Formal Synthesis of (-)-Siccanin Using an Enantioselective Domino Wacker/Carbonylation/Methoxylation Reaction

Article abstract of DOI:10.1055/s-0035-1560752

A formal synthesis of (-)-siccanin was achieved through an enantioselective domino Wacker/carbonylation/methoxylation reaction as the key step to form the chroman ring with a quaternary stereogenic center with 95% ee. The pendant cyclohexyl moiety was introduced through a two-step aldol condensation.

Full text of DOI:10.1055/s-0035-1560752

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, 96–100
letter
96
L. F. Tietze et al.
Letter
Synlett
Formal Synthesis of (–)-Siccanin Using an Enantioselective Domi-
no Wacker/Carbonylation/Methoxylation Reaction
Lutz F. Tietze*
Pd(TFA)2, CO, MeOH
(R,R)-Bn-BOXAX
24 h, 71%, 93% ee
OH
OMe
O
OH
OMe
OH
A
H
Stefan Jackenkroll
Dhandapani Ganapathy
Johannes R. Reiner
E
H
H
C
D
B
O
O
HO
H
siccanin
Institute of Organic and Biomolecular Chemistry,
Georg-August-University Göttingen,
Tammannstraße 2, 37077 Göttingen, Germany
ltietze@gwdg.de
Dedicated to Professor Steven V. Ley on the occasion of his 70th birthday
Received: 07.09.2015
Accepted after revision: 01.10.2015
Published online: 20.10.2015
Siccanin (1) is a potent antifungal agent that shows
strong activity against several pathogenic fungi and it has
been demonstrated in clinical trials that the compound is
highly effective against surface mycosis.3 In addition, it
shows significant inhibition against the growth of Tricho-
phyton mentagrophytes and blocks species-selective succi-
nate dehydrogenase.4 The siccanochromenes (e.g., 2 and 3)
possess potent antibacterial, cytotoxic, antifungal, and in-
secticidal activities.5 Several compounds of this family are
regarded as intermediates in the biosynthesis of siccanin.
Despite the biological importance and structurally chal-
lenging features of siccanin (1), there is only one enantiose-
lective synthesis of this compound described so far, which
was developed by Trost et al.6 They used a Pd-catalyzed
asymmetric allylic alkylation and a radical epoxy olefin cy-
clization as key steps with diol 4 as a late intermediate.7 Re-
cently, Barrero et al. reported a synthesis of siccano-
chromene F (3) from (+)-3,4-dihydro-γ-ionone, isolated
from Bellardia trixago.8
As part of our ongoing research towards the enantiose-
lective domino construction of quaternary stereogenic car-
bon centers in natural product synthesis, we identified diol
4 as a ready target for the formal total synthesis of siccanin
(1).9 We envisaged that 4 would be easily accessible from si-
lyl enol ether 6 and chiral chroman 5, which, in turn, could
be obtained from 7 by a palladium-catalyzed asymmetric
domino Wacker/carbonylation/methoxylation reaction
(Scheme 1).10
DOI: 10.1055/s-0035-1560752; Art ID: st-2015-d0705-l
Abstract A formal synthesis of (–)-siccanin was achieved through an
enantioselective domino Wacker/carbonylation/methoxylation reaction
as the key step to form the chroman ring with a quaternary stereogenic
center with 95% ee. The pendant cyclohexyl moiety was introduced
through a two-step aldol condensation.
Key words natural products, domino reaction, aldol reaction, transi-
tion-metal catalysis, enantioselective reactions
Siccanin (1) and the structurally related siccano-
chromenes 2 and 3 are fungal metabolites that were first
isolated from the culture broth of Helminthosporium siccans
(Figure 1).1 Siccanin (1) is a structurally fascinating fused
pentacyclic chroman with two quaternary carbon stereo-
genic centers. X-ray crystallography and spectroscopic
analysis unveiled the structure and absolute configuration
with an unusual cis,syn,cis-fused A,B,C-ring system.2
OH
O
OH
D
A
H
E
H
H
B
C
O
O
H
1
2
siccanin
siccanochromene A
OH
OH
OH
Our approach commenced with the enantioselective
domino Wacker/carbonylation/methoxylation reaction of
alkenyl phenol 7 in the presence of palladium (II)-trifluoro-
acetate (5 mol%), chiral (R,R)-Bn-BOXAX ligand 10 (20
mol%) and p-benzoquinone as reoxidant under an atmo-
sphere of carbon monoxide in methanol at room tempera-
ture. The reaction afforded chiral chroman 5 in 71% yield
and with 95% ee (Scheme 2).11 Upon careful reduction of 5
O
H
3
siccanochromene F
Figure 1 Siccanin (1) and siccanochromenes 2–3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 96–100

97
L. F. Tietze et al.
Letter
Synlett
OH
OMe
OH
O
OH
D
A
H
E
H
B
H
C
O
H
O
4
1
siccanin
OMe
OMe
OTMS
O
enantioselctive domino
Wacker/carbonylation/
methoxylation
MeO
O
HO
7
6
5
Scheme 1 Retrosynthetic analysis of Siccanin (1)
with diisobutylaluminum hydride (DIBAL-H) at –78 °C in
toluene, aldehyde 8 was obtained in 81% yield along with
16% over-reduced alcohol 9. However, to obtain enantio-
pure aldehyde 8 and working on a large scale, 5 was quanti-
tatively reduced to give 9 by using lithium aluminum hy-
dride in diethyl ether at room temperature. The product
was then purified by preparative HPLC on a chiral phase
(IA-column) allowing an increase of the ee value to 99%. En-
antiopure 9 was subsequently oxidized to provide aldehyde
8 with 2-iodoxybenzoic acid (IBX) with 78% yield (Scheme
2).
The next challenging step in the synthesis was the aldol
reaction of aldehyde 8 with silyl enol ether 6, which was
readily accessible on a large scale by following a reported
protocol.12 Initially, aldehyde 8 and TMS enol ether 6 were
reacted with BF3·OEt2 in CH2Cl2–Et2O (9:1) at –78 °C. After
full conversion of 8, attempts were made to conduct a dehy-
dration of the primarily formed aldol adduct 11 by acidic
workup and activation of the alcohol moiety and subse-
quent elimination by using DEAD/PPh3,13 MsCl/DBU,14 or
Ac2O/pyridine, respectively. Unfortunately, all attempts at
the elimination were unsuccessful. To circumvent this prob-
lem, crude aldol adduct 11 was reacted with Burgess re-
agent15 15 (Figure 2) under microwave irradiation at 80 °C
in toluene to give the desired α,β-unsaturated ketones (E)-
12 and (Z)-13 in 8 and 20% yield, together with 13% yield of
constitutional isomer (E)-14 (Table 1, entry 1). To improve
the yield of (E)-12 and to suppress the formation of (E)-14,
several other milder conditions were investigated. Reason-
able results were achieved by transmetalation of the TMS
enol ether 6 with methyl lithium followed by a second
transmetalation with ZnCl2, and subsequent addition of al-
dehyde 8 to the formed Zn-enolate and elimination with
Martin’s sulfurane16 16. In this way, (E)-12 and (Z)-13 were
obtained in 44 and 16% yield, respectively (entry 4).
O
CF3
Ph
S
CF3
CF3
O
S
Ph
O
O
Ph
Et3N
N
OMe
CF3
Ph
O
Martin's sulfurane (16)
Burgess reagent (15)
Figure 2 Structures of the reagents used herein
OMe
OMe
OMe
a)
b)
O
O
MeO
O
H
O
HO
8
7
(R)-5
O
N
OMe
R
R
N
O
d)
c)
HO
O
(R,R)-Bn-BOXAX
(10)
(R)-9
Scheme 2 Synthesis of aldehyde 8: Reagents and conditions: (a) Pd(TFA)2 (5 mol%), (R,R)-Bn-BOXAX (10) (20 mol%), p-benzoquinone (4.0 equiv),
MeOH, CO (1 atm), r.t., 24 h, 71%, 93% ee; (b) DIBAL-H (2.5 equiv), toluene, –78 °C, 20 min, 81% (R)-8, 16% (R)-9; (c) LiAlH4 (1.1 equiv), Et2O, 0 °C→r.t.,
3 h, quant.; (1) IBX (2.0 equiv), DMSO, r.t., 2 h, 78%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 96–100

98
L. F. Tietze et al.
Letter
Synlett
Table 1 Aldol Condensation of Aldehyde 8 and Silyl Enol Ether 6
OMe
OMe
OTMS
O
a)
b)
O
O
H
O
HO
OMe
6
8
11
OMe
δ (1'-H) = 6.70 ppm
δ (1'-H) = 6.71 ppm
OMe
O
O
H
O
H
1'
+
+
1'
O
O
1'
O
H
δ (1'-H) = 5.68 ppm
(E)-12
(Z)-13
(E)-14
Entry
Conditions (a)
Conditions (b)
Yield (%)
(E)-12
(Z)-13 (E)-14
1
2
3
4
8, BF3·OEt2, 6, CH2Cl2/Et2O, –78 °C, 23 h
15, toluene, 80 °C, MW, 30 min
16, CH2Cl2, 0 °C to r.t., 30 min
16, CH2Cl2, 0 °C to r.t., 3 h
16, CH2Cl2, 0 °C to r.t., 2 h
8
21
47
44
20
14
7
13
–
i. 6, MeLi, THF, 0 °C, 30 min; ii. 8, –78 °C, 4 h
i. 6, MeLi, Et2O, 0 °C, 1 h; ii. MgBr2·OEt2, 0 °C, 40 min iii. 8, –78 °C, 16 h
i. 6, MeLi, THF, 0 °C, 30 min; ii. ZnCl2, –78 °C, 1 h; iii. 8, –78 °C, 16 h
–
16
–
For the continuation of our synthesis, the chemoselec-
tive hydrogenation of the α,β-unsaturated ketone (E)-12
was investigated. The best results were obtained by per-
forming the reaction with palladium on charcoal (10 mol%)
in CH2Cl2 at room temperature under a hydrogen atmo-
sphere (1 atm) for 18 hours. A diastereomeric mixture of 17
and 18 (1:1.1 ratio) with 86% yield was obtained, which
could be separated by preparative HPLC on a chiral IB col-
umn (Scheme 3). In addition, based on reported protocols,
several homogeneous hydrogenation reaction conditions
were carried out. Interestingly, neither hydrogenation of
(E)-18 using Wilkinson, Crabtree or a ruthenium catalyst
with a BINAP backbone nor Noyori’s transfer hydrogenation
procedures were successful.
different chemical shifts of the vinyl proton 1'-H into ac-
count. The magnetic anisotropy of the carbonyl group in
(E)-12 and the side-product (E)-14 exerts a strong deshield-
ing effect on 1'-H, whereas the carbonyl group in isomer
(Z)-13 does not have such an effect. The assignments for
(E)-12 and (Z)-13 were further supported by NOE experi-
ments.
The next step in the synthesis involved the transforma-
tion of the carbonyl group into an olefin moiety. Initially,
the non-basic Lombardo methylenation was applied; un-
fortunately, the reaction did not afford any product. Wittig
reaction of 17 with the ylide of MePPh3Br and t-BuOK
formed in situ in THF also did not give the desired com-
pound. However, from this reaction we learned that, based
on NMR analysis of the recovered starting material, the ste-
reochemical integrity of the α-position of ketone 17 is not
affected under basic conditions. Thus, when t-BuOK used in
the Wittig reaction was replaced by the more basic n-BuLi
under reflux conditions, the reaction afforded 38% alkene
19 and 57% recovered starting material. Finally, Peterson
olefination of 17 gave the best yields. For this reaction,
trimethylsilylmethyl magnesium, which was obtained from
chloromethyltrimethylsilane, magnesium and LiCl, was
added to ketone 17 to afford the corresponding diastereo-
meric alcohols in a 1:1 ratio. Subsequently, the alcohol mix-
ture was reacted with NaH in THF at 100 °C under micro-
wave irradiation to yield alkene 19 in 85% yield over two
steps (Scheme 4). We note here that a similar problem had
been encountered by us in the synthesis of desogestrel; in
that case, Peterson olefination was the only way to intro-
duce a methylene group starting from a cyclic ketone.17
The double bond geometry of the α,β-unsaturated ke-
tones (E)-12, (Z)-13, and (E)-14 was assigned by taking the
OMe
O
Pd/C
(10 mol%)
H2 (1 atm)
CH2Cl2, r.t.
18 h
O
H
OMe
17
O
OMe
+
86%
O
O
O
(E)-12
H
18
Scheme 3 Hydrogenation of α,β-unsaturated ketone (E)-12
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 96–100

99
L. F. Tietze et al.
Letter
Synlett
OMe
this work
HO
OMe
O
OH
OMe
OH
OMe
a)
HO
a)
O
O
H
H
17
O
O
19
H
H
4
22
[α]D = +43.9
(c = 0.50, CHCl3)
b)
[α]D = –8.4
(c = 0.60, CHCl3)
O
OH
OH
OMe
Trost et al.
OH
A
H
OH
E
ref. 7
OMe
OH
OMe
H
H
C
D
HO
HO
B
O
O
ref. 7
H
1
4
siccanin
O
O
H
H
Scheme 4 Reagents and conditions: (a) i. TMSCH2MgCl, LiCl, Et2O, 0 °C
to r.t., 20 h; ii. NaH, THF, 100 °C, MW, 16 h; (b) AD-mix-β, MeSO2NH2
(1.0 equiv), t-BuOH–H2O (1:1), 5 d, 90%.
4
22
[α]D = –4.8
(c = 1.70, CHCl3)
[α]D = +27.0
(c = 1.70, CHCl3)
Scheme 6 Comparison of the specific rotations of compounds 4 and
22 obtained in the present work with those reported by Trost et al. Re-
agents and conditions: (a) DDQ (3.0 equiv), benzene, 80 °C, 2 h, 63%.
To complete the formal synthesis of siccanin (1), alkene
19 was subjected to Sharpless dihydroxylation with AD-
mix-β in the presence of methanesulfonamide in t-BuOH–
H2O (1:1) at room temperature to give 4 exclusively as a sin-
gle diastereomer in 90% yield (Scheme 4). As already men-
tioned, diol 4 is a late intermediate in the synthesis of sic-
canin (1) developed by Trost et al.6
We also transformed the diastereomeric ketone 18 ob-
tained in the hydrogenation of (E)-12 into diols 20 and 21
(Scheme 5) and treated diol 4 with DDQ to obtain the corre-
sponding chromene 22 (Scheme 6).
In summary, we have developed a short, efficient formal
synthesis of (–)-siccanin (1) by using an enantioselective
domino Wacker/carbonylation/methoxylation reaction to
access chroman 11 and a two-step aldol condensation to in-
stall the pendent cyclohexyl moiety.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft (DFG), the State of
Lower Saxony, the VW-Foundation and the Fonds der Chemischen In-
dustrie for generous support. S.J. thanks the CaSuS Program and J.J.R.
the Konrad Adenauer Stiftung for a Ph.D. scholarship. D.G.P thanks
the Georg-August-University for a postdoctoral fellowship.
OH
OMe
HO
O
OMe
H
20
O
a,b)
Supporting Information
+
O
OH
OMe
Supporting information for this article is available online at
H
HO
http://dx.doi.org/10.1055/s-0035-1560752.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
18
O
H
References and Notes
21
(1) (a) Ishibashi, K. J. J. Antibiot., Ser. A 1962, 15, 161. (b) Nozoe, S.;
Suzuki, T.; Okuda, S. Tetrahedron Lett. 1968, 3643. (c) Nozm, S.;
Hirai, K. Tetrahedron 1971, 6073. (d) Nozoe, S.; Hirai, K.;
Snatzke, F.; Snatzke, G. Tetrahedron 1974, 30, 2773.
(2) (a) Nozoe, S.; Suzuki, K. T. Tetrahedron 1971, 27, 6063. (b) Hirai,
K.; Nozoe, S.; Tsuda, K.; Iitaka, Y.; Shirasawa, M. Tetrahedron
Lett. 1967, 2177.
(3) (a) Kitano, N.; Kondo, F.; Kusano, K.; Ishibashi, K. US 397429,
1976. (b) Matsuki, M.; Hanatsu, H.; Watanabe, T.; Ogasawara,
A.; Mikami, T.; Matsumoto, T. Biol. Pharm. Bull. 2006, 29, 919.
(c) Ishibashi, K.; Hirai, K.; Arai, M.; Sugasawa, S.; Endo, A.;
Yasumura, A.; Matsuda, H.; Muramatsu, T. Annu. Rep. Sankyo
Res. Lab. 1970, 22, 1.
Scheme 5 Synthesis of diols 20 and 21. Reagents and conditions:
(a) i. TMSCH2MgCl, LiCl, Et2O, 0 °C to r.t., 20 h; ii. NaH, THF, 100 °C,
MW, 16 h; (b) AD-mix-β, MeSO2NH2 (1.0 equiv), t-BuOH–H2O (1:1), 4 d,
91%, dr = 4:1.
A comparison of the specific rotation of compounds 4
and 22 in our work and those reported in the work of Trost
et al. implies a pronounced improvement in enantiopurity
by using the new synthetic approach (Scheme 6).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 96–100

100
L. F. Tietze et al.
Letter
Synlett
(4) Belloti, M. G.; Riviera, L. Chemioterapia: International Journal of
the Mediterranean Society of Chemotherapy 1985, 4, 431.
(5) Hirai, K.; Suzuki, K. T.; Nozoe, S. Tetrahedron 1971, 27, 6057.
(6) (a) Trost, B. M.; Shen, H. C.; Surivet, J. P. Angew. Chem. Int. Ed.
2003, 42, 3943. (b) Racemic:Kato, M.; Matsumura, Y.; Heima, K.;
Fukamiya, N.; Kabuto, C.; Yoshikoshi, A. Tetrahedron 1987, 43,
711. (c) Racemic:Trost, B. M.; Fleitz, F. J.; Watkins, W. J. J. Am.
Chem. Soc. 1996, 118, 5146.
(7) Trost, B. M.; Shen, H. C.; Surivet, J. P. J. Am. Chem. Soc. 2004, 126,
12565.
(8) Castillo, A.; Silva, L.; Briones, D.; Quílez del Moral, J. F.; Barrero,
A. F. Eur. J. Org. Chem. 2015, 3266.
(9) (a) Tietze, L. F.; Jackenkroll, S.; Hierold, J.; Ma, L.; Waldecker, B.
Chem. Eur. J. 2014, 20, 8628. (b) Tietze, L. F.; Ma, L.; Reiner, J. R.;
Jackenkroll, S.; Heidemann, S. Chem. Eur. J. 2013, 19, 8610.
(c) Tietze, L. F.; Jackenkroll, S.; Raith, C.; Spiegl, D. A.; Reiner, J.
R.; Ochoa-Campos, M. C. Chem. Eur. J. 2013, 19, 4876. (d) Tietze,
L. F.; Wolfram, T.; Holstein, J. J.; Dittrich, B. Org. Lett. 2012, 14,
4035. (e) Tietze, L. F.; Stecker, F.; Zinngrebe, J.; Sommer, K. M.
Chem. Eur. J. 2006, 12, 8770.
phase was dried over MgSO4 and the solvent was removed in
vacuo. Column chromatography on silica gel (n-hexane–Et2O
10:1→8:2) gave ester (R)-5 (544 mg, 2.06 mmol, 71%, 95% ee) as
a colorless oil; [α]D = 8.2 (c = 0.50, CHCl3, 24.0 °C). 1H NMR (300
MHz, CDCl3): δ = 1.42 (s, 3 H, 2'-CH3), 1.85 (dt, J = 13.8, 6.8 Hz,
1 H, 3'-Ha), 1.99 (dt, J = 13.8, 6.8 Hz, 1 H, 3'-Hb), 2.26 (s, 3 H, 7'-
CH3), 2.55–2.66 (m, 4 H, 2-H2, 4'-H2), 3.68 (s, 3 H, 1-OCH3), 3.79
(s, 3 H, 5'-OCH3), 6.24, 6.29 (2 × s, 2 H, 6'-H, 8'-H). 13C NMR (125
MHz, CDCl3): δ = 16.4 (C-4'), 21.5 (7'-CH3), 24.6 (2'-CH3), 30.3
(C-3'), 43.5 (C-2), 51.5 (1-OCH3), 55.3 (5'-OCH3), 74.2 (C-2'),
102.9, 110.4 (C-6', C-8'), 106.8 (C-4a'), 137.1 (C-7'), 153.5 (C-5'),
157.5 (C-8a'), 170.9 (C-1). IR (ATR): 2936, 2856, 1734, 1619,
1584, 1352, 1224, 1103, 1020, 811 cm–1
max (lg ε) = 208.0 (4.678), 272.0 (3.087) nm. Analytical HPLC
. UV (MeCN):
λ
(Daicel Chiracel OD; 4.6 × 250 mm, 5 μm, n-hexane–i-PrOH
98:2; 0.8 mL/min; 234 nm): tR = 18.2 [(–)-(S)-5, 2.3%], 26.6 [(+)-
(R)-5, 97.7%] min; 95% ee. MS (ESI): m/z (%) = 551.3 (99) [2M +
Na]+, 303.1 (11) [M + K]+, 287.1 (100) [M + Na]+, 265.2 (91) [M +
H]+. HRMS (ESI): m/z [M + H]+ calcd for C15H20O4 (264.32):
265.1434; found: 265.1434; m/z [M + Na]+ calcd: 287.1251;
found: 287.1254.
(10) Domino Reactions: Concepts for Efficient Organic Synthesis;
Tietze, L. F., Ed.; Wiley-VCH: Weinheim, 2014.
(12) (a) Rubottom, G. M.; Mott, R. C. J. Org. Chem. 1979, 44, 1731.
(b) Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63,
2308. (c) Reetz, M. T.; Kindler, A. J. Organomet. Chem. 1995, 502,
C5.
(13) Olpp, T.; Brückner, R. Angew. Chem. Int. Ed. 2003, 44, 1610.
(14) Smith, A. B. III.; Nolen, E. G.; Shirai, R.; Blase, F. R.; Ohta, M.;
Chida, N.; Hartz, R. A.; Fitch, D. M.; Clark, W. M.; Sprengeler, P.
A. J. Org. Chem. 1995, 60, 7837.
(15) O’Grodnick, J. S.; Ebersole, R. C.; Wittstruck, T.; Caspi, E. J. Org.
Chem. 1974, 39, 2124.
(16) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327.
(17) Tietze, L. F.; Krimmelbein, I. Chem. Eur. J. 2008, 14, 1541.
(11) Experimental Procedure for the Preparation of (R)-5: A solu-
tion of palladium(II) trifluoroacetate (48.2 mg, 145 μmol,
5 mol%) and the Bn-BOXAX ligand (R,R)-10 (332 mg, 580 μmol,
20 mol%) in MeOH (10 mL) was stirred at r.t. for 15 min. Alkenyl
phenol 7 (598 mg, 2.90 mmol, 1.00 equiv) in MeOH (7 mL) and
p-benzoquinone (1.25 g, 11.6 mmol, 4.00 equiv) were added at
r.t. and CO gas (1 atm) was passed through the resulting reac-
tion mixture for 5 min. After stirring at r.t. under a CO atmo-
sphere (1 atm) for 19 h, the reaction was quenched at r.t. by
addition of 1 M aq HCl (50 mL). The aqueous phase was
extracted with MTBE (3 × 25 mL) and the combined organic
phases were washed with 1 M aq NaOH (3 × 25 mL). The organic
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 96–100