Bio-inspired oxidative phenolic coupling: Total synthesis of the diarylether heptanoid (±)-pterocarine

Article abstract of DOI:10.1016/j.tetlet.2017.04.015

The diaryletherheptanoid natural product, pterocarine, is expeditiously synthesized using a bioinspired intramolecular oxidative phenolic coupling of acerogenin G. The cyclization precursor is prepared from a simple cinnamic acid derivative in three high yielding synthetic operations. The key oxidative coupling is inspired by biosynthetic hypotheses; however, the oxidative coupling proceeds with concomitant hydroxylation of the diphenyl ether motif.

Full text of DOI:10.1016/j.tetlet.2017.04.015

Tetrahedron Letters xxx (2017± xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bio-inspired oxidative phenolic coupling: Total synthesis of the
diarylether heptanoid (± ±-pterocarine
a
b,
⇑
M. Quamar Salih , Christopher M. Beaudry
a
Bayer, U.S. 8400 Hawthorne Rd, Kansas City, MO 64120, USA
53 Gilbert Hall, Oregon State University, Corvallis, OR 97331, USA
b
1
a r t i c l e i n f o
a b s t r a c t
Article history:
The diaryletherheptanoid natural product, pterocarine, is expeditiously synthesized using a bioinspired
intramolecular oxidative phenolic coupling of acerogenin G. The cyclization precursor is prepared from
a simple cinnamic acid derivative in three high yielding synthetic operations. The key oxidative coupling
is inspired by biosynthetic hypotheses; however, the oxidative coupling proceeds with concomitant
hydroxylation of the diphenyl ether motif.
Received 8 March 2017
Revised 28 March 2017
Accepted 4 April 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Oxidative coupling
Biomimetic
Natural product
Introduction
The diaryletherheptanoids (DAEHs± are a family of more than
1
two dozen natural products isolated from woody plants (Fig. 1±.
Their cyclophanic molecular architecture is characterized by a
medium sized ring made of a diphenylether and a heptanoid ansa
bridge, exemplified by the relatively simple DAEHs acerogenins L
(1± and C (2±.
Individual DAEH family members are distinguished by a higher
oxidation state of the ansa bridge (e.g. 3 and 4± or by alkoxy groups
that decorate the diphenylether motif (e.g. 5 and 6±. Perhaps the
most interesting aspect of the DAEH structure is that some family
members (e.g. 5 and 6± are chiral non-racemic molecules that exist
in stable enantiomeric conformations that racemize only slowly at
Fig. 1. Selected diaryletherheptanoid natural products.
2
high temperatures (e.g. >200 °C±. As a result of these observations,
the DAEHs have attracted the attention of several synthetic
groups, including our own.
little success. Whiting and Wood attempted to oxidize 9 to a biphe-
nyl; however, unexpected byproduct 10 was observed. Note that
3
2,4
8
DAEH biosynthesis has long been postulated to involve an
intramolecular oxidative phenolic coupling of a linear precursor
in this cyclization, the para-substituted phenyl ring of the cyclo-
phane bears fewer oxygen substituents, which is not the pattern
seen in DAEH natural products such as 5 and 6. To the best of
our knowledge, no DAEH has been prepared using an oxidative
phenolic coupling of this type.
A bio-inspired oxidative coupling reaction would represent an
expeditious synthetic strategy to DAEH natural products from rel-
atively simple cyclization substrates. If successful, such a reaction
could be used to rapidly prepare DAEH natural products and con-
geners for subsequent studies (i.e. racemization measurements,
cytotoxicity studies, etc.±. We decided to investigate such a
5
,6
(
Scheme 1±. Specifically, oxidative coupling of acerogenin G (7±
could lead to 1, 2, or to biphenylheptanoid acerogenin E (8±.
Furthermore, experimental evidence from feeding experiments
with isotopically enriched primary metabolites in Acer nikoense
7
supports such a cyclization in the biosynthesis of the acerogenins.
Attempts to affect such a cyclization in the laboratory have met
⇑
Corresponding author.
E-mail address: christopher.beaudry@oregonstate.edu (C.M. Beaudry±.
http://dx.doi.org/10.1016/j.tetlet.2017.04.015
040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Salih M.Q., Beaudry C.M. Tetrahedron Lett. (2017±, http://dx.doi.org/10.1016/j.tetlet.2017.04.015

2
M.Q. Salih, C.M. Beaudry / Tetrahedron Letters xxx (2017) xxx–xxx
Table 1
Oxidative cyclization of acerogenin G (7±.
Entry
Conditions
PhI(OAc± , K
PhI(TFA± , K
SeO , K CO , dioxane, H
Salcomine (1 equiv.±, MeOH, DMF
Result/yield (%±
1
2
2
CO
CO
3
, CF
, CF
3
CH
CH
2
OH
OH
O
No rxn
No rxn
No rxn
No rxn
No rxn
Decomp
Decomp
Decomp
2
3
4
5
6
7
8
9
1
1
2
2
3
3
2
Scheme 1. Biosynthetic considerations of the acerogenins.
2
2
3
2
FeCl
VOCl
KMnO
Fe(CN±
(NH Ce(NO
Pb(OAc± , CH
PbO , HOAc
3
, O
, CH
, K
2
, Et
2
O,
D
3
2
Cl
2
4
2
CO
, K
3
, EtOH
K
3
6
2
CO
, MeCN
Cl
3
, EtOH
±
4 2
3
±
6
Decomp
0
1
4
2
2
15 (ꢀ5%±
2
15 (20%± + 16 (7%± + 7 (40%±
prisingly, the cyclization occurs with concomitant oxidative
hydroxylation of the diphenylether, and with esterification of a
resident phenol, leading to acetyl pterocarine (15± and its regioiso-
mer (16±. The regiochemistry of the reaction was relatively modest,
favoring 15 in an approximate 3:1 ratio. Interestingly, the reaction
was completely chemoselective, and we found no evidence of for-
mation of any biphenylheptanoid such as 8.
Scheme 2. Synthesis of acerogenin G (7±.
We know of no other reported oxidative phenolic coupling
(
inter- or intramolecular± that occurs with concomitant oxidation
cyclization in a relatively uncomplicated DAEH system, and we
elected to investigate the cyclization of 7 to 1, 2, or biarylheptanoid
24
of the diphenylether motif. In the oxidation of 7, the mechanistic
order of oxidation steps is unclear; we did not detect any uncy-
clized acetoxylated intermediates or any acerogenins (i.e. 1 or 2±
in the product mixture. However, it is possible that once formed,
the cyclophane ring strain renders the phenyl group more prone
to oxidative hydroxylation. Whether or not such a cyclophane
hydroxylation has biosynthetic relevance for hydroxylated or
methoxylated DAEHs such as 5 or 6 is unclear.
With the successful preparation of 15, we advanced this mate-
rial to pterocarine (5±. Separation of 15 and 16 was possible using
standard chromatography. Although chemical shift considerations
suggested the major product was properly assigned as structure
8. We speculated that control of the regio- and chemoselectivity
could be possible through judicious choice of the oxidant.
Results and discussion
Preparation of key substrate 7 was accomplished using standard
transformations (Scheme 2±. Cinnamic acid derivative 11 is a
9
known commercially available molecule that was converted to
the corresponding phosphonate (12± following standard condi-
1
0
tions. Horner–Wadsworth–Emmons reaction with aldehyde 13
gave dienone 14 in high yield. Reduction of 14 resulted in hydro-
genation of both carbon–carbon double bonds and hydrogenolysis
of the benzyl ethers to give cyclization substrate 7 in near quanti-
tative yield.
1
5, establishing the structure of 15 and 16 was not straightfor-
ward. However, hydrolysis of 15 gave pterocarine (5±, which we
had previously prepared, and the physical and spectral properties
of both samples were a complete match (Scheme 3±. To the best
of our knowledge, this represents the first synthesis of a DAEH nat-
ural product by a bio-inspired cyclization reaction.
Our attempts to realize an oxidative cyclization of 7 began using
standard oxidants with literature precedent for similar oxidative
In summary, we have discovered conditions that promote a bio-
inspired oxidative cyclization of a simple diarylheptanoid, acero-
genin G, to give a diaryletherheptanoid. This cyclization proceeds
with concomitant oxidative hydroxylation of the diphenylether
group and with esterification of a resident phenol. Saponification
of the cyclization product gives pterocarine (5±.
transformations of phenols (Table 1±. Reagents containing hyper-
valent iodine (BAIB, PIFA±11 gave no reaction and forcing conditions
(
(
i.e. elevated temperatures± led to decomposition. Other oxidants
1
2
13
14
SeO
2
,
3
salcomine, FeCl ± did not lead to oxidation of the sub-
15
16
17
strate. Some transition metal oxidants (VOCl3, KMnO
4
,
MnO
and CAN ± gave complex mixtures of products that
did not contain the desired cyclophanes.
2
,
1
8
19
3 6
K Fe(CN± ,
20
Encouragingly, use of Pb(OAc±
amounts of cyclophane products that we tentatively assigned as
5; however, attempts to optimize the transformation with this
oxidant were unsuccessful. We next evaluated PbO as a reagent
for the oxidative cyclization, as it is an oxidant that has been used
4
as an oxidant gave trace
1
2
for the conversion of phenols to phenoxyl radicals.2
1,22
Gratify-
ingly, this oxidant affected the oxidation of 7 to 15 and 16. The
reaction is quite clean (no by products± and is moderately high
2
3
yielding based on recovery of 40% of the starting material. Sur-
Scheme 3. Synthesis of (± ±-pterocarine (5±.
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M.Q. Salih, C.M. Beaudry / Tetrahedron Letters xxx (2017) xxx–xxx
3
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Acknowledgment
1
8
We gratefully acknowledge the National Science Foundation for
support of our research group under Grant Number 1465287.
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Please cite this article in press as: Salih M.Q., Beaudry C.M. Tetrahedron Lett. (2017±, http://dx.doi.org/10.1016/j.tetlet.2017.04.015