Application of Cp2TiCl-Promoted Radical Cyclization: A Unified Strategy for the Syntheses of Iridoid Monoterpenes

Article abstract of DOI:10.1021/acs.joc.8b00752

An expedient approach toward the unified total syntheses of (+)-iridomyrmecin, (-)-isoiridomyrmecin, (+)-7-epi-boschnialactone, (+)-teucriumlactone, and (-)-dolichodial in chirally pure forms starting from readily available (+)-β-citronellene is delineated combining step economy and simplicity. Highlights include a Ti(III)-mediated reductive epoxide opening-cyclization for the construction of the core cyclopenta[c]pyran skeleton of the iridoid lactones with complete diastereoselectivity for the newly created bridgehead stereogenic centers. Subsequent transformations facilitate a short access to (+)-teucriumlactone and (-)-dolichodial and formal access to potentially other iridoids.

Full text of DOI:10.1021/acs.joc.8b00752

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Article
Application of Cp2TiCl-Promoted Radical Cyclization: A
Unified Strategy for the Syntheses of Iridoid Monoterpenes
Hina P. A. Khan, Dipendu Das, and Tushar Kanti Chakraborty
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00752 • Publication Date (Web): 16 May 2018
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Application of Cp2TiCl-Promoted Radical Cyclization: A Unified Strategy for
the Syntheses of Iridoid Monoterpenes
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Hina P. A. Khan, Dipendu Das and Tushar Kanti Chakraborty*
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Department of Organic Chemistry, Indian Institute of Science, Bengaluru ꢀ560012, India
ABSTRACT:
An expedient approach toward the unified total syntheses of (+)ꢀiridomyrmecin, (ꢀ)ꢀ
isoiridomyrmecin, (+)ꢀ7ꢀepiꢀboschnialactone, (+)ꢀteucriumlactone and (ꢀ)ꢀdolichodial in chirally
pure forms starting from readily available (+)ꢀβꢀcitronellene is delineated combining step
economy and simplicity. Highlights include a Ti(III)ꢀmediated reductive epoxide openingꢀ
cyclization for the construction of the core cyclopenta[c]pyran skeleton of the iridoid lactones
with complete diastereoselectivity for the newly created bridgehead stereogenic centers.
Subsequent transformations facilitate a short access to (+)ꢀteucriumlactone, (ꢀ)ꢀdolichodial and
formal access to potentially other iridoids.
INTRODUCTION
A large repertoire of structurally diverse cyclopentane monoterpenoids have been isolated from
myriad plant families and various species of Iridomyrmex,1 a genus of ants, in which they occur
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as defensive secretions and is also known to exhibit highly excitative activity towards cats and
other Felidae animals.1a,2 In this perspective, iridoids are representative of a notable and highly
recognized group of cyclopenta[c]pyran monoterpenoids with wide ranging biological activity
profiles extensively chronicled in many traditional and folk medicine for centuries in the
treatment of inflammation, anxiety, hypertension, cough and skin disorder.3
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Figure 1. Structures of major naturally occurring iridoids.
Interestingly, in spite of their confined molecular framework, they hold contiguous stereogenic
centers and are characterized by a cyclopentane ring cisꢀfused to a dihydropyran or δꢀlactone.4
Many approaches have been published over the years5ꢀ11 to obtain this privileged scaffold owing
to their therapeutic potential as drug candidates and thus the furtherance in the synthesis of
iridoids (Figure 1) is still on urge. To mention few notable works, Hofferberth et al. accessed
various iridoid monoterpenes in a divergent manner from a common citronellolꢀderived aminal
intermediate obtained by enamine/enal cycloaddition reaction.9a,b Mulzer et al. described the free
radical cyclization pathway of acyclic chirally Cꢀ2ꢀsubstituted 1ꢀhexenyl radicals to construct
iridoid carbon framework.5d Syntheses of dihydronepetalactone and dolicholactone were
achieved by Jahn et al. in 10 steps starting from (S)ꢀcitronellol.11b
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Diversifying our previous work to access cyclopentano lactone mediated by Cp2Ti(III)Cl
followed by concomitant intramolecular cyclization,12 now we are aiming to detail a variable and
concise approach to gain access to a handful of iridoid monoterpene lactones in an
enantiomerically divergent manner starting from (+)ꢀβꢀcitronellene.
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RESULTS AND DISCUSSION
Taking advantage of the Cp2TiClꢀmediated reductive epoxide openingꢀcyclization, we
envisioned a stereoselective divergent synthesis to assemble the core skeleton of iridoid lactones
1ꢀ5. Retrosynthetically, we envisioned a direct route to iridomyrmecin (1), isoiridomyrmecin (2),
7ꢀepiꢀboschnialactone (4) arising from the epoxides 10 and 11, which have the complete carbon
skeleton of the natural products, following a Ti(III)ꢀmediated reductive epoxide cleavageꢀ
cyclization protocol (Scheme 1). Epoxides 10 and 11 in turn could be obtained from the α,βꢀ
unsaturated ester intermediates 12 and 13 originating from (+)ꢀβꢀcitronellene (14) via ozonolysis
followed by Wittig olefination. The access to teucriumlactone (3) was envisaged to be derived
Scheme 1. Divergent retrosynthetic analysis.
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from 1 and 2 through a selenoxide elimination (Scheme 1). Complete reduction of 1, 2 and 3
would lead to the corresponding diols that could serve as pivotal intermediates for the synthesis
of other iridoids (5-8) and iridoalkaloid 9 (Figure 1).
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To evaluate the potentiality of the above analysis (Scheme 1), we embarked toward the synthesis
of the requisite epoxides 10 and 11 bearing an α,βꢀunsaturated ester moiety. Given the
background, the synthesis commenced with the conversion of (+)ꢀβꢀcitronellene (14) to the
known aldehyde 1513 through ozonolysis, followed by Wittig olefination to deliver the dienyl
esters 12 and 1314 in almost quantitative yield (Scheme 2). Selective epoxidation of the terminal
alkene with mꢀCPBA at 0 °C successfully provided the desired epoxides 10 and 1114, a
cyclization precursor for the key Ti(III)ꢀmediated radical cyclization.
Scheme 2. Preparation of the epoxy esters 10 and 11.
Implementation of our crucial step of reductive epoxide cleavage of epoxides 10 and 11
mediated by [Cp2TiCl] (generated in situ from Cp2TiCl2 and activated Zn dust) followed by 5ꢀ
exoꢀtrig cyclization onto the α,βꢀunsaturated ester moiety successfully furnished the targeted
iridolactones, iridomyrmecin (1) and isoiridomyrmecin (2) (as 1:1.1 epimeric mixture, Scheme
3) and 7ꢀepiꢀboschnialactone (4) (Scheme 4) in 77% and 82% yields, respectively. The most
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likely attainable transition state for the Ti(III)ꢀmediated 5ꢀexoꢀtrig radical cyclization with
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subsequent intramolecular lactonization is shown in the scheme.
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The epimeric mixture of 1 and 2, in small quantity, was subjected to preparative thin layer
chromatography to afford iridomyrmecin (1) and isoiridomyrmecin (2) in 37% and 34% isolated
yields, respectively.15 The data of both were identical with those in the literature.5dꢀf,15a The
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absolute values of the optical rotations of 1 ([α]D20 +200.1 (c 0.28, CCl4)) and 2 ([α]D20 ꢀ55.48 (c
25.5
0.40, CCl4)) were found almost identical with those of the natural compounds, [α]D
+210 (c
0.976, CCl4) and [α]D ꢀ59 (c 0.562, CCl4), respectively, confirming their optical purity.16
Obviously, the idea of the preparative thin layer chromatography was far from ideal to deal in
large scale and thus, to address this concern, the epimeric mixture of 1 and 2 was subjected to
DIBALꢀH (1.0 equiv) reduction to provide the corresponding lactols, which were then resolved
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Scheme 3. Ti(III)ꢀmediated radical cyclization and synthesis of various iridoids, 1-3 and 5-9.
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into two pairs of two diastereomers and were separated using 230ꢀ400 mesh silica gel column
chromatography (3% EtOAc in hexane). The stereochemical output of the composition of the
diastereomers in each pair was confirmed on oxidation with PCC separately to give
iridomyrmecin (1) and isoiridomyrmecin (2) in almost quantitative yields.
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Taking advantage of the epimeric mixture of 1 and 2, synthesis of teucriumlactone (3) was
accomplished utilizing a selenium based twoꢀstep protocol (Scheme 3).17 Selenylation of the
epimeric mixture was followed by selenoxide elimination using 30% aq. H2O2ꢀpy to secure the
exocyclic double bond of teucriumlactone (3)9b along with a minute quantity of the double bond
isomerized product (easily separable through silica gel column chromatography). The absolute
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value of the optical rotation of 3, [α]D +142.25 (c 0.65, benzene), was found almost identical
with that of the natural compound, [α]D20 +145.3 (c 4.5, benzene).9c
Reduction of the δꢀlactone moiety in teucriumlactone (3) with DIBALꢀH furnished an
intermediate diol9 which paved the way towards the synthesis of dolichodial (5) and
dolicholactone (6). Whereas swinging the diol in the other way around following the selective
protectionꢀoxidation protocol described by Hofferberth et al.9b endowed the formal synthesis of
dolicholactone (6), it was transformed into dolichodial (5) under Swern oxidation18 condition in
74% yield (Scheme 3). The spectroscopic data of dolichodial (5) thus obtained (Scheme 3) was
identical with the literature report,9 indicating an accomplishment of the synthesis. Optical
rotation, [α]D24 ꢀ57.48 (c 0.27, CHCl3), was identical with that of the reported compound, [α]D24 ꢀ
58.1 (c 0.36, CHCl3).9
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Scheme 4. Synthesis of 7ꢀepiꢀboschnialactone (4) and subsequent conversion to 1-3.
Iridomyrmecin (1) and isoiridomyrmecin (2) after separation were independently subjected to
LAH reduction19 to give the corresponding diols5d,19 which could be directed towards the
synthesis of dihydronepetalactone (7) and isodihydronepetalactone (8) on further treatment with
catalytic amount of Pd(OAc)2.20 Also, the intermediate diol obtained after reduction of
iridomyrmecin (1) leads the way to access iridoalkaloid δꢀskythantine (9) as reported earlier
(Scheme 3).5a,d
Next, the spectroscopic data of 7ꢀepiꢀboschnialactone (4) obtained by Ti(III)ꢀmediated reaction
(Scheme 4) was found to be identical with the reported values,5c indicating an accomplishment of
the synthesis. Stereochemical outcome was ascertained by optical rotation, [α]D20 +92.66 (c 0.98,
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CCl4), comparable with that of the reported compound, [α]D +82 (c 0.5, CCl4).5c,21 Finally, the
formation of the target molecule 4 in its desired stereochemistry was unambiguously confirmed
by single crystal Xꢀray crystallographic analysis (Scheme 4, see the supporting information for
details).
Successful execution of 7ꢀepiꢀboschnialactone (4) was further utilized to formally access
iridomyrmecin (1) (44% overall yield over 7 steps; formal synthesis), isoiridomyrmecin (2) (40%
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overall yield over 5 steps; formal synthesis) and teucriumlactone (3) (44% overall yield over 6
steps; formal synthesis) outlined in Scheme 4. Methylation at the αꢀposition of lactone 4 in a
conventional way15 selectively furnished isoiridomyrmecin (2, dr 7:1) which on epimerization
would result in the formation of iridomyrmecin (1).4a,22 On the other hand, introduction of the αꢀ
methylene functionality present in teucriumlactone (3) could be achieved in two simple steps
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following a modified route via αꢀfomylation of lactone 4 in 74% of yield (Scheme 4).23 Highly
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stereoselective hydrogenation was achieved using PtO2/H2 instead of PdꢀC/H2
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condition, we also realized the isomerization of the double bond) to install the third stereogenic
center present in iridomyrmecin (1) which, in turn, on epimerization reverted back to
isoiridomyrmecin (2) (Scheme 4).22
CONCLUSION
In conclusion, an efficient unified approach to a plethora of iridoid monoterpenes was developed
in a divergent manner starting from (+)ꢀβꢀcitronellene. Cp2TiClꢀmediated reductive epoxide
cleavage and radical cyclization demonstrate a wellꢀamenable method to assemble the core
skeleton of iridolactones en route to diverse iridoid monoterpenes in highly stereoselective
manner. Synthesis of (+)ꢀiridomyrmecin (1), (ꢀ)ꢀisoiridomyrmecin (2), (+)ꢀ7ꢀepiꢀboschnialactone
(4) were achieved in 4 steps with 25%, 23% and 60% overall yields, respectively. Moreover, the
potential utility of the route was nicely articulated by the total synthesis of (+)ꢀteucriumlactone
(3, in 6 steps) and (ꢀ)ꢀdolichodial (5, in 8 steps) 32% and 22% overall yields, respectively. Even
though not executed, the designed approach is also amenable for the synthesis of other iridoid
natural products, such as 6-8 and the related monoterpene alkaloid 9. Further exploration of this
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strategy for the synthesis of highly functionalized iridoids/cyclopentanoid natural products are
under investigation and will be reported in due course.
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General Experimental Details:
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All the reactions were carried out under inert atmosphere in ovenꢀdried glassware using dry
solvents, unless otherwise stated. All chemicals purchased from commercial suppliers were used
as received unless otherwise stated. Reactions and chromatography fractions were monitored by
Merck silica gel 60 Fꢀ254 glass TLC plates and visualized using UV light, 7% ethanolic
phosphomolybdic acidꢀheat or 2.5% ethanolic anisaldehyde (with 1% AcOH and 3.3% conc.
H2SO4)ꢀheat as developing agents. Flash column chromatography was performed with 100ꢀ200
mesh silica gel and yields refer to chromatographically and spectroscopically pure compounds.
Instrumentation:
All NMR spectra were recorded in CDCl3 on a 400 MHz instruments at 300 K and are calibrated
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to residual solvent peaks (CHCl3 7.26 ppm and 77.0 ppm). For HꢀNMR, data are reported as
follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = double of
doublet, ddd = doublet of doublet of doublet, t = triplet, td = triplet of doublet, q = quartet, dq =
doublet of quartet, quint = quintet, sext = sextet, m = multiplet), coupling constants (Hz) and
integration. Infrared (FTꢀIR) spectra were recorded on PerkinElmer Spectrum BX
spectrophotometer and reported in νmax in cmꢀ1. High resolution mass spectrometry (HRMS) was
performed on Micromass QꢀTOF Micro instrument. Optical rotations were measured on JASCO
Pꢀ2000 polarimeter. Melting point is uncorrected and was determined in capillary tube on Buchi
melting point Mꢀ560 apparatus. XꢀRay crystallographic structure was collected on a Bruker
ApexꢀII CCD diffractometer.
Experimental Procedures and Characterization Data:
Preparation of the aldehyde 15:
The required aldehyde 15 was synthesized by ozonolysis following the literature procedure13 and
the spectroscopic data were in full accord with those reported.
General procedure for HWE olefination:
To a solution of the aldehyde 15 (1.50 g, 13.38 mmol, 1.0 equiv) in CH2Cl2 (40 mL) was added
phosphorane reagent (1.1 equiv) at 0 °C. The solution was stirred overnight at room temperature
and then concentrated in vacuo to an oily, white residue. Flash column chromatography (silica
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gel, 8% EtOAc in hexane) afforded the required α,βꢀunsaturated ester (quantitative yield) as a
clear oil.
Data for 12: Yield 2.42 g, quantitative as colorless oil.
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Rf = 0.7 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 6.74 (td, J = 7.5, 1.0
Hz, 1H), 5.72ꢀ5.62 (m, 1H), 5.01ꢀ4.93 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.19ꢀ2.09 (m, 3H), 1.82
(br s, 3H), 1.46ꢀ1.39 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 168.3, 143.9, 142.2, 127.7, 113.2, 60.4, 37.5, 35.3, 26.4, 20.2, 14.3, 12.3; IR
νmax (neat, cm–1) 3149, 1708, 1487, 1367, 1240, 1147, 1049, 1002, 970, 914; HRMS (ESI)
calcd for C12H20O2Na 219.1361 ([M + Na]+), found 219.1360.
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Data for 13: Prepared following the literature procedure14 and the spectroscopic data were in full
accord with those reported. Yield 2.61 g, quantitative as colorless oil.
General procedure for the preparation of the epoxides 10 and 11:
To a solution of the dienyl ester 12 or 13 (1.0 equiv) in CH2Cl2 (3.0 mL/mmol) was added mꢀ
CPBA (77%, 1.1 equiv) portionꢀwise at 0 °C. The reaction mixture was stirred overnight and
warmed to room temperature. The reaction was then quenched with saturated aqueous Na2SO3
and extracted with ethyl acetate. After washing with saturated aqueous NaHCO3 solution, water
and brine, the solvent was dried over anhydrous Na2SO4. After concentration, purification by
column chromatography (silica gel, 10% EtOAc in hexane) afforded the epoxides as colorless
oils.
Data for 10: Scale of reaction 2.0 g, 10.19 mmol; yield 1.81 g, 84% (dr 1.6:1, syn:anti) as
colorless oil.
Rf = 0.6 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) (major isomer) δ 6.78ꢀ
6.69 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.79ꢀ2.75 (m, 1H), 2.74ꢀ2.69 (m, 1H), 2.54 (dd, J = 4.9,
2.8, 1H), 2.32ꢀ2.18 (m, 3H), 1.85ꢀ1.81 (m, 3H), 1.74ꢀ1.32 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.05
(d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1, 141.5, 128.1, 60.5, 56.6, 46.7, 35.7,
32.2, 26.2, 16.8, 14.3, 12.4; IR νmax (neat, cm–1) 2964, 1708, 1543, 1390, 1265, 1178, 1126,
1026, 975, 956, 837; HRMS (ESI) calcd for C12H20O3Na 235.1310 ([M + Na]+), found
235.1313.
Data for 11: Prepared following the literature procedure14 and the spectroscopic data were in full
accord with those reported in the literature. Scale of reaction 2.0 g, 10.98 mmol; yield 1.98 g,
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91% (dr 1.9:1, syn:anti) as colorless oil. For H NMR and 13C NMR spectra, see supporting
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information.
General procedure for Cp2TiCl-mediated radical cyclization
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In a flame dried round bottom flask containing dry THF (30 mL/mmol) were added activated Zn
(9.0 equiv) and Cp2TiCl2 (3.0 equiv) under inert atmosphere and stirred for 1 h at room
temperature (color changed from deep red to green). Into this solution, the epoxide (1.0 equiv) in
THF (15 mL/mmol) was cannulated at room temperature under N2 atmosphere and continuously
stirred for 40 h. The reaction mixture was quenched with saturated aqueous NH4Cl and stirred
for an additional 15 min. The solvent was evaporated in vacuo and extracted with diethyl ether,
washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo afforded the crude
compounds of interest.
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Preparation of iridomyrmecin (1) and isoiridomyrmecin (2):
General procedure outlined above for Cp2TiClꢀmediated radical cyclization was followed. Scale
of reaction 1.0 g, 4.71 mmol; yield 610 mg (77%, epimeric mixture of 1 and 2); (purification by
flash column chromatography, 15% EtOAc in hexane) as viscous colorless oil.
Data for iridomyrmecin (1): Yield 14.5 mg (37%, white solid); (purification by preparative thin
layer chromatography on 30 mg scale)5d.
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Rf = 0.61 (silica gel, 30% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 4.26 (dd, J = 11.7
and 3.0 Hz, 1H), 4.18 (d, J = 11.7 Hz, 1H), 2.78ꢀ2.54 (m, 2H), 1.91ꢀ1.74 (m, 4H), 1.15 (d, J =
6.6 Hz, 3H), 1.05 (d, J = 6.0 Hz, 3H), 1.11ꢀ0.95 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 176.2,
67.9, 45.5, 41.2, 37.9, 37.3, 34.1, 29.8, 18.3, 12.7; IR νmax (neat, cm–1) 3300, 2926, 1746, 1643,
1455, 1380, 1280, 1158, 1109, 1021; HRMS (ESI) calcd for C10H16O2Na 191.1048 ([M + Na]+),
found 191.1049; optical rotation [α]D20 +200.1 (c 0.28, CCl4).
Data for isoiridomyrmecin (2): Yield 13.4 mg (34%, white solid); (purification by preparative
thin layer chromatography on 30 mg scale)5d,15
.
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Rf = 0.6 (silica gel, 30% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 4.34 (dd, J = 11.2,
6.1 Hz, 1H), 3.94 (t, J = 11.2 Hz, 1H), 2.35ꢀ2.24 (m, 1H), 2.15ꢀ2.08 (m, 1H), 2.06ꢀ1.99 (m, 2H),
1.91ꢀ1.85 (m, 1H), 1.69ꢀ1.60 (m, 1H), 1.31ꢀ1.24 (m, 2H), 1.18 (d, J = 6.5 Hz, 3H), 1.04 (d, J =
6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.4, 69.4, 45.2, 43.1, 39.0, 38.2, 35.6, 33.0, 19.1,
13.9; IR νmax (neat, cm–1) 3301, 2926, 2361, 1746, 1647, 1455, 1380, 1248, 1169, 1018; HRMS
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(ESI) calcd for C10H16O2Na 191.1048 ([M + Na]+), found 191.1047; optical rotation [α]D
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55.48 (c 0.40, CCl4).
Preparation of teucriumlactone (3):
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A solution of the epimeric mixture of 1 and 2 (60 mg, 0.36 mmol, 1.0 equiv) in dry THF (1.5
mL) was slowly added over a 10ꢀmin period to a cooled (ꢀ78 °C) solution of lithium
diisopropylamide [prepared from diisopropylamine (0.12 mL, 0.82 mmol) and nꢀbutyllithium
(0.42 mL of 1.80 M, 0.76 mmol) in hexane] in dry tetrahydrofuran (1.5 mL). After 30 min, a
solution of PhSeCl (75 mg, 0.39 mmol, 1.1 equiv) in dry tetrahydrofuran (1.0 mL) was added at ꢀ
78 °C. After addition was complete the reaction mixture was warmed to room temperature over 2
h. The reaction was then quenched with saturated aqueous NH4Cl and extracted with ethyl
acetate. After washing with water and brine, the solvent was dried over anhydrous Na2SO4. After
concentration, the crude product was subjected to the next reaction without further purification.
The crude residue of the selenenylated lactone was dissolved in CH2Cl2 (6 mL) and pyridine (1
mL) followed by H2O2 (1 mL, 30% w/w) were added. The mixture was then heated under reflux
for 10 min, diluted with Et2Oꢀwater and extracted with Et2O. After washing with 1 N HCl, water
and brine, the solvent was dried over anhydrous Na2SO4. After filtration and concentration in
vacuo, the resulting residue was purified by flash column chromatography (silica gel, 12%
EtOAc in hexane) to afford 3 (37 mg, 62% yield) as colorless liquid.
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Rf = 0.5 (silica gel, 30% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 6.06ꢀ6.00 (m, 1H),
5.49ꢀ5.43 (m, 1H), 4.17 (dd, J = 11.3, 4.0 Hz, 1H), 4.04 (dd, J = 11.4, 5.0 Hz, 1H), 3.18ꢀ3.09 (m,
1H), 2.15ꢀ2.06 (m, 1H), 1.98ꢀ1.78 (m, 3H), 1.48ꢀ1.36 (m, 1H), 1.29ꢀ1.15 (m, 1H), 1.07 (d, J =
13
6.3 Hz, 3H); C NMR (100 MHz, CDCl3) δ 169.4, 140.4, 124.6, 68.2, 45.3, 41.8, 36.8, 34.9,
33.9, 18.9; IR νmax (neat, cm–1) 3300, 2952, 2923, 1737, 1596, 1459, 1371, 1307, 1260, 1218,
1153, 1118, 1020, 910; HRMS (ESI) calcd for C10H14O2Na 189.0891 ([M + Na]+), found
189.0895; optical rotation [α]D20 +142.25 (c 0.65, benzene).
DIBAL-H reduction of 3 to its corresponding diol compound:
To a solution of 3 (30 mg, 0.18 mmol, 1.0 equiv) in CH2Cl2 (3 mL) was slowly added DIBALꢀH
(1.0 M solution in toluene, 0.6 mL) at ꢀ78 ºC. After being stirred for 2 h at 0 ºC, the reaction
mixture was quenched with slow addition of methanol and saturated aqueous Rochelle salt at 0
ºC. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with water, brine and dried over sodium sulfate, filtered,
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and concentrated in vacuo. The crude residue was purified by flash column chromatography
(silica gel, 40% EtOAc in hexane) to furnish the corresponding diol (29 mg, 95%).
Rf = 0.52 (silica gel, 80% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 5.18ꢀ5.15 (m, 1H),
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4.92 (s, 1H), 4.10 (s, 2H), 3.52ꢀ3.45 (m, 1H), 3.45ꢀ2.85 (m, 3H), 2.75ꢀ2.66 (m, 1H), 1.92ꢀ1.71
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(m, 3H), 1.68ꢀ1.52 (m, 2H), 1.16ꢀ1.08 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 150.3, 111.2, 68.1, 63.1, 51.6, 44.0, 37.2, 33.7, 30.9, 20.8; IR νmax (neat, cm–1) 3321,
2948, 2866, 1647, 1456, 1027, 897; HRMS (ESI) calcd for C10H18O2Na 193.1204 ([M + Na]+),
found 193.1210; optical rotation [α]D24.5 ꢀ5.43 (c 0.6, CCl4).
Preparation of Dolochodial (5):
To a solution of oxalyl chloride (38 µL, 0.44 mmol, 3.0 equiv) in dry CH2Cl2 (2 mL) at –78 °C,
DMSO (68 µL, 0.95 mmol, 6.5 equiv) was added slowly, in drop wise manner, with stirring
under nitrogen atmosphere. After 15 min stirring, previously prepared diol (25 mg, 0.147 mmol,
1.0 equiv) dissolved in dry CH2Cl2 (1 mL) was cannulated into the reaction mixture. After 15
min of stirring at –78 °C, Et3N (0.2 mL, 1.47 mmol, 10.0 equiv) was added and stirred for
another 30 min at –78 °C. Then the reaction mixture was warmed to 0 °C and quenched with
saturated aqueous NH4Cl solution and extracted with Et2O. The combined organic layers were
washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was
purified by flash column chromatography (silica gel, 10% EtOAc in hexane) to furnish
dolichodial 5 (18 mg, 74%).
Rf = 0.7 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 9.42 (d,
J = 2.6 Hz, 1H), 6.29 (d, J = 1.1 Hz, 1H), 6.13 (s, 1H), 3.35ꢀ3.26 (m, 1H), 2.82ꢀ2.74 (m, 1H),
2.51ꢀ2.38 (m, 1H), 2.11ꢀ2.01 (m, 1H), 1.94ꢀ1.85 (m, 1H), 1.78ꢀ1.66 (m, 1H), 1.32ꢀ1.23 (m, 1H),
1.09 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.4, 194.6, 149.8, 134.9, 60.1, 39.9,
34.4, 33.5, 30.1, 20.5; IR νmax (neat, cm–1) 2925, 2854, 1741, 1647, 1514, 1117, 1023; HRMS
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(ESI) calcd for C10H14O2Na: 189.0891 ([M + Na]+), found 189.0892; optical rotation [α]D
ꢀ
57.48 (c 0.27, CHCl3).
Preparation of 7-epi-boschnialactone (4):
General procedure outlined above for Cp2TiClꢀmediated radical cyclization was followed to
prepare 4. Scale of reaction 500 mg, 2.52 mmol; yield 318 mg as a white solid, 82% after
purification by flash column chromatography (15% EtOAc in hexane). Crude solid was
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crystallized in crystals suitable for Xꢀray crystallographic analysis from 5% EtOAc/hexane [m.p.
= 57.6–58.9 ºC (lit.15a 57ꢀ58 ºC), see ORTEP presentation, Figure S1].
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Rf = 0.4 (silica gel, 30% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 4.27 (dd, J = 11.5,
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4.3 Hz, 1H), 4.10 (dd, J = 11.5, 4.7 Hz, 1H), 2.66ꢀ2.54 (m, 2H), 2.38ꢀ2.30 (m, 1H), 2.05ꢀ1.97
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(m, 1H), 1.91ꢀ1.75 (m, 3H), 1.30ꢀ1.09 (m, 2H), 1.05 (d, J = 6.0 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 173.7, 68.9, 44.5, 37.4, 34.7 (2C), 34.5, 33.3, 18.6; IR νmax (neat, cm–1) 2952, 1747,
1456, 1383, 1246, 1167, 1076, 1045, 971; HRMS (ESI) calcd for C9H14O2Na: 177.0891 ([M +
Na]+), found 177.0892; optical rotation [α]D20 +92.66 (c 0.98, CCl4).
Formal synthesis of teucriumlactone (3) from 7-epi-boschnialactone (4):
NaH dispersion in mineral oil (60%, 260 mg, 6.5 mmol, 10 equiv), contained in a dry threeꢀ
necked flask to which an addition funnel, condenser, and mechanical stirrer were attached, was
washed three times with dry hexane and suspended in dry Et2O (9 mL) under N2 atmosphere. A
mixture of 4 (100 mg, 0.65 mmol) and ethyl formate (5 mL, dried over K2CO3 and distilled from
P2O5) was slowly added to the stirred suspension, immediately following the addition of absolute
ethanol (2.4 mL), at a rate that maintained a gentle reflux of the reaction solvent. After stirring
overnight, the reaction mixture was cooled to room temperature and the precipitated solids were
rapidly filtered by suction and the resulting solid material was washed well with dry Et2O and
dried in vacuo to give the sodium salt of αꢀformyl lactone as a light tan powder.
To a solution of the sodium salt of αꢀformyl lactone in dry THF (10 mL) was added a solution of
30% aq. HCHO (5.2 mL) and the resulting solution was refluxed for 18 h. After cooling, the
reaction mixture was quenched with 4 N HCl and extracted with Et2O. The combined organic
layers were washed with water, brine and dried over sodium sulfate, filtered, and concentrated in
vacuo. The crude residue was purified by flash column chromatography (silica gel, 12% EtOAc
in hexane) to furnish 3 (80 mg, 74%). The spectroscopic data were in full accord with the
previous one as well as with the literature report.
Formal synthesis of iridomyrmecin (1) from teucriumlactone (3):
To a solution of 3 (20 mg, 0.12 mmol, 1.0 equiv) in MeOH (3 mL) was added PtO2 (27 mg). The
reaction vessel was then evacuated and refilled with H2 (1 atmospheric pressure). The reaction
mixture was stirred overnight under hydrogen atmosphere and then filtered through a short pad
of Celite and further washed with MeOH. The combined organic extracts were concentrated in
vacuo to give the crude product, which was purified by flash column chromatography (silica gel,
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15% EtOAc in hexane) to furnish 3 (19 mg, quant.). The spectroscopic data were in full accord
with the previous one as well as with the literature report.
Formal synthesis of isoiridomyrmecin (2) from 7-epi-boschnialactone (4):
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A solution of 4 (30 mg, 0.19 mmol, 1.0 equiv) in dry THF (1.5 mL) was added dropwise using a
syringe at ꢀ78 °C under argon to a solution of LDA [prepared from diisopropylamine (44 µL,
0.31 mmol) and nꢀbutyllithium in hexane (0.17 mL of 1.7 M, 0.29 mmol)] in THF (1.5 mL) at ꢀ
78 °C and the mixture was stirred at the same temperature for 30 min. Methyl iodide (35 µL,
0.57 mmol, 3.0 equiv) was added and then stirred for 30 min at ꢀ78 °C, then allowed to warm to
room temperature over 2 h. The reaction was quenched by aqueous ammonium chloride and
extracted with Et2O. The organic layer was washed with water, brine, dried over Na2SO4 and
concentrated to leave an oil, which was submitted to preparative thin layer chromatography to
give 2 (21 mg, 67%)15. The spectroscopic data were in full accord with the previous one as well
as with the literature report.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
1
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Copies of H and C NMR spectra of products and Xꢀray crystallographic data (ORTEP) of 4
(PDF).
CIF data for 4 (CIF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: tushar@iisc.ac.in
Author Contributions
H.P.A.K and D.D contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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Authors gratefully acknowledge the financial support by SERB, New Delhi, India for JC Bose
Fellowship (T.K.C., SERB No.: SR/S2/JCBꢀ30/2007) and IISc, Bangalore for research
fellowship to H.P.A.K. The authors are also thankful to Department of Organic Chemistry, IISc
for providing the spectroscopic and analytical data.
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Org. Chem. 2013, 78, 7318ꢀ7323. (c) Pagnoni, U. M.; Pinetti, A.; Trave, R.; Garanti, L.
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