Asymmetric Synthesis of Protected Cyclohexenylamines and Cyclohexenols by Rhodium-Catalyzed [2+2+2] Cycloaddition

Article abstract of DOI:10.1002/anie.201608952

It has been established that cationic rhodium(I)/axially chiral biaryl bis(phosphine) complexes catalyze the asymmetric [2+2+2] cycloaddition of 1,6-enynes with electron-rich functionalized alkenes, enamides, and vinyl carboxylates, to produce the corresponding protected cyclohexenylamines and cyclohexenols. Interestingly, regioselectivity depends on structures of substrates. The present cycloaddition was successfully applied to the enantioselective total synthesis of (?)-porosadienone by using the amide moiety as a leaving group.

Full text of DOI:10.1002/anie.201608952

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International Edition: DOI: 10.1002/anie.201608952
German Edition: DOI: 10.1002/ange.201608952
Asymmetric Catalysis
Asymmetric Synthesis of Protected Cyclohexenylamines and
Cyclohexenols by Rhodium-Catalyzed [2+2+2] Cycloaddition
Koji Masutomi, Haruki Sugiyama, Hidehiro Uekusa, Yu Shibata, and Ken Tanaka*
Abstract: It has been established that cationic rhodium(I)/
axially chiral biaryl bis(phosphine) complexes catalyze the
asymmetric [2+2+2] cycloaddition of 1,6-enynes with elec-
tron-rich functionalized alkenes, enamides, and vinyl carbox-
ylates, to produce the corresponding protected cyclohexenyl-
amines and cyclohexenols. Interestingly, regioselectivity
depends on structures of substrates. The present cycloaddition
was successfully applied to the enantioselective total synthesis
of (À)-porosadienone by using the amide moiety as a leaving
group.
Chiral cycloalkyl amine and alcohol derivatives are widely
found in the pharmaceutical and perfume industries, and six-
membered ones are particularly important.[1] For the stereo-
selective construction of six-membered carbocycles, the
transition metal catalyzed asymmetric [2+2+2] cycloaddition
of a,w-diynes or enynes with unsaturated compounds is
a useful method.[2] For this transformation, cationic rhodium-
(I)/axially chiral biaryl bis(phosphine) complexes are known
as highly active and selective catalysts.[3] In 2005, the groups of
Evans and Shibata independently reported the rhodium(I)-
catalyzed enantioselective [2+2+2] cycloaddition of 1,6-
enynes with alkynes.[4] Following these pioneering works,
our research group reported the cationic rhodium(I)/H8-
binap complex catalyzed regio-, diastereo-, and enantioselec-
tive [2+2+2] cycloaddition of 1,6-enynes with acrylamides
(Scheme 1a).[5–9] We anticipated that if high reactivity and
selectivity of the reactions using acrylamides arise not from
their electron-deficient nature but high coordination ability,
highly coordinative electron-rich enamides[10] would also be
suitable cycloaddition partners toward 1,6-enynes. Herein, we
disclose the cationic rhodium(I) complex catalyzed regio-,
diastereo-, and enantioselective [2+2+2] cycloaddition of 1,6-
enynes (1) with enamides and vinyl carboxylates (2). This new
strategy is capable of providing bicyclic protected cyclo-
hexenylamines and cyclohexenols with unexpected structure-
dependent regioselectivity (3 vs. 4) as well as an excellent
level of stereocontrol (Scheme 1b).
Scheme 1. Rhodium-catalyzed asymmetric [2+2+2] cycloaddition of
1,6-enynes with alkenes.
We first examined the reaction of the 1,6-enyne 1a and N-
vinyl acetamide (2a) in the presence of a cationic rhodium-
(I)/(R)-H8-binap catalyst (Table 1). Pleasingly, the desired
[2+2+2] cycloaddition proceeded at room temperature to
give the bicyclic protected cyclohexenylamine 3aa with high
Table 1: Optimization of reaction conditions for rhodium-catalyzed
asymmetric [2+2+2] cycloaddition of 1a and 1b with 2a.[a]
Entry 1 (R)
Ligand
Rh
(mol%) [%][b]
Conv. Yield [%][c]
ee [%]
1
2
3
4
1a (Me) (R)-H8-binap 10
1a (Me) (R)-binap 10
1a (Me) (R)-segphos 10
>99 (À)-3aa/92
85 (À)-3aa/52
89 (À)-3aa/71
77 (À)-3aa/71
98 (À)-3aa/81
>99 (À)-3ba/51
>99 (À)-3ba/51
>99 (À)-3ba/63
98
97
98
98
98
99
>99
99
[*] K. Masutomi, Y. Shibata, K. Tanaka
Department of Chemical Science and Engineering
Tokyo Institute of Technology
1a (Me) (R)-H8-binap
1a (Me) (R)-H8-binap
5
5
5
5
5
5[d]
6
O-okayama, Meguro-ku, Tokyo 152-8550 (Japan)
E-mail: ktanaka@apc.titech.ac.jp
Homepage: http://www.apc.titech.ac.jp/~ktanaka/
1b (H)
1b (H)
1b (H)
(R)-H8-binap
(R)-binap
(R)-segphos
7
8
H. Sugiyama, H. Uekusa
Department of Chemistry, Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
[a] [Rh(cod)2]BF4 (0.010 mmol), ligand (0.010 mmol), 1 (0.10–
0.20 mmol), 2a (0.11–0.22 mmol), and CH2Cl2 (1.5 mL) were used.
[b] Determined by 1H NMR spectroscopy. [c] Yield of isolated product.
[d] At 408C. cod=1,5-cyclooctadiene, Ts=4-toluenesulfonyl.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608952.
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yield and ee value (entry 1). Screening of axially chiral biaryl
bis(phosphine) ligands (entries 1–3) revealed that the use of
(R)-H8-binap afforded 3aa with the highest yield and ee value
(entry 1). Unfortunately, decreasing the catalyst loading to
5 mol % resulted in incomplete conversion at room temper-
ature (entry 4). Complete conversion was reached at 408C,
while the yield of 3aa was lower than that of entry 1 (entry 5).
Next, we screened ligands in the reaction of the terminal 1,6-
enyne 1b and 2a (entries 6–8). As 1b showed high reactivity,
complete conversion was reached at low catalyst loading
(5 mol %) and room temperature. When using (R)-H8-binap
and (R)-binap as ligands, 3ba was obtained in moderate yields
as a result of the homo-[2+2+2] dimerization of 1b (entries 6
and 7). Fortunately, the use of (R)-segphos suppressed the
undesired dimerization (entry 8).
only 2a but also the tertiary enamide 2b reacted with 1a to
give the cyclohexene 3ab with high ee value, even though the
yield of 3ab was lower than 3aa. Interestingly, the reaction of
1a and N-vinylphthalimide (2c) furnished the cyclohexene
3ac with high ee value along with diene 5ac. With regard to
the substituent R1 on the 1,6-enynes, not only methyl-
substituted but also the phenyl-substituted 1,6-enyne 1c and
terminal 1,6-enyne 1b reacted with 2a–c to give cyclohexenes
3ca-cc and 3ba in moderate to high yields with high ee values.
The formation of the diene 5cc from 2c as a minor product
was the same as that of diene 5ac. Not only tosylamide- (1a–
c) but also malonate-linked 1,6-enynes (1d–f) reacted with
2a–c to give the cyclohexenes 3da, 3dc, 3eb, and 3 fc in
moderate to good yields with high ee values. With regard to
the substitutent R2 in the 1,6-enynes, the ethyl-substituted 1,6-
enyne 1g was also capable of reacting with 2a-c and N-
methyl-N-vinyl acetamide (2d) to give the cyclohexenes 3ga–
gd in moderate to high yields with high ee values. The relative
and absolute configurations of (À)-3ba were determined by
an X-ray crystallographic analysis.[11]
With the optimized reaction conditions in hand, we tested
the generality of the reaction by using (R)-H8-binap and (R)-
segphos as ligands (Scheme 2). With regard to enamides, not
Next, we examined the reactions of the tosylamide- and
malonate-linked 1,6-enynes 1h and 1i, respectively, possess-
ing the monosubstituted alkene moiety, with 2a and 2b
(Scheme 3). The expected cycloadducts 3 were not observed,
but instead the regioisomers 4 were obtained as major
products.[12] Interestingly, the ee values of 4 were higher
than those of 3. In addition, the vinyl carboxylates 2e-i also
Scheme 3. Rhodium-catalyzed asymmetric [2+2+2] cycloaddition of
1,6-enynes (1), possessing the monosubstituted alkene moiety, with
alkenes 2. [Rh(cod)2]BF4 (0.010–0.020 mmol), (R)-binap (0.010–
0.020 mmol), 1 (0.20 mmol), 2 (0.22–0.60 mmol), and CH2Cl2 (1.5 mL)
were used. The cited yields are of the isolated products. [a] 2e
(1.0 mL) and CH2Cl2 (0.5 mL) were used.
Scheme 2. Rhodium-catalyzed asymmetric [2+2+2] cycloaddition of
1,6-enynes (1), possessing the 1,1-disubstituted alkene moiety, with
alkenes 2. [Rh(cod)2]BF4 (0.010–0.020 mmol), ligand (0.010–
0.020 mmol), 1 (0.20 mmol), 2 (0.22 mmol), and CH2Cl2 (1.5 mL) were
used. The cited yields are of the isolated products.
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reacted with the tosylamide-linked 1,6-enyne 1h to give 4he–
hi with high ee values.[12] Importantly, the compounds 4 were
obtained as sole products without formation of 3, although the
yields of 4 were low to moderate. The malonate-linked 1,6-
enyne 1i also reacted with 2i to give 4ii with high ee value.
Finally, the terminal 1,6-enyne 1j was also capable of reacting
with 2e to give 4je in good yield with high ee value, although
2e was used as a solvent to minimize the rapid homo-[2+2+2]
dimerization of 1j. The reactions of the 1,6-enynes 1a, 1b, and
1e, possessing the 1,1-disubstituted alkene moiety, with 2e
were also examined, but the corresponding addition products
3–5 were not obtained at all. The relative and absolute
configurations of (+)-4hg were determined by an X-ray
crystallographic analysis.[11]
Plausible mechanisms for the formation of 3–5 are shown
in Scheme 4. The 1,6-enyne 1 reacts with rhodium to generate
the rhodacyclopentene A. Regioselective insertion of 2a-d
into A generates the rhodacycle B. Coordination of the amide
carbonyl oxygen atom to rhodium in B might suppress b-
hydride elimination which leads to 5,[13] and thus reductive
elimination proceeds to give 3. As N-vinylphthalimide (2c) is
less coordinative because of conformational rigidity, the b-
hydride elimination products 5 were generated along with 3.
In contrast, the formation of 4 was limited to cases of the 1,6-
enynes 1h-j, possessing the monosubstituted alkene moiety,
as shown in Scheme 3. This limitation might arise from
feasibility of the alkene insertion step. The 1,6-enyne 1 reacts
with 2 and rhodium to generate the rhodacyclopentene C.
Insertion of the pendant alkene moiety of 1 into C generates
the rhodacycle D and subsequent reductive elimination
affords 4. This insertion might be possible only for the
sterically less demanding monosubstituted alkene. In con-
trast, the vinyl carboxylates 2e–i react with 1h–j to give 4
exclusively, but enamides 2a,b react with 1h,i to give not only
4 but also 3. The higher coordination ability of the amide
carbonyl than the ester carbonyl might allow the formation of
the rhodacycle E as well as C, although the formation of 3 via
A may also be included.
Scheme 5. Transformations of chiral bicyclic cyclohexenes 3 and 4.
mCPBA=m-chloroperbenzoic acid.
tives, which are core structures of several active pharmaceut-
ical ingredients (Scheme 5).[14] Epoxidation of 3aa and 3ba
with mCPBA (m-chloroperoxybenzoic acid) afforded 6aa
and 6ba, which possesss four consecutive stereogenic centers,
as single diastereomers. Hydrogenation of 3ba afforded 7ba
with perfect diasteroselectivity, although hydrogenation of
tetrasubstituted alkene 3aa did not proceed. Similarly,
epoxidation and hydrogenation of 4je afforded 8 and 9,
respectively, although a significant amount of diastereomer 8’
was generated.
Another synthetic utility of the present cycloaddition is
shown in the enantioselective total synthesis of (À)-poros-
adienone [(À)-10],[15] in which the amide moiety of 3 is
utilized as a leaving group (Scheme 6). (À)-Porosadienone
and its reductant (porosadienol) were found in natural oils,[15]
and any component in these oils showed cytotoxic activity.[15d]
The total synthesis of (Æ)-porosadienone was achieved in
1995, while the overall yield is only 4% over six steps,[16] and
the asymmetric total synthesis has not been reported to date.
In the first step, the rac-1,6-enyne (Æ)-1k was prepared from
the commercially available b-keto ester 11 by a one-pot
propargylation and allylation. Next, the [2+2+2] cycloaddi-
Transformations of 3 and 4 with retention of the amide
and ester moieties enable the asymmetric synthesis of
heteroatom-substituted chiral octahydro-isoindole deriva-
Scheme 6. Enantioselective total synthesis of (À)-porosadienone
[(À)-10]. THF=tetrahydrofuran.
Scheme 4. Plausible mechanisms for formation of 3–5.
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In conclusion, we have established that cationic rhodium-
(I)/axially chiral biaryl bis(phosphine) complexes catalyze the
asymmetric [2+2+2] cycloaddition of 1,6-enynes with elec-
tron-rich functionalized alkenes, enamides, and vinyl carbox-
ylates, to produce the corresponding protected cyclohexenyl-
amines and cyclohexenols. Interestingly, regioselectivity
depends on structures of substrates. The present cycloaddition
was successfully applied to the enantioselective total synthesis
of (À)-porosadienone by using the amide moiety as a leaving
group.
Acknowledgements
This work was supported by ACT-C from JST and MEXT
KAKENHI Grant Number JP 25105714. K.M. thanks JSPS
research fellowship for young scientists. We thank Takasago
for the gift of segphos and H8-binap, and Umicore for
generous support in supplying the rhodium complex.
[8] For the nickel-catalyzed [2+2+2] cycloaddition of 1,6-enonynes
with enones, see: J. Seo, H. M. P. Chui, M. J. Heeg, J. Mont-
gomery, J. Am. Chem. Soc. 1999, 121, 476.
[9] For the nickel-catalyzed [2+2+2] cycloaddition of two enones
with alkynes, see: a) S. Ogoshi, A. Nishimura, M. Ohashi, Org.
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Mori, Y. Hoshimoto, M. Ohashi, S. Ogoshi, Org. Lett. 2015, 17,
6018.
Keywords: asymmetric catalysis · cycloadditions · enamides ·
reaction mechanisms · rhodium
[10] K. Tanaka, M. Takahashi, H. Imase, T. Osaka, K. Noguchi, M.
Hirano, Tetrahedron 2008, 64, 6289; See also Ref. [6a].
[11] CCDC 1503872 [(À)-3ba] and CCDC 1503873 [(+)-4hg] con-
tain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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Received: September 13, 2016
Published online: && &&, &&&&
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Communications
Asymmetric Catalysis
K. Masutomi, H. Sugiyama, H. Uekusa,
Y. Shibata, K. Tanaka*
&&&& — &&&&
Asymmetric Synthesis of Protected
Cyclohexenylamines and Cyclohexenols
by Rhodium-Catalyzed [2+2+2]
Cycloaddition
2+2+2=6: It has been established that
cationic rhodium(I)/axially chiral biaryl
bis(phosphine) complexes catalyze the
asymmetric [2+2+2] cycloaddition of 1,6-
enynes with electron-rich functionalized
alkenes, enamides, and vinyl carboxy-
lates, to produce the corresponding pro-
tected cyclohexenylamines and cyclohex-
enols. Regioselectivity depends on struc-
tures of substrates. The present cyclo-
addition was used in the enantioselective
total synthesis of (À)-porosadienone.
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