Total synthesis of isofregenedadiol

Article abstract of DOI:10.1021/ol201336x

The first total synthesis of isofregenedadiol, a bicyclic diterpene isolated from H. Viscosum, is reported starting from a d-(-)-pantolactone chiral pool. A one-pot quadruple reaction sequence comprising an enyne ring-closing metathesis/cross-metathesis/D

Full text of DOI:10.1021/ol201336x

ORGANIC
LETTERS
Total Synthesis of Isofregenedadiol#
2011
Vol. 13, No. 14
3690–3693
Suresh E. Kurhade, Abbas I. Sanchawala,‡ Velayutham Ravikumar, Debnath Bhuniya,
and D. Srinivasa Reddy*,†
Discovery Chemistry, Advinus Therapeutics Ltd., Quantum Towers, Plot No. 9,
Rajiv Gandhi Infotech Park, Phase-I, Hinjewadi, Pune, 411057, India. †Present address:
National Chemical Laboratory (CSIR), Dr. Homi Bhabha Road, Pune, 411008, India.
ds.reddy@ncl.res.in
Received May 18, 2011
ABSTRACT
The first total synthesis of isofregenedadiol, a bicyclic diterpene isolated from H. Viscosum, is reported starting from a D-(À)-pantolactone chiral
pool. A one-pot quadruple reaction sequence comprising an enyne ring-closing metathesis/cross-metathesis/DielsÀAlder/aromatization for the
construction of a target skeleton is the highlight of the present synthesis.
Isofregenedadiol 1 is a tetrahydronaphthalenic diterpe-
nic diol isolated from Halium Viscosum (La Fregeneda).1
This compound’s skeleton can be considered as a new kind
of rearranged labdane with an aromatized B ring.2 Although
biological activity for this compound was not reported,
the related labdanes have shown interesting antibacterial,
antifungal, antiprotozoal, and anti-inflammatory activ-
ities. The assigned structure and absolute configuration
were confirmed through preparation of its diacetate2 from
7-1abden-3β,15-diol 3 by Marcos et al.3 An interesting
‡ Summer project student from postgraduate school for biological studies,
Ahmednagar College, Ahmednagar, India.
# Advinus Publication No. ADV-A-007.
(1) Marcos, I. S.; Jorge, A.; Diez, D.; Basabe, P.; Lithgow, A. M.;
Sexmero., M. J.; Garrido, N. M.; Urones, J. G. Phytochemistry 1996, 41,
1155–1157.
(2) See other natural products with related skeleton: (a) Urones,
J. G.; Marcos, I. S.; Garrido, N. M.; Moro, R. F. Phytoehemistry 1990,
29, 3042–3044. (b) Urones, J. G.; Marcos, I. S.; Basabe, P.; Garrido,
Figure 1. Structures of natural products.
N. M.; Jorge, A.; Moro, R. F.; Lithgow, A. M. Tetrahedron 1993, 49,
6079–6088. (c) Timmermann, B. N.; Hoffmann, J. J.; Jolad, S. D.;
Schram, K. H. Y.; Klenck, R. E.; Bates, R. B. J. Org. Chem. 1982, 47,
4114–4416. (d) Zdero, C.; Bohlmann, F.; Niemeyer, H. M. Phytochem-
istry 1991, 30, 3689–3691.
(3) Marcos, I. S.; Basabe, P.; Laderas, M.; Diez, D.; Jorge, A.;
Rodilla, J. M.; Moro, R. F.; Lithgow, A. M.; Barata, I. G.; Urones,
J. G. Tetrahedron 2003, 59, 2333–2343.
(4) See previous references from this group where a (À)-pantolactone
chiral pool was used in the total synthesis: (a) Reddy, D. S.; Srinivas, G.;
Rajesh, B. M.; Kannan, M.; Rajale, T. V.; Iqbal, J. Tetrahedron Lett.
2006, 47, 6373–6375. (b) Hajare, A.; Datrange, L.; Vyas, S.; Bhuniya, D.;
Reddy, D. S. Tetrahedron Lett. 2010, 51, 5291–5293. (c) Hajare, A.;
Ravikumar, V.; Khaleel, S.; Bhuniya, D.; Reddy, D. S. J. Org. Chem.
2011, 76, 963–966.
side-chain migration reaction and ring B aromatizations were
the key steps in the conversion of labdane 3 to 2 (Figure 1).3
(5) Selected references for tandem enyne metathesis/DielsÀAlder
reactions: (a) Bentz, D.; Laschat, S. Synthesis 2000, 12, 1766–1773.
(b) Kotha, S.; Sreenivasachary, N.; Brahmachary, E. Eur. J. Org. Chem.
2001, 4, 787–792. (c) Yang, Y.-K.; Tae, J. Synlett 2003, 2017–2020.
ꢀ
(d) Rosillo, M.; Domınguez, G.; Casarrubios, L.; Amador, U.; Perez-Castells,
´
M. J. Org. Chem. 2004, 69, 2084–2093. (e) Majumdar, K. C.; Rahaman,
H.; Muhuri, S.; Roy, B. Synlett 2006, 466–468. (f) Evanno, L.; Deville,
A.; Bodo, B.; Nay, B. Tetrahedron Lett. 2007, 48, 4331–4333.
(g) Ben-Othman, R.; Othman, M.; Coste, S.; Decroix, B. Tetrahedron
2008, 64, 559–567. (h) Subrahmanyam, A. V.; Palanichamy, K.;
Kaliappan, K. P. Chem.;Eur. J. 2010, 16, 8545–8556.
r
10.1021/ol201336x
Published on Web 06/23/2011
2011 American Chemical Society

Here, we report the first total synthesis of 1 in an enantios-
pecific manner starting from D-(À)-pantolactone.4
presence of CuI, and the resulting secondary alcohol was
protected as TBS ether to furnish compound 7.11 Deprotec-
tion of the PMB group in 7 and Swern oxidation pro-
vided the aldehyde, which was immediately treated with a
BestmannÀOhira reagent12 to yield the enyne 4 (Scheme 2).
Retrosynthesis is presented in Scheme 1. We envisioned
securing the target natural product 1 through a key one-pot
quadruple reaction process by combining two metatheses,
DielsÀAlder and aromatization steps.5À8 The present four-
step one-pot sequence in the synthesis of natural prodcuts is
novel. However, tandem enyne metathesis/DielsÀAlder have
been widely employed in synthesis and the sequence compris-
ing enyne metathesis/cross metathesis/DielsÀAlder is less
common.5,6 The synthesis is planned using an appropriate
enyne 4, alkene 5,9 and 2-butyne. Enyne 4 and cross-metath-
esis partner alkene 5 could be prepared from D-(À)-panto-
lactone and S-(À)-citronellol, respectively.
Scheme 2. Synthesis of Key Enyne Precursor 4
Scheme 1. Retrosynthesis
Having the key enyne precursor 4 in hand, initially we
have synthesized the isofregenedadiol skeleton in a sequen-
tial manner as described in Scheme 3. In the presence of
Grubbs’ second generation catalyst, enyne 4 underwent
RCM to produce diene 8 in 94% yield. The second metath-
esis (cross) using the same catalyst (5 mol %) and an excess
of 5 (∼10 equivalents) under reflux conditions resulted in
the desired compound 9. After a few attempts13 and replacing
2-butyne with dimethylacetylenedicarboxylate (DMAD),
the DA reaction occurred smoothly which was immedi-
ately oxidized to 10 in 59% yield over two steps.14
Our synthesis commenced with the preparation of known
epoxide 610 from commercially available D-(À)-pantolactone.
It was regioselectively opened with an allyl Grignard in the
Scheme 3. Synthesis of Isofregenedadiol Skeleton through Se-
quential Method
(6) Selected references for tandem enyne metathesis/cross metathesis/
DielsÀAlder reactions. (a) Kotha, S.; Halder, S.; Brahmachary, E.;
Ganesh, T. Synlett 2000, 853–855. (b) Kotha, S.; Halder, S.; Brahmachary,
E. Tetrahedron 2002, 58, 9203–9208. (c) Lee, H.-Y.; Kim, H. Y.; Tae, H.;
Kim, B. G.; Lee, J. Org. Lett. 2003, 5, 3439–3442. (d) Park, H.; Hong,
Y-L; Kim, Y. B.; Choi, T.-L. Org. Lett. 2010, 12, 3442–3445.
(7) For selected reviews for synthesis of aromatic compounds using
RCM, see: (a) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem.,
Int. Ed. 2006, 45, 2664–2670. (b) Otterlo, W. A. L.; de Koning, C. B.
Chem. Rev. 2009, 109, 3743–3782.
(8) Selected reviews on metathesis: (a) Mori, M Materials 2010, 3,
2087–2140. (b) Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748–
3759. (c) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760–3765.
(d) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem.;Eur. J.
2008, 14, 5716–5726. (e) Brik, A. Adv. Synth. Catal. 2008, 350, 1661–
1675. (f) Kotha, S.; Meshram, M.; Tiwari, A. Chem. Soc. Rev. 2009, 38,
2065–2092. (g) Giessert, A. J.; Diver, S. T. Chem. Rev. 2004, 104, 1317–
1382. (h) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1–18. (i) Mori, M.
In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
Germany, 2003; Vol. 2, pp176À204 and references cited therein.
(9) Breitenbach, R.; Chiu, C. K.-F.; Massett, S. S.; Meltz, M.;
Murtiashaw, C. W.; Pezzullo, S. L.; Staigers, T. Tetrahedron: Asymme-
try 1996, 2, 435–442.
€
(10) Brabander, J. D.; Vanhesschet, K.; Vandewalle, M. Tetrahedron
Lett. 1991, 32, 2821–2824.
(11) See related references associated with epoxide ring opening
reactions: (a) Huynh, C.; Derguini-Boumechal, F.; Linstrumell, G.
Tetrahedron Lett. 1979, 17, 1503–1506. (b) Hirsch, J. A.; Truc, V. C.
J. Org. Chem. 1986, 51, 2218–2227.
(12) Muller, S.; Liepold, B.; Bestmann, H. J. Synlett 1996, 521–522.
(13) Performing the reaction (DA step) with 2-butyne at an elevated
temperature in a sealed tube did not produce the desired compound. The
low yield in a straightforward DA step with DMAD may be explained by
the presence of a Z-isomer (∼20% based on NMR); however, we did not
recover the unreacted Z-isomer.
Org. Lett., Vol. 13, No. 14, 2011
3691

Having established the scheme in sequential manner,
next, we attempted the planned key one-pot quadruple
reaction sequence. After a few attempts, one-pot sequence
proceeded smoothly to furnish the desired tetrahydro-
naphthalene derivative 10 in 42% overall yield (Scheme 4).
The reaction times are chosen for the addition of sub-
sequent reagents and catalysts based on thin-layer chro-
matography (tlc) monitoring at each step. In a typical
procedure, a mixture of enyne 4 (1 mmol) and alkene
5 (8 mmol) was dissolved in toluene, degassed for 10 min
in a stream of argon, and then treated with 9 mol % of
Grubbs’ second generation catalyst in one portion. After
being stirred at 50 °C for 12 h, additional amounts of
alkene 5 (2 mmol) and catalyst (1 mol %) were added and
stirring was continued for 6 h at 50 °C. At this stage,
DMAD (2 mmol) was added to the reaction mixture,
heated at 110 °C for 10 h, and cooled to room temperature,
and DDQ (1.2 mmol) was added and stirring continued at
room temperature for 16 h. The reaction mixture was
filtered through a plug of Celite pad and washed with
dichloromethane. The crude product obtained after the
evaporation of solvent was purified by silica gel column
chromatography to furnish the desired compound 10 in
42% yield.15 The diester 10 was transformed to the natural
product isofregenedadiol 1 by using LiAlH4 reduction,
conversion of the diol to dibromide,16 and deprotection of
the benzyl group (Scheme 4). The spectral data of synthetic
isofregenedadiol1 werecomparedwiththoseofthe natural
product and found to be identical. In addition, we have
corresponding diacetate 2 and compared the optical rota-
tion with the reported value in the literature.1
Figure 2. ORTEP diagram of the synthetic isofregenedadiol.
During this process, we have prepared a known inter-
mediate diene 8 as a bonus (Scheme 3). The spectral data
(1H and 13C NMR) of the diene 8 was compared with that
of 8 from Snyder’s group,17 and both were found to be
identical. Previously, this diene 8 was converted to 3(S)-
hydroxytanshinone 13 and 3(S),17-dihydroxytanshinone
14 through an ultrasound-promoted DielsÀAlder cycload-
dition with corresponding o-quinones followed by removal
of the TBS group (Scheme 5).17,18 Hence our effort can be
regarded as formal syntheses of 3(S)-dihydroxytanshinone17
and 3(S),17-dihydroxytanshinones.18 It is noteworthy to
mention that the same diene 8 was prepared in racemic
form by Marsaioli et al. and utilized for the synthesis of
rearranged unsaturated drimane derivatives.19
Scheme 5. Formal Synthesis of 3(S)-Hydroxytanshinone and
3(S),17-Dihydroxytanshinone
Scheme 4. Synthesis of Isofregenedadiol and Its Diacetate
through One-Pot Quadruple Reaction Process
In short, we have described the first total synthesis of
isofregenedadiol 1, a bicyclic diterpene using a one-pot
(14) As our main focus is on a tandem one-pot process, we did not
attempt further optimization of the scheme at this stage.
(15) The analytical data (1H, 13C, IR, and MS) of all the products are
in good agreement with the proposed structures. Copies of spectra are
provided in the Supporting Information.
(16) During the conversion of primary alcohols to corresponding
bromides using CBr4/PPh3, alcohol 12 was obtained as a major product
through deprotection of the OTBS group. See related references: Lee, A.
S.-Y.; Yeh, H.-C.; Shie, J.-J. Tetrahedron Lett. 1998, 39, 5249–5252.
Yadav, J. S.; Mishra, R. K. Tetrahedron Lett. 2002, 43, 5419–5422. The
minor product TBS ether 11 converted to 12 by using TFA in aq. THF.
(17) Haiza, M.; Lee, J.; Snyder, J. K. J. Org. Chem. 1990, 55, 5008–
5013.
confirmed the assigned structure without any ambiguity
with the help of single crystal X-ray analysis (ORTEP
diagram is shown in Figure 2). However, no optical
rotation of diol 1 was reported in the literature. To further
confirm its absolute configuration, we have prepared the
(18) Zhang, J.; Duan, W.; Cai, J. Tetrahedron 2004, 60, 1665–1669.
~
(19) de Miranda, D. S.; da Conceic-ao, G. J. A.; Zukerman-Schpector,
J.; Guerrero, M. C.; Schuchardt, U.; Pinto, A. C.; Rezende, C. M.;
Marsaioli, A. J. J. Braz. Chem. Soc. 2001, 12, 391–402.
3692
Org. Lett., Vol. 13, No. 14, 2011

quadruplereaction sequence. Inaddition, formalsyntheses
of two biologically interesting natural products 3(S)-
hydroxytanshinone 13 and 3(S),17-dihydroxytanshinone
14 are claimed through a common intermediate diene 8.
Dr. Binoy K. Saha, Department of Chemistry, Pondicherry
University, Pondicherry for X-ray crystal structure
determination and analysis. We thank reviewers for
their help in refining the manuscript and suggesting addi-
tional refs.
Acknowledgment. We are grateful to Drs. Rashmi
Barbhaiya and Kasim Mookhtiar for their support and
encouragement. Help from the analytical department in
recording spectral data is appreciated. We acknowledge
help from Drs. Vedavati Puranik and Rahul Banerjee,
Center for Materials Characterization, NCL, Pune and
Supporting Information Available. Experimental pro-
cedures, copies of spectra and spectroscopic data for all
new compounds. CIF file of the X-ray crystal structure
analysis of isofregenedadiol 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 14, 2011
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