Stereoselective Total Syntheses of Polyacetylene Plant Metabolites via Ester-Tethered Ring Closing Metathesis

Article abstract of DOI:10.1021/acs.joc.6b02987

Total syntheses of five naturally occurring polyacetylenes from three different plants are described. These natural products have in common an E,Z-configured conjugated diene linked to a di- or triyne chain. As the key method to stereoselectively establis

Full text of DOI:10.1021/acs.joc.6b02987

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Article
Stereoselective total syntheses of polyacetylene plant
metabolites via ester-tethered ring closing metathesis
Bernd Schmidt, and Stephan Audörsch
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02987 • Publication Date (Web): 13 Jan 2017
Downloaded from http://pubs.acs.org on January 13, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Stereoselective total syntheses of polyacetylene plant metabolites via ester-tethered ring
closing metathesis
Bernd Schmidt* and Stephan Audörsch
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Universitaet Potsdam, Institut fuer Chemie, KarlꢀLiebknechtꢀStraße 24ꢀ25, Dꢀ14476 Potsdamꢀ
Golm, Germany.
eꢀmail: bernd.schmidt@uniꢀpotsdam.de
Table of contents graphic:
Abstract: Total syntheses of five naturally occurring polyacetylenes from three different
plants are described. These natural products have an E,Zꢀconfigured conjugated diene linked
to a diꢀ or triyne chain in common. As the key method to stereoselectively establish the E,Zꢀ
diene part, an esterꢀtethered ringꢀclosing metathesis/baseꢀinduced eliminative ring opening
sequence was used. The results presented herein do not only showcase the utility of this
tethered RCM variant, but have also prompted us to suggest that the originally assigned
absolute configurations of chiral polyacetylenes from Atractylodes macrocephala should be
revised or at least reconsidered.
Introduction
The term “polyacetylene” applies to polymers with conjugated double bonds (i. e. polymers of
1
acetylene), but also to members of a large class of natural products which share CꢀCꢀtriple
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
bonds in the main carbon chain as a common structural entity. Confusingly, compounds with
2
ꢀ8
just one CꢀCꢀtriple bond are also referred to as “polyacetylenes”. The first polyacetylene
natural product, Zꢀdehydromatricaria ester, was isolated in 1826 from Artemisia vulgaris, but
9
not recognized as an acetylene at that time. Several decades later, Arnaud correctly assigned
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
an acetylenic structure to tairic acid, a constituent of Picramnia species and Semmler
discussed inter alia acetylenic structures for the natural product carlina oxide, which had been
isolated from the carline thistle Carlina acaulis. Semmler eventually suggested the
constitution of an allenic isomer, based on the assumption that acetylenes are simply to
11
unstable to occur in nature. The correct structure, depicted in figure 1, was assigned many
years later by Gilman et al. based on total synthesis and comparison with the analytical data of
1
2
the natural product (Figure 1).
Figure 1. Early examples of naturally occurring acetylenic compounds.
Since then hundreds of polyacetylenes have been isolated, not only from plants (which are
2
still an important source), but also from insects, fungi, bacteria, moss and lichens. As for
natural products in general, marine organisms have become increasingly important and
6,13
thoroughly investigated sources of polyacetylenes over the past few years. Another current
prominent facet of polyacetylene research is the controversy of their role in human
7
,8
nutrition.
polyacetylenes.
Sprague),which both contain oenanthetol,
Some edible plants, in particular from the family Apiaceae, are rich in
4,14
Dill (Anethum graveolens) and ajowan (Trachyspermum ammi
2
,15
are popular members of this family. Another
example is parsnip, which has a total polyacetylene content of more than 7.5 mg per gram of
2
ACS Paragon Plus Environment

Page 3 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
6
dried plant material, mostly falcarindiol. The cytotoxicity of falcarindiol and related
polyacetylenes might be an explanation for the health promoting and chemopreventive effects
16
of edible plants from the Apiaceae family. In contrast to these food plants, other members of
the family Apiaceae are highly toxic, and in these cases polyacetylenes have been identified
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
7
as potent toxins. An example is waterꢀhemlock (Cicuta virosa), which contains cicutoxin
and the structurally closely related oenanthotoxin. Although both compounds affect the
neuronal action potential leading to strong neurotoxicity, the C14ꢀdeoxygenated metabolite
17
cicutol shows no effect on neuronal action potentials. The identification of certain
polyacetylenes as toxicants has probably discredited the role of these phytochemicals in food
1
7
plants in general. The same study revealed a significant quantitative difference in the
neuronal action potential between cicutoxin and isocicutoxin, which differ only in the
configuration of the C8ꢀC9ꢀdouble bond (Figure 2).
Figure 2. Examples for toxic and nonꢀtoxic polyacetylene natural products.
Conjugated dieneꢀdiyne and dieneꢀtriyne patterns are common in polyacetylene natural
products. They are biosynthetically derived from fatty acids, which are dehydrogenated
through the action of desaturases, leading to double bonds at specific sites of the carbon chain,
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
normally in high Zꢀselectivity. Further dehydrogenation of these double bonds to alkynes
proceeds in the presence of acetylenases. Certain acetylenases, however, may promote Eꢀ
5
selective dehydrogenations, depending on the substrate. The biosynthetic formation of E,Eꢀ
configured conjugated dienes, for the example of the sex pheromone of the African cotton
leafworm Spodoptera littoralis, has been attributed to a bifunctional desaturase that abstracts
hydrogen from both allylic positions of a Zꢀconfigured alkene. Depending on the substrate,
the same desaturase may also produce Z,Eꢀconfigured dienes or mixtures of E,Eꢀ and Z,Eꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
18
dienes.
Recently, the isolation and structural characterization of seven new and eight known
polyacetylenes from the rhizomes of Atractylodes macrocephala Koidz, a flowering plant of
the family Compositae, was achieved by Yao and Yang through a bioactivityꢀguided
19
approach. The rhizomes of the plant have been used in traditional Chinese medicine for a
long time, inter alia to treat malfunctions of the spleen and associated symptoms such as
inappetance and abdominal distension. In their study, Yao and Yang focused on the
2
0
previously described antiꢀinflammatory activity of Atractylodes macrocephala rhizomes by
testing the inhibitory activity of crude extracts and isolated compounds, named
19
atractylodemaynes, against NO production. The authors conclude that the polyacetylenic
metabolites contribute significantly to the antiꢀinflammatory activity of the rhizomes.
Compared to other polyacetylene containing plants, Atractylodes macrocephala Koidz
contains a remarkably high number of Z,Eꢀconfigured dieneꢀdiynes: six out of 15
19
polyacetylenes isolated by Yao and Yang are Z,Eꢀconfigured. A literature search for this
structural entity revealed that other Z,Eꢀdieneꢀdiꢀ or triynes have previously been isolated
from other plant sources, but that the Z,Eꢀconfiguration appears to be much less common than
the E,Eꢀconfiguration. An example is the E,Z,Eꢀdieneꢀdiyneꢀene compound 5, which has been
isolated along with several other polyacetylenes from the fruits of water dropwort (Oenanthe
21
aquatica), a toxic plant endemic to marshy areas in Europe. The E,Zꢀdieneꢀtriyne compound
4
ACS Paragon Plus Environment

Page 5 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6 was isolated from the flowering plant Leucanthemum adustum, but no spectroscopic data
2,22
have been reported (Figure 3).
Although not phototoxic to human skin, compound 6 was
23
24
found to have antibiotic effects against Candida albicans and other pathogens upon UVꢀ
irradiation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Naturally occurring polyacetylenes with E,Zꢀdieneꢀdi(tri)yne moieties.
The configurational diversity and their sensitivity towards oxidation and light makes these
natural products challenging target molecules for chemical synthesis. The motivation for
organic chemists to become engaged in the total synthesis of polyacetylenes is not only to
showcase a certain synthetic methodology, but also to contribute to structure elucidation by
19
confirming, revising or completing structural assignments. For instance, Yao and Yang
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
assigned a tentative absolute configuration to the chiral atractylodemaynes 2, 3 and 4 based on
comparison of their specific rotations with the value reported by Nakai et al. for atractyloyne
25
(
7), which was isolated by these authors from Atractylodes chinensis. By using Mosher’s
method, Nakai et al. assigned a 12Sꢀconfiguration to (+)ꢀatractyloyne (7). Yao and Yang
isolated the same natural product from Atractylodes macrocephala Koidz and also found a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
positive value for the specific rotation, but concluded that (+)ꢀ7 is 12Rꢀconfigured (sic!).
Based on this correlation, Yao and Yang assigned a 12Sꢀconfiguration to atractylodemaynes F
2) and C (4), which were found to be levorotatory, but with a rather small value for the
specific rotation. Compound 3, which had previously been isolated from the same plant by
(
26
others without a reported specific rotation, was reisolated by Yao and Yang in the course of
their study. They found a positive value for the specific rotation, and concluded by analogy
19
that 3 should have a 12Rꢀconfiguration. We thought that a total synthesis of these
polyacetylenes from a chiral pool starting material with a reliably assigned absolute
configuration might substantiate or disprove these structural assignments.
Synthetic methods that have previously been used in total syntheses of polyacetylenes related
27ꢀ31
to those shown in figures 2 and 3 are Pdꢀcatalyzed cross coupling reactions
and a
32
nucleophilic addition to pyrylium salts for the stereoselective construction of E,Eꢀ and Z,Eꢀ
configured dienes, respectively. Recently, a flexible synthetic approach to both E,Eꢀ and Z,Eꢀ
dienes based on the electrocyclic ring opening of transꢀ and cisꢀcyclobutenes has been
3
3ꢀ35
developed.
For the synthesis of the diꢀ or triyne pattern in polyacetylenes mostly Cuꢀ and
36ꢀ38
Pdꢀcatalyzed couplings of the Glaserꢀ or CadiotꢀChodkiewiczꢀtype have been used.
3
9ꢀ42
Our group has recently disclosed a novel type of tethered RCM
reaction to access
43
44
(
2Z,4E)ꢀdienoates and dienoic acids in high yields and very high stereoselectivities. The
sequence starts from allylbutenoates 10 (synthesized from allylic alcohols 9 and vinylacetic
acid (8)) which are then converted in a one pot reaction to the carboxylates 13 via RCM and
baseꢀinduced eliminative ring opening of the intermediate lactones 11. The carboxylates 13
6
ACS Paragon Plus Environment

Page 7 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
are alkylated to yield dienoates 14. The ester group in compounds 14 is available for
functional group transformations, e. g. – as required for the target molecules in question ꢀ to
45
terminal alkynes 15 using CoreyꢀFuchs homologation or related reactions. For the
construction of the diꢀ or triyne part transition metal catalyzed C(sp)ꢀC(sp) coupling reactions
were envisaged (Scheme 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Synthetic plan for E,Zꢀconfigured dieneꢀdiꢀ(triꢀ)ynes using an RCMꢀring openingꢀ
alkylation sequence.
In a preliminary communication we have recently reported the first total synthesis of
46
atractylodemayne A (1, figure 3) along these lines. Herein we report an extension of this
approach to the chiral atractylodemaynes 2, 3 and 4, and to the unnamed natural products 5
and 6. To the best of our knowledge, none of these natural products has previously been
synthesized.
Results and discussion
Our first concern was to identify conditions that allow the alkynylative carbonyl
homologation of esters 14 to dieneꢀynes 15 with conservation of the E,Zꢀdiene configuration.
From previous experience we knew that 2Z,4Eꢀpentadieneꢀ1ꢀols, the reduction products of
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
esters 14, tend to decompose upon purification and storage. The corresponding aldehydes are
chemically more stable and can be purified by chromatography, but undergo slow
43
isomerization to the E,Eꢀisomers. It is therefore advisable to convert the esters 14 to the
required terminal alkynes 15 without delay and with a minimum of purification steps.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
3
Orienting experiments were performed with aldehyde (2Z,4E)ꢀ17a. The BestmannꢀOhiraꢀ
reagent was discarded from the outset, because α,βꢀunsaturated aldehydes are known to react
with concomitant conjugate addition of methanol (the nucleophile required for activation of
4
7
BestmannꢀOhira’s reagent). Instead, an alkynylation of (2Z,4E)ꢀ17a with lithiated TMSꢀ
48,49
diazomethane was initially investigated (Scheme 2).
Scheme 2. Orienting experiments for carbonylꢀtoꢀalkyne homologation.
The expected dieneꢀyne 15a was indeed obtained, but only in low yield and with extensive
isomerization of the Zꢀconfigured double bond. Next, we investigated a CoreyꢀFuchsꢀtype
45
homologation by treating (2Z,4E)ꢀ17a with [Ph
3
PCHBr
2
]Br•CH
3
CN (known as Wolkoff’s
t
50
reagent) in the presence of KOBu as a base. The expected triene 18a was isolated in 80%
45
yield and reacted with butyllithium to induce triple bond formation. Although isolated only
8
ACS Paragon Plus Environment

Page 9 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
in low yield, the required dieneꢀyne 15a was formed without any Z,Eꢀisomerization or double
bond migration. We sought to improve this transformation by using a protocol devised by
Rassat and coworkers, who conducted the carbonyl olefination step and the subsequent
t
51
alkynylation in a oneꢀpot fashion, using KOBu as a base for both transformations.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 15a was again obtained as a single isomer and in a slightly increased overall yield
of 30% (Scheme 2). We discovered at this point that the success of the oneꢀpot protocol
t
strongly depends on the quality of the KOBu used. Due to its sensitivity to atmospheric
humidity, it is advisable to use only recently opened containers when performing this reaction.
Rather than improving the carbonylꢀtoꢀalkyne homologation for this (2Z,4E)ꢀpentadienal any
further, we decided at this stage to test Rassat’s one pot method in the synthesis of
polyacetylenes 5 and 6 (figure 3).
Total synthesis of (5E,7Z,13E)-pentadeca-5,7,13-trien-9,11-diyn-4-ol (5). For the total
synthesis of polyacetylene 5 the C6ꢀC15ꢀfragment 15b was required as a precursor for the
C(sp)ꢀC(sp)ꢀcross coupling. Our synthesis of 15b starts from the commercially available αꢀ
hydroxy pentanoate 19, which was first protected as its TBSꢀether 20. Compound 20 was
converted to the allylic alcohol 9b in oneꢀpot as a 6 : 1 mixture of diastereomers. As the
newly generated stereocentre is not part of the target structure, the relative configuration of
the major diastereomer of 9b was not elucidated by spectroscopic means. Steglich
5
2
esterification of 9b with vinyl acetic acid (8) furnished the precursor 10b for the RCM step.
43
Under our previously established conditions, 10b was converted to (2Z,4E)ꢀ17b in a one
flask sequence by using a catalytic amount of second generation Grubbs’ catalyst (A) to
induce the RCM, followed by addition of NaHMDS to trigger the stereoselective ring
5
3
opening, and finally addition of Meerwein’s salt to trap the intermediate Naꢀcarboxylate as
the ethyl ester (2Z,4E)ꢀ14b. The ester was reduced to the corresponding dienol, which was
immediately oxidized to the pentadienal (2Z,4E)ꢀ17b without prior purification, using Dessꢀ
54
Martin periodinane. Although the aldehyde can be fully characterized, it should be used in
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the next step without delay, to avoid undesirable double bond isomerization. For the
subsequent aldehydeꢀtoꢀalkyne homologation we used, compared to the orienting experiments
t
shown in scheme 2, increased amounts of Wolkoff’s reagent and KOBu from the outset. It
was also found to be advisable to perform this reaction under the exclusion of light, as dieneꢀ
ynes such as 15b decompose when exposed to daylight or artificial light over prolonged
periods of time. In due consideration of these precautions, 15b was isolated in 75% yield as a
single geometrical isomer without noticeable decomposition (Scheme 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Synthesis of C6ꢀC15ꢀpart of polyacetylene 5.
As a C(sp)ꢀC(sp)ꢀcross coupling partner and C1ꢀC5 building block (E)ꢀ1ꢀbromopentꢀ3ꢀenꢀ1ꢀ
yne (24) was envisaged. A suitable and storable precursor for this labile reagent is the TMSꢀ
5
5
acetylene 23, which had previously been synthesized via a Sonogashira coupling and via a
56
CoreyꢀFuchs homologation of crotonaldehyde (21). We chose the latter method, which
5
6
proceeds via the gemꢀdibromoalkene 22. In accord with the original report we found that
this compound is quite unstable and refrained from any attempts to characterize this
intermediate. It was instead immediately treated with methyllithium and TMSꢀchloride to
furnish enyne 23 (Scheme 4).
Scheme 4. Synthesis of C1ꢀC5 part of polyacetylene 5.
10
ACS Paragon Plus Environment

Page 11 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3
8,57
55
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For the CadiotꢀChodkiewicz coupling
the bromoacetylene 24 was required. It was
58
obtained using Isobe’s method by treatment of 23 with Nꢀbromosuccinimide (NBS) in the
presence of AgNO
3
. Due to its limited stability, 24 was not characterized and stored, but
synthesized on demand (Scheme 5). In its orginal version, the CadiotꢀChodkiewicz coupling
59
is a Cu(I)ꢀcatalyzed reaction. Later several improved variants were discovered, in particular
with the aim to avoid the undesired formation of homocoupling products. Particularly
noteworthy in this regard was the introduction of Pdꢀcocatalysts, which allow the synthesis of
60
unsymmetrical diynes in higher yields and improved selectivities at lower temperatures.
Examples for Pdꢀcatalyzed CadiotꢀChodkiewicz couplings which proceed in the absence of
61,62
any Cu(I)ꢀpromoter are not completely unknown, but scarce.
Scheme 5. Completion of total synthesis of polyacetylene 5 (see table 1 for details).
In the absence of a Cu(I)ꢀcatalyst no conversion of the terminal alkyne 15b was observed
(
Table 1, entry 1). A similar result was obtained for the protocol devised by Wang and
63
coworkers, who found that phosphine ligands can significantly enhance the reactivity of
Cu(I)ꢀcatalysts in the C(sp)ꢀC(sp) cross coupling reaction, even in the absence of a Pdꢀ
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
cocatalyst (entry 2). The catalyst combination of Pd(PPh ) Cl and CuI, introduced by Wityak
3
2
2
6
0
and Chan, turned out to be successful insofar as the starting material was completely
consumed, but the selectivity was reproducibly unsatisfactory. Under these conditions the
desired cross coupling product 25 and the homocoupling product 26 were isolated as an
inseparable 1 : 1 mixture (scheme 5 and table 1, entry 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a)
Table 1. Optimization of conditions for the C(sp)ꢀC(sp)ꢀcoupling of 15b and 24.
entry Solvent
T
Catalyst(s) (mol %) Additive(s)
Ratio
Product
(equiv.)
25 : 26 (Yield)
i
b)
1
2
DMF
20 °C Pd(PPh ) (5.0)
HNPr (2.1)
ꢀꢀ
ꢀꢀ
ꢀꢀ
3 4
2
c)
ethanol 78 °C CuI (10.0)
K CO (2.1);
< 5%
2
3
3
P(oꢀtol) (0.2)
i
c,d)
3
4
5
THF
HNPr
THF
20 °C Pd(PPh ) Cl (5.0), HNPr (2.1)
1 : 1
ꢀꢀ
3
2
2
2
CuI (10.0)
70 °C Pd(OAc)
CuI (2.0)
20 °C Pd(PPh
CuI (10)
24 generated from 23 (2.0 equiv.) immediately prior to cross coupling. No conversion.
i
e)
2
2
(1.8), [NBu
4
]Br (0.03) 7 : 1
25 (64%)
f)
i
3
)
2
Cl
2
(5.0), HNPr
2
(2.1)
ꢀꢀ
26 (87%)
a)
c)
b)
d)
Not determined. Quantitative conversion to an inseparable mixture of products 25 and 26.
Product contaminated with homocoupling product 26; yield was estimated from the H NMR
e)
1
f)
spectrum. Without addition of bromoacetylene 24.
The formation of homocoupling products such as 26 from terminal alkynes is generally
5
7
64
65
considered to be an oxidative process. Various oxidants, inter alia chloroacetone, iodine
6
6
or air have been used in combination with Pdꢀ and Cuꢀcatalysts to produce symmetrical
diynes selectively. Recently, Lei and coworkers proposed that symmetrical diynes as
byproducts of cross coupling reactions might also originate from a disproportionation of the
catalytic Pdꢀbisacetylideꢀintermediate I into two symmetrical bisacetylides II and III, which
12
ACS Paragon Plus Environment

Page 13 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6
7
would, upon reductive elimination, produce the homocoupling products IV and V. This
disproportionation is in competition with the reductive elimination of the desired
unsymmetrical diyne VI from the Pdꢀbisacetylide I (Scheme 6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
7
Scheme 6. Reductive elimination vs. disproportionation according to Lei et al.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In light of this mechanistic scenario, Lei and coworkers reasoned that the extent of
homocoupling should decrease significantly if the catalyst loading is reduced, which would in
turn require a more active catalyst. Based on this assumption, the authors introduced a
protocol for a ligand free CadiotꢀChodkiewicz coupling that uses very small catalyst loadings
67
of Pd(OAc)
2
, CuI as a cocatalyst and NBu
4
Br as an additive. The additive is believed to
stabilize Pdꢀnanoparticles, which might play an important role in this catalytic reaction.
Gratifyingly, this protocol turned out to be successful for the cross coupling of 15b and 24,
although we had to increase the catalyst loading substantially compared to the original
conditions to achieve quantitative conversion. This might be the reason why the formation of
homocoupling product 26 was not fully suppressed, but the ratio of 25 : 26 was nevertheless
considerably improved to 7 : 1 (entry 4). While the disproportionation scenario as outlined in
scheme 6 can explain the formation of the byproduct 26 up to a certain extent, the formation
of larger amounts of homocoupling product, as in entry 3, points at a competing oxidative
homocoupling. However, the absence of an obvious oxidizing agent under these conditions
appears to be inconsistent with this assumption. To test whether formation of 26 occurs to a
substantial extent through a pathway other than the above mentioned disproportionation, 15b
was reacted under the same conditions as in entry 3, but without addition of the
bromoacetylene 24 (entry 5). The dimer 26 was selectively formed and isolated in high yield.
14
ACS Paragon Plus Environment

Page 15 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A similar homocoupling of terminal alkynes in the presence of the same Pdꢀ and Cuꢀcatalysts
and in the absence of intentionally added oxidant had previously been reported by Fairlamb et
68
al. It was later shown that this homocoupling is indeed an oxidative process, because
rigorous exclusion of air leads to an interruption of the reaction after the first catalytic cycle.
This experimental finding was supported by theoretical calculations, which suggested that a
closure of the catalytic cycle in the absence of any oxidant would require the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
69
thermodynamically unfavourable formation of molecular hydrogen.
The final step of the total synthesis of polyacetylene 5 was the cleavage of the TBSꢀether. In a
first attempt to remove the protecting group TBAFꢀtrihydrate was used. Although elevated
temperatures were avoided in consideration of the high sensitivity of large conjugated πꢀ
systems, we surprisingly observed the formation of a 1 : 1 mixture of the desired compound
(5E,7Z,13E)ꢀ5 and its geometrical isomer (5E,7Z,13Z)ꢀ5. Interestingly, the (5E,7Z)ꢀdiene
moiety was not affected, but only the double bond at C13 underwent partial isomerization,
remarkably from E to Z. The 13Zꢀconfiguration of the isomerized sideproduct was proved by
the appearance of a new dq for the proton at C14 with coupling constants of 10.8 Hz and 7.0
Hz. A successful and selective deprotection of 25 was eventually achieved by using HFꢀ
pyridine, giving the desired (5E,7Z,13E)ꢀ5 in 46% yield. In summary, this polyacetylene was
synthesized in eight steps and 3.8% overall yield. In the original publication by Vincieri et al.,
1
describing the isolation and structure elucidation of 5, selected H NMR data were reported
which match those found by us for the synthetic compound very well. The authors did not
21
comment on the absolute configuration of the natural product or report any chiroptical data.
Total synthesis of (3E,5Z)-trideca-3,5-dien-7,9,11-triyn-1-ol (6). For the total synthesis of
this polyacetylene dieneꢀyne 15c was required as a precursor for the CadiotꢀChodkiewicz
coupling. Its synthesis started from propaneꢀ1,3ꢀdiol (27), which was first monoprotected to
70
2
8. Several methods and reagents for the oxidation of 28 to the corresponding aldehyde
were tested, such as ParikhꢀDoeringꢀoxidation, 2ꢀiodoxybenzoic acid (IBX), DessꢀMartin’s
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reagent or pyridinium chlorochromate (PCC). These methods all gave the aldehyde in yields
varying between 30% and 60%, but reproducibility was found to be difficult. The main reason
for this is most likely the high volatility of the aldehyde, which results in loss of material upon
workup. For these reasons we sought a method that would allow a convenient workup of the
reaction mixture and did not require the removal of high boiling byproducts. In our hands,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
1ꢀ73
Anelli’s TEMPOꢀbromide catalyzed oxidation
synthesis of volatile aldehydes, because a biphasic solvent system is used. Excess oxidant
NaOCl) and coproducts of the oxidation reaction (NaCl, water) remain in the aqueous phase,
turned out to be the best method for the
(
whereas the organic solvent can be removed at or slightly below atmospheric pressure. The
dried and concentrated solution of the aldehyde was immediately reacted with
vinylmagnesium bromide to give the allylic alcohol 9c reliably in a satisfactory yield. From
this point the synthesis of 15c was accomplished in analogy to 15b (scheme 3) via Steglich
esterification, RCMꢀring opening, reductionꢀoxidation to the aldehyde (2Z,4E)ꢀ17c and
t
eventually alkynylative homologation with Wolkoff’s reagent and KOBu . The yields for the
individual steps are similar to those obtained en route to 15b (Scheme 7).
Scheme 7. Synthesis of C6ꢀC13ꢀpart of polyacetylene 6.
1
) TEMPO (2.1 mol %)
KBr (0.1 equiv.)
TBSCl (0.8 equiv.)
OH NaH (1.0 equiv.)
NaOCl (aq, 2.6 equiv.)
8
, DCC, DMAP (cat.)
OH CH Cl /aq. buffer (pH = 8.6)
OH
2
2
CH Cl , 0 °C to 20 °C
2
2
HO
THF, 20 °C
TBSO
2) H C=CHMgBr, Et O, 0 °C TBSO
2
2
2
7
28 (82%)
9c (71%)
A (3.0 mol %), CH Cl (0.1 M), 40 °C, 1 h
then add NaHMDS (1.2 equiv), 0 °C to 20 °C
2
2
1) DIBAlꢀH, CH Cl , 20 °C
2 2
O
O
2) B (1.25 equiv.), CH Cl , 20 °C
2 2
O
EtO
then add Et3OBF4, 20 °C
TBSO
TBSO
1
0c (82%)
(2Z,4E)ꢀ14c (81%)
1
) [Ph PCHBr ]Br•CH CN (3.0 equiv)
3
t
2
3
O
KOBu (2.8 equiv), THF, 20 °C
TBSO
t
TBSO
2
) KOBu (6.0 equiv), THF, 20 °C
(
2Z,4E)ꢀ17c (82%)
15c (74%)
For the next step in the total synthesis of polyacetylene 6, the CadiotꢀChodkiewicz coupling,
the bromoacetylene 32 was required. In analogy to the in situ generation of coupling partner
16
ACS Paragon Plus Environment

Page 17 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
24 we synthesized the TMSꢀacetylene 31 as a storable precursor (Scheme 8). Different routes
7
4
to this compound, e. g. via C(sp)ꢀC(sp) coupling, have been described in the literature. In
spite of the moderate yield we found the desilylative monolithiation of bisꢀTMS butadiyne 30
and the subsequent trapping of its lithioacetylide with methyl iodide to be more practical,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
5,76
because the desired pentadiyne 31 can be rapidly obtained in gram quantities.
BisꢀTMSꢀ
butadiyne 30 was synthesized from commercially available hexachlorobutadiene (29) via
7
7
dehalogenation and trapping with TMSꢀchloride, as described previously. For the in situ
generation of bromoacetylene 32 we first tested the same conditions used to obtain 24 (NBS
and a substoichiometric amount of AgNO
3
in acetone), but the conversion was unsatisfactory.
Better results were obtained under conditions previously established by Fiandanese et al., who
76
used an excess of AgF in combination with NBS for the synthesis of 32. These researchers
78
and others have investigated C(sp)ꢀC(sp) couplings of 32 with terminal alkynes for the
synthesis of other polyacetylene natural products. Cross coupling reactions of 32 with dieneꢀ
ynes such as 15c have, however, not yet been described. For this coupling we tested initially
the same conditions as for the synthesis of polyacetylene 5 (table 1, entry 4). This resulted
only in very low conversion to the desired product, which prompted us to increase the
amounts of all catalysts. This led eventually to the formation of coupling product 33 in
moderate yield, but without noticeable formation of any homocoupling products. For the final
deprotection step the wellꢀproven conditions from the synthesis of 5 were used. In summary,
we accomplished the first synthesis of the natural product (3E,5Z)ꢀtridecaꢀ3,5ꢀdienꢀ7,9,11ꢀ
triynꢀ1ꢀol (6) in eight steps and an overall yield of 3.4%. No NMR data were published for the
22
natural product with this particular double bond configuration, but for the (3E,5E)ꢀisomer,
1
13
which has been isolated from a different Chrysanthemum species, both H and C NMR data
79
were reported.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 8. Completion of the total synthesis of polyacetylene 6.
Me Si
3
BuLi (4.0 equiv.)
Cl
Cl
Cl
Me SiCl (2.0 equiv.)
3
Cl
Cl
THF, 78 °C
Me3Si
Cl
SiMe3
29
30 (78%)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeLi•LiBr (1.1 equiv)
MeI (1.1 equiv)
AgF (2.4 equiv)
NBS (2.4 equiv)
CH3CN, 20 °C
THF, 78 °C
3
1 (42%)
Br
3
2
Pd(OAc)2 (8.0 mol %)
CuI (10 mol %)
TBSO
1
5c
NBu Br (9.0 mol %)
4
i
HNPr , 70 °C
2
HF•py
THF
HO
TBSO
6
(48%)
33 (30%)
Total syntheses of chiral polyacetylenes 2, 3 and 4 from Atractylodes macrocephala
Koidz. As outlined in the introduction, a main motivation for the total synthesis of these
natural products was to clarify the confusing and ambigous correlations of their absolute
19
configuration and the sign of specific rotation. Yao’s and Yang’s assignments refer to an
25
absolute configuration/specific rotation correlation previously made by Nakai et al. for
atractyloyne (7). To establish an unambigous correlation via total synthesis we required a
starting material with well established absolute configuration, preferably from a chiral pool
source. A suitable precursor in this regard should be Sꢀbutaneꢀ1,2,4ꢀtriol (Sꢀ34), which can be
synthesized in one step from Lꢀmalic acid through reduction with boraneꢀdimethylsulfide
80
complex, but is also commercially available. Dieneyne Sꢀ15e was envisaged as a common
precursor for the three polyacetylenes 2, 3 and 4. To minimize selectivity problems during the
introduction of the ester groups at C12 and C14 (and in the case of atractylodemayne C at C1)
18
ACS Paragon Plus Environment

Page 19 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
we decided to perform the CadiotꢀChodkiewicz couplings with Sꢀ15h and Sꢀ15i (Scheme 10)
in which each ester group is already located at the correct position. By the same token, Sꢀ15e
and Sꢀ15d were disregarded as precursors for the cross coupling step, because this variant
would necessitate the laborious differentiation of three OHꢀgroups at a late stage of the
synthesis. Performing the C(sp)ꢀC(sp) coupling with Sꢀ15d would furthermore require an
acidꢀcatalyzed deprotection in the presence of the large and hence sensitive fully conjugated
πꢀsystem. For economical reasons, the synthesis of Sꢀ15e was first elaborated for the racemate
and the optimized conditions were then applied to the enantiomerically pure series (Scheme
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
).
Scheme 9. Synthesis of C6ꢀC14 part of chiral atractylodemaynes.
Triol Sꢀ34 was selectively protected as the sixmembered acetal Sꢀ35, following a literature
81
procedure. Oxidation of the primary alcohol to the aldehyde failed with DessꢀMartin’s
periodinane, and Anelli’s protocol resulted in a cleavage of the acetal. Eventually, the
3
oxidation was accomplished using SO •pyridine as previously described by Nachbauer and
8
1
Brückner. The aldehyde was immediately reacted with vinylmagnesium bromide to the
allylic alcohol (S,RS)ꢀ36, which was isolated in moderate yield as a 1 : 1 mixture of
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
diastereomers. A vinylation of this aldehyde using divinylzinc had previously been reported
82
with a very similar outcome. From allylic alcohol (S,RS)ꢀ36 the synthesis of dieneꢀyne Sꢀ
5d was accomplished through the same sequence of steps and in similar yields as described
1
above for the dieneꢀynes 15b,c. Deprotection of Sꢀ15d to the diol Sꢀ15e was achieved
selectively and nearly quantitatively with a catalytic amount of pꢀTSA in methanol. The next
step required a monoacetylation of the OHꢀgroup at C14. Some optimization was necessary to
achieve an acceptable conversion to Sꢀ15f and suppress the formation of the diacetate Sꢀ15g at
the same time. For the optimization study racꢀ15e was used (Table 2).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Optimization of monoꢀacetylation conditions for 15e.
entry solvent
Temperature
20 °C
Base (equiv)
Reagent (equiv)
15f
15g
(Yield)
10%
a)
a)
(
Yield)
i
1
2
DMF
NEtPr
2
(2.0)
H
3
CCO
2
H (2.0) 40%
b)
TBTU (1.0)
i
i
i
c)
THF
THF
−90 °C → 20 °C NEtPr
−90 °C → 20 °C NEtPr
−90 °C → 20 °C NEtPr
2
2
2
(2.0)
(2.0)
(3.0)
H
3
3
3
CCOCl (1.4) 50%
n. d.
c)
3
4
5
6
7
H
H
H
H
H
H
CCOCl (1.7) 50%
CCOCl (2.2) 45%
CCOCl (1.2) 20%
CCOCl (2.1) 40%
CCOCl (1.1) 50%
CCOCl (1.0) 40%
n. d.
CH
CH
CH
CH
CH
2
Cl
Cl
Cl
Cl
Cl
2
5%
c)
2
2
2
2
2
2
2
2
0 °C
0 °C
collidine (2.0)
3
3
3
3
n. d.
i
NEtPr
2
2
2
(2.6)
(2.0)
(1.6)
20%
i
c)
0 °C → 20 °C NEtPr
0 °C → 20 °C NEtPr
n. d.
i
c)
8
n. d.
a)
Yields from experiments carried out under the same conditions were rounded to the nearest
b)
c)
5%. TBTU: N,N,N',N'ꢀtetramethylꢀOꢀ(benzotriazolꢀ1ꢀyl)uroniumtetrafluoroborat. n. d. not
detected.
20
ACS Paragon Plus Environment

Page 21 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
An esterification protocol developed by Twibanire and Grindley, which has been proposed to
8
3
differentiate between primary and secondary alcohol groups within the same molecule,
worked only with limited success for the problem at hand (entry 1). Another protocol, which
was especially developed for selective monoacetylations of primary alcohols by Yamamoto
and coworkers, uses a slight excess of acetylchloride, an amine base and dichloromethane at
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
4
−78 °C. We tested a number of variations, including a solvent switch to THF (entries 2 and
3). Under these conditions no diacetate 15g was observed, but conversion of the starting
material remained incomplete and the monoacetate 15f was isolated in ca. 50% yield. In
dichloromethane this product was isolated in a slightly lower yield, but along with a small
amount of 15g (entry 3). Eventually, we discovered that for the monoacetylation of this
particular diol Yamamoto’s protocol is best modified by increasing the temperature to 0 °C
and by using not more than 1.1 equivalents of acetyl chloride (entry 7). Larger amounts of
acetyl chloride will result in the formation of substantial amounts of diacetate 15g and a
diminished yield of monoacetate 15f (entry 6). With an equimolar amount of acetyl chloride
no diacetate was formed, but the yield of 15f decreased to ca. 40% (entry 8).
The optimized conditions for the selective C14ꢀesterification were applied to Sꢀ15e and the
monoacetate Sꢀ15f was obtained in fair yield. For the synthesis of atractylodemayne F (2) the
C12ꢀisobutyrate Sꢀ15h was required as a cross coupling precursor. This compound was
cleanly obtained by acylation with the acid chloride, but addition of DMAP as a catalyst was
mandatory. The synthesis of senecioate Sꢀ15i, the precursor for polyacetylene 3 and Sꢀ
atractylodemayne C (4), turned out to be surprisingly complicated. First attempts to acylate
the secondary alcohol at C12 proceeded with unsatisfactory rates of conversion. When we
tried to mend this problem by using senecioyl chloride and an amine base in large excess
together with a catalytic amount of DMAP we observed a quantitative esterification, but
discovered the formation of a significant amount of the isomerized byproduct Sꢀ15i’.
Deconjugation reactions of similarly substituted α,βꢀunsaturated carbonyl compounds have
22
ACS Paragon Plus Environment

Page 23 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8
5
been reported previously as unintentional side reactions, but have also been exploited
8
5ꢀ87
synthetically. However, much stronger bases, in particular lithium amides,
or amine bases
88
in combination with irradiation are normally used to initiate this deconjugation. It might,
however, be possible that an amine base in combination with DMAP initiates an elimination
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
9
of HCl from senecioyl chloride to a b,gꢀunsaturated ketene, which then reacts with the
alcohol Sꢀ15f to Sꢀ15i’. In our case, we found after some experimentation that the undesired
deconjugation can be fully suppressed by using pyridine as a base without DMAP as an
additional acylation catalyst. The desired senecioate Sꢀ15i was isolated in 61% yield as a
single isomer. With Sꢀ15h and Sꢀ15i in hand we performed the C(sp)ꢀC(sp) cross coupling
reactions to conclude the syntheses. We used the haloacetylenes 38a,b as coupling partners,
46
which were synthesized as described in our previous communication. Both haloacetylenes
underwent the CadiotꢀChodkiewicz coupling with the established Pd(OAc) ꢀCuIꢀNBu Brꢀ
2
4
catalyst system in comparable yields and without noticeable formation of any homocoupling
products. SꢀAtractylodemayne F (Sꢀ2) and the unnamed polyacetylene Sꢀ3 were obtained in
yields of 43% and 47%, respectively, for the last step. SꢀAtractylodemayne C (Sꢀ4) was
synthesized from Sꢀ3 via acetylation with acetyl chloride (Scheme 10).
All NMRꢀ and HRMSꢀdata obtained by us for the synthetic compounds match those reported
1
9
26
by Yao and Yang for the natural products 2, 3 and 4 and by Chen for polyacetylene 3 very
well. However, significant discrepancies were found for the specific rotations and the
assigned absolute configurations. The values and configurational assignments reported by
19
Yao and Yang for the natural products are listed in figure 3. Unfortunately, no chiroptical
data were reported in Chen’s previous study on the plant constituents from Atractylodes
2
6
macrocephala. The respective values obtained by us for the synthetic compounds are shown
in scheme 10. Based on our total syntheses from the chiral pool derived starting material Lꢀ
malic acid we can state that the 12Sꢀconfigured atractylodemaynes Sꢀ2, Sꢀ3 and Sꢀ4 are
without exception dextrorotatory. The same is true for the truncated dieneꢀynes Sꢀ15dꢀi,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
whereas the dieneꢀyne 15a (scheme 2) with the reverse configuration at the allylic position is
levorotatory. This observation clearly contradicts Yao’s and Yang’s statement made for the
chiral polyacetylenes from Atractylodes macrocephala that “[α]
D
value is positive for the Rꢀ
19
form and negative for the Sꢀform”. It rather supports Nakai’s correlation (based on Mosher’s
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
D
method) between a positive [α] value and a C12Sꢀconfiguration for the structurally related
25
atractyloyne (Sꢀ7), although we would like to emphasize that configurational assignments
based on comparison of optical rotations of structurally related compounds have only limited
reliability. The confusing and contradictory configurational assignments might have been
caused in part by the fact that Nakai et al. state in the discussion section that (+)ꢀatractyloyne
25
is Sꢀconfigured, but depict the structure of the Rꢀisomer in the corresponding figures.
Scheme 10. Completion of total syntheses of polyacetylenes 2,3 and 4.
24
ACS Paragon Plus Environment

Page 25 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
We suggest that at least for the naturally occurring compound 3, for which both Yao and
2
D
2
19
23
Yang ([α]
+60.9 (c 0.30, methanol)) and we ([α]
D
+78.8 (c 0.12, methanol)) obtained
reasonably congruent [α] values, the absolute configuration should be revised from 12R to
D
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12S. We are unable to state conclusively whether the 12Sꢀconfiguration assigned to naturally
occurring atractylodemaynes C (4) and F (2) should be revised solely based on their negative
[
α]
D
values, because the absolute values reported for the optical rotation of the natural
22
19
22
19
products 2 ([α]D −2.5 (c 0.11, methanol)) and 4 ([α]D −7.7 (c 0.05, methanol)) are
2
D
1
strikingly small compared to those obtained by us for the synthetic compounds Sꢀ2 ([α]
22
D
+83.9 (c 0.10, methanol)) and Sꢀ4 ([α]
+31.5 (c 0.09, methanol)). Due to these significant
discrepancies we believe that it might be advisable to redetermine the optical rotation values
for naturally occurring atractylodemaynes and to reconsider the assigned absolute
configuration. We can not comment on the reasons for the discrepancies in this specific case,
but in general several factors might be responsible for the distortion of optical rotation values,
e. g. the presence of very small amounts of strongly optically active impurities with the
opposite sign of rotation, partial racemization during isolation or other chemical
transformations which might occur after structure elucidation by NMR and prior to the
measurement of the optical rotation. In the course of this study we discovered a distorting
effect that falls into the latter category, which prompted us to resynthesize atractylomeayne F
(2) and change our standard characterization protocols in the aftermath. Due to the small
amounts of material available at the final stage of the total syntheses the same sample was
used for the nonꢀdestructive characterization methods NMR and optical rotation. First, NMR
spectra were recorded to confirm identity and purity of the product, and optical rotation
measurements were then performed after removing the deuterated solvent and redissolving the
sample in methanol. When the optical rotation of atractylodemayne F (2) was first measured,
3
the sample had been dissolved in CDCl for an unusually long period of time. When we
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
D
discovered the considerable difference between Yao’s and Yang’s and our own [α] value,
the sample was recovered from the methanol solution and resubmitted to NMR analysis to
check the identity of the compound. Interestingly, inspection of the NMR spectra revealed the
presence of an additional set of signals. The second compound was identified as the 2Zꢀ
isomer of atractylodemayne F (2Zꢀ2). It probably results from an E/Zꢀisomerization of the C2ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C3ꢀdouble bond catalyzed by small amounts of acid liberated from the solvent CDCl . The
3
3
isomerization stopped after ten days in CDCl at a ratio of 2 : 1 of 2Eꢀ2 and 2Zꢀ2. The optical
2
0
rotation value measured for this sample ([α]D +63.5 (c 0.26, methanol)) was considerably
21
smaller than the value obtained for a sample of resynthesized atractylodemayne F ([α]
83.9 (c 0.10, methanol)) which had not been in contact with CDCl . After recording the
optical rotation value the identity of this sample was checked by NMR (Scheme 11).
Scheme 11. Partial isomerization of 2Eꢀ2 to 2Zꢀ2 in CDCl
D
+
3
3
.
As a consequence, the two other atractylodemaynes Sꢀ3 and Sꢀ4 were NMRꢀspectroscopically
characterized in CD Cl . The chemical shift values found in this solvent are very similar to
2
2
19
3
the values reported by Yao and Yang in CDCl , but the E/Zꢀisomerization reaction did not
occur. This is in line with the assumption that this process is indeed acid catalyzed.
Conclusions
In summary we demonstrated that an unconventional type of tethered RCM reaction, that
combines RCM of allylbutenoates with a highly diastereoselective elimination reaction to
give Z,Eꢀconfigured conjugated dienes, is a useful method for the stereoselective synthesis of
26
ACS Paragon Plus Environment

Page 27 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
various naturally occurring polyacetylenes with a fully conjugated E/Zꢀdieneꢀdiꢀ or ꢀtriyneꢀ
backbone. For the example of three recently discovered atractylodemaynes we could establish
an unambigous correlation between the sign of optical rotation and the absolute configuration
of the C12ꢀstereocentre, which is derived from the chiral pool compound Lꢀmalic acid. Based
on these results we propose that the configurational assignments of polyacetylenes isolated
from Atractylodes macrocephala should be reconsidered. Finally, our observations during
chiroptical characterization of the synthesized natural products suggest that a change in
standard characterization protocols, which are probably common in many laboratories, might
improve the reliability of optical rotation values.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General methods. All experiments were conducted in dry reaction vessels under an
1
atmosphere of dry nitrogen. Solvents were purified by standard procedures. H NMR spectra
3 3
were obtained at 300 MHz, 500 MHz or 600 MHz in CDCl with CHCl (δ = 7.26 ppm) as an
13
internal standard. Coupling constants are given in Hz. C NMR spectra were recorded at 75
MHz, 125 MHz or 151 MHz in CDCl with CDCl (δ = 77.1 ppm) as an internal standard.
3
3
Whenever the solubility or stability of the sample or signal separation were insufficient in
3 6 6 6 5
CDCl , it was replaced by one of the following solvents: C D (C D H as internal standard for
1
13
H NMR spectroscopy, δ = 7.16 ppm, C
128.1 ppm); CD Cl (CHDCl
6
D
6
as internal standard for C NMR spectroscopy, δ
1
=
2
2
2
as internal standard for H NMR spectroscopy,
δ
= 5.32 ppm,
(acetoneꢀd
3
as internal standard
1
3
CD
2
Cl
2
as internal standard for C NMR spectroscopy,
δ
= 53.8 ppm); acetoneꢀd
COCD
6
5
1
as internal standard for H NMR spectroscopy, δ = 2.05 ppm, CD
3
13
for C NMR spectroscopy, δ = 29.8 ppm). IR spectra were recorded as ATRꢀFTIR spectra.
−1
Wavenumbers (
ν
) are given in cm . The peak intensities are defined as strong (s), medium
(m) or weak (w). Lowꢀ and high resolution mass spectra were obtained by EIꢀTOF or ESIꢀ
TOF.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 61
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Alkynylation of aldehyde (2Z,4E)-17a with lithiotrimethylsilyldiazomethane. A solution
i
of HNPr (0.18 mL, 1.30 mmol) in dry THF (5 mL) was cooled to 0 °C. BuLi (0.50 mL, 2.5
2
M in hexane, 1.30 mmol) was added dropwise and the reaction stirred for 0.5 h at 0 °C. After
cooling to −78 °C TMSCHN (0.75 mL; 2.0 M in hexanes, 1.50 mmol) was added dropwise
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and the mixture was stirred for 0.5 h at this temperature. A solution of aldehyde (2Z,4E)ꢀ17a
(222 mg, 1.00 mmol) in THF (5 mL) was added dropwise and stirring was continued for 1 h
at −78 °C. At this point the reaction was brought to ambient temperature and heated to 70 °C
for 3 h. After recooling to 0 °C the reaction was quenched with brine, the organic layer was
separated and the aqueous layer extracted with MTBE (three times 20 mL). The combined
organic phases were dried with Na SO and evaporated in vacuo. The residue was purified by
2
4
column chromatography using a hexane/MTBE mixture (20 : 1 v/v)) as eluent to furnish 15a
(68 mg, 0.31 mmol, 31%) as an inseparable mixture of geometrical isomers: yellowish oil;
1
NMRꢀdata for the 3Eꢀisomer of 15a were obtained from the mixture: H NMR (300 MHz,
CDCl
5.2, 7.4 Hz, 1H), 5.60 (dd, J = 15.6, 2.3 Hz, 1H), 4.55 (dt, J = 7.1, 6.9 Hz, 1H), 4.16 – 4.03
m, 1H), 3.60 (t, J = 7.8 Hz, 1H), 3.04 (d, J = 2.4 Hz, 1H), 1.72 – 1.49 (m, 8H), 1.49 – 1.36
3
) δ 6.65 (dd, J = 15.7, 10.8 Hz, 1H), 6.33 (dd, J = 15.2, 10.9 Hz, 1H), 5.77 (dd, J =
1
(
(
13
3
m, 2H); C NMR (75 MHz, CDCl ) δ 142.3, 134.1, 131.7, 111.3, 110.4, 82.7, 80.2, 76.2,
69.2, 36.4, 35.6, 25.3, 24.1, 24.0.
S)-2-((1E,3Z)-6,6-Dibromohexa-1,3,5-trien-1-yl)-1,4-dioxaspiro[4.5]decane (18a). The
(
compound should be synthesized and handled under exclusion of light. It decomposes slowly
on storage and should therefore be used in further transformations without delay. To a
t
suspension of Wolkoff's reagent (1.110 g, 2.00 mmol) in THF (10 mL) was added KO Bu
(213 mg, 1.90 mmol) and the mixture was stirred for 10 minutes at ambient temperature.
Aldehyde (2Z,4E)ꢀ17a (222 mg, 1.00 mmol) was then added to the suspension. If the
conversion was incomplete after 1 h (TLC), in a second flask Wolkoff's reagent (1.11 g, 2.00
t
mmol) in THF (10 mL) was reacted with KO Bu (213 mg, 1.90 mmol) in THF (10 mL) for 10
28
ACS Paragon Plus Environment

Page 29 of 61
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
minutes. This solution was then added to the reaction mixture. After full conversion of the
aldehyde, the reaction was quenched by the addition of a satd. aq. NH Cl solution. The
4
organic layer was separated, and the aqueous layer was extracted with MTBE (three times 20
2 4
mL). The combined organic layers were dried with Na SO and evaporated in vacuo. The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
residue was purified by column chromatography on silica using hexane/MTBE mixtures (20 :
1
1 (v/v)) to furnish 18a (326 mg, 0.86 mmol, 86%): yellow oil; H NMR (300 MHz, CDCl ) δ
3
7
.35 (dd, J = 10.8, 0.8 Hz, 1H), 6.63 (dd, J = 15.0, 11.3 Hz, 1H), 6.17 (dd, J = 11.1, 11.1 Hz,
H), 6.01 (dd, J = 10.9 Hz, 10.9, 1H), 5.82 (dd, J = 15.0, 7.3 Hz, 1H), 4.59 (dt, J = 7. 1, 6.9
1
Hz, 1H), 4.11 (dd, J = 8.1, 6.3 Hz, 1H), 3.61 (dd, J = 8.0, 7.8 Hz, 1H), 1.69 – 1.55 (m, 8H),
1
3
1.45 – 1.36 (m, 2H); C NMR (75 MHz, CDCl
3
) δ 134.9, 132.3, 131.5, 127.9, 126.1, 110.5,
+
9
3.6, 76.4, 69.1, 36.4, 35.6, 25.3, 24.1, 24.0. No [M ] signal was observed in HRMS under
90
various ionization conditions.
(
S)-2-((1E,3Z)-Hexa-1,3-dien-5-yn-1-yl)-1,4-dioxaspiro[4.5]decane (15a). The compound
should be synthesized and handled under exclusion of light! Synthesis from 18a: Compound
8a (316 mg, 0.83 mmol) was dissolved in THF (10 mL) and cooled to −78 °C. BuLi (800
1
µL, 2.5 M in hexane, 2.00 mmol) was added dropwise and the reaction was stirred for 0.5 h at
this temperature. The reaction was warmed to 0 °C and stirreed for another 0.5 h at this
temperature. After quenching with sat. aq. NH
and the aqueous layer was extracted with MTBE/hexane (2 : 1, three times 30 mL). The
combined organic extracts were dried with Na SO , the organic extract was concentrated and
4
Cl solution the organic layer was separated
2
4
dryꢀloaded on silica. The residue was purified by column chromatography on silica using
hexane/MTBE (20 : 1 (v/v)) micture as eluent to furnish 15a (40 mg, 0.18 mmol, 21%). Oneꢀ
pot synthesis from (2Z,4E)ꢀ17a: Wolkoff’s reagent [Ph
3
PCHBr
2
3
]Br•CH CN (3.00 g, 5.4
t
mmol) was suspended in dry and degassed THF (25 mL). KOBu (0.59 g, 5.3 mmol) was
added and the mixture was stirred for 10 minutes at ambient temperature. (2Z,4E)ꢀ17a (0.52
g, 2.3 mmol) was added and the mixture was stirred for 20 minutes. If the conversion was
29
ACS Paragon Plus Environment