Adventures and Detours in the Synthesis of Hydropentalenes

Article abstract of DOI:10.1055/s-0040-1707226

Functionalized hydropentalenes (i.e., bicyclo[3.3.0]octanones) constitute important building blocks for natural products and for ligands for asymmetric catalysis. The assembly and tailored functionalization of this convex roof-shaped scaffold is challenging and has motivated a variety of synthetic approaches including our own contributions, which will be presented in this account. 1 Introduction 2 Biosynthesis of Hydropentalenes 3 Hydropentalenes through the Pauson-Khand Reaction 4 Hydropentalenes through Transannular Oxidative Cyclization of Cycloocta-1,4-diene 5 Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Dodecahydrocyclopenta[ a ]indenes 6 Functionalization of Bicyclo[3.3.0]octan-1,4-diones to Crown Ether Hybrids 7 Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Cylindramide 8 Tandem Ring-Opening Metathesis/Ring-Closing Metathesis/Cross-Metathesis of Bicyclo[2.2.1]heptanes 9 Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Geodin A 10 Hydropentalenes through Enantioselective Desymmetrization of Weiss Diketones 11 Functionalization of Weiss Diketones by Carbonyl Ene Reactions 12 Functionalization of the Weiss Diketone to Cylindramide and Geodin A Core Units 13 Biological Properties of Bicyclo[3.3.0]octanes 14 Hydropentalenes through Vinylcyclopropane Cyclopentene Rearrangement 15 Functionalization of Bicyclo[3.3.0]octanes toward Chiral Dienes 16 Miscellaneous Syntheses of Hydropentalenes 17 Conclusion and Outlook.

Full text of DOI:10.1055/s-0040-1707226

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M. Deimling et al.
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Adventures and Detours in the Synthesis of Hydropentalenes
Max Deimlinga ◊
Anna Zensa ◊
Natja Parka
Christine Hessa
Simon Klenka
Zarfishan Dilrubaa,b
Angelika Baroa
Sabine Laschat*a
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a Institut für Organische Chemie, Universität Stuttgart,
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
sabine.laschat@oc.uni-stuttgart.de
b Department of Chemistry, University of Leicester,
University Road, Leicester, LE1 7RH, UK
◊ These coauthors contributed equally to this work.
Received: 16.06.2020
Accepted after revision: 30.06.2020
Published online: 18.08.2020
1 Introduction
The bicyclo[3.3.0]octane (hydropentalene) unit is an
important constituent of several natural products and bio-
logically active compounds covering a broad range of struc-
tural complexity. Selected examples include ptychanolide
(1; Figure 1), a sesquiterpenoid from the liverwort Ptychan-
thus striatus (lehm. et lindenb.);1,2 carbacyclin (2) and clin-
prost (4), which are prostaglandin analogues and platelet
aggregation inhibitors;3,4 and the diterpenes silphiperfo-
lene (5),5 (–)-5-oxo-silphiperfolene (6),6 neorogiolane (8),7
hirsutene (3),8 and modhephene (9).9 Other examples in-
clude (–)-retigeranic acid A (10),10 an antibacterial sester-
terpenoid isolated from a Himalayan lichen and the antibi-
otic pentalenolactone A (7) produced by Streptomyces
UC5319, which specifically inhibits glyceraldehyde-3-phos-
phate dehydrogenase in Trypanosoma brucei.11
We were particularly fascinated by the class of acylte-
tramic macrolactams, consisting of such structurally relat-
ed members as the cytotoxin cylindramide A (11) from the
Pacific sponge Halichondria cylindrata,12 and geodin A (12)
from the sponge Geodia sp., which shows anthelmintic
properties against the nematode Haemonchus contortus.13
Aburatubolactam A (14) from the bacterium Streptomyces
sp. SCRC A-20 is an inhibitor of anionic superoxides,14 and
alteramide A (13), isolated from the marine bacterium Al-
termonas sp. shows cytotoxic activity.15
DOI: 10.1055/s-0040-1707226; Art ID: st-2020-a0350-a
Abstract Functionalized hydropentalenes (i.e., bicyclo[3.3.0]octa-
nones) constitute important building blocks for natural products and
for ligands for asymmetric catalysis. The assembly and tailored func-
tionalization of this convex roof-shaped scaffold is challenging and has
motivated a variety of synthetic approaches including our own contri-
butions, which will be presented in this account.
1
2
3
4
Introduction
Biosynthesis of Hydropentalenes
Hydropentalenes through the Pauson–Khand Reaction
Hydropentalenes through Transannular Oxidative Cyclization of
Cycloocta-1,4-diene
5
6
7
8
Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Dodecahy-
drocyclopenta[a]indenes
Functionalization of Bicyclo[3.3.0]octan-1,4-diones to Crown
Ether Hybrids
Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Cylindra-
mide
Tandem Ring-Opening Metathesis/Ring-Closing Metathe-
sis/Cross-Metathesis of Bicyclo[2.2.1]heptanes
Functionalization of Bicyclo[3.3.0]octan-1,4-dione to Geodin A
Hydropentalenes through Enantioselective Desymmetrization of
Weiss Diketones
9
10
11
12
Functionalization of Weiss Diketones by Carbonyl Ene Reactions
Functionalization of the Weiss Diketone to Cylindramide and
Geodin A Core Units
13
14
Biological Properties of Bicyclo[3.3.0]octanes
Hydropentalenes through Vinylcyclopropane Cyclopentene Re-
arrangement
15
16
17
Functionalization of Bicyclo[3.3.0]octanes toward Chiral Dienes
Miscellaneous Syntheses of Hydropentalenes
Conclusion and Outlook
Therefore, there is a strong interest in the development
of methods for synthesizing the bicyclo[3.3.0]octane unit.
When we started our work on acyltetramic macrolactams,
only few synthetic studies on this unique natural product
class had been reported, and therefore we had to struggle in
a relatively unexplored land. Another of our motivations
was the lack of knowledge on the biological modes of ac-
Key words bicyclooctanes, diene ligands, hydropentalenes, natural
product synthesis
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Deimling et al.
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Biographical Sketches
(Clockwise from top left) Sabine Laschat
studied chemistry at the University of Würz-
burg (1982–1987) and did her Ph.D. studies
at the University of Mainz under the supervi-
sion of Horst Kunz (1988–1990). After post-
doctoral studies with Larry E. Overman at
the University of California, Irvine (1990–
1991), followed by her habilitation at the
University of Münster, she was appointed an
associate professor at TU Braunschweig
(1997–2002). Since 2002, she has been a
full professor of organic chemistry at the
University of Stuttgart. She was a speaker of
the Collaborative Research Centre SFB 706
‘Selective Catalytic Oxidations of C–H Bonds
with Molecular Oxygen’ (2005–2010), and
served as Vice Rector for Research and Tech-
nology of the University of Stuttgart (2010–
2012) and as speaker of the Project House
‘NanoBioMater’. Her research interests in-
clude liquid crystals, natural product synthe-
sis, and chemoenzymatic syntheses.
Max Deimling studied chemistry at the
University of Stuttgart, where he received
his B.Sc. degree in 2015 and M.Sc. degree in
2017. Currently he is pursuing his Ph.D.
studies at the Institute of Organic Chemistry
in the Laschat research group. His research
interests are in the area of diene-ligand de-
sign and asymmetric catalysis.
chemistry at the University of Stuttgart
(2000–2005). Since completing her Ph.D.
thesis on the development of synthetic
methods on the road to Geodin A in the
Laschat research group in 2009, she has tak-
en on various positions in quality manage-
ment in the pharmaceutical/medical-device
industry.
Angelika Baro studied chemistry at the
Georg-August-Universität Göttingen (Ger-
many), where she received her Ph.D. degree
in clinical biochemistry (1987). Since 1991,
she has been responsible for scientific docu-
mentation and publication at the Institute of
Organic Chemistry of the University of
Stuttgart.
Simon Klenk studied chemistry at the Uni-
versity of Stuttgart (2008–2013). His M.Sc.
thesis in the Laschat research group dealt
with hydropentalenes. Since completing his
Ph.D. thesis (2013–2018) on supramolecu-
lar chemistry of proteins at the Leibniz Insti-
tute for Molecular Pharmacology (Berlin)
under the supervision of Christian Hacken-
berger, he has been developing RNA assays
and analytical methods in the pharmaceuti-
cal industry.
Natja Park studied chemistry at the Uni-
versity of Stuttgart and the École de Chimie,
Polymères et Matériaux in Strasbourg
(2003–2008). After completion of her Ph.D.
thesis on the synthesis of tetramic acid mac-
rolactams in the Laschat research group in
2013, she began her career as a research
chemist in the field of synthetic rubber
(2014–2015), and then moved on to techni-
cal project management in the field of
chemical anchors (2016 to date).
Zarfishan Dilruba studied for her
M.Chem. degree at the University of Leices-
ter (2016–2020). In her third year of her
studies, she joined the Laschat research
group (ERASMUS project) and worked on
the synthesis of chiral diene ligands (2019).
In her final year of study, she produced her
M.Chem. thesis on metal processing using
iodine in deep eutectic solvents under the
supervision of Professor Abbott (2020).
Anna Zens studied chemistry at the Uni-
versity of Stuttgart and received her B.Sc.
degree in 2013 and her M.Sc. degree in
2016. Currently she is pursuing her Ph.D.
studies at the Institute of Organic Chemistry
in the Laschat research group. In her Ph.D.
thesis, she focused on the development of
new synthetic methods for polyquinanes.
Christine Hess (née Hofmann) studied
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

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M. Deimling et al.
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HO2C
H
(HSAF) 15b (Figure 3), a broad-spectrum antimycotic isolat-
ed from Lysobacter enzymogenes str. C3 that is structurally
identical to dihydromaltophilin, identified the genes coding
for a hybrid polyketide synthase-nonribosomal peptide
synthase (PKS-NRPS), a sterol desaturase, a ferredoxin re-
ductase and an arginase.18 More recently, Shen, Du, and
their co-workers obtained a more detailed insight into the
biosynthesis of HSAF 15b.19
O
H
3
HO
O
H
carbacyclin (2)
O
H
H
ptychenolide (1)
hirsutene (3)
HO
C5H11
O
H
O
CO2Me
4
O
X
HO
CO2Me
H
As shown in Figure 3, two polyunsaturated hexaketide
fragments are linked by an ornithine (Orn) unit, followed by
installation of the tetramate subunit through Claisen and
Dieckmann condensations.19 According to Shen and Du, the
redox enzyme OX3 takes the role of a gatekeeper and cata-
lyzes a reductive [2+3]-cycloaddition with loose stereospe-
cificity.19 Only those intermediates with the correct stereo-
chemistry of the first cyclopentane ring are further pro-
cessed by subsequent redox enzymes OX2 and OX4,
forming the second and third ring. Thus, the original hy-
pothesis18 that the cyclohexane ring is generated before the
hydropentalene unit was ruled out by these results.19 Note
that the Clardy20 and Blodgett21 groups demonstrated the
existence of a common biosynthetic origin for polycyclic ac-
yltetramic macrolactams from phylogenetically diverse
bacteria, and discovered novel members of this natural
product family, whereas Gulder22 and Zhang23 and their re-
spective co-workers reconstructed the biosynthesis of
ikarugamycin.
H
H
clinprost (4)
C5H11
pentalenolactone A (7)
HO
X = H2 silphiperfol-6-ene (5)
X = O 5-oxosilphiperfol-6-ene (6)
H
H
H
H
HO2C
neorogiolane (8)
modhephene (9)
(–)-retigeranic acid A (10)
O
O
H
H
HN
H
NH
HO
OH
H
H
H
O
O
HO
NH
O
NH
O
OH
OH
cylindramide (11)
alteramide (13)
O
H
N
H
OH
O
HN
HO
O
N
H
H
HO
H
O
NH
O
O
1
/
2 Mg2+
O
geodin A (12)
aburatubolactam (14)
Figure 1 Selected hydropentalene-containing natural products
Pauson–Khand
VCP rearrangement
O
O
O
R4
O
R1
H
H
H
H
R4
[2+2+2]
C
R1
R4
R3
tion of these compounds. Only limited information was
available at that time, despite the wealth of information re-
garding the chemistry and biology of tetramic acids.16
As will be discussed below, these initial endeavors di-
versified rapidly and brought us a variety of synthetic chal-
lenges. On the other hand, new areas were opened, such as
asymmetric catalysis with bicyclo[3.3.0]octane-derived di-
ene ligands.
The current account discusses hydropentalene chemis-
try and applications from our personal perspective. Figure 2
provides an overview of the various retrosynthetic discon-
nections. Relevant work by other groups has been included
whenever appropriate. A more-general overview for inter-
ested readers is given in the recommended reviews, which
also cover the parent antiaromatic pentalenes and their co-
ordination compounds.17
R3
Ar
O
H
H
H
H
O
R3
R1
R4
SR2
R3
X
Ar
R2
O
OR5
R4
O
RCM
H
H
H
H
+ [O]
R3
CM
R4
R3
ROM
R5O
oxidative transannular cyclization
tandem ROM–RCM–CM
Shapiro reaction
Pauson–Khand
H
H
H
H
NHTs
Y
Y
Y
Y
Y
O
O
N
Y
[2+2+2]
H
H
R2
R2
R2
H
H
H
O
Y
Y
Y
Y
Y
Y
Y
R2
+
C
OLi
Y
H
H
H
H
H
R2
OH
asymmetric deprotonation/alkylation
O
carbonyl-ene reaction
O
+
Y
Y
O
2 Biosynthesis of Hydropentalenes
H
H
H
H
Figure 2 The various retrosynthetic pathways to hydropentalene de-
rivatives described below
Early biosynthetic studies by the Du group on the ac-
yltetramic macrolactam heat-stable antifungal factor
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

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M. Deimling et al.
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FNR
H2N
O
NAD(P)H
NAD(P)+
S-PKS
Orn
HN
PKS/NRPS
hexaketide
H
H+
O
H–
O
NH2
Claisen/Dieckmann
condensations
H
S-NRPS
O
hexaketide
NH
S-PKS
reductive [2+3]
cycloaddition
O
O
O
lysobacterene A
OX3
OH
H+
FNR
NAD(P)H
O
O
NAD(P)+
HN
HN
H–
H
H
H
OX2
H
H
O
O
cycloaddition
NH
NH
H
H
O2
H
H–
HO
O
O
FAD
OH
FAD
OH
OH
NAD(P)H NAD(P)+
O
H
3-deOH alteramide C
lysobacterene B
NAD(P)+
H2O
FNR
OX4
extended Michael addition
H
H
HO
N
O
H
N
O
H
H+
H
H
H
H
O
H
H
H
NH
NH
H
H
HO
HO
O
O
15a
OH
3-deOH HSAF 15b OH
Figure 3 Proposed biosynthesis of the tricyclic system in HSAF 15a/15b19
3 Hydropentalenes through the Pauson–
Khand Reaction
(trimethylsilyl)acetylene might be beneficial in achieving a
cleaner reaction and suppressing multiple co-cyclizations.27
Gratifyingly, this approach worked quite well (Scheme 2).
Hydropentalenes 16 and 17 can be synthesized from cy-
clopentadiene (19) and alkynes 20 (R = H, SiMe3) by a
Pauson–Khand reaction, followed by functionalization, for
example by conjugate addition (Scheme 1).
O
H
H
R
H
for 21
Me2CuLi
R
Me
TMS +
Et2O, 0 °C
R
R
H
O
O
18a (46%)
endo-22 (27%)
endo-23 (42%)
24 (89%)
25 (quant.)
Bu4NOH
THF, 12 h
O
O
R1
8
1
2
R1
R1
7
+
1) –20 °C, 1 h 2)
19
22,24 23,25
3
5
R = TMS
H
6
4
NMO, CH2Cl2
R2
16 (R1 = H)
17 (R1 = SiMe3)
18
19
20
TMS
Co2(CO)6
16,17 R2 17 yield 16 yield
Scheme 1 Retrosynthetic route through the Pauson–Khand reaction
21
a
b
Me 49%
Bu 62%
Ph 70%
63%
77%
90%
1) –20 °C, 20 min
2) 19, NMO, CH2Cl2
c
The Pauson–Khand reaction, i.e. the co-cyclization of an
alkyne, an alkene, and carbon monoxide, is a powerful
method for accessing cyclopentenones.24 The original
method utilized stoichiometric amounts of Co2(CO)8 as a
metal mediator and a CO source. Much work has been de-
voted to facilitating the displacement of CO from the cobalt
complex by additives to develop catalytic versions of the re-
action and to replace CO by surrogates, such as aldehydes.25
However, when we stepped into this area, progress was
slow and only limited knowledge was available on intermo-
lecular Pauson–Khand reactions, even with simple sub-
strates such as cyclopentadiene.26 Whereas Becheanu re-
ported only a disappointingly low yield of 9% for the Pau-
son–Khand reaction of acetylene with cyclopentadiene in
the presence of Co2(CO)8,27a we surmised that the use of
O
O
H
H
H
H
for 18a
R22CuLi
R1
R1
Et2O, 0 °C
R2
18a R1 = TMS (84%)
18b R1 = H (93%)
17a–c R1 = TMS
16a–c R1 = H
Bu4NOH
Et2O, 1 h
Bu4NOH
Et2O, 3 or 12 h
Scheme 2
In particular, after some optimization of the reaction,
we found that a brief exposure of the (trimethylsilyl)acety-
lene cobalt complex 21 with NMO prior to addition of cy-
clopentadiene 19 at –20 °C improved the yield of bicyc-
lo[3.3.0]octadienone 18a to 84% without any byproducts.
When the reaction time was extended to one hour, the
yield of the desired cyclopentenone 18a decreased consid-
erably to 46%, and competing cobalt-mediated [4+2]-cyc-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

E
M. Deimling et al.
Account
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loaddition of cyclopentadiene (19) to (trimethylsilyl)acety-
lene, followed by a Pauson–Khand reaction with (trimeth-
ylsilyl)acetylene–cobalt complex 21 took place, from which
the tricyclic endo-product 22 was isolated in 27% yield. The
bicyclo[3.3.0]octadienone 18a could be further elaborated
by conjugate addition of cuprate, providing the trans-prod-
ucts 17, which was subsequently desilylated to 16 by treat-
ment with tetrabutylammonium hydroxide (TBAOH) in
Et2O.28
More recently, the Riera group demonstrated the utility
of trifluoromethyl as a removable steering group that can
be released from -substituted Pauson–Khand products by
treatment with DBU in nitromethane/H2O.29 Furthermore,
Reira reported that ethylene glycol as an additive can sig-
nificantly accelerate intermolecular Pauson–Khand reac-
tions, doubling the yields, even for challenging combina-
tions such as cyclopentene/(trimethylsilyl)acetylene or cy-
clopentene/N-Boc-propargylamine.30
O
O
H
H
R22CuLi, Et2O
R1
R1
H
H
R2
31
32
34 R1
R2 yield (%)
1) O3, CHCl3, –78 °C
Pr
Pr
Bu
Ph
87 >99:1
84 >99:1
82 >99:1
2) NaHB(OAc)3
reflux, 3 h
C5H11 Bu
HO
AcO
HO
O
O
H
H
lipase chirazyme L1
R1
R1
, THF, 40 °C
HO
OAc
H
R2
H
R2
34
33
Scheme 4
monoacetate 34 in up to 87% yield with excellent regiose-
lectivity (≤99:1).
Note that no satisfactory solution has yet been found to
the problem of developing catalytic intermolecular Pauson–
Khand reactions.33 In particular, catalytic asymmetric ver-
sions are rare.34 This is in stark contrast to the various cata-
lytic Pauson–Khand reactions that provide access to enan-
tiomerically enriched bicyclo[3.3.0]octenones 35 from
enynes 36 (Scheme 5).35 In pioneering work, the Buchwald
group employed chiral ansa-titanocene catalysts,36 as well
as BINOL phosphites and Co2(CO)8,37 whereas Narasaka and
co-workers used [RhCl(CO)2]2 and 1 atm of CO,38 and the
Chung group used Ru/Co nanoparticles.39,40 Croatt and
Wender and Lee and Kwong have summarized various
modifications of the catalytic intramolecular Pauson–
Khand reaction and related [2+2+1]-cycloadditions.25a,b
In an earlier work, we found that chlorinated solvents
such as CH2Cl2 could be replaced by either an ionic liquid
such as 1-butyl-3-methylimidazolium hexafluorophos-
phate ([bmim]PF6) or
a two-phase system such as
[bmim]PF6/methylcyclohexane (MCH) in intermolecular
Co2(CO)8-mediated Pauson–Khand reactions in the pres-
ence of NMO at room temperature with good yields and re-
gioselectivities for bicyclic alkenes, such as norbornene (26)
(Scheme 3).31
R1
Ph
R1
H
H
Co2(CO)8
Ph
+
R1
+
NMO (6 equiv)
r.t., 0.5 h
H
27
H
28
Ph
O
O
26
20b,c
EWG
EWG
*
EWG
EWG
R1 solvent
O
+
CO
H
CH2Cl2
[bmim]PF6
[bmim]PF6/MCH 85%
92%
71%
–
–
–
R
35
R
36
Me CH2Cl2
[bmim]PF6
78%
63%
96 : 4
94 : 6
Scheme 5 Retrosynthesis of the intramolecular Pauson–Khand reac-
H
H
tion
Co2(CO)8
Ph
+
NMO (6 equiv)
r.t., 0.5 h
A unique sequential intramolecular co-cyclization/con-
jugate reduction sequence employing stoichiometric
amounts of Co4(CO)12 in i-PrOH has been developed by the
Krafft group.41 Presumably, the reaction proceeds via the
hydridocobalt species HCo(CO)4, with the hydride delivered
from the i-PrOH solvent, as shown by deuteration experi-
ments. Although the intramolecular catalytic Pauson–
Khand reaction provides efficient access to hydropen-
talenes 35 in both chiral and achiral fashions (Scheme 5),
and the cyclization precursors 36 are conveniently available
through reaction of diethyl malonate anion with allylic or
propargylic halides, it should be noted that a geminal-
disubstituted unit is often required in the cyclization pre-
cursor to exert a Thorpe–Ingold effect and to drive the co-
cyclization to completion. Consequently, unsubstituted de-
rivatives lacking the two electron-withdrawing groups have
been described in the literature much less frequently.42,43,44a
It should be pointed out that the Carretero group has devel-
H
30
Ph
20b
O
29
CH2Cl2
[bmim]PF6
40%
<1%
Scheme 3
However, to our great dismay these conditions com-
pletely failed for cyclopentene (29), and the corresponding
hydropentalene 30 could be detected in trace amounts only.
At first glance, the limitation to bicyclic alkenes seemed
to be a serious disadvantage. However, it turned out that
tricyclic hydropentalenes such as 31 could be conveniently
functionalized by a three-step sequence consisting of con-
jugate addition of an organocuprate, ozonolysis, and reduc-
tive workup with NaHB(OAc)3 to provide the corresponding
diols, which were submitted to regioselective acetylation
with lipase (Scheme 4).32 After some experimentation, chi-
razyme L1 was found to give the best results, providing the
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F
M. Deimling et al.
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oped an elegant method for obtaining enantiomerically
pure (S)-1-tert-butylsulfinylenynes such as 36a
gram amounts of the appropriate hydropentalene building
blocks, we turned our attention to the transannular oxida-
tive cyclization of cycloocta-1,4-diene (COD) (42; Scheme
8).
(Scheme 6).44b,45 The required enynes 36 were obtained
through a Horner–Wadsworth–Emmons (HWE) olefination
from phosphonates 37. As shown for 36a, subsequent ther-
mal Pauson–Khand reaction and reductive removal of the
sulfoxide auxiliary provided the enantiomerically pure hy-
dropentalene 35a in excellent yield and with high enantio-
meric excess.
At a first glance, the method adopted by the Prakash
group seemed advantageous because the oxidation re-
quired only a stoichiometric amount of iodosobenzene di-
acetate (1.3 equiv) (Method A; Scheme 9).47 However, de-
spite an acceptable yield of 75%, the major diastereomer
41a could not be separated from the minor diastereomers
41b and 41c, and thus this method was not further consid-
ered for the synthesis of chiral bicyclo[3.3.0]octanones. On
the other hand, the Pd-catalyzed cyclization required
O
tBu
O
S
O
1) nBuLi, THF, –78 °C
(EtO)2P
S
tBu
O
2)
37
36a
trans/cis 56:44
H
81%
48
34 mol% of Pd(OAc)2 and 2.3 equivalents of Pb(OAc)4 and
1) Co2(CO)8
2) MeCN, ΔT
50%
O
gave 70% of the racemic diacetate 41b as a single diastereo-
mer, which could be subjected directly to saponification
and lipase-catalyzed optical resolution to give the
monoacetate 41d, diacetate 41b, and diol 41e (Method B;
Scheme 9).49,50
H
H
H
S
tBu
O
Zn, NH4Cl, THF
92%
O
35a (>96% ee)
38 (dr >98:2)
Scheme 6
AcO
RO
AcO
H
H
H
A or B
+
+
In a complementary approach to the various Pauson–
Khand routes, Barluenga et al. used Fischer carbene com-
plexes as precursors for the co-cyclization with vinyllithi-
um reagents, giving rise to bicyclo[3.3.0]octenones 40 in
good yields (Scheme 7).46 Both chromium and tungsten
Fischer carbene complexes could be used. In the case of
tungsten carbenes carrying menthyl units, high enantiose-
lectivities were obtained.
H
41a
major (75%)
–
H
41b
minor (R = Ac)
R = Ac (70%)
R = H (rac)
H
41c
minor
–
OAc
OR
OAc
42
A: PhI(OAc)2, HOAc
B: Pb(OAc)4, Pd(OAc)2
lipase
AcO
AcO
HO
H
H
H
+
+
H
41d
H
41b
H
41e
OH
OAc
OH
1) Dowex
R2O
M(CO)5
Swern
O
2) Swern
O
O
H
H
1) THF, –78 °C→r.t.
2) aq NH4Cl
+
Li
R1
H
40
R1
39
H
H
O
O
M
R1
OR2 yield (%)
(S,S)-43
(R,R)-43
ee (%)
Cr Ph
Cr 4-ClC6H4
Cr 4-F3CC6H4 OMe
Cr 4-MeOC6H4 OMe
OMe
OMe
65
68
71
58
Scheme 9
W
W
W
W
Ph
4-ClC6H4
4-F3CC6H4 OR*
4-MeOC6H4 OR*
OR*
OR*
61
62
52
45
95
>99
96
As chiral diketones 43 were obtainable by Swern oxida-
tion of the diols on a gram scale, this route was used in a
total synthesis of cylindramide (11), as discussed below.51
O
OR* =
Ph
80
Scheme 7
5 Functionalization of Bicyclo[3.3.0]octan-
1,4-dione to Dodecahydrocyclopenta[a]in-
denes
4 Hydropentalenes through Transannular
Oxidative Cyclization of Cycloocta-1,4-diene
After struggling with the Pauson–Khand reaction for
some time, and bearing in mind that multistep total syn-
theses of natural products might eventually require multi-
A Diels–Alder reaction with electron-rich dienes ap-
peared to provide rapid access to the tricyclic dodecahydro-
cyclopenta[a]indene system. However, this approach was
soon discarded because yields of the BF3·OEt2-mediated [4 +
2]-cycloaddition of enone 44a with Danishefsky diene 45
did not exceed 5%, and the reaction was always compro-
mised by C=C double-bond isomerization, giving a 1:1 mix-
ture of tricyclic compounds 46 and 47 (Scheme 10).52
OR
+
[O]
RO
41
42
Scheme 8 Retrosynthesis of hydropentalene from COD and [O]
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

G
M. Deimling et al.
Account
Synlett
addition of hydropentalene 56, which could be traced back
to the enone 44 and an organometallic reagent 57, the for-
mer being traced back to the C2-symmetrical diketone 43.
O
OMe
H
+
O
OTMS
H
44a
O
45
1) BF3·OEt2, CH2Cl2, –7 °C, 10 min
2) HCl, r.t.
OH
OH
5%
HN
HN
O
O
O
O
O
O
H
H
H
NH
OH
NH
OH
H
H
H
H
H
O
O
O
O
H
O
H
H
O
O
46
1
O
47
1
O
H
H
H
H
:
O
discodermide (53)
maltophilin (54)
Scheme 10
ABC ring system
O
O
H
H
Dienedione 50 was therefore chosen as an alternative
building block. One-pot bromination/acetalization of 43
and base-mediated elimination gave the diene 49. Cleavage
of the diacetal with PPTS gave the dihydropentalenedione
50 in 85% yield and 99% ee (Scheme 11).
aldol
H
O
OH
X
X
H
H
H
56
H
RO
RO
55
X = H, Br
O
O
H
H
X
O
O
H
–
H
PhN+Me3Br3
THF
M
H
H
O
RO
O
43
44
57
Br
Br
(CH2OH)2
84%
O
O
Scheme 13
H
H
O
O
O
NaOMe
DMSO
93%
(R,R)-43
48
O
O
H
H
O
PPTS, acetone
85%
As shown in Scheme 14, conjugate addition of the un-
saturated Grignard reagent to enone 44a in the presence of
CuCN, TMEDA, and TMSCl provided the desired -substitut-
ed ketone 58 as an equimolar mixture (47:53) of two iso-
mers, albeit in a moderate yield of 42%. In addition, diacetal
59 and diketone 60 were isolated in yields of 3 and 25%, re-
spectively. These two byproducts made us suspicious re-
garding epimerization at the -carbon. To our great sur-
prise, NMR analysis revealed a completely different story.
During acidic workup and chromatography on silica, an
acetal migration took place that resulted in racemization
rather than epimerization. Despite this serious drawback,
H
H
O
(R,R)-50 (99% ee)
49
Scheme 11
Unfortunately, further functionalization of this C2-sym-
metrical building block 50 by sequential conjugate addi-
tions met with difficulties (Scheme 12). Although the addi-
tion of a homoallylic Grignard reagent to rac-50 gave the
desired mono-1,4-adduct 51 in 63% yield, subsequent hyd-
roboration with either 9-BBN or catecholborane resulted in
a competing Weitz–Scheffer epoxidation of the enone and
1,2-reduction to the allylic alcohol. When the correspond-
ing alkoxy-terminated Grignard reagents were employed,
no trace of the desired 1,4-adducts were detected.
O
H
O
H
O
(R,R)-44a
R =
O
O
O
H
H
H
2) HCl
1) RMgBr, CuCN, TMEDA
TMSCl, THF, –78 °C
BrMg
3) chromatography
O
O
O
H
O
R
H
H
H
H
H
H
H
H
O
O
O
O
O
rac-50
51 (63%)
52
4
3a
6a
+
+
+
3a
6a
4
ClMg
BrMg
O
O
OH
OMe
OBn
H
H
H
H
R
O
R
O
R
O
O
59 (3%)
58 42%, 47:53
60 (25%)
Scheme 12
(CH2OH)2, TsOH, quant.
TsOH, acetone, quant.
1) BH3·THF, 0 °C→r.t., 3 h
2) NaOH, H2O2, 45 °C, 2 h
To gain access to the tricyclic core units of the tetramic
acid macrolactams discodermide (53),53 isolated from the
sponge Discodermia dissoluta,54,55 and maltophilin (54),56,57
we envisaged the use of the tricyclic hydroxyketone 55 as a
synthetic precursor (Scheme 13).58 We hoped that com-
pound 55 might be obtained from an intramolecular aldol
O
H
O
H
1) TsOH, acetone
98%
O
OH
O
2) (COCl)2, DMSO
95%
O
H
H
O
O
61 (45%)
62
Scheme 14
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

H
M. Deimling et al.
Account
Synlett
Hydropentalenone 44b was treated with a Grignard re-
agent to obtain the 1,2-addition product 66 (Scheme 16).
Oxidative 1,3-transposition of the tertiary allylic alcohol
gave the -substituted ketone 67, and subsequent hydroge-
nolysis and Swern oxidation of the terminal hydroxy group
gave the bicyclic keto aldehyde 68 in 91% yield. Aldol con-
densation in the presence of t-BuOK gave the tricyclic de-
rivative 69.58 Despite the poor yield of 18%, no evidence for
a retro-aldol reaction was found.
O
1) PhN+Me3Br3–, THF
(CH2OH)2
H
43
Br
2) NaOMe/MeOH
3) PPTS, acetone
O
H
O
44b (64%)
1) RMgBr, CuCN, TMEDA, TMSCl
2) HCl
3) BH3·THF, 0 °C→r.t., 3 h
4) NaOH, H2O2, 45 °C, 2 h
OH
OH
O
H
H
H
H
H
OH
OH
OH
Br
Br
Br
+
+
O
O
O
H
O
O
O
6 Functionalization of Bicyclo[3.3.0]octan-
1,4-diones to Crown Ether Hybrids
63a (20%)
63b (32%)
64 (40%)
(COCl)2, DMSO, –78 °C; Et3N
O
H
O
O
H
H
H
H
OH
+
O
Biological studies of cylindramide (11) revealed that the
cytotoxicity of the natural product was affected by both the
hydropentalene unit and by the Ca2+ concentration. In other
words, the cytotoxicity decreased significantly upon addi-
tion of Ca2+ salts, suggesting the formation of tetramic acid
macrolactam–Ca2+ complexes with a concomitant decrease
in the intracellular Ca2+ concentration. Taking inspiration
from Crane and Gademann’s concept of truncated natural
products,59,60 we speculated that hybrids consisting of the
bioactive hydropentalene unit and a Ca2+-binding crown-
ether unit might be able to mimic the action of the natural
product 11. As an additional aim, we hoped to reduce the
synthetic effort required to assemble the hydroxyornithine
unit and convert it into the final macrocyclic tetramic acid
lactam.
Br
Br
Br
O
O
O
+
H
O
O
O
56 (1:1 with 55, 59%)
55 (15%)
65 (20%)
Scheme 15
the suitability of the aldol strategy was tested. Compounds
58 were converted into the diacetal 59, which was subject-
ed to hydroboration, acetal cleavage, and Swern oxidation to
give the aldehyde 62. Although treatment with LDA appeared
to provide the hydroxy ketone, hydrolytic workup resulted in
a retro-aldol reaction, and aldehyde 62 was re-isolated.
This outcome forced us to step back and use the bromi-
nated hydropentalenone 44b as
a key intermediate
(Scheme 15), available in three steps from diketone 43.
Conjugate addition of the cuprate and subsequent hydrobo-
ration gave the diastereomeric alcohols 63a and 63b in
yields of 20 and 32%, respectively, together with 40% of ke-
tone 64. This mixture was directly submitted to Swern oxi-
dation to yield a mixture of three products, which gave us
some nightmares. Column chromatography provided 59%
of a 1:1 mixture of 55/56 and 65. In CDCl3 solution and
upon storage in the freezer, a retro-aldol reaction from hy-
droxy ketone 55 to keto aldehyde 56 was observed, whereas
treatment with a base (e.g., t-BuOK, KHMDS, LDA) or with
silica gel shifted the equilibrium toward the aldol product.
Because Ca2+ has an ionic radius of 106 pm, which is in-
termediate between those of Na+ (98 pm) and K+ (133 pm),
15-crown-5 (∅ 170–120 pm) and 18-crown-6 (∅ 260–
330 pm)61 were chosen as target structures for the hybrid
compounds. To access the bicyclo[3.3.0]octan-1,2-diol 73 as
a key intermediate for a twofold Williamson etherification,
the acetal-protected monoketone 70 was used as starting
material (Scheme 17). Conversion of 70 into the tosylhydra-
zone and subsequent Shapiro reaction gave the alkene 71 in
82% yield over the two steps. Shi epoxidation and basic re-
gioselective epoxide opening with KOH in DMSO–H2O un-
der microwave conditions delivered the desired trans-diol
73 in 93% yield; this was treated with the ditosylate 74 in
the presence of t-BuOK to give the 15-crown-5 hybrid 75a
in 60% yield, whereas the larger 18-crown-6 hybrid 75b
was obtained in only 29% yield. Acidic hydrolysis of the ace-
OBn
OH
H
H
BrMg
OBn
4
4
PCC
44b
THF, 0 °C
OBn
CH2Cl2
O
O
H
H
O
O
O
66
67 (46% from 44b)
tal and
a three-step Nicolaou oxidation gave the
1) H2, Pd/C, EtOAc
2) (COCl)2, DMSO
91%
bicyclo[3.3.0]octaenone–15-crown-5 hybrid 76a in 15%
yield. The larger homologue 76b could not be isolated. It
should be emphasized that the direct twofold Williamson
etherification of enone 77 with the ditosylate was not pos-
sible.62
H
H
H
KOtBu, THF, 0 °C
18%
O
O
O
H
H
O
O
O
O
69
68
Scheme 16
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

I
M. Deimling et al.
Account
Synlett
72%
TfO
1) H2N-NHTs
2) BuLi
TMEDA
O
H
H
H
H
Shi
O
O
O
epoxidation
93%
O
H
H
H
1) (CH2OH)2
TsOH
Me2CuLi
Cl
82%
O
O
(R,R)-43
+
dr >95:5
H
H
O
O
O
2) LDA
TMSCl
IBX·MPO
O
O
O
70
71
72
H
H
H
O
O
O
N
78
79 (47%)
80 (39%)
NTf2
KOH (10 equiv), DMSO, H2O
microwave, 170 °C
93%
O
O
TMS, tBuLi
O
O
1)
2) HC(OMe)3, BF3·OEt2
3) NaBH4, MeOH
OH
O
H
H
H
TsO
O
OTs
3 steps
m = 3,4
H
OMe
OMe
S
74
4)
OH
H
H
H
H
KOtBu, DMF
microwave, 80 °C
N
N
O
O
n
N
N
H
O
O
75a (60%)
b (29%)
73
5) AIBN, Bu3SnH
6) K2CO3, MeOH
O
4 steps
75, 76
a
b
82 (57%)
81 (78%)
O
n
1
2
N3
H
O
O
I
N
1)
CO2Me Pd(PPh3)4, CuI
OTBS
O
OH
H
H
H
O
2) PPTS, acetone
3) NaHMDS, then
O
OH
n
H
O
76a (15%)
b (0%)
O
O
O
O
O
77
S
N
O
N
N
N
Scheme 17
Ph
O
OTBS
N3
CO2Me
N
H
H
H
O
7 Functionalization of Bicyclo[3.3.0]octan-
1,4-dione to Cylindramide
O
O
H
83 (53%)
HN
HO
O
1) PPh3, THF
2) toluene, Δ
H
Our total synthesis to cylindramide (11) is presented in
Scheme 18. Starting dione (R,R)-43, which was obtained as
shown in Scheme 10, was converted into the enantiomeri-
cally pure enone 78. The latter was submitted to conjugate
addition of lithium dimethylcuprate, followed by trapping
with (5-chloropyridin-2-yl)triflimide, to provide a mixture
of the desired enol triflate 80 together with the ketone 79,
which could be converted into the enol triflate 80 in 72%
yield. Pd-catalyzed reduction of 80 with Et3SiH, acetal
cleavage, and Nicolaou oxidation gave the dienone 81.
Conjugate addition of a propargyl cuprate, trapping
with trimethyl orthoformate, Barton–McCombie deoxygen-
ation, and desilylation gave the alkyne building block 82.
The stage was now set for a Sonogashira coupling, removal
of the acetal, and Julia olefination to provide the pincer-
shaped hydropentalene derivative 83 in 53% yield. The end-
game required a Staudinger reduction of the azide, concom-
itant macrolactamization, Lindlar hydrogenation of the
enyne, desilylation with HF in acetonitrile, and Dieckmann
condensation, finally delivering cylindramide (11) in 29
steps (18 linear steps) and 2.1% overall yield.49,50
O
3) H2, Pd/BaSO4
4) HF, MeCN
5) NaOMe/MeOH
NH
O
11 (50%)
OH
Scheme 18
hydropentalenes from norbornenes,63 based on the seminal
work of the groups of Blechert,64 Hoveyda,65 Plumet,66
Hagiwara,67 Aubé,68 and Funel69 (Scheme 19).
Key steps in the Phillips strategy are a chain elongation
through cross-metathesis of the ,-unsaturated N-acylox-
azolidinone 87, a subsequent asymmetric Diels–Alder reac-
tion with cyclopentadiene (19) utilizing the Evans auxiliary
for stereocontrol, removal of the auxiliary, and conversion
into the enone 85a via the Weinreb amide (2 steps), and
Grignard reaction. Subsequent ROM/RCM/CM provided the
pincer-type compound 84a, which was then elaborated in
eight further steps to the natural product 11 (Scheme 20).
Cylindramide (11) was isolated in 29 steps and 0.44% over-
all yield.
The Phillips group further utilized this tandem
ROM/RCM strategy in total syntheses of aburatubolactam
(14)70 and geodin A (12).71 This time, the synthesis com-
8 Tandem Ring-Opening Metathesis/Ring-
Closing Metathesis/Cross-Metathesis of Bicy-
clo[2.2.1]heptanes
O
O
R1
RCM
CM
H
ROM
R2
R2
R1
Parallel to our own synthetic endeavors, Hart and Phillips
developed a tandem ring-opening/ring-closing/cross-
metathesis (ROM/RCM/CM) approach to the preparation of
H
84
86
85
Scheme 19 Retrosynthesis of a ROM/RCM/CM sequence according to
Hart and Phillips63
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

J
M. Deimling et al.
Account
Synlett
dehyde 93 might be obtained from the -allyl-substituted
ketone 97, for which a diastereoselective allylation of enone
98 was planned, the latter again being derived from keto-
acetal 70a (Route B).
1) 19, Et2AlCl, CH2Cl2
2) a. LiOH, H2O2, THF
b. HCl·HN(OMe)Me, DMAP
O
O
O
R
N
O
3) H2C=CHMgBr, THF
OTIPS
Bn
87
85a (49%)
R = H
OTIPS
Grubbs II, 59%
Grubbs II (4 mol%)
CH2Cl2, 40 °C
O
O
OTIPS
R =
olefination/dienamidation
2
O
O
O
H
OTIPS
HN
O
H
H
H
HO
H
8 steps
11
deprotection/
oxidation/
olefination
O
O
O
O
OTBS
NH
O
H
O
92
84a (59%, E/Z 2:1)
1/2 Mg+
O
12
O
O
Scheme 20
OH
H
H
route A
O
O
O
OTBS
menced with an organocatalytic [4+2]-cycloaddition with
but-2-en-3-one (88) and cyclopentadiene (19) in the pres-
ence of MacMillan’s catalyst 89 (Scheme 21). A Saegusa oxi-
dation, followed by the tandem ROM/RCM sequence pro-
vided hydropentalene 84b, which was converted in 12 fur-
ther steps into the natural product 14. Aburatubolactam
(14) was isolated in 1.0% overall yield over 23 steps.
H
O
H
93
O
O
94
route B
CO2H
H
H
O
R
O
O
H
97
H
O
95
[3,3]σ Claisen–Ireland
allylation
H
H
O
R
O
89
O
O
OAc
88
+
19
O
LiHMDS
O
(20 mol%)
H
O
96
H
O
H2O
TMSCl, then
Pd(OAc)2
98
O
H
H
O
N
90 (65%)
85b (80%)
O
NH
Grubbs I (2.5 mol%)
H2C=CH2 (1 atm)
89
Ph
O
O
H
70a
SnBu3
H
H
H
10 steps
Scheme 22
H
H
O
O
O
91
14
84b (90%)
O
2 steps
By Route A, deprotonation of ketoacetal 70a with LDA
and treatment with chloromethyl acetate followed by re-
duction with NaBH4 gave the secondary alcohol 99, which
was nosylated and treated with DBU in toluene at 90 °C
(Scheme 23). Unfortunately, E2 elimination favored an anti-
orientation of C–H and C–ONs; consequently the undesired
regioisomeric alkene 96b was isolated in 61% yield. When
alcohol 99 and the Burgess reagent were used, a 7:1 mix-
ture of the desired regioisomer 96a and 96b was formed,
albeit in a disappointingly low yield of 5% after HPLC sepa-
ration. We therefore decided to abandon Route A.
Scheme 21 Aburatubolactam precursor hydropentalene 84b accord-
ing to Phillips70
Very recently, Kotha et al. used a sequence of Fischer in-
dole synthesis, N-allylation, and ring rearrangement me-
tathesis for the synthesis of azapolyquinanes.72
9 Functionalization of Bicyclo[3.3.0]octan-
1,4-dione to Geodin A
OH
H
1) LDA
Cl
O
1) NsCl, DMAP
2) DBU, toluene
O
70a
96a + 96b
To access the geodin A target, we envisaged two differ-
ent synthetic strategies using dienal 92 and the corre-
sponding precursor aldehyde 93 as key intermediates
(Scheme 22). Aldehyde 93 could be derived from lactol 94
and its precursor, the carboxylic acid 95 (Route A), which, in
turn, should be obtainable by a Claisen–Ireland [3,3]-sig-
matropic rearrangement from the allylic acetate 96. The lat-
ter might be derived from keto acetal 70a. Alternatively, al-
2) NaBH4, MeOH
O
OAc
0% 61%
H
anti elimination
O
99 (60%)
Burgess 96a/96b = 7:1
H
+
O
O
OAc
OAc
H
O
96a (5%)
H
O
96b
Scheme 23
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

K
M. Deimling et al.
Account
Synlett
In accord with Route B, the exocyclic benzyl ester was
installed by treatment of ketoacetal 70a with LiHMDS and
benzyl cyanoformate; this was followed by NaBH4 reduc-
tion to give the -hydroxy ester 100 in 49% yield (Scheme
24). Three methods were probed for the elimination toward
the benzyl enoate 98a. A two-step radical elimination via
the intermediate thioimidazolide (Method A) gave only
40% of the elimination product 98a. Treatment of 100 with
Burgess reagent proceeded in a disappointingly low yield of
26% (Method B). However, a classical two-step mesyla-
tion/base-mediated elimination proceeded uneventfully in
80% yield over the two steps (Method C).73
clo[3.3.0]octane derivative pseudo-C2-107 (Scheme 25),
whereas the corresponding core unit of alteramide A (13)
and aburatubolactam (14) can be traced back to the pseudo-
Cs symmetrical bicyclo[3.3.0]octane derivative pseudo-Cs-
107. These two scaffolds might come from diastereo- and
regioselective functionalization of ketone 106.
H
H
H
H
H
H
base
B*
R1
R
R1
R
O
O
O
O–
H
H
H
103
H
104
H
H
H
meso (achiral)
chiral enolate
R2
A
R2
R2
swapping protecting
groups
H
H
OH
H
H
R1
R1
R
1) LiHMDS
NCCO2Bn
methods
A–C
O
O
O
O
70a
R
B
2) NaBH4
O
O
OBn
OBn
H
106
H
105
H
H
98a
O
O
100 (49%)
1) base B*
2) R3
C
O
SiMe3
dr 89:11
(o-tolO)2P
102
CO2Et
R3
R2
R2
TBAF, HMPA
H
H
H
R1
R1
R
+
H
H
H
O
O
1) O3, DMS
1) LiAlH4
2) TBSCl
O
R
2) 102, NaH
93
H
R3
3) DIBAL;
O
O
OTBS
OBn
pseudo-Cs-107
pseudo-C2-107
MnO2
H
O
O
20%
101 (84%)
97a (66%)
Scheme 25
methods
A: 1) thiocarbonyldiimidazole, DMAP, quant.;
2) allylSnBu3, AIBN, 40%
B: Burgess, 26%
C: 1) MsCl, NEt3, 90%; 2) DBU, toluene, 90 °C, 89%
Protective-group swapping leads to the precursor ke-
tone 105, which can be traced back to Weiss diketone 103,75
a commercially available starting material that is easily
synthesized on a gram scale. Our approach was inspired
by seminal contributions from the groups of Simpkins,76
Koga,77 Leonard,78 and Gais79 on the enantioselective de-
symmetrization of meso ketones through deprotonation
with chiral lithium amide bases and subsequent electro-
philic trapping of the chiral enolates.
Scheme 24
Considerable experimentation was necessary to get the
allylation to run. In the end, diastereoselective allylation
was achieved with allyl(trimethyl)silane, HMPA, and TBAF,
giving the desired trans-1,4-adduct 97a in 66% yield
(dr 89:11).74
After reduction of the ester unit, TBS protection of the
resulting alcohol, ozonolytic cleavage of the C=C double
bond, and reductive workup, the resulting aldehyde was
submitted to HWE olefination, DIBAL reduction, and MnO2
oxidation to give the enal fragment 93, suitable for further
manipulation towards geodin A.
As illustrated in Scheme 26, an enantioselective de-
symmetrization employing the phenylethylamine-derived
Simpkin’s base (R,R)-B* and subsequent electrophilic
quenching worked quite well, giving acceptable yields and
good enantiomeric ratios, as long as activated and sterically
less-demanding electrophiles were used.80 Both silyl ethers
and acetals were tolerated as protecting groups.
Having established this monofunctionalization, we
were interested in whether the newly created stereogenic
center would exert any stereocontrol during a second
deprotonation/alkylation of the other half of the hydropen-
talene core.80 As shown in Table 1, this twofold desymme-
trization was indeed successful. The configuration of the
chiral base had a strong influence on the regio- and diaste-
reoselectivity. Whereas the (R,R)-base preferentially gave
the pseudo-C2 isomer with a C2/Cs ratio of 4:1 to 3:1 and a
matched diastereoselectivity (>98:2), the pseudo-Cs isomer
was favored in the presence of the (S,S)-base in a C2/Cs ratio of
1:4 and with a matched diastereoselectivity of >99:1 (Table 1).
As discussed in Section 6, our aim was to produce trun-
cated cylindramide derivatives carrying the hydropental-
ene unit and a crown ether or flexible oligoethylene chain
10 Hydropentalenes through Enantioselec-
tive Desymmetrization of Weiss Diketones
As discussed above, the oxidative co-cyclization of COD
(42) provides convenient access to the hydropentalenes.
However, from an environmental point of view, the reac-
tion sequence is rather hazardous, requiring 12 g of
Pd(OAc)2 and 1 kg of Pb(OAc)4 per 240 mL of 42. Conse-
quently, an alternative route was sought. Moreover, we
hoped that symmetry might be used as a guiding principle
to access complex natural product families such as the te-
tramic acid macrolactams. In that particular case, the hy-
dropentalene core unit of cylindramide (11) and geodin A
(12) can be traced back to the pseudo-C2 symmetrical bicy-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

L
M. Deimling et al.
Account
Synlett
Table 1 Asymmetric Deprotonation/Alkylation of Ketone 106a
allyl
allyl
allyl
H
H
Cl
Cl
Ph
Ph
N
Ph
Ph
H2
O
OX
O
OX
OX
(R,R)-B*
allyl
H
H
H
H
H
R3
R3
R3
R3
1) B*
pseudo-C2-107
O
OX
N
2) R3-I
H2
allyl
(S,S)-B*
H
106
X = TBDPS
107
R3
O
OX
O
a
b
H
H
=
Me allyl
pseudo-Cs-107
pseudo-C2
pseudo-Cs
107
B*
(R,R)
C2/Cs
79:21
yield (%)
dr
yield (%)
dr
a
b
a
b
58
28
16
17
99.5:0.5
98:2
matched
matched
15
9
65:35
52:48
mismatched
mismatched
matched
(R,R)
(S,S)
(S,S)
76:24
21:79
20:80
13:87
29:71
mismatched
mismatched
60
68
100:0
1:99
matched
a Ketone 106 derived from 105 after protective-group swapping (see Scheme 25).
that would mimic the Ca2+-binding hydroxyornithine unit
in the natural product.81 As shown in Scheme 27, in a first
attempt the chiral silylenol ether 108b was treated sequen-
tially with MeLi and the triethylene glycol iodide (TEG-I),
but no trace of the desired TEG hydropentalene 105h could
be isolated.
um reagents were used for deprotonation. In contrast,
deprotonation of 112 with LDA and subsequent electrophil-
ic trapping with methyl, allyl, or TEG iodides provided the
desired -substituted ketones 105 after oxidative cleavage
of the hydrazone unit with NaIO4, albeit in low yields
(Scheme 27).
In an alternative attempt, the synthesis of chiral N-tosyl
azoenes from silylenol ether 108b was investigated. Treat-
ment with NBS or NIS provided the -substituted ketones
109b and 109c. However, when NCS was employed, diaste-
reoselective chlorination of the silylenolether took place,
yielding 110 in 76% yield with no trace of the ketone 109a.
Unfortunately, this approach was another dead end, and the
-halo ketones 109 could not be converted into the azoenes
111 (Scheme 27).
O
O
1) MeLi
I
O
2)
O 3
O
H
H
H
O
O
O
O
O
O
OTES
H
105h (0%)
108b
O
Both N,N-dimethylhydrazine (112) and the correspond-
ing N-tosylhydrazine were reluctant reactants in the asym-
metric deprotonation/alkylation sequence when alkyllithi-
1)
H
N X, 2) HOAc
O
X
H
H
O
O
O
O
O
+
OTES
H
H
1) BuLi, B*, THF
–100 °C
H
Cl
TBSO
B* =
O
TBSO
OTES
109
110 (76%)
2) TESCl, –78°C
1) H2N-NHTs
2) NaHCO3
H
104a
H
108a
109
a
b
c
H
X
Cl Br
I
1) MeLi, THF, 0 °C
2) Me-I, T (°C)
O
O
N
Ts
Cl
Ph
Ph
N
N
H2
Me
H
–40 °C: 68%, dr 98:2, er 96:4
–10 °C: 71%, dr 99:1, er 91:9
–50→0 °C: 30%, dr 99:1, er 80:20
H
X
TBSO
O
111 (0%)
H
R
H
H
1) LDA
2) R-I
105a
O
N
O
R2
N
O
H
H
1) BuLi, B*, THF, –100 °C
2) TESCl, –78°C
3) NaIO4
O
O
O
O
O
H
H
105
O
O
112
3) MeLi, THF, 0 °C
4) R2-I, –40 °C
O
105
R
yield (%) dr
H
104b
H
b
c
Me
allyl
35
5
98:2
97:3
105 R2
=
yield de
ee
105b–e
b
c
d
e
Me
64% 86% 88%
70% 98% 84%
65% 96% 65%
35% 92% 82%
O
O
f
1
90:10
78:22
O 2
O 3
allyl
prenyl
Bn
g
10
Scheme 26
Scheme 27
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

M
M. Deimling et al.
Account
Synlett
OMOM
OMOM
OH
11 Functionalization of Weiss Diketones by
Carbonyl Ene Reactions
H
H
H
H
+
TBSO
TBSO
OH
To obtain building blocks with the 1,2-disubstitution
pattern required for acyltetramic macrolactams, a de-
symmetrization through a carbonyl-ene reaction and sub-
sequent enzymatic resolution was probed by using the
OTBS-protected ketone 104a as a starting material (Scheme
28).82
117b dr 95:5 (18%)
117a (66%)
1) 9-BBN, THF, r.t.
2) H2O2, NaOH, r.t.
dr 81 : 19
OMOM
H
H
MOMCl, iPr2NEt
rac-114
TBSO
CH2Cl2, 0 °C→r.t.
path A
path B
rac-116 (78%)
bromination
1) tosylation
2) Kolbe nitrile
3) reduction
OH
H
H
X
MeP+Ph3 Br–, KOtBu
H
H
TBSO
O
TBSO
reduction (A)
TBSO
THF, r.t., 3 h
92%
TBSO
H
104a
H
113
Wittig (B)
1,3,5-trioxane (1 equiv),
MAPH (3 equiv), CH2Cl2
H
H
118a X = CHO (24%, A)
b X = Br (82%, B)
119 (79%, A)
(9%, B)
–78 °C, 3 h
OH
OH
H
H
H
Scheme 29
TBSO
TBSO
+
H
rac-114 (91%) 99:1
115
Luckily, initial experiments with -methyl and -allyl
bicyclo[3.3.0]octanone tosylhydrazones 120a and 120b, re-
spectively, revealed an excellent regioselectivity in favor of
the less-substituted C=C double bond (Scheme 30).84 How-
ever, for the -allyl-substituted elimination product 121b, a
significant degree of racemization was observed (56% ee) in
contrast to the corresponding methyl-substituted product
121a, where the stereochemistry was almost retained (80%
ee). Presumably, the erosion of optical purity of 121b was
due to a thermal [3,3]-sigmatropic Cope rearrangement of
the alkene.
MS 4 Å, lipase PS-D
51% conv., 94% ee
OH
OAc
OH
H
H
H
TBSO
+
TBSO
H
114b
114a
Scheme 28
Wittig olefination provided the starting exocyclic
alkene 113. After considerable experimentation with vari-
ous Lewis acids, we found that Maruoka’s methylaluminum
bis(2,6-diphenylphenoxide) (MAPH; 3 equiv) mediated the
carbonyl-ene reaction of trioxane with alkene 113 to give
the regioisomeric product 114 in 91% yield (dr 99:1). Opti-
cal resolution was then achieved through lipase-catalyzed
acylation to give the homoallylic alcohol with 94% ee at 51%
conversion.
Carbonyl-ene product rac-114 was further manipulated
by MOM-protection and hydroboration to give the two
MOM-protected diols 117a and 117b in yields of 66 and
18% (dr 95:5), respectively (Scheme 29).
Me
H
O
O
H
121a
54%
nBuLi, TMEDA, –78 °C → r.t.
80% ee
R
R
H
H
O
O
NHTs
O
O
H2N-NHTs
N
O
H
H
105b,c
120a (R = Me, 61%, E/Z = 89:11)
120b (R = allyl, 80%, E/Z = 80:20)
quant.
56% ee
nBuLi, TMEDA, –78 °C → r.t.
Alternatively, chain extension was possible through to-
sylation, Kolbe nitrile synthesis, reduction to aldehyde
118a, and finally reduction to alcohol 119 (Scheme 29, Path
A). On the other hand, bromination of rac-114 and Grignard
reaction of 118b with formaldehyde gave alcohol 119 in a
poor yield (Path B).
allyl
H
H
H
O
O
O
O
H
121c
allyl
121b
Scheme 30
12 Functionalization of the Weiss Diketone
to Cylindramide and Geodin A Core Units
Taking this limitation into consideration, we decided to
keep the allylic moiety in the ‘other half’ of the bicyc-
lo[3.3.0]octane unit, which is not prone to sigmatropic rear-
rangement. As shown in Scheme 31, ketone 107a was con-
verted into the N-tosylhydrazone, followed by deprotection
of the silyl ether and oxidation to the -allyl ketone 122,
which was subjected to the Shapiro reaction to provide the
desired alkene 123 in 54% yield.
Introduction of a C=C double bond through a Shapiro re-
action was probed as means of accessing the core units of
the acyltetramic macrolactams 11 and 12. We were partic-
ularly worried regarding the regioselectivity of the Shapiro
protocol.83
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

N
M. Deimling et al.
Account
Synlett
The -unsubstituted ketone 107c was directly submit-
ted to Shapiro reaction to give the alkene 124 in 70% yield
as a 1:1 diastereomeric mixture. Further elaboration in
three steps gave the target compound 125, albeit in a disap-
pointingly low yield of 10%. Despite these drawbacks, the
core units 123 and 125 of cylindramide (11) and geodin A
(12) were successfully prepared.
Table 2 Cytotoxicity of Pentalene Derivatives against Two Cell Lines
Determined by the MTT testa,b
OR
OR
OTs
H
H
H
H
OH
OH
OTs
O
O
O
H
H
O
O
O
126a
126b
73a
allyl
H
H
H
O
OR
O
OR
O
OR
OR
13 Biological Properties of Bicyclo[3.3.0]oc-
tanes
H
H
H
allyl
127
pseudo-C2-107a
pseudo-Cs-107a
H
H
H
O
RO
O
Biological studies on cylindramide (11) revealed a pro-
nounced cytotoxicity against various cancer cell lines85 that
was Ca2+ dependent. A closer examination of derivatives
differing in both the macrocyclic unit and in the bicy-
clo[3.3.0]octane unit showed that both parts contribute to
the pharmacophore. For example, when the bicyclo[3.3.0]
unit was replaced by cyclopentanes, the IC50 values de-
creased to 3% of the original value. This result motivated us
to perform further structure–activity studies on a library of
hydropentalenes [Table 2 and Table S1 (SI)].86 From this
screening, two derivatives 50 and 132 with the highest ac-
tivity were selected for a cluster analysis employing natural
products with a known mode of action. Clustering was
found with tubulysin B, griseofulvin, and nocodazol, which
are compounds that interfere with microtubule polymer-
ization and spindle formation. We therefore proposed a mi-
crotubuli-affecting mode of action. Tubulin and F-actin
were identified by target-fishing experiments.
O
H
128
H
129
H
130
allyl
allyl
OR
OH
OR
O
H
H
H
O
O
OR
O
H
77a
H
131
H
O
O
132
O
O
R = TBDPS
O
O
O
O
H
O
O
H
H
H
O
O
O
O
H
O
H
O
O
50
76a
133b
Entry
Compound
L-929 mouse fibroblast KB-3-1
IC50 [μg/mL]
IC50 [μg/mL]
1
2
126a
126b
73a
18
17
>40
3
–
–
3
11
–
4
127
Moreover, the dihydropentalenedione 50 induced actin
and tubulin polymerization. It was also evident from the bi-
ological-screening data that the bicyclo[3.3.0]octanone–
crown ether hybrids 76a and 76b did not meet our expecta-
tions, displaying little or no cytotoxicity compared with the
most active hydropentalenes 50 and 132.
5
C2-107a
Cs-107a
128
10
7
–
6
–
7
2.2
>40
3
–
8
129
–
9
130
–
10
11
12
13
14
15
77a
10
15
0.6
0.4
20
35
>40
11
6
131
132
allyl
allyl
H
H
H
H
50
–
TsHN
BuLi, TMEDA
N
O
O
76a
26
30
122 (57%)
123 (54%)
133b
1) H2N-NHTs 3) DMP
2) TBAF
a MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.
b For further derivatives, see Table S1 (Supporting Information).
allyl
11
H
O
OR
107 R3
R = TBDPS
a
c
Me
H
H
R3
12
107a,c
14 Hydropentalenes through Vinylcyclopro-
pane Cyclopentene Rearrangement
1) H2N-NHTs
2) BuLi, TMEDA
allyl
H
allyl
H
1) MCPBA, NaHCO3
2) LDA, TMEDA
OR
OR
Inspired by Hudlicky’s seminal contributions87 and by
the more recent work of Zou and Louie on the transition-
metal-catalyzed vinylcyclopropane–cyclopentene rear-
3) DMP
H
H
O
124 (70%, dr 1:1)
125 (10%)
Scheme 31
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

O
M. Deimling et al.
Account
Synlett
O
R2
O
O
O
O
H
O
H
H
R2
R2
H
CuSO4
R1
S
R2
R1
R2
N2
toluene
R1
LiOtBu
R1
R1
S
R2
134
135
Br
A
B
R1
136
138
136
135a–c
X
H
yield (%)
dr
135 R1 R2
A
B
A
B
Scheme 32
a
b
c
H
H
Me
Ph 38 58 73:27 67:33
Me 64 49 80:20 80:20
H
20 19 100:0
50:50
rangement,88 we surmised that partially activated vinylcy-
clopropanes carrying only one nearby carbonyl group
might be suitable precursors to access hydropentalenes
(Scheme 32).
Scheme 34
[2+1]-annulation of unsaturated -diazo ketones 138 re-
quired six steps from commercially available starting mate-
rials (Route A, Scheme 34).89
H
H
Having solved this issue, it took us endless optimiza-
tions to figure out the proper conditions for the Ni-cata-
lyzed vinylcyclopropane rearrangement. Among the vari-
ous tested Ni N-heterocyclic carbene catalysts Ni(SIPr)2
[SI = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-
2-ylidene], prepared in situ from SIPr·HCl, t-BuOK, and
Ni(COD)2, gave the best results, although ring opening al-
ways compromised the yields. To our great dismay, the vi-
nylcyclopropanes, which were hardest to make, i.e. the vici-
nal-substituted compounds 135c and 135d were much
more prone to undergo the desired vinylcyclopropane rear-
rangement. On the other hand, vinylcyclopropanes 135a
and 135b with a terminal substituted C=C double bond
were obtained in decent yields, but unfortunately reacted only
sluggishly to give the bicyclo[3.3.0]octenes 134 (Scheme 35).90
S
S
R2
Br
R2
R1
CH2Cl2 or acetone
73–98%
R1
Br
136
O
O
H
LiOtBu
DMSO
O
H
H
H
H
n
H
H
+
R2
R2
n
n
R1
R1
135a–f (n = 1)
137a–f (n = 2)
H
endo-135, 137
exo-135, 137
O
O
O
H
H
H
H
H
H
H
H
H
Ph
Me
H
H
H
135b
49%, dr = 80:20
O
H
H
H
Me
135a
135c
58%, dr = 67:33
O
19%, dr = 50:50
O
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
Et
H
135d
23%, dr = 80:20
O
135e
135f
8%, dr = 50:50
43%, dr = 50:50
O
H
O
H
H
H
H
H
H
H
H
H
Ph
O
O
Ph
H
H
Ph
Me
H
H
endo-5a/exo-5a
H
H
H
H
137c
67:33
Me
H
H
H
137a
137b
30%, dr = 56:44
53%, dr = 73:27
O
H
19%, dr = 47:53
O
H
H
O
H
134a 0%
139 5%
H
H
H
H
H
O
Me
H
H
H
H
endo-5b/exo-5b
H
80:20
H
H
137e
12%, dr = 35:65
H
137f
Ph
137d
H
O
H
H
H
R2
(a)
H
18%, dr = 31:69
23%, dr = 35:65
H
134b 0%
R1
O
H
H
Scheme 33 Synthesis of vinylcyclopropanes 135 and 137. Compounds
135d and 135e were prepared by Route A (Scheme 34).89
endo-5c/exo-5c
80:20
135a–d
Me
Et
H
H
The required vinylcyclopropanes 135 might come from
cyclopentenone and allylsulfonium salts 136 (Scheme
33).89,90 The synthesis of the vinylcyclopropanes was found
to be strongly dependent on the substitution pattern. For
example, terminally substituted sulfonium salts (R2 ≠ H)
gave higher yields than vicinally substituted salts (R1 ≠ H).
In addition, the base, solvent, and counterion affected the
yield and selectivity. The most annoying side reaction was
the [2,3]-sigmatropic rearrangement, resulting in the for-
mation of -allyl sulfides rather than vinylcyclopro-
panes.89,90
134c 23%
O
Me
H
endo-5d/exo-5d
Cl
80:20
N
N
H
H
134d 22%, dr = 84:16
SIPr·HCl
(a): Ni(COD)2 (10 mol%), SIPr·HCl (20 mol%), KOtBu (20 mol%)
toluene, 120 °C, 3–22 h
Scheme 35
Computational studies confirmed the experimental re-
sults. Note that only endo-vinylcyclopropanes endo-135c
and endo-135d were reactive in the Ni catalysis, whereas
the exo-vinylcyclopropanes exo-135c and exo-135d re-
mained completely unreactive. This behavior could be ra-
tionalized by means of DFT calculations which showed that
the catalytic intermediate arising from endo-135c with vici-
Despite these disadvantages this approach delivered the
desired vinylcyclopropanes 135 in two steps (Route B,
Scheme 34), whereas the corresponding Cu-catalyzed
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

P
M. Deimling et al.
Account
Synlett
O
O
n
nal substitution had short half-lives of the order of seconds
or minutes, whereas intermediates derived from exo-135b
with terminal substituent at the C=C bond had half-lives of
the order of days.
diene 140
PhB(OH)2
140a
140b
yield
141 yield
%ee
%ee
(a)
a
b
80% 93
93% 84
73% 75
78% 73
n
a n = 1
b n = 2
Ph
141a,b
diene 140
143 yield
yield
%ee %ee
O
O
Ph
PhB(OH)2
–
a
b
<1%
59% 89
45% 88
R
R
1% 10
(a)
142a R = Me
143a,b
b R = 2-furyl
15 Functionalization of Bicyclo[3.3.0]oc-
tanes toward Chiral Dienes
(a) [RhCl(C2H4)2]2 (1.5 mol%), 140 (3.3 mol%)
KOH, 1,4-dioxane/H2O, 50 °C
diene: 140a
O
140b
140a
O
O
O
Chiral dienes have entered the field of asymmetric ca-
talysis as a result of the seminal discoveries of the groups of
Hayashi,91 Carreira,92 and Grützmacher93 that a diene can
exert efficient stereocontrol in asymmetric transition-met-
al catalysis.94
+
Ph
Ph
n
141c
(Z)-141d
(E)-141d
141e (n = 1), 141f (n = 2)
141e 80%, 76% ee
141f 86%, 87% ee
74%, 70% ee
87%, Z/E = 75:25
82% ee 50% ee
Scheme 37
As mentioned above in Sections 9 and 10, symmetry ar-
guments fascinated and puzzled us for quite a while. Hav-
ing obtained gram quantities of the chiral bicyclo[3.3.0]oc-
tan-1,4-dione 43 as a key intermediate during the cylindra-
mide total synthesis, we hoped that this compound and its
optical antipode might be valuable precursors for chiral di-
ene ligands. The synthesis of the diene ligands 140 com-
When we used a strategy similar to that shown in
Scheme 36 for the synthesis of dienes 144 from Weiss dike-
tone 103, we noticed that, depending on the base, consider-
able amounts of the undesired Cs-symmetrical (achiral) di-
ene 145 were formed (Scheme 38). For example, treatment
of Weiss diketone 103 with a chiral Simpkins base, trapping
with triflimide, and subsequent Suzuki cross-coupling with
phenylboronic acid delivered the dienes 144a and 145a in
71% yield as an 84:16 regioisomeric mixture.100 For ligands
with other substituents, similar results were obtained, re-
quiring laborious preparative HPLC separations to gain ac-
cess to the pure C2-symmetrical dienes 144. Attempts to
solve the purification issue by selective formation of Pd–di-
ene complexes were only partially successful. It should be
emphasized that Strand recently solved this problem of ra-
cemic and meso ligands in an elegant way101 by selective
complexation of the rac-diene with [Rh(ethene)2Cl]2, while
the meso-diene did not form a stable Rh complex, in agree-
ment with our own observations.100 Strand was able to ob-
tain diastereomerically pure monomeric Rh diene binaph-
thylamine complexes by treatment of the rac-Rh diene
complex with (R)-binaphthyldiamine.101 The enantiomeri-
cally pure diene was finally isolated after decomplexation
with COD.
menced
with
(3aR,6aR)-bicyclo[3.3.0]octan-1,4-dione
(R,R)-43, which was treated with phenyllithium followed by
elimination with POCl3 to give the 1,4-diphenyldiene 140a
(Scheme 36).95 Alternatively, the dione (R,R)-43 was con-
verted into a bisenol triflate and submitted to Fe-catalyzed
Negishi cross-coupling to yield the 1,4-dibenzyldiene 140b.
Ph
O
Bn
H
H
H
1) PhLi
2) POCl3
1) 2-PyNTf2
2) KHMDS
3) BnMgCl
Fe(acac)3
H
140a
H
H
140b
Ph
O
Bn
(R,R)-43
Scheme 36
The two ligands displayed complementary activities in
the Rh-catalyzed 1,4-additions of arylboronic acids to
enones. Whereas the 1,4-diphenyldiene 140a gave higher
yields and enantioselectivities of cyclic enones than did the
1,4-dibenzyldiene 140b, the former was completely inac-
tive upon employment of acyclic enones. In contrast, 1,4-
dibenzyldiene 140b provided the corresponding 1,4-addi-
tion products in decent yields and good ee values (Scheme
37). The scope of substrates and reagents could be further
extended to seven-membered rings and vinylboronates.96
Note that the Lin group published almost simultaneous re-
ports on the same ligand.97
H
O
O
Ph
N
Li
Ph
· LiCl
H
103
(S,S)-B*·LiCl
3) PhB(OH)2, PdCl2(PPh3)2 or
BnMgCl, Fe(acac)3
1) base B*, THF, −78 °C
2) 2-PyNTf2, –78→0 °C
H
H
R
yield
144/145
84:16
84:16
Motivated by a series of papers by the Kantchev group98
dealing with in silico catalysis through DFT methods, we be-
came interested in the C2-symmetrical 2,5-disubstituted bi-
cyclo[3.3.0]octan-1,4-diene 144a. Despite the much larger
distance of the substituents R from the Rh center (com-
pared with the diene ligand 140a), a high ee value was ex-
pected for the 1,4-addition products derived from aliphatic
enones (Scheme 38).99
R
R
+
R
R
Ph
Bn
a
b
71%
61%
H
H
144
145
PhB(OH)2
O
O
Ph
[Rh], ligand 144
KOH, 1,4-dioxane/
H2O, 50 °C
142c
143c 24%, 3% ee (144a)
calcd. 99.9% ee98
29%, 6% ee (144b)
Scheme 38
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

Q
M. Deimling et al.
Account
Synlett
After making all these efforts to obtain regioisomerical-
ly and enantiomerically pure ligands, we were very disap-
pointed in their poor catalytic performance in 1,4-addi-
tions. Fortunately, it turned out that dienes 144 were suit-
able catalysts for Rh-catalyzed 1,2-addition of phenylboroxine
to N-tosylimines 146. After some optimization, N-tosylimi-
nes 146 with various substitution patterns were converted
into the secondary amines 147, in most cases in high yields
and with excellent enantioselectivities (Scheme 39).
(e.g., H2O), and a surfactant, such as a sugar amphiphile
C8G1.103 These MEs have a sponge-like nanostructure with
channels measuring 55 Å that provide excellent liquid con-
finement, in particular for multicomponent reactions in-
volving substrates, catalysts, additives, and products with
various polarities. We were able to demonstrate, for the
first time, that such MEs permit the Rh-catalyzed 1,2-addi-
tion even when dienes 140 of different polarities were em-
ployed (Scheme 40). Furthermore, preliminary kinetic ex-
periments revealed a rate increase in the ME as compared
with conventional solvent mixtures such as 1,4-dioxane–
H2O.102
Ph
B
Ts
O
B
O
B
Ts
N
HN
Ph
O
Ph
The promising results of the roof-shaped bicyc-
lo[3.3.0]octadienes in asymmetric catalysis motivated sev-
eral groups worldwide to step into this area and to develop
novel hydropentalene-derived ligands.104–106 A brief over-
view is given in Scheme 41.106
2.5 mol% [RhCl(C2H4)2]2
Ph
6 mol% ligand 144b
3.1 M KOH, THF, 60 °C
R
R
146
147
146, 147
yield (%) ee (%)
R
H
a
b
c
d
e
4-Cl
4-OMe 29
3-F
2-Me
86
99
97
99
98
97
Bn
Bn
91
99
H
144b
3-OMe 99
O
O
OH
Ar
H
H
H
H
Scheme 39
O
O
H
H
H
H
O
O
HO
Ar
We were curious as to whether the HPLC separation of
rac- and meso-dienes 144 and 145 is really necessary, and
we speculated that mixtures rather than isolated dienes
might be used in the catalysis. In comparing the catalytic
1,2-addition of the pure (R,R)-dibenzyl-diene 144b with
that of a 67:38 mixture of the C2 and Cs forms, the latter
provided the product 147a in similar yield but with re-
duced enantioselectivity. Presumably, this resulted either
from diluted stereocontrol in the case of the ‘innocent’ Cs
diene 145b or a racemic background catalysis in the case of
C2/Cs interconversion through C=C bond isomerization. The
latter possibility came to our mind, because attempts to ob-
tain crystals from a Rh(Cs diene) complex resulted in the
exclusive crystallization of the Rh(C2 diene) complex. Such
a Rh-catalyzed C=C isomerization is much more likely, ac-
cording to DFT calculations, and agrees well with experi-
mental findings obtained by the Strand group.101
(R,R)-49
(R,R)-50
(R,R)-148
(S,S)-140a
(e.g. Ar = Ph)
149
Scheme 41
Very recently, Peng and Wang reported the conversion
of chiral diene (S,S)-140a through hydroboration into the
bicyclic bisboranes 150a and 150b, which were employed
as organocatalysts for the hydrogenation of imines 151
(Scheme 42).107
Ar
H
kinetic control
HBArF2, 25 °C
thermodynamic control
HBArF2, 80 °C
Ar
Ar
H
H
H
Ar
(S,S)-140a
ArF2B
BArF
ArF2B
BArF
2
2
H
H
150b
Ar
Ar
150a
Ph
Ph
bisborane 150a
N
HN
(Ar = Ph, 2 mol%)
Ph
Ph
More recently, bicyclo[3.3.0]octadienes and the result-
ing Rh complexes were probed in microemulsions (MEs) as
nonconventional solvents.102 MEs are stable single-phase
emulsions of a hydrophobic solvent (oil), a polar solvent
toluene, H2, 50 bar
100% conv.
151
152 (62% ee)
Scheme 42
16 Miscellaneous Syntheses of Hydropen-
talenes
R
H
H
R
140
140
a
c
d
e
f
In this section, we would like to draw the reader’s atten-
tion to some recent synthetic approaches towards hydro-
pentalenes. An organocatalytic enantioselective Wittig re-
action of meso-triketone 153 using chiral phosphines (S,S)-
MeDuPhos (154a) and (S,S)-iPrDuPhos (154b) was devel-
oped by the Werner group, providing the (R)- and (S)-bicy-
clo[3.3.0]octenediones 155 in 90 and 54% ee, respectively
(Scheme 43).108
O
R = H OC6H13
OH
O
O
3
2
polarity
Ph
B
Ts
HN
O
B
O
B
Ph
Ph
O
Ph
diene
146a
2.5 mol% [RhCl(C2H4)2]2
3.1 M KOH, ME, 60 °C
5 mol% diene
140a 93%, >99% ee
140c 82%, 95% ee
140f 95%, 97% ee
Cl
147a
Scheme 40
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

R
M. Deimling et al.
Account
Synlett
154b (5 mol%)
HSi(OMe)3
Na2CO3
154a (5 mol%)
HSi(OMe)3
Na2CO3
Ph3PAuCl (3 mol%)
AgBF4 (3 mol%)
CH2Cl2, r.t.
OH
O
O
O
O
H
Me
Br
toluene
125 °C, 20 h
toluene
125 °C, 8 h
HO
H
153
O
O
161
162 (87%)
Me
R
[Au]
R
P
P
Me
R
R
O
O
H
(S)-155
(54% ee, R/S 23:77)
(R)-155
(90% ee, R/S 95:5)
154a R = Me
b R = iPr
H
Scheme 43
ventricos-7(13)-ene (163)
Scheme 46
The Ding group disclosed an unprecedented Lewis acid
mediated retro-Dieckmann fragmentation/vinylogous
Dieckmann cyclization cascade of tetracyclic ketone 156 to
enone 157 for the installation of a bicyclo[3.3.0]octane unit
in a total synthesis of the diterpenoid (–)-rhodomollanol A
(158; Scheme 44).109
As already mentioned in Section 14, the laborious syn-
thesis of starting materials containing small rings often
compromises the efficiency of subsequent catalytic steps.
This problem was elegantly circumvented by Carreira and
co-workers in their total synthesis of (–)-merochlorin A
(166; Scheme 47).114 The key bicyclo[3.3.0]octenone inter-
mediate 165 was obtained by enantiospecific Au-catalyzed
tandem 1,3-acyloxy migration/Nazarov/aldol reaction from
acyclic precursor 164.
OBz
H
H
O
O
(TMSOCH2)2
TMSOTf
HO
Me
Me
CH2Cl2, r.t.
Me
O
Me
O
O
156
LA
OBz
OBz
O
O
H
H
H
H
SbF6
HO
Me
(tBu)2P Au NCMe
HO
Me
O+
Me
O
Me
Me
OAc
O
OH
R
H
Me
(5 mol%)
Me
O
LA–
O
R
157 (72%)
THF, H2O (0.2 vol%)
–10 °C
Me
O
Me
H
H
O
164
R = -(CH2)3OBz
165 (73%, dr 3:1, 97% ee)
OH
H
O
H
OH
H
HO
Me
Me
HO
HO
O
Me
O
(–)-rhodomollanol A (158)
Me
Cl
Scheme 44
Me
Me
Me
(–)-merochlorin A (166) Me
Scheme 47
Oxidation of the spirocyclic homoallylic alcohol 159,
followed by SmI2-mediated cyclization, gave the triquinane
160, as reported by the Tu group (Scheme 45).110 SmI2-me-
diated radical cascade cyclizations were utilized by Procter
and co-workers for the construction of quaternary stereo-
centers.111
The asymmetric total synthesis of (–)-merrilactone A
(169) was accomplished by a site-selective deprotonation of
the cyclooctenedione 167 with a subsequent transannular
aldol reaction to give hydropentalene 168 as a key step
(Scheme 48).115
HO
1) PDC, CH2Cl2
OH
O
O
Me
H
Me
Ph
Ph
2) SmI2, HMPA
site-selective
deprotonation
tBuOH, THF
HO
OH
O
O
O
159
160 (50%)
O
HOMe
F3C
PDC = pyridinium dichromate
Me
F3C
CF3
O
CF3
Scheme 45
167
168
Me
Me
O
O
Gold-catalyzed ring expansions have been successfully
employed for a variety of hydropentalene-containing natu-
ral products.112 For example, the Toste group reported an
Au-catalyzed ring expansion of cyclopropanol 161, fol-
lowed by a semipinacol shift, to give the hydropentalene
subunit of the angular triquinane ventricos-7(13)-ene (163;
Scheme 46).113
O
HO
O
Me
O
(–)-merrilactone A (169)
Scheme 48
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

S
M. Deimling et al.
Account
Synlett
17 Conclusion and Outlook
References
(1) Singh, V.; Chandra, G.; Mobin, S. M. Synlett 2008, 3111.
(2) Takeda, R.; Naoki, H.; Iwashita, T.; Hirose, Y. Tetrahedron Lett.
1981, 22, 5307.
(3) Whittle, B. J. R.; Moncada, S.; Whiting, F.; Vane, J. R. Prostaglan-
dins 1980, 19, 605.
(4) Bund, J.; Gais, H.-J.; Schmitz, E.; Erdelmeier, I.; Raabe, G. Eur. J.
Org. Chem. 1998, 1319.
(5) (a) Dickson, J. K.; Fraser-Reid, F. J. Chem. Soc., Chem. Commun.
1990, 1440. (b) Paquette, L. A.; Roberts, R. A.; Drtina, G. J. Am.
Chem. Soc. 1984, 106, 6690.
The current account summarizes our efforts in the syn-
thesis and applications of bicyclo[3.3.0]octanes over the
last 20 years. This demonstrated the value of the hydropen-
talene scaffold in relation to natural product chemistry and
biologically active compounds. One lesson learned was that
key intermediates from natural product chemistry can fer-
tilize new directions in catalysis, and vice versa. On the oth-
er hand, it should be kept in mind that small molecules of-
ten cause nightmares for the preparative organic chemist.
This is particularly true for the bicyclo[3.3.0]octanes. There
are several reasons for this challenging chemistry. The con-
vex roof-shape of the bicyclo[3.3.0]octane unit results in a
spherical shape, leading to high volatility of many members
of this compound family. Therefore, special care has to be
taken during workup and purification to avoid product loss.
Furthermore, the roof-shape causes a severe steric bias to-
ward endo-attack compared with exo-attack of incoming
reagents. Often, even standard transformations fail or give
low yields due to steric restrictions caused by neighboring
groups. In addition, even simple functionalizations or func-
tional-group interconversions, such as addition or removal
of a single hydroxy group, can change the polarity in a
much more pronounced way as compared with the intro-
duction of a hydroxy group onto a larger molecule (e.g.,
MW 800 or above). Thus, polarity and solubility issues play
an important role in the chemistry of hydropentalenes. The
old saying ‘Every magic comes with price tag’ also apply to
hydropentalenes. Nevertheless, the field is certainly not
closed, and applications in the direction of materials sci-
ence are on the horizon, awaiting to be discovered.
(6) Bohlmann, F.; Zdero, C.; Bohlmann, R.; King, R. M.; Robinson, H.
Phytochemistry 1980, 19, 579.
(7) (a) Srikrishna, A.; Gowri, V. Tetrahedron: Asymmetry 2007, 18,
1663. (b) Guella, G.; Pietra, F. Helv. Chim. Acta 2000, 83, 2946.
(8) (a) Nozoe, S.; Furukawa, J.; Sankawa, U.; Shibata, S. Tetrahedron
Lett. 1976, 17, 195. (b) Chandler, C. L.; List, B. J. Am. Chem. Soc.
2008, 130, 6737.
(9) Wender, P. A.; Dreyer, G. B. J. Am. Chem. Soc. 1982, 104, 5805.
(10) (a) Sugawara, H.; Kasuya, A.; Iitaka, Y.; Shibata, S. Chem. Pharm.
Bull. 1991, 39, 3051. (b) Zhang, J.; Wang, X.; Li, S.; Li, D.; Liu, S.;
Lan, Y.; Gong, J.; Yang, Z. Chem. Eur. J. 2015, 21, 12596.
(11) (a) Cane, D. E.; Sohng, J.-K.; Williard, P. G. J. Org. Chem. 1992, 57,
844. (b) Liu, Q.; Yue, G.; Wu, N.; Lin, G.; Li, Y.; Quan, J.; Li, C.-C.;
Wang, G.; Yang, Z. Angew. Chem. 2012, 124, 12238; Angew.
Chem. Int. Ed. 2012, 51, 12072. (c) Cane, D. E.; Sohng, J.-K. Bio-
chemistry 1994, 33, 6524.
(12) Kanazawa, S.; Fusetani, N.; Matsunaga, S. Tetrahedron Lett.
1993, 34, 1065.
(13) (a) Capon, R. J.; Skene, C.; Lacey, E.; Gill, J. H.; Wadsworth, D.;
Friedel, T. J. Nat. Prod. 1999, 62, 1256. (b) Capon, R. J. Eur. J. Org.
Chem. 2001, 633.
(14) Bae, M.-A.; Yamada, K.; Ijuin, Y.; Tsuji, T.; Yazawa, K.; Tomono,
Y.; Uemura, D. Heterocycl. Commun. 1996, 2, 315.
(15) Shigemori, H.; Bae, M.-A.; Yazawa, K.; Sasaki, T.; Kobayashi, J.
J. Org. Chem. 1992, 57, 4317.
(16) For reviews, see: (a) Petermichl, M.; Schobert, R. Synlett 2017,
654. (b) Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16,
4203.
Funding Information
(17) (a) Cloke, F. G. N.; Green, J. C.; Kilpatrick, A. F. R.; O’Hare, D.
Coord. Chem. Rev. 2017, 344, 238. (b) Hopf, H. Angew. Chem.
2013, 125, 12446; Angew. Chem. Int. Ed. 2013, 52, 12224.
(c) McCarroll, A. J.; Walton, J. C. Angew. Chem. 2001, 113, 2282;
Angew. Chem. Int. Ed.; 2001, 40, 2224. (d) Cloke, F. G. N. Pure
Appl. Chem. 2001, 73, 233. (e) Butenschön, H. Angew. Chem. Int.
Ed. 1997, 36, 1695. (f) Griesbeck, A. G.; Deufel, T.; Malisch, W.;
Neumayer, M.; Gunzelmann, N. In Stereoselective Reactions of
Metal-Activated Molecules, Proceedings of the 2nd Symposium,
Würzburg, Germany, Sept. 21, 1994; Werner, H.; Sundermeyer,
J., Ed.; Vieweg: Braunschweig, 1995, 165.
(18) Yu, F.; Zaleta-Rivera, K.; Zhu, X.; Huffman, J.; Millet, J. C.; Harris,
S. D.; Yuen, G.; Li, X.-C.; Du, L. Antimicrob. Agents Chemother.
2007, 51, 64.
(19) (a) Li, Y.; Wang, H.; Liu, Y.; Jiao, Y.; Li, S.; Shen, Y.; Du, L. Angew.
Chem. 2018, 130, 6329; Angew. Chem. Int. Ed. 2018, 57, 6221.
(b) Li, Y.; Chen, H.; Ding, Y.; Xie, Y.; Wang, H.; Cerny, R. L.; Shen,
Y.; Du, L. Angew. Chem. 2014, 126, 7654; Angew. Chem. Int. Ed.
2014, 53, 7524. (c) Xu, L.; Wu, P.; Wright, S. J. Du L.; Wei, X.
J. Nat. Prod. 2015, 78, 1841.
Generous financial support by the Deutsche Forschungsgemeinschaft
(DFG, project number 358283783 - SFB 1333, subproject B3), the
Ministerium für Wissenschaft, Forschung und Kunst des Landes
Baden-Württemberg, the Fonds der Chemischen Industrie and the
European Commission (ERASMUS fellowship for Z.D.) is gratefully ac-
knowledged.
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Acknowledgements
This work would not have been possible without many past and pres-
ent co-workers. We would like to thank (in alphabetical order) Timo
Anderl, Armand Becheanu, Nicolai Cramer, Sarah Helbig, Michael
Krebs, Vanessa Oesker (née Lutz), and Tina Mühlhäuser, whose con-
tributions can be found in the list of references.
Supporting Information
Supporting information for this article is available online at
(20) Blodgett, J. A. V.; Oh, D.-C.; Cao, S.; Currie, C. R.; Kolter, R.;
Clardy, J. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 11692.
(21) Qi, Y.; Ding, E.; Blodgett, J. A. V. ACS Synth. Biol. 2018, 7, 352.
https://doi.org/10.1055/s-0040-1707226.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

T
M. Deimling et al.
Account
Synlett
(22) (a) Greunke, C.; Glöckle, A.; Antosch, J.; Gulder, T. A. M. Angew.
Chem. 2017, 129, 4416; Angew. Chem. Int. Ed. 2017, 56, 4351.
(b) Antosch, J.; Schaefers, F.; Gulder, T. A. M. Angew. Chem. 2014,
126, 3055; Angew. Chem. Int. Ed. 2014, 53, 3011.
(45) Carretero, J. C.; Adrio, J. Synthesis 2001, 1888.
(46) Barluenga, J.; Álvarez-Fernández, A.; Suárez-Sobrino, A. L.;
Tomás, M. Angew. Chem. 2012, 124, 187; Angew. Chem. Int. Ed.
2012, 51, 183.
(23) Zhang, G.; Zhang, W.; Zhang, Q.; Shi, T.; Ma, L.; Zhu, Y.; Li, S.;
Zhang, H.; Zhao, Y.-L.; Shi, R.; Zhang, C. Angew. Chem. 2014, 126,
4940; Angew. Chem. Int. Ed. 2014, 53, 4840.
(24) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watt, W. E. J. Chem. Soc. D.
1971, 36a.
(47) Moriarty, R. M.; Duncan, M. P.; Vaid, R. K.; Prakash, O. Org.
Synth. 1990, 68, 175.
(48) Henry, P. M.; Davies, M.; Ferguson, G.; Phillips, S.; Restivo, R.
J. Chem. Soc., Chem. Commun. 1974, 112.
(49) Cramer, N.; Laschat, S.; Baro, A.; Schwalbe, H.; Richter, C. Angew.
Chem. 2005, 117, 831; Angew. Chem. Int. Ed. 2005, 44, 820.
(50) Cramer, N.; Buchweitz, M.; Laschat, S.; Frey, W.; Baro, A.;
Mathieu, D.; Richter, C.; Schwalbe, H. Chem. Eur. J. 2006, 12,
2488.
(51) (a) For selected examples of the use of diketone 42 or diol 40e
in natural product syntheses; (+)-kelsoene: Mehta, G.; Srinivas,
K. Tetrahedron Lett. 2001, 42, 2855. (b) (–)-pepluanol B: Zhang,
J.; Liu, M.; Wu, C.; Zhao, G.; Chen, P.; Zhou, L.; Xie, X.; Fang, R.;
Li, H.; She, X. Angew. Chem. 2020, 132, 3994; Angew. Chem. Int.
Ed. 2020, 59, 3966.
(52) (a) Krebs, M.; Laschat, S. ARKIVOC 2012, (iii), 5. (b) Krebs, M. Dis-
sertation; Universität Stuttgart: Germany, 2013.
(53) Gunasekera, S. P.; Gunasekera, M.; McCarthy, P. J. Org. Chem.
1991, 56, 4830.
(54) Kobayashi, J.; Ishibashi, M. Chem. Rev. 1993, 93, 1753.
(55) Blodgett, J. A. V.; Oh, D.-C.; Cao, S.; Currie, C. R.; Kolter, R.;
Clardy, J. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 11692.
(56) Jakobi, M.; Winkelmann, G.; Kaiser, D.; Kempter, C.; Jung, G.;
Berg, G.; Bahl, H. J. Antibiot. 1996, 49, 1101.
(57) Graupner, P. R.; Thornburgh, S.; Mathieson, J. T.; Chapin, E. L.;
Kemmitt, G. M.; Brown, J. M.; Snipes, C. E. J. Antibiot. 1997, 50,
1014.
(58) Krebs, M.; Kalinowski, M.; Frey, W.; Claasen, B.; Baro, A.;
Schobert, R.; Laschat, S. Tetrahedron 2013, 69, 7373.
(59) Crane, E. A.; Gademann, K. Angew. Chem. 2016, 128, 3948;
Angew. Chem. Int. Ed. 2016, 55, 3882.
(60) Wach, J.-Y.; Gademann, K. Synlett 2012, 163.
(61) Hollemann, A. F. Lehrbuch der Anorganischen Chemie; Wiberg,
E., Ed.; de Gruyter: Berlin, 1995.
(62) Park, N. Dissertation; Universität Stuttgart: Germany, 2013, see
Supporting Information for detail.
(63) Hart, A. C.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 1094.
(64) Stragies, R.; Blechert, S. Synlett 1998, 169.
(65) Schrock, R. R.; Hoveyda, A. H. Angew. Chem. 2003, 115, 4740;
Angew. Chem. Int. Ed. 2003, 42, 4592.
(66) Arjona, A.; Csáky, A. G.; Plumet, J. Eur. J. Org. Chem. 2003, 611.
(67) Hagiwara, H.; Katsumi, T.; Endou, S.; Hoshi, T.; Suzuki, T. Tetra-
hedron 2002, 58, 6651.
(68) Wrobleski, A.; Sahasrabudhe, K.; Aubé, J. J. Am. Chem. Soc. 2004,
126, 5475.
(69) Funel, J.-A.; Prunet, J. Synlett 2005, 235.
(70) Henderson, J. A.; Phillips, A. J. Angew. Chem. 2008, 120, 8627;
Angew. Chem. Int. Ed. 2008, 47, 8499.
(71) Phillips, J. A.; Hart, A. C.; Henderson, J. A. Tetrahedron Lett. 2006,
47, 3743.
(25) For reviews, see: (a) Croatt, M. P.; Wender, P. A. Eur. J. Org. Chem.
2010, 19. (b) Lee, H.-W.; Kwong, F.-Y. Eur. J. Org. Chem. 2010,
789. (c) Blanco-Urgoiti, J.; Añorbe, L.; Pérez-Serrano, L.;
Domínguez, G.; Pérez-Castells, J. Chem. Soc. Rev. 2004, 33, 32.
(d) Gibson, S. E.; Stevenazzi, A. Angew. Chem. 2003, 115, 1844;
Angew. Chem. Int. Ed. 2003, 42, 1800. (e) Brummond, K. M.;
Kent, J. L. Tetrahedron 2000, 56, 3263. (f) Chung, Y. K. Coord.
Chem. Rev. 1999, 188, 297. (g) Geis, O.; Schmalz, H.-G. Angew.
Chem. 1998, 110, 955; Angew. Chem. Int. Ed. 1998, 37, 911.
(26) For some preliminary work, see: (a) Khand, I. U.; Pauson, P. L.;
Habib, M. J. A. J. Chem. Res., Synop. 1978, 348. (b) Schore, N. E.;
La Belle, B. E.; Knudsen, M. J.; Hope, H.; Xu, X.-J. J. Organomet.
Chem. 1984, 272, 435.
(27) (a) Becheanu, A. Dissertation; Universität Stuttgart: Germany,
2006. (b) Becheanu, A.; Bell, T.; Laschat, S.; Baro, A.; Frey, W.;
Steinke, N.; Fischer, P. Z. Naturforsch., B: J. Chem. Sci. 2006, 61,
589.
(28) For a kinetic study of related intermolecular Pauson–Khand
reactions, see: Cabot, R.; Lledó, A.; Revés, M.; Riera, A.;
Verdaguer, X. Organometallics 2007, 26, 1134.
(29) Aiguabella, N.; del Pozo, C.; Verdaguer, X.; Fustero, S.; Riera, A.
Angew. Chem. 2013, 125, 5463; Angew. Chem. Int. Ed. 2013, 52,
5355.
(30) Cabré, A.; Verdaguer, X.; Riera, A. Synthesis 2017, 49, 3945.
(31) Becheanu, A.; Laschat, S. Synlett 2002, 1865.
(32) Becheanu, A.; Baro, A.; Laschat, S.; Frey, W. Eur. J. Org. Chem.
2006, 2215.
(33) (a) Laschat, S.; Becheanu, A.; Bell, T.; Baro, A. Synlett 2005, 2547.
(b) Gibson, S. E.; Kaufmann, K. A. C.; Loch, J. A.; Steed, J. W.;
White, A. J. P. Chem. Eur. J. 2005, 11, 2566.
(34) Orgué, S.; León, T.; Riera, A.; Verdaguer, X. Org. Lett. 2015, 17,
250.
(35) For a review, see: Shibata, T. Adv. Synth. Catal. 2006, 348, 2328.
(36) (a) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 9450. (b) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 5881.
(37) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. 2002, 67, 3398.
(38) Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem. 2001,
624, 73.
(39) Park, K. H.; Son, S. U.; Chung, Y. K. Chem. Commun. 2003, 1898.
(40) For a review of the Pauson–Khand reaction with nanoparticles,
see: Park, K. H.; Chung, Y. K. Synlett 2005, 545.
(41) (a) Boñaga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795.
(b) Krafft, M. E.; Boñaga, L. V. R.; Wright, J. A.; Hirosawa, C. J. Org.
Chem. 2002, 67, 1233.
(42) For a review of Pauson–Khand reactions in natural product syn-
thesis, see: Shi, L.; Yang, Z. Eur. J. Org. Chem. 2016, 2356.
(43) For a review of intermolecular Pauson–Khand reactions, see:
Gibson, S. E.; Mainolfi, N. Angew. Chem. 2005, 117, 3082.
(44) For selected examples, see: (a) Adrio, J.; Rodríguez Rivero, M.;
Carretero, J. C. Org. Lett. 2005, 7, 431. (b) Rodríguez Rivero, M.;
Adrio, J.; Carretero, J. C. Synlett 2005, 26.
(72) Kotha, S.; Reddy Keesari, R.; Ansari, S. Synthesis 2019, 51, 3989.
(73) Hofmann, C. Dissertation; Universität Stuttgart: Germany, 2013,
see Supporting Information for detail.
(74) Hofmann, C.; Baro, A.; Laschat, S. Synlett 2008, 1618.
(75) (a) Bertz, S. H.; Cook, J. M.; Gawish, A.; Weiss, U. Org. Synth.
1986, 64, 27. (b) Kubiak, G.; Cook, J. M.; Weiss, U. J. Org. Chem.
1984, 49, 561.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U

U
M. Deimling et al.
Account
Synlett
(76) For reviews, see: (a) O’Brien, P. J. Chem. Soc., Perkin Trans. 1
1998, 1439. (b) O’Brien, P. J. Chem. Soc., Perkin Trans. 1 2001, 95.
(c) Simpkins, N. S. Quim. Nova 1995, 18, 295. (d) Simpkins, N. S.
Chem. Soc. Rev. 1990, 19, 335. (e) Cox, P. J.; Simpkins, N. S. Tetra-
hedron: Asymmetry 1991, 2, 1.
(77) (a) Sugasawa, K.; Shindo, M.; Noguchi, H.; Koga, K. Tetrahedron
Lett. 1996, 37, 7377. (b) Aoki, K.; Noguchi, H.; Tomioka, K.; Koga,
K. Tetrahedron Lett. 1993, 34, 5105. (c) Izawa, H.; Shirai, R.;
Kawasaki, H.; Kim, H.-d.; Koga, K. Tetrahedron Lett. 1989, 30,
7221. (d) Shirai, R.; Tanaka, M.; Koga, K. J. Am. Chem. Soc. 1986,
108, 543.
(78) Leonard, J.; Ouali, D.; Rahman, S. K. Tetrahedron Lett. 1990, 31,
739.
(79) Vaulont, I.; Gais, H.-J.; Reuter, N.; Schmitz, E.; Ossenkamp, R. K.
L. Eur. J. Org. Chem. 1998, 805.
(80) Lutz, V.; Baro, A.; Fischer, P.; Laschat, S. Eur. J. Org. Chem. 2010,
1149.
(96) Helbig, S.; Axenov, K. V.; Tussetschläger, S.; Frey, W.; Laschat, S.
Tetrahedron Lett. 2012, 53, 3506.
(97) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc.
2007, 129, 5336.
(98) (a) Kantchev, E. A. B. Chem. Sci. 2013, 4, 1864. (b) Qin, H.-L.;
Chen, X.-Q.; Shang, Z.-P.; Kantchev, E. A. B. Chem. Eur. J. 2015,
21, 3079.
(99) For other theoretical work, see: Sieffert, N.; Boisson, J.; Py, S.
Chem. Eur. J. 2015, 21, 9753.
(100) Mühlhäuser, T.; Savin, A.; Frey, W.; Baro, A.; Schneider, A. J.;
Döteberg, H.-G.; Bauer, F.; Köhn, A.; Laschat, S. J. Org. Chem.
2017, 82, 13468.
(101) Melcher, M. C.; Alves da Silva, B. R.; Ivšić, T.; Strand, D. ACS
Omega 2018, 3, 3622.
(102) Deimling, M.; Kirchhof, M.; Schwager, B.; Qawasmi, Y.; Savin, A.;
Mühlhäuser, T.; Frey, W.; Claasen, B.; Baro, A.; Sottmann, T.;
Laschat, S. Chem. Eur. J. 2019, 25, 9464.
(81) Klenk, S. Master’s Thesis; Universität Stuttgart: Germany, 2013,
see Supporting Information for detail.
(82) Anderl, T.; Emo, M.; Laschat, S.; Baro, A.; Frey, W. Synthesis
2008, 1619.
(103) Kahlweit, M.; Strey, R. Angew. Chem. Int. Ed. 1985, 24, 654.
(104) For reviews, see: (a) Nagamoto, M.; Nishimura, T. ACS Catal.
2017, 7, 833. (b) Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. Synlett 2011,
1345.
(83) (a) Shapiro, R. H.; Lipton, M. F.; Kolonko, K. J.; Buswell, R. L.;
Capuano, L. A. Tetrahedron Lett. 1975, 16, 1811. For reviews, see:
(b) Shapiro, R. H. Org. React (N. Y.) 1976, 23, 405. (c) Adlington,
R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55. (d) Caille, J.
C.; Farnier, M.; Guilard, R. Can. J. Chem. 1986, 64, 824.
(84) Lutz, V.; Park, N.; Rothe, C.; Krüger, C.; Baro, A.; Laschat, S. Eur. J.
Org. Chem. 2013, 761.
(85) Cramer, N.; Helbig, S.; Baro, A.; Laschat, S.; Diestel, R.; Sasse, F.;
Mathieu, D.; Richter, C.; Kummerlöwe, G.; Luy, B.; Schwalbe, H.
ChemBioChem 2008, 9, 2474.
(86) Lutz, V.; Mannchen, F.; Krebs, M.; Park, N.; Krüger, C.; Raja, A.;
Sasse, F.; Baro, A.; Laschat, S. Bioorg. Med. Chem. 2014, 22, 3252.
(87) Hudlicky, T.; Becker, D. A.; Fan, R. L.; Kozhushkov, S. I. In
Houben-Weyl, Methoden der Organischen Chemie, Vol. E17c; de
Meijere, A., Ed.; Thieme: Stuttgart, 1997.
(88) Zuo, G.; Louie, J. Angew. Chem. 2004, 116, 2327; Angew. Chem.
Int. Ed. 2004, 43, 2277.
(89) Zens, A.; Seubert, P.; Kolb, B.; Wurster, M.; Holzwarth, M.;
Mannchen, F.; Forschner, R.; Claasen, B.; Kunz, D.; Laschat, S.
Synthesis 2018, 50, 2367.
(90) Zens, A.; Bauer, F.; Kolb, B.; Mannchen, F.; Seubert, P.;
Forschner, R.; Flaig, K. S.; Köhn, A.; Kunz, D.; Laschat, S. Eur. J.
Org. Chem. 2019, 6285.
(91) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem.
Soc. 2003, 125, 11508.
(105) For hydropentalene-derived dienes, see: (a) Wang, L.; Wang, Z.-
Q.; Xu, M.-H.; Lin, G.-Q. Synthesis 2010, 3263. (b) Shao, C.; Yu,
H.-J.; Wu, N.-Y.; Tian, P.; Wang, R.; Feng, C.-G.; Lin, G.-Q. Org.
Lett. 2011, 13, 788. (c) Cui, Z.; Yu, H.-J.; Yang, R.-F.; Gao, W.-Y.;
Feng, C.-G.; Lin, G.-Y. J. Am. Chem. Soc. 2011, 133, 12394.
(d) Yang, H.; Xu, M. Chin. J. Chem. 2013, 31, 119. (e) Liao, Y.-X.;
Xing, C.-H.; Hu, Q.-S. Org. Lett. 2012, 14, 1544. (f) Yu, H.-J.; Shao,
C.; Cui, Z.; Feng, C.-G.; Lin, G.-Q. Chem. Eur. J. 2012, 18, 13274.
(g) Cui, Z.; Chen, Y.-J.; Gao, W.-Y.; Feng, C.-G.; Lin, G.-Q. Org. Lett.
2014, 16, 1016. (h) Chen, Y.-J.; Chen, Y.-H.; Feng, C.-G.; Lin, G.-Q.
Org. Lett. 2014, 16, 3400. (i) Zhang, Q.; Stockdale, D. P.; Mixdorf,
J. C.; Topczewski, J. J.; Nguyen, H. M. J. Am. Chem. Soc. 2015, 137,
11912.
(106) (a) Feng, C.-G.; Wang, Z.-Q.; Shao, C.; Xu, M.-H.; Lin, G.-Q. Org.
Lett. 2008, 10, 4101. (b) Wang, Z.-Q.; Feng, C.-G.; Zhang, S.-S.;
Xu, M.-H.; Lin, G.-Q. Angew. Chem. 2010, 122, 5916; Angew.
Chem. Int. Ed. 2010, 49, 5780. (c) Zhang, S.-S.; Wang, Z.-Q.; Xu,
M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 5546. (d) Pecchioli, T.;
Christmann, M. Org. Lett. 2018, 20, 5256.
(107) Tu, X.-S.; Zeng, N.-N.; Li, R.-Y.; Zhao, Y.-Q.; Xie, D.-Z.; Peng, Q.;
Wang, X.-C. Angew. Chem. 2018, 130, 15316; Angew. Chem. Int.
Ed. 2018, 57, 15096.
(108) Werner, T.; Hoffmann, M.; Deshmukh, S. Eur. J. Org. Chem. 2014,
6630.
(109) Gao, J.; Rao, P.; Xu, K.; Wang, S.; Wu, Y.; He, C.; Ding, H. J. Am.
Chem. Soc. 2020, 142, 4592.
(110) Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y. Q. Angew. Chem. 2004,
116, 1734; Angew. Chem. Int. Ed. 2004, 43, 1702.
(92) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 1628.
(93) Maire, P.; Deblon, S.; Breher, F.; Geier, J.; Böhler, C.; Rüegger, H.;
Schönberg, H.; Grützmacher, H. Chem. Eur. J. 2004, 10, 4198.
(94) For reviews, see: (a) Defieber, C.; Grützmacher, H.; Carreira, E.
M. Angew. Chem. 2008, 120, 4558, Angew. Chem. Int. Ed. 2008,
47, 4482. (b) Johnson, J. B.; Rovis, T. Angew. Chem. 2008, 120,
852; Angew. Chem. Int. Ed. 2008, 47, 840. (c) Müller, D.;
Alexakis, A. Chem. Commun. 2012, 48, 12037. (d) Maksymowicz,
R. M.; Bissette, A. J.; Fletcher, S. P. Chem. Eur. J. 2015, 21, 5668.
(95) Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W.
Adv. Synth. Catal. 2007, 349, 2331.
(111) Huang, H.-M.; He, Q.; Procter, D. J. Synlett 2020, 31, 45.
(112) Garayalde, D.; Nevado, C. Beilstein J. Org. Chem. 2011, 7, 767.
(113) Sethofer, S. G.; Staben, S. T.; Hung, O. Y.; Toste, F. D. Org. Lett.
2008, 10, 4315.
(114) Brandstätter, M.; Freis, M.; Huwyler, N.; Carreira, E. M. Angew.
Chem. 2019, 131, 2512; Angew. Chem. Int. Ed. 2019, 58, 2490.
(115) Inoue, M.; Sato, T.; Hirama, M. Angew. Chem. 2006, 118, 4961;
Angew. Chem. Int. Ed. 2006, 45, 4843.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–U