The First Total Synthesis of the Antimicrobial Sesquiterpenes (±)-Enokipodins A and B

Article abstract of DOI:10.1055/s-2003-45003

Efficient first total synthesis of antimicrobial sesquiterpenes enokipodins A and B (1 and 2, respectively) and formal total synthesis of cuparene-1,4-diol (5) and cuparene-1,4-quinone (7) have been accomplished starting from 2,5-dimethoxy-4-methyl-acetop

Full text of DOI:10.1055/s-2003-45003

374
LETTER
The First Total Synthesis of the Antimicrobial Sesquiterpenes ( )-Enokipodins
A and B
First
Total
Synthe
.
sis of Sesquit
S
erpenes
(
)-E
r
nokipodi
i
ns
A
a
k
nd B rishna,* M. Srinivasa Rao
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
E-mail: ask@orgchem.iisc.ernet.in
Received 15 October 2003
Abstract: Efficient first total synthesis of antimicrobial sesquiter-
penes enokipodins A and B (1 and 2, respectively) and formal total
synthesis of cuparene-1,4-diol (5) and cuparene-1,4-quinone (7)
have been accomplished starting from 2,5-dimethoxy-4-methyl-
acetophenone employing Claisen rearrangement and ring-closing
metathesis reaction as key steps.
Key words: sesquiterpenes, enokipodins A and B, ring-closing
metathesis, Claisen rearrangement
Flammulina velutipes (Curt.: Fr.) Sing. (Enokitake in
Japanese) is a fresh edible mushroom frequently consum-
ed in Japan. The natural compounds isolated (proteins,
polysaccharides, glycolproteins, etc.) from the body of
F. velutipes are known to have potent antitumor and
immunomodulatory activities.1 Recently, Takahashi and
Figure 1
co-workers have reported2 the bioassay guided isolation
of four new sesquiterpenes enokipodins A–D (1–4)
(Figure 1) from the mycelial culture medium of F. velu-
tipes. Enokipodins A–D (1–4) exhibited significant
antimicrobial activity against a fungus Cladosporium her-
barum, and Gram-positive bacteria Staphylococcus au-
reus and Bacillus subtilis. Structurally, enokipodins A–D
(1–4) are related to the less oxidised sesquiterpenes cu-
parene-1,4-diol (5) isolated3 from the Japanese liverwort
Lejeunea aquatica, HM-1 6 isolated4 from phytopatho-
genic fungus Helicobasidium mompa and the cuparene-
1,4-quinone 7 (Figure 1) isolated5 from the liverwort
Radula javanica, and more oxidised pigments lagopodins
and helicobasidins.6 The cuparenoid sesquiterpenes pose
Scheme 1
significant challenge because of the difficulty associated
in the generation of two adjacent quaternary carbon atoms
As the enokipodin A (1) is a hemiketal, the cyclopen-
in a cyclopentane ring and the regiochemical incorpora-
tion of polysubstituted aromatic ring. Despite the reported
significant microbial activity, there is no report on the
synthesis of enokipodins 1–4. Very recently, Mukherjee
and co-workers reported the first total synthesis of HM-1
methyl ether, cuparene-1,4-diol (5) and cuparene-1,4-
quinone (7).7 The interesting biological properties associ-
ated with the enokipodins prompted us to develop a meth-
odology for the synthesis of these sesquiterpenes. Herein,
we report the first total synthesis of ( )-enokipodins A and
B (1 and 2, respectively) along with a formal total synthe-
sis of cuparene-1,4-diol (5) and cuparene-1,4-quinone (7).
tanone 8 was identified as an ideal precursor for the gen-
eration of the enokipodins A and B (1 and 2, respectively)
as well cuparenediol 5 and quinone 7 (Scheme 1). A com-
bination of Claisen rearrangement and ring closing meta-
thesis (RCM)8 reaction based strategy was envisaged for
the synthesis of 8 starting from 2,5-dimethoxy-4-methyl-
acetophenone (9) (readily available by Friedel–Crafts
acylation of 2,5-dimethoxytoluene)9 via the cinnamyl al-
cohol 10 and the dienol 11. The synthetic sequence is de-
picted in Scheme 2. Thus, Horner–Wadsworth–Emmons
reaction of the acetophenone 9 with triethyl phosphono-
acetate and NaH generated the cinnamate 12, which on
regioselective reduction with LiAlH4 in Et2O at low tem-
perature furnished the allyl alcohol 10. A one-pot Claisen
rearrangement10 of the allyl alcohol 10 with ethyl vinyl
SYNLETT 2004, No. 2, pp 0374–0376
0
2.
0
2.
2
0
0
4
Advanced online publication: 18.12.2003
DOI: 10.1055/s-2003-45003; Art ID: D25503ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Total Synthesis of Sesquiterpenes (±)-Enokipodins A and B
375
ether in the presence of mercuric acetate in a sealed tube hand, direct oxidation of the dimethyl ether 8 with ceric
at 175 °C furnished g,d-unsaturated aldehyde 13. Alterna- ammonium nitrate (CAN) in aqueous MeCN furnished
tively, the aldehyde 13 was also prepared via the enokipodin B 2 in a near quantitative yield. Huang–Min-
Johnson’s orthoester variant of Claisen rearrangement of lon modified Wolff–Kishner reduction of the cyclopen-
the cinnamyl alcohol 10 employing triethyl orthoacetate tanone 8 with hydrazine hydrate KOH in digol furnished
and propionic acid in a sealed tube at 180 °C followed by the HM-1 methyl ether 17, whose conversion to cuparene-
conversion of the resultant ester into the aldehyde 13 by 1,4-diol (5) and cuparene-1,4-quinone (7) has already
LiAlH4 reduction and PCC oxidation strategy. Grignard been reported.7 The synthetic enokipodins A and B have
1
reaction of the aldehyde 13 with vinylmagnesium bro- exhibited spectral data (IR, H and 13C NMR and mass)
mide furnished a 1:1 diastereomeric mixture of the key in- identical to those of natural products.2
termediate dienol 11. RCM reaction of the diastereomeric
mixture of the dienol 11 with 5 mol% of Grubbs’ first gen-
In conclusion, we have developed the first total synthesis
of ( )-enokipodins A and B employing a combination of
eration catalyst furnished a 1:1 diastereomeric mixture of
Claisen rearrangement and RCM reactions as key steps.
the cyclopentenol 14 in near quantitative yield, which on
Starting from the readily available acetophenone 9, eno-
oxidation with pyridinium chlorochromate (PCC) and
kipodin A and enokipodin B were obtained in 9 steps in
NaOAc generated the cyclopentenone 15. One-step di-
20.0% and 24.4% overall yields, respectively. In addition,
alkylation of the enone 15 with NaH and MeI created the
a formal total synthesis of cuparene-1,4-diol (5) and
second quaternary carbon and generated the enone 16,
cuparene-1,4-quinone (7) has also been accomplished.
which on hydrogenation with 5% palladium over carbon
Currently, we are investigating the synthesis of optically
as the catalyst at one atmosphere pressure of hydrogen
active enokipodins and their higher oxidised analogues
logopodins and helicobasidins for evaluating their biolog-
ical potential.
(balloon) furnished the cyclopentanone 8. Finally, deme-
thylation of 8 with BBr3 furnished directly the enokipodin
A 1 (mp 135–136 °C; lit.2 138.5–138.9 °C). On the other
Yields refer to isolated and chromatographically pure compounds.
1
All compounds exhibited spectral data (IR, H and 13C NMR and
Mass) consistent with the structures. Selected spectral data for the
enone 15: IR (neat): 1714 cm–1. 1H NMR (300 MHz, CDCl3–CCl4):
d = 7.70 (d, J = 6.9 Hz, 1 H, H-3), 6.63 (s, 1 H, Ar-H), 6.56 (s, 1 H,
Ar-H), 6.09 (d, J = 6.9 Hz, 1 H, H-2), 3.75 (s, 3 H, OCH3), 3.73 (s,
3 H, OCH3), 2.70, 2.50 (AB q, J = 18.6 Hz, 2 H, CH2CO), 2.15 (s,
3 H, Ar-CH3), 1.54 (s, 3 H, tert-CH3). 13C NMR (75 MHz, CDCl3–
CCl4): d = 208.7 (C, C=O), 169.8 (CH, C-3), 151.3 (C), 151.1 (C),
131.3 (CH, C-2), 131.0 (C), 125.8 (C), 114.8 (CH, C-6¢), 109.6 (CH,
C-3¢), 55.9 (CH3, OCH3), 55.5 (CH3, OCH3), 50.3 (CH2, C-5), 47.1
(C, C-4), 27.6 (CH3, tert-CH3), 16.1 (CH3, Ar-CH3). MS: m/z (%) =
246 (96) [M+], 231 (100), 216 (16), 203 (15), 188 (14), 173 (15),
128 (12), 115 (19), 91 (18). HRMS: m/z [M + 1] calcd for C15H19O3:
247.1334; found: 247.1337. For the enone 16: IR (neat): 1707,
1600, 1505, 1393, 1375, 1213, 1044, 861, 834, 789 cm–1. 1H NMR
(300 MHz, CDCl3–CCl4): d = 7.84 (d, J = 6.0 Hz, 1 H, H-3), 6.66
(s, 1 H, Ar-H), 6.45 (s, 1 H, Ar-H), 6.10 (d, J = 6.0 Hz, 1 H, H-2),
3.78 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 2.19 (s, 3 H, Ar-CH3),
1.48 (s, 3 H, tert-CH3), 1.24 (s, 3 H, tert-CH3), 0.65 (s, 3 H, tert-
CH3). 13C NMR (75 MHz, CDCl3–CCl4): d = 214.2 (C, C=O), 170.2
(CH, C-3), 151.6 (C), 151.5 (C), 129.8 (C), 127.0 (CH, C-2), 125.8
(C), 114.6 (CH, C-6¢), 111.2 (CH, C-3¢), 56.0 (CH3, OCH3), 55.4
(CH3, OCH3), 54.8 (C, C-5), 50.9 (C, C-4), 25.8 (CH3), 20.1 (CH3),
16.2 (2 C, CH3). MS: m/z (%) = 274 (42) [M+], 260 (17), 259 (100),
244 (13), 229 (12), 216 (10). HRMS: m/z [M + Na] calcd for
C17H22O3Na: 297.1467; found: 297.1466. For the cyclopentanone 8:
IR (neat): 1735, 1505 cm–1. 1H NMR (300 MHz, CDCl3–CCl4): d =
6.78 (s, 1 H, Ar-H), 6.62 (s, 1 H, Ar-H), 3.78 (s, 3 H, OCH3), 3.70
(s, 3 H, OCH3), 2.65–2.30 (m, 3 H), 2.18 (s, 3 H, Ar-CH3), 2.15–
1.90 (m, 1 H), 1.37 (s, 3 H, tert-CH3), 1.20 (s, 3 H, tert-CH3), 0.67
(s, 3 H, tert-CH3). 13C NMR (75 MHz, CDCl3–CCl4): d = 221.4 (C,
C=O), 151.9 (C), 151.4 (C), 132.5 (C), 125.2 (C), 114.4 (CH, C-6¢),
111.2 (CH, C-3¢), 56.0 (CH3, OCH3), 54.8 (CH3, OCH3), 52.7 (C),
48.9 (C), 34.3 (CH2), 32.7 (CH2), 23.7 (CH3), 21.9 (CH3), 21.7
(CH3), 16.0 (CH3). MS: m/z (%) = 276 (92) [M+], 261 (28), 227 (16),
205 (100), 192 (27), 177 (32), 175 (24), 174 (22), 149 (24), 105
(15), 91 (28). HRMS: m/z [M + 1] calcd for C17H25O3: 277.1803;
found: 277.1803. For enokipodin A ( )-1: IR (neat): 3390, 1288,
1194, 1146, 1036, 992, 943, 905 cm–1. 1H NMR (300 MHz, CDCl3–
Scheme 2 Reagents,
conditions
and
yields:
(a)
(EtO)2P(O)CH2COOEt, NaH, THF, reflux, 5 h, 88%; (b) LiAlH4,
Et2O, –70 °C to r.t., 2 h, 91%; (c) CH2=CHOEt, Hg(OAc)2, sealed tu-
be, 100 °C, 10 h; 175 °C, 48 h, 63%; (d) i. CH3C(OEt)3, EtCOOH,
sealed tube, 180 °C, 48 h, 70%; ii. LAH, Et2O, –40 °C to r.t., 2 h, 92%;
iii. PCC-silica gel, CH2Cl2, r.t., 1 h, 87%; (e) CH2=CHMgBr, THF,
r.t., 1 h, 88%; (f) 5 mol% PhCH=Ru(Cl)2(PCy3)2, CH2Cl2, r.t., 4 h,
95%; (g) PCC, NaOAc, CH2Cl2, r.t., 1 h, 86%; (h) NaH, THF–DMF,
MeI, r.t., 12 h, 77%; (i) H2, 5% Pd/C, EtOH, 1 h, 92%; (j) BBr3,
CH2Cl2, 0 °C to r.t., 4 h, 78%; (k) CAN, CH3CN–H2O, r.t., 1 h, 95%;
(l) NH2NH2.H2O, digol, 120 °C, 3 h; KOH, digol, 190 °C, 12 h, 75%;
(m) ref:7
Synlett 2004, No. 2, 374–376 © Thieme Stuttgart · New York

376
A. Srikrishna and M. S. Rao
LETTER
CCl4): d = 6.54 (s, 1 H, Ar-H), 6.50 (s, 1 H, Ar-H), 4.34 (s, 1 H, OH),
2.77 (s, 1 H, OH), 2.17 (s, 3 H, Ar-CH3), 2.25–2.00 (m, 2 H), 1.87
(ddd, J = 12.3, 11.1, 6.9 Hz, 1 H), 1.76 (ddd, J = 12.3, 9.6, 3.3 Hz,
1 H), 1.23 (s, 3 H, tert-CH3), 1.09 (s, 3 H, tert-CH3), 0.80 (s, 3 H,
tert-CH3). 13C NMR (75 MHz, CDCl3–CCl4): d = 147.5 (C), 146.1
(C), 131.1 (C), 122.4 (C), 116.9 (CH, C-5), 111.0 (CH, C-2), 109.6
(C, HO-C-O), 47.3 (C), 43.3 (C), 38.2 (CH2), 34.8 (CH2), 18.5
(CH3), 16.0 (CH3), 15.5 (2 × C, CH3). MS: m/z (%) = 248 (37) [M+],
178 (9), 177 (100), 162 (32), 149 (67). HRMS: m/z calcd [M + Na]
for C15H20O3Na: 271.1310; found: 271.1307. For enokipodin B ( )-
2: IR (neat): 1732, 1650, 1346, 1251, 1066, 998, 932, 842 cm–1.
1H NMR (300 MHz, CDCl3–CCl4): d = 6.66 (s, 1 H, H-5), 6.55 (q,
J = 1.5 Hz, 1 H, H-2), 2.55–2.20 (m, 3 H), 2.04 (d, J = 1.5 Hz, 3 H,
olefinic-CH3), 1.87 (ddd, J = 12.7, 8.0, 3.0 Hz, 1 H), 1.32 (s, 3 H,
tert-CH3), 1.22 (s, 3 H, tert-CH3), 0.75 (s, 3 H, tert-CH3). 13C NMR
(75 MHz, CDCl3–CCl4): d = 219.9 (C, C=O), 187.8 (C, C=O), 187.5
(C, C=O), 153.5 (C), 144.4 (C), 135.3 (CH), 134.1 (CH), 52.3 (C),
49.0 (C), 33.7 (CH2), 31.2 (CH2), 23.2 (CH3), 22.3 (CH3), 20.6
(CH3), 15.0 (CH3). MS: m/z (%) = 246 (3) [M+], 218 (20), 203 (12),
190 (47), 175 (100), 161 (21), 147 (16). HRMS: m/z [M + Na] calcd
for C15H18O3Na: 269.1154; found: 269.1166. For HM-1 methyl
ether 17: IR (neat): 1504, 1389, 1372, 1260, 1212, 1181, 1048, 861,
808, 704 cm–1. 1H NMR (300 MHz, CDCl3–CCl4): d = 6.77 (s, 1 H,
Ar-H), 6.60 (s, 1 H, Ar-H), 3.77 (s, 3 H, Ar-OCH3), 3.73 (s, 3 H, Ar-
OCH3), 2.55–2.40 (m, 1 H), 2.17 (s, 3 H, Ar-CH3), 1.85–1.50 (m, 5
H), 1.34 (s, 3 H, tert-CH3), 1.14 (s, 3 H, tert-CH3), 0.70 (s, 3 H, tert-
CH3). 13C NMR (75 MHz, CDCl3–CCl4): d = 152.6 (C), 151.1 (C),
133.9 (C), 124.4 (C), 115.0 (CH, C-6¢), 112.1 (CH, C-3¢), 56.0
(CH3, OCH3), 55.5 (CH3, OCH3), 51.4 (C), 44.6 (C), 41.9 (CH2),
40.0 (CH2), 27.6 (CH3), 26.0 (CH3), 23.4 (CH3), 20.8 (CH2), 16.0
(CH3, Ar-CH3). MS: m/z = 262 (91) [M+], 248 (15), 205 (21), 192
(45), 191 (23), 179 (100), 177 (30), 165 (33), 152 (32), 149 (26).
Acknowledgement
We thank Prof. Tahara at Hokkaido University for providing the
copies of the spectra of natural enokipodins A and B; and the
Council of Scientific and Industrial Research for the financial
support.
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Synlett 2004, No. 2, 374–376 © Thieme Stuttgart · New York