Ring strain and total syntheses of modified macrocycles of the isoplagiochin type

Article abstract of DOI:10.3762/bjoc.5.71

Macrocycles of the bisbibenzyl-type are natural products that are found exclusively in bryophytes (liverworts). The molecular framework of the subtype "isoplagiochin" is of substantial structural interest because of the chirality of the entire molecule, w

Full text of DOI:10.3762/bjoc.5.71

Ring strain and total syntheses of modified
macrocycles of the isoplagiochin type
Andreas Speicher*, Timo Backes, Kerstin Hesidens and Jürgen Kolz
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 71.
Department 8.1 Chemistry – Organic Chemistry, Saarland University,
66041 Saarbrücken, Germany
doi:10.3762/bjoc.5.71
Received: 23 July 2009
Email:
Accepted: 19 November 2009
Published: 01 December 2009
Andreas Speicher* - anspeich@mx.uni-saarland.de
* Corresponding author
Editor-in-Chief: J. Clayden
Keywords:
© 2009 Speicher et al; licensee Beilstein-Institut.
License and terms: see end of document.
axially chiral biaryl; isoplagiochin; macrocycle; ring strain; total
synthesis
Abstract
Macrocycles of the bisbibenzyl-type are natural products that are found exclusively in bryophytes (liverworts). The molecular
framework of the subtype “isoplagiochin” is of substantial structural interest because of the chirality of the entire molecule, which
arises from two biaryl axes in combination with two helical two-carbon units in a cyclic arrangement. From a structural as well as a
synthetic point of view we report on the total synthesis of compounds which possess more rigid two-carbon biaryl bridges like stil-
bene (E or Z) or even tolane moieties which were introduced starting with a Sonogashira protocol. The McMurry method proved to
be a powerful tool for the cyclization to these considerably ring-strained macrocycles.
Introduction
The cyclic bisbibenzyls isoplagiochin C (1) and D (2) were isol-
ated from the liverworts Plagiochila fruticosa [1], Plagiochila
deflexa [2], Herbertus sakuraii [3] and Lepidozia fauriana [4]
(Figure 1). Recently, an increasing number of different bio-
logical activities of phenolic compounds of the bisbibenzyl type
were reported [5-12].
Furthermore, the isoplagiochin framework proved to be of
substantial structural interest because of the chirality of the
entire molecule. The existence of atropoisomers [3] prompted
Figure 1: Structures of isoplagiochins C (1) and D (2) (with aryl frag-
ments a–d and possible conformational barriers A–D).
us to perform detailed studies on the chirality of 1 and 2
including HPLC-CD experiments. Assuming the existence of
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Beilstein Journal of Organic Chemistry 2009, 5, No. 71.
three formal stereogenic elements A–C (Figure 1), a total of up
to 23 = 8 conformers (four diastereomers with their enan-
tiomers) in principle are possible for 1 (and analogously for 2)
(Figure 2). The ethylene bridge D is more flexible in these two
molecules. Temperature dependent NMR investigations did not
provide any evidence for the existence of different diastereo-
mers configurationally stable within the NMR timescale. AM1-
based conformational analysis and MD investigations clearly
confirmed the biaryl axis A to be configurationally stable at
room temperature due to the second (more flexible) biaryl axis
B, an (even more flexible) helical stilbene unit C and their
combination with the ring-strain of the entire molecule.
By experimental and quantum chemical CD (circular
dichroism) investigations, the absolute configuration of the first
natural compound of this type, isoplagiochin C from P. deflexa,
was established as (PA)-1 and the energy of racemization was
Scheme 1: Stereochemical correlation for 1 and 2. (*: configuration-
ally stable, (*): configurationally semi-stable; o: configurationally
unstable).
calculated and measured to be 102 kJ/mol, approximately [13]. The natural compounds isoplagiochin D (2) and C (1) possess
The enantiomers (PA)-1 and (MA)-1 are each manifested in the two saturated ethylene bridges (between rings a–d and b–c) or
four imaginable, rapidly interconverting diastereomers whereby just one cis-configurated double bond (’stilbene bridge’)
the C2 conformations were estimated as the global minima between rings a–d. From a structural as well as a synthetic point
(Figure 2). Similar experiments and calculations were of view we were interested in compounds which possess
performed for isoplagiochin D (2) and for some chlorinated de- various unsaturated stilbene (E or Z) or even tolane bridges
rivatives. The stereochemical correlation between isoplagiochin between the two biaryl units a–b and c–d. These structures
C (1) and isoplagiochin D (2) was also confirmed experiment- should be more rigid with respect to the ring strain enhanced by
ally by hydrogenolysis of enantiopure samples of (PA)-1 to give geometrically fixed two-carbon bridges. But for ring strain
and (PA)-2 (Scheme 1), and of (MA)-1 to give and (MA)-2, considerations, the real cyclization product possessing at least
respectively, without any racemization [14].
additional phenolic protecting groups should be studied.
Figure 2: Possible stereoisomers of 1 as conformers C1–C4 relative to the configurationally stable biaryl axis A with the stereo descriptors P or M.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 71.
Results and Discussion
Indeed, temperature dependent 1H NMR investigations from
In our total syntheses of the racemic natural compounds 1 and 2 −20 up to 55 °C resulted in coalescence of the methoxy signals.
reported previously [15] the common and crucial precursor was By an approximation method [16] as well as by exact line form
the tetramethyl ether 3. Surprisingly and in contrast to the NMR analysis [17] the rotation barrier could be calculated to ~66 kJ/
results mentioned above for 1, closer NMR examination now mol indicating that the conformers are stable within the NMR
revealed two sets of signals for 3 indicating two conformers time scale but cannot be separated. By 2D NMR experiments
(ratio 1.3 : 1) stable within the NMR time scale. This can be (COSY, HSQC, HMBC) at 100 °C four sharp signals could be
interpreted as due to a much less flexible axis B resulting from assigned to the methoxy groups in rings a–d (Figure 3).
the stereochemically more demanding methoxy groups in the
o,o′-positions (Figure 3).
To gain insight into possible ring strain limitations for the
preparation and stability of modified macrocycles of the isopla-
giochin type we performed molecular mechanic and semi-
empirical calculations for tetramethyl protected target com-
pounds. Together with the molecules “in hand” they clearly
demonstrated that the bridge between a–d should be saturated
or at least a Z double bond as in the natural compounds 1 (cf. 3)
and 2 (cf. 4). An E double bond or an alkyne moiety are not
well tolerated (see e.g. 8, 9), even in the system with the lowest
possible strain, a saturated b–c-bridge. This can be deduced
mainly from the substantial angular strain in the alkyne moiety
(see 8) or from the distortion in the (E)-alkene moiety (see 9) as
well as in torsion stress looking at the aromatic rings a and d in
both candidates. The obvious reason for these effects is the
para-insertion of the aryl moiety d into the macrocyclic system.
In contrast, for the bridge b–c, the Z and E double bond as well
as a tolane bridge should be more easily realizable with respect
to angular strain and torsion stress (see compounds 5–7 in
Table 1).
As a consequence of these results we were interested in the
syntheses of the new bisbibenzyl frameworks 5–7. Our previ-
ously reported total syntheses of the racemic natural com-
pounds 1 and 2 [15,19] or some derivatives [20] could not be
adopted because they do not give rise to specific double bond
geometry or even an alkyne moiety between rings b and c.
Our new strategy of synthesis involved a consecutive coupling
of the rings a-b-c-d whereby the two-carbon bridge b–c would
be introduced by a Sonogashira type reaction yielding an alkyne
moiety (see 7), from which a Z double bond (for 5) or an E
double bond may be obtainable by Lindlar-type hydrogenation
and (for 6) by subsequent Z → E isomerization (Scheme 2). The
final ring closure using a McMurry protocol (probably more
rigorous for ring-strained frameworks than the Wittig-protocol
in the syntheses of 3/4) should give rise only to the Z geometry
at the a–d stilbene bridge.
The a–b part 14 [15] of the target molecules was prepared by
Suzuki coupling of the boronic acid 12 with its precursor 11,
readily available from 3-bromo-4-methoxybenzaldehyde (10)
[21] by an improved procedure [22]. The aldehyde 13 was
Figure 3: Temperature dependent 1H NMR and assignment of
methoxy signals in the tetramethyl ether 3.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 71.
Table 1: AM1 energies [18], angular strain and torsion stress of different modified macrocycles of the isoplagiochin type.
Compound
Molecular energya and
ring-strain
Compound
Molecular energya and
ring-strain
−7300
−7432
no torsion
low
α ~126°
no torsion
low
−7160
−7167
α = 128°
β = 130°
β′ = 132°
moderate
α ~129°
β = 119°
β′ = 128°
moderate
−7025
α = 129°
β = 168°
β′ = 175°
moderate
−7130
α = 155°
high
−7274
α = 120°
α′ = 123°
high
aThe calculations are given for the conformations resembling the most stable PA-1C2 conformer (see Figure 1). No significant deviations were observed
for other conformers. Note that molecular energy values should only be compared for isomeric compounds.
transformed into the terminal alkyne 14 by chain extension [23] workup liberating the aldehyde group – in a satisfactory yield of
(Scheme 3).
the mixed tolane 16 as the a-b-c precursor (Scheme 4).
The coupling of the terminal alkyne 14 with the iodoarene 15 Two different building blocks 22 and 26 were prepared as the
[24] as the “c” building block using a typical Sonogashira “d” ring for Suzuki coupling with the bromoarene 16
protocol [Pd(PPh3)4, CuI, Et3N] gave – even under an (Scheme 5). First, iodination of 3-hydroxybenzoic acid (18)
argon–hydrogen atmosphere [25] – only 30% yield beside the followed by double methylation and saponification of the
undesired homo-coupling product 17. A modified and palla- methyl ester yielded 4-iodo-3-methoxybenzoic acid (19) which
dium free procedure, however [26], resulted – after acidic could be reduced in two steps [27] to the benzylic alcohol 20
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Beilstein Journal of Organic Chemistry 2009, 5, No. 71.
Scheme 2: Strategy of synthesis for the macrocycles 5–7.
Scheme 3: Preparation of the terminal alkyne 13 as a–b part (TBATB = tetrabutylammonium tribromide).
Scheme 4: Sonogashira-type coupling to the tolane 16.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 71.
[28]. Protection as the THP acetal 21 was essential before and in higher overall yield directly from the bromoarene 16 and
preparing the boronic acid 22. Previously (see [15]), we the arylboronate 26.
reported on a synthesis of 22 starting with the bromination of
3-methoxybenzyl alcohol to 4-bromo-3-methoxybenzyl alcohol. Indeed, the cyclization of 28 to the macrocycle 7 bearing an
In contrast to the original contribution [29] bromination lead to “alkyne bridge” was successful in moderate yield using a
the formation of 2-bromo-5-methoxybenzyl alcohol, exclusive- McMurry protocol (Scheme 7) [32]. Hydrogenation of the
ly.
tolane 28 using Lindlar conditions selectively afforded the (Z)-
alkene 29 from which the (E)-alkene 30 could be obtained
Second, the triflate 24 was obtained from vanillin (23) and was selectively as well by an isomerization method [33,34]. From
further dioxane-protected at the aldehyde function (to 25) and both acyclic precursors 29 and 30 the macrocycles 5 and 6
directly transformed into the arylboronate 26 using pinacol- could be obtained analogously to 7. In all cases and as expected,
borane [30].
the new stilbene bridge was formed in the Z geometry exclu-
sively. For the new compounds 5–7 conformational studies by
Suzuki coupling of the boronic acid 22 with the bromoarene 16 measuring temperature dependent NMR spectra clearly indi-
under carefully optimized conditions followed by acidic workup cated significant rotational barriers of about 70 kJ/mol for the
afforded the hydroxyaldehyde 27 as precursor for cyclization biaryl axis B (see Supporting Information for each compound).
(Scheme 6). A cyclization protocol for the intramolecular These values, however, in comparison with the calculation for
Wittig reaction, well established [15,20] for the synthesis of the compound 3 (see Figure 3) indicate that the conformational
tetramethyl ether of isoplagiochin C (1), however failed in this flexibility of the macrocycles now synthesized is not signifi-
case. This might be due to the enhanced ring strain. Since the cantly diminished with respect to this second biaryl axes. This
McMurry reaction would provide more rigorous conditions for result is also in accordance with the only moderately enhanced
the formation of ring-strained frameworks, the hydroxyalde- ring strain predicted for 5–7 compared to the parent compounds
hyde 27 was oxidized to the dialdehyde 28. It is worth 3/4 (refer to Table 1).
mentioning that 28 could be obtained more straightforwardly
Scheme 5: Synthesis of the d building blocks 21 and 26. aThe original procedure in diluted ammonia [31] was replaced because deflagration to
detonation was observed in some cases due to formation of nitrogen iodide (NI3). bAttempts to direct reduction of the methyl ester or the carboxylic
acid using e. g. LiAlH4 failed due to concomitant deiodination. cProtection of the aldehyde was obligatory to prevent exclusive pinacolborane reduc-
tion. ddppf: 1,1′-bis(diphenylphosphino)ferrocene.
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Scheme 6: Synthesis of the tolane precursors 27 and 28 for cyclization.
Scheme 7: Synthesis of the modified macrocycles 5–7 from the dialdehyde precursors 28–30.
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