Total synthesis of ovalifoliolatin B, acerogenins A and C

Article abstract of DOI:10.1016/j.tetlet.2008.01.135

A short and concise route for the synthesis of ovalifoliolatin B, a highly strained macrocyclic diaryl ether heptanoid natural product that also provides quick access to acerogenins A and C natural products has been reported.

Full text of DOI:10.1016/j.tetlet.2008.01.135

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Tetrahedron Letters 49 (2008) 2103–2105
Total synthesis of ovalifoliolatin B, acerogenins A and C
G. D. Kishore Kumar, Amarnath Natarajan *
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-0650, USA
Received 29 August 2007; revised 28 January 2008; accepted 30 January 2008
Available online 6 February 2008
Abstract
A short and concise route for the synthesis of ovalifoliolatin B, a highly strained macrocyclic diaryl ether heptanoid natural product
that also provides quick access to acerogenins A and C natural products has been reported.
Ó 2008 Elsevier Ltd. All rights reserved.
Macrocyclic diaryl ether heptanoid (MDEH) natural
products form a subgroup of the diarylheptanoid family
of natural products. Compounds of this class exhibit a wide
range of biological activities that include, anti-cancer, anti-
inflammatory, anti-fungal, and anti-bacterial effects.1 The
common structural core is a diaryl ether moiety connected
by seven carbon atoms. The presence of a c,d trans-double
bond and a para-substituted phenyl ring in the macrocycle
makes ovalifoliolatin B a simple albeit challenging target.2
The MDEH acerogenin C has the same structural core as
ovalifoliolatin B except the c,d trans-double bond in the
macrocycle.
In the first reported synthesis of acerogenin C, the linear
diaryl heptanoid was constructed using the dianion chem-
istry of methyl acetoacetate followed by an intra-molecular
hydrogen bond directed macrocyclization.3 This strategy
was subsequently used for the synthesis of acerogenins A,
B, L, and Aceroside.4 The need for 1-fluoro-2-nitro-4-alkyl
substituted aryl moiety for the key macrocyclization step
and the removal of the nitro group post macrocyclization
increased the number of steps in this approach. A more
direct route used Ullmann reaction to cyclize a linear
diarylheptanoid to generate acerogenins C and A.5 The lin-
ear diarylheptanoid was generated through the selective
reduction of the double bond in an a,b-unsaturated enone.
In this approach, the selective reduction of the enone and
the cyclization proved challenging. In a recent report,
acerogenins C and A were synthesized via a series of
cross-aldol condensation reactions followed by the Ull-
mann macrocylization.6 Herein we report the first total
synthesis of ovalifoliolatin B in which a cross-metathesis
reaction was used to set up the c,d trans-double bond,
and the resulting linear diarylheptanoid was cyclized under
Ullmann conditions.
Ring closing metathesis (RCM) has emerged as a pow-
erful tool for macrocyclization.7 The presence of a c,d
trans-double bond in ovalifoliolatin B suggests that the
use of RCM as the final macrocyclization step would be
prudent. Therefore, our approach relied on generating
ovalifoliolatin B from the two fragments 5 and 6 as out-
lined in Scheme 1.
Fragment 5 is a known compound8 and can be synthe-
sized in three steps from isovanillin. Fragment 6 can be
synthesized in
a
single step by the addition of
butenylmagnesiumbromide to the Weinreb amide of
4-bromo-phenylpropanoic acid.9 Fragments 5 and 6 were
*
Corresponding author. Tel.: +1 409 772 9748; fax: +1 409 772 9818.
Scheme 1. Retrosynthesis of ovalifoliolatin B.
E-mail address: amnatara@utmb.edu (A. Natarajan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.135

2104
G. D. Kishore Kumar, A. Natarajan / Tetrahedron Letters 49 (2008) 2103–2105
Scheme 2. Synthesis of diarylether 7.
coupled using a CuI mediated Ullmann reaction to gener-
ate diarylether 7 (Scheme 2).10 Our attempts to carry out
RCM on diarylether 7, under several conditions, were
unsuccessful.11 RCM was attempted with nearly all combi-
nations with the following variations: catalysts (Grubbs I
and II; Hoveyda–Grubbs I and II); solvents (DCM,
THF, benzene, toluene); dilutions (2, 4 and 8 mM), and
Temperature (rt, reflux and 150–170 °C in toluene).9
To probe the possible ring strain and electronic effects
on the RCM, analogs 8–11 were synthesized (Fig. 1).
Although we did observe the consumption of starting
material under several RCM conditions, we were unable
to isolate the corresponding macrocycle. At elevated tem-
peratures the NMR signals that correspond to the c,d-ole-
fin disappeared while the styrene signals remained.
Therefore we decided to reverse the sequence of reactions
viz., cross-metathesis followed by macrocyclization under
Ullmann conditions.
Fig. 2. MM2 minimized structures of 1 and 13.
mediated ring closure5 of 12 led to the isolation of ovalifol-
iolatin B (1) and its cis-isomer in 13:1 ratio. The stereo-
chemistry of the double bond in the two isomers was
1
defined by the coupling constants from H NMR.
The MM2 minimized structures showed that the two
aromatic rings in 1 and 13 are almost perpendicular to each
other. The macrocyclic ring strain in 1 and 13 is exemplified
by bond angles ꢀ125° for the olefin carbons (sp2) and bond
angles ꢀ115° for the carbons (sp3) adjacent to the ketone
(Fig. 2).
Synthesis of acerogenin C methyl ether (4) was accom-
plished by the reduction of the double bond (1 and 13).4
Alternatively, reduction of the double bond in 12 followed
by ring closure also resulted in the isolation of 4 in higher
As expected, cross-metathesis between styrene (5) and
bromo olefin (6) led to the isolation of 12 as an inseparable
mixture of stereoisomers (Scheme 3). A copper oxide
Fig. 1. RCM attempted intermediates.
Scheme 3. Synthesis of ovalifoliolatin B (1).
Scheme 4. Synthesis of acerogenins A and C.

G. D. Kishore Kumar, A. Natarajan / Tetrahedron Letters 49 (2008) 2103–2105
2105
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yields (50% vs 28%). The higher yields during ring closure
in the saturated system can be attributed to reduced strain.
Acerogenin C (3) and acerogenin A (2) were synthesized
following reported methods (Scheme 4).4
In summary, we report the first total synthesis of a
strained MDEH natural product ovalifoliolatin B which
was further elaborated to acerogenins C and A.
2. Reddy, V. L. N.; Ravinder, K.; Srinivasulu, M.; Goud, T. V.; Reddy,
S. M.; Srujankumar, D.; Rao, T. P.; Murty, U. S.; Venkateswarlu, Y.
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Acknowledgment
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Financial support from UTMB is gratefully
acknowledged.
Supplementary data
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7. RCM review on sterically and electronically demanding system: Sieck,
S. R.; Hanson, P. R. Chemtracts 2006, 19, 280–294.
Experimental procedures and complete characterization
of the natural products (1–3) and the intermediates are
available. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2008.01.135.
8. Castedo, L.; Borges, J. E.; Marcos, C. F.; Tojo, G. Synth. Commun.
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9. See Supplementary data for experimental and analytical data.
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References and notes
1. (a) Ishida, J.; Kozuka, M.; Wang, H.-K.; Konoshima, T.; Tokuda,
H.; Okuda, M.; Yang Mou, X.; Nishino, H.; Sakurai, N.; Lee, K.-H.;