Synthesis of the guaianolide ring system via cycloaddition of a bicyclic carbonyl ylide with allyl propiolate

Article abstract of DOI:10.1021/ol1012185

(Equation Presented). A cyclic carbonyl ylide with a trans-annulated cyclopentane ring was generated by a Rh₂(OAc)₄-catalyzed reaction from a diazoketone precursor and trapped with allyl propiolate. The 1,3-dipolar cycloaddition led to the stereoselective formation of an oxygen-bridged polycycle. Via Curtius degradation, the cycloadduct was transformed to the ring skeleton typical of the sesquiterpene family of guaianolides.

Full text of DOI:10.1021/ol1012185

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3418-3421
Synthesis of the Guaianolide Ring
System via Cycloaddition of a Bicyclic
Carbonyl Ylide with Allyl Propiolate
Vaidotas Navickas,† Dmitry B. Ushakov,† Martin E. Maier,*,† Markus Stro¨bele,‡
and H.-Ju¨rgen Meyer‡
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen, Auf der Morgenstelle 18,
72076 Tu¨bingen, and Abteilung fu¨r Festko¨rperchemie und Theoretische Anorganische
Chemie, Institut fu¨r Anorganische Chemie, UniVersita¨t Tu¨bingen, Ob dem Himmelreich 7,
72074 Tu¨bingen
martin.e.maier@uni-tuebingen.de
Received May 26, 2010
ABSTRACT
A cyclic carbonyl ylide with a trans-annulated cyclopentane ring was generated by a Rh2(OAc)4-catalyzed reaction from a diazoketone
precursor and trapped with allyl propiolate. The 1,3-dipolar cycloaddition led to the stereoselective formation of an oxygen-bridged
polycycle. Via Curtius degradation, the cycloadduct was transformed to the ring skeleton typical of the sesquiterpene family of guaianolides.
Terpenes represent one of the largest groups of natural
products. These secondary metabolites can be divided into
subgroups based on the number of isoprenoid units.1 A
large subgroup is sesquiterpenes which originate from
farnesyl diphosphate.2 Among various ring systems that
result from this precursor, the perhydroazulene skeleton,
which is characterized by fused five- and seven-membered
rings, is quite common. The core structures might differ
in the oxidation level and the relative stereochemistry at
the ring fusion. Some of these guaiane-type terpenes
feature an oxygen bridge in the seven-membered ring
(Figure 1).3
A recent addition to oxygen-bridged guaianes are the
englerins (6-8), sesquiterpenes that were isolated from the
Figure 1. Examples for oxo-bridged guaiane-type natural products.
plant extract of Phyllanthus engleri (Figure 2).4 Besides
the structural features, the biological activity, for example
† Institut fu¨r Organische Chemie.
of englerin A (6), is remarkable in that it turned out to be
highly selective and potent against various cell lines that are
involved in renal cancer. Accordingly, englerin A (6) became
a prominent target for total synthesis. In the original
‡ Institut fu¨r Anorganische Chemie.
(1) Breitmaier, E. Terpene, 2nd ed.; Wiley-VCH: Weinheim, 2005; ISBN
3527314989.
(2) Cane, D. E. Chem. ReV. 1990, 90, 1089–1103.
10.1021/ol1012185  2010 American Chemical Society
Published on Web 06/29/2010

Scheme 1. Retrosynthetic Plan for Construction of
Oxygen-Bridged Guaianolides Based on a Carbonyl
Ylide-Alkyne 1,3-Dipolar Cycloaddition
Figure 2. Correct structure of (-)-englerin A (6).
publication,4 the absolute stereochemistry was not known,
and the enantiomer of 6 was depicted. This issue could be
clarified in nice work by the group of M. Christmann.5 They
prepared ent-6 [(+)-englerin A] from cis,trans-nepetalactone,
a terpene which can be obtained by distillation of com-
mercially available catnip. Quite recently, two conceptually
similar total syntheses for (-)-englerin A appeared.6,7 In both
cases, the tricyclic ring system was fashioned by gold(I)-
catalyzed cyclization of an enyneketone.8 In addition, the
Nicolaou/Chen group achieved the synthesis of englerin A
via a [5 + 2] cycloaddition to create the [3.2.1]oxabicyclic
ring system followed by annulation of the cyclopentane ring.9
In planning a synthesis for oxygen-bridged guaianolides,10
like englerin A, the stereochemistry at the fusion bond needs
to be considered. This issue might be addressed by epimer-
ization en route to the target skeleton.11 Besides five- or
seven-membered rings, natural products, like (+)-aroma-
dendrene12 or other easily available precursors13 with a
guaianolide structure, might serve as starting materials. The
key feature of our retrosynthesis is a bimolecular carbonyl
ylide-alkyne cycloaddition reaction (Scheme 1).14,15 The
advantage of this strategy is the simultaneous formation of
the oxygen bridge in the course of the cycloaddition. Thus,
after appropriate functional group interconversions, carbonyl
ylide 11 would be combined with a propiolate 12. The
intermediate carbonyl ylide should be available by rhod-
ium(II)-catalyzed decomposition of diazoketoester 13. The
latter can be traced back to (R)-(-)-carvone (14). The
hydroxyl group at C9 would be generated from the carboxylic
acid azide. The expectation was that the dipolarophile would
approach the carbonyl ylide 11 opposite to the C4 methyl
group.
The results of this strategy are described below (Scheme
2). Starting from commercially available (R)-(-)-carvone
(14), the highly substituted cyclopentane 16 (Scheme 2) was
prepared utilizing a five- step sequence that relies on epox-
idation of the enone, regioselective epoxide opening, and a
Favorskii rearrangement resulting in ring contraction to a
cyclopentanecarboxylate.16,17 Removal of the THP protecting
group gave alcohol 16 on a multigram scale. The hydroxyl
(3) (a) Orientalol, F.; Peng, G.-P.; Tian, G.; Huang, X.-F.; Lou, F.-C.
Phytochemistry 2003, 63, 877–881. (b) Pubinernoid, B.; Huang, S.-X.; Yang,
J.; Xiao, W.-L.; Zhu, Y.-L.; Li, R.-T.; Li, L.-M.; Pu, J.-X.; Li, X.; Li, S.-
H.; Sun, H.-D. HelV. Chim. Acta 2006, 89, 1169–1175. (c) 3: Sutthivaiyakit,
S.; Nakorn, N. N.; Kraus, W.; Sutthivaiyakit, P. Tetrahedron 2003, 59,
9991–9995. (d) 4: Stierle, A. A.; Stierle, D. B.; Goldstein, E.; Parker, K.;
Bugni, T.; Baarson, C.; Gress, J.; Blake, D. J. Nat. Prod. 2003, 66, 1097–
1100. (e) 5: Wang, H.-X.; Liu, C.-M.; Liu, Q.; Gao, K. Phytochemistry
2008, 69, 2088–2094.
(14) For reviews, see: (a) Padwa, A.; Weingarten, M. D. Chem. ReV.
1996, 96, 223–270. (b) Padwa, A. HelV. Chim. Acta 2005, 88, 1357–1374.
(c) Singh, V.; Krishna, U. M.; Vikrant; Trivedi, G. K. Tetrahedron 2008,
64, 3405–3428. (d) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577–6605.
(e) Muthusamy, S.; Krishnamurthi, J. Top. Heterocycl. Chem. 2008, 12,
147–192.
(4) Ratnayake, R.; Covell, D.; Ransom, T. T.; Gustafson, K. R.; Beutler,
J. A. Org. Lett. 2009, 11, 57–60.
(15) For representative bimolecular examples, see: (a) Pirrung, M. C.;
Lee, Y. R. Tetrahedron Lett. 1994, 35, 6231–6234. (b) Hodgson, D. M.;
Bailey, J. M.; Villalonga-Barber, C.; Drew, M. G. B.; Harrison, T. J. Chem.
Soc., Perkin Trans. 1 2000, 3432–3443. (c) Wood, J. L.; Thompson, B. D.;
Yusuff, N.; Pflum, D. A.; Mattha¨us, M. S. P. J. Am. Chem. Soc. 2001, 123,
2097–2098. (d) Nakamura, S.; Hirata, Y.; Kurosaki, T.; Anada, M.; Kataoka,
O.; Kitagaki, S.; Hashimoto, S. Angew. Chem., Int. Ed. 2003, 42, 5351–
5355. (e) Nakamura, S.; Sugano, Y.; Kikuchi, F.; Hashimoto, S. Angew.
Chem., Int. Ed. 2006, 45, 6532–6535. (f) Hirata, Y.; Nakamura, S.;
Watanabe, N.; Kataoka, O.; Kurosaki, T.; Anada, M.; Kitagaki, S.; Shiro,
M.; Hashimoto, S. Chem.sEur. J. 2006, 12, 8898–8925. (g) Snider, B. B.;
Wu, X.; Nakamura, S.; Hashimoto, S. Org. Lett. 2007, 9, 873–874. (h)
Kim, C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew. Chem.,
Int. Ed. 2008, 47, 4009–4011. (i) Shimada, N.; Anada, M.; Nakamura, S.;
Nambu, H.; Tsutsui, H.; Hashimoto, S. Org. Lett. 2008, 10, 3603–3606. (j)
Suga, H.; Higuchi, S.; Ohtsuka, M.; Ishimoto, D.; Arikawa, T.; Hashimoto,
Y.; Misawa, S.; Tsuchida, T.; Kakehi, A.; Baba, T. Tetrahedron 2010, 66,
3070–3089.
(5) Willot, M.; Radtke, L.; Ko¨nning, D.; Fro¨hlich, R.; Gessner, V. H.;
Strohmann, C.; Christmann, M. Angew. Chem., Int. Ed. 2009, 48, 9105–
9108.
(6) Zhou, Q.; Chen, X.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 3513–
3516
.
(7) Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chem., Int.
Ed. 2010, 49, 3517–3519
.
(8) Jimenez-Nunez, E.; Molawi, K.; Echavarren, A. M. Chem. Commun.
2009, 7327–7329.
(9) Nicolaou, K. C.; Kang, Q.; Ng, S. Y.; Chen, D. Y.-K. J. Am. Chem.
Soc. 2010, 132, 8219–8222.
(10) For reviews, see: (a) Schall, A.; Reiser, O. Eur. J. Org. Chem.
2008, 2353–2364. (b) Foley, D. A.; Maguire, A. R. Tetrahedron 2010, 66,
1131–1175.
(11) See, for example: Lange, G. L.; Gottardo, C.; Merica, A. J. Org.
Chem. 1999, 64, 6738–6744.
(12) Gijsen, H. J. M.; Kanai, K.; Stork, G. A.; Wijnberg, J. B. P. A.;
Orru, R. V. A.; Seelen, C. G. J. M.; Van der Kerk, S. M.; De Groot, A.
Tetrahedron 1990, 46, 7237–7246.
(16) Lee, E.; Lim, J. W.; Yoon, C. H.; Sung, Y.-s.; Kim, Y. K. J. Am.
Chem. Soc. 1997, 119, 8391–8392
(17) Andrews, S. P.; Ball, M.; Wierschem, F.; Cleator, E.; Oliver, S.;
Ho¨genauer, K.; Simic, O.; Antonello, A.; Hu¨nger, U.; Smith, M. D.; Ley,
.
(13) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem. Soc. 2006,
128, 6931–6937.
S. V. Chem.sEur. J. 2007, 13, 5688–5712
.
Org. Lett., Vol. 12, No. 15, 2010
3419

Scheme 2
.
Synthesis of Diazoketone 22 from (R)-(-)-Carvone
Scheme 3. Rh2(OAc)4-Catalyzed Carbonyl Ylide Formation and
Subsequent 1,3-Dipolar Cycloaddition with Allyl Propiolate
for 15 min led to the formation of cycloaddition product 24
as a single isomer. Lower temperatures and longer reaction
times gave inferior results [80 °C, 1 h (80%); 60 °C, 12 h
(50%)]. The cycloadduct 24 turned out to be sensitive to
epimerization, for example, upon silica gel chromatography,
leading exclusively to the corresponding cis-isomer. There-
fore, crude ketodiester 24 was selectively reduced with
NaBH4 and the resulting alcohol converted to TES-ether 25
in 59% over three steps. At this stage we were not able to
unambiguously determine the stereochemistry of the newly
formed centers. This could be clarified at a later stage (vide
infra).
Further functionalization of the seven-membered ring
called for degradation of the acrylate to a keto function. This
could be achieved via a classical Curtius rearrangement/
hydrolysis sequence (Scheme 4).22 It was found that the allyl
ester could be easily cleaved using 10 mol % of RhCl(PPh3)3
in an ethanol/water mixture at 100 °C in 84% yield.23 In
contrast, palladium-based methods failed to provide car-
boxylic acid 26. Now, acid 26 was converted to azide 27 by
reaction with NaN3 in the presence of trichloracetonitrile and
PPh3.24 Upon heating, azide 27 rearranged to the vinyl
isocyanate which under acidic conditions was selectively
hydrolyzed to ketone 28. It should be noted that under these
conditions [HCl (5%), THF, rt] no deprotection of the TES
group was observed. Subsequent reduction with NaBH4
provided alcohol 29 as a single isomer. At this stage, key
NOESY cross peaks between 1-H/8-H, 4-H/5-H, and 5-H/
6-H (guaianolide numbering) suggested a structure of 29
where the oxygen bridge is on the opposite site with respect
to the C4 methyl group (Scheme 4). Nevertheless, we
continued with further functional group manipulations that
would allow for either a chemical correlation with a known
compound or an X-ray structure. Silyl protection to bis-silyl
ether 30 served as an entry point for further synthetic
modifications which aimed at conversion of the ester to an
isopropyl group. Accordingly, addition of freshly prepared
MeMgI (6 equiv) to ester 30 at 0 °C gave tertiary alcohol
31 in quantitative yield. While a radical deoxygenation did
group was then removed yielding ester 17 using the
Barton-McCombie protocol18 on the corresponding xan-
thogenate. At this stage, we tried epimerization at C5
(guaiane numbering); however, this was not successful with
several bases (DBU, iPr2EtN, LDA, Et3N). Therefore, the
ester was reduced to the alcohol which was then converted
to aldehyde 18 by Parikh-Doering oxidation19 on a 25 g
scale (87%). Base-induced epimerization of aldehyde 18 was
achieved with DBU in refluxing toluene leading to trans
orientation of the aldehyde group with respect to the larger
isopropenyl group (trans/cis ) 2:1). Subsequent ozonolysis
of aldehyde 19 and reaction with ethyl diazoacetate, catalyzed
by tin(II) chloride,20 provided ꢀ-ketoester 20 as a single
isomer in 66% over two steps (the other diastereomer was
not detected). Finally, a diazotransfer reaction with sulfonyl
azide21 21 furnished diazoketone 22. This sequence allowed
us to prepare gram quantities of diazo ꢀ-ketoester 22 starting
from (R)-(-)-carvone.
With diazoketone 22 in hand, we studied the intramolecu-
lar carbonyl ylide formation promoted by Rh2(OAc)4 and
its subsequent cycloaddition (Scheme 3). We decided to use
allyl propiolate (23) as a dipolarophile due to ease of further
functionalization. After careful experimentation, we found
that heating of a mixture containing allylester 23, 1 mol %
of Rh2(OAc)4, and diazo compound 22 in toluene (100 °C)
(18) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574–1585.
(19) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
(22) See, for example: Prusov, E.; Maier, M. E. Tetrahedron 2007, 63,
10486–10496.
(20) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258–
3260.
(23) Oppolzer, W.; Lienard, P. HelV. Chim. Acta 1992, 75, 2572–2582,
and references cited therein.
(21) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709–1716.
(24) Kim, J.-G.; Jang, D. O. Synlett 2008, 2072–2074.
3420
Org. Lett., Vol. 12, No. 15, 2010

Scheme 4
.
Transformation of Cycloadduct 25 into Oxa-Bridged
Guaianolides 33 and 34
Figure 3. Rendering of the X-ray structure of tricyclic compound
34.
cyclopentane methyl group. Calculations (Spartan 08) showed
a half chair conformation of the six-membered carbonyl ylide
(see Supporting Information). One explanation for the
diastereoselectivity might be pyramidalization of the reacting
centers in the dipole.26,27
In summary, we demonstrated that oxo-bridged guaiane-
type structures can be accessed via a rhodium(II)-catalyzed
carbonyl ylide formation/cycloaddition strategy. In the case
at hand, (R)-(-)-carvone served as a chiral starting material
which allowed us to prepare diazo ꢀ-ketoester 22. A high
facial selectivity was observed in the cycloaddition step. On
the tricyclic cycloadduct 24, the seven-membered ring was
functionalized via Curtius rearrangement/hydrolysis sequence
of an unsaturated carbonyl azide. Further studies on the facial
selectivity of related cycloadditions and application of the
present strategy toward the total synthesis of oxa-bridge
sesquiterpenes (Figure 1) is in progress in our laboratory.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. In addition, a 10 month
DAAD fellowship for D. B. Ushakov (Universita¨t Tu¨bingen)
is acknowledged as well. This work was carried out within
the framework of COST action CM0804 - Chemical Biology
with Natural Products.
not work, neither on the corresponding xanthogenate nor
trifluoro acetate, alcohol 31 could be easily dehydrated with
Burgess reagent25 (MeO2CN-SO2N+Et3) to give alkene 32
which led to guaianolide 33 via catalytic hydrogenation. TES
deprotection on alkene 32 could be achieved with TBAF to
give alkenediol 34 in reasonable yield.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds reported
and copies of NMR spectra for important intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Crystallization of 34 from a hexane/diethyl ether mixture
provided crystals suitable for X-ray analysis (Figure 3)
indicating the configuration of the stereocenters and confor-
mation of the structure. The C3 methylene group could not
be exactly localized. The X-ray structure additionally proved
the facial selectivity in the cycloaddition step which cor-
roborated the NOESY data of compound 29. It is difficult
to rationalize the facial selectivity of the cycloaddition
reaction with the dipolarophile approaching syn to the
OL1012185
(26) (a) Sato, M.; Murakami, M.; Sunami, S.; Kaneko, C.; Furuya, T.;
Kurihara, H. J. Am. Chem. Soc. 1995, 117, 4279–4287. (b) Haddad, N.;
Abramovich, Z. J. Org. Chem. 1995, 60, 6883–6887. (c) Kolakowski, R. V.;
Williams, L. J. Nat. Chem. 2010, 2, 303–307
(27) For a review, see: Vazquez, S.; Camps, P. Tetrahedron 2005, 61,
5147–5208
.
(25) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973,
38, 26–31.
.
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