Synthesis and characterization of cyclopropylpolyketides: A combined experimental and theoretical study

Article abstract of DOI:10.1002/ejoc.200701140

The first open-chain cyclopropylpolyketides were prepared and characterized by experimental and computational methods. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701140

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200701140
Synthesis and Characterization of Cyclopropylpolyketides: A Combined
Experimental and Theoretical Study
Thomas Rahn,[a,b] Haijun Jiao,[b] Wolfgang Baumann,[b] Anke Spannenberg,[b] and
Peter Langer*[a,b]
Keywords: Cyclopropanes / Density functional theory / Ketones / Conformations
The first open-chain cyclopropylpolyketides were prepared
and characterized by experimental and computational meth-
ods.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
A great variety of pharmacologically important natural
products are biosynthetically derived from poly(β-oxo)-
carboxylic acids (polyketides).[1] Polyketides and related
1,3-oligocarbonyl derivatives also represent important syn-
thetic building blocks (e.g. for the synthesis of polyols by
stereoselective reduction).[2] Harris and co-workers reported
the biomimetic synthesis of various polyketides A based on
the condensations of 1,3-dicarbonyl dianions or 1,3,5-
tricarbonyl trianions with carboxylic acid derivatives (Fig-
ure 1).[3] Tetraketides and their higher homologues are un-
stable and rapidly undergo an intramolecular aldol conden-
sation to give polyhydroxylated arenes. Therefore, open-
chain polyketides are unknown to date. An exception are
3,5-dioxopimelates which contain two terminal ester groups
and thus cannot undergo an intramolecular aldol conden-
sation.[4] The same is true for hitherto unknown oligocyclo-
propanes B which are, in a formal sense, analogues of poly-
ketides lacking the CH-acidic methylene groups.[5,6] Cy-
clopropyl-based molecular architectures are of considerable
theoretical and structural interest.[7] In recent years, versa-
tile synthetic approaches to open-chain oligocyclopro-
panes[8] and σ-[n]helicenes[9] have been developed. Trispiro-
[2.1.2.1.2.1]dodecane-4,8,12-trione, which can be regarded
as a cyclic cyclopropyltriketide, was prepared in low yield
by a Zn/Cu-mediated transformation of 1-bromocyclo-
propanecarboxylic chloride.[10]
Figure 1. General structures of open-chain polyketides.
Results and Discussion
Our strategy for the synthesis of cyclopropylpolyketides
relies on a straightforward sequence of chain elongation by
acylation and subsequent cyclopropanation (Scheme 1,
Table 1). The K2CO3-mediated[11] cyclopropanation of 1-
(cyclopropyl)butane-1,3-dione and benzoylacetone with
1,2-dibromoethane afforded the cyclopropanes 2a and
2b.[12] The LDA-mediated reaction of 2a with cyclopro-
panecarboxylic chloride gave 3a in up to 65% yield. Like-
wise, the condensation of 2b with cyclopropanecarboxylic
chloride and benzoyl chloride afforded 3b and 3c, respec-
tively. Products 3a–c exist as mixtures of keto-enol tauto-
mers. The cyclopropanation of 3a–c with 1,2-dibromoeth-
ane afforded the desired cyclopropyltriketides 4a–c. During
the optimization, the stoichiometry and the concentration
played an important role. The structure of 4c was indepen-
dently confirmed by an X-ray crystal structure analysis
(Figure 2).[13]
The reaction of dimethyl cyclopropane-1,1-dicarboxylate
(5) with 1-cyclopropylethan-1-one afforded 7 which was
transformed into triketide 8 (Scheme 2). The best yield of 7
was obtained when sodium methoxide and MTBE were
used as base and solvent, respectively. Noteworthy, the use
of KOtBu or LDA was unsuccessful, as it led to a retro-
Claisen reaction.
[a] Institut für Chemie, Universität Rostock,
Albert-Einstein-Straße 3a, 18059 Rostock, Germany
Fax: +49-381-498-6411
E-mail: peter.langer@uni-rostock.de
[b] Leibniz Institut für Katalyse e. V. an der Universität Rostock,
Albert-Einstein-Straße 29a, 18059 Rostock, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
The NaOMe-mediated reaction of 5 with 2a afforded the
cyclopropyltetraketide 9 which represents a rare example of
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T. Rahn, H. Jiao, W. Baumann, A. Spannenberg, P. Langer
SHORT COMMUNICATION
an open-chain tetraketide (Scheme 3). The cyclopropan-
ation of 9 proved to be unsuccessful under various condi-
tions.
Scheme 3. Synthesis of cyclopropyltetraketide 9. Conditions: i: (1)
NaOMe, MTBE, 30 °C, 3 h, (2) HCl (10%).
Scheme 1. Synthesis of cyclopropyltriketides 4a–c. Conditions: i:
1,2-dibromoethane (2.0 equiv.), K2CO3 (4.0 equiv.), DMSO, 20 °C,
8 h; ii: (1) LDA (1.2 equiv.), THF, –78 °C, 1 h, (2) acyl chloride,
–78 Ǟ 20 °C, 12 h.
We have also carried out B3LYP6-311+G(d,p)[14] density
functional theory computations on the structural and
energetic properties of the cyclopropylpolyketides using
the Gaussian 03 program package.[15] The B3LYP/6-
311+G(d,p) method has been benchmarked on the basis of
the comparison between the computed and experimentally
determined relative energy and structural parameters of di-
cyclopropyl ketone (Figure 3).
Table 1. Synthesis of cyclopropyltriketides 4a–c.
2
3,4
R1
R2
% of 2[a]
% of 3[a]
% of 4[a]
a
b
b
a
b
c
cPr
Ph
Ph
cPr
cPr
Ph
70
75
75
65
47
22
30
64
30
[a] Isolated yields.
Figure 3. Conformation and energy of dicyclopropyl ketone.
It has been shown experimentally that dicyclopropyl
ketone possesses one syn/syn and one syn/anti conforma-
tion.[16] The syn/syn conformer (93%) has two cyclopropyl
rings pointing towards the oxygen atom of the carbonyl
group; the syn/anti conformer (7%) has one cyclopropyl
ring pointing towards and one pointing away from the car-
bonyl group. Along with the perfect agreement of the bond-
ing parameters (see Supporting Information), the computed
relative free energy of 1.78 kcal/mol gives a ratio of
92.3%:7.7% which is also in perfect agreement with the ex-
periment.
Figure 2. ORTEP plot of 4c.
The computed most stable conformer of 4c (Figure 4) is
in perfect agreement with the X-ray crystal structure analy-
sis (Figure 2). The two cyclopropyl rings have a syn confor-
mation to the central carbonyl group, and the carbonyl
groups of the benzoyl groups also exist in a syn conforma-
tion to the cyclopropyl rings (syn/syn; syn/syn). A closer
inspection shows that the C1–O1 and C2–C10 bonds exist
in an eclipsed orientation with a torsional angle of 9.55°
(calcd. 0.04°), and the C2–C11 and C3–O2 bonds are also
in an eclipsed orientation with a torsional angle of –15.11°
(calcd. –18.05°). Apart from the syn/syn; syn/syn conformer,
we have found another conformer having a syn/syn confor-
mation of the two cyclopropyl groups to the central ketone
group, but an anti/anti conformation of the two benzoyl
Scheme 2. Synthesis of cyclopropyltriketide 8. Conditions: i: (1)
NaOMe, MTBE, 30 °C, 3 h, (2) HCl (10%); ii: 1,2-dibromoethane
(2.0 equiv.), K2CO3 (4.0 equiv.), DMSO, 20 °C, 8 h.
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Synthesis and Characterization of Cyclopropylpolyketides
substituents. However, the latter conformer is 9.32 kcal/mol
higher in energy than the former one, and thermodynami-
cally not competitive (Figure 4). Detailed inspection of the
IR spectrum of 4c (ATR) shows two sharp C=O bands (as-
signed to the central and to the benzoyl carbonyl groups)
which have been confirmed by the computations. This result
shows that only one conformer is present.
Experimental Section
General Procedure for the Synthesis of Cyclopropyloligoketides 4:
To a suspension of K2CO3 (4.0 equiv.) in DMSO (0.3–0.5 mL/
mmol) was added 3 (1.0 equiv.). To the reaction mixture was added
dropwise dibromoethane (2.0 equiv.) at 20 °C with vigorous stir-
ring. After stirring at 20 °C for 8 h, K2CO3 was removed by fil-
tration. The solid was thoroughly washed with diethyl ether. The
filtrate was washed with water until the yellow colour had disap-
peared, dried (Na2SO4) and concentrated in vacuo. The residue was
purified by column chromatography (hexane/EtOAc, 2:1) to give
product 4.
Synthesis and Spectroscopic Data of 4a: Starting with 3a (0.500 g,
2.27 mmol), dissolved in
a suspension of K2CO3 (0.784 g,
5.68 mmol) in DMSO (0.7 mL) and 1,2-dibromoethane (0.2 mL,
2.27 mmol), 4a was isolated as a colorless oil (0.17 g, 30%). 1H
NMR (400 MHz, CDCl3): δ = 0.89 and 1.02 (2 m, 2 H each, CH2),
1.63 (AAЈBBЈ, 4 H, CH2), 1.86 (tt, 2 H, CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 12.0 (CH2), 17.6 (CH), 19.3 (CH2), 43.2
(C), 202.1, 205.5 (CO) ppm. IR (neat): ν = 3096 (m), 3011 (s), 1681
˜
(s, br.), 1570 (m), 1444 (s), 1392 (s, br.), 1319 (s), 1280 (s), 1198
(m), 1107 (s), 1085 (s), 1061 (s), 1006 (s), 953 (m), 936 (w), 922 (w),
893 (m), 841 (w) cm–1. MS (EI, 70 eV): m/z (%) = 246 (0.3) [M+],
218 (82.9), 203 (17.7), 177 (19.4), 121 (15.0), 69 (100). C15H18O3
(246.30): calcd. C 73.15, H 7.37; found C 73.30, H 7.36.
Figure 4. Conformation and energy of 4c.
For triketide 4a also two conformers were found which
have structures like those of derivative 4c. In one conformer
all cyclopropyl rings are oriented syn to the carbonyl
groups, while the other one has a cyclopropylcarbonyl
group anti to the cyclopropyl groups. However, both con-
formers are very close in free energy (0.06 kcal/mol) which
results in an equilibrium ratio of 52%:48% (Figure 5). The
IR spectrum of 4a (neat) shows a broad C=O band which
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, compound characterization, copies
of VT-NMR spectra, and details of the computations.
Acknowledgments
1
suggests that more than one conformer is present. H and
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
13C NMR experiments at about –100 °C may also be taken
as evidence of such an interconversion with a low activation
barrier (line broadening observed predominantly for the
CH2 signals of the central cyclopropane). However, as nei-
ther coalescence nor the region of slow exchange were
reached, the nature of interconverting species remains
speculative.
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The first open-chain cyclopropylpolyketides were pre-
pared and characterized by experimental and computa-
tional methods. We currently study the chemical behavior
of cyclopropylpolyketides and the synthesis of higher
homologues.
Eur. J. Org. Chem. 2008, 971–974
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T. Rahn, H. Jiao, W. Baumann, A. Spannenberg, P. Langer
SHORT COMMUNICATION
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Received: November 30, 2007
Published Online: January 15, 2008
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Eur. J. Org. Chem. 2008, 971–974