Synthesis of eunicellane-type bicycles embedding a 1,3-cyclohexadiene moiety

Article abstract of DOI:10.3762/bjoc.14.222

The first synthesis of diterpenoid eunicellane skeletons incorporating a 1,3-cyclohexadiene moiety is presented. Key step is a lowvalent titanium-induced pinacol cyclization that proved to be perfectly diastereoselective. Determination of the relative configuration of the diol was aided by the conversion to the diastereomer by oxidation and reduction. Conformational analysis of some of the resulting diols obtained under McMurry conditions was complicated by the presence of several conformers of similar energy. The pinacol coupling appears to start at the ketone, as indicated by the selective reduction of non-cyclizing cyclohexane systems that were synthesized from limonene oxide. The title compounds and their synthetic precursors are prone to aromatization on contact with air oxygen. Attempted synthesis of cyclohexene-containing eunicellane bicycles by elimination of water from tertiary alkynyl carbinols afforded novel allene systems. Our study may be of help towards the total synthesis of solenopodin or klysimplexin derivatives.

Full text of DOI:10.3762/bjoc.14.222

Synthesis of eunicellane-type bicycles embedding a
1,3-cyclohexadiene moiety
Alex Frichert1, Peter G. Jones2 and Thomas Lindel*1,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2461–2467.
1Institute of Organic Chemistry, TU Braunschweig, Hagenring 30,
38106 Braunschweig, Germany, Fax: (+49) 531-391-7744 and
2Institute of Inorganic and Analytical Chemistry, TU Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
doi:10.3762/bjoc.14.222
Received: 07 July 2018
Accepted: 05 September 2018
Published: 20 September 2018
Email:
Thomas Lindel* - th.lindel@tu-braunschweig.de
Associate Editor: J. S. Dickschat
* Corresponding author
© 2018 Frichert et al.; licensee Beilstein-Institut.
License and terms: see end of document.
§ http://www.oc.tu-bs.de/lindel
Keywords:
conformational analysis; low valent titanium; marine natural products;
pinacol coupling; ten-membered rings
Abstract
The first synthesis of diterpenoid eunicellane skeletons incorporating a 1,3-cyclohexadiene moiety is presented. Key step is a low-
valent titanium-induced pinacol cyclization that proved to be perfectly diastereoselective. Determination of the relative configura-
tion of the diol was aided by the conversion to the diastereomer by oxidation and reduction. Conformational analysis of some of the
resulting diols obtained under McMurry conditions was complicated by the presence of several conformers of similar energy. The
pinacol coupling appears to start at the ketone, as indicated by the selective reduction of non-cyclizing cyclohexane systems that
were synthesized from limonene oxide. The title compounds and their synthetic precursors are prone to aromatization on contact
with air oxygen. Attempted synthesis of cyclohexene-containing eunicellane bicycles by elimination of water from tertiary alkynyl
carbinols afforded novel allene systems. Our study may be of help towards the total synthesis of solenopodin or klysimplexin deriv-
atives.
Introduction
Eunicellane-type diterpenoids share an [8.4.0] bicyclic skeleton and R (3, klysimplexin R) [3] from Eunicella labiata, cladieuni-
(1, Figure 1). In many cases, an additional oxygen bridge is celline F from Cladiella sp. [4] and eunicellol A (4) from the
present between positions 4 and 7, or 2 and 9, but there are also soft coral Gersemia fruticose [5]. Magdalenic acid (5) was iso-
interesting eunicellanes without oxygen bridge, the majority of lated from the plant Vellozia magdalenae [6]. Recently, prehy-
which has been isolated from marine corals. These comprise the dropyrene (6) was discovered as biosynthetic intermediate
solenopodins A–D (2, solenopodin D) from Solenopodium towards the diterpene hydropyrene from the Gram-positive
stechei [1], an unnamed eunicellane [2] and the klysimplexins Q bacterium Streptomyces clavuligerus [7]. The six- and ten-
2461

Beilstein J. Org. Chem. 2018, 14, 2461–2467.
membered rings of eunicellane diterpenoids can be either cis or of the benzene moiety. Systems embedding a cyclohexadiene
trans fused, and the ten-membered ring may contain (Z)- or (E)- ring should be more versatile, e.g., by allowing regio- and
double bonds. None of them has been synthesized.
stereoselective hydrogenation and oxygenation towards partial
structures present in compounds 2–6. In addition, we expected
that the higher hydrogen count and the non-planarity of the
envisaged 1,3-cyclohexadiene ring would allow the determina-
tion of the diastereoselectivity of the coupling step more
precisely than in the case of aromatic 8 that exists as mixture of
two conformers in CDCl3.
Thus, it was to be explored how open-ring cyclohexadiene pre-
cursors would be synthesized and behave under McMurry
conditions, and how stable the resulting [8.4.0]bicycles would
be. Normally, McMurry conditions lead to the formation of
alkenes, but medium-sized ring 1,2-diols have also been ob-
tained (TiCl4/Zn [12-17] or TiCl3/Zn-Cu [18-20]), often as mix-
ture of diastereomers. The use of samarium diiodide to achieve
the pinacol coupling was not advised, since we had observed
that intially formed ketyl radicals would add to the alkyne
moiety [11], even if there are examples, where this was not the
case [21,22]. Access to partially unsaturated eunicellane
systems could also be of interest for studies on biosynthesis and
chemical interconversion [7,10].
Results and Discussion
Dihydrocarvone 9 was converted to the enolate and quenched
with ethyl cyanoformate in the presence of DMPU affording an
inconsequential 5.6:1 mixture of diastereomers favoring 10
(3J3H-4H 12.2 Hz vs 4.8 Hz, Scheme 1). The cyclohexadiene
Figure 1: Bicyclic eunicellane-type diterpenes.
A series of eunicellane-type bicycles containing a cyclohexene system of 11 was formed after deprotonation of 10 (LiHMDS)
partial structure served as intermediates of the total syntheses of and quenching with triflic anhydride. All compounds carrying
the sarcodictyins, the eleuthesides, and of eleutherobin [8,9]. the 1,3-cyclohexadiene motif were prone to aromatization and
The benzene-containing eunicellane derivative 7 (Figure 2) was had to be protected from contact with air and higher tempera-
obtained synthetically starting from the cembranoid sarcophy- tures. Removal of solvents was performed below 21 °C and all
toxide from the soft coral Sarcophytum glaucum [10].
compounds were stored under argon at −18 °C. Sonogashira
coupling (PdCl2(PPh3)2) of dienol triflate 11 with alkyne 12
[11] provided C20 ester 13 in a good yield of 86%. However,
after hydrolysis of the 1,3-dioxolane moiety to ketoester 14 it
proved to be impossible to induce any McMurry cyclization in-
volving the two carbonyl groups of the system. Only starting
material was isolated. We had hoped that the ester might partic-
ipate in the cyclization, since there is precedence of accessing
medium-sized ring ethyl vinyl ethers when employing TiCl3/
LiAlH4/NEt3 in DME instead of TiCl4/Zn/pyridine [23].
Figure 2: Synthetic eunicellane-type compounds with benzene partial
structure.
Direct reduction of ester 14 to the aldehyde proved to be sur-
prisingly difficult with either DIBAL-H or LiAlH4, when the
We have shown that eunicellane 8 containing a benzene partial alkynyl side chain was in place. Thus, we reduced the ester
structure can be accessed efficiently via pinacol cyclization of a function of dienol triflate 11 to the alcohol (DIBAL-H, DCM,
ketoaldehyde precursor [11]. However, compound 8 proved to −78 °C), followed by oxidation to aldehyde 15 (IBX,
be very resistant towards any attempt of partial hydrogenation Scheme 2). Fortunately, the cyclohexadiene moiety survived the
2462

Beilstein J. Org. Chem. 2018, 14, 2461–2467.
Scheme 1: Access to ketoester 14 that did not cyclize to the ethyl vinyl ether under McMurry conditions.
oxidation conditions, which was not the case when using PCC
or MnO2. Subsequent Sonogashira coupling to 16 and deprotec-
tion to 17 worked satisfyingly. As in the case of a benzene
partial structure (8), it was a diol that was formed from 17 under
McMurry conditions (20 equiv TiCl4, 40 equiv Zn, THF, rt). No
alkene was detected.
McMurry-type pinacol cyclizations have shown varying degrees
of diastereoselectivity, which means that every single example
has to be explored independently. The assignment of the config-
uration and preferred conformation of product 18 was con-
ducted on the basis of NOESY NMR experiments. Our analysis
was aided by the observation that the 2-epimer 19 was acces-
sible by oxidation of 18 to the acyloin (IBX, MeCN) and subse-
quent reduction (LiAlH4, THF, Scheme 2). Diastereomers 18
and 19 show distinct sets of NMR signals. The largest chemical
shift differences are observed for the secondary carbinol group
(δ2-H 5.18, δC2 73.1 for 18 vs δ2-H 4.14, δC2 87.2 for 19). For
diol 18, we observed key NOESY correlations between carbinol
2-H (δ 5.18) and one of the C5 methylene hydrogens (δ 2.37)
and between 14-H (δ 2.43) and 3-CH3 (δ 1.20, Figure 3). For
each of the four diastereomers with 14R configuration we found
one conformation (MM2) placing 2-H and one 5-H in prox-
imity. Moreover, those conformations are within 10 kJ/mol
range of each other. However, only one of those conformations
shows the required short distance between 14-H and 3-CH3,
making the configuration (2R,3S,14R) probable for diastereo-
mer 18. In the preferred conformation of 18, all non-sp3-
Scheme 2: Synthesis of the 1,3-cyclohexadiene-containing eunicel-
lane-type [8.4.0]bicycle 18 by McMurry coupling to the diol, followed by
two-step epimerization at C2.
2463

Beilstein J. Org. Chem. 2018, 14, 2461–2467.
hybridized carbon atoms of the ring system and the adjacent coupling constant proved that the isopropyl and ethoxycarbonyl
atoms are located almost in plane, whereas the isopropyl group groups both assume an equatorial position in a chair conforma-
and ring carbons C3 and C4 are located on opposite sides of that tion.
plane. Since the oxidation/reduction sequence has affected the
configuration at C2, diastereomer 19 is assigned the configura- We were not able to obtain an X-ray analysis of cyanohydrin
tion (2S,3S,14R). For diastereomer 19, 2-H did not show a 22, but of one diastereomer (30) of an analog where the OTBS
NOESY correlation to 5-Hβ, but instead a correlation to 14-H, was replaced by a methoxy group (Scheme 4, obtained by
to the isopropyl methine hydrogen, and to 3-CH3. In addition, ethoxycarbonylation of 28) [25]. In agreement with the NMR
3-CH3 correlates with both methylene hydrogens at C4. We data, cyanohydrin 30 adopts a chair conformation in the crystal.
found only two conformers of the (2S,3S,14R) diastereomer that The 1H NMR spectra of diastereomers 29 and 30 differ charac-
meet those constraints. One of them is shown in Figure 3.
teristically regarding the chemical shift of the hydroxy proton
which appeared as a sharp signal at 5.25 ppm (CDCl3) for 29
and as a broad peak at 3.00 ppm for 30. This can be explained
by the presence of an intramolecular hydrogen bond that is
possible only in the case of 29. Since the 1H NMR spectrum of
cyanohydrin 22 exhibits a sharp hydroxy peak at 5.29 ppm, we
derive the relative configuration shown in Scheme 4.
From cyanohydrin 22 HCN was eliminated by treatment with
diluted NaOH (100%, Scheme 3). The resulting ketone 23
reacted with lithiated alkyne 12 affording diastereomerically
pure tertiary alcohol 24 (63%) that showed a broad hydroxy
signal in the 1H NMR spectrum at 2.61 ppm. This indicates that
the alkynyl side chain had been introduced from the same side
as the ethoxycarbonyl group. By conversion of the ester to an
aldehyde group and deprotection we obtained the subject of
study, the putative cyclization precursor 25 (71%). In an
orienting reaction, treatment of 25 with TiCl4/Zn did not lead to
pinacol cyclization and we have evidence that the aldehyde
group stayed in place and the keto group had been reduced.
Installation of a TMS group at the tertiary alcohol moiety of 25
(TMSOTf, 2,6-lutidine) formed 26, which was simply reduced
at the keto function on reaction with TiCl4/Zn/pyridine (27,
Scheme 3) without cyclization. As before, the aldehyde had
stayed in place. Interestingly, treatment of 25 with samarium
diiodide afforded the primary alcohol and left the keto group
unchanged. Still, no cyclization took place.
Figure 3: Preferred conformations of diastereomeric diols 18 and 19
including decisive NOESY correlations.
One could think that endocyclic elimination of water from 24 to
the α,β-unsaturated ester would afford a cyclohexene system
that would regain the ability of undergoing pinacol cyclization,
The transfer of the pinacol McMurry route to the formation of because the bridge of the [8.4.0] system would become a double
eunicellane-type bicycles with two sp3 centers as bridgeheads bond. However, standard protocols (MsCl/Et3N or p-TsOH)
will not be straight-forward. This became clear on our attempts failed. We also synthesized the (E)-isomer of 24, compound 31,
to cyclize model compound 25 that was synthesized within nine via Sonogashira coupling with the (E)-isomer [11] of 12. Chlo-
steps (Scheme 3). For the synthesis of 25, we started from the rinated allene 32 was formed from 31 as the only product on
known limonene oxide-derived diol 20 [24] that was hydro- treatment with SOCl2/pyridine, presumably after chlorosulfona-
genated, oxidized, and silylated at the tertiary alcohol moiety tion, followed by chlorine transfer and loss of SO2 (Scheme 5).
(81%). Reaction of deprotonated 21 with ethyl cyanoformate There is precedence that elimination towards the cyclohexene
afforded cyanohydrin 22 by attack of liberated cyanide at the can be a competing process [26]. The configuration of the
carbonyl carbon following the ethoxycarbonylation. The 3JHH allene moieties could not be elucidated.
2464

Beilstein J. Org. Chem. 2018, 14, 2461–2467.
Scheme 3: Assembly of the envisaged cyclization precursor 27.
Interestingly, treatment of 31 with Tf2O/pyridine afforded 4-substituted N-triflyldihydropyridine derivatives on reaction of
allenyl triflone 34, with 13C NMR signals of the allene center pyridine (4 equiv) with Tf2O (1.5 equiv) in the presence of aryl
and the triflyl-substituted carbon at δ 203.7 and 113.5 ppm, re- nucleophiles that occurred already at −30 °C within 30 min.
spectively. The sequence probably commences with pyridine- Conversion to the corresponding pyridine derivatives was
assisted conversion of propargylic alcohol 31 to the propargyl possible on treatment with KOt-Bu at −23 °C, presumably with
triflate, which looses triflate, forming propargyl cation 33. formation of potassium triflinate [27]. In our case, pyridine was
Since a triflone is formed rather than a triflate, reduction of the used as solvent and the reaction mixture was heated up to
incoming nucleophile must have taken place, probably before 70 °C. This could allow pyridine itself taking the double role of
incorporation. Corey and Tian reported the formation of nucleophile and base, leading to the formation of pyridinium
2465

Beilstein J. Org. Chem. 2018, 14, 2461–2467.
phile at the cyclohexane carbon, followed by [2,3]-sigmatropic
rearrangement [31].
Conclusion
With the synthesis of the [8.4.0]bicycles 18 and 19 that contain
a 1,3-cyclohexadiene partial structure, we have made progress
towards the synthesis of a small group of bicyclic diterpenoids
sharing the eunicellane skeleton. Closure of the ten-membered
ring by pinacol cyclization proved to be possible, if the six-
membered ring is either aromatic or a 1,3-cyclohexadiene, but
failed for systems with two sp3 centers as bridgeheads. The ten-
membered ring of benzene-containing 8 adopts two distinct
major conformations in CDCl3, whereas diastereomeric diols 18
and 19 prefer only one, which were elucidated by NOESY spec-
troscopy. In upcoming studies we will address the synthesis of
systems that contain a cyclohexene ring keeping the sp2–sp2
bridge of the product from the beginning, and of precursors in
which one of the centers will be sp2- and the other sp3-
hybridized. Examples of the latter have already been obtained in
form of allenes 32 and 34 that will now have to be elaborated
further.
Scheme 4: Structure analysis of diastereomeric cyanohydrins 29 and
30.
Supporting Information
Supporting Information File 1
Experimental procedures, spectroscopical data, X-ray
analysis of 30, and NMR spectra plots.
triflinate. It has also been reported that the triflinate anion can
be generated from 2,6-lutidine/Tf2O [28] or Et3N/Tf2O [29].
Allenyl triflone 34 could be formed by attack of triflinate as
S-nucleophile [30] at the chain carbon of propargyl cation 33.
An alternative would be the attack of triflinate as O-nucleo-
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-222-S1.pdf]
Scheme 5: Formation of allenes 32 and 34 from sterically crowded propargylic alcohol 31.
2466

Beilstein J. Org. Chem. 2018, 14, 2461–2467.
19.Ferri, F.; Brückner, R.; Herges, R. New J. Chem. 1998, 22, 531–546.
doi:10.1039/a709205i
Acknowledgements
We thank Merck KGaA (Darmstadt, Germany) for chromatog-
raphy materials. BASF Group (Ludwigshafen, Germany) and
Honeywell Specialty Chemicals Seelze GmbH (Seelze,
Germany) are thanked for the donation of solvents.
20.Williams, D. R.; Heidebrecht, R. W. J. Am. Chem. Soc. 2003, 125,
1843–1850. doi:10.1021/ja0279803
21.Nicolaou, K. C.; Sorensen, E. J.; Discordia, R.; Hwang, C.-K.;
Minto, R. E.; Bharucha, K. N.; Bergman, R. G. Angew. Chem. 1992,
104, 1094–1096. doi:10.1002/ange.19921040838
22.Comanita, B. M.; Heuft, M. A.; Rietveld, T.; Fallis, A. G. Isr. J. Chem.
2000, 40, 241–253. doi:10.1560/7j4f-d8bg-3fqr-e3td
23.McMurry, J. E.; Miller, D. D. J. Am. Chem. Soc. 1983, 105, 1660–1661.
doi:10.1021/ja00344a045
ORCID® iDs
Thomas Lindel - https://orcid.org/0000-0002-7551-5266
References
24.Blair, M.; Andrews, P. C.; Fraser, B. H.; Forsyth, C. M.; Junk, P. C.;
Massi, M.; Tuck, K. L. Synthesis 2007, 1523–1527.
doi:10.1055/s-2007-966033
1. Bloor, S. J.; Schmitz, F. J.; Hossain, M. B.; Van der Helm, D.
J. Org. Chem. 1992, 57, 1205–1216. doi:10.1021/jo00030a031
2. Ortega, M. J.; Zubía, E.; Salvá, J. J. Nat. Prod. 1997, 60, 485–487.
doi:10.1021/np970026c
25.Crystallographic Data Centre as supplementary publications no.
CCDC-1853640. Copies of the data can be obtained free of charge
from http://www.ccdc.cam.ac.uk/data_request/cif.
26.Masters, K.-S.; Flynn, B. L. J. Org. Chem. 2008, 73, 8081–8084.
doi:10.1021/jo800682n
3. Chen, B.-W.; Chao, C.-H.; Su, J.-H.; Tsai, C.-W.; Wang, W.-H.;
Wen, Z.-H.; Huang, C.-Y.; Sung, P.-J.; Wu, Y.-C.; Sheu, J.-H.
Org. Biomol. Chem. 2011, 9, 834–844. doi:10.1039/c0ob00351d
4. Chen, Y.-H.; Tai, C.-Y.; Su, Y.-D.; Chang, Y.-C.; Lu, M.-C.;
Weng, C.-F.; Su, J.-H.; Hwang, T.-L.; Wu, Y.-C.; Sung, P.-J.
Mar. Drugs 2011, 9, 934–943. doi:10.3390/md9060934
5. Angulo-Preckler, C.; Genta-Jouve, G.; Mahajan, N.; de la Cruz, M.;
de Pedro, N.; Reyes, F.; Iken, K.; Avila, C.; Thomas, O. P. J. Nat. Prod.
2016, 79, 1132–1136. doi:10.1021/acs.jnatprod.6b00040
6. Pinto, A. C.; Pizzolatti, M. G.; de A. Epifanio, R.; Frankmölle, W.;
Fenical, W. Tetrahedron 1997, 53, 2005–2012.
27.Corey, E. J.; Tian, Y. Org. Lett. 2005, 7, 5535–5537.
doi:10.1021/ol052476z
28.Ambrose, M. G.; Binkley, R. W. J. Org. Chem. 1983, 48, 674–677.
doi:10.1021/jo00153a011
29.Netscher, T.; Bohrer, P. Tetrahedron Lett. 1996, 37, 8359–8362.
doi:10.1016/0040-4039(96)01930-2
30.Hendrickson, J. B.; Giga, A.; Wareing, J. J. Am. Chem. Soc. 1974, 96,
2275–2276. doi:10.1021/ja00814a061
doi:10.1016/s0040-4020(96)01183-0
31.Braverman, S.; Pechenick, T.; Zafrani, Y. Tetrahedron Lett. 2001, 42,
1391–1393. doi:10.1016/s0040-4039(00)02255-3
7. Rinkel, J.; Rabe, P.; Chen, X.; Köllner, T. G.; Chen, F.; Dickschat, J. S.
Chem. – Eur. J. 2017, 23, 10501–10505. doi:10.1002/chem.201702704
8. Nicolaou, K. C.; Ohshima, T.; Hosokawa, S.; van Delft, F. L.;
Vourloumis, D.; Xu, J. Y.; Pfefferkorn, J.; Kim, S. J. Am. Chem. Soc.
1998, 120, 8674–8680. doi:10.1021/ja9810639
License and Terms
9. Castoldi, D.; Caggiano, L.; Panigada, L.; Sharon, O.; Costa, A. M.;
Gennari, C. Angew. Chem. 2005, 117, 594–597.
This is an Open Access article under the terms of the
Creative Commons Attribution License
doi:10.1002/ange.200461767
Angew. Chem., Int. Ed. 2005, 44, 588–591.
(http://creativecommons.org/licenses/by/4.0). Please note
that the reuse, redistribution and reproduction in particular
requires that the authors and source are credited.
doi:10.1002/anie.200461767
10.Nii, K.; Tagami, K.; Matsuoka, K.; Munakata, T.; Ooi, T.; Kusumi, T.
Org. Lett. 2006, 8, 2957–2960. doi:10.1021/ol0608404
11.Al Batal, M.; Jones, P. G.; Lindel, T. Eur. J. Org. Chem. 2013,
2533–2536. doi:10.1002/ejoc.201300178
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
12.Kato, N.; Kataoka, H.; Ohbuchi, S.; Tanaka, S.; Takeshita, H.
J. Chem. Soc., Chem. Commun. 1988, 354–356.
(https://www.beilstein-journals.org/bjoc)
doi:10.1039/c39880000354
13.Swindell, C. S.; Fan, W. J. Org. Chem. 1996, 61, 1109–1118.
doi:10.1021/jo9519367
The definitive version of this article is the electronic one
which can be found at:
14.Yamato, T.; Fujita, K.; Okuyama, K.-i.; Tsuzuki, H. New J. Chem. 2000,
24, 221–228. doi:10.1039/b001145m
doi:10.3762/bjoc.14.222
15.Sergeeva, E. V.; Rozenberg, V. I.; Antonov, D. Y.; Vorontsov, E. V.;
Starikova, Z. A.; Fedyanin, I. V.; Hopf, H. Chem. – Eur. J. 2005, 11,
6944–6961. doi:10.1002/chem.200500413
16.Saisyo, T.; Shiino, M.; Shimizu, T.; Paudel, A.; Yamato, T.
J. Chem. Res. 2008, 479–483. doi:10.3184/030823408x338701
17.Castagnolo, D.; Contemori, L.; Maccari, G.; Avramova, S. I.; Neri, A.;
Sgaragli, G.; Botta, M. ACS Med. Chem. Lett. 2010, 1, 416–421.
doi:10.1021/ml100118k
18.Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Nantermet, P. G.; Claiborne, C. F.;
Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. Soc. 1995, 117,
645–652. doi:10.1021/ja00107a008
2467