Catalytic enantioselective total synthesis of (+)-torrubiellone C

Article abstract of DOI:10.1021/ol201692h

Silyl-protected (R)-methyl 2-(hydroxymethyl)butanoate was obtained by an enantioselective Ir-catalyzed hydrogenation in high yield and selectivity. Elaboration of this building block via Takai and Stille reactions gave a protected hydroxy polyene chain, w

Full text of DOI:10.1021/ol201692h

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4368–4370
Catalytic Enantioselective Total Synthesis
of (þ)-Torrubiellone C
Henning J. Jessen,† Andreas Schumacher, Fabian Schmid, Andreas Pfaltz, and
Karl Gademann*
University of Basel, Department of Chemistry, 4056 Basel, Switzerland
karl.gademann@unibas.ch
Received June 23, 2011
ABSTRACT
Silyl-protected (R)-methyl 2-(hydroxymethyl)butanoate was obtained by an enantioselective Ir-catalyzed hydrogenation in high yield and
selectivity. Elaboration of this building block via Takai and Stille reactions gave a protected hydroxy polyene chain, which was coupled to a
5-hydroxyphenyl-4-hydroxy-2-pyridone derivative by a modified HornerꢀWadsworthꢀEmmons reaction. Deprotection gave synthetic (þ)-
torrubiellone C, which led to the assignment of the configuration of the natural product as (R).
Fungi that selectively infect and ultimately kill insects
are physically controlling their insect hosts through a
variety of interactions, some of which are postulated to
be mediated by small molecules.1 Among those, 5-phenyl-
2-pyridone-polyenes2 are found in several entomopatho-
genic fungi all over the world. The ecological function of
these compounds remains unclear, which is surprising
given their ubiquitous occurrence. Generic cytotoxicity
or insecticidal activity appears, however, to be unlikely.2
Therefore, one hypothesis includes that these compounds
are involved in controlling the insect host by the producer.
In addition to these fascinating biological phenomena,
the structural problem associated with these polyene pyr-
idones, and in particular the configuration of the stereo-
genic center(s) in the side chain, often required the use of
total synthesis for their ultimate assignment. We were
intrigued by the question if the recently reported3 torru-
biellone C (1, isolated from spiders in Nam Nao National
Park, Thailand) is of the same chirality (homochiral
according to the original definition) compared to other
members of this family such as 2ꢀ5, originally isolated
from different animals such as e.g. the mulberry small
weevil, Baris deplanata, for compound 4.4 The homochir-
ality of compounds found across fungi infesting various
insect species could point to a common evolutionary
ancestry of this class of compounds.
From a synthetic point of view, a structural feature of
polypropionates is often represented by arraysof (skipped)
methyl groups and many methods for their preparation
have been developed.5 Several members of the 5-phenyl-
2-pyridone family display this pattern, which was ad-
dressed by our studies on the total synthesis of pyridone
alkaloids.6 In contrast, the hydroxymethyl group in torru-
biellone C 1 leads to a different synthetic problem, i.e. the
stereoselective preparation of a hydroxymethyl-ethyl
(4) Takahashi, S.; Kakinuma, N.; Uchida, K.; Hashimoto, R.;
Yanagisawa, T.; Nakagawa, A. J. Antibiot. 1998, 51, 596–598.
(5) (a) Banfi, L.; Guanti, G. Synthesis 1993, 1029–1056. (b) Myers,
A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason,
J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511. (c) Masamune, S.; Choy,
W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24
1–30. (d) Zhou, J.; Burgess, K. Angew. Chem., Int. Ed. 2007, 46, 1129–
1131. (e) Des Mazery, R.; Pullez, M.; Lopez, F.; Harutyunyan, S. R.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966–9967.
(f) Negishi, E.; Tan, Z.; Liang, B.; Novak, T. Proc. Natl. Acad. Sci. U.S.
A. 2004, 101, 5782–5787. (g) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res.
2007, 40, 1402–1411. (h) Rein, C.; Demel, P.; Outten, R. A.; Netscher, T.;
Breit, B. Angew. Chem., Int. Ed. 2007, 46, 8670–8673.
† Present address: Institute of Organic Chemistry, University of Z€urich.
(1) Reviews: (a) Rohlfs, M.; Churchill, A. C. L. Fungal Genet. Biol.
2011, 48, 23–34. (b) Molnar, I.; Gibson, D. M.; Krasnoff, S. B. Nat.
Prod. Rep. 2010, 27, 1241–1275. (c) Roy, H. E.; Steinkraus, D. C.;
Eilenberg, J.; Hajek, A. E.; Pell, J. K. Annu. Rev. Entomol. 2006, 61
331–357.
(2) Review: Jessen, H. J.; Gademann, K. Nat. Prod. Rep. 2010, 27,
1168–1185.
(3) Isaka, M.; Chinthanom, P.; Supothina, S.; Tobwor, P.; Hywel-Jones,
N. L. J. Nat. Prod. 2010, 73, 2057–2060.
(6) Jessen, H. J.; Schumacher, A.; Shaw, T.; Pfaltz, A.; Gademann,
K. Angew. Chem., Int. Ed. 2011, 50, 4222–4226.
r
10.1021/ol201692h
Published on Web 07/28/2011
2011 American Chemical Society

substituted stereogenic center.7 Furthermore, only a few
synthetic approaches to related structures such as pyrido-
vericin 4 have been reported with low enantiomeric purity
or low yields.7c,8
Table 1. Identification of Optimal Conditions for the Catalytic
Hydrogenation
substrate ligand H2 temp conversiona
eea,b [%]
entry
PG =
L
[bar] [°C]
[%]
(configuration)
1
H
100 25
50 25
50 25
50 25
50 25
50 25
50 25
50 25
50 25
0
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
2
TBS
L1a
L1b
L1c
L1d
L2a
L3b
L1a
L2a
L3b
L1a
L2a
L3b
L3b
L3b
L3b
81 (R)
74 (R)
62 (R)
79 (R)
59 (S)
82 (R)
72 (R)
67 (S)
89 (R)
57 (R)
76 (S)
88 (R)
87 (R)
86 (R)
90 (R)
In addition, as pyridone alkaloids have recently been
shown to be neuritogenic6,9 and no biological activity had
been assigned to torrubiellone C 1,3 we were intrigued
to synthesize this compound for further biological assays.
We wanted to avoid the use of enantiomerically pure
startingmaterials, chiralauxiliaries, orenzymaticreactions
as previously reported7 and, therefore, planned to develop
a catalytic enantioselective hydrogenation for the prepara-
tion of the enantiomerically enriched key building block
(R)-methyl 2-(hydroxymethyl)butanoate.
The synthesis began with the preparation of a suitable
precursor for enantioselective hydrogenation. We and
others have previously demonstrated that R,β-unsaturated
esters are valuable substrates for Ir-catalyzed enantiose-
lective hydrogenations, allowing for the generation of the
prerequisite stereogenic center.5d,g,6 (E)-Methyl 2-(hydro-
xymethyl)but-2-enoate and the Si-protected derivatives as
substrates for the hydrogenation could be prepared in
multigram amounts (E/Z > 95:5) in four or five steps
starting from methyl acrylate, following a previously
published procedure (Table 1).10
3
TBS
4
TBS
5
TBS
6
TBS
7
TBS
8
TIPS
9
TIPS
10
11
12
13
14
15
16
TIPS
50
0
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
50 25
50 25
50 25
75 25
25 25
50
0
a Determined for the corresponding hydroxyester on a chiral GC
column. b (R) corresponds to (þ), (S) to (ꢀ).
double bond in the unprotected hydroxyester could not
be hydrogenated in the presence of Ir-catalysts even under
forcing conditions (entry 1 and SI). Strikingly, control
experiments with the Noyori Ru-BINAP catalyst also gave
conversions below 1%. The introduction of a TBS-pro-
tecting group (entries 2ꢀ7) successfully tackled this general
reactivity problem, and conversions usually above 99%
could be achieved.
A variety of conditions were evaluated to identify the
optimal procedure (Table 1; for a more detailed analysis
see Supporting Information (SI)). Unfortunately, the
(7) (a) Senanayake, C. H.; Larsen, R. D.; Bill, T. J.; Liu, J.; Corley,
E. G.; Reider, P. J. Synlett 1994, 199–200. (b) Loubinoux, B.; Viriot-
Chauveau, C.; Sinnes, J. L. Tetrahedron Lett. 1992, 33, 2145–2148. (c)
Zhang, Q.; Rivkin, A.; Curran, D. P. J. Am. Chem. Soc. 2002, 124, 5774–
5781. (d) Xie, X.-G.; Wu, X.-W.; Lee, H.-K.; Peng, X.-S.; Wong,
H. N. C. Chem.;Eur. J. 2010, 16, 6933–6941. (e) Katsumata, A.; Setsu,
F.; Tokunaga, Y.; Fukumoto, K. J. Org. Chem. 1996, 61, 677. (f)
Wullschleger, C. W.; Gertsch, J.; Altmann, K.-H. Org. Lett. 2010, 12,
1120–1123. (g) Izquierdo, I.; Plaza, M. T.; Rodriguez, M.; Tamayo, J.
Tetrahedron: Asymmetry 1999, 10, 449–456. (h) Yadav, J. S.; Nanda, S.;
Bashkar Rao, A. Tetrahedron: Asymmetry 2001, 12, 3223–3234. (i)
Panek, J. S.; Jain, N. F. J. Org. Chem. 2001, 66, 2747–2756.
(8) Baldwin, J. E.; Adlington, R. M.; Conte, A.; Irlapati, N. R.;
Marquez, R.; Pritchard, G. J. Org. Lett. 2002, 4, 2125–2127.
(9) (a) Cheng, Y.; Schneider, B.; Riese, U.; Schubert, B.; Li, Z.;
Hamburger, M. J. Nat. Prod. 2004, 67, 1854–1858. (b) Jessen, H. J.;
Barbaras, D.; Hamburger, M.; Gademann, K. Org. Lett. 2009, 11
3446–3449.
However, the screening of different chiral N,P-ligands
with TBS-protected substrate did not result in the identi-
fication of a catalyst producing an enantiomeric purity
above 82% ee (entry 7, analyzed by GC on chiral station-
ary phase after cleavage of the Si-protecting group; see
also SI). Introduction of bulkier Si groups (entries 8ꢀ16)
addressed this problem without losing the excellent con-
version with a low catalyst loading. With the TBDPS-
protected substrate and ligand L3b, very good enantios-
electivity was observed (88% ee, entry 13), which could be
increased to 90% ee by lowering the temperature (entry
16). Similar selectivity was observed with the TIPS-pro-
tected derivative (89% ee, entry 10).
(10) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2151–2161.
Org. Lett., Vol. 13, No. 16, 2011
4369

With optimal conditions identified, the hydrogenation
was successfully reproduced several times on a 1 mmol
scale of substrate 6 (1 mol % of Ir-catalyst, ligand L3b,
0 °C, 16 h, 50 bar of H2 in CH2Cl2, 0.2 M), which resulted
in sufficient material for the preparation of the side chain
oftorrubiellone C 1 (Scheme 1). After hydrogenation, ester
7 was reduced with DIBAL-H and oxidized with TPAP
under careful control of the temperature to avoid racemi-
zation. The obtained aldehyde was subjected to a Takai
olefination11 yielding iodoolefin 8 as an inseparable mix-
ture of E/Z isomers (E/Z = 6:1). Iodoolefin 8 was coupled
with stannane 912 to smoothly produce the homologated
alcohol 10. At this stage, the E/Z ratio could be increased
to 15:1 by flash chromatography on silica gel. After
oxidation and flash chromatography, the prerequisite
aldehyde 11 for the envisaged HornerꢀWadsworthꢀ
Emmons (HWE) reaction13 was obtained in good yield
and with an increased E/Z ratio (18:1).
was feasible, and the mixture was finally treated with 5%
TFA in CH2Cl2 for 10 min, yielding torrubiellone C 1 as a
mixture of E/Z isomers. The isomerically pure synthetic
natural product was finally obtained by recrystallization
from MeOH/CH2Cl2/pentane (1:4:16) in a combined yield
of 54% over the last three steps. The analytical data of the
synthetic material were found to be identical in all respects
in comparison with the published values,3 except for the
inverted [R]D value. The configuration of naturally occur-
ring (ꢀ)-torrubiellone C 1 is therefore assigned as (R). As a
consequence, the hydroxylated natural product 1 is homo-
chiral to, e.g., pretenellin B 2 or farinosone A.6
Scheme 2. Synthesis of (þ)-Torrubiellone C 1
Scheme 1. Preparation of the Side Chain 11
HWE coupling of the unsaturated aldehyde to the
known6 functionalized pyridone phosphonate 12 was
achieved in good yield following the previously described
conditions (Scheme 2).6 A mixture of THF/water and
LiOH as a base were found to be essential to suppress side
reactions. The reaction was conducted under exclusion of
light in degassed solvents. Thus, protected torrubiellone C
13 was obtained in 45% yield and an E/Z ratio of >12:1
in favor of the desired all-E isomer. Cleavage of the methyl
ether occurred in the presence of freshly crystallized
LiI/pyridinium chloride in degassed THF at 60 °C.6 These
conditions were found to suppress the pronounced ten-
dency of the side chain to isomerize. However, partial
isomerization of one of the double bonds was observed.
At this stage, no separation of the isomers was possible and
the mixture was further deprotected with TBAF in THF.
Again, no separation by flash chromatography or HPLC
In conclusion, the synthetic approach described yielded
the enantiomeric natural product (þ)-torrubiellone C 1 in
24 steps (13 step longest linear sequence). Salient features
of this modular synthesis are the Ir-catalyzed enantiose-
lective hydrogenation for the efficient preparation of (R)-
methyl 2-(hydroxymethyl)butanoate as well as the mod-
ified HWE reaction to introduce a polyene moiety directly
to a highly functionalized pyridone core structure without
racemization. The neuritogenic properties of torrubiellone
C as well as an enantioselective total synthesis of related
pyridovericin 4 are currently under investigation.
Acknowledgment. K.G. is a European Young Investi-
gator (EURYI). We thank the Swiss National Science
Foundation (PE002-117136/1, 200020-129494) and the
DFG (JE 572/1-1).
(11) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
7408–7410.
(12) Lai, M.-T.; Li, D.; Oh, E.; Liu, H.-W. J. Am. Chem. Soc. 1993,
115, 1619–1628.
(13) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733–1738.
4370
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