First total synthesis of yanuthones: Novel farnesylated epoxycyclohexenoid marine natural products

Article abstract of DOI:10.1016/j.tetlet.2005.05.118

The total synthesis of the recently isolated marine natural products of mixed biosynthetic origin, yanuthones A, B, C and 22-deacylyanuthone A, has been accomplished following a short regio- and stereocontrolled approach involving the key intermediacy of

Full text of DOI:10.1016/j.tetlet.2005.05.118

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5219–5223
First total synthesis of yanuthones: novel farnesylated
epoxycyclohexenoid marine natural products
*
Goverdhan Mehta and Subhas Chandra Pan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 11 April 2005; revised 17 May 2005; accepted 25 May 2005
Available online 13 June 2005
Abstract—The total synthesis of the recently isolated marine natural products of mixed biosynthetic origin, yanuthones A, B, C and
22-deacylyanuthone A, has been accomplished following a short regio- and stereocontrolled approach involving the key intermedi-
acy of 2-farnesyl-p-benzoquinone.
Ó 2005 Elsevier Ltd. All rights reserved.
Hybrid natural products derived through mixed biosyn-
thetic pathways evoke intrinsic synthetic interest as they
embody diverse structural fragments. In the year 2000,
2
Ireland and co-workers reported the isolation and
was further shown that the oligosporon group of natu-
ral products exhibit antibacterial, cytotoxic and
nematocidal effects. The structural uniqueness of these
farnesylated epoxyquinone natural products coupled
with their diverse occurrence and wide ranging bioac-
tivity profile aroused our synthetic interest. In this
letter, we disclose a simple and general strategy that
has resulted in the first total synthesis of several yanut-
hones in racemic form.
1
structure elucidation of eight bioactive farnesylated
epoxy cyclohexenoids 1–8 with various oxy-substitution
patterns from an Aspergillus niger isolate obtained from
tissue homogenates of an orange Aplidium sp. ascidian.
These natural products were named yanuthones A–E,
and derivatives, as shown in Chart 1. They exhibited
weak antimicrobial activity against methicillin resistant
Staphylococcus aureus and vancomycin resistant Entero-
coccus. More recently, deacetoxyyanuthone A 9, a close
congener of 1–8, along with other related compounds
has been isolated from a marine isolate of genus Penicil-
lium sp. and shown to display mild antibacterial activity
against methicillin resistant and multidrug resistant
In formulating a general synthetic approach to yanut-
hones and other farnesylated epoxycyclohexenoid
natural products, Chart 1, we recognized the pivotal role
of 2-farnesyl-p-benzoquinone 12 as the starting point.
6
Quite surprisingly, while 12 has been found in Nature,
its synthesis, to our knowledge, has only been reported
once. There is also a report in the patent literature
7
a
7b
3
S. aureus (MIC, 50 lg/ml).
following a somewhat circuitous route. Our initial
engagement therefore was to devise a convenient access
to 12 from readily available starting materials and this
objective was achieved following YamamotoÕs recent
There have also been earlier literature reports of the
isolation of farnesylated epoxycyclohexenoid natural
products derived through the combination of the shi-
8
a
8b
adaptation of a previously described protocol for
the direct dehydrative coupling between polyprenyl alco-
hols and phenols. Thus, when a mixture of commercially
available p-methoxyphenol 13 and (E,E)-farnesol 14 was
exposed to scandium(III) triflate (30 mol %), 2-farnesyl-
hydroquinone monomethyl ether 15 was obtained
(Scheme 1). Ceric ammonium nitrate (CAN) oxidation
2
–5
kimate and mevalonate pathways.
research groups of Anke and co-workers and Rickards
For example, the
4
5
and co-workers have reported the structure elucidation
of the oligosporon group of antibiotics, for example,
oligosporon 10 and oligosporol B 11 (Chart 1) from
the culture strains of Arthrobotrys oligospora from
Netherlands and Australian isolates, respectively. It
9
of 15 delivered the key 2-farnesyl-p-benzoquinone 12
precursor smoothly and in just two steps (Scheme 1).
The next task was to elaborate the quinone moiety pres-
ent in 12 to the requisite epoxy-cyclohexenoid functional
array present in yanuthones 1–8, in a stereocontrolled
*
0
Corresponding author. Tel.: +91 8022932850; fax: +91
023600936; e-mail: gm@orgchem.iisc.ernet.in
8
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.118

5220
G. Mehta, S. C. Pan / Tetrahedron Letters 46 (2005) 5219–5223
O
1
8
12
O
1
R1
O
2
2
15
OR3 R2
O
1-8
OH
OH
9
R1
R2
R3
Compound
Yanuthone A 1
Yanuthone B 2
H
H
OH,
O
H
Ac
Ac
OH
O
Yanuthone C 3
Yanuthone D 4
H
H
OAc,
H
H
OAc
O
O
O
O
HO CH3
HO CH3
10
O
OH
OH
O
Yanuthone E 5
H
OH,
OH,
H
H
OH
OH
O
1
-Hydroxy A 6
-Hydroxy C 7
OH
Ac
1
OH
H
OAc,
OH,
H
H
H
OAc OH
11
2
2-Deacetyl A 8
H
Chart 1.
manner. For this purpose, a tactic recently highlighted
22-deacetylyanuthone A. Further, when 8 was subjected
to an acyl transfer reaction under a carefully controlled
regime (low temperature and close TLC monitoring), a
readily separable mixture (2:1) of yanuthone A 1 and
yanuthone C 3 was formed. The spectral data of our
synthetic 1 and 3 were found to be identical with those
reported for the natural products (Scheme 2).
1
0
by us in the syntheses of several epoxyquinone natural
products was adopted. Thus, Diels–Alder reaction of 2-
farnesyl-p-quinone 15 with cyclopentadiene was regio-
9
and stereoselective and furnished the endo-adduct 16
in good yield (Scheme 1). Base-mediated epoxidation
on the enedione moiety in topologically biased 16 oc-
curred as anticipated from the convex face to furnish
exclusively the exo-epoxyquinone derivative 17. DBU-
mediated hydroxymethylation of 17 was stereoselective
The relative stereochemistry of the yanuthones and
other compounds displayed in Chart 1, particularly the
C-15 hydroxyl stereochemistry, has been primarily
(
exo-face preference) and regioselective (10:1) with pre-
2
–4
dominant C–C bond formation ÔparaÕ with respect to9
the farnesyl chain to furnish hydroxymethyl dione 18.
At this stage, a quick check was made on the efficacy
of our strategy by subjecting the tricyclic dione 18 to
assigned
on the basis of the JH-14,H-15 coupling con-
stants, which typically were found to be in the range
of 2.5–3.0 Hz for the cis-stereochemical disposition.
2
While comparison of these J values was made with
9
retro-Diels–Alder reaction to furnish enedione 19, acet-
ylation of which led to 2 whose spectral data were found
some model epoxycyclohexenones having a cis-disposi-
tion, the coupling constant data for the corresponding
compounds with H-14 and H-15 in a trans-relationship
were not available. We therefore decided to further se-
cure the stereochemical assignment of the C-15 hydroxyl
in the yanuthones by preparing the C-15 epimers of
yanuthones 1, 3 and 8 for comparison purposes.
Towards this end, enedione 19 was reduced with DI-
BAL-H to furnish 22-deacetyl-epi-yanuthone A 21 in a
2
,9
to be identical with those reported for the natural
product yanuthone B (Scheme 1).
Encouraged by this convenient access to the natural
product yanuthone B, we ventured to extend our strat-
egy to other yanuthones, which besides other functional
group adjustments required installation of the requisite
hydroxyl group stereochemistry at C-15 corresponding
to the natural products. Taking a cue from our recent
1
3
regio- and stereocontrolled reduction (Scheme 3).
The opposite stereochemical outcome during the
DIBAL-H reduction of tricyclic 18 and monocyclic 19
underscores the importance of tight stereoelectronic
control, engendered by the vicinal environment for alu-
minium coordination, in these reductions. Carefully
controlled acetylation of 21 furnished a mixture of epi-
yanuthone A 22 and epi-yanuthone C 23 (2:1). The
JH-14,H-15 coupling constants in the epi-series 21–23 were
1
1
contra-intuitive observation, the tricyclic hydroxy-
dione 18 was subjected to DIBAL-H reduction, employ-
ing two equivalents of the reagent, to furnish the
exo-hydroxy product 20 in a remarkable regio- and
9
,12
stereocontrolled operation
(Scheme 2). Retro-Diels–
Alder reaction in 20 led to 8, which was found to be
2
,9
spectroscopically identical with the natural product

G. Mehta, S. C. Pan / Tetrahedron Letters 46 (2005) 5219–5223
5221
OH
OH
a
OMe
OMe
15
13
b
O
H
O
c
H
O
O
16
12
d
H
H
O
e
O
H
HO
O
O
O
O
17
18
f
O
O
O
g
O
O
OAc
OH
O
Yanuthone B 2
Scheme 1. Reagents and conditions: (a) (E,E)-farnesol 14, Sc(OTf)
19
3
(30 mol %), toluene, 0–5 °C, 18 h, 45%; (b) CAN, CH
3
CN–H
2
O (1:1), 0 °C,
1
.5 h, 76%; (c) cyclopentadiene, MeOH, 0 °C, 2 h, 88%; (d) 10% Na CO
2
3
, 50% H
2
O
2
, 0 °C, 2 h, 85%; (e) DBU, 35% formalin, THF, 0 °C, 2 h, 86%; (f)
diphenyl ether, 240 °C, 6 min, 74%; (g) Ac
2
O, pyridine, DMAP, DCM, 0 °C, 90%.
O
H
a
O
b
O
1
8
22
HO
15
OH OH
HO
O
20
2
2- Deacetyl A 8
c
O
O
O
O
+
OAc OH
(2:1)
OH OAc
Yanuthone C 3
Yanuthone A 1
Scheme 2. Reagents and conditions: (a) DIBAL-H (2.0 equiv), THF, À78 °C, 30 min, 62%; (b) diphenylether, 240 °C, 12 min, 69%; (c) Ac
2
O,
pyridine, DCM, À20 °C, 80% based on the recovery of S.M.

5222
G. Mehta, S. C. Pan / Tetrahedron Letters 46 (2005) 5219–5223
O
a
19
O
2
2
1
5
OH OH
21
b
O
O
O
O
+
(
2:1 )
OAc OH
OH OAc
epi-yanuthone C 23
epi-yanuthone A 22
Scheme 3. Reagents and conditions: (a) DIBAL-H (2.0 equiv), THF, À78 °C, 30 min, 71%; (b) Ac O, pyridine, DCM, À20 °C, 80% based on the
2
recovery of S.M.
found to be in the range of 1.3–1.6 Hz, indicating a trans
relationship of these protons and fully secured the ste-
reochemistry of the yanuthones.
9. All new compounds were characterized on the basis of IR,
H and C NMR and HRMS data. Spectral data for
1
13
1
selected compounds: compound 12: H NMR (300 MHz,
CDCl
(
3
3
) d 6.78–6.68 (m, 2H), 6.56–6.52 (m, 1H), 5.18–5.07
m, 3H), 3.14 (d, 2H, J = 7.5 Hz), 2.14–1.97 (m, 8H), 1.68 (s,
In summary, we have accomplished the first total synthe-
sis of the marine natural products yanuthones A–C and
13
H), 1.64 (s, 3H), 1.60 (s, 6H); C NMR (75 MHz, CDCl3)
d 187.9, 187.6, 148.5, 140.2, 136.7, 136.3, 135.5, 132.3, 131.3,
2
2-deacetylyanuthone A from commercially available
1
1
24.3, 123.7, 117.6, 39.6, 27.4, 26.7, 26.4, 25.7, 17.7, 16.2,
6.1. Compound 18: H NMR (400 MHz, CDCl ) d 6.07 (s,
3
1
p-methoxyphenol through the intermediacy of 2-far-
nesyl-p-benzoquinone involving a short, general and
stereocontrolled sequence. The strategy outlined here is
amenable to adaptation for the synthesis of other mem-
bers of the farnesylated epoxycyclohexenoid family.
1H), 6.05 (s, 1H), 5.09–5.05 (m, 2H), 4.92 (t, 1H, J =
5.4 Hz), 4.38 (d, 1H, J = 11.6 Hz), 3.81 (d, 1H, J = 11.2 Hz),
3.42 (s, 1H), 3.31 (br s, 2H), 2.87 (d, 1H, J = 3.2 Hz), 2.64–
2
1
.62 (m, 2H), 2.07–1.95 (m, 8H), 1.69 (s, 3H), 1.60 (s, 9H),
1
3
.53 (d, 1H, J = 9.6 Hz), 1.46 (d, 1H, J = 9.6 Hz); C NMR
) d 205.8, 204.7, 140.9, 138.1, 138.0,
135.4, 131.5, 124.3, 123.7, 114.8, 68.2, 67.8, 61.8, 53.9, 45.9,
4.3, 43.4, 39.7, 26.7, 26.4, 25.8, 25.6, 17.7, 16.4, 16.1;
(
100 MHz, CDCl
3
Acknowledgements
4
+
This work was supported by the Chemical Biology Unit
of JNCASR at the Indian Institute of Science.
HRMS (ES) m/z calcd for
47.2511, found: 447.2526. Compound 2: H NMR
300 MHz, CDCl ) d 6.53 (t, 1H, J = 1.8 Hz), 5.09–4.96
m, 3H), 4.96 (dd, 1H, J = 1.8, 16.8 Hz), 4.81 (dd, 1H,
27 36 4
C H O Na [M+Na] :
1
4
(
(
3
References and notes
J = 1.8, 16.8 Hz), 3.67 (s, 1H), 2.89 (dd, 1H, J = 8.1,
4.7 Hz), 2.63 (dd, 1H, J = 6.9, 14.7 Hz), 2.14 (s, 3H),
2.07–1.97 (m, 8H), 1.68 (s, 3H), 1.64 (s, 3H), 1.59 (s, 6H);
1
1
2
. (a) Mehta, G.; Singh, V. Chem. Soc. Rev. 2002, 31, 324–
34; (b) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S.
1
3
3
C NMR (75 MHz, CDCl ) d 192.1, 192.0, 169.8, 143.1,
3
Angew. Chem., Int. Ed. 2003, 42, 3996–4028.
. Bugni, T. S.; Abbanat, D.; Bernan, V. S.; Maiese, W. M.;
Greenstein, M.; Wagoner, R. M. V.; Ireland, C. M. J. Org.
Chem. 2000, 65, 7195–7200.
141.2, 135.5, 132.3, 131.3, 124.3, 123.7, 114.7, 62.4, 59.4,
57.5, 39.7, 26.7, 26.3, 25.7, 25.2, 20.6, 17.7, 16.4, 16.0;
HRMS (ES) m/z calcd for C H O Na [M+Na] :
+
2
4
32
5
1
423.2147, found: 423.2158. Compound 8: H NMR
(500 MHz, CDCl ) d 5.96 (s, 1H), 5.14–5.05 (m, 2H), 5.00
(t, 1H, J = 7.3 Hz), 4.68 (d, 1H, J = 8.4 Hz), 4.45 (d, 1H,
3
4
5
6
. Li, X.; Choi, H. D.; Kang, J. S.; Lee, C.; Son, B. W. J.
Nat. Prod. 2003, 66, 1499–1500.
. Stadler, M.; Sterner, O.; Anke, H. Z. Naturforsch. 1993,
C48, 843–850.
. Anderson, M. G.; Jarman, T. B.; Rickards, R. W. J.
Antibiot. 1995, 48, 391–398.
. Angela, P. L.; Eliseo, A.; Diaz, P. D.; Maria, A. Rev.
Colom. Quim. 2000, 29, 25–37 (Chem. Abstr. 2000, 136,
3
J = 15.0 Hz), 4.39 (d, 1H, J = 15.0 Hz), 3.72 (d, 1H,
J = 2.8 Hz), 2.81 (dd, 1H, J = 8.0, 15.5 Hz), 2.72 (d,
1H, J = 8.5 Hz), 2.51 (dd, 1H, J = 7.0, 15.5 Hz), 2.27 (br
s, 1H), 2.07–1.95 (m, 8H), 1.68 (s, 3H), 1.64 (s, 3H), 1.60 (s,
1
3
3H), 1.59 (s, 3H); C NMR (100 MHz, CDCl ) d 193.7,
3
156.7, 140.1, 135.3, 131.5, 124.3, 123.8, 120.9, 115.9, 66.0,
62.9, 61.4, 59.0, 39.8, 26.7, 26.4, 25.9, 25.8, 17.8, 16.4, 16.1;
229385).
+
HRMS (ES) m/z calcd for C H O Na [M+Na] :
7
8
. (a) Bouzbouz, S.; Kirschleger, B.; Villieras, J. Bull. Soc.
Chim. Fr. 1997, 134, 67–84; (b) Pearce, B. C. US Patent
2
2
32
4
1
383.2198, found: 383.2206. Compound 1: H NMR
5318993, 1994 (Chem. Abstr. 1994, 122, 16309).
(500 MHz, CDCl ) d 5.93 (d, 1H, J = 1.3 Hz), 5.11–5.06
3
. (a) Ishibashi, H.; Ishihara, K.; Yamamoto, H. J. Am.
Chem. Soc. 2004, 126, 11122–11123; (b) Tsuchimoto, T.;
Tobita, K.; Hiyama, T.; Fukuzawa, S. J. Org. Chem. 1997,
(m, 2H), 5.01 (t, 1H, J = 7.4 Hz), 4.87 (d, 1H, J = 15.7 Hz),
4.78 (d, 1H, J = 15.7 Hz), 4.61 (s, 1H), 3.72 (d, 1H,
J = 3.0 Hz), 2.80 (dd, 1H, J = 8.0, 15.5 Hz), 2.52 (dd, 1H,
J = 6.8, 15.6 Hz), 2.13 (s, 1H), 2.09–1.95 (m, 8H), 1.68 (s,
62, 6997–7005.

G. Mehta, S. C. Pan / Tetrahedron Letters 46 (2005) 5219–5223
5223
1
H), 1.64 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H); C NMR
3
3
(
Lett. 2004, 45, 1985–1987; (c) Mehta, G.; Pan, S. C. Org.
Lett. 2004, 6, 811–813; (d) Mehta, G.; Pan, S. C. Org. Lett.
2004, 6, 3985–3988; (e) Mehta, G.; Pan, S. C. Tetrahedron
Lett. 2005, 46, 3045–3048.
100 MHz, CDCl ) d 193.2, 170.5, 151.8, 140.2, 135.3,
3
1
2
31.5, 124.3, 123.8, 122.4, 115.7, 65.5, 62.9, 61.4, 58.9, 39.8,
6.7, 26.4, 25.7, 25.9, 20.8, 17.8, 16.4, 16.1; HRMS (ES) m/z
+
Na [M+Na] : 425.2304, found:
calcd for
C
24
H
34
O
5
11. Mehta, G.; Pujar, S. R.; Ramesh, S. S.; Islam, K.
Tetrahedron Lett. 2005, 46, 3373–3376.
1
4
6
1
4
1
1
3
25.2288. Compound 3: H NMR (500 MHz, CDCl ) d
.14 (d, 1H, J = 1.6 Hz), 5.91 (d, 1H, J = 1.0 Hz), 5.35 (d,
H, J = 5.0 Hz), 5.13–5.07 (m, 2H), 5.01 (t, 1H, J = 6.8 Hz),
.27 (d, 1H, J = 16.0 Hz), 4.22 (d, 1H, J = 16.0 Hz), 3.71 (d,
H, J = 2.8 Hz), 2.83 (dd, 1H, J = 8.0, 15.5 Hz), 2.51 (dd,
H, J = 7.2, 15.5 Hz), 2.22 (s, 3H), 2.13–1.97 (m, 8H), 1.68
12. The stereo- and regiochemical outcome in the DIBAL-H
reduction of 18 can be rationalized in terms of the initial
coordination of aluminium with the hydroxyl group and
the carbonyl group as shown below. This effectively blocks
the preferred exo-face, precludes additional coordination
of the epoxy oxygen with DIBAL-H and activates the
carbonyl group for regioselective reduction. Consequently,
reduction takes place from the hindered endo-face (see
arrows) of the tricyclic system to deliver the observed
product 20.
1
3
(
(
s, 3H), 1.64 (s, 3H), 1.59 (s, 3H), 1.57 (s, 3H); C NMR
100 MHz, CDCl ) d 193.4, 170.2, 152.4, 140.0, 134.9,
29.7, 124.7, 124.0, 123.5, 122.4, 115.4, 66.8, 61.6, 60.2,
5.7, 39.4, 26.9, 26.5, 25.5, 25.4, 20.5, 17.4, 16.1, 15.7;
3
1
5
+
HRMS (ES) m/z calcd for
4
24 34 5
C H O Na [M+Na] :
1
25.2304, found: 425.2314. Compound 21: H NMR
(
(
1
2
1
1
500 MHz, CDCl ) d 6.00 (s, 1H), 5.09–5.03 (m, 3H), 4.62
br s, 1H), 4.53 (d, 1H, J = 15.2 Hz), 4.34 (d, 1H, J =
3
H
O
5.2 Hz), 3.67 (d, 1H, J = 1.4 Hz), 3.03 (d, 1H, J = 7.0 Hz),
.79 (dd, 1H, J = 7.9, 15.0 Hz), 2.56 (dd, 1H, J = 6.6,
5.0 Hz), 2.27 (br s, 1H), 2.10–1.97 (m, 8H), 1.68 (s, 3H),
O
iBu
Al
iBu O
1
3
.65 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H); C NMR (100 MHz,
) d 194.8, 155.7, 140.1, 135.3, 131.4, 124.3, 123.9,
22.1, 115.9, 64.5, 64.1, 60.2, 59.8, 39.7, 26.7, 26.4, 25.7,
O
CDCl
3
H
1
1
1
1
1
Al
3
7.7, 16.3, 16.0. 22: H NMR (300 MHz, CDCl ) d 6.01 (s,
iBu
iBu
H), 5.09–5.02 (m, 3H), 4.83 (d, 1H, J = 16.2 Hz), 4.77 (d,
H, J = 16.5 Hz), 4.55 (s, 1H), 3.66 (s, 1H), 2.81 (dd, 1H,
J = 8.4, 15.6 Hz), 2.57 (br s, 1H), 2.53 (dd, 1H, J = 8.4,
5.3 Hz), 2.14 (s, 3H), 2.07–1.95 (m, 8H), 1.68 (s, 3H), 1.64
(
1
13. In the case of the more flexible epoxycyclohexenone 19,
the regio- and stereochemical course of the DIBAL-H
reduction is directed by coordination with the epoxy
oxygen and intramolecular hydride delivery from the same
face, as shown below, to result in the observed stereo-
chemistry of 21.
1
s, 3H), 1.60 (s, 3H), 1.56 (s, 3H); C NMR (75 MHz,
3
CDCl ) d 193.3, 170.7, 150.7, 140.0, 135.2, 131.4, 124.3,
3
1
2
23.9, 122.4, 115.9, 64.0, 63.3, 60.5, 59.6, 39.7, 20.7, 26.4,
5.8, 25.7, 20.6, 17.7, 16.4, 16.1. Compound 23: H NMR
1
(
3
300 MHz, CDCl ) d 6.19 (s, 1H), 5.83 (s, 1H), 5.18–4.98 (m,
3
1
(
H), 4.25–4.18 (m, 2H), 3.56 (d, 1H, J = 1.5 Hz), 2.80 (dd,
H, J = 8.4, 16.2 Hz), 2.56 (dd, 1H, J = 6.9, 15.6 Hz), 2.15
s, 3H), 2.10–1.95 (m, 8H), 1.68 (s, 3H), 1.63 (s, 3H), 1.60 (s,
O
1
3
3
1
6
1
3
H), 1.55 (s, 3H); C NMR (100 MHz, CDCl ) d 193.4,
iBu
70.3, 151.5, 140.0, 135.2, 131.4, 124.3, 124.2, 123.8, 115.9,
4.2, 62.5, 59.5, 58.2, 39.7, 26.7, 26.5, 25.7, 25.5, 20.7, 17.7,
6.3, 16.0.
O
Al
H
iBu
O
iBu
O
iBu
1
0. (a) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44,
569–3572; (b) Mehta, G.; Ramesh, S. S. Tetrahedron
Al
3