Remote induction of asymmetry in [13]-macro-dilactone topology by a single stereogenic center

Article abstract of DOI:10.1039/b807562j

Analysis of a series of unsaturated [13]-macro-dilactones showed that the configuration of a single carbon dictates the planar chirality of a macrocycle backbone and in turn remotely switches the facial display of an embedded alkene unit. The Royal Society of Chemistry.

Full text of DOI:10.1039/b807562j

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Remote induction of asymmetry in [13]-macro-dilactone topology by a
single stereogenic centerw
W. Sean Fyvie and Mark W. Peczuh*
Received (in College Park, MD, USA) 6th May 2008, Accepted 17th June 2008
First published as an Advance Article on the web 29th July 2008
DOI: 10.1039/b807562j
Analysis of a series of unsaturated [13]-macro-dilactones showed
that the configuration of a single carbon dictates the planar
chirality of a macrocycle backbone and in turn remotely switches
the facial display of an embedded alkene unit.
Medium rings containing an embedded (E)-alkene are known
to take up left- or right-handed helical topologies whose
absolute configurations are defined by a planar chirality.1,2
Individual factors influencing the configuration of the macro-
cycle include size,3,4 points of articulation,5,6 and substituents
that adorn the ring.7 Interplay between these features governs
the energetics of transannular interactions and ultimately the
low energy conformation of a given structure.
Reported here is a novel example where a single stereogenic
center dictates the planar chirality of a [13]-macro-dilactone
prepared by a ring closing metathesis (RCM) reaction. Inverting
the stereochemistry at the key stereocenter was found to invert
the handedness of the macrocyclic backbone. Control of planar
chirality in a macrocycle based on this effect has consequences
on the facial selectivity in reactions of the ring alkene and also
on the molecule’s ability to interact with biological targets.
Scheme 1 Products of DMDO-mediated epoxidation followed by
Zemplen transesterification (NaOCH3–MeOH) of bicycles (1–4) in-
cluding (two step) yields of the appropriate dimethyl 4,5-epoxy-
octanedioates.
We recently reported on the epoxidation of carbohydrate-
fused [13]-macro-dilactones.8 In the dimethyldioxirane
(DMDO) mediated epoxidation of 1 and 2 (Scheme 1) oppo-
site alkene faces reacted to give, after transesterification,
enantiomeric epoxy-octanedioates 5 and 6 with high selectiv-
ity. The switch in stereoselectivity was dramatic considering
the only difference was the configuration9,10 at the C2 atom.
Structural information from X-ray crystallographic data on 2
and the epoxide derived from it showed that 2 presented the
pro-S,S face of the ring alkene for reaction with electrophiles.
Further comparison of the X-ray structures of the alkene- and
epoxide-containing macro-dilactones showed that, aside from
the epoxide oxygen, they had the same macrocyclic conforma-
tion. In the present work we endeavoured to define the
minimum structural requirement that could recapitulate the
observed conformational switch. To that end, we first approxi-
´
mated the pyranose skeleton of 1 and 2 with a functionalized
cyclohexane as in 3 and 4.
Based on our rationale, 3 and 4 represented readily acces-
sible ‘‘pseudo’’ enantiomers of 1 and 2. The syntheses of 3 and
4 started from the diols (1S,2S)-2-(hydroxymethyl)cyclo-
hexanol and (1R,2S)-2-(hydroxymethyl)cyclohexanol, respec-
tively.11 Similar to our earlier strategy, the diols were acylated
with 4-pentenoic acid then cyclized by RCM.12 Epoxidation
and transesterification provided a functional read-out on the
configuration of the new macro-dilactones. In accordance with
the ‘‘pseudo’’ enantiomer model, cis-fused macro-dilactone 3
provided the (4R,5R)-epoxy-octanedioate 5 and the trans-
fused 4 gave the (4S,5S)-enantiomer. The results supported
our prediction that the alkene topology of 4 was enantiomeric
to 1 whereas that of 3 was enantiomeric to 2. Evidence in
support of this argument came from comparison of the crystal
structures corresponding to the epoxide derived from 2 and the
epoxide derived from 3.13 Fig. 1 depicts the enantiomeric
relationship of the macrocyclic backbone in these two struc-
tures where 3[epox]z contains a right-handed helical twist and
2[epox] a left-handed one. Stereogenic centers elsewhere on the
pyranose apparently did not influence the backbone
Department of Chemistry, University of Connecticut, Storrs, CT
06269, USA. E-mail: mark.peczuh@uconn.edu;
Fax: +1-860-486-2981; Tel: +1-860-486-1605
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data for all intermediates
in the preparation of 3, 4 and 7; full data on the determination of facial
selectivity of 3 and 4; crystallographic reports for 3[epox], 4[epox] and
7. CCDC reference numbers 686765–686767. For ESI and crystal-
lographic data in CIF or other electronic format see
DOI: 10.1039/b807562j
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Fig. 1 Crystal structures, centered on the epoxide ring oxygen, of the
[13]-macro-dilactone epoxides derived from 2 and 3. The enantiomeric
macrocycle topology is emphasized by coloring atoms that are part of
the macrocycle while shading those that are not.
Fig. 2 Structural features of [13]-macro-dilactone 7. (A) Top view of
(R)-7 with red boxes defining the three planar units in the macrocycle.
(B) Newman projection of S (left) and R (right) configurations
depicting the eclipsing relationship of C2 with its CQO oxygen. The
methyl group is positioned on the outside of the macrocycle.
conformation of the macro-dilactone. In fact, careful inspec-
tion of the macro-dilactone structures in Scheme 1 suggested
that the key factor governing the shape of these molecules is
the absolute configuration at C2 of the macrocycle. Note that
macro-dilactones 1 and 3 with the S configuration at C2 gave 5
whereas those with the R configuration (2 and 4) gave 6. We
hypothesized that the configuration of the other stereocenter
(C3) in 3 and 4 was of little or no consequence for determining
the planar chirality of the corresponding macro-dilactones.
In order to gauge the importance of the stereochemistry at
the C2 position and to determine how important the fused ring
feature was for maintaining the macrocyclic topology, we
prepared macro-dilactone 7. For 7, there is only one stereo-
genic center with the sole substituent on the macrocyclic
backbone being a methyl group in place of the erstwhile
pyranose/cyclohexane moiety. Macrocycle 7 was prepared
from racemic 1,3-butanediol following the acylation/RCM
route. Surprisingly, the new macro-dilactones appeared to be
of one atropisomer for each enantiomeric configuration.14 It
seemed that 7 was a racemic mixture of only two enantiomeric
[13]-macro-dilactones. One (E)-alkene configuration was being
formed for each of the R and S configured molecules. This
observation proved to be consistent with the structure of 7
(vide infra) and the thermodynamic conditions15 of the RCM
reaction. We reasoned that the backbone of the macro-dilac-
tone fell into one of two low energy sinks exhibiting the
classic helical chirality akin to that known for (þ)- and (ꢁ)-
(E)-cyclooctene.16 Overall, the results showed that the magni-
tude of the effect arising from the stereochemistry at C2 was
greater than anticipated.
(C4–O5–C6–C7 ¼ 175.11, C12–C13–O1–C2 ¼ 178.51).17 To-
gether these three units comprise 12 of the 13 atoms in the
macrocycle and likely make a significant contribution to its
rigidity.18 The only atom not in a planar motif is C3. It is
expected that a [13]-macro-dilactone similar to those reported
here, but having substitution at C3 rather than C2 would give
macro-dilactones of both planar chiralities for each C3 con-
figuration.14 This is because the symmetry contained in the
diene starting material would render the C3 substituents
homotopic. There would be no energetic preference for one
(E)-alkene geometry over another. By virtue of the s-trans
conformation of the ester, C2 is eclipsed with its carbonyl
oxygen and positions its substituents either into the macro-
cycle or away from it (Fig. 2). Along with the other ester
carbon (C4), C2 is unique in disposing its substituents in this
way. The other sp3 carbons (C3, C7, C8, C11, C12) dispose
their substituents in either a pseudo-axial or pseudo-equatorial
manner. This preference to put the most sterically demanding
substituent on the outside of the ring determines the handed-
ness of the helix backbone twist. The descent into either the
right- or left-handed helical twist driven by the methyl group is
facilitated by the loss of rotational freedom imparted by the
planar units. As a result, this stereogenic center governs the
overall molecular topology based on these features (Fig. 3).
In conclusion, we have demonstrated that a methyl group
can chaperone the macrocyclic backbone skeleton of
[13]-macro-dilactones into of one of two enantiomeric con-
formations. The handedness of the macrocycle’s helical twist is
governed by the configuration of the stereogenic center in the
context of one of the planar units of the macro-dilactone. The
effect is pronounced enough so that by modifying the config-
uration of the key backbone carbon (C2/C4) with something
as simple as a methyl group, a complete switch in the facial
presentation of the reactive alkene five atoms/bonds away
occurs. In fact, this effect persists even in the presence of other
substituents (as in the case of the cyclohexyl- or pyranosyl-
substituted macro-dilactones) on the macrocyclic backbone.
Finally, the structural features enumerated here, which enable
such consummate conformational stereocontrol, will find
Racemic 7 formed a crystalline solid that was analyzed by
X-ray crystallography.y The unit cell from the crystal structure
contained both enantiomers of 7 related by a center of
symmetry. From the data was developed a model describing
the effects of the sole stereocenter on the conformation of the
macrocycle. We speculated that the effects observed in this
minimal [13]-macro-dilactone (7) would translate to the fused
bicyclic macro-dilactones.
The major architectural features that govern macrocycle
topology are the three planar units in the macrocycle5,6 and
the stereogenic carbon at C2 (Fig. 2). The first planar unit in 7
is the alkene unit itself—including the two allylic carbons
adjacent to it (C8–C9–C10–C12 dihedral ¼ 174.81). Similarly,
both esters in 7 adopt the archetypal s-trans conformation
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1 U. Nubbemeyer, Eur. J. Org. Chem., 2001, 1801.
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Fig. 3 (A) Overlay of (R)- and (S)-7 superimposed along the
C12–C13–O1–C2 dihedral angle from the X-ray data. R is displayed
in blue and S in green. The view emphasizes the influence of the chiral
center and its pendant methyl group in governing the macrocyclic
configuration. (B) Side view of the macrocyclic backbones of (S)-7
(left) and (R)-7 (right).
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´
application in organic synthesis and biological chemistry.
Given a facile transesterification reaction, the stereoselective
epoxidation reactions of alkenes embedded in the [13]-macro-
dilactones reported here could be developed into an organo-
catalytic process using chiral 1,3-diols as auxiliaries. Alterna-
tively, the key structural features governing this system may be
integral to understanding the structure/conformation of
macrocyclic natural products and to the design of novel
natural product like molecules with desired biological
activities.
8 W. S. Fyvie and M. W. Peczuh, J. Org. Chem., 2008, 73, 3626.
9 The anomeric stereochemistry for 1 and 2 is also opposite (a versus
b), but the earlier investigation (ref. 8) showed this to be incon-
sequential. Numbering of atoms in the macrocycles follows that for
1 in Scheme 1.
10 Related examples of remote asymmetric induction in a macro-
cyclization reaction have been reported. See: (a) E. I. Troyansky,
R. F. Ismagilov, V. V. Samoshin, Y. A. Strelenko, D. V. Demchuk,
G. I. Nishikin, S. V. Lindeman, V. N. Khrustalyov and Y. T.
Struchkov, Tetrahedron, 1995, 51, 11431; (b) Y. Jia, M.
Bois-Choussy and J. Zhu, Angew. Chem., Int. Ed., 2008, 47, 4167.
11 Diols were prepared by DIBAL reduction of (S)-a-hydroxymethyl
cyclohexanone. The hydroxymethyl cyclohexanone was prepared
by a proline catalyzed enantioselective aldol reaction. See: J. Casas,
This research was supported by an NSF CAREER award to
MWP (CHE-CHE-0546311). We thank Chris Incarvito of
Yale University for the collection of the X-ray crystallographic
data.
H. Sunden and A. Cordova, Tetrahedron Lett., 2004, 45, 6117.
´
New compound syntheses and characterization details are in the
ESIw.
12 The (E)-alkene configured [13]-macro-dilactones were the major
products observed in the preparation of 3, 4 and 7.
13 Crystallographic data for 3[epox] (and 4[epox]z) could not confirm
absolute stereochemistry. The absolute stereochemistry shown is
consistent with the enantioselectivity of the aldol used to prepare
the starting diols (see ref. 11).
14 If both atropisomers were present, we would expect two diaster-
eomeric pairs of enantiomers.
15 A. Furstner, K. Radkowski, C. Wirtz, R. Goddard, C. W.
Lehmann and R. Mynott, J. Am. Chem. Soc., 2002, 124, 7061.
16 E. L. Eliel and S. H. Wilen, Chirality in Molecules Devoid of
Chiral Centers, in Stereochemistry of Organic Compounds, John
Wiley & Sons, New York, 1994, pp. 1172–1175.
17 (a) E. L. Eliel and S. H. Wilen, Conformation of Acyclic Mole-
cules, in Stereochemistry of Organic Compounds, John Wiley &
Sons, New York, 1994, pp. 618–620; (b) P. I. Nagy, F. R. Tejada, J.
G. Sarver and W. S. Messer, Jr, J. Phys. Chem. A, 2004, 108,
10173.
Notes and references
z X-Ray quality crystals of 3[epox] were obtained by slow evaporation
from hexanes. C15H22O5, M ¼ 282.33, orthorhombic, a ¼ 6.4153(13),
b ¼ 12.269(3), c ¼ 18.605(4) A, U¼1464.4(5) A3, T ¼ 173(2) K, space
group P212121,
Z
¼
4 3801 reflections measured, 2021 unique
(Rint ¼ 0.0000, Friedel pairs were not merged.). The final wR(F2)
was 0.1022 (all data). CCDC 686766.
y X-Ray quality crystals of 7 were obtained by slow evaporation from
hexanes. C12H18O4,
M
¼
226.26, monoclinic,
a
¼
7.8101(16),
b ¼ 18.266(4), c ¼ 9.2291(18) A, U ¼ 1218.5(4) A3, T ¼ 173(2) K,
space group P21/n, Z ¼ 4, 5332 reflections measured, 3180 unique
(Rint ¼ 0. 0.0614). The final wR(F2) was 0.1376 (all data). CCDC
686767.
z X-Ray quality crystals of 4[epox] were obtained by slow evaporation
from hexanes. C15H22O5, M ¼ 282.33, monoclinic, a ¼ 7.0375(14), b ¼
11.004(2), c ¼ 9.6494(19) A, U ¼ 728.3(3) A3, T ¼ 173(2) K, space
18 The rigidity of the macrocycle (7) is evidenced by the chemical shift
dispersion between each of the geminal protons attached to C3 and
C4. The unique nature of these signals clearly defines their diaster-
eotopic relationship. See ESI for these dataw.
group P21, Z ¼ 2, 3617 reflections measured, 2167 unique (Rint
¼
0.0000, Friedel pairs were not merged). The final wR(F2) was 0.0956
(all data). CCDC 686765.
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This journal is The Royal Society of Chemistry 2008
4030 | Chem. Commun., 2008, 4028–4030