Total synthesis of (+)-asperolidec by iridium-catalyzed enantioselective polyene cyclization

Article abstract of DOI:10.1002/anie.201307187

Domino rings: A general synthetic entry into labdane-type diterpenoids has been developed based on an iridium-catalyzed enantioselective polyene cyclization cascade. The potential of this process is demonstrated in the first total synthesis of the tetranorlabdane diterpene asperolideC (PMB=p-methoxybenzyl, TMS= trimethylsilyl). Copyright

Full text of DOI:10.1002/anie.201307187

Angewandte
Chemie
DOI: 10.1002/anie.201307187
Natural Product Synthesis
Total Synthesis of (+)-Asperolide C by Iridium-Catalyzed
Enantioselective Polyene Cyclization**
Oliver F. Jeker, Alberto G. Kravina, and Erick M. Carreira*
The labdane diterpenes encompass a structurally diverse class
of natural products that are widely distributed in terrestrial
and marine organisms.[1] Many of these compounds exhibit
notable biological properties, such as antibacterial,[2] antimu-
tagenic,[3] cytotoxic,[4] anti-inflammatory, and analgesic activ-
ities.[5] Various procedures have been developed for their
preparation,[6] including isolation from natural sources and
chemical or biological manipulation.[7] Herein we report the
first total synthesis of asperolide C (1, Scheme 1), a tetranor-
Scheme 1. Labdane skeleton, structure of asperolide C (1) and asym-
metric catalytic polycyclization.
labdane diterpenoid isolated from Aspergillus wentii EN-48,[8]
through a unique asymmetric catalytic polycyclization cas-
cade which is reminiscent of its biogenesis. A number of
enantioselective polyolefin cyclizations have been reported in
the literature.[9] It is interesting to note, however, that
applications of these processes in natural product synthesis
are scarce, with only two reports emanating from the
Yamamoto research group.[10]
Scheme 2. Proposed biosynthesis of labdane-type diterpenoids (labda-
13-en-8-yl diphosphate cation omitted for conciseness) and iridium-
catalyzed polyene cyclization.
The carbon skeleton common to labdane-type diterpe-
noids is assembled biosynthetically from (E,E,E)-geranylger-
anyl diphosphate (3) through a polyolefin cyclization path-
way, which is consistent with the hypotheses of Stork and
Eschenmoser.[11,12] The currently accepted mechanism
involves protonation-initiated cyclization of 3, enabled by
class II diterpene cyclases, to generate a labda-13-en-8-yl
diphosphate cation (Scheme 2).[13] This intermediate typically
suffers deprotonation of the C(17) methyl group to produce
copalyl pyrophosphate 4. The allylic diphosphate in 4 then
engages in other rearrangement and/or cyclization reactions
followed by a series of downstream biosynthetic modifica-
tions that lead to the introduction of additional functionality.
It is estimated that a significant number of polycyclic
diterpenoids (ca. 7000) arise from this initial cyclization
event.
As part of our program on the study of iridium-catalyzed
enantioselective transformations,[14] we became interested in
their application to the synthesis of complex molecules. A
particularly useful set of reactions that we recently disclosed
includes the asymmetric cyclization of polyunsaturated allylic
alcohols.[15,16] It was envisioned that this method, which
employed arenes to conclude the cationic cascades, might
be expanded in new ways to provide a general entry into the
alicyclic labdane core. Significantly, this would require the use
of an allyl silane as a terminating group. Accordingly, linear
[*] O. F. Jeker, A. G. Kravina, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie
Eidgençssische Technische Hochschule Zꢀrich
HCI H335, Wolfgang-Pauli-Strasse 10
CH-8093 Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[**] We are grateful to Dr. B. Schweizer and M. Solar for X-ray
crystallographic analysis. Dr. M.-O. Ebert, R. Arnold, R. Franken-
stein, and P. Zumbrunnen are acknowledged for NMR spectro-
scopic measurements. A.G.K. thanks the Oskar Jeger Stipendium
for generous financial support. The Swiss National Science
Foundation is acknowledged for funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307187.
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allylic alcohol 5 (Scheme 2) would be subjected to conditions
that generate p-allyl iridium complex 6. This reactive
intermediate would then undergo a series of stereoselective
cyclizations before suffering loss of the Me3Si group to form
the exomethylene in 7. The trans-decalin system thus
obtained would be a valuable intermediate in the synthesis
of various labdane or labdane-type diterpenoids.
attempts with TBAF or para-toluenesulfonic acid led to
decomposition of the material, PPTS (10 mol%) was found to
catalyze the desired transformation. However, as a result of
the poor stability of the product in acidic media, the reaction
was usually halted at 60% conversion.[22] Re-subjection of the
recovered starting material led to allylic alcohol 13 in 81%
combined yield.
The synthesis of asperolide C (1) commenced with the
preparation of vinyl ketone 8 (Scheme 3), which was obtained
from commercially available g-butyrolactone in three steps.
With polyene precursor 13 in hand, the pivotal iridium-
catalyzed cyclization cascade was examined (Scheme 4).
Gratifyingly, reaction of 13 under standard conditions with
[{Ir(cod)Cl}2] (3.2 mol%) and (R)-16 (12.8 mol%) as catalyst
precursors, along with Zn(OTf)2 (16 mol%) as a Lewis acid
delivered decalin 15 with excellent stereoselectivity (d.r. =
9:1, e.r. = 98:2) and in 73% yield.[15,23]
Scheme 3. Reagents and conditions: a) LiHMDS (1.25 equiv), tBu-
Me2SiCl (1.25 equiv), THF/HMPA, ꢀ788C, d.r. >95:5, 95%; b) PhNTf2
(1.5 equiv), CsF (2.5 equiv), (MeOCH2)2, RT, d.r.>95:5, 96%; c) 11
(1.5 equiv), [Pd(dppf)Cl2]·CH2Cl2 (10 mol%), Ph3As (10 mol%),
Cs2CO3 (2.5 equiv), THF/DMF/H2O, 08C to RT, d.r.=10:1, 62%;
d) 9-BBN (1.1 equiv), THF, 08C to RT; then 14 (1.0 equiv), [Pd-
(dppf)Cl2]·CH2Cl2 (2.7 mol%), NaOH (3.0 equiv), THF/H2O, 08C to
RT, 61%; e) PPTS (10 mol%), MeOH, RT, 81% (2 iterations).
PMB=p-methoxybenzyl, TBS=tert-butylsilyl, dppf=1,1’-bis(diphenyl-
phosphino)ferrocene, PPTS=pyridinium p-toluenesulfonate, HMPA=
hexamethylphosphoramide, HMDS=hexamethyldisilazane, Tf=tri-
fluoromethanesulfonyl, 9-BBN=9-borabicyclo[3.3.1]nonane.
Scheme 4. Iridium-catalyzed enantioselective polyene cyclization
cascade.
The synthesis of asperolide C (1) continued with depro-
tection of 15 followed by stepwise oxidation of the liberated
primary hydroxy group. The carboxylic acid thus obtained
was treated with trimethylsilyldiazomethane to afford the
corresponding methyl ester (62% over 4 steps, Scheme 5).
Epoxidation of the exomethylene group with freshly prepared
DMDO at ꢀ208C proceeded from the sterically more
accessible a face to deliver oxirane 17 in moderate yield
(45%, 66% brsm). Exposure of 17 to trifluoroacetic acid in
anhydrous CH2Cl2 at 08C led to selective epoxide opening
and efficient cyclization to furnish lactone 18 (70%).[24]
With the tricyclic scaffold of the target constructed, the
final stages of the total synthesis were addressed. After
masking the primary hydroxy group in 18 as a TBS ether
(TBSCl, imidazole, DMAP, 89%), Lemieux–Johnson oxida-
tion afforded aldehyde 19 in 81% yield. Introduction of the
quaternary center at C(4) by enolate alkylation was compli-
cated by the presence of a g-lactone (pKa ꢁ 20). We reasoned
that the direct alkylation of an aldehyde (pKa ꢁ 17) could
offer the necessary chemoselectivity in the deprotonation
event. In the experiment, treatment of a solution of 19 in THF
at ꢀ208C with tBuOK (1.25 equiv),[25] followed by addition of
iodomethane (1.25 equiv) and warming to 08C delivered 20 as
a single isolable product. Pinnick oxidation of aldehyde 20 to
the corresponding carboxylic acid (76%) and cleavage of the
TBS group (74%) completed the first total synthesis of
asperolide C (1). The 1H and 13C NMR spectra of the
synthetic material were in agreement with those reported
Initial attempts to directly transform enone 8 to enol triflate
10 (LiHMDS, 2-NTf2-5-chloropyridine, THF, ꢀ788C) proved
unsuccessful. Therefore, a two-step protocol was examined,
which involved conversion of 8 into enol silane 9 followed by
exchange of the silyl group with the required triflate.
Formation of 9 under standard conditions was hampered by
polymerization of 8. However, the desired intermediate could
be obtained in good yield (95%) and excellent Z selectivity
(d.r. > 95:5) when 8 was added to a premixed solution of
LiHMDS and tert-butyldimethylsilyl chloride in THF at
ꢀ788C, using HMPA as a cosolvent. Enol triflate 10 was
obtained with complete retention of the olefin geometry by
treatment with triflic fluoride, generated in situ following the
procedure of Corey and co-workers (96%).[17] Cross-coupling
of enol triflate 10 and boronic acid 11 was achieved under the
conditions of Johnson and Braun, by using [Pd(dppf)Cl2]
(10 mol%) as
a catalyst in combination with Ph3As
(10 mol%) as a coligand and Cs2CO3 as a base to produce
the desired product 12 in 62% yield (Z/E = 10:1).[18–20] The
terminal olefin in diene 12 was hydroborated with 9-BBN and
the resulting trialkylborane was directly subjected to B-alkyl
Suzuki coupling with known vinyl iodide 14 to afford the
desired polyene (61%).[15,21] Removal of the TBS protective
group required carefully chosen conditions. Whereas
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[1] a) I. Chinou, Curr. Med. Chem. 2005, 12, 1295 – 1317; b) A. F.
Barrero, M. M. Herrador, P. Arteaga, J. F. Arteaga, A. F.
Arteaga, Molecules 2012, 17, 1448 – 1467.
[2] M. Singh, M. Pal, R. P. Sharma, Planta Med. 1999, 65, 2 – 8.
[3] M. Miyazawa, H. Shimamura, S. Nakamura, H. Kameoka, J.
Agric. Food Chem. 1995, 43, 3012 – 3015.
[4] H. Itokawa, H. Morita, I. Katou, K. Takeya, A. J. Cavalheiro,
R. C. B. de Oliveira, M. lshige, M. Motidome, Planta Med. 1988,
54, 311 – 315.
[5] H. Morita, H. Itokawa, Planta Med. 1988, 54, 117 – 120.
[6] B. Z. S. Awen, M. Nozawa, H. Hagiwara, Org. Prep. Proced. Int.
2008, 40, 317 – 363.
[7] L. M. T. Frija, R. F. M. Frade, C. A. M. Afonso, Chem. Rev. 2011,
111, 4418 – 4452.
Scheme 5. Reagents and conditions: a) DDQ (1.1 equiv), pH 7 buffer,
CH2Cl2, RT, 98%; b) DMP (1.5 equiv), CH2Cl2, RT, 80%; c) NaClO2
(4.0 equiv), NaH2PO4 (6.0 equiv), 2-methyl-2-butene (70 equiv),
tBuOH/H2O, RT; then Me3SiCHN2 (1.1 equiv), MeOH, 08C to RT,
79%; d) DMDO (1.1 equiv), acetone, ꢀ788C to ꢀ208C, 45% (66%
brsm); e) CF3CO2H (1.2 equiv), CH2Cl2, ꢀ208C to 08C, 70%; f) tBu-
Me2SiCl (3.0 equiv), imidazole (6.0 equiv), DMAP (10 mol%), CH2Cl2,
RT, 89%; g) OsO4 (20 mol%), NaIO4 (5.0 equiv), 2,6-lutidine
(2.0 equiv), 1,4-dioxane/H2O, RT, 81%; h) tBuOK (1.25 equiv), MeI
(1.25 equiv), THF, ꢀ208C to 08C, 36%; i) NaClO2 (6.0 equiv),
NaH2PO4 (6.0 equiv), 2-methyl-2-butene (30 equiv), tBuOH/H2O, RT,
76%; j) TBAF (1.5 equiv), THF, 08C, 74%. DDQ=2,3-dichloro-5,6-
dicyanobenzoquinone, DMP=Dess–Martin periodinane, DMDO=di-
methyldioxirane, DMAP=4-dimethylaminopyridine, TBAF=tetra-n-
butylammonium fluoride, brsm=based on recovered starting material.
[8] H.-F. Sun, X.-M. Li, L. Meng, C.-M. Cui, S.-S. Gao, C.-S. Li, C.-G.
Huang, B.-G. Wang, J. Nat. Prod. 2012, 75, 148 – 152.
[9] a) K. Ishihara, S. Nakamura, H. Yamamoto, J. Am. Chem. Soc.
1999, 121, 4906 – 4907; b) Y.-J. Zhao, B. Li, L.-J. S. Tan, Z.-L.
Shen, T.-P. Loh, J. Am. Chem. Soc. 2010, 132, 10242 – 10244;
c) K. Surendra, E. J. Corey, J. Am. Chem. Soc. 2012, 134, 11992 –
11994; d) A. Sakakura, A. Ukai, K. Ishihara, Nature 2007, 445,
900 – 903; e) S. Rendler, D. W. C. MacMillan, J. Am. Chem. Soc.
2010, 132, 5027 – 5029; f) R. R. Knowles, S. Lin, E. N. Jacobsen, J.
Am. Chem. Soc. 2010, 132, 5030 – 5032; g) C. A. Mullen, A. N.
Campbell, M. R. Gagnꢀ, Angew. Chem. 2008, 120, 6100 – 6103;
Angew. Chem. Int. Ed. 2008, 47, 6011 – 6014; h) S. G. Sethofer, T.
Mayer, F. D. Toste, J. Am. Chem. Soc. 2010, 132, 8276 – 8277.
[10] a) K. Ishihara, H. Ishibashi, H. Yamamoto, J. Am. Chem. Soc.
2001, 123, 1505 – 1506; b) H. Ishibashi, K. Ishihara, H. Yama-
moto, J. Am. Chem. Soc. 2004, 126, 11122 – 11123.
[11] a) G. Stork, A. W. Burgstahler, J. Am. Chem. Soc. 1955, 77,
5068 – 5077; b) A. Eschenmoser, L. Ruzicka, O. Jeger, D.
Arigoni, Helv. Chim. Acta 1955, 38, 1890 – 1904; c) P. A. Stadler,
A. Eschenmoser, H. Schinz, G. Stork, Helv. Chim. Acta 1957, 40,
2191 – 1298; d) A. Eschenmoser, D. Arigoni, Helv. Chim. Acta
2005, 88, 3011 – 3050.
[12] For more recent discussions, see a) L. Kꢁrti, R.-J. Chein, E. J.
Corey, J. Am. Chem. Soc. 2008, 130, 9031 – 9036; b) R. A. Yoder,
J. N. Johnston, Chem. Rev. 2005, 105, 4730 – 4756.
[13] R. J. Peters, Nat. Prod. Rep. 2010, 27, 1521 – 1530.
[14] For selected examples, see a) J. Y. Hamilton, D. Sarlah, E. M.
Carreira, Angew. Chem. 2013, 125, 7680 – 7683; Angew. Chem.
Int. Ed. 2013, 52, 7532 – 7535; b) S. Krautwald, D. Sarlah, M. A.
Schafroth, E. M. Carreira, Science 2013, 340, 1065 – 1068.
[15] M. A. Schafroth, D. Sarlah, S. Krautwald, E. M. Carreira, J. Am.
Chem. Soc. 2012, 134, 20276 – 20278.
[16] For pioneering studies from other research groups involving Ir-
catalyzed cyclizations with C-nucleophiles, see a) Q.-L. Xu, L.-
X. Dai, S.-L. You, Org. Lett. 2012, 14, 2579 – 2581; b) S. Streiff, C.
Welter, M. Schelwies, G. Lipowsky, N. Miller, G. Helmchen,
Chem. Commun. 2005, 2957 – 2959.
for the natural product. It should be noted that asperolide C
(1) was originally isolated as an inseparable 3:4 mixture with
the known terpene botryosphaerin, which precluded thor-
ough characterization. With a pure sample of 1 in hand, we
26
could measure its optical rotation for the first time (½aꢂD ¼
+ 2.5 (c = 0.25, MeOH)).
In conclusion, the first total synthesis of the tetranorlab-
dane diterpenoid asperolide C (1) has been achieved. This
study represents a rare example of the use of an enantiose-
lective polyene cyclization reaction in a natural product
synthesis and the first that strategically relies on modern
iridium catalysis to construct the carbobicyclic core scaffold.
Additionally, the described route features a series of cross-
coupling reactions to efficiently assemble the linear polyene
precursor. Specifically, the Pd-mediated coupling of a dienol
triflate with Me3SiCH2B(OH)2 provides a novel access route
to allylic silanes. Moreover, a chemo- and diastereoselective
alkylation of an aldehyde enolate was employed to complete
the target structure. The synthetic strategy provides a general
entry into the labdane-type diterpenoids and has significant
potential for enabling the total synthesis of other terpene
natural products.
[17] Y. Mi, J. V. Schreiber, E. J. Corey, J. Am. Chem. Soc. 2002, 124,
11290 – 11291.
[18] C. R. Johnson, M. P. Braun, J. Am. Chem. Soc. 1993, 115, 11014 –
11015.
[19] Cross-coupling under the conditions reported by Negishi and co-
workers (X. Zeng, M. Qian, Q. Hu, E. Negishi, Angew. Chem.
2004, 116, 2309 – 2313; Angew. Chem. Int. Ed. 2004, 43, 2259 –
2263) delivered the E isomer of 12 as the major product (X.
Zeng, Q. Hu, M. Qian, E. Negishi, J. Am. Chem. Soc. 2003, 125,
13636 – 13637).
Received: August 15, 2013
Published online: && &&, &&&&
[20] The olefin geometry of 12 and the corresponding E isomer were
unambiguously assigned by 2D NMR experiments (NOESY).
[21] For a review on the B-alkyl Suzuki – Miyaura cross-coupling
reaction, see S. R. Chemler, D. Trauner, S. J. Danishefsky,
Keywords: biomimetic synthesis · cyclization · diterpenes ·
iridium · total synthesis
.
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Angew. Chem. 2001, 113, 4676 – 4701; Angew. Chem. Int. Ed.
2001, 40, 4544 – 4568.
reaction: A. F. Barrero, J. F. Sꢂnchez, J. Elmerabet, D. Jimꢀnez-
Gonzꢂlez, F. A. Macꢃas, A. M. Simonet, Tetrahedron 1999, 55,
7289 – 7304.
[22] As determined by 1H NMR analysis of the crude reaction
mixture.
[25] a) E. Alvarez-Manzaneda, R. Chahboun, E. Alvarez, J. M.
Ramos, J. J. Guardia, I. Messouri, I. Chayboun, A. I. Mansour,
A. Dahdouh, Synthesis 2010, 3493 – 3503; b) T. N. Thompson,
M. G. Sierra, J. D. McChesney, J. Org. Chem. 1985, 50, 4447 –
4450.
[23] The relative and absolute configuration of the polyene cycliza-
tion product were determined by X-ray diffraction analysis of
a derivative (see the Supporting Information).
[24] Precedence for this transformation came from a report by
Barrero et al. who described a closely related process as a side
4
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Communications
Natural Product Synthesis
O. F. Jeker, A. G. Kravina,
E. M. Carreira*
&&&& — &&&&
Total Synthesis of (+)-Asperolide C by
Iridium-Catalyzed Enantioselective
Polyene Cyclization
Domino rings: A general synthetic entry
into labdane-type diterpenoids has been
developed based on an iridium-catalyzed
enantioselective polyene cyclization cas-
cade. The potential of this process is
demonstrated in the first total synthesis
of the tetranorlabdane diterpene aspero-
lide C (PMB=p-methoxybenzyl, TMS=
trimethylsilyl).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!