanthones by a Dieckmann condensation. This general method allows for the first time the enantioselective access to these classes of natural products and should be applicable to other members of the tetrahydroxanthone and chromone lactone families. Cohesive synthetic strategy: The first asymmetric total syntheses of mycotoxins (+)-lachnone C and (-)-diversonol were achieved with the enantioselective domino vinylogous aldol-oxa-Michael reaction as the key step (see scheme).

Full text of DOI:10.1002/chem.201102192

DOI: 10.1002/chem.201102192
A Unified Strategy for the Asymmetric Total Syntheses of Diversonol and
Lachnone C
Manuel C. Brçhmer,[a] Emmanuel Bourcet,[a] Martin Nieger,[b] and Stefan Brꢀse*[a]
Abstract: A unified synthetic strategy
for the asymmetric syntheses of the
natural products diversonol and lach-
none C was developed by using the
domino vinylogous aldol–oxa-Michael
reaction as the enantioselective key
step. Further transformations include
obtained chromone lactones, a class of
mycotoxins, can further be converted
to tetrahydroxanthones by a Dieck-
mann condensation. This general
method allows for the first time the
enantioselective access to these classes
of natural products and should be ap-
plicable to other members of the tetra-
hydroxanthone and chromone lactone
families.
Keywords: asymmetric synthesis ·
diversonol
· domino reactions ·
lachnone · natural products · tetra-
hydroxanthones
dihydroxylation, lactol-opening by
a
Wittig-reaction, and lactonization. The
Introduction
Tetryhydroxanthones are a fast
growing class of mycotoxins
with interesting biological ac-
tivities. The secalonic acids
(compounds of type 1) are
symmetric or unsymmetric
dimers of blennolides A–C
(2a–2c) and show cytostatic,
antibacterial, and anti-HIV
properties.[1] Diversonol (3) is
a
secondary metabolite first
isolated by Turner in 1978
from P. diversum.[2] Lachnones
C–E (4a–4c) belong to a class
of chromone lactones isolated from the filamentous fungus
Nicolaou et al. by connection of the outer rings followed by
a domino deallylation–oxa-Michael reaction sequence.[7] Re-
cently, the Porco group published a very elegant and short
approach to blennolides B and C (2b and 2c) employing a
vinylogous addition of siloxyfurans to benzylpyryliums fol-
lowed by a Dieckmann cyclization.[8]
The only enantioselective approaches to this class of com-
pounds were undertaken by Tietze[9] and by our group[10]
and led to the synthesis of dehydroxydiversonol. However,
the introduction of the 4-hydroxy group was up to now not
possible.
Lachnum sp. BCC 2424.[3]
Different strategies for the racemic synthesis of blenno-
lides and diversonol have been published to date. Our group
used the domino oxa-Michael–aldol reaction[4] between a
substituted salicylaldehyde and 4-hydroxycyclohexenone as
key step for the first syntheses of diversonol (3)[5] and blen-
nolide C (2c).[6] The same compounds were synthesized by
[a] Dipl.-Chem. M. C. Brçhmer,+ Dr. E. Bourcet,+ Prof. Dr. S. Brꢀse
Institute of Organic Chemistry
Recently, Pescitelli and Krohn proposed the absolute con-
figuration of 3 on the means of TDDFT ECD calcula-
tions.[11]
Karlsruhe Institute of Technology (KIT) Campus South
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax : (+49)721-608-48581
E-mail: braese@kit.edu
Our goal is to establish a general method for the asym-
metric synthesis of this class of compounds. We assumed
that the vinylogous aldol–oxa-Michael domino reaction,
which was developed in our group[12] some years ago and
has been used later for the syntheses of dehydroxydiverso-
nol,[10] a-tocopherol,[13] confluentin, and daurichromenic
[b] Dr. M. Nieger
Laboratory of Inorganic Chemistry
University of Helsinki, 00014 Helsinki (Finland)
[+] These authors have contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102192.
13706
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 13706 – 13711

FULL PAPER
acid,[14] is particularly suitable for the construction of both
the lachnone and the tetrahydroxanthone structures.
Herein, we report the first enantioselective syntheses of
epi-lachnone C (epi-4a), lachnone C (4a) and diversonol (3)
as well as the determination of their absolute configurations.
Results and Discussion
The asymmetric domino reactions between salicylaldehydes
5 and prenal (7) were performed with Jørgensenꢂs cata-
lysts[15] (R)-8 and (S)-8 and gave, depending of the catalyst
used, tricyclic lactols 6a and 6b in 99% enantiomeric excess
(ee) and 83% ee, respectively (Scheme 1). The absolute con-
figuration of 6a was determined by analysis of the crystal
structure (Figure 1).
To introduce the required hydroxy group, we first used a
model compound and envisaged the direct a-hydroxylation
of lactone 9, which could be easily obtained by oxidation of
6c[10] using Davisꢂ oxaziridine.[16] However, no product could
be isolated, probably due to the instability of the mentioned
lactone with strong bases. We could successfully circumvent
this problem by an elimination–dihydroxylation sequence,
which gave a separable mixture of diols 12c and 13c in 58%
overall yield (Scheme 2).
Scheme 1. Reagents and conditions: a) (R)-8 (0.3 equiv), benzoic acid
(0.3 equiv), toluene, then 7 (syringe pump), RT, 72 h, 63% (99% ee);
b) (S)-8 (0.3 equiv), benzoic acid (0.3 equiv), toluene, then 7 (syringe
pump), RT, 72 h, 67% (83% ee).
could easily be separated by column chromatography
(Scheme 3). The absolute configuration of diol 13b could be
proven by X-ray structure analysis and is very likely S,S,S,S
(Hooftꢂs y-parameter=0.08(85))[17] (Figure 1)).
This strategy was then also applied for lactols 6a and 6b.
Elimination with methanesulfonyl chloride (MsCl) gave the
enolethers 11a/11b in excellent yields (90/92%). Dihydroxy-
lation with N-methylmorpholine-N-oxide (NMO)/OsO4
gave ꢀ4.5:1 mixtures of diols 12a/13a and 12b/13b, which
For the synthesis of epi-lachnone C (epi-6), diol 12a was
opened using a Wittig reaction. Interestingly, the outcome
of the reaction was strongly dependent on temperature and
the phosphonate used (Table 1). When performed in hot tol-
uene, the reaction of diol 12a with the stabilized ylide A
Figure 1. Visualizations of the X-ray structures of lactol 6a (top left, one of the two crystallographic independent molecules), lactone 9 (top right), diol
13b (bottom left, one of the two crystallographic independent molecules), and epi-lachnone epi-4a (bottom, right); displacement parameters are drawn
at 50% probability level.[18]
Chem. Eur. J. 2011, 17, 13706 – 13711
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13707

S. Brꢀse et al.
Table 1. Conditions and product yields for the reaction of 12a.
Entry
Reagent/Solvent
T
[8C]
Yield 14
Yield 15
[%][a]
[%][a]
a
b
c
A/toluene
B/THF
A/THF
100
32
–
85
43
68
–
À78 to 0
60
Scheme 2. Reagents and conditions: a) PCC, CH2Cl2, 6 h, RT, 80%;
b) MsCl (2.5 equiv), NEt3 (8.0 equiv), THF, 08C to RT, 3 h, 86%;
c) NMO (4.0 equiv), OsO4 (0.1 equiv), acetone/H2O 9:1, RT, 4 d, 67%
(4:1 ratio of 12c and 13c).
dure using p-toluenesulfonic acid (TsOH) in refluxing ben-
zene, followed by hydrogenation with Pd/BaSO4 (95%) and
gave a mixture of the desired alkene 14 and tetracyclic com-
pound (15, see Table 1). The latter was the only product
formed when phosphonate B was used. Eventually, alkene
14 could selectively be obtained as a single E isomer by low-
ering the temperature to 608C (Table 1).
Hydrogenation of 14 (in 90% yield) followed by lactoni-
zation with TsOH gave the desired lactone epi-16 in poor
yield (39%) due to formation of ether epi-17 (in 42%
yield). However, both products could be converted to
ketone epi-18. Lactone epi-16 was oxidized to epi-18 (98%)
with pyridinium chlorochromate (PCC), whereas ether epi-
17 could be converted to epi-18 (90%) in a three step proce-
benzylic oxidation with Mn
deprotection of the phenolic hydroxyl group with MgI2-
(Et2O)2 (98%) and the benzylic tert-butyldiphenylsilyl
(TBDPS)-ether with tetrabutylammonium fluoride (TBAF)
gave (À)-epi-lachnone C (epi-4a) in 57% yield (Scheme 4).
A representation of the X-ray structure of epi-4a is shown
in Figure 1.
The same reaction sequence was performed for the syn-
thesis of lachnone C (4a), starting from diol 13a. Wittig re-
action (78%), hydrogenation (97%) and treatment with
TsOH gave a mixture of lactone 16 (18%) and ether 17
(64%). Both were converted to 18 by either PCC oxidation
of 16 (90%) or by the previ-
ACHTUNGRTEN(NUNG OAc)3/tBuOOH (83%). Final
AHCTUNGTRENNUNG
ously described three step pro-
cedure starting from 17 (41%
over three steps). Deprotec-
tion of the methyl ether (99%)
and the TBDPS group (39%)
gave 4a (Scheme 5). Although
the aD value of the synthesized
compound is higher than in
the literature, a positive value
indicates that it has the same
absolute configuration as the
natural product.
We then turned our focus on
the synthesis of diversonol (3).
We presumed that chromone
lactone 19 should be a precur-
sor for Dieckmann condensa-
tion to tetrahydroxanthone 20
(Scheme 6). This was recently
described by Porco et al. as the
“retrobiomimetic” synthesis,[8]
although chromone lactones
Scheme 3. Reagents and conditions: a) MsCl (2.5 equiv), NEt3 (8.0 equiv), THF, 08C to RT, 3 h, 90%;
b) NMO (4.0 equiv), OsO4 (0.1 equiv), acetone/H2O 9:1, RT, 4 d, 86% (4.4:1 ratio of 12a and 13a); c) MsCl
(2.5 equiv), NEt3 (8.0 equiv), THF, 08C to RT, 3 h, 92%; d) NMO (4.0 equiv), OsO4 (0.1 equiv), acetone/H2O
9:1, RT, 4 d, 80% (4.7:1 ratio of 12b and 13b).
are probably formed by a hy-
drolysis/lactonization sequence
of tetrahydroxanthones.[19,20]
13708
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 13706 – 13711

Total Syntheses of Diversonol and Lachnone C
FULL PAPER
tBuOOH (66%) gave chro-
mone lactone ent-19 as the
precursor for the Dieckmann
cyclization (Scheme 7). ent-19
was also obtained from the
minor diol 13b by using a simi-
lar reaction sequence as previ-
ously described for the synthe-
ses of lachnone C (4a) and
epi-lachnone C
(epi-4a;
Scheme 8).
Scheme 4. Reagents and conditions: a) Pd (5% wt)/BaSO4 (0.05 equiv), H2 (1 bar), EtOAc, RT, 1 h, 90%; b)
p-TsOH (0.1 equiv), THF, RT, 24 h, 81% (1:1.1 ratio of epi-16 and epi-17); c) PCC (1.3 equiv), CH2Cl2, 3.5 h,
98%; d) p-TsOH (0.05 equiv), benzene, reflux, 16 h, 90%; e) Pd (5% wt)/BaSO4 (0.05 equiv), H2 (1 bar),
The Dieckmann condensa-
tion of chromone lactone ent-
19 using NaOMe as a base[8]
gave tetrahydroxanthone ent-
20 in 41% yield (Scheme 9).
Deprotection of the methyl
ether with BBr3 gave triol 32
(81%), which was converted
to diversonol in two further
steps according to Nicolaou
et al.[7] Comparison of the aD
with published data[11] showed
that the enantiomer of natural
(+)-diversonol was synthe-
sized. No traces of the other
enantiomer were detected by
HPLC, which indicated enan-
tiomer enrichment during the
synthesis. The result was con-
firmed by comparison of the
circular dichroism (CD) spec-
tra of synthesized diversonol
(Figure 2) and an authentic
EtOAc, RT, 1 h, 95%; f) MnACTHNUTRGNENUG(OAc)3 (0.2 equiv), tBuOOH (10 equiv), 3 ꢃ MS, EtOAc, RT, 4 d, 83%; g) Mg
(2.6 equiv), I2 (2.4 equiv), benzene/Et2O 2:1, 2.5 h; then epi-18, reflux, 16 h, 98%; h) TBAF (1.3 equiv), THF,
RT, 1 h, 57%.
Scheme 5. Reagents and conditions: a) Ph3P=CHCO2Et, THF, reflux, 4 h, 78%; b) Pd (5% wt)/BaSO4
(0.05 equiv), H2 (1 bar), EtOAc, RT, 2.5 h, 97%; c) p-TsOH (0.1 equiv), THF, RT, 3 d, 18% 16 and 64% 17;
d) PCC (1.3 equiv), CH2Cl2, 5 h, 90%; e) p-TsOH (0.05 equiv), benzene, reflux, 16 h, 91%; f) Pd (5% wt)/
BaSO4 (0.05 equiv), H2 (1 bar), EtOAc, RT, 12 h, 87%; g) MnACTHNUTRGNEU(GN OAc)3 (0.2 equiv), tBuOOH (10 equiv), 3 ꢃ
MS, EtOAc, RT, 4 d, 52%; h) Mg (2.6 equiv), I2 (2.4 equiv), benzene/Et2O 2:1, 2.5 h; then epi-18, reflux, 16 h,
99%; i) TBAF (1.3 equiv), THF, RT, 1 h, 39%.
As the precursor for 19 is the minor diol 13b, we first
turned our attention to the synthesis of 19 from major diol
12b, which implies an inversion of the hydroxyl group.
Opening of lactol 12b by Wittig reaction gave unsaturated
ester 21 in 83% yield. Selective tert-butyldimethylsilyl
(TBS) protection of the benzylic hydroxyl group (85%) and
hydrogenation (54%) gave ester 23 through compound 22.
Mesylation of the free alcohol led to concomitant elimina-
tion of the TBS ether (61%). Hydrolysis of the ester 24
gave a mixture of acid 25 (72%) and lactone 26 (4%),
whereas the acid could be converted to 26 by Cs2CO3 pro-
moted lactonization (79%). Hydrogenation of the double
Figure 2. Circular dichroism (CD) spectrum of natural (+)-diversonol
(grey line) and unnatural (À)-diversonol (black line) in methanol.
bond (79%) and benzylic oxidation with MnACTHNUGTRENUNG(OAc)3/
sample kindly provided by Dr. G. Pescitelli and Prof. K.
Krohn. Herewith, we proved the absolute configuration of
natural diversonol to be 5S,5aS,8S,8aR.
Scheme 6. Planned retrobiomimetic conversion of lactone 19 to tetrahy-
droxanthenone 20 as a precursor of diversonol (3).
Chem. Eur. J. 2011, 17, 13706 – 13711
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13709

S. Brꢀse et al.
Conclusion
We have established the first
asymmetric syntheses of diver-
sonol (3), lachnone C (4a) and
epi-lachnone C (epi-4a). The
strategy should be applicable
for the syntheses of many
members of the tetrahydroxan-
thone and chromone lactone
families. As both (R)- and (S)-
Jørgensen catalysts are com-
mercially available, both enan-
tiomers of each target mole-
cule are accessible.
Experimental Section
Scheme 7. Reagents and conditions: a) Ph3P=CHCO2Et (1.5 equiv), THF, 608C (sealed tube), 12 h, 83%;
b) TBSOTf (1.02 equiv), 2,6-lutidine (1.5 equiv), CH2Cl2, 08C, 1.5 h, 85%; c) Pd (5% wt)/BaSO4 (0.05 equiv),
H2 (1 bar), EtOAc, RT, 12 h, 54%; d) MsCl (1.5 equiv), NEt3 (1.5 equiv), DMAP (0.1 equiv), CH2Cl2, 08C to
RT, 3 h, 61%; e) LiOH (1.5 equiv), dioxane/H2O 4:1, RT, 18 h, 72% 25, 4% 26; f) Cs2CO3 (6.0 equiv), 18-
crown-6 (2.5 equiv), toluene, 908C, 79%; g) Pd (5% wt)/BaSO4 (0.05 equiv), H2 (1 bar), EtOAc, RT, 1 h, 79%;
For full experimental details see the
Supporting Information.
h) MnACHTUNGTRENNUNG(OAc)3 (0.2 equiv), tBuOOH (10 equiv), 3 ꢃ MS, EtOAc, RT, 4 d, 66%.
Acknowledgements
We gratefully acknowledge the finan-
cial support by the “Landesgraduier-
tenfçrderung Baden-Wꢄrttemberg”
(fellowship to M. C. B.) and “la
rꢅgion Rhꢆne-Alpes” (fellowship to
E. B.). We thank Prof. J. A. Porco, Jr.
for helpful discussions. We thank Dr.
J. Bꢄrck for the measurement of the
CD spectra and Prof. K. Krohn and
Dr. G. Pescitelli for providing
sample of natural diversonol.
a
[1] a) A. Stoll, J. Renz, A. Brack,
Helv. Chim. Acta 1952, 35,
2022–2034; b) I. Kurobane, S.
Iwahashi, A. Fukuda, Drugs
Exp. Clin. Res. 1987, 13, 339–
344; c) G. Liao, J. Zhou, H.
Wang, Z. Mao, W. Xiao, H.
Wang, Z. She, Y. Zhu, Oncol.
Rep. 2010, 23, 387–395; d) for a
review: S. Brꢀse, A. Encinas, J.
Keck, C. F. Nising, Chem. Rev.
2009, 109, 3903–3990.
Scheme 8. Reagents and conditions: a) Ph3P=CCO2Et (1.5 equiv), THF, 608C (sealed tube), 15 h, 98%; b) Pd
(5% wt)/BaSO4 (0.05 equiv), H2 (1 bar), EtOAc, RT, 1 h, 74% 28, 14% 29; c) p-TsOH (0.1 equiv), THF, RT,
12 h, 94%; d) p-TsOH (0.05 equiv), benzene, reflux, 20 h, 88%; e) Pd (5% wt)/BaSO4 (0.05 equiv), H2 (1 bar),
EtOAc, RT, 1 h, 79%; f) CSA (0.1 equiv), THF, reflux, 12 h, 93%; g) Mn
(10 equiv), 3 ꢃ MS, EtOAc, RT, 4 d, 66%.
ACHTUNGRTEN(NUNG OAc)3 (0.2 equiv), tBuOOH
[2] W. B. Turner, J. Chem. Soc.
Perkin Trans. 1 1978, 1621.
[3] V. Rukachaisirikul, S. Chantar-
uk, W. Pongcharoen, M. Isaka,
S. Lapanun, J. Nat. Prod. 2006,
69, 980–982.
[4] For reviews about oxa-Michael
reactions, see: a) C. F. Nising, S.
Brꢀse, Chem. Soc. Rev. 2008, 37,
1218–1228; b) C. F. Nising, S.
Brꢀse, Chem. Soc. Rev., DOI:
10.1039/C1CS15167C, in press.
Scheme 9. Reagents and conditions: a) NaOMe (2.0 equiv), THF, 08C, 1 h, 41%; b) BBr3 (10 equiv), CH2Cl2,
RT, 16 h, 81%; c) MMPP (0.75 equiv), EtOH, RT, 30 min; d) NaBH4 (1.0 equiv), MeOH/CH2Cl2 1:1, À788C,
5 min, 52% over two steps. MMPP=magnesium monoperoxyphthalate hexahydrate.
13710
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 13706 – 13711

Total Syntheses of Diversonol and Lachnone C
FULL PAPER
[5] C. F. Nising, U. K. Ohnemꢄller, S. Brꢀse, Angew. Chem. 2006, 118,
313–315; Angew. Chem. Int. Ed. 2006, 45, 307–309.
[6] E. M. C. Gꢅrard, S. Brꢀse, Chem. Eur. J. 2008, 14, 8086–8089.
[7] K. C. Nicolaou, A. Li, Angew. Chem. 2008, 120, 6681–6684; Angew.
Chem. Int. Ed. 2008, 47, 6579–6582.
[14] K. Liu, W.-D. Woggon, Eur. J. Org. Chem. 2010, 1033–1036.
[15] J. Franzꢅn, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjærsgaard,
K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 18296–18304.
[16] F. A. Davis, L. C. Vishwakarma, J. M. Billmers, J. Finn, J. Org.
Chem. 1984, 49, 3241.
[8] T. Qin, R. P. Johnson, J. A. Porco, Jr., J. Am. Chem. Soc. 2011, 133,
1714–1717.
[17] R. W. W. Hooft, L. H. Straver, A. L. Spek, J. Appl. Crystallogr. 2008,
41, 96–103.
[9] L. F. Tietze, D. A. Spiegl, F. Stecker, J. Major, C. Raith, C. Große,
Chem. Eur. J. 2008, 14, 8956–8963.
[18] CCDC-825881 (6a), 825882 (9), 825883 (13b), and 825884 (epi-4a)
contain the supplementary crystallographic data for this paper (ex-
cluding structure factors). These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[19] N. Tabata, H. Tomoda, K. Matsuzaki, S. Omura, J. Am. Chem. Soc.
1993, 115, 8558–8564.
[20] N. Tabata, H. Tomoda, Y. Iwai, S. Omura, J. Antibiot. 1996, 49, 267–
271.
[10] N. Volz, M. C. Brçhmer, M. Nieger, S. Brꢀse, Synlett 2009, 550–553.
[11] I. N. Siddiqui, A. Zahoor, H. Hussain, I. Ahmed, V. U. Ahmad, D.
Padula, S. Draeger, B. Schulz, K. Meier, M. Steinert, T. Kurtꢇn, U.
Flçrke, G. Pescitelli, K. Krohn, J. Nat. Prod. 2011, 74, 365–373.
[12] a) B. Lesch, J. Torꢀng, S. Vanderheiden, S. Brꢀse, Adv. Synth. Catal.
2005, 347, 555–562; b) B. Lesch, J. Torꢀng, M. Nieger, S. Brꢀse, Syn-
thesis 2005, 1888–1900.
[13] K. Liu, A. Chougnet, W.-D. Woggon, Angew. Chem. 2008, 120,
5911–5913; Angew. Chem. Int. Ed. 2008, 47, 5827–5829.
Received: July 17, 2011
Published online: November 11, 2011
Chem. Eur. J. 2011, 17, 13706 – 13711
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13711