Total synthesis of (+)-Herboxidiene from two chiral lactate-derived ketones

Article abstract of DOI:10.1021/ol202210k

A substrate-controlled synthesis of (+)-herboxidiene from two lactate-derived chiral ketones is described. Remarkably, most of the carbon backbone was constructed through highly stereoselective titanium-mediated aldol reactions and an Ireland-Claisen rear

Full text of DOI:10.1021/ol202210k

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5350–5353
Total Synthesis of (þ)-Herboxidiene from
Two Chiral Lactate-Derived Ketones
€
Miquel Pellicena, Katrina Kramer, Pedro Romea,* and Felix Urpı*
ꢀ
´
´
Departament de Quımica Organica, Universitat de Barcelona,
Carrer Martı i Franques 1-11, 08028 Barcelona, Catalonia, Spain
ꢀ
´
ꢁ
pedro.romea@ub.edu; felix.urpi@ub.edu
Received August 15, 2011
ABSTRACT
A substrate-controlled synthesis of (þ)-herboxidiene from two lactate-derived chiral ketones is described. Remarkably, most of the carbon
backbone was constructed through highly stereoselective titanium-mediated aldol reactions and an IrelandꢀClaisen rearrangement.
Furthermore, an oxa-Michael cyclization and a high-yield Suzuki coupling were used to assemble the pyran ring and the diene moiety respectively.
During the past few years, those engaged in the synthesis
of natural products are paying increasing attention to the
development of more efficient strategies and synthetic
methodologies in the endless pursuit of the ideal synthesis.1
Now, it is widely accepted that any synthetic endeavor
should provide the target in a few steps and in high yields,
taking advantage of selective transformations to assemble
the carbonꢀcarbon backbone and carbonꢀheteroatom
bonds as well as minimizing manipulation of protecting
groups and other functional groups.1,2 With these ideas in
mind, we envisaged that some titanium-mediated aldol
methodologiesdevelopedby our group might pavethe way
to a new synthetic approach for (þ)-herboxidiene (1 in
Scheme 1).
affect plasma cholesterol4 and to be active against
several tumoral cell lines.5 This appealing biological
activity and its enticing structural features have at-
tracted much attention, and several total syntheses
have been reported.6 Herein, we describe a very effi-
cient synthesis based on highly stereoselective sub-
strate-controlled reactions from two chiral lactate-
derived ketones, without requiring any other source
of chirality.
As outlined in Scheme 1, our retrosynthetic analysis
for (þ)-herboxidiene relies on the conversion of the
epoxide to the corresponding alkene and the strategic
disconnection of the C9ꢀC10 bond. These early trans-
forms provide two fragments of similar size and struc-
tural complexity, iodoalkene 2 and alkyne 3, which
could then be assembled through a palladium-catalyzed
Isolated from Streptomyces sp. A7847 at Monsanto,3
(þ)-herboxidiene, also named GEX1A, was identified
as a polyketide metabolite with potent and highly
selective phytotoxic properties. It was later shown to
(4) Koguchi, Y.; Nishio, M.; Kotera, J.; Omori, K.; Ohnuki, T.;
Komatsubara, S. J. Antibiot. 1997, 50, 970–971.
(5) Hasegawa, M.; Miura, T.; Kuzuya, K.; Inoue, A.; Ki, S. W.;
Horinouchi, S.; Yoshida, T.; Kunoh, T.; Koseki, K.; Mino, K.; Sasaki,
R.; Yoshida, M.; Mizukami, T. ACS Chem. Biol. 2011, 6, 229–233.
(6) (a) Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K.
J. Chem. Soc., Perkin Trans. 1 1999, 955–968. (b) Banwell, M.; McLeod,
M.; Premraj, R.; Simpson, G. Pure Appl. Chem. 2000, 72, 1631–1634. (c)
Zhang, Y.; Panek, J. S. Org. Lett. 2007, 9, 3141–3143. (d) Murray, T. J.;
Forsyth, C. J. Org. Lett. 2008, 10, 3429–3431. (e) Ghosh, A. K.; Li, J.
Org. Lett. 2011, 13, 66–69.
(1) (a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S.
Angew. Chem., Int. Ed. 2000, 39, 44–122. (b) Gaich, T.; Baran, P. S.
J. Org. Chem. 2010, 75, 4657–4673.
(2) (a) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197–201. (b)
Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38,
3010–3021. (c) Roulland, E. Angew. Chem., Int. Ed. 2011, 50, 1226–1227.
(3) Isaac, B. G.; Ayer, S. W.; Elliott, R. C.; Stonard, R. J. J. Org.
Chem. 1992, 57, 7220–7226.
r
10.1021/ol202210k
Published on Web 09/13/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Analysis of (þ)-Herboxidiene
cross-coupling reaction. Following this analysis, we
anticipated that the successful construction of 2 would
mainly depend on an oxa-Michael cyclization of con-
jugated ester 4, and a substrate-controlled aldol reac-
tion from chiral ketone 6, followed by reduction of the
resulting aldol product to furnish diol 5. Alkyne 3
would come from an IrelandꢀClaisen rearrangement
of ester 7, which could be prepared by selective functio-
nalization of diol 8. This, in turn, would arise through a
stereoselective one-pot aldolꢀreduction transforma-
tion from chiral ketone 9. In summary, our synthetic
approach was based on a convergent strategy that
depends on the stereocontrol provided by appropriate
substrate-controlled reactions from intermediates re-
presented in Scheme 1.
The synthesis of the C1ꢀC9 fragment (2) began
with the titanium-mediated aldol addition7 of the
lactate-derived ethyl ketone 68 to 3-butenal9 (Scheme 2).
As expected, it afforded the aldol product 10 (dr g97:3 by
1H NMR) in 84% yield, which was converted stereo-
selectively (dr 94:6, 96%) to diol 6 through an internal-
hydride delivery using (Me4N)HB(OAc)3.10 Finally,
HoveydaꢀGrubbs II catalyzed11 cross-metathesis of
diol 5 with ethyl acrylate furnished conjugated ester 4
in 90% yield (E/Z g 97:3). Hence, the stage was set for
the construction of the pyran ring.
Scheme 2. Early Steps of the Synthesis of C1ꢀC9 Fragment
Initially, we expected the oxa-Michael cyclization12 of 4
to lead to cis pyran 11c stereoselectively under thermo-
dynamic conditions, since all the substituents in the six-
membered heterocycle lie at equatorial positions (Scheme 3).
Nevertheless, preliminary experiments with t-BuOK
afforded trans pyran 11t as the major diastereomer. After
considerable investigation, we found that Fuwa’s condi-
tions (DBU, toluene, 100 °C)13 provided an inseparable
1.8:1 mixture of 11cꢀ11t diastereomers in 80% yield.
Then, BartonꢀMcCombie removal of the C5-hydroxy
group under tin-free conditions,14 followed by chromato-
graphic purification of the reaction mixture, furnished the
desired ester containing the cis pyran ring (12c) in 54%
yield. Importantly, treatment of the minor diastereomer
12t with t-BuOK rendered 12c as a single diastereomer
in 61% yield,15 which indicated that the hydroxyl group
at C5 was responsible for the poor stereocontrol of the
(7) (a) Solsona, J. G.; Romea, P.; Urpı
2003, 5, 519–522. (b) Solsona, J. G.; Romea, P.; Urpı
´
, F.; Vilarrasa, J. Org. Lett.
, F. Tetrahedron
´
Lett. 2004, 45, 5379–5382.
ꢁ
(8) Ferrero, M.; Galobardes, M.; Martı
´
n, R.; Montes, T.; Romea, P.;
Rovira, R.; Urpı, F.; Vilarrasa, J. Synthesis 2000, 1608–1614.
´
(9) Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L. Synth.
Commun. 1998, 28, 3675–3679.
(10) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560–3578.
(11) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
(13) (a) Fuwa, H.; Saito, A.; Sasaki, M. Angew. Chem., Int. Ed. 2010,
49, 3041–3044. (b) Fuwa, H.; Yamaguchi, H.; Sasaki, M. Tetrahedron
2010, 66, 7492–7503.
(14) Chatgilialoglu, C. Chem.;Eur. J. 2008, 14, 2310–2320.
(15) This retro-Michael reaction was not observed with DBU.
Am. Chem. Soc. 2000, 122, 8168–8179.
(12) Larrosa, I.; Romea, P.; Urpı
2683–2723.
´
, F. Tetrahedron 2008, 64,
Org. Lett., Vol. 13, No. 19, 2011
5351

oxa-Michael cyclization. Finally, hydrogenolysis of the
benzyl ether and Swern oxidation of the resultant alcohol
afforded ketone 13, which was submitted to Takai
conditions16 to deliver the C1ꢀC9 fragment 2 in three
steps, as an E/Z 90:10 mixture in 50% yield.
stabilizes the boat-like transition state TS-II leading to
trans pyran 11t (Scheme 4).18
Scheme 4. Oxa-Michael Cyclization of Dihydroxy Ester 4
Scheme 3. Tetrahydropyran Construction and Final Steps of the
Synthesis of C1ꢀC9 Fragment
Having prepared the C1ꢀC9 fragment, we focused on
the synthesis of alkyne 3, the C10ꢀC19 fragment (see
Scheme 1). We envisaged that it could be constructed from
a sequential transformation consisting of a highly stereo-
selective titanium-mediated aldol addition of chiral ketone
98 to methacrolein followed by reduction of the resultant
aldolate with LiBH4.19 As expected, this one-pot transfor-
mation afforded all syn diol 8 (dr g97:3 by 1H NMR) in
81% yield (Scheme 5). Remarkably, the four stereocenters
required for the synthesis of 3 had been installed in a single
step with absolute stereocontrol. Then, selective monoa-
cylation of the less sterically hindered hydroxyl group of 8
using Clarke’s conditions20 and methylation of the result-
ing hydroxy ester with (Me3O)BF4/proton sponge furn-
ished key intermediate 7 in 66% yield. The crucial
IrelandꢀClaisen rearrangement was next addressed.21
After a thorough optimization, it was found that treatment
of 7 with LiHMDS in 4:1 THF/DMPU at ꢀ78 °C pro-
duced a lithium enolate that could be trapped with
TBSCl.22 Then, the resulting ketene silyl acetal underwent
a clean [3,3] sigmatropic rearrangement to furnish a silyl
ester, which was reduced with LiAlH4 to afford alcohol 14
The lack of stereocontrol of the cyclization of a dihy-
droxyR,β-unsaturatedestersuchas4 has been reportedfor
a few related substrates.17 Some of these precedents have
also established that the protection of the C5 hydroxyl
group allows the cis pyran to be obtained stereoselectively.
Takingadvantageof these reports and ourownexperience,
and assuming that the cyclization to cis pyran 11c must
proceed through transition state TS-I in which all the
substituents are placed at equatorial positions, we hy-
pothesize that the poor stereoselective cyclization of 4
may be due to an intramolecular hydrogen bond that
(16) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408–7410.
1
(17) For related unexpected lack of stereocontrol of oxa-Michael
cyclizations, see: (a) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.;
Campos, K. R. J. Am. Chem. Soc. 1999, 121, 6816–6826. (b) Bates,
R. W.; Song, P. Synthesis 2010, 2935–2942. (c) Wang, B.; Hansen, T. M.;
Wang, T.; Wu, D.; Weyer, L.; Ying, L.; Engler, M. M.; Sanville, M.;
Leitheiser, C.; Christmann, M.; Lu, Y.; Chen, J.; Zunker, N.; Cink,
R. D.; Ahmed, F.; Lee, C.-S.; Forsyth, C. J. J. Am. Chem. Soc. 2011, 133,
as a single diastereomer (dr g97:3 by H NMR). Swern
(19) (a) Nebot, J.; Figueras, S.; Romea, P.; Urpı
hedron 2006, 62, 11090–11099. (b) Esteve, J.; Matas, S.; Pellicena, M.;
Velasco, J.; Romea, P.; Urpı, F.; Font-Bardia, M. Eur. J. Org. Chem.
2010, 3146–3151. (c) Esteve, J.; Jimenez, C.; Nebot, J.; Velasco, J.;
Romea, P.; Urpı, F. Tetrahedron 2011, 67, 6045–6056.
´
, F.; Ji, Y. Tetra-
´
ꢁ
´
ꢁ
1484–1505. (d) Ferrie, L.; Boulard, L.; Pradaux, F.; Bouzbouz, S.;
(20) (a) Clarke, P. A. Tetrahedron Lett. 2002, 43, 4761–4763. (b)
Clarke, P. A.; Kayaleh, N. E.; Smith, M. A.; Baker, J. R.; Bird, S. J.;
Chan, C. J. Org. Chem. 2002, 67, 5226–5231.
(21) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem.
Soc. 1976, 98, 2868–2877. (b) Ireland, R. E.; Wipf, P.; Armstrong, J. D.,
III. J. Org. Chem. 1991, 56, 650–657.
Reymond, S.; Capdevielle, P.; Cossy, J. J. Org. Chem. 2008, 73,
1864–1880.
(18) Although intramolecular hydrogen bonds have never been
invoked to rationalize the stereochemical outcome of an oxa-Michael
cyclization, there are reports about the role of metal chelation on such
transformations: (a) Kanematsu, M.; Yoshida, M.; Shishido, K. Angew.
Chem., Int. Ed. 2011, 50, 2618–2620. (b) Fuwa, H.; Noto, K.; Sasaki, M.
Org. Lett. 2011, 13, 1820–1823.
(22) Magauer, T.; Martin, H. J.; Mulzer, J. Chem.;Eur. J. 2010, 16,
507–519.
5352
Org. Lett., Vol. 13, No. 19, 2011

oxidation of 14 and treatment of the resultant aldehyde
under modified OhiraꢀBestmann conditions23 delivered 3
as a single diastereomer in 90% yield. Importantly, the
latter reaction was carried out at ꢀ78 °C to avoid epimer-
ization of the C12-stereocenter.24
ester 16 with TMSOK27 furnished (þ)-herboxidiene in
93% yield.28
Scheme 6. Assembly of Fragments 2 and 3 and Endgame
Scheme 5. Synthesis of C10ꢀC19 Fragment
With both fragments 2 and 3 in hand, we faced the
construction of the diene moiety (Scheme 6). After ex-
ploring several possibilities, we found that the most
efficient approach involved hydroboration of 3 with
catecholborane in the presence of catalytic amounts of
dicyclohexylborane, followed by hydrolysis of the resul-
tant boronate to give the corresponding boronic acid
(Arase conditions).25 Suzuki coupling of this boronic acid
and iodoalkene 2 proceeded in a straightforward manner
and provided diene 15 in 91% yield.26 Having prepared
the carbon backbone of (þ)-herboxidiene, the endgame
entailed removal of the silyl ether and epoxidation of the
resultant bis-homoallylic alcohol as described in previous
syntheses6 (53% yield). Finally, saponification of ethyl
In summary, the synthesis of (þ)-herboxidiene 1 has
been accomplished from two lactate-derived chiral ke-
tones, without requiring other sources of chirality, in a
14-step sequence and 8% overall yield. Most of these steps
involve highly stereoselective carbonꢀcarbon (aldol reac-
tions, IrelandꢀClaisen rearrangement, Suzuki coupling)
or carbonꢀoxygen (oxa-Michael cyclization) bond-form-
ing reactions, and other strategic redox processes. These
features, the lack of protecting groups (the only protecting
groups used along the whole synthesis are placed in the
starting chiral ketones), and the reduced number of con-
cession steps give this substrate-controlled synthesis a high
ideality number (57%) according to Baran’s definition.1b
€
(23) (a) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett
€
H. J. Synthesis 2004, 59–62.
(24) Trost, B. M.; Sieber, J. D.; Qian, W.; Dhawan, R.; Ball, Z. T.
1996, 521–522. (b) Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann,
Acknowledgment. Financial support from the Spanish
ꢁ
Ministerio de Ciencia e Innovacion (MICINN) and Fondos
FEDER (Grant CTQ2009-09692), and the Generalitat de
Catalunya (2009SGR825), as well as a doctorate studentship
Angew. Chem., Int. Ed. 2009, 48, 5478–5481.
(25) (a) Arase, A.; Hoshi, M.; Mijin, A.; Nishi, K. Synth. Commun.
1995, 25, 1957–1962. (b) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc.
2003, 125, 13531–13540. (c) Shirakawa, K.; Arase, A.; Hoshi, M.
Synthesis 2004, 1814–1820.
ꢁ
(FPU, Ministerio de Educacion) to M.P., are acknowledged.
(26) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(b) Marko., I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996, 37,
2507–2510.
(27) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25,
5831–5834.
(28) Spectroscopic data of synthetic 1 matched those previously
reported. See Supporting Information.
Supporting Information Available. Experimental pro-
cedures and physical and spectroscopic data, including
ꢁ
1
copies of H and 13C NMR spectra and proofs of the
stereochemistry of 11c and 8. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5353