Enantioselective Construction of 5-6-5 Tricyclic Lactone Framework Bearing a Quaternary Bridgehead Carbon via Rh-Catalyzed Asymmetric [2+2+2] Cycloaddition of Enediynes

Article abstract of DOI:10.1002/adsc.202100513

Herein, we report a Rh-catalyzed asymmetric [2+2+2] cycloaddition of ene-yne-yne enediynes to generate enantio-enriched tricyclic cyclohexadienes bearing a quaternary bridgehead carbon. We found that the Rh-Phanephos complex is an appropriate catalyst for the cycloaddition of enediynes bearing an unsubstituted propiolate terminus, whereas Rh-biaryl bisphosphine catalysts, which have been widely used for asymmetric cycloadditions of alkynes and alkenes, are not applicable for the reaction of such enediynes. Several control experiments suggest that the reaction using the Rh-Phanephos complex exclusively proceeds via a rhodacyclopentadiene intermediate, unlike when using a Rh-biaryl bisphosphine complex that can form a rhodacyclopentadiene intermediate as well as a rhodacyclopentene intermediate in a substrate-dependent manner. (Figure presented.).

Full text of DOI:10.1002/adsc.202100513

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Very Important Publication
Enantioselective Construction of 5-6-5 Tricyclic Lactone
Framework Bearing a Quaternary Bridgehead Carbon via Rh-
Catalyzed Asymmetric [2+2+2] Cycloaddition of Enediynes
Takeshi Yasui,a,* Yuya Nakazato,a Koutarou Kurisaki,a and
Yoshihiko Yamamotoa,*
a
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences,
Nagoya University,
Furo-cho Chikusa, Nagoya 464-8603, Japan
E-mail: t-yasui@ps.nagoya-u.ac.jp; yamamoto-yoshi@ps.nagoya-u.ac.jp
Manuscript received: April 27, 2021; Revised manuscript received: June 23, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100513
natural products exhibiting significant biological activ-
Abstract: Herein, we report a Rh-catalyzed asym-
metric [2+2+2] cycloaddition of ene-yne-yne
ities, such as pleurotin, perforanoid A, and seco-
prezizaane-type sesquiterpenes (Figure 1).[3] In partic-
enediynes to generate enantio-enriched tricyclic
ular, the last natural product family consists of
cyclohexadienes bearing a quaternary bridgehead
diversely oxygenated congeners, some of which have
carbon. We found that the Rh-Phanephos complex is
attracted considerable attention because of their potent
an appropriate catalyst for the cycloaddition of
neurotrophic activities, such as jiadifenolide, jiadife-
enediynes bearing an unsubstituted propiolate termi-
nin, and jiadifenoxolane A.[4] In addition to these
nus, whereas Rh-biaryl bisphosphine catalysts,
natural products, Danishefsky et al. and Theodorakis
which have been widely used for asymmetric cyclo-
et al. reported that simplified analogues display higher
additions of alkynes and alkenes, are not applicable
potency in terms of their neurite outgrowth activity
for the reaction of such enediynes. Several control
when compared to their parent natural products.[5]
experiments suggest that the reaction using the Rh-
Accordingly, a diverse structural exploration of these
Phanephos complex exclusively proceeds via a
molecules may lead to the discovery of drug candidates
rhodacyclopentadiene intermediate, unlike when
for managing neurodegenerative diseases, such as
using a Rh-biaryl bisphosphine complex that can
Parkinson’s and Alzheimer’s disease.
form a rhodacyclopentadiene intermediate as well as
a rhodacyclopentene intermediate in a substrate-
dependent manner.
The transition metal-catalyzed intramolecular [2+2+
2] cycloaddition of alkynes and alkenes is a practical
method used to construct polycyclic frameworks from
simple acyclic precursors.[6] We previously reported a
Ru-catalyzed [2+2+2] cycloaddition of enediynes to
Keywords: Cycloaddition; Rhodium; Asymmetric
generate racemic lactone-fused cyclohexadienes bearing
synthesis; Lactones; Reaction mechanisms
a quaternary bridgehead carbon at the C9 position
(Scheme 1a).[7] Tricyclic cyclohexadienes have great
potential as versatile platforms for the synthesis of
The catalytic enantioselective construction of quater- diverse analogues of the aforementioned natural products
nary stereocenters has been an important topic in using diastereoselective transformations based on the
organic synthesis.[1] In particular, the enantiocontrol of stereochemistry of the C9 stereocenter. In fact, we
those at the bridgehead carbon has been a formidable demonstrated the diastereoselective transformations of
challenge in the synthesis of biologically active natural the cyclohexadiene platform toward the construction of
products.[2] We have been involved in the development diverse scaffolds bearing oxygen-containing functional
of the efficient method of the construction of a 5-6-5 groups. Very recently, we also achieved the introduction
tricyclic lactone framework bearing quaternary bridge- of a methyl group at the C5 position in a highly
head carbons since this motif is found in complex diastereoselective manner, leading to the construction of
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been reported to date.[11] Herein, we report a Rh-
catalyzed asymmetric [2+2+2] cycloaddition of ene-
yne-yne enediynes to prepare enantio-enriched tricyclic
cyclohexadienes bearing a quaternary bridgehead car-
bon (Scheme 1c). In this reaction, the Rh-Phanephos
complex can facilitate the reaction of enediynes
bearing an unsubstituted propiolate terminus, while the
Rh-BINAP complex is an efficient catalyst for the
reaction of enediynes possessing a substituted propio-
late terminus. Interestingly, several control experiments
suggest that the Rh-Phanephos complex-catalyzed
reaction exclusively proceeds via a rhodacyclopenta-
diene intermediate, unlike the Rh-BINAP complex-
catalyzed reaction that can proceed via a rhodacyclo-
pentadiene intermediate as well as a rhodacyclopentene
intermediate in a substrate-dependent manner.[12]
Figure 1. Representative natural products containing a 5-6-5
tricyclic lactone framework with quaternary bridgehead car-
bons.
We initiated our study using the reaction of 1a (R=
H) bearing an unsubstituted propiolate terminus
because it can lead to the straightforward synthesis of
neurotrophic natural product analogs bearing a hydro-
gen atom at the C7 position. However, the reaction of
1a catalyzed by a cationic Rh(I)-(S)-BINAP complex,
which is one of the most widely used catalysts for the
asymmetric [2+2+2] cycloaddition reactions of
alkynes and alkenes,[13] gave a complex mixture of
products and the yield of the desired lactone (2a) was
very low, albeit with high enantioselectivity
(Scheme 2). On the other hand, the introduction of a
methyl group at the propiolate terminus (3a) afforded
lactone 4a in 85% yield with high enantioselectivity.
These results suggest that the propiolate moiety in 1a
interrupts the desired cyclization under the reaction
conditions when using the Rh-BINAP catalyst, which
may be attributed to the high reactivity of the
unsubstituted propiolate moiety.[14]
To address this issue, we examined the effects of
various chiral phosphine ligands (Table 1). Biaryl
bisphosphine ligands such as (S)-H8-BINAP (L2) and
(S)-Segphos (L3) gave similar results to those obtained
when using (S)-BINAP (L1) (entries 1–3). In sharp
contrast, the use of (R,R)-DIOP (L4) and (S,S)-Me–
Scheme 1. Synthetic strategy for functionalized tricyclic lac-
tones.
a tricyclic lactone scaffold with two quaternary bridge- DuPhos (L5) afforded tricyclic lactone 2a in 25–28%
head carbons.[8] Therefore, controlling the stereochemis- yields with low enantioselectivities, along with dimeri-
try of the C9 bridgehead stereocenter in the cyclo- zation products 5 and 6 in 31–34% and 26–32% yields,
hexadiene platform is crucial for the enantioselective respectively (entries 4 and 5). Remarkably, good yields
synthesis of various functionalized tricyclic lactones and high enantioselectivities were achieved when using
using this synthetic strategy.
The asymmetric [2+2+2] cycloaddition of ene-
diynes can be facilitated using a chiral phosphine-Rh
complex.[9,10] For example, Shibata and co-workers
reported a Rh-catalyzed asymmetric [2+2+2] cyclo-
addition of yne-ene-yne enediynes to provide enantio-
enriched tricyclic cyclohexadienes. However, the prod-
ucts were limited to tricyclic cyclohexadienes without
a quaternary stereocenter (Scheme 1b).[9b] On the other
hand, a transition metal-catalyzed asymmetric [2+2+
2] cycloaddition of ene-yne-yne enediynes has not
Scheme 2. Rh-catalyzed asymmetric [2+2+2] cycloaddition
of 1a and 3a.
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bulkier anion, BArF, produced the highest enantioselec-
tivity (entry 10). Intriguingly, the cycloaddition of 3a
using L6 generated product 4a in a very low yield,
unlike that observed when using L1. This result
suggests that L6 is an efficient ligand for the cyclo-
addition of enediynes 1 bearing an unsubstituted
propiolate terminus, while L1 is appropriate for the
cycloaddition of enediynes 3 bearing a substituted
propiolate terminus.
Table 1. Optimization of reaction conditions.[a]
The scope of enediynes 1 was then investigated
using a catalytic amount of [Rh(cod)2]BArF and L6.
The results are summarized in Table 2. The reaction of
enediynes bearing phenyl (1b) and 4-bromophenyl
(1c) groups on the alkene moiety produced products
2b and 2c in high yields with high enantioselectivities.
The reaction of enediyne 1d bearing a 4-meth-
oxyphenyl group required a higher catalyst loading and
heat to proceed with product 2d obtained in 62% yield
with 91.5:8.5 er. The introduction of 3-thienyl (1e),
methoxycarbonyl (1f), and benzyloxymethyl (1g)
groups on the alkene moiety produced 2e–g with good
to high enantioselectivities. With respect to the tether
moieties, methylene-tethered enediyne 1h and malo-
nate-tethered enediyne 1i were efficiently transformed
into their corresponding products (2h and 2i) in high
yields with high enantioselectivities. In contrast, the
introduction of tosylamide as a tether of the enyne
moiety (1j) caused a significant decrease in the
enantioselectivity. Lactam 2k was successfully ob-
tained from amide-tethered enediyne 1k in a good
yield with high enantioselectivity. The absolute config-
uration of 2a was determined to be R using X-ray
crystallographic analysis of 7, which was derived from
2a over four steps (Scheme S2).[16] Next, we also
investigated the scope of enediynes 3 using a catalytic
amount of [Rh(cod)2]BF4 and L1. Cyclohexadiene
products bearing aryl groups at the C7 position, such
as phenyl (4b), 4-bromophenyl (4c), and 4-meth-
oxyphenyl (4d), were obtained in 90–94% yields with
Entry
X
L
Time 2a
5
6
Er of 2a[d]
(min) (%)[b] (%)[c] (%)[c] (+):(À )
1
2
3
4
5
6
7
BF4 L1 300
BF4 L2 300
BF4 L3 120
BF4 L4 120
BF4 L5 30
BF4 L6 60
BF4 L7 300
BF4 L6
SbF6 L6 13
BArF L6
21
30
20
28
25
69
6
<1
<1
<1
34
31
4
<3
ND
ND
ND
<1
<1
<1
26
32
12
<8
2
97.5:2.5
96:4
94.5:5.5
36.5:63.5
44:56
3.5:96.5
8:92
3.5:96.5
4.5:95.5
2:98
8[e]
9[e]
10[e]
8
92
76
85
6
2
8
[a] Pre-activation of the rhodium catalyst was performed under
H2 atmosphere before addition of 1a to the reaction mixture.
[b] Isolated yield.
[c] NMR yield.
[d] Er values were determined by HPLC analysis.
[e] 1a was added drop-wise over 3 min.
(R)-Phanephos (L6),[15] although 5 and 6 were obtained high enantioselectivities. Enediynes bearing tert-
in 4% and 12% yields, respectively (entry 6). In terms butyldimethylsilyl ether (3e), methoxymethyl ether
of the absolute configuration, the (À )-isomer of 2a (3f), and 4-bromobenzoate (3g) moieties were toler-
was formed as the major isomer during the reaction ated under the reaction conditions and their corre-
using L6, although the (+)-isomer was predominant sponding cyclohexadienes (4e–g) were obtained in
when using L1. (R,R)-Me-Ferrocelane (L7) was also high yields with good to high enantioselectivities. The
investigated in the reaction. However, it resulted in a major enantiomer of 4g was determined to be the (S)-
low conversion and 2a was obtained in a low yield isomer based on X-ray crystallographic analysis.[16]
(entry 7). From these results, it was elucidated that L6 Cyclopentane-fused tetracyclic cyclohexadiene 4h was
was the most effective among the ligands screened in obtained in 63% yield with good enantioselectivity.
this reaction. Notably, the slow addition of 1a over The reaction of enediynes possessing benzyloxymethyl
3 min improved the yield of 2a (92% yield), which (3i) and phenyl (3j) groups at the alkene moiety
can be attributed to the reduction in the formation of required higher catalyst loading and prolonged reaction
dimerization products 5 and 6 due to the low times because of their relatively low reactivity,
concentration of 1a present in the reaction mixture providing desired products 4i and 4j in moderate
(entry 8). Finally, we investigated the effect of the yields. Tosylamide was applicable as a tether in the
counter anion. Although replacing BF4 with SbF6 enyne moiety, affording product 4k in 94% yield with
slightly reduced the enantioselectivity (entry 9), a good enantioselectivity. However, the use of malonate-
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Table 2. Substrate scope.[a]
[a] Pre-activation of the rhodium catalyst was performed under H2 atmosphere before addition of enediynes to the reaction mixture.
Er values were determined by HPLC analysis.
[b] Enediyne 1 was slowly added over 20 min.
[c] 5 mol% of the catalyst was used.
[d]
°
The reaction was performed at 50 C.
[e] Enediyne 1 was slowly added over 3 min.
tethered enediyne 3l resulted in product 4l with a RhÀ Csp2 bond generates intermediate V, which is the
decreased enantioselectivity. The introduction of an enantio-determining step in this pathway. Finally,
amide as a tether in the diyne moiety (3m) reduced the cyclohexadiene products were obtained through reduc-
reactivity and enantioselectivity.
tive elimination. In path B, the ene-yne oxidative
There are two possible pathways for the Rh- coupling initially occurs to form rhodacyclopentene
catalyzed enantioselective cycloaddition of enediynes, intermediate IV via complex III, which is the enantio-
which occurs via a rhodacyclopentadiene or rhodacy- determining step. Subsequently, alkyne insertion into
clopentene intermediate. A plausible reaction mecha- the RhÀ Csp2 bond of intermediate IV generates
nism is illustrated in Scheme 3. In path A, complex I is intermediate V. Finally, reductive elimination produces
initially formed via coordination of the Rh catalyst to the tricyclic product and the Rh catalyst is regenerated.
the diyne moiety in the enediyne, followed by the yne- The substrate scope of the cycloaddition of enediynes
yne oxidative coupling to generate rhodacyclopenta- was sometimes limited because of the difference in the
diene intermediate II. Alkene insertion into the enantio-determining step in paths A and B. The groups
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molecular or intermolecular cycloadditions of two
alkynes and one alkene because Rh-biaryl bisphos-
phine complexes can proceed via either a rhodacyclo-
pentadiene intermediate or a rhodacyclopentene inter-
mediate in a substrate-dependent manner.[9b,13e,f] In fact,
several control experiments using ene-yne-yne ene-
diynes indicate that the Rh-L1 complex can facilitate
the yne-yne coupling as well as the ene-yne coupling
in a substrate-dependent manner (vide infra). With
respect to the dimerization reaction, 5 and 6 can be
obtained from intermediate II upon reaction with
another substrate molecule. Considering that 5 and 6
were obtained when using non-biaryl bisphosphine
ligands, such as L4–L6 (Table 1, entries 4–6), these
ligands would contribute predominantly to path A.
To gain insight into the reaction mechanism of the
cycloaddition of enediynes, several control experiments
Scheme 3. Plausible reaction mechanism.
of Shibata and Tanaka reported that enantioselectivity were performed (Scheme 4). The cycloaddition of 1a in
is highly dependent on the substrate used in intra- the presence of an excess amount of methyl propargyl
Scheme 4. Control experiments. [a] NMR yields are shown. [b] Isolated yield. [c] 10 mol% of the catalyst was used.
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ether afforded product 2a in 4% yield along with to the formation of the (À )-isomers of 18 and 19. These
phthalide 8 (87% yield), which was derived from results indicate that the reaction using the Rh-L6 complex
intermediate II and methyl propargyl ether exclusively proceeds via intermediate II, unlike when
(Scheme 4a).[17] Remarkably, bicyclic ether products, using the Rh-L1 complex.
which can be obtained from intermediate IV and methyl
To evaluate the steric environment of the catalytic
propargyl ether, were not detected. In contrast, the same pockets of the Rh-L1 and Rh-L6 complexes, we
reaction using a catalytic amount of [Rh(cod)2]BF4 and analyzed topographic steric maps based on the density
L1 produced 8 in 11% yield along with 2a (11% yield). functional theory (DFT)-optimized structures of their
1
Notably, H NMR analysis of the crude product mixture ethylene complexes. The maps show the elevation from
showed that two major signals corresponding to the the metal center with a coloring scheme from blue to red,
vinylic protons, which were derived from bicyclic ether similar to classical physical maps used for geographical
9, are observed at δ 6.0 and 5.7 ppm (Figure S3). features, which indicate the amount of space occupied by
However, identification of the other signals was difficult the ligands.[18] These maps suggest that the catalytic
because of the complexity of the signals, which can be pocket of the Rh-L6 complex is sterically more hindered
ascribed to several regioisomers possessing benzoyl than that of the Rh-L1 complex (buried %VBur was
moieties formed via alkyne trimerization of the propiolate 51.5% for L1 and 54.7% for L6; Figure 2). Considering
moiety with two methyl propargyl ether molecules. the steric hindrance and conformational rigidity of L6,
Therefore, hydrolysis of the crude product mixture was the reactivity of the Rh-L6 complex can be easily
performed to remove the benzoyl group, which gave the affected by the bulkiness of the substrates, leading to
corresponding alcohol (9’) in 58% yield. This result selective recognition of a diyne moiety, including an
indicates that the reaction using the Rh-L1 complex tends unsubstituted propiolate terminus. On the other hand, the
to proceed via path B, even though the unsubstituted Rh-L1 complex has a relatively large cavity and is
propiolate moiety in 1a has relatively high reactivity. conformationally more flexible when compared to the
However, it cannot be ruled out that the generation of 9
results from the cycloaddition of the enyne moiety and
methyl propargyl ether after the formation of the benzoyl
moiety. The cycloaddition of 3a was then carried out in
the same manner as used for 1a (Scheme 4b). Phthalide
10a was obtained as the major product when using the
Rh-L6 complex, while bicyclic ether 11a was obtained
in 38% yield when using the Rh-L1 complex. Notably,
phthalide 10j was obtained from 3j as the major product
when using the Rh-L1 complex, which can be assumed
that the bulkiness of the phenyl group at the alkene
moiety suppressed the ene-yne coupling to allow the yne-
yne coupling. Furthermore, we performed the cyclo-
addition of enediynes 12–15 leading to 5-6-6 or 6-6-5
tricyclic lactones 16–19 (Scheme 4c). Regarding the
cycloaddition of enediynes 12 and 13, which tends to
proceed via the oxidative cyclization of the 1,6-enyne
moiety rather than that of the 1,7-diyne moiety, the
reaction using the Rh-L6 complex did not proceed, while
16 and 17 were obtained in 66% and 56% yields,
respectively, when using the Rh-L1 complex. In contrast,
the reaction of enediynes 14 and 15 proceeded in both
methods. The reactions using the Rh-L6 complex
afforded 18 and 19 in 53% and 43% yields, respectively.
When the Rh-L1 complex was applied, 18 and 19 were
obtained in 33% and 57% yields, respectively. Remark-
ably, in terms of the enantioselectivities of 18 and 19, the
same configuration of their enantiomers was observed in
both cases when using L1 and L6, unlike that observed
when using 1a as the substrate (Table 1, entry 1 vs. 10).
This was attributed to the yne-yne coupling of 14 and 15
Figure 2. Topographic steric maps of Rh-L1-ethylene and Rh-
L6-ethylene complexes based on the DFT-optimized structures
(ethylene ligands are omitted).
being more favorable over the ene-yne coupling even
when using L1. Therefore, in these cases, the asymmetric
induction via path A becomes predominant, which leads
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10 min under Ar atmosphere. The reaction tube was evacuated and
refilled with H2 using a balloon, which was repeated 3 times. After
Rh-L6 complex, which would allow it to react with an
enyne moiety as well as a diyne moiety.
°
stirring at 30 C for 1 h under H2 atmosphere, the reaction tube
Finally, we demonstrated the diastereoselective syn-
thesis of 2l, which can be transformed into tricyclic
lactone 20 over several steps (Scheme 5).[8] The [2+2
+2] cycloaddition of (S)-1l using [Rh(cod)2]BArF and
(R)-Phanephos provided (4S,5aS)-2l with good diaster-
eoselectivity (86:14 dr), although the Ru-catalyzed
cycloaddition of (S)-1l resulted in very low diaster-
eoselectivity (45:55 dr). On the other hand, the use of
(S)-Phanephos instead of (R)-Phanephos afforded
(4S,5aR)-2l in 76% yield with 11:89 dr, indicating that
the diastereoselectivity of this reaction was controlled
by the catalyst rather than the substrate.
was evacuated and refilled with Ar using a balloon, which was
repeated 3 times. To the resulting mixture was added a solution of
enediyne 1a (61 mg, 0.30 mmol) in dry degassed CH2Cl2
(2.0 mL) dropwise over 3 min by using a syringe pump. The
°
solution was stirred at 30 C for 5 min. The resulting solution was
concentrated and purified by column chromatography on silica gel
(hexane/EtOAc=3:1) to give 2a (49 mg, 85% yield, 98:2 er) as a
white solid.
Acknowledgements
This research was partially supported by the Platform Project
for Supporting Drug Discovery and Life Science Research
(Basis for Supporting Innovative Drug Discovery and Life
Science Research (BINDS) from AMED under Grant Number
JP21am0101099) and JSPS KAKENHI (Grant Number
JP16KT0051).
In summary, we developed a Rh-catalyzed asymmet-
ric [2+2+2] cycloaddition of ene-yne-yne enediynes to
prepare enantio-enriched tricyclic cyclohexadienes bear-
ing a quaternary bridgehead carbon. We found that the
Rh-Phanephos complex is an appropriate catalyst for the
reaction of enediynes bearing an unsubstituted propiolate
terminus, while the Rh-BINAP complex is suitable for
the cycloaddition of enediynes possessing a substituted
propiolate terminus. Several control experiments revealed
that the Rh-Phanephos catalyst has unique properties that
differ from Rh-biaryl bisphosphine catalysts in the [2+2
+2] cycloaddition of enediynes. Unlike when using the
Rh-BINAP complex that can form a rhodacyclopenta-
diene intermediate as well as a rhodacyclopentene
intermediate in a substrate-dependent manner, the Rh-
Phanephos complex-catalyzed reaction exclusively pro-
ceeds via a rhodacyclopentadiene intermediate, which
may be ascribed to the relatively narrow cavity of the
Rh-Phanephos complex compared to that of the Rh-
BINAP complex. We believe that these findings will lead
to development of related asymmetric cycloisomerization
reactions based on the selective recognition of multiple
bonds of unsaturated substrates, such as 1,6-diynes
bearing an unsubstituted propiolate terminus in this case.
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Med. 2020, 74, 648–671.
Experimental Section
Representative procedure for the [2+2+2] cycloaddition of
enediyne 1a: (R)-Phanephos (L6, 1.7 mg, 0.0030 mmol) and
[Rh(cod)2]BArF (3.5 mg, 0.0030 mmol) were dissolved in dry
°
degassed CH2Cl2 (1.0 mL) and the mixture was stirred at 30 C for
Scheme 5. Diastereoselective synthesis of 2l via the [2+2+2]
cycloaddition of (S)-1l with the Rh-Phanephos catalysis.
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Enantioselective Construction of 5-6-5 Tricyclic Lactone
Framework Bearing a Quaternary Bridgehead Carbon via Rh-
Catalyzed Asymmetric [2+2+2] Cycloaddition of
Enediynes
Adv. Synth. Catal. 2021, 363, 1–9
T. Yasui*, Y. Nakazato, K. Kurisaki, Y. Yamamoto*