Concise Syntheses of ?"12-Prostaglandin J Natural Products via Stereoretentive Metathesis

Article abstract of DOI:10.1021/jacs.8b12816

δ¹²-Prostaglandin J family is recently discovered and has potent anticancer activity. Concise syntheses of four δ¹²-prostaglandin J natural products (7-8 steps in the longest linear sequences) are reported, enabled by convergent stereoretentive cross-metathesis. Exceptional control of alkene geometry was achieved through stereoretention.

Full text of DOI:10.1021/jacs.8b12816

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Communication
Concise Syntheses of #12-Prostaglandin J
Natural Products via Stereoretentive Metathesis
Jiaming Li, Tonia S. Ahmed, Chen Xu, Brian M. Stoltz, and Robert H. Grubbs
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12816 • Publication Date (Web): 12 Dec 2018
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D12
Concise Syntheses of -Prostaglandin J Natural Products via Stere-
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Jiaming Li†, Tonia S. Ahmed†, Chen Xu*,†,‡, Brian M. Stoltz*,† and Robert H. Grubbs*,†
†The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United States
‡Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong
518000, China
Supporting Information Placeholder
12
12
Scheme 1. D -Prostaglandin J Natural Products and Retro-
synthetic Analysis
ABSTRACT:
D -Prostaglandin J family is recently discov-
ered and has potent anti-cancer activity. Concise syntheses
α-chain
1
5
8
12
of four D -prostaglandin J natural products (7–8 steps in the
COOH
COOH
Me
10
12
14
15
Me
longest linear sequences) are reported, enabled by conver-
gent stereoretentive cross-metathesis. Exceptional control of
alkene geometry was achieved through stereoretention.
ω-chain
O
O
OH
Δ12-prostaglandin J2 (1)
(Δ12-PGJ2)
15-deoxy-Δ12,14-prostaglandin J2 (2)
(15d-PGJ2)
COOH
Me
COOH
17
Me
O
O
OH
Prostaglandins are an important class of naturally occur-
ring molecules that are found in mammalian tissues and ex-
hibit a broad range of biological functions and widespread
medical applications.1 Efforts directed toward the synthesis
of various prostaglandins has had a profound effect on the
development of new strategies and tactics employed in the
field of synthetic chemistry, emanating from the seminal
Δ12-prostaglandin J3 (3)
(Δ12-PGJ3)
15-deoxy-Δ12,14-prostaglandin J3 (4)
(15d-PGJ3)
Three-component
coupling
Stereoretentive
metathesis
COOH
Me
Me
O
O
OH
Δ12-PGJ3 (3)
studies of Corey beginning in the 1960’s.2 The recently dis-
OTBS
22
12
1 4
covered D -prostaglandin J family ( – , Scheme 1) features
BocO
BocO
kinetic
BrMg
resolution
a unique cross-conjugated dienone motif and appealing anti-
+
+
3
12
O
3
cancer activity. D -PGJ3 ( ), for example, was isolated as a
secondary metabolite and was shown to selectively induce
apoptosis of leukemia stem cells over normal hematopoietic
stems cells with high potency.4 Studies of its stability, bioa-
Me
O
(±)-6
O
(R)-6
OTBS
21
group manipulation with concomitant waste generation.
From a strategic perspective, chemoselectivity among multi-
ple alkenes has also been another concern, especially in the
later stages. Stereoselective and alkene-chemoselective me-
tathesis catalysts are in demand to realize a convergent syn-
thesis from simple alkene building blocks.
12
vailability, and hypersensitivity make D -PGJ3 an intriguing
drug candidate for leukemia treatment.5 Synthetic efforts
12
toward D -prostaglandin J compounds began in 2003, with a
12
1
2
number of syntheses of D -PGJ2 ( ) and 15d-PGJ2 ( ) re-
ported through various approaches.6 Elegant contributions
A series of cyclometallated ruthenium-based catalysts (e.g.
12
3
to the total synthesis of D -PGJ3 ( ) were reported by Nico-
Ru-1 Ru-2
, Figure 1) were recently developed by Grubbs
,
and co-workers,
laou and co-workers7 and more recently by the Aggarwal
11
and enabled Z-selective metathesis
group.8 A number of D -PGJ3 analogues were also accessi-
12
through a favored syn-metallacyclobutane intermediate
(Figure 1, Path A). More recently, catechodithiolate-based
ble via a streamlined synthesis developed by Nicolaou and
co-workers9 to enable a comprehensive structural-activity
relationship (SAR) study of their anti-cancer activities.
Olefin cross-metathesis is a convergent method for build-
ing C–C double bonds in natural product syntheses;10 how-
ever, it has seldom been applied in the previous syntheses of
Ru-3
catalyst
and its dithiolate variants were developed by
Hoveyda group and showed high Z-selectivity in ring-
opening metathesis polymerizations, ring-opening cross-
metathesis, and cross-metathesis with Z-olefins.12 In fact,
high kinetic E-selectivity in cross-metathesis with E-starting
12
D -PGJ family. Most importantly, conventional metathesis
Ru-3
, the sIPr analogue
Ru-
materials was also observed with
catalysts typically gave imperfect control of alkene geometry.
Previous syntheses relied on the semi-hydrogenation of al-
kynes or Wittig reactions, requiring multi-step functional
4,
and other less bulky fast-initiating analogues developed by
Materia Inc. and the Grubbs group,13 that defined these cata-
lysts as stereoretentive. The origin of the stereoretention
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Z-selective metathesis catalysts:
21
gnard reagent, w-chain aldehyde , and a chiral cyclopente-
iPr
iPr
Me
1
2
3
4
5
6
7
8
(R)-6
(R)-6
can be used as a
none
. The O-Boc group of
N
N
N
N
Me
traceless stereoinductive group to set the C8 stereocenter.17
Me
12
1
We initially aimed to synthesize D -PGJ2 ( ). Chiral cy-
Ru
Ru
O
O
(R)-6
was prepared from furfuryl alcohol in a
clopentenone
O
O
N
O
O
N
O
O
iPr
iPr
Ru-1
Stereoretentive metathesis catalysts:
three-step process including a kinetic resolution method
developed by Reiser and coworkers (Scheme 2A).18 The w-
Ru-2
10
7
was prepared from hexanal ( ) through
chain aldehyde
iPr
iPr
iPr
iPr
Me
Me
asymmetric Keck allylation,19 TBS protection, and ozonoly-
sis (Scheme 2B). With all the starting materials for the three-
component coupling in hand, CuBr•Me2S and LiCl facilitat-
ed the diastereoselective conjugate addition of the allyl mag-
nesium bromide. The enolate formed can then be trapped
by the subsequently added w-chain aldehyde electrophile,
and the O-Boc group was eliminated in the course of the
aldol reaction to form the desired cyclopentenone. Elimina-
N
N
Me
Me
N
N
Me
S
Me
Cl
Cl
9
S
Ru
Ru
10
11
12
13
14
15
16
17
18
19
20
21
22
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S
O
S
iPr
O
iPr
Cl
Cl
Ru-3
Ru-4
Model of Z-selectivity:
Ar
N
N
Ar
N
N
11
tion with MsCl and DMAP favored 12E-product
as the
major product in reasonable yield (45% over 2 steps, Scheme
2D).
Ru
Ru
O
O
Path A
O
N
O
N
O
O
11
Stereoretentive metathesis was then evaluated on
11
.
Model of Stereoretention:
Since
stereoretentive metathesis catalysts, we considered a sym-
13
cannot react with another terminal alkene using
Ar
Ar
N
N
Z-selective
S
metric Z-alkene as the coupling partner, which could also
12
Ru
α
α
be made by homodimerization of readily available
through stereoretentive metathesis. With 1 mol% loading of
Ru-4
S
Path B
Ar
Ar
N
N
β
Cl
S
as the catalyst, 98% conversion could be achieved by
applying dynamic vacuum to remove the by-product, cis-3-
Ru
Ar
Ar
N
N
S
11
were added into the
hexene (bp 66–68 ºC) from the reaction mixture. Next,
S
Ru
Cl
Ru-4
with an additional 5 mol% catalyst
α
α
S
Path C
E-selective
14
reaction mixture, and the alcohol product could be isolat-
ed in 95% yield in high Z-selectivity (>99% Z). This result
established the efficacy of an efficient one-pot, stereoreten-
tive homodimerization/cross-metathesis strategy to build
the C5 Z-alkene. In contrast, synthesis of PGE2 and PGF2a
required a large excess of gaseous butene and more compli-
cated operations in the previously reported methylene cap-
ping strategy.14 Ley oxidation and deprotection of the TBS
β
Figure 1. Z-selective and Stereoretentive Metathesis Catalysts
and Models of Their Stereoselectivity
was attributed to the formation of a side-bound metallacy-
clobutane intermediate, of which the a-substituents are
forced down to minimize steric interactions with the bulky
N-aryl groups of the NHC. As a result, when starting with Z-
alkenes, the b-substituent points down to generate Z-alkene
products (Figure 1, Path B). When starting with E-alkenes,
however, the b-substituent has to point up into the open
space between two N-aryl groups, leading to the generation
of E-alkene products, albeit with slower rates (Figure 1, Path
C). Cross-metathesis between two terminal alkenes is not
possible with stereoretentive metathesis catalysts, however,
because the intermediate methylidene species are unstable
and lead to catalyst decomposition.12d A methylene capping
strategy was recently reported as a remedy to this problem,
enabling the cross-metathesis of two terminal alkenes.14
Despite the unique properties of these stereoretentive cata-
lysts, to date, limited synthetic evaluation of these catalysts
14
group of
in aqueous HF furnished the natural product
D -prostaglandin J2 ( ) in 89% yield over the last two steps.
The same three-component coupling sequence was per-
12
1
16
formed to obtain , and the enal functionality of aldehyde
15 16
was well tolerated in the aldol step.
to the standard one-pot stereoretentive homodimeriza-
17
was then subjected
tion/cross-metathesis conditions, and alcohol
was ob-
tained in excellent yield (93% yield, Scheme 2D) with high
Z-selectivity (>99% Z). The C14 E-alkene tolerated the
reaction, consistent with the much slower reaction of E-
13
Ru-4
alkenes with
as seen previously. We also assessed the
16
17
proceeded with a small loss in enanti-
(R)-6
enantiopurity of intermediates and . Three-component
16
coupling product
has been conducted.15 Herein, we present a total synthesis of
opurity (88% ee) from
(>99% ee), but the metathesis
12
17
product was obtained without significant erosion of enan-
tiopurity (87% ee). This result demonstrates that stereore-
1 4
the olefin-enriched D -prostaglandin J natural products –
by implementing a concise stereoretentive metathesis ap-
proach. This also sets a perfect test ground to evaluate the
reactivity, chemoselectivity, and functional group compati-
Ru-4
tentive metathesis with catalyst
also retained the stere-
17
gave 15-deoxy-D -prostaglandin J2 ( ) in 68% yield.
ochemistry of the C8 stereocenter. Ley oxidation of again
12,14
12
2
bility of these newly developed metathesis catalysts.
Retrosynthetically, D -PGJ3 ( ) for example can be simpli-
fied into a truncated prostaglandin structure
stereoretentive metathesis (Scheme 1). A three-component
coupling strategy can be applied toward the synthesis of
using a relatively simple and commercially available allyl Gri-
12
3
Synthesis of D -prostaglandin J3 ( ) began with the prepa-
3
21
could also be generated from stereoretentive
18
ration of the w-chain aldehyde . We envisioned the Z-
21
22
by use of
alkene in
16
metathesis. First, we obtained chiral alcohol through a
22
,
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Scheme 2. Synthetic Route to D -PGJ Natural Products
1
2
3
4
Pd2(dba)3•CHCl3
A.
B.
Cs2CO3
(R,R)-DACH
p-methoxyphenol
CH2Cl2
TiCl4, Ti(Oi-Pr)4
(R)-BINOL
allyl stannane
Ag2O, CH2Cl2
HO
BocO
BocO
O3
Me2S/Et3N
CH2Cl2/MeOH
(Boc)2O
Et3N, THF
Me
O
Me
O
Me
(95%)
(41%, > 99% ee)
(55%, > 95% ee)
OR
(93%)
OTBS
10
7
O
O
(±)-6
O
(R)-6
TBSCl,imidazole
CH2Cl2 (79%)
5
8: R = H
9: R = TBS
5
6
7
8
9
H2O
C.
Cl
MeI
CaCO3
MeCN/H2O
microwave
180 ºC, 15 min
(82%)
cis-3-hexene
Ru-4 (4 mol%)
THF
O
Ref. 20
O
O
S
S
O
O
NH HN
Me
(58%)
S
S
OR
O
(94%)
OTBS
OTBS
(88%, > 99:1 Z/E)
PPh2 Ph2P
OH
20
21
TBSCl,imidazole
CH2Cl2 (95%)
18: R = H
19: R = TBS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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60
(R,R)-DACH
furfuryl alcohol
Three-component coupling
Oxidation/ deprotection
Stereoretentive homodimerization/ cross-metathesis
D.
HO
12 (8 equiv)
Me
1. CuBr.Me2S, LiCl, allylMgBr
THF, –78 ºC
then 10, THF, –78 ºC
Ru-4 (1 mol%)
toluene, 23 ºC, dynamic vacuum
O
Me
10
HO
OH
13 (98% conversion)
OTBS
then 11,
Ru-4 (5 mol%)
THF, 40 ºC
1. TPAP, NMO•H2O
MeCN
2. HF, MeCN
OH
COOH
Me
Me
Me
2. MsCl, DMAP, CH2Cl2
(45% over 2 steps)
(89% over 2 steps)
O
(95%, > 99:1 Z/E)
O
O
OTBS
(1 equiv)
OH
OTBS
14
Δ12-PGJ2 (1)
11
O
Me
12
15
vide supra
OH
TPAP, NMO•H2O
MeCN
COOH
Me
vide supra
Me
Me
(41% over 2 steps)
(68%)
(93%, > 99:1 Z/E)
O
O
O
15d-PGJ2 (2)
16 (88% ee)
17 (87% ee)
BocO
O
Me
12
OH
Me
21
OTBS
O
(R)-6
+
vide supra
OTBS
24 (31%)
vide supra
Me
O
O
23 (44%, > 99:1 Z/E)
OTBS
(40% over 2 steps)
O
OTBS
OH
22
1. TPAP, NMO•H2O
MeCN
2. HF, MeCN
25
OH
(8 equiv)
COOH
Me
Z-selective
cross-metathesis
Ru-2 (20 mol%)
Me
THF, 40 ºC
Ar bubbling
(60% over 2 steps)
O
O
OH
Δ12-PGJ3 (3)
OTBS
23 (52%, > 99:1 Z/E) + 26 (<2%)
12
O
Me
OH
27
vide supra
COOH
Me
1. PCC, CH2Cl2
vide supra
2. NaClO2,
NaH2PO4,
2-methyl-2-butene
t-BuOH/H2O
Me
Me
(36% over 2 steps)
O
O
O
29 (36%, > 99:1 Z/E)
28
15d-PGJ3 (4)
+
30 (~12%), 31 (yield n.d.)
(12% from 28)
By-products from metathesis reactions:
E.
F.
Ar
N
N
trisubstituted
metallacyclobutane
intermediate
OH
OH
Ru
OH
OH
with Ru-2:
O
O
O
O
O
N
OTBS
O
26
30
31
highly unfavorable
23
and the desired alcohol product was obtained in only 44%
yield.
Alternatively, we chose to use cyclometallated catalyst
reported chiral pool strategy with (R)-epichlorohydrin as the
starting material (Scheme 2C).20 TBS protection of the al-
cohol and subsequent removal of the 1,3-dithiol gave alde-
Ru-
20
hyde . Stereoretentive metathesis of
20
2
to circumvent the crossover of alkene reactivity. Because
with an excess
Ru-4
amount of cis-3-hexene using catalyst
(4 mol%) afford-
in good yield (88%) with high Z-
21
tri-substituted metallacyclobutane intermediates are highly
unfavorable with this cyclometallated catalyst, this pathway
can be easily avoided (Scheme 2E).21 Chemoselective cross-
25
metathesis of 5-hexen-1-ol ( ) with the allyl group of
23
furnished the desired product in good yield (52%) with a
21
ed w-chain aldehyde
selectivity (>99% Z). The short synthesis of aldehyde
proved that a broad range of functional groups, including
aldehydes, can be tolerated without protecting group manip-
22
22
26
(less than 2%, Scheme 2F).
ulations using stereoretentive catalysts. Then,
thesized through the standard three-component coupling
(R)-6
was syn-
trace amount of by-product
24
The RCM product was not observed under these condi-
tions. The side-reaction of C17 internal Z-alkene could be
attributed to ethylene produced or the residual ruthenium
methylidene species in the solution. Then, Ley oxidation of
sequence from
closing metathesis (RCM) with
product (31% yield) bearing an unusual 9-membered ring,
(Scheme 2D). Surprisingly, fast ring-
Ru-4 24
yielded
as a by-
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and deprotection of the TBS group with aqueous HF pro-
Page 4 of 5
23
ria, Inc. is thanked for generous donations of catalysts. A. W.
Sun, E. R. Welin, and Y. Xu are thanked for helpful discussion
and input on this manuscript. Dr. Scott C. Virgil (Caltech) is
thanked for assistance with chiral-SFC and HPLC separation. K.
Chen from F. H. Arnold lab is thanked for his help with Biotage
separation. Dr. David VanderVelde (Caltech) and Dr. Mona
Shahgholi (Caltech) are acknowledged for help in structural
determination and characterizations.
12
1
2
3
4
5
6
7
8
3
vided D -prostaglandin J3 ( ) in 8 linear steps.
4
Finally, in the synthesis of 15d-PGJ3 ( ), crossover of me-
tathesis reactivity between the allyl group and the C17 Z-
28
could also be expected. Standard stereoreten-
alkene of
Ru-4
tive metathesis conditions with
provided desired prod-
30
29
31
and (Scheme
uct
in 36% yield and by-products
2F).22 Compared to D -PGJ3 ( ) synthesis, where the steric
12
3
bulk of the OTBS group may be beneficial to achieving good
28
chemoselectivity, has no such steric hindrance. However,
Dedicated to Professor E. J. Corey on the occasion of his 90th
birthday.
9
28
no RCM of was observed, possibly due to the ring strain
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
of RCM product. Though
29
could not be separated from
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, the mixture was subjected to PCC oxidation and Pinnick
oxidation conditions23, allowing us to isolate 15-deoxy-D
-
12,14
4
28
prostaglandin J3 ( ) (12% yield from ).
In conclusion, we report a concise and convergent syn-
thesis of four D -prostaglandin J natural products in shorter
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The Supporting Information is available free of charge on the
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Characterization data, and experimental data (PDF)
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AUTHOR INFORMATION
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2
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Corresponding Authors
*rhg@caltech.edu
*stoltz@caltech.edu
*xuc@sustc.edu.cn
bayashi, Y. Highly Efficient Total Synthesis of Δ12-PGJ2, 15-Deoxy-Δ12,14
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Pulukuri, K. K.; Yu, R.; Rigol, S.; Heretsch, P.; Grove, C. I.; Hale, C. R. H.;
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ORCID
Jiaming Li:
Tonia S. Ahmed:
Chen Xu:
Brian M. Stoltz:
Robert H. Grubbs:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(8) Pelšs, A.; Gandhamsetty, N.; Smith, J. R.; Mailhol, D.; Silvi, M.;
Watson, A. J. A.; Perez-Powell, I.; Prévost, S.; Schützenmeister, N.; Moore,
We acknowledge funding from NIH (R01GM031332 and
R01GM080269) and NSF CHE 150216. T.S.A. acknowledges
NSF for support through a graduate research fellowship. Mate-
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Insert Table of Contents artwork here
COOH
Me
COOH
iPr
iPr
iPr
Me
O
N
N
O
OH
iPr
Δ12-PGJ2
Cl
15d-PGJ2
S
8 steps
Ru
7 steps
S
O
iPr
COOH
Me
Cl
COOH
Stereoretentive metathesis
Me
O
O
OH
Δ12-PGJ3
8 steps
15d-PGJ3
7 steps
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