Towards the total synthesis of neurotrophically active tashironins: rapid construction of the tetracyclic core through a tandem oxidative dearomatization-IMDA reaction-RCM protocol

Article abstract of DOI:10.1016/j.tetlet.2007.10.052

An exceptionally short (three step) strategy involving tandem oxidative dearomatization, intramolecular Diels-Alder (IMDA) reaction and RCM has been devised to generate the complete carbon framework present in tashironin-type sesquiterpenoid natural produ

Full text of DOI:10.1016/j.tetlet.2007.10.052

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Tetrahedron Letters 48 (2007) 8865–8868
Towards the total synthesis of neurotrophically active tashironins:
rapid construction of the tetracyclic core through a tandem
oxidative dearomatization–IMDA reaction–RCM protocol
Goverdhan Mehta* and Pulakesh Maity
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 23 August 2007; revised 2 October 2007; accepted 11 October 2007
Available online 14 October 2007
Abstract—An exceptionally short (three step) strategy involving tandem oxidative dearomatization, intramolecular Diels–Alder
(IMDA) reaction and RCM has been devised to generate the complete carbon framework present in tashironin-type sesquiterpenoid
natural products.
Ó 2007 Elsevier Ltd. All rights reserved.
In 2001 research groups led by Fukuyama1 and
Schmidt,2 almost concurrently, reported the isolation
and structure determination of several novel polycyclic
sesquiterpenoid natural products 1–5 from Illicium
merrillianum and Illicium floridanum, respectively. In
structural terms, these complex natural products with
dense and diverse oxygen functionalities are close sib-
lings of tashironin 13 and are based on the biogenetically
interesting allo-cedrane4 framework 6. These tashironin-
type sesquiterpenoids embody basic cage-like oxa-tetra-
cyclic architecture 7. Although functional embellish-
ments and stereochemical intricacies present in 1–5
hold considerable appeal for total synthesis endeavours,
it was the unusual observation1 that 11-O-debenzoyltas-
hironin 2 induces neurite outgrowth in fetal rat neurons
at concentrations as low as 0.1 lM, which captured the
attention of synthetic chemists attention towards this
class of compounds, particularly 2. Indeed, very recen-
tly, the first total synthesis of O-debenzoyltashironin 2
was accomplished by the group of Danishefsky.5
ible strategy for the rapid acquisition of the tetracyclic
core 7, embodying the entire C15 sesquiterpene frame-
work with adequate functional group distribution, to
target the natural products and also to generate diversity
around this novel scaffold to explore its therapeutic
potential.
H
H
OH
OH
10
15
OH
HO
RO
2
O1
14
O
11
8
3
9
6
5
4 OH
7
OH
O
12
13
HO
1 R = Bz, Tashironin
3
2 R = H, 11-O-Debenzoyltashironin
H
H
OH
OH
HO
HO
O
O
O
OH
OH
HO
HO
4
5
As part of our ongoing interest6 in the total synthesis of
several sesquiterpenoid skeleta that surface en route the
complex and intricate biogenetic pathway from farnesyl
pyrophosphate to seco-prezizaenes,3,7 we were drawn
towards the synthesis of 2 and its siblings. Initial focus
in the early endeavours aimed at 1,2 was to devise a flex-
O
O
RO
6
7
While searching for potential routes to the core tetra-
cyclic structure 7, which could be conveniently adapted
and amplified towards natural products 1,2, it occurred
*
Corresponding author. Tel.: +91 80 2293 2850; fax: +91 80 2360
0936; e-mail: gm@orgchem.iisc.ernet.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.052

8866
G. Mehta, P. Maity / Tetrahedron Letters 48 (2007) 8865–8868
O
CH3
O
OH
RO
RO
CH3
H3CO
H3C
O
O
RCM
FGI
+
H3C
COOH
H3C
H3C
11
12
CH3
CH3
7
8
a
IMDA
O
O
O
OH
RO
O
H3CO
CH3
oxidative
dearomatization
CH3
RO
O
O
OCH3
O
O
H3C
H3C
H3C
CH3
CH3
13
10
9
14
Scheme 1. Retrosynthetic analysis of the tetracyclic core 7 from the
aromatic precursor 10.
b
O
O
H3CO
H3CO
CH3
to us that a short access to the required tetracyclic
system could be devised by coupling an intramolecular
Diels–Alder reaction (IMDA) with RCM cyclization
(9!8!7) in a tandem fashion as depicted retrosynthet-
ically in Scheme 1. It was anticipated that the masked
o-benzoquinone 98 required for the desired IMDA reac-
tion could be generated through the oxidative dearo-
matization of an aromatic precursor such as 10.
Appropriately substituted aromatic compound 10 could
be crafted from readily available benzenoid derivatives
through routine manoeuvers.
O
O
c
O
O
H3C
16
H3C
CH3
CH3
15
Scheme 2. Reagents and conditions: (a) Pb(OAc)4, DCM, rt, 30 min,
66%; (b) toluene, reflux, 3.5 h, 74%; (c) Grubbs’ I catalyst (10 mol %),
benzene, reflux, 4 h, 91%.
o-benzoquinone monoketal intermediate.8 Exposure of
a mixture of tetra- substituted aromatic 119 and
(2Z,4E)-2-methyl-2,4-hexadien-1-ol 1711 to the oxidant
bis(trifluoroacetoxy) iodobenzene (BTIB) led to pentaene
18, which was isolated in a modest 40% yield along
with a considerable amount of the corresponding
p-benzoquinone derived from phenol 11, Scheme 3.
Thermal activation of 18 in refluxing toluene resulted
in a regio and stereoselective intramolecular Diels–Alder
reaction via the transition state 19 to furnish the tricyclic
compound 20,12 Scheme 3. Tricycle 20 was now set for
the RCM reaction. Thus, tetracycle 21 was readily real-
ized from 20 in the presence of Grubbs’ I catalyst. The
structure of 21 was fully secured through X-ray crystal
structure determination (Fig. 1).13
As a validation of the overall feasibility of the retrosyn-
thesis indicated in Scheme 1, it was considered expedient
to initially set up the IMDA reaction through dearoma-
tization of readily assembled 1,2,3,4-tetrasubstituted
precursor 11 under modified Wessely oxidation condi-
tions.9,10 Accordingly, o-allylphenol derivative 11 was
oxidized with lead tetraacetate in the presence of
(2Z,4E)-2-methyl-2,4-hexadienoic acid 1211 to furnish
stable o-benzoquinone derivative 13 in 66% isolated
yield after chromatographic separation.12 Several intra-
molecular [4+2]-cycloaddition pathways are possible in
the dearomatized pentaene 13, but in practice, a single
tricyclic product 15 was obtained in refluxing toluene,
in a fair yield, through the preferred endo-transition
state 14, Scheme 2. The desired regio- and stereochemi-
cal outcome and the mode of this intramolecular cyclo-
addition is a consequence of the Z-geometry present in
the tethered double bond acting as the dienenophile.
The two alkenyl side arms in 15 were now well posi-
tioned for effecting the RCM reaction. Indeed, exposure
of 15 to Grubbs’ I catalyst furnished the tetracyclic lac-
tone 1612 in excellent yield, Scheme 2. Functionally well
endowed tetracyclic lactone 16 embodies many of the
key features of the natural products 1,2, in particular,
the correct disposition of the C11, C6 and C5 quater-
nary centers.
While the arrival at tetracycle 21 in just three steps from
the aromatic precursor 11 was a satisfying outcome, the
placement of the C1 methyl group in the five-membered
ring had still to be negotiated to complete access to the
tashironin framework. Towards this end, appropriate
aromatic precursor 22 was prepared14 and its oxidative
dearomatization with BTIB in the presence of Z,E-di-
enol 1711 was undertaken to furnish pentaene 23 as a
mixture (1:1.2) of inseparable diastereomers, Scheme 4.
The diastereomeric mixture 23 was subjected to thermal
activation to induce the IMDA reaction along the lines
observed above in the case of 18. As was expected, in
this case, a mixture of tricyclic diastereomers 24 was
realized through stereoselective cycloaddition. RCM
reaction on 24 proved problematic and a mixture of tet-
racyclic diastereomers 25, 26 was obtained only in poor
The success of the oxidative dearomatization–IMDA
reaction under Wessely conditions10 in 11, Scheme 2,
encouraged us to implement the retrosynthetic protocol
shown in Scheme 1 involving an appropriate mixed

G. Mehta, P. Maity / Tetrahedron Letters 48 (2007) 8865–8868
8867
CH3
CH3
OH
OH
H3CO
H3C
H3CO
H3C
+
+
H3C
H3C
CH2OH
CH2OH
22
17
11
17
a
a
O
O
O
H3CO
H3CO
CH3
CH3
O
H3CO
O
CH3
O
b
O
OCH3
H3C
H3C
O
CH3
CH3
23
H3C
24
CH3
19
18
c
b
O
O
O
H3CO
H3CO
O
O
O
H3CO
H3CO
CH3
+
O
O
c
H3C
H3C
CH3
CH3
25
26
H3C
H3C
CH3
CH3
20
21
Scheme 4. Reagents and conditions: (a) PhI(OCOCF3)2, THF, rt, 5 h,
42%; (b) toluene, reflux, 20 h, 73%; (c) Grubbs’ II catalyst (20 mol %),
benzene, reflux, 25%.
Scheme 3. Reagents and conditions: (a) PhI(OCOCF3)2, THF, rt, 5 h,
40%; (b) toluene, reflux, 20 h, 76%; (c) Grubbs’ I catalyst (10 mol %),
benzene, reflux, 8 h, 86%.
sequentially orchestrated steps. The model studies out-
lined here should pave the way for the total synthesis
of this family of natural products and given the brevity
and generality of this approach, it should also make
available many analogues. Efforts in this direction are
in progress and will be disclosed in due course.
Acknowledgements
P.M. is a recipient of a research fellowship from CSIR,
Government of India. Support of this research from the
Chemical Biology Unit of JNCASR, Bangalore is
greatly appreciated. G.M. is a CSIR Bhatnagar Fellow
and a Humboldt Forschungpreis Awardee at the Frei
University, Berlin.
Figure 1. ORTEP diagram of compound 21 with 50% ellipsoidal
probability.
References and notes
yield, perhaps a reflection of the prevailing stereochem-
ical constraints for the RCM process. Several variations
in catalyst (Grubbs’ I and II), use of additives (titanium
isopropoxide, etc.) and change in solvent and tempera-
ture did not lead to significant improvement in yields
and efforts in this direction are still continuing. Yet, it
is gratifying to note that the complete tetracyclic frame-
work of the C15-tashironins could be put in place in just
three steps from aromatic precursor 22 and Z,E-dienol
partner 17, Scheme 4.
1. Huang, J.-M.; Yokoyama, R.; Yang, C.-S.; Fukuyama, Y.
J. Nat. Prod. 2001, 64, 428–431.
2. Schmidt, T. J.; Muller, E.; Fronzek, F. R. J. Nat. Prod.
¨
2001, 64, 411–414.
3. Fukuyama, Y.; Shida, N.; Kodama, M. Tetrahedron Lett.
1995, 36, 583–586.
4. Tomita, B.; Hirose, Y. Phytochemistry 1973, 12, 1409–
1414.
5. Cook, S. P.; Polara, A.; Danishefsky, S. J. Am. Chem. Soc.
2006, 128, 16440–16441.
6. Mehta, G.; Singh, R. Angew. Chem., Int. Ed. 2006, 45,
953–955.
7. Huang, J.-M.; Yang, C.-S.; Tanaka, M.; Fukuyama, Y.
Tetrahedron 2001, 57, 4691–4698.
8. Selected lead references on the application of masked o-
benzoquinones in synthesis, see: (a) Carlini, R.; Higgs, K.;
Rodrigo, R.; Taylor, N. Chem. Commun. 1998, 65–66; (b)
Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35,
In summary, the functionally embellished and stereo-
chemically defined C15 tetracyclic core present in tashi-
ronin-type bioactive natural products has been
accessed in just three steps from an appropriately
crafted aromatic precursor employing oxidative dearo-
matization, an IMDA reaction and RCM as the three

8868
G. Mehta, P. Maity / Tetrahedron Letters 48 (2007) 8865–8868
856–866; (c) Magdziak, D.; Meek, S. J.; Pettus, T. R. R.
303.1596; found: 303.1588. Compound 16. Mp 107.0–
107.8 °C; IR (neat) 2955, 1782, 1743 cmꢀ1 1H NMR
Chem. Rev. 2004, 104, 1383–1430; (d) Hsu, P.-O.; Pedd-
inti, R. K.; Chittimala, S. K.; Liao, C. C. J. Org. Chem.
2005, 70, 9156–9167.
;
(300 MHz, CDCl3) d 6.48 (d, J = 8.1 Hz, 1H), 5.96–5.92
(m, 1H), 5.88 (d, J = 8.1 Hz, 1H), 5.74–5.72 (m, 1H), 3.83
(s, 3H), 3.15 (td, J = 1.8 Hz, J = 3.3 Hz, 1H), 2.67–2.65
(m, 1H), 2.17 (d, J = 15.6 Hz, 1H), 1.27 (s, 3H), 1.24 (s,
3H); 13C NMR (75 MHz, CDCl3) d 199.3, 175.5, 135.2,
134.7, 133.6, 126.4, 98.6, 63.3, 61.7, 55.9, 53.3, 49.6, 31.3,
18.3, 13.5; HRMS(ES) m/z calcd for C15H17O4 (M+H+):
261.1127; found: 261.1130. Compound 20. IR (neat) 2946,
9. Tetrasubstituted aromatic precursor 11 was readily pre-
pared as follows:
OH
O
OCH3
CH3
OCH3
CH3
Br
K2CO3, 95%
1
1736, 1449 cmꢀ1; H NMR (300 MHz, CDCl3) d 6.09 (d,
J = 8.1 Hz, 1H), 5.85–5.71 (m, 2H), 5.54–5.42 (m, 1H),
5.15–5.07 (m, 3H), 3.79 (1/2ABq, J = 8.7 Hz, 1H), 3.69 (1/
2ABq, J = 9.0 Hz, 1H), 3.63 (s, 3H), 2.42 (dd, J = 7.2,
J = 14.7 Hz, 1H), 2.15 (dd, J = 7.2, J = 14.7 Hz, 1H), 1.79
(d, J = 10.5 Hz, 1H), 1.72 (dd, J = 1.5, J = 7.2 Hz, 3H),
1.22 (s, 3H), 0.88 (s, 3H); 13C NMR (75 MHz, CDCl3) d
204.6, 134.2, 133.6, 132.2, 130.1, 126.9, 118.4, 101.5, 71.7,
54.4, 54.2, 52.4, 51.3, 48.9, 32.9, 18.1, 18.0, 13.7;
HRMS(ES) m/z calcd for C18H24O3Na (M+Na+):
311.1623; found: 311.1621. Compound 21. Mp 104.7–
neat, sealed tube
190 oC, 76%
OH
OH
OCH3
CH3
OCH3
CH3
+
o
:
p
= 3:1
11
105.1 °C; IR (neat) 3057, 2944, 1727 cmꢀ1 1H NMR
;
10. (a) Wessely, F.; Sinwel, F. Monatsh. Chem. 1950, 81,
1055–1070; (b) Yates, P.; Auksi, H. Can. J. Chem. 1979,
57, 2853–2863.
11. (2Z,4E)-2-methyl-2,4-hexadienoic acid 12 and (2Z,4E)-2-
methyl-2,4-hexadien-1-ol 17 were conveniently prepared
as shown below:
(300 MHz, CDCl3) d 6.35 (d, J = 7.8 Hz, 1H), 5.93–5.89
(m, 1H), 5.77 (d, J = 8.4 Hz, 1H), 5.69–5.67 (m, 1H), 3.85
(1/2ABq, J = 8.4 Hz, 1H), 3.77 (1/2ABq, J = 8.4 Hz, 1H),
3.65 (s, 3H), 3.17 (dd, J = 3.0, J = 15.3 Hz, 1H), 2.55 (s,
1H), 2.17 (d, J = 15.6 Hz, 1H), 1.23 (s, 3H), 1.07 (s, 3H);
13C NMR (75 MHz, CDCl3) d 203.4, 135.5, 134.3, 132.6,
127.0, 100.9, 71.9, 62.7, 59.3, 54.4, 52.6, 43.3, 31.6, 20.7,
13.1; HRMS(ES) m/z calcd for C15H18O3Na (M+Na+):
269.1154; found: 269.1154.
CH3
CO2Et
(RO)2POCHCO2Et
O
H3C
H3C
H3C
H3C
CH3
KHMDS, 50%
R = TFE
NaOH
84%
13. X-ray data were collected at 291 K on a SMART CCD–
BRUKER diffractometer with graphite monochromated
˚
CH2OH
CH3
CO2H
CH3
Mo Ka radiation (k = 0.7107 A). The crystal structure was
DIBAL-H
96%
solved by direct methods (SIR92) and refined by full-
matrix least-squares method on F 2 using SHELXL-97.
Compound 21: C15H18O3, MW = 246.29, crystal system:
monoclinic, space group: P21/n, cell parameters:
12
17
˚
˚
˚
12. All new compounds were fully characterized on the basis
of IR, 1H NMR, 13C NMR and HRMS spectral data.
Spectral data of selected compounds: Compound 13. IR
a = 6.5131 (8) A, b = 27.854 (3) A, c = 7.1359 (9) A,
3
˚
b = 102.856(2)°,
V = 1262.1(3) A ,
Z = 4,
qcalc =
1.296 g cmꢀ3, F(000) = 528, l = 0.089 mmꢀ1, number of
l.s. parameters = 166, R1 = 0.0451 for 1572 reflections
with I > 2r(I) and 0.0660 for all 2086 data. wR2 = 0.1056,
GOF = 1.044 for all data. Crystallographic data have
been deposited with the Cambridge Crystallographic Data
Centre, CCDC-658170.
(neat) 2917, 1707, 1678 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 7.15–7.07 (m, 1H), 6.66 (d, J = 6.3 Hz, 1H),
6.46 (d, J = 11.4 Hz, 1H), 6.08 (dd, J = 1.8,
J = 6.6 Hz, 1H), 6.02–5.92 (m, 1H), 5.89–5.80 (m, 1H),
5.14–5.07 (m, 2H), 3.42 (s, 3H), 3.15 (dd, J = 6.6,
J = 16.5 Hz, 1H), 3.02 (dd, J = 5.7, J = 16.2 Hz, 1H),
2.02 (s, 3H), 1.86 (s, 3H), 1.81 (d, J = 6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 192.3, 165.7, 144.4, 143.1,
138.0, 136.7, 134.9, 133.6, 128.9, 121.9, 121.8, 116.9, 95.2,
50.9, 32.5, 20.4, 18.5, 16.9; HRMS(ES) m/z calcd for
C18H22O4Na (M+Na+): 325.1416; found: 325.1432. Com-
14. Aromatic precursor 22 was accessed as follows:
OH
O
OCH3
CH3
OCH3
CH3
Br
K2CO3, 95%
pound 15. IR (neat) 2977, 1794, 1739 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 6.25 (d, J = 8.1 Hz, 1H), 5.88 (d,
J = 8.4 Hz, 1H), 5.78–5.65 (m, 1H), 5.63–5.52 (m, 1H),
5.15–5.09 (m, 2H), 4.88 (ddd, J = 1.5, J = 11.1,
J = 12.3 Hz, 1H) 3.83 (s, 3H), 2.45 (dd, J = 6.9,
J = 14.4 Hz, 1H) 2.17 (dd, J = 7.2, J = 14.1 Hz, 1H),
1.97 (d, J = 11.1 Hz, 1H), 1.70 (dd, J = 1.8, J = 6.6 Hz,
3H), 1.22 (s, 3H), 1.06 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 201.1, 174.9, 133.6, 133.0, 132.6, 132.5, 123.7,
119.2, 108.3, 58.0, 55.7, 54.7, 54.3, 52.2, 32.8, 17.9, 16.3,
13.9; HRMS(ES) m/z calcd for C18H23O4 (M+H+):
neat, sealed tube
180 oC, 82%
OH
OH
OCH3
CH3
OCH3
CH3
+
o : p = 5:1
22