Stereoselective synthesis of dienyl-carboxylate building blocks: Formal synthesis of inthomycin C

Article abstract of DOI:10.1021/ol401226y

A direct synthesis of stereodefined halodienes is reported. Those key building blocks enable a concise access to polyenic products, as demonstrated in a modular synthesis of Inthomycin C.

Full text of DOI:10.1021/ol401226y

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Stereoselective Synthesis of
Dienyl-Carboxylate Building Blocks:
Formal Synthesis of Inthomycin C
†
†
‡
†
‡
ꢀ ꢀ
ꢀ
Caroline Souris, Frederic Frebault, Ashay Patel, Davide Audisio, K. N. Houk, and
Nuno Maulide*,†
Max-Planck-Institut fu€r Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mu€lheim
an der Ruhr, Germany, and University of California, Los Angeles, Department of
Chemistry and Biochemistry, 607 Charles E. Young Drive East, Los Angeles,
California 90095-1569, United States
maulide@mpi-muelheim.mpg.de
Received May 2, 2013
ABSTRACT
A direct synthesis of stereodefined halodienes is reported. Those key building blocks enable a concise access to polyenic products, as
demonstrated in a modular synthesis of Inthomycin C.
Dienyl carboxylate and carbinol subunits are fundamental
structural scaffolds present in various natural products1
(Figure 1). Through simple modifications in the diene
substitution pattern and olefin geometry, Nature is able
to access remarkable structural diversity. Such functiona-
lized conjugated dienes are conventionally built from
simple mono-olefinic fragments2 through, e.g., cross-
coupling,3,4 metathesis,5 or olefination reactions.6 Con-
trolling the configuration of the double bond arrays
generated during such transformations represents a major
challenge.
† Max-Planck-Institut f€ur Kohlenforschung.
‡ University of California, Los Angeles.
(1) Hopf, H.; Maas, G. In The Chemistry of Dienes and Polyenes;
Rappoport, Z., Ed.; Wiley: Chichester, U.K., 1997.
(2) For a recent review on diene synthesis, see: De Paolis, M.;
Chataigner, I.; Maddaluno, J. Top. Curr. Chem. 2012, 327, 87.
(3) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Neigishi, E., Ed.; Wiley: Chichester, 2002.
(4) (a) Beletskaya, I. P.; Cheprakov, A. V. Metal Complexes as
Catalysts for CꢀC Cross Coupling Reactions. In Comprehensive Co-
ordination Chemistry II; McCleverty, J. A., Meyer, T. J., Eds.; Elsevier Ltd.:
Oxford, 2004; Vol. 9, pp 305ꢀ368. (b) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457. (c) Miyaura, N. J. Organomet. Chem. 2002, 653, 54.
(d) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722.
(5) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003.
Figure 1. Examples of natural products containing a dienyl-
carboxylate or -carbinol moiety.
The use of stereodefined mono-olefinic fragments as build-
ing blocks for cross-coupling reactions leading to the di- or
polyenyl frameworks of interest is a strategy that has
gained prominence.7 An elegant example of such a tactic
is the development by Burke of an assembly of so-called
(6) Modern Carbonyl Olefination: Methods and Applications; Takeda,
T., Ed.; Wiley-VCH: Weinheim, 2004.
r
10.1021/ol401226y
XXXX American Chemical Society

MIDA-boronate building blocks that allow the deploy-
ment of iterative cross-couplings en route to polyenic
natural products.8 Nevertheless, the syntheses of the basic
mono-olefinic fragments are typically multistep and man-
date the introduction of a halide and organometallic
residue in each fragment. We report herein a strategy for
the direct preparation of dienyl carboxylate building
blocks that significantly streamlines the total synthesis of
polyene natural products.9ꢀ11
During our studies on allylic alkylation of lactone 1a,12
we have discovered an unexpected halide ring opening relying
on the use of alkali halide salts. As shown in Scheme 1aꢀb,
clean ring opening of lactone 1a with either NaI or LiBr
provides almost exclusively trans-halocyclobutenes 2aꢀb in
quantitative yields. Furthermore, nucleophilic chlorination
of 1a with HCl selectively affords cis-chlorocyclobutene 2c
with similar efficiency (Scheme 1c).
These thermally stable halocyclobutenes and their ester
or amide derivatives are prone to 4π-electrocyclic conro-
tatory ring opening13,14 upon heating. Surprisingly, the
iodocyclobutene 2a and derivatives undergo productive
ring opening leading to a mixture of diene geometrical
isomers.15,16 In contrast, 2b and the brominated carboxylate
analogues thereof afford the (E,E)-halodienes 4aꢀd cleanly
upon refluxing in THF.17 In a complementary fashion, the
cis-4-chlorocyclobut-2-ene carboxylic acid 2c18 can be readily
derivatized and unravelled to deliver the (Z,E)-dienyl car-
boxylates 5aꢀd (Scheme 1c).
Scheme 1. Direct Synthesis of Halocyclobutenes and Their
Ring-Opening Reactionsa
In order to determine the factors controlling the reactivity
and stereoselectivity of the ring openings of 2aꢀc, we model-
ed these 4π-electrocyclic ring-opening reactions computat-
ionally.19 Computations indicate that the electrocyclic ring-
opening reactions of the disubstituted cyclobutenes 2aꢀc are
all exergonic and thus irreversible with a ΔGrxn ranging from
ꢀ11 kcal/mol for 2b and 2c to ꢀ14 kcal/mol for 2a. The high
temperatures required for the ring openings of 2aꢀc are con-
sistent with the computed free energy barriers (∼30 kcal/mol).
The transition structures for the ring opening of 2a, 2b, and
2c are shown in Figure 2.20
Donors such as iodide stabilize the transition state by
interacting with the transition state LUMO.21 The iodide
substituent is a weaker donor than chloride or bromide,
explaining a 10-fold difference in the rate of reaction of 2a
and 2b.
a * Overall isolated yield from lactone 1a. ** Isolated yield after
recrystallization.
The stereochemical outcomes of the electrocyclic reac-
tions of 2bꢀc are in agreement with the model regarding
(7) (a) Eto, K.;Yoshino, M.;Takahashi, K.;Ishihara, J.;Hatakeyama,
S. Org. Lett. 2011, 13, 5398. (b) O’Neil, G. W.; Phillips, A. J. J. Am.
Chem. Soc. 2006, 128, 5340. (c) Schmidt, B.; Kunz, O. Eur. J. Org. Chem.
2012, 1008.
(13) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. 1969, 8,
781. See ref 12f and references cited therein.
(8) (a) Woerly, E. M.; Struble, J. R.; Palyam, N.; O’Hara, S. P.; Burke,
M. D. Tetrahedron 2011, 67, 4333. (b) Gillis, E. P.; Burke, M. D. Aldrichi-
mica Acta 2009, 42, 17. (c) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2007, 129, 6716. (d) Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am.
Chem. Soc. 2008, 130, 466. (e) Woerly, E. M.; Cherney, A. H.; Davis, E. K.;
Burke, M. D. J. Am. Chem. Soc. 2010, 132, 6941. (f) Fujita, K.; Matsui, R.;
Suzuki, T.; Kobayashi, S. Angew. Chem., Int. Ed. 2012, 51, 7271.
(9) For previous syntheses of (2E,4E)-5-iodo-2,4-dienoic acid and
ester derivatives, see: (a) Abarbri, M.; Parrain, J. L.; Duchene, A.;
Thibonnet, M. Synthesis 2006, 2951. (b) Batsanov, A. S.; Knowles, J. P.;
Samsam, B.; Whiting, A. Adv. Synth. Catal. 2008, 350, 227.
(10) For previous syntheses of (2E,4E)-5-bromo-2,4-dienoic esters,
see: (a) Macdonald, G.; Alcaraz, L.; Wei, X. D.; Lewis, N. J.; Taylor,
R. J. K. Tetrahedron 1998, 54, 9823. (b) Zeng, F. X.; Negishi, E. Org.
Lett. 2002, 4, 703. (c) Crombie, L.; Horsham, M. A.; Jarrett, S. R. M.
Tetrahedron Lett. 1989, 30, 4299. (d) Wei, X. D.; Taylor, R. J. K.
Tettrahedron Lett. 1998, 39, 3815. (e) Wei, X. D.; Taylor, R. J. K. J. Org.
Chem. 2000, 65, 616.
(14) For isolated examples of electrocyclic ring opening of cyclobu-
tenes in the context of natural products synthesis, see: (a) Trost, B. M.;
McDougal, P. G. J. Org. Chem. 1984, 49, 458. (b) Nicolaou, K. C.; Vega,
J. A.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2001, 40, 4441. (c)
Schreiber, S. L.; Santini, C. J. Am. Chem. Soc. 1984, 106, 4038. (d)
Ogawa, S.; Urabe, D.; Yokokura, Y.; Arai, H.; Arita, M.; Inoue, M.
Org. Lett. 2009, 11, 3602.
(15) Brune, H. A.; Schwub, W. Tetrahedron 1969, 25, 4375.
(16) For comparison with (2E,4Z)-5-iodo-2,4-dienoic ester and
(2Z,4E)-5-iodo-2,4-dienoic ester, see: Wang, G. W.; Mohan, S.; Negishi,
E. I. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 11344. See SI for details.
(17) A larger scale reaction afforded 2.5 g of diene 4b in 95% yield
from the lactone 1a.
(18) Pirkle, W. H.; Mckendry, L. H. J. Am. Chem. Soc. 1969, 91,
1179. See also ref 12d.
(19) Computational experiments were carried out using the
M06ꢀ2X/6-31þG(d,p) model chemistry with Gaussian 09. For the
reaction of 2c, the core electrons of iodine were modelled using the
LAN2LDZ pseudopotential. Additional details regarding the computa-
tional methods employed as well as the full citation for Gaussian are
provided in the Supporting Information.
(11) For previous syntheses of (2Z,4E)-5-chloro-2,4-dienoic ester
derivative, see: Takeda, A.; Tsuboi, S. J. Org. Chem. 1973, 38, 1709.
ꢀ
(12) (a) Frebault, F.; Luparia, M.; Oliveira, M. T.; Goddard, R.;
Maulide, N. Angew. Chem., Int. Ed. 2010, 49, 5672. (b) Luparia, M.;
ꢀ
Oliveira, M. T.; Audisio, D.; Frebault, F.; Maulide, N. Angew. Chem.,
(20) Comparing the barriers of 2a and 2b, we found that ring opening
of 2a proceeds with a ΔG‡ of 29.8 kcal/mol, whereas the reaction of 2b
has a ΔG‡ of 28.7. This 1.1 kcal/mol difference leads to a 10-fold greater
reaction rate for 2b compared to its iodo-analogue 2a.
(21) Dolbier, W.; Koroniak, H.; Houk, K.; Sheu, C. Acc. Chem. Res.
1996, 29, 471.
Int. Ed. 2011, 50, 12631. (c) Luparia, M.; Audisio, D.; Maulide, N.
Synlett 2011, 735. (d) Audisio, D.; Luparia, M.; Oliveira, M. T.; Klutt,
D.; Maulide, N. Angew. Chem., Int. Ed. 2012, 51, 7314. (e) Niyomchon,
S.; Audisio, D.; Luparia, M.; Maulide, N. Org. Lett. 2013, 15, 2318. (f)
Souris, C.; Luparia, M.; Frebault, F.; Audisio, D.; Fares, C.; Goddard,
R.; Maulide, N. Chem.;Eur. J. 2013, 19, 6566.
B
Org. Lett., Vol. XX, No. XX, XXXX

formed by subsequent isomerization of the allowed (E,E)
product.
We next sought to demonstrate the synthetic utility of
these dienyl-carboxylates.24 Inthomycin C (Scheme 2), iso-
lated in 1991,25 was shown to reduce prostate cancer cell
growth as well as to possess selective in vitro antimicrobial
activity. Our retrosynthetic analysis is shown in Scheme 2,
breaking the natural product down to three simple fragments
4e, 6, and 7. We envisioned that the bromo diene 4e would
undergo cross-coupling with a suitable organometallic part-
ner 6 delivering a triene. Further functional group intercon-
version and Mukaiyama aldol reaction with silylketene acetal
7 would ultimately allow the preparation of Inthomycin C.
Figure 2. Lowest energy conrotatory transition structures for
the ring opening of 2a, 2b, and 2c. ΔH‡ and ΔG‡ are given in red
below the corresponding transition structure. The enthalpy and
free energy values in blue are the differences between the
disfavored (not shown) and preferred transition states. Energies
are given in kcal/mol.
Scheme 2. Retrosynthetic Strategy towards Inthomycin C
the torquoselectivity of the 4π-electrocyclic ring opening of
cyclobutenes.21 In the ring opening of halocyclobutenes,
strong n donors rotate outward in order to maximize orbital
overlap between the high energy, nonbonding orbital of the
donor, and the transition state LUMO (σ*).22 Indeed,
computations show that the conrotatory transition state
of ring opening in which the halide rotates outward is 13ꢀ
14 kcal/mol lower in energy than the alternative where the
halide rotates inward (Figure 2). Conversely, strong accep-
tors, such as aldehydes, tend to rotate inward in order to
maximize the overlap of their relatively low energy acceptor
orbital with the transition state HOMO (σ).
In order to obtain validation for the strategy outlined in
Scheme 2, we briefly evaluated the reactivity of the stereo-
defined diene building blocks in cross-coupling reactions
(Scheme 3).26 For instance, Suzuki couplings employing
aryl and vinyl boronic acids proceeded to deliver the
corresponding substituted dienoic esters 8aꢀc. Sonogashira
reactions could be performed in good yields with silyl-,
alkyl-, and aryl-substituted terminal alkynes, and various
Stille cross-couplings were also successful.27 Similarly,
cross-coupling onto the (Z,E)-chloro-dienes 5cꢀd took
place without loss of the diene geometrical configuration
(Scheme 4), an important observation.28 To the best of our
knowledge, this is an unprecedented use of doubly vinylo-
gous chloride esters in cross-coupling reactions.
The ΔΔG‡ valuesoftrans-substituted cyclobutenes2aꢀc
(13ꢀ15 kcal/mol) demonstrate the clear preference of the
halide substituent for outward rotation. In the ring open-
ing of trans-disubstituted 2aꢀb, both the acid23 and the
halide rotate outward, whereas in the ring opening of cis-
isomer 2c the acid is forced to rotate inward in the presence
of the strong chloride donor. The similarity in the barriers
of the trans- and cis-disubstituted cyclobutene ring open-
ings are in agreement with prior computational work
which indicates that the acid has only a small preference
for outward rotation.23
While the formation of the (E,E)-iododiene via electro-
cyclic reaction of 2a follows the explanation provided
above, the (E,Z)-iododiene cannot be formed under thermal
conditions via a pericyclic mechanism, as the reaction would
have to proceed through a forbidden, disrotatory transition
state.13 Such a transition state is inaccessible due to its
prohibitively high energy. Instead, this (E,Z) isomer is likely
Armed with this knowledge, we could then confidently
complete the synthesis of Inthomycin C (Scheme 5). As
shown, lithium bromide smoothly opened the methyl sub-
stituted lactone 1b. As before, a single trans-cyclobutenyl
(25) (a) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.;
Katayama, C.; Iwadare, S.; Shizuri, Y.; Mitomo, R.; Nakano, F.;
Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1073. (b) Henkel, T.; Zeeck,
A. Liebigs Ann. Chem. 1991, 367.
(26) For use of a (2E,4E)-5-bromo-2,4-dienoic ester in a cross-coupling
reaction, see:Crombie, L.;Horsham, M. A.;Jarrett, S. R. M.J. Chem. Soc.,
Perkin Trans. 1 1991, 1511. See also ref 10b, 10d.
(27) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org.
Lett. 2005, 7, 3805.
(28) Giannerini, M.; Fananas-Mastral, M.; Feringa, B. L. J. Am.
Chem. Soc. 2012, 134, 4108.
(29) Henaff, N.; Whiting, A. Org. Lett. 1999, 1, 1137.
(30) Garcia Garcia, P.; Lay, F.; Rabalakos, C.; List, B. Angew.
Chem., Int. Ed. 2009, 48, 4363.
(31) (a) Senapati, B. K.; Gao, L.; Lee, S. I.; Hwang, G. S.; Ryu, D. H.
Org. Lett. 2010, 12, 5088. (b) Webb, M. R.; Donald, C.; Taylor, R. J. K.
Tetrahedron Lett. 2006, 47, 549. (c) Webb, M. R.; Addie, M. S.;
Crawforth, C. M.; Dale, J. W.; Franci, X.; Pizzonero, M.; Donald, C.;
Taylor, R. J. K. Tetrahedron 2008, 64, 4778. (d) Yoshino, M.; Eto, K.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Biomol. Chem. 2012,
10, 8164.
(22) Niwayama, S.; Houk, K. N. Tetrahedron Lett. 1992, 33, 883.
(23) (a) Niwayama, S.; Houk, K. N.; Kusumi, T. Tetrahedron Lett.
€
1994, 35, 527. (b) Lee, P. S.; Sakai, S.; Horstermann, P.; Roth, W. R.;
Kallel, E. A.; Houk, K. N J. Am. Chem. Soc. 2003, 125, 5839.
(24) (a) For a review of the Stille reaction in polyene natural product
synthesis, see: Pattenden, G.; Sinclair, D. J. J. Organomet. Chem. 2002,
653, 261. For a selected application of the Suzuki reaction in natural
product synthesis, see ref 8e.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Scope of Cross-Coupling Reactions of
(2E,4E)-5-Bromo-2,4-dienoic Derivatives 4cꢀd
Scheme 5. Modular Formal Synthesis of Inthomycin C
diene fragment upon ring opening. Cross-coupling onto
these subunits allows ready access to natural product-like
polyene substructures without erosion of the geometrical
purity. The utility of this strategy is showcased by a
modular short formal synthesis of Inthomycin C. We are
currently pursuing the application of these and related
approaches to the total syntheses of diverse polyene nat-
ural products.
Scheme 4. Suzuki Cross-Coupling of (2Z,4E)-5-Chloro-dienoic
Derivatives 5cꢀd
Acknowledgment. We are grateful to the Max-Planck
€
Society and the Max-Planck Institut fur Kohlenforschung
for funding. This work was funded by the DFG (Grant
MA 4861/3-1). The project “SusChemSys” is cofinanced
by the European Regional Development Fund (ERDF)
and the state of NRW (Germany) under the Operational
Programme “Regional Competitiveness and Employ-
ment” 2007ꢀ2013. A.P. and K.N.H. thank the National
Institute of General Medical Science, NIH (GM 36700) for
funding. A.P acknowledges the support of CBI training
program (T32 GM 008496). Computational studies were
performed using the Hoffman2 cluster at UCLA as well as
resources provided by Extreme Science and Engineering
Discovery Environment (XSEDE) program supported by
the NSF (OCI-1053575).
bromide 2d was obtained. Further amide coupling and 4π
electrocyclic ring opening afforded 2-methyl-5-bromodie-
noic amide 4e as a single geometrical isomer. Stille cross-
coupling with vinyl stannane 6,29 followed by reduction to
the aldehyde 11 and organocatalytic Mukaiyama aldol
reaction with silylketene acetal 7, then led to product 12 in
50% yield.30 The conversion of 12 to Inthomycin C has
been previously reported.31 This modular assembly of
substituents around dienes such as 4e allows considerable
flexibility in the context of total synthesis.
In summary, we have reported herein a direct route to
functionalized and stereodefined halodiene carboxylate
building blocks, which proceeds through electrocyclic ring
opening of readily available halocyclobutene precursors.
Appropriate control of stereochemical information at the
cyclobutene level ensures access to a suitably configured
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for new compounds,
computational details. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX