Total synthesis of chaetoquadrins H and i

Article abstract of DOI:10.1055/s-0032-1318333

The first total syntheses of the chromone-containing natural products chaetoquadrins H and I are reported, using an aldol reaction and an acid-catalyzed deprotection/cyclization/elimination sequence. Chaetoquadrin H was isolated from the ascomycete Chaetomium quadrangulatum and exhibits potent mouse liver monoamine oxidase (MAO) inhibitory activity. Chaetoquadrin I was not isolated in sufficient quantity to enable biological evaluation. The synthesis of the title compounds provides a useful starting point for a medicinal chemistry program focused on chaetoquadrin natural products. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318333

LETTER
▌723
letter
Total Synthesis of Chaetoquadrins H and I
Total Synthesis of Chaetoquadrins H and I
U Bin Kim, Andrew F. Dalebrook, Daniel P. Furkert, Margaret A. Brimble*
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received: 04.02.2013; Accepted: 12.02.2013
OH
OH
OH
Abstract: The first total syntheses of the chromone-containing nat-
ural products chaetoquadrins H and I are reported, using an aldol re-
action and an acid-catalyzed deprotection/cyclization/elimination
sequence. Chaetoquadrin H was isolated from the ascomycete
Chaetomium quadrangulatum and exhibits potent mouse liver
monoamine oxidase (MAO) inhibitory activity. Chaetoquadrin I
was not isolated in sufficient quantity to enable biological evalua-
tion. The synthesis of the title compounds provides a useful starting
point for a medicinal chemistry program focused on chaetoquadrin
natural products.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
chaetoquadrin A (1)
chaetoquadrin B (2)
chaetoquadrin C (3)
O
O
Key words: monoamine oxidase inhibitors, natural products, spiro-
ketal compounds, aldol reaction
O
O
O
O
OH
O
OH
2'
2'
In 2002 Fujimoto and co-workers reported the structures
of five chromone-containing natural products, chaeto-
quadrins A–E, that exhibit monoamine oxidase (MAO)
inhibitory properties.1 A second publication in 2003 re-
ported six additional MAO-inhibiting natural products
named chaetoquadrin F–K.2 Our ongoing interest in the
synthesis of aromatic spiroketals3 prompted our recently
reported synthesis of chaetoquadrins A–C.4 The compar-
atively potent MAO inhibitory activity of chaetoquadrin
H (4; IC50 2.3 × 10–4 M) and the limited amount of chae-
toquadrin I (5) available from natural sources also attract-
ed our attention, hence we embarked on the synthesis of
these bis-pyranone chaetoquadrins H (4) and I (5) (Figure 1).
O
O
O
chaetoquadrin H (4)
chaetoquadrin I (5)
Figure 1 Structures of chaetoquadrins A–C (1–3) and chaeto-
quadrins H (4) and I (5)
yield (Scheme 2). The subsequent hydroboration-oxida-
tion of 12 using Me2S·BH3 afforded primary alcohol 13 in
moderate yield. Throughout the course of this work, the
hydroboration-oxidation of compounds related to olefin
12 proved to be challenging, often resulting in low yields
and decomposition of the starting olefins. It was crucial to
perform the oxidative peroxide workup as quickly as pos-
sible. The subsequent oxidation of alcohol 13 with 2-io-
doxybenzoic acid (IBX)6 in dimethyl sulfoxide (DMSO)
smoothly afforded the desired aldehyde 7.
Our strategy to prepare the bis-pyranone chaetoquadrins
H (4) and I (5) was similar to our approach to prepare the
spiroketal chaetoquadrins A–C (1–3).3 The retrosynthetic
analysis for chaetoquadrin I (5) is illustrated below
(Scheme 1). We envisaged constructing the pyranone ring
through an acid-catalyzed deprotection/cyclization/elimi-
nation sequence applied to 1,3-diketone 6. In turn, the lat-
ter would be assembled by aldol reaction of aldehyde 7
with ketone 8. Aldehyde 7 would be accessible through
hydroboration-oxidation of terminal olefin 9, which can
be prepared from noreugenin (10) in three steps.4 Wacker
oxidation of a protected derivative of terminal olefin 11
enables access to methyl ketone 8.
With aldehyde 7 in hand, our attention turned to the syn-
thesis of the requisite aldol partner, methyl ketone 8. To-
wards this end, (S)-pent-4-en-2-ol (11) was protected with
EOM-Cl to afford EOM-protected olefin 14 in good yield.
Subjection of terminal olefin 14 to Wacker oxidation
conditions7 provided methyl ketone 8 in reasonable yield
(Scheme 3).
With aldehyde 7 and ketone 8 in hand, we were then set to
execute the key aldol coupling. Disappointingly, aldol re-
actions mediated by lithium diisopropylamide (LDA) or
potassium hexamethyldisilazide (KHMDS) as the base
were unsuccessful. Fortunately, use of Paterson’s aldol
conditions8,9 delivered the desired β-hydroxy ketone 15 in
moderate yield (Scheme 4). Initial attempts to oxidize β-
hydroxy ketone 15 under a variety of standard conditions
(Swern, IBX-DMSO, DMP, TPAP/NMO) led to poor
yields and/or elimination of the sensitive hydroxyl moi-
ety. Eventually, application of the oxidation protocol de-
veloped specifically for β-hydroxy ketones involving IBX
Our initial target was ethoxymethyl ether (EOM) protect-
ed aldehyde 7. The acid labile EOM protecting group5 was
chosen with the final acid-catalyzed deprotection/cycliza-
tion/elimination sequence in mind. Phenol 9 was treated
with EOM-Cl to furnish EOM-protected olefin 12 in good
SYNLETT 2013, 24, 0723–0726
Advanced online publication: 06.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318333; Art ID: ST-2013-D0115-L
© Georg Thieme Verlag Stuttgart · New York

724
U B. Kim et al.
LETTER
EOMCl, NaH, DMAP
THF, 0 °C, 4 h
chaetoquadrin I (5)
OH
OEOM
86%
O
O
OEOM
O
O
OEOM
11
14
PdCl2 CuCl, O2
65%
H2O–DMF, r.t., 5 h
aldol
O
O
OEOM
6
8
O
O
OEOM
O
Scheme 3 Synthesis of methyl ketone 8
O
OEOM
H
proceed under a wide range of acidic or basic conditions.
Pleasingly, the spectroscopic data obtained for synthetic
chaetoquadrin I (5) were in good agreement with those re-
ported for the natural product.2
O
8
7
The structure of chaetoquadrin H (4) features an addition-
al methyl group at C-2' in comparison to chaetoquadrin I
(5). Accordingly, a similar strategy for the synthesis of
chaetoquadrin I (5) was employed to complete the total
synthesis of chaetoquadrin H (4; Scheme 5). Aldol reac-
tion between enantiopure α-methyl aldehyde 164 and
methyl ketone 8 mediated by LDA as the base, afforded β-
hydroxy ketone 17 in moderate yield.13 IBX-mediated
oxidation10 of 17 then furnished 1,3-diketone 18. Hydro-
OH
O
O
OH
11
O
9
ref. 4
O
OH
genolysis using 10% Pd/C as catalyst followed by treat-
11
ment with NaHSO4·SiO2
effected the EOM
deprotection/cyclization/elimination sequence, affording
O
OH
chaetoquadrin H (4).14 The spectroscopic data for synthet-
noreugenin (10)
Scheme 1 Retrosynthetic analysis of chaetoquadrin I (5)
O
O
OEOM
OH
O
OEOM
(+)–Ipc2BCl, Et3N
Et2O, –78 °C, 4 h
O
O
OH
O
O
OEOM
EOMCl, NaH
THF, 0 °C, 4 h
7
+
8
30%
O
86%
O
O
15
9
12
IBX, EtOAc
Δ, 5 h
1. Me2S⋅BH3, THF
0 °C, 2 h
2. NaOH–H2O2
43%
O
O
OEOM
O
O
OEOM
O
O
OEOM
O
O
O
OEOM
OH
O
IBX, DMSO
r.t., 2 h
6
80%
NaHSO4⋅SiO2
CHCl3, r.t., 30 min
40% (two steps)
O
O
7
13
Scheme 2 Synthesis of aldehyde 7
O
O
in ethyl acetate at reflux10 efficiently delivered 1,3-dike-
tone 6, which could be used without further purification.
Gratifyingly, acid-catalyzed double EOM deprotec-
tion/cyclization/elimination in the presence of
NaHSO4·SiO211 afforded the desired natural product chae-
toquadrin I (5).12 No oxa-Michael addition of the weakly
nucleophilic hydrogen-bonded phenol of 5 to the pyra-
none was observed and this transformation also did not
O
O
OH
O
chaetoquadrin I (5)
Scheme 4 Total synthesis of chaetoquadrin I (5)
Synlett 2013, 24, 723–726
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Chaetoquadrins H and I
725
(3) For selected examples, see: Yuen, T.-Y.; Brimble, M. A.
Org. Lett. 2012, 14, 5154; and references within.
(4) Kim, U. B.; Furkert, D. P.; Brimble, M. A. Org. Lett. 2013,
15, 658.
(5) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups
in Organic Synthesis, 4th ed.; Wiley: Hoboken, 2007, 383.
(6) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537.
ic chaetoquadrin H (4) were again in excellent agreement
with those reported in the literature.2
O
O
OBn
O
H
+
8
O
(7) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth. 1984, 62,
9.
16
i-Pr2NH
n-BuLi
THF, –78 °C
2 h
(8) Cergol, K. M.; Coster, M. J. Nat. Protoc. 2007, 2, 2568.
(9) Aldol reaction between 7 and 8: A two-necked, round-
bottom flask was charged with (+)-Ipc2BCl (210 mg, 0.66
mmol) and placed under high vacuum for 1 h to remove
traces of HCl. Et2O (2 mL) was added and the mixture was
cooled to –78 °C. NEt3 (0.1 mL, 0.72 mmol) was added
followed by a solution of ketone 8 (100 mg, 0.63 mmol) in
Et2O (1 mL). The resultant white suspension was warmed to
0 °C and stirred for 40 min. The reaction mixture was cooled
to –78 °C and aldehyde 7 (100 mg, 0.31 mmol) in Et2O (2
mL) was added. The reaction mixture was stirred at –78 °C
for 4 h then quenched by addition of aqueous pH 7 buffer
solution (1 mL), MeOH (0.5 mL) and 30% H2O2 solution
(0.5 mL), warmed to r.t. and stirred for 1 h. The mixture was
then diluted with H2O (10 mL) and EtOAc (10 mL), the
layers separated, and the aqueous layer was further extracted
with EtOAc (3 × 5 mL). The combined organic extracts
were washed with saturated aqueous NaHCO3 (5 mL), brine
(5 mL), dried over MgSO4, and concentrated in vacuo. The
crude material was purified by flash chromatography
(EtOAc–hexanes, 2:1) to yield β-hydroxy ketone 15 (44 mg,
30%) as an inseparable mixture of diastereoisomers (1:1)
and as a colourless oil. 1H NMR (300 MHz, CDCl3): δ =
1.13–1.30 (m, 9 H), 1.60–1.78 (m, 2 H), 2.29 (s, 3 H), 2.40–
2.63 (m, 3 H), 2.69–2.98 (m, 3 H), 3.55 (q, J = 7.24 Hz, 2 H),
3.81–3.92 (m, 2 H), 3.89 (s, 3 H), 3.93–4.04 (m, 1 H), 4.11–
4.28 (m, 1 H), 4.63–4.72 (m, 2 H), 5.12–5.23 (m, 2 H), 5.99
(s, 1 H), 6.63 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 15.0
(CH3), 15.2 (CH3), 19.6 (CH2), 19.9 (CH3), 20.6 (CH3), 35.9
(CH2), 36.0 (CH2*), 50.4 (CH2), 50.5 (CH2*), 50.9 (CH2),
51.0 (CH2*), 56.0 (CH3), 63.3 (CH2), 65.7 (CH2), 67.2 (CH),
67.3 (CH*), 69.6 (CH), 69.7 (CH*), 93.7 (CH2), 93.8
(CH2*), 95.3 (CH), 100.5 (CH2), 111.2 (C), 111.5 (CH),
122.0 (C), 155.2 (C), 158.1 (C), 161.8 (C), 163.5 (C), 177.0
(C), 209.6 (C), 209.7 (C*). IR (film): 2974, 1709, 1655,
1600, 1446, 1388, 1341, 1260, 1177, 1107, 1046, 990 cm–1.
43%
O
OBn
OH
O
OEOM
O
O
17
IBX, EtOAc
64%
O
Δ, 2 h
O
O
OBn
O
OEOM
O
18
1. Pd/C (10%), H2, EtOAc
r.t., 30 min
2. NaHSO4⋅SiO2
CHCl3, r.t., 2 h
44% (two steps)
O
O
2'
O
O
OH
O
chaetoquadrin H (4)
Scheme 5 Total synthesis of chaetoquadrin H (4)
+
HRMS (ESI): m/z [M + H]+ calcd for C25H37O9 : 481.2432;
In conclusion, the first total synthesis of the bis-pyranone
natural products chaetoquadrins H (4) and I (5) are report-
ed herein. An aldol reaction was used to unite the two key
fragments. Oxidation of the resulting β-hydroxy ketones
15 and 18 followed by execution of a deprotection/cycli-
zation/elimination sequence enabled facile synthesis of
the two natural products, chaetoquadrins H (4) and I (5).
found: 481.2417.
(10) Bartlett, S. L.; Beaudry, C. M. J. Org. Chem. 2011, 76, 9852.
(11) Breton, G. W. J. Org. Chem. 1997, 62, 8952.
(12) Synthesis of Chaetoquadrin I (5): To a solution of β-
hydroxyketone 15 (19 mg, 0.04 mmol) in EtOAc (2 mL) was
added 2-iodoxybenzoic acid (100 mg, 0.36 mmol) and the
reaction mixture was heated to reflux for 5 h. The reaction
mixture was then allowed to cool to r.t. and filtered through
a plug of cotton wool. The solvent was removed in vacuo to
give 1,3-diketone 6, which was dissolved in CHCl3 (1 mL).
NaHSO4·SiO211 (20 mg) was added and the reaction mixture
was stirred for 1 h. The reaction mixture was filtered through
cotton wool and the filtrate loaded directly on a preparative
TLC plate (EtOAc–hexanes, 2:1) to yield chaetoquadrin I (5;
5.5 mg, 40% over two steps). [α]D20 –10.8 (c 0.05, CHCl3)
{lit.2 [α]D20 –40.8 (c 0.05, CHCl3)}. 1H NMR (300 MHz,
CDCl3): δ = 1.44 (d, J = 6.1 Hz, 3 H), 2.33–2.39 (m, 2 H),
2.36 (s, 3 H), 2.43–2.50 (m, 2 H), 2.83–3.02 (m, 2 H), 3.88
(s, 3 H), 4.38–4.53 (m, 1 H), 5.22 (s, 1 H), 6.05 (s, 1 H), 6.36
(s, 1 H), 12.8 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 19.6
Acknowledgment
The authors would like to thank The University of Auckland for a
doctoral scholarship (U.B.K).
References and Notes
(1) Fujimoto, H.; Nozawa, M.; Okuyama, E.; Ishibashi, M.
Chem. Pharm. Bull. 2002, 50, 330.
(2) Fujimoto, H.; Nozawa, M.; Okuyama, E.; Ishibashi, M.
Chem. Pharm. Bull. 2003, 51, 247.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 723–726

726
U B. Kim et al.
LETTER
(CH2), 20.6 (CH3), 20.6 (CH3), 33.8 (CH2), 42.8 (CH2), 56.0
(CH3), 75.8 (CH), 89.5 (CH), 104.2 (CH), 105.2 (C), 109.1
(CH), 111.3 (C), 157.0 (C), 159.0 (C), 163.2 (C), 166.6 (C),
177.8 (C), 182.6 (C), 193.5 (C). IR (film): 2928, 1660, 1493,
1448, 1343, 1174 cm–1. HRMS (ESI): m/z [M + H]+ calcd for
38.1 (CH), 38.6 (CH*), 46.6 (CH2), 48.1 (CH2*), 50.8 (CH2),
50.9 (CH2*), 56.0 (CH3), 56.1 (CH3*), 63.3 (CH2), 63.4
(CH2*), 69.0 (CH), 69.6 (CH), 69.7 (CH*), 71.2 (CH*), 77.0
(CH2), 93.8 (CH2), 93.9 (CH2*), 95.4 (CH), 95.7 (CH*),
111.9 (CH), 112.2 (C), 121.0 (C), 121.4 (C*), 128.2 (CH),
128.3 (CH*), 128.5 (CH), 128.6 (CH*), 129.0 (CH), 129.1
(CH*), 137.2 (C), 137.5 (C*), 156.7 (C), 156.8 (C*), 158.3
(C), 158.4 (C*), 162.2 (C), 162.3 (C*), 163.4 (C), 163.5
(C*), 176.9 (C), 177.0 (C*), 209.6 (C), 210.7 (C*). IR (film):
2971, 2932, 1709, 1655, 1600, 1444, 1389, 1341, 1202,
1129, 1034 cm–1. HRMS (ESI): m/z [M + H]+ calcd for
+
C19H21O6 : 345.1333; found: 345.1341.
(13) Aldol reaction between 16 and 8: A solution of
diisopropylamine (0.04 mL, 0.25 mmol) in THF (1 mL) was
cooled to –78 °C. n-BuLi (1.6 M in hexanes, 0.24 mmol,
0.15 mL) was carefully added by using a syringe and the
mixture was stirred for 1 h at the same temperature. The
reaction mixture was then warmed to 0 °C for 10 min, then
cooled to –78 °C. A solution of ketone 8 (39 mg, 0.24 mmol)
in THF (1 mL) was cooled to –78 °C and added to the LDA
mixture by using a cannula, maintaining the temperature of
all of the reactants at –78 °C. The solution of aldehyde 16
(36 mg, 0.11 mmol) in THF (1 mL) was then cooled to –
78 °C and added to the mixture dropwise by using a cannula.
The reaction mixture was stirred at this temperature for 2 h,
then NH4Cl (4 mL) was added and reaction mixture was
allowed to warm to r.t. The reaction mixture was extracted
with EtOAc (3 × 4 mL) and the combined organic extracts
were washed with brine (6 mL), dried over MgSO4, and
purified by flash column chromatography (EtOAc–hexanes,
1.5:1) to yield β-hydroxy ketone 17 (22 mg, 43%) as an
inseparable mixture of diastereomers (1:1) as a colourless
oil. 1H NMR (400 MHz, CDCl3): δ = 0.78 (d, J = 7.14 Hz,
1.5 H), 0.84 (d, J = 6.76 Hz*, 1.5 H), 1.14–1.22 (m, 6 H),
1.73–1.98 (m, 2 H), 2.23–2.71 (m, 6 H), 2.31 (s, 1.5 H), 2.32
(s*, 1.5 H), 3.47–3.59 (m, 2 H), 3.76–3.87 (m, 1 H), 3.88 (s,
1.5 H), 3.90 (s*, 1.5 H), 4.07–4.19 (m, 1 H), 4.59–4.69 (m,
2 H), 4.87–4.95 (m, 1 H), 4.99–5.09 (m, 1 H), 6.04 (s,
0.5 H), 6.05 (s*, 0.5 H), 6.65 (s, 0.5 H), 6.67 (s*, 0.5 H),
7.29–7.44 (m, 3 H), 7.56–7.66 (m, 2 H). 13C NMR (100
MHz, CDCl3): δ = 13.7 (CH3), 15.1 (CH3), 15.2 (CH3*), 15.4
(CH3), 20.0 (CH3), 20.7 (CH3*), 25.9 (CH2), 27.3 (CH2*),
+
C30H39O8 : 527.2639; found: 527.2622.
(14) Synthesis of chaetoquadrin H (4): 1,3-diketone 18 (10 mg,
0.02 mmol) was taken up in EtOAc (1 mL), 10% Pd/C (16
mg) was added, and the reaction mixture was stirred under
an atmosphere of hydrogen for 30 min. The mixture was
filtered through cotton wool and the solvent was removed in
vacuo. The crude product was dissolved in CHCl3 (1 mL),
NaHSO4·SiO211 (15 mg) was added, and the mixture was
stirred for 2 h. The reaction mixture was filtered through
cotton wool and the filtrate was loaded directly on a
preparative TLC plate (EtOAc–hexanes, 3:1) to yield
chaetoquadrin H (4; 3 mg, 44% over two steps). [α]D20 –41.3
(c 0.15, CHCl3) {lit.2 [α]D20 –57.2 (c 0.2, CHCl3)}. 1H NMR
(300 MHz, CDCl3): δ = 1.17 (d, J = 6.7 Hz, 3 H), 1.44 (d, J =
6.5 Hz, 3 H), 2.24–2.42 (m, 2 H), 2.35 (s, 3 H), 2.63–2.81
(m, 2 H), 2.89–3.05 (m, 1 H), 3.87 (s, 3 H), 4.29–4.45 (m,
1 H), 5.11 (s, 1 H), 6.04 (s, 1 H), 6.34 (s, 1 H), 12.85 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 17.6 (CH3), 20.5 (CH3),
20.6 (CH3), 27.3 (CH2), 39.1 (CH), 42.9 (CH2), 56.0 (CH3),
75.8 (CH), 89.5 (CH), 103.3 (CH), 105.2 (C), 109.1 (CH),
110.8 (C), 157.0 (C), 159.2 (C), 163.4 (C), 166.6 (C), 181.3
(C), 182.7 (C), 193.7 (C). IR (film): 2935, 1661, 1598, 1494,
1449, 1343, 1127 cm–1. HRMS (ESI): m/z [M + H]+ calcd for
+
C20H23O6 : 359.1489; found: 359.1487.
Synlett 2013, 24, 723–726
© Georg Thieme Verlag Stuttgart · New York

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