Transforming terpene feedstock into polyketide architecture

Article abstract of DOI:10.1039/c0cc02332a

The Cu-catalyzed synthesis of skipped 1,4-dienes from allylic acetates and vinyl-Grignard reagents is key to bidirectional modifications of acyclic terpene acetates. As a result, trisubstituted double bond containing subunits can be readily transferred into complex polyketides from inexpensive bulk terpenes.

Full text of DOI:10.1039/c0cc02332a

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Transforming terpene feedstock into polyketide architecturewz
Philipp Winter, Carine Vaxelaire, Christoph Heinz and Mathias Christmann*
Received 2nd July 2010, Accepted 24th August 2010
DOI: 10.1039/c0cc02332a
The Cu-catalyzed synthesis of skipped 1,4-dienes from allylic
acetates and vinyl-Grignard reagents is key to bidirectional
modifications of acyclic terpene acetates. As a result, trisubstituted
double bond containing subunits can be readily transferred into
complex polyketides from inexpensive bulk terpenes.
In contrast to terpene biosynthesis which has a sudden
increase in complexity through cationic cyclization events,
polyketide complexity grows in a rather sequential fashion
by two- and three-carbon building blocks. Instead of
mimicking the intricate biosynthetic machinery of polyketide
synthases, a potential shortcut lies in the possibility to
disconnect polyketides into larger fragments. When pondering
over the retrosynthesis of ripostatin B,11 a potent RNA
polymerase inhibitor,12 we realized that 22 out of its 30 carbon
atoms could—in principle—be derived from two molecules of
epoxygeranyl acetate (blue), phenyl- and vinylmagnesium
bromide (red) as starting materials. The key transformation
in such an approach would be the coupling of the Grignard
reagents with the allylic acetates.
The focus on target-oriented synthesis of biologically active
molecules is shifting toward more economic1 and sustainable
chemical processes.2 Among many approaches3 to quantify
synthetic efficiency, it has been recently suggested4 along the
lines of Hendrickson’s (1975) definition5 to use the quotient
(construction reactions + strategic redox reactions)/total
number of reaction steps as a yardstick for the ‘‘ideality’’ of
a given synthesis. We feel that this definition undervalues the
importance of minimizing construction steps, i.e. the overall
number of C–C-bond forming reactions. Our group’s research
is dedicated to making larger substructures within natural
products6 available from terpene feedstock,7 fermentation or
catalytic build-up reactions,8 e.g. telomerizations.9
While the substitution of allylic acetates with phenyl- and
alkylmagnesium halides using Li2CuCl4 was precedented by
Gansauer et al.,13 surprisingly, apart from particular examples
¨
of Pd-catalyzed couplings with vinylstannanes,14 no general
and scalable method for the synthesis of 1,4-dienes15,16
(skipped dienes) from allylic acetates has been reported to
our knowledge.
As a step toward this goal, we have embarked on the use of
oxidized monoterpenes in conjunction with the development
of efficient C–C bond forming reactions. Following this loose
strategic blueprint, we recently completed the synthesis
of englerin A10 from the epoxide of the readily available
monoterpene nepetalactone (Fig. 1).
The use of those previously established catalytic conditions
(Li2CuCl4 in THF) with vinylmagnesium bromide as the
nucleophile met limited success as only 23% of the desired
substitution product 2a was detected. After extensive
optimization,17 we found that using copper(I)-bromide
dimethylsulfide complex (20 mol% in THF) afforded 70% of
the desired substitution product. The yield could be further
improved by using 1.5 equivalents of vinylmagnesium bromide
with copper(I)-iodide (20 mol%) as catalyst in a solvent
mixture of tetrahydrofuran/dimethylsulfide (10 : 1) giving rise
to 88% of the skipped 1,4-diene 2a (Scheme 1).
In this communication, we would like to disclose a strategy
for the conversion of epoxygeranyl acetate (1a) and related
molecules into 1,4-dienes and representative subsequent
conversions into polyketide building blocks using organo-
catalytic and transition metal catalyzed reactions.
In order to probe the generality (functional group tolerance,
integrity of the trisubstituted double bond configuration) of
this reaction, we applied our best conditions to the vinyl
substitution of a variety of allylic acetates (Table 1). Both
epoxygeranyl and epoxyneryl acetate afforded the expected
1,4-dienes with complete retention of the configuration of the
allylic double bond (entries 1 and 2) in good to excellent yields.
In this instance, the epoxide serves as a handle in subsequent
transformations, readily converted to an aldehyde moiety
upon treatment with sodium periodate. In addition, their
parent derivatives (entries 3 and 4) reacted smoothly to give
the desired trienes. In the presence of non-allylic acetates, only
Fig. 1 Terpene epoxides and substructure analysis within ripostatin B.
TU Dortmund University, Otto-Hahn-Str. 6, D-44227 Dortmund,
Germany. E-mail: mathias.christmann@udo.edu;
Fax: +49 231 755 5363; Tel: +49 231 755 7854
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Synthetic
procedures, optimization of reaction conditions and characterization
of compounds. See DOI: 10.1039/c0cc02332a
Scheme 1 Optimized conditions for the synthesis of 1,4-dienes.
c
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Table 1 Investigation of the substrate scope
Yielda
(%)
Entry Substrate
Product
1
88
2
3
4
69
76
90
Scheme 2 Reagents and conditions: (a) NaIO4, THF/H2O (2 : 1),
20 1C; (b) (1) 4ꢀTFA, K2S2O8, LiCl, Cu(TFA)2ꢀxH2O, acetonitrile,
water, 4 1C, (2) NaBH4, 0 1C, (3) NaOH, EtOH, H2O, 20 1C;
(c) 2-methyl-1,3-dithiane, n-BuLi, THF, 20 1C; (d) PhI(TFA)2,
CaCO3, MeOH/acetonitrile (9 : 4), 20 1C.
Interestingly, the ripostatin C12–24 subunit 9 bearing a
skipped arene-ene moiety can be prepared in a similar approach
from epoxygeranyl acetate 1a (Scheme 3). Substitution with
phenylmagnesium chloride is followed by periodate cleavage
of the epoxide. In order to show the general potential of
combining the allylic substitution with an organocatalytic
aldol reaction with acetone,21 we obtained the quite advanced
fragment 9 in just three synthetic steps from 1a. The major
byproduct 10 can be converted to 9 with significantly higher
enantioselectivity than for the direct aldol reaction using an
oxa-Michael addition developed by List et al.22
5
6
54
52
7
8
66
47
Finally, we want to provide an example for the further
functionalization of the terminal alkene moiety in 2a.
Apart from possible hydroborations, oxidative cleavage and
cross-metathesis reactions, we want to use the hydroformylation
reaction for the introduction of a free aldehyde functionality
on one end of the aliphatic chain while the epoxide on the
other terminus remains a masked aldehyde (Scheme 4). Using
2 mol% of Rh(acac)(CO)2 and Xantphos23 as the ligand, we
obtained the unbranched aldehyde 12 in virtually quantitative
yield. We think that this model compound represents a useful
and orthogonally functionalized fragment for the natural
product dolabelide D.24
9
58
78
10
a
Isolated yields.
those in the allylic position are substituted in good to moderate
yield while the others remain unaffected (entries 5 to 8).
Furthermore, the presence of free alcohols is well tolerated
at the expense of one additional equivalent of Grignard
reagent (entries 9 and 10).
In order to showcase the bidirectional modification of
epoxydiene 2a and its potential use in the synthesis of polyketides,
we converted it into the C5–C15 fragment of ripostatin B
(Scheme 2). The four-step synthetic sequence commenced with
the cleavage of the epoxide moiety to yield dienal 3.
MacMillan et al.18 recently reported the elegant conversion of
aldehydes into epoxides using SOMO organocatalysis. Applying
this methodology, we were able to isolate the terminal epoxide 5
in an unoptimized 56% yield and with 95% ee. Epoxide
opening19 (5 - 6) followed by the oxidative removal of the
dithiane20 afforded hydroxyketone 7 in good yield.
Scheme 3 Reagents and conditions: (a) Li2CuCl4, PhMgCl, THF,
0 1C; (b) NaIO4, THF/H2O (2 : 1), 20 1C; (c) D-proline, i-PrOH,
acetone, 20 1C; (d) 11, Cl3CCO2H, H2O2, dioxane, 32 1C, then
P(OEt)3.
c
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S. Reyer, Angew. Chem., Int. Ed., 2009, 48, 3598.
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Scheme 4 Reagents and conditions: (a) Rh(acac)(CO)2, Xantphos,
toluene, H2/CO (20 bar), 60 1C.
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15 For an excellent overview, see: T. K. Macklin and G. C. Micalizio,
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16 (a) G. W. Kabalka and M. Al-Masum, Org. Lett., 2006, 8, 11;
In conclusion, we have developed a simple protocol for the
Cu-catalyzed substitution of allylic acetates with vinyl
Grignard reagents that is tolerant towards a variety of
functional groups. A possible ramification of this method is
the reduction of construction steps in the total synthesis of
polyketides. In particular, the efficient conversion of terpene
acetate derivatives into polyketide building blocks is a harbinger
of their increasing importance as cheap and renewable
resource in complex molecule synthesis.
(b) A. Furstner, O. Larionov and S. Flugge, Angew. Chem., Int.
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17 See the ESIz.
18 M. Amatore, T. D. Beeson, S. P. Brown and D. W. C. MacMillan,
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c
396 Chem. Commun., 2011, 47, 394–396
This journal is The Royal Society of Chemistry 2011