De Novo Asymmetric Synthesis of Phoracantholide J

Article abstract of DOI:10.1021/acs.orglett.6b02432

A de novo asymmetric total synthesis of the macrolide natural product (S)-phoracantholide J has been achieved in 10 steps from the commodity chemicals (1-pentyne, ethyl acrylate, acetaldehyde, and hydrogen). The asymmetry of the route was introduced by a Noyori reduction of a 3-yn-2-one, which makes the route equally amenable to the synthesis of either enantiomer. In addition, this route relies upon an alkyne zipper, a hydroalkynylation, and a macrolactonization to complete the synthesis.

Full text of DOI:10.1021/acs.orglett.6b02432

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Letter
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De Novo Asymmetric Synthesis of Phoracantholide J
Kenneth F. Avocetien,†,§ Jiazhen J. Li,†,§ Xiaofan Liu,†,§ Yanping Wang,*,† Yalan Xing,*,‡
and George A. O’Doherty*,†
†Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States
‡Department of Chemistry, William Paterson University, 300 Pompton Road, Wayne, New Jersey 07470, United States
S
* Supporting Information
ABSTRACT: A de novo asymmetric total synthesis of the
macrolide natural product (S)-phoracantholide J has been
achieved in 10 steps from the commodity chemicals (1-pentyne,
ethyl acrylate, acetaldehyde, and hydrogen). The asymmetry of
the route was introduced by a Noyori reduction of a 3-yn-2-one,
which makes the route equally amenable to the synthesis of either
enantiomer. In addition, this route relies upon an alkyne zipper, a hydroalkynylation, and a macrolactonization to complete the
synthesis.
Scheme 1. Retrosynthesis of Phoracantholide J
s part of a larger effort aimed at the de novo asymmetric
A
synthesis of polyketide macrolactone natural products,1
we became interested in gaining synthetic access to both
enantiomers of phoracantholide J (Figure 1). Both enantiomers
of the 10-membered ring macrolide natural product can be
found in nature, where they serve as pheromones.2 In 1976, the
C-9 (R)-enantiomer ((ent)-1) of the volatile phoracantholide J
was discovered first as a secretion from the metasternal gland of
the Australian beetles, Phoracantha synonyma.3 More recently,
the C-9 (S)-enantiomer of phoracantholide J was isolated from
the femoral glands of the Madagascarian frog, Mantidactylus
multiplicatus.4 In the beetle, the secretion of (R)-phoracantho-
lide J has been shown to serve as a chemical defense
mechanism. In contrast, the biological role of (S)-phoracan-
tholide J (1) has not been verified but due to its association
with the frog’s femoral gland suggests that it functions as a sex
pheromone.
synthesis, there were three subsequent syntheses. Chenevert
was able to prepare either enantiomer of phoracantholide J
using an enzymatic acylation catalyst for the chiral resolution of
racemic alcohol ( )-7 along with a ring closing metathesis.8 To
address the issue of alkene stereochemistry, Posner developed
an elegant ring fragmentation/macrolactonization approach to
(R)-phoracantholide J from cyclopentanone via hemiketal 6.9
More recently, Schulz developed an enantioselective route to
either enantiomer of phoracantholide J from a resolution of
racemic propylene oxide (( )-3) and a Wittig olefination to
control the alkene stereochemistry.4 The enantio-divergent
biological roles of phoracantholide J piqued our own interest in
its de novo asymmetric synthesis, as it would allow access to
both enantiomers. In particular, we were interested in a
synthesis of phoracantholide J that featured the use of the
Figure 1. Phoracantholide J (1) and enantiomer (ent)-1.
Not long after the discovery of (R)-phoracantholide J, it
yielded to total synthesis (Scheme 1). The first two racemic
syntheses were reported by Petrzilka5 and later by Malherbe
and Bellus6 using Claisen chemistry. The first asymmetric
synthesis was accomplished by Mori in 1983.7 The synthesis
began with (S)-3-hydroxybutric acid and occurred through an
alkynyl anion alkylation of iodide 4, followed by Lindlar
reduction and macrolactonization.
While the Mori synthesis was lengthy, requiring 20 total
steps, it nicely handled the alkene stereochemistry and
macrolactone formation. In the years following the first
Received: August 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02432
Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters
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Noyori reduction followed by an alkyne zipper reaction. Herein
we describe our successful efforts at the development of a
practical de novo asymmetric synthesis of either enantiomer of
phoracantholide J.
Table 1. Hydroalkynylation of Ethyl Acrylate
Previously, we10 and others11 have shown that the two-step
sequence of a Noyori hydrogen transfer asymmetric reduction12
followed by a KAPA promoted alkyne zipper reaction13 can be
used to convert achiral ynones into ω-yn-ols (8 to 9) in good
yields and enantiomeric purity (Scheme 2). Examples of the
synthetic potential of the approach is outlined in Scheme 2. In
an effort to show the synthetic utility of the ω-yn-ol products,
we and others have shown that 9 can be transformed into the
key component of various natural products, such as the γ-alkoxy
spiroketal of broussonetine11a and cephalosporolides,11b the ω-
alkoxy polyol portion of aspicilin,11c the alkoxy β-lactone
portion of THL,10b,c and finally, the ω-alkoxy ester portion of
merremoside D10a (Scheme 2).
c
L/C ratio
15/
b
yield
(%)
a
entry
alkyne/catalyst/ligand
(mol %)
16
1
2
3
14a/Ru3(CO)12/[PPN]Cl
14a/Ru3(CO)12/[PPN]Cl
10:2
2:2
1:1
1:2
3:2
48
20
25
14a/Pd2(dba)3·CHCl3/
(o-tol)3P
4:4
4
14a/Pd(OAc)2/Cy3P
4:4
10:2
2:2
NA
2:1
1:1
5:4
1:1
1:1
1:1
trace
75
39
5
6
14b/Ru3(CO)12/[PPN]Cl
14b/Ru3(CO)12/[PPN]Cl
14b/Pd(OAc)2/(t-Bu)3P
14b/Pd(OAc)2/(o-tol)3P
14b/Pd(OAc)2/Cy3P
Scheme 2. Use of the Noyori/Alkyne Zipper in Synthesis
7
4:4
33
8
4:4
20
9
4:4
28
10
14b/Pd2(dba)3·CHCl3/
(o-tol)3P
4:4
32
11
14b/Pd2(dba)3·CHCl3/
(t-Bu)3P
4:4
1:1
32
12
13
14b/Pd2(dba)3·CHCl3/PPh3
14b/Pd(OAc)2/NHC
4:4
3:3
1:2
18
0
NA
a
Entries 1−4 were performed in NMP at 95 °C, entries 5−10 were in
b
THF at 60 °C, and entries 11−13 were in THF at rt. The ratio
1
between the isomers 15b/(2E,4E)-16b was determined by H NMR.
c
Yield was isolated yield of the above isomeric mixture, which was
purified by HPLC.
In order to search for the optimal conditions for the
hydroalkynylation, we chose to study the achiral des-methyl
substrates 14a/b (Table 1). Because we were concerned with
the compatibility of the hydroalkynylation reaction with free
alcohols, we set out to prepare both ynol 14a and its TBS-
protected variant 14b. In our survey of the literature for
hydroalkynylation reaction, we found two distinct catalyst
systems.14,15 The first uses a Pd(II)/phosphine system, and the
second uses a trimeric Ru(0)carbonyl catalyst with the cationic
PPN ligand (Ph3PNPPh3Cl). Our initial survey of both
the Pd and Ru catalyst systems with hexynol 14a (entries 1−4)
suggested the poor compatibility of the reaction to primary
alcohols. That is to say, significantly improved yields of addition
products (15b/16b) were observed when we exposed the TBS-
protected hexynol 14b to the same reaction conditions (entries
5−13). Both catalyst systems gave the hydroalkynylation
addition products along with the isomerization products,
dienoates 16a and 16b. The Ru3(CO)12/PPN consistently
gave better yields of addition products. By increasing the
ligand-to-metal ratio (PPN:Ru) and minimizing the reaction
time, the direct addition product 15b could be maximized
(entry 5).
Retrosynthetically, we envisioned that phoracantholide J 1
could come from a macrolactonization of hydroxyacid 10,
which in turn could come from a Lindlar catalyzed cis-reduction
of alkyne 11 (Scheme 3). Of particular interest was whether the
4-ynoate ester 11 could be prepared by a transition metal
catalyzed hydroalkynylation of ethyl acrylate with hepta-1-yn-6-
ol (12). If so, we believed that ynol 12 could be prepared from
conjugated ynone 5 by a Noyori/zipper reaction sequence,
which in turn can be prepared from 1-pentyne (13) and
acetaldehyde.
Scheme 3. Retrosynthesis of (S)-Phoracantholide J
After the success of the model system in Table 1, we turned
our attention to the real substrate. The synthesis of TBS-
protected ynol 18 began with the lithiation of 1-pentyne (13)
and the addition of the resulting anion to acetaldehyde to form
racemic ( )-17 (Scheme 4). The absolute stereochemistry of
(S)-17 was installed by an oxidation and asymmetric reduction
sequence, which involved a MnO2 propargylic alcohol oxidation
B
DOI: 10.1021/acs.orglett.6b02432
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 4. Noyori/Alkyne Zipper Route to Alkyne 18
Scheme 5. Synthesis of (S)-Phoracantholide J
and an (S,S)-Noyori catalyzed reduction with HCO2Na as the
stoichiometric reductant. Exposing enantiomerically enriched
(S)-17 to excess KAPA reagent proceeded in excellent yield to
give 12 without any erosion of stereochemistry. The protection
of 12 as a TBS-ether occurred without incident using TBSCl/
imid to give TBS-ether 18.
With the desired substrate 18 in hand, we next investigated
its performance in the hydroalkynylation of ethyl acrylate
(Table 2). Subjecting 18 to our previously optimized
conditions (entry 1) gave a good yield of addition product
19 with a minimal amount of isomerization. As before, the Pd-
catalyst systems gave lower yields of addition product 19 with
an increased amount of isomerization product 20. Similarly, we
found that lowering the ligand-to-metal ratio increased the
amount of the isomerization of 19 to 20.
under Lindlar’s conditions to give cis-alkene 21 (85%). The
required seco-acid 10 was prepared by NaOH promoted ester
hydrolysis of 21. Finally, subjecting 10 to the typical Yamaguchi
lactonization conditions provided phoracantholide J (1) in a
50% yield.16 Synthetic 1 thus obtained processed identical
spectral data as those reported for the natural material.4
In conclusion, a de novo asymmetric total synthesis of
phoracantholide J was developed from achiral ynone 5 in eight
steps and 15% overall yield. As the synthesis uses an
asymmetric Noyori hydrogen transfer reaction to install the
chiral center in 1, the synthesis is compatible with the
production of either enantiomers of phoracantholide J. In
addition to providing access to (S)- and (R)-phoracantholide J,
the synthesis demonstrates the utility of the Ru catalyzed
hydroalkynylation reaction in complex molecule synthesis.
Table 2. Synthesis of 18 via Hydroalkynylation of Ethyl
Acrylate
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02432.
Experimental procedures and spectral data for all new
compounds (PDF)
c
L/C ratio
(mol %)
19/20
b
yield
(%)
a
entry
catalyst/ligand
ratio
AUTHOR INFORMATION
Corresponding Authors
■
1
2
3
4
5
6
7
Ru3(CO)12/[PPN]Cl
Ru3(CO)12/[PPN]Cl
Ru3(CO)12/[PPN]Cl
Pd(OAc)2/(t-Bu)3P
Pd(OAc)2/(t-Bu)3P
Pd(OAc)2/(o-tol)3P
Pd(OAc)2/NHC
10:2
6:2
2:2
4:4
4:4
4:4
3:3
3:1
1:1
1:10
1:1
2:1
1:1
NA
70
45
40
35
30
16
0
*E-mail: wang.yanp@husky.neu.edu (Y.W.)
*E-mail: XINGY@wpunj.edu (Y.X.)
*E-mail: G.ODoherty@neu.edu (G.A.O.)
Author Contributions
§K.F.A., J.J.L., and X.L. are co-first authors; the order is
a
Entries 1−3 were performed in NMP at 95 °C, entry 4 was in THF at
rt, entries 5−6 were in benzene at rt, and entry 7 was in THF at 60 °C.
alphabetical.
Notes
b
1
The ratio between the isomers 19/20 was determined by H NMR.
c
The authors declare no competing financial interest.
Yield was isolated yield of the above isomeric mixture, which was
purified by HPLC.
ACKNOWLEDGMENTS
This work was supported by research grants from the NIH
(GM09025901) and NSF (CHE-1565788).
■
With the optimized conditions for the hydroalkyne identified,
the reaction was scaled up for the synthesis (Scheme 5). Thus,
on a 1 g scale, under these optimized conditions, alkyne 18
reacted with ethyl acrylate to give 19 in a 53% yield. With
ample quantities of 19 in hand, the TBS-group was removed
with TBAF to give alcohol 11 (95%). The alkyne was reduced
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DOI: 10.1021/acs.orglett.6b02432
Org. Lett. XXXX, XXX, XXX−XXX