Propene as an Atom-Economical Linchpin for Concise Total Synthesis of Polyenes: Piericidin A

Article abstract of DOI:10.1021/jacs.8b08974

A concise and convergent total synthesis of piericidin A is disclosed. The synthesis hinges on the utilization of propene as a synthetic linchpin to merge the properly elaborated alkyne fragments, leading to the 1,3,6-triene motif of piericidin A. Utilization of propene as a unique alkene, capable of sequential coupling with two alkynes, is further illustrated in the context of various 1,3,6-triene products. The latter process proceeds with high atom economy and efficiently gives rise to complex frameworks from readily accessible alkyne substrates. This strategic C-C bond formation offers an orthogonal paradigm in the design of synthetic routes, leading to higher step economy and more efficient syntheses of polyunsaturated natural products.

Full text of DOI:10.1021/jacs.8b08974

Subscriber access provided by University of South Dakota
Communication
Propene as an Atom Economical Linchpin for
Concise Total Synthesis of Polyenes; Piericidin A
Barry M. Trost, and Hadi Gholami
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08974 • Publication Date (Web): 01 Sep 2018
Downloaded from http://pubs.acs.org on September 1, 2018
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 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 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.
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 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Propene as an Atom Economical Linchpin for Concise Total Synthe-
sis of Polyenes; Piericidin A
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
Barry M. Trost* and Hadi Gholami
Department of Chemistry, Stanford University, Stanford, California 94305-5580, United States
Supporting Information Placeholder
ABSTRACT: A concise and convergent total synthesis
of piericidin A is disclosed. The synthesis hinges on the
utilization of propene as a synthetic linchpin to merge
the properly elaborated alkyne fragments, leading to the
1,3,6–triene motif of piericidin A. Utilization of propene
as a unique alkene, capable of sequential coupling with
two alkynes, is further illustrated in the context of vari-
ous 1,3,6–triene products. The latter process proceeds
with high atom economy and efficiently gives rise to
complex frameworks from readily accessible alkyne
substrates. This strategic C–C bond formation offers an
orthogonal paradigm in the design of synthetic routes,
leading to higher step economy and more efficient syn-
theses of polyunsaturated natural products.
Scheme 1. A linchpin strategy to construct 1,3,6-
trienes featuring the alkene–alkyne coupling
a. natural products bearing 1,3,6-triene motif
OH
O
MeO
MeO
OR
MeO
N
MeO
H
10
O
Coenzyme Q10 (3)
Piericidin A1 (1) R = H
Piericidin B1 (2) R = Me
OH
O
O
Kalipyrone (5)
O
MeO
Actinopyrone A (4)
O
OMe
OH
HO
H
O
O
Granuloside (6)
b. access to 1,3,6-triene motif
current state of the art
cross coupling: Stille, Negishi, etc.
Piericidin A (1) and B (2) are notable members of a
family of natural products isolated from Streptomyces
mobaraensis and S. pactam.1 This class of molecules
contains a highly substituted pyridine fragment with a
lipophilic side chain. The structural resemblance of pie-
ricidin natural products to coenzyme Q10 (3, dashed box,
Scheme 1) results in fascinating biological activity of
this family.2 Piericidin A, for instance, is a potent inhibi-
tor (with nM activity) of protein I complex, which is the
first step in the mitochondrial respiration.3 The impres-
sive biological activity of these natural products along
with their intriguing structural features has stimulated
the development of efficient and convergent synthetic
strategies so that structure function relationships can be
more profitably explored. Two particularly elegant con-
tributions to the synthesis of piericidin A are reported by
the Boger4 and the Lipshutz group.5,6
olefination: Julia, HWE, etc.
R2
R4
our approach
R1
R3
2nd alkene-alkyne coupling
R2
1st alkene-alkyne coupling
R4
synthetic linchpin
R1
R3
1st alkene-alkyne coupling
2
nd alkene-alkyne coupling
R2
R4
R1
R3
✰ > 2500 natural prodcut hits
(Dictionary of Natural Products)
✰ 40 drug hits (Drugbank)
fragments with propene as a synthetic linchpin. Sequen-
tial alkene–alkyne coupling reactions were envisioned as
the key transformation to deliver the featured moiety
with high atom, step, and redox economy (Scheme 1,
b).8 This strategic C–C bond formation is modular in
design and by simple switching the order of the two al-
kene-alkyne couplings, isomeric trienes with comple-
mentary substitution pattern about the central double
bond can be obtained (Scheme 1, b). This flexibility al-
lows rapid access to analogues of a compound for li-
brary synthesis and screening. The synthetic utility of
this approach is demonstrated in the concise total syn-
Central to the structure of piericidins and many other
natural products and drug molecules is a 1,3,6-triene
motif (highlighted by the large numbers of structures in
Scheme 1).1a, 7 Traditionally, access to such a motif re-
lies on utilization of olefination methodologies in con-
junction with various cross coupling reactions. We aim
to devise an alternative convergent strategy in which the
1,3,6-triene can be obtained via coupling of two alkyne
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
thesis of piericidin A and, more generally, in the synthe-
deliver the alkyne 14 in good yield and diastereoselec-
tivcity.13, 9
To synthesize the second alkyne fragment (7), the
1
2
3
4
5
6
7
8
sis of various examples bearing the highlighted triene
moiety, thus leading to a practical strategy to such mo-
tifs.
known 2-pyridone 15,5 which can be readily prepared
from ethyl 2-methyl acetoacetate, was utilized (Scheme
2). Halogenation of the methyl group on the C6 position
of 15 was envisioned to provide a path for installation of
the propynyl moiety. A radical mediated bromination
successfully gave rise to the bromopyridone 16 in nearly
quantitative yield. The product 16 was utilized without
any chromatographic purification. Propynyllithium addi-
tion to 16 in the presence of catalytic copper (I) iodide
delivered the alkyne 17 in good yield. The pyridone core
in 17 was elaborated to the fully substituted pyridine 7
via a novel concurrent methylative debenzylation reac-
tion that was carried out using methyl triflate. In paral-
lel, the PMB group in 17 can also be readily removed
using TFA to give 2-pyridone 18 in good yield.5 These
three analogues (17, 18, and 7) were proposed as the
possible alkynes for coupling with alkyne 14 through
propene as the linchpin.
Retrosynthetically, piericidin A can be obtained from
alkynes 7 and 8 via their sequential coupling with pro-
pene (eq 1). Coupling of propene with alkyne 8 should
proceed first, then the resulting product must be coupled
with alkyne 7 to obtain the triene motif embedded in the
natural product. Alkyne 8 could be synthesized from
chiral propargylic alcohol 9 via the Marshall−Tamaru
reaction.9 Furthermore, we aimed to evolve a catalytic
asymmetric alkynylation, which sets the absolute con-
figuration of the natural product.
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
OH
MeO
OH
(eq 1)
MeO
OH
N
1
OH
MeO
MeO
+
+
OR
N
9
8
7
Scheme 3. Coupling of the alkyne fragments with
propene
propene
Our synthesis commenced with the direct prepara-
tion of chiral alcohol 9 using our reported asymmetric
alkynylation of acetaldehyde employing dinuclear zinc
ProPhenol as catalyst (Scheme 2).10 Since propyne must
be used as the alkynyl nucleophile, the reported method-
ology needs to be adjusted to accommodate the gaseous
alkyne. Conveniently, diethyl zinc under an atmospheric
pressure of propyne (i.e. via a balloon) generated the
desired propynyl zinc reagent for the asymmetric addi-
tion to acetaldehyde. Further optimization of the reaction
revealed an enabling effect of THF as co-solvent to de-
liver the propargylic alcohol 9 in good yield and high
enantioselectivity (see Table S1 for additional de-
tails).11In contrast, a common alternative procedure us-
ing the asymmetric reduction of an ynone requires three
steps to deliver alcohol 9.12 To complete the synthesis of
alkyne 14, the Marshall−Tamaru propargylation was
implemented using the mesylate 12 and aldehyde 13 to
[Ru] (10 mol%)
acetone (0.1 M)
OR
R = H (14)
OR
–78 ºC to rt
(R = H <45%)
(R = TBS >98%)
R = H (20)
R = TBS (21)
TBSOTf
2,6-Lutidine
(80%)
[Ru] : [CpRu(CH3CN)3]PF6
R = TBS (19)
OH
OH
1-hexene
[Ru] (10 mol%)
MeO
MeO
O
acetone (0.5 M)
rt
95% (>98:2 l:b)
O
N
N
PMB 17
PMB
22
OH
MeO
O
OTBS
21 + 17
1
N
[Ru] (10 mol%)
23
linear (l)
PMB
CH2Cl2/DMF
(0.12 M), rt
45% (4:1 l:b)
(60% brsm)
OH
MeO
OTBS
O
N
24
branched (b)
PMB
With the alkynes from both sides in hand, the key
sequential alkene–alkyne couplings with propene were
pursued (Scheme 3). First, coupling of alkyne 14 with
propene was investigated. Due to the gaseous nature of
propene, the challenge of introducing this alkene for
coupling with 14 in the presence of catalytic ruthenium
complex needed to be addressed. To that end, perform-
ing the coupling reaction under atmospheric pressure of
propene (i.e. via balloon) proved to be incompetent to
deliver the desired product. To improve the efficiency of
coupling, the reaction vessel containing the ruthenium
catalyst was connected to a balloon of propene (bp = –
47.6 ºC) and the vessel was cooled to –78 ºC (dry-
ice/acetone bath) to condense an appropriate amount of
propene (~1 ml/mmol of alkyne). A solution of alkyne
14 in acetone was then added to the reaction mixture at –
Scheme 2. Preparation of the alkyne fragments
(R,R)-ProPhenol
OH
Ph3PO, Et2Zn
O
MsCl, Et3N
+
PhMe/THF, 0 ºC
(70%, 96:4 er)
CH2Cl2, –78 ºC
(95%)
10
11
9
OMs
13, [Pd(dppf)Cl2], InI
O
THF/HMPA (3:1)
(76%, ~10:1 anti:syn)
13
OH
12
14
OH
OH
OH
MeO
O
MeO
O
propyne
n-BuLi
MeO
NBS
AIBN
CCl4
(>98%)
N
N
CuI, THF
(80%)
O
N
PMB
15
PMB Br
16
PMB
17
OH
OH
MeO
MeO
MeO
O
MeOTf
TFA
(81%)
DCE, 75 ºC
(78%)
N
N
H
7
18
2
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
78 ºC, the balloon was removed and the reaction vessel
this optimized condition with the 1,4-diene 21 gave low
conversion and unsatisfactory yield of the coupled prod-
uct (<45% conversion, <35% yield).
1
2
3
4
5
6
7
8
was sealed and allowed to warm to room temperature.
This procedure effectively led to complete consumption
of 14, and the double coupling of propene with two mol-
ecules of alkyne 14 was not observed due to the pres-
ence of excess propene. Despite the improved conver-
sion of 14, the isolated yield of the coupled product 20,
did not exceed ~45% (see table S2). Multiple unidenti-
fied side products accounted for the remaining mass bal-
ance. Gratifyingly, employing TBS protected alcohol 19,
under the same conditions delivered the 1,4-diene 21 in
nearly quantitative yield.14 The coupled product 21 was
utilized in the following reactions without further purifi-
cation.
An alternative strategy to reduce the coordination of
the pyridine with ruthenium involves derivatization of
the pyridyl OH with an electron withdrawing substitu-
ent. We chose Teoc as such a group to alleviate the elec-
tronic properties of the pyridine nitrogen (Scheme 4).
Substrate 25 was synthesized in 98% yield using Teoc
chloride,15 and was subjected to the coupling reaction
with 1,4-diene 21. With minimal optimization which
showed better selectivity using [Cp*Ru163]PF6 complex,
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
Table 1. Exploring the synthetic utility of the sequen-
tial alkene-alkyne coupling via linchpin strategy
To test the feasibility of alkynes 17, 18, and 7 for the
second alkene–alkyne coupling, their reactions with 1-
hexene as a model alkene was evaluated (Scheme 3).
Alkynes 18 and 7 proved to be unreactive towards cou-
pling with 1-hexene, presumably due to deactivation of
ruthenium catalyst via the coordination of the pyridine in
7 or unprotected 2-pyridone in 18. Alkyne 17, on the
other hand, underwent coupling with 1-hexene and gave
rise to the coupled product 22 in high yield and selectivi-
ty. With this notion, the coupling of alkyne 17 with 1,4-
diene 21 was carried out and the desired product 23 was
obtained in 35% yield (60% brsm) along with the minor
branched coupled product 24. Formation of the coupled
product 23 proved the success of the proposed linchpin
strategy. Unfortunately, the subsequent removal of the
PMB group on 23 could not be accomplished.
R2
R1
R3
R4
R2
R4
R1
R3
Ru
1st couplinga
Ru
2nd couplingb
36a-k
1st alkyne
2
nd alkyne
1,3,6-triene product
entry
TBSO
TBSO
1
32
OH
36a (83%)
36b (80%)
HO
HO
2
3
TBSO
OH
33
28
OTBS
TMS
OH
TMS
HO
34
36c (54%, >3:1 b:l)
4
5
33
36d (52%)
Scheme 4. Completion of the total synthesis of pieri-
cidin A
OTeoc
OH
Teoc:
NaH
TeocCl
TMS
13
OH
MeO
MeO
MeO
O
29
36e (56%, 76% brsm) OH
HO
tBuOH
(98%)
O
MeO
N
N
7
25
6
7
OH
32
32
OTeoc
36f (63%)
36g (72%)
21
OTBS
MeO
MeO
OH
[Cp*Ru(CH3CN)3]PF6
(10 mol%)
Acetone (0.25 M)
OH
OH
OTBS
26
branched (b)
N
OH
9
OH
(60%)
(71% brsm, 4:1 l:b)
+
OTeoc
MeO
MeO
8
OTBS
TBAF
HO
Piericidin A (1)
N
THF 50 ºC
(87%)
35
30
36h (66%)
36i (60%)
27
linear (l)
HO
9
We then turned to an alternative strategy to enable
the alkyne 7 to serve as the coupling partner in the reac-
tion with polyene 21. As indicated before, this alkyne
failed to undergo coupling with 1-hexene, presumably
due to coordination of its basic nitrogen to the ruthenium
catalyst. We envisioned to block the pyridine nitrogen in
7 with a proton to prevent the latter deactivation of the
catalyst, thus allowing the coupling reaction to ensue.
Indeed, addition of 2.0 equivalents of camphor sulfonic
acid (CSA) allowed for complete consumption of 7 in
the coupling reaction with 1-hexene. However, using
OH
33
31
OTBS
OTBS
10
OH
32
19
HO
36j (71%)
OH
OTBS
32-TBS
11
36k (49%)c
13
OH
OH
aCoupling of these alkynes with propene was performed on 0.5 – 1.0 mmol scale
in the presence of 3 – 7 mmol% [CpRu(CH3CN)3]PF6 as catalyst in acetone (0.1
M). bThe coupling of these alkynes was carried out on 0.1 mmol scale using 10
mmol% [Cp*Ru(CH3CN)3]PF6 in acetone (0.25 M). cThe TBS group was cleaved
during this reaction.
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
the coupled products (26 and 17) were isolated in a 60%
combined yield (71% brsm) with 4:1 linear:branched
ratio, which can be readily separated. Indeed, the car-
bonate moiety of the Teoc group was crucial for the suc-
cess of the coupling reaction, whereas masking the hy-
droxyl group in 7 with TBS did not give access to the
coupled products. The Teoc and TBS groups in 27 were
concurrently removed with TBAF, delivering piericidin
A in 87% yield.
Page 4 of 6
seven longest linear sequence and eleven total steps,
representing the most efficient approach to date in term
of step economy. Alongside our synthetic efforts, some
notable reactions have been explored, including catalytic
asymmetric propynylation of acetaldehyde, selective
radical bromination and novel methylative debenzyla-
tion of the pyridone core. Significantly, gaseous reagents
have been exploited in the asymmetric alkynylation of
acetaldehyde as well as in the ruthenium catalyzed al-
kene-alkyne coupling. Propene as a linchpin has been
utilized for sequential coupling with two alkynes to give
rise to the triene motifs, which can be found in numer-
ous natural products. The accessibility of structurally
varied alkynes as starting materials due to the intrinsic
chemical behavior of C-1 and C-3 of the alkynes allows
tremendous structural flexibility in building the requisite
substrates for this linchpin strategy.
1
2
3
4
5
6
7
8
9
With successful implementation of the total synthesis
of piericidin A that hinged on the utilization of propene
as an efficient synthetic linchpin, we aimed to demon-
strate the general utility of this strategy (Table 1). The
couplings of propene with the first set of alkynes (high-
lighted in blue in Table 1) proceeded with nearly quanti-
tative yields and the resulting 1,4-dienes were entered
into coupling with the second set of alkyne (showed in
green) without any prior purification. As has been
demonstrated previously,17 the regioselectivity of the
coupling is generally governed by the stereo–electronic
properties of the coupling alkynes. Thus, linear and
branched coupled products can be accessed by manipu-
lation of the coupling alkyne fragments. Additionally,
the branched/linear ratio, as highlighted in the total syn-
thesis of piericidin A, can be modulated to some extent
by the judicious choice of conditions and ruthenium
complexes.16 Terminal alkynes are generally branched-
selective coupling partners. Nonetheless, sterically hin-
dered terminal alkynes such as 28 favor linearly coupled
products. Thus, triene 36c can be obtained in good yield
and linear selectivity with the hindered terminal alkyne
28 and the second coupling with an unhindered terminal
alkyne (34) favored the branched C–C bond formation.
Of note, in the case of reaction with 34, the terminal
alkyne undergoes the coupling reaction chemoselective-
ly to give rise to 36c, while the TMS protected alkyne
stays intact due to different steric bulk and reactivity.
Polyenes 36d – 36k are naturally occurring side chains.
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
ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental procedures, analytical data (1H-NMR, 13C-
NMR, MS, IR, and [α ]D ) for all new compounds,
additional reaction optimization tables (PDF )
AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
REFERENCES
1. (a) Takahashi, N.; Suzuki, A.; Tamura, S., J. Am. Chem. Soc.
1965, 87, 2066; (b) Takahash.N; Suzuki, A.; Tamura, S., Agric.
Biol. Chem. 1966, 30, 1; (c) Takahashi, N.; Suzuki, A.; Kimura,
Y.; Miyamoto, S.; Tamura, S., Tetrahedron Lett. 1967, 1961; (d)
Takahashi, N.; Suzuki, A.; Kimura, Y.; Miyamoto, S.; Tamura,
S.; Mitsui, T.; Fukami, J., Agric. Biol. Chem. 1968, 32, 1115; (e)
Takahashi, N.; Yoshida, S.; Suzuki, A.; Tamura, S., Agric. Biol.
Chem. 1968, 32, 1108.
2. Overvad, K.; Diamant, B.; Holm, L.; Holmer, G.; Mortensen, S.
A.; Stender, S., Eur. J. Clin. Nutr. 1999, 53, 764.
For example, polyene 36g leads to kalipyrone ,
16 7c 36i to
the polyene side chain of granuloside 16, 7f and 36j to the
3. (a) Jeng, M.; Hall, C.; Crane, F. L.; Takahashi, N.; Tamura, S.;
Folkers, K., Biochemistry 1968, 7, 1311; (b) Snoswell, A. M.;
Cox, G. B., Biochim. Biophys. Acta 1968, 162, 455; (c) Storey,
B. T., Pharmacol. Ther 1980, 10, 399; (d) Esposti, M. D.,
Biochim. Biophys. Acta, Bioenerg. 1998, 1364, 222; (e) Okun, J.
G.; Lummen, P.; Brandt, U., J. Biol. Chem. 1999, 274, 2625; (f)
Esposti, M. D., Genome Biol. Evol. 2016, 8, 126.
4. (a) Schnermann, M. J.; Boger, D. L., J. Am. Chem. Soc. 2005,
127, 15704; (b) Schnermann, M. J.; Romero, F. A.; Hwang, I.;
Nakamaru-Ogiso, E.; Yagi, T.; Boger, D. L., J. Am. Chem. Soc.
2006, 128, 11799.
14 7a, 7b
side chain of actinopyrone
.
As previously speci-
fied, the order of coupling of the alkyne fragments with
propene determines the position of the central double
bond in the triene motif. Thus, 36j and 36k structurally
differ only in the placement of the central double bond.
Both regioisomers can be accessed using the same start-
ing materials simply by switching the order of coupling
sequence. This flexibility in accessing trienes of a com-
pound can be beneficial in analogues syntheses and
preparation of libraries (see the SI for the proposed cata-
lytic cycles).
5. Lipshutz, B. H.; Amorelli, B., J. Am. Chem. Soc. 2009, 131,
1396.
6. (a) Schmidtchen, F. P.; Rapoport, H., J. Am. Chem. Soc. 1977,
99, 7014; (b) Keaton, K. A.; Phillips, A. J., J. Am. Chem. Soc.
2006, 128, 408; (c) Kikuchi, R.; Fujii, M.; Akita, H.,
Tetrahedron-Asymmetry 2009, 20, 1975; (d) Hoecker, J.;
Gademann, K., Org. Lett. 2013, 15, 670.
7. (a) Yano, K.; Yokoi, K.; Sato, J.; Oono, J.; Kouda, T.; Ogawa,
Y.; Nakashima, T., J. Antibiot. 1986, 39, 38; (b) Yano, K.;
Yokoi, K.; Sato, J.; Oono, J.; Kouda, T.; Ogawa, Y.; Nakashima,
T., J. Antibiot. 1986, 39, 32; (c) Graber, M. A.; Gerwick, W. H.,
In summary, we report a divergent and concise total
synthesis of piericidin A, featuring a linchpin strategy
empowered by alkene–alkyne coupling reactions. The
efficiency of the strategy is reflected in the step count of
the synthesis. Starting with the known pyridone 15 (pre-
pared in 3 steps), piericidin A has been realized with
4
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
J. Nat. Prod. 1998, 61, 677; (d) Hosokawa, S.; Yokota, K.;
Imamura, K.; Suzuki, Y.; Kawarasaki, M.; Tatsuta, K.,
Tetrahedron Lett. 2006, 47, 5415; (e) Yang, F.; Newsome, J. J.;
Curran, D. P., J. Am. Chem. Soc. 2006, 128, 14200; (f)
Cutignano, A.; Moles, J.; Avila, C.; Fontana, A., J. Nat. Prod.
2015, 78, 1761.
1
2
3
4
8. (a) Trost, B. M., Science 1991, 254, 1471; (b) Trost, B. M.,
Angew. Chem. Int. Ed. Engl. 1995, 34, 259; (c) Wender, P. A.;
Verma, V. A.; Paxton, T. J.; Pillow, T. H., Acc. Chem. Res.
2008, 41, 40; (d) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W.,
Angew. Chem. Int. Ed. 2009, 48, 2854.
5
6
7
8
9
9. Marshall, J. A., J. Org. Chem. 2007, 72, 8153.
10. Trost, B. M.; Quintard, A., Angew. Chem. Int. Ed. 2012, 51,
6704.
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
11. (a) Xiao, Y.; Wang, Z.; Ding, K., Chem. Eur. J. 2005, 11, 3668;
(b) Trost, B. M.; Bartlett, M. J., Acc. Chem. Res. 2015, 48, 688.
12. (a) Coleman, R. S.; Lu, X.; Modolo, I., J. Am. Chem. Soc. 2007,
129, 3826; (b) Muri, D.; Carreira, E. M., J. Org. Chem. 2009,
74, 8695; (c) Schmidt, T.; Kirschning, A., Angew. Chem. Int. Ed.
2011, 51, 1063.
13. (a) Marshall, J. A.; Grant, C. M., J. Org. Chem. 1999, 64, 696;
(b) Marshall, J. A.; Chobanian, H. R.; Yanik, M. M., Org. Lett.
2001, 3, 3369.
14. Based on our previous reports (see ref. 17), free alcohols are
generally tolerated under the ruthenium catalyzed alkene–alkyne
coupling conditions. Nonetheless, these ruthenium (2+)
complexes can act as Lewis acid. Thus, alcohol 14 and its
coupled product (20) that contain a free hydroxyl group that is
allylic as well as homoallylic are presumably prone to
elimination or other side product formation under this condition.
15. (a) Shute, R. E.; Rich, D. H., Synthesis 1987, 1987, 346; (b)
Guo, F.; Dhakal, R. C.; Dieter, R. K., J. Org. Chem. 2013, 78,
8451.
16. For instance, employing less bulkier cp-ruthenium instead of
cp*-ruthenium catalyst in the coupling reaction between 21 and
25 led to the linear and branched products with nearly 1:1 ratio.
Additionally, solvent and additives have been shown to have
impact on the linear/branched ratio as well as the reaction
conversion and yield (see ref. 17).
17. (a) Trost, B. M.; Pinkerton, A. B.; Toste, F. D.; Sperrle, M., J.
Am. Chem. Soc. 2001, 123, 12504; (b) Trost, B. M.; Toste, F. D.;
Pinkerton, A. B., Chem. Rev. 2001, 101, 2067; (c) Trost, B. M.;
Frederiksen, M. U.; Rudd, M. T., Angew. Chem. Int. Ed. 2005,
44, 6630; (d) Trost, B. M.; Cregg, J. J., J. Am. Chem. Soc. 2015,
137, 620; (e) Trost, B. M.; Stivala, C. E.; Fandrick, D. R.; Hull,
K. L.; Huang, A.; Poock, C.; Kalkofen, R., J. Am. Chem. Soc.
2016, 138, 11690.
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
1
2
Insert Table of Contents artwork here
3
4
5
6
synthetic
linchpin
R2
R1
R3
R4
R2
R4
R1
R3
Ru
Ru
atom-economical entry
to 1,3,6-triene motif
1st coupling
2nd coupling
7
8
9
N
OMe
OMe
OH
Piericidin A
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
OH
6
ACS Paragon Plus Environment