Total synthesis and stereochemical assignment of (-)-zenkequinone B

Article abstract of DOI:10.1055/s-0032-1317519

The first enantioselective total synthesis and a concise racemic synthesis of zenkequinone B are reported here by utilizing a sequential enyne metathesis, Diels-Alder and aromatization reactions. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317519

LETTER
▌2931
letter
Total Synthesis and Stereochemical Assignment of (–)-Zenkequinone B
Total Synthesis of (–)-Zenkequinone B
Devendar G. Vanga, Krishna P. Kaliappan*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India
Fax +91(22)25723480; E-mail: kpk@chem.iitb.ac.in
Received: 01.09.2012; Accepted after revision: 08.10.2012
zenkequinone B, thereby assigning the absolute configu-
ration of the natural product.
Abstract: The first enantioselective total synthesis and a concise
racemic synthesis of zenkequinone B are reported here by utilizing
a sequential enyne metathesis, Diels–Alder and aromatization reac-
tions.
Our strategy for the synthesis of racemic zenkequinone B
(1) is shown in Scheme 1. We envisioned that the angular
Key words: Sharpless epoxidation, enyne metathesis, Diels–Alder benz[a]anthraquinone skeleton of zenkequinone B (1)
reaction, total synthesis
could be synthesized from diene 13 and dienophile 12
through a Diels–Alder reaction and aromatization. Based
on our earlier experience,12,13 we envisioned that diene 13
Angucyclinone1,2 antibiotics, characterized by
a
could be easily prepared from enyne 14 via an intramolec-
ular enyne metathesis, and the enyne 14 could be traced
back to the ketone 15 in a couple of steps. The proposed
strategy appears to be rapid and attractive compared to the
existing synthesis.
benz[a]anthraquinone skeleton, display a wide range of
biological activities such as antitumor, antifungal, antivi-
ral properties, platelet aggregation, and enzyme inhibitory
behavior.3 To date, more than 200 angucyclinones have
been isolated, mainly from Streptomyces sp., and they
continue to attract synthetic chemists’ attention due to
their broad biological profile and intriguing structural fea-
tures. Several strategies have been developed by various
research groups to construct the tetracyclic skeleton of an-
gucyclinone. Among them the Diels–Alder reaction has
been most widely used method for the successful synthe-
ses of a range of angucyclinones.4–9 Zenkequinone B, a
member of this family, was isolated recently from the
stem bark of Stereospermum zenkeri by Lenta et al.10 in
2007 and successfully used as a folk medicine to cure fe-
ver and microbial infections. After evaluation of six mul-
tiresistant strains of pathogens, it was shown to exhibit the
best antimicrobial activity (MIC 9.50 mg/mL) against
Gram-negative Pseudomonas aeruginosa.10
OH
O
O
O
OR
+
O
1: ( )-zenkequinone B
12
13
OR
O
15
14
The first and only racemic total synthesis of (±)-zenkequi-
none B has been reported11 recently by Yung-Son et al. in
five steps from the readily available 2-(chloromethyl)-
9,10-dimethoxyanthracene utilizing TiCl4-promoted in-
tramolecular cyclization to get the tetracyclic framework.
In continuation of our longstanding interest in the synthe-
sis of angucyclinone natural products12 and also in ex-
ploiting the synthetic utility of sequential enyne
metathesis and Diels–Alder reaction,13 we developed in-
terest in the synthesis of zenkequinone B. We had earlier
reported12b,c an enantioselective approach to the syntheses
of YM-181741, (+)-ochromycinone, (+)-rubiginone B2,
(–)-tetrangomycin, and MM-47755, and recently a unified
strategy for the syntheses of tetrangulol, kanglemycin M,
X-14881-E, and anhydrolandomycinone (Figure 1).12a
Herein we report a concise total synthesis of (±)-zenke-
quinone B and the first enantioselective synthesis of (–)-
Scheme 1 General retrosynthetic analysis
As shown in Scheme 2, our synthesis of (±)-zenkequinone
B (1) commenced with the addition of allylmagnesium
bromide to ketone 15 to furnish enyne 1614 which was
then refluxed with Grubbs’ first-generation catalyst (17)15
to generate the diene 18 in 80% yield. Having synthesized
diene in good quantity, the final and key one-pot Diels–
Alder reaction of diene 18 with 1,4-naphthoquinone 12
followed by aerobic oxidative aromatization with silica
gel and Et3N was attempted. Pleasingly, this one-pot reac-
tion proceeded cleanly to afford (±)-zenkequinone B (1)
in 85% yield. The spectroscopic data of the synthetic ma-
terial were in good agreement with the natural product in
all aspects, and thus, we have accomplished the shortest
total synthesis of (±)-zenkequinone B (1)10,11 in 68% over-
all yield from the known enyne 1614 (Scheme 2).
SYNLETT 2012, 23, 2931–2934
Advanced online publication: 09.11.2012
DOI: 10.1055/s-0032-1317519; Art ID: ST-2012-D0732-L
© Georg Thieme Verlag Stuttgart · New York
After completing the racemic synthesis of zenkequinone
B, we then looked at the possibility of accomplishing an
enantioselective total synthesis of zenkequinone B, as it is
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2932
D. G. Vanga, K. P. Kaliappan
LETTER
OH
O
O
R2
R6
HO
+
1: ( )-zenkequinone B
O
O
R5
O
O
R3
R4
R7
R1
O
2: R1 = OH, R2 = Me, R3 = H
(+)-ochromycinone
3: R1 = OMe, R2 = Me, R3 = H
7: R4 = OH, R5 = H, R6 = Me, R7 = H
tetrangulol
8: R4 = OH, R5 = H, R6 = CH2OH, R7 = H
(+)-rubiginone B2
kanglemycin M
4: R1 = OH, R2 = CH2OH, R3 = H
YM-181741
9: R4 = OMe, R5 = H, R6 = Me, R7 = H
X-14881-E
5: R1 = OH, R2 = Me, R3 = OH
10: R4 = OH, R5 = OH, R6 = Me, R7 = H
(–)-tetrangomycin
anhydrolandomycinone
6: R1 = OMe, R2 = Me, R3 = OH
MM-47755
11: R4 = OH, R5 = H, R6 = Me, R7 = OH
dehydrorabelomycin
Figure 1 Angucyclinone antibiotics of our interest
As delineated in Scheme 4, our synthetic strategy for the
asymmetric synthesis of zenkequinone B began with the
Sharpless asymmetric epoxidation16 of allylic alcohol 23
to provide epoxy alcohol 24 in 92% yield and 90% enan-
tionmeric excess (Mosher ester analysis).
OH
O
OH
allyl bromide
Mg, THF
17, CH2Cl2
16
reflux, 8 h
80%
0 °C to r.t.
3 h, 92%
15
18
OH
OH
OH
OBn
O
O
O
O
i) toluene, 80–100 °C
12 h
+
+
ii) silica gel, Et3N
CHCl3, 4 h
85% (for 2 steps)
O
O
O
O
20
19
12
(±)-zenkequinone B (1)
12
18
PCy3
Cl
Ru
OBn
OH
Ph
Cl
17
PCy3
HO
HO
Scheme 2 Racemic synthesis of (±)-zenkequinone B
23
22
21
important to elucidate its absolute configuration which Scheme 3 Retrosynthetic analysis for (–)-zenekequinone B
had not been determined. With this objective, we designed
a simple and efficient strategy for the asymmetric synthe-
Reductive opening of the epoxide was then successfully
accomplished using Red-Al to furnish the 1,3-diol 22 in
94% yield. The diol was subsequently protected as a ben-
zylidene derivative by treatment with benzaldehyde di-
methylacetal in the presence of PTSA to provide 25 in
quantitative yield. A regioselective opening of the benzyl-
idene derivative 25 with DIBAL-H delivered the primary
alcohol 26 with concomitant protection of the tertiary al-
cohol as benzyl ether in 81% yield. Oxidation of alcohol
26 with IBX and subsequent Wittig reaction of the result-
ed crude aldehyde afforded enyne 21 in 82% yield.
sis of zenkequinone B as shown in Scheme 3. To this end,
our first goal was to synthesize the diene 2019 in enantio-
merically enriched form, which obviously could be gener-
ated from the enyne 21 via enyne metathesis. Of further
interest was to utilize Sharpless asymmetric epoxidation16
followed by a reductive opening of the resulting epoxide
to introduce the lone quaternary chiral center. Thus, we
envisaged that the known allylic alcohol 2317 would serve
as the appropriate starting material for the proposed asym-
metric synthesis of zenkequinone B.
Synlett 2012, 23, 2931–2934
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (–)-Zenkequinone B
2933
conditions. After extensive experimentation, the benzyl
group was eventually cleaved using DDQ to furnish (–)-
zenkequinone B in 87% yield. The structure of 1921 was
confirmed by NMR, mass, IR analyses, and all recorded
data were in good accordance with the published data. The
enantiomeric excess of (–)-zenkequinone B (19) was de-
termined to be ≥84% according to chiral HPLC [tR of (–)-
19/(+)-19 = 33.15:38.05]18. Furthermore, the specific ro-
tation of our synthetic zenkequinone B {19; [α]D25 –195.33
(c 0.06, acetone)} was comparable with that of reported9b
value {[α]D25 –236 (c 0.05, acetone), Scheme 5}. In addi-
tion, CD spectra (see the Supporting Information) of 19
displayed a negative Cotton effect near λ = 344 nm.
Hence, the asymmetric synthesis of 1 from enantioen-
riched epoxyalcohol 24 proves the 2R absolute configura-
tion of (–)-zenkequinone B unequivocally.
D
-(–)-DIPT, 4 Å MS
Ti(Oi-Pr)4, TBHP
O
HO
HO
Red-Al, THF
CH2Cl2, –20 °C
0 °C to r.t., 5 h
94%
3 h, 92%, 90% ee
23
24
Ph
H
O
OBn
O
OH
DIBAL-H
CH2Cl2
benzaldehyde
dimethylacetal
HO
HO
–20 °C, 3 h
81%
PTSA, CH2Cl2
r.t., 2 h, quant.
22
26
25
OBn
i) IBX, EtOAc
reflux, 2 h
ii) PPh3MeBr
OBn
17, CH2Cl2
In summary, we have successfully accomplished a short
and efficient total synthesis of (±)-zenkequinone B in 68%
overall yield (three steps). We also have achieved the first
enantioselective synthesis of (–)-zenkequinone B in 42%
overall yield (eight steps) by employing an intramolecular
enyne metathesis, Diels–Alder reaction, and aromatiza-
tion as key steps.
reflux, 8 h
92%
n-BuLi, THF
0 °C, 30 min
82% (for 2 steps)
20
21
Scheme 4 Enantioselective synthesis of diene
Having the enyne 21 in hand, the key ring-closing enyne
metathesis and Diels–Alder reaction were left to complete
the synthesis of zenkequinone B. As expected, the ring-
closing enyne metathesis worked very well with Grubbs’
first-generation catalyst 17 to afford diene 20 in excellent
yield (Scheme 4).
Acknowledgment
We thank DST, New Delhi for financial support. K.P.K. thanks
DST for the award of Swarnajayanti fellowship. D.G.V. thanks
UGC, New Delhi for a fellowship.
Supporting Information for this article is available online at
OBn
OBn
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
O
O
O
i) toluene, 80–100 °C
12 h
References and Notes
+
ii) silica gel, Et3N, CHCl3
4 h, 91% (for 2 steps)
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O
12
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20
27
80–100 °C, 12 h
ii) DDQ, CH2Cl2
12 h
DDQ, CH2Cl2
pH 7 buffer, 12 h
87%
75% (for 2 steps)
OH
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O
19
Scheme 5 Enantioselective total synthesis of (–)-zenkequinone B
After having the required diene in good quantity as well
as in high enantiomeric excess we investigated the Diels–
Alder reaction. In this regard, treatment of diene 20 with
1,4-naphthoquinone 12 followed by silica gel/Et3N-medi-
ated oxidative aromatization provided the tetracyclic
compound 2720 in 91% yield. Unfortunately, all our ef-
forts to cleave the benzyl group using a Lewis acid follow-
ing our earlier report12a were unsuccessful under various
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2931–2934

2934
D. G. Vanga, K. P. Kaliappan
LETTER
with respect to the catalyst) for 6 h to remove the metal
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impurities. Evaporation of the solvent and purification by
silica gel flash column chromatography (10% EtOAc in
hexanes) provided 1,3-diene 20 (460 mg, 92%); Rf = 0.7
(EtOAc–hexanes, 1:9); [α]D21 +67.6 (c 3.6, CHCl3). IR
(neat): 2929, 2846, 1645, 1614, 1513, 1462, 1378, 1247,
1129, 1098, 1036, 821, 758 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.35–7.28 (m, 4 H), 7.26–7.20 (m, 1 H), 6.37
(dd, J = 17.5, 10.7, Hz, 1 H), 5.64 (s, 1 H), 5.08 (d, J = 17.5
Hz, 1 H), 4.93 (d, J = 10.7 Hz, 1 H), 4.51, 4.44 (ABq, J =
18.0 Hz, 2 H), 2.45 (d, J = 18.2 Hz, 1 H), 2.40–2.32 (m, 1 H),
2.20 (d, J = 18.2 Hz, 1 H), 2.17–2.12 (m, 1 H), 1.97–1.90 (m,
1 H), 1.78–1.71 (m, 1 H), 1.30 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 139.9, 139.5, 135.4, 128.4, 127.4, 127.2, 127.0,
110.6, 73.6, 63.6, 37.6, 32.6, 23.6, 22.1. ESI-HRMS: m/z
calcd for C16H20O [M + Na]+: 251.1412; found: 251.1404.
(20) (R)-2-(Benzyloxy)-2-methyl-1,2,3,4-
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tetrahydrotetraphene-7,12-dione (27)
A solution of naphthoquinone 12 (228 mg, 1.44 mmol) and
diene 20 (300 mg, 1.31 mmol) in toluene was heated at 80 °C
for 12 h and then at 100 °C for 2 h. After the solvent was
removed in vacuo, the crude Diels–Alder adduct was
dissolved in CHCl3 (2 mL), treated with Et3N (1 mL) and
silica gel (1 g) and stirred for 4 h. The solvent was removed
in vacuo and purified by a silica gel flash column
chromatography (20% EtOAc in hexanes) to afford the
tetracycle 27 (460 mg, 91%) as a pale yellow solid; Rf = 0.6
(EtOAc–hexanes, 1:3); mp 163–165 °C; [α]D21 –233.55 (c
1.1, CHCl3). IR (neat): 3021, 2961, 2926, 2857, 1663, 1581,
1566, 1454, 1326, 1299, 1270, 1099, 1045, 740 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.24–8.19 (m, 2 H), 8.16 (d, J
= 8.0 Hz, 1 H), 7.79–7.71 (m, 2 H), 7.52 (d, J = 8.0 Hz, 1 H),
7.15–7.05 (m, 5 H), 4.53, 4.43 (ABq, J = 11.7 Hz, 2 H), 3.85
(d, J = 19.0 Hz, 1 H), 3.26–3.20 (m, 1 H), 3.22 (d, J = 19.0
Hz, 1 H), 2.92–2.85 (m, 1 H), 2.22–2.17 (m, 1 H), 1.87–1.79
(m, 1 H), 1.56 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ =
185.9, 183.7, 145.0, 139.6, 138.7, 135.2, 134.3, 134.1,
133.4, 133.3, 132.7, 131.7, 128.2, 127.2, 127.1, 126.5,
125.2, 72.9, 63.8, 39.9, 32.1, 27.6, 25.4. ESI-HRMS: m/z
calcd for C26H22O3 [M + Na]+: 405.1467; found: 405.1475.
(21) (–)-Zenkequinone B (19)
A solution of benzyl ether 27 (50 mg, 0.13 mmol) in a
mixture of CH2Cl2 (10 mL) and pH 7 buffer (0.5 mL) at 0 °C
was treated with DDQ (59 mg, 0.26 mmol) portionwise and
allowed to stir at r.t. for 12 h. The reaction mixture was
treated with a sat. solution of NaHCO3 and extracted with
CH2Cl2. The organic layer was washed with brine, dried
(Na2SO4), concentrated, and purified by silica gel column
chromatography to afford target compound 19 (33 mg, 87%)
as a pale yellow solid; Rf = 0.40 (EtOAc–hexanes, 1:2); mp
202–204 °C; [α]D21 –195.33 (c 0.06, acetone). IR (neat):
3463, 3082, 2961, 2927, 1663, 1579, 1561, 1368, 1329,
1303, 1275, 1092, 1045, 759 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.21–8.15 (m, 2 H), 8.11 (d, J = 8.0 Hz, 1 H),
7.76–7.70 (m, 2 H), 7.50 (d, J = 8.0 Hz, 1 H), 3.57 (d, J =
18.8 Hz, 1 H), 3.35 (d, J = 18.8 Hz, 1 H), 3.27–3.18 (m, 1 H),
2.91 (dt, J = 16.4, 4.4 Hz, 1 H), 1.98–1.92 (m, 1 H), 1.85–
1.77 (m, 1 H), 1.47 (s, 3 H). ESI-HRMS: m/z calcd for
C19H16O3 [M + Na]+ 315.0997; found: 315.0994.
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(18) HPLC separation conditions: The ee value was determined
by CHIRALCEL OD-H, n-hexane–2-PrOH = 90:10, flow
rate: 0.5 mL/min, λ = 256 nm.
(19) (R)-[(1-Methyl-4-vinylcyclohex-3-
enyloxy)methyl]benzene (20)
A solution of enyne 21 (500 mg, 2.19 mmol) in CH2Cl2 (60
mL) was treated with Grubbs’ first-generation catalyst (17;
133 mg, 7 mol%) and then refluxed for 8 h. The reaction
mixture was cooled to r.t. and stirred with DMSO (50 equiv
Synlett 2012, 23, 2931–2934
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