Diastereoselective Rhodium Catalyzed [4 + 2] Cycloisomerization of Allenes

Article abstract of DOI:10.1021/acs.orglett.1c00554

A diastereoselective [4 + 2] cycloisomerization of asymmetric allenyl dienes is reported. The asymmetric dienyl allenes are synthesized using the method reported by Ma. These substrates readily undergo diastereoselective intramolecular rhodium catalyzed [4 + 2] cycloisomerization analogous to thermal intramolecular Diels-Alder reactions. Overall, 29 examples are presented with tethers possessing nitrogen, oxygen, and carbon. Diastereoselectivities range from 99:1 to 90:10 in most examples.

Full text of DOI:10.1021/acs.orglett.1c00554

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Letter
Diastereoselective Rhodium Catalyzed [4 + 2] Cycloisomerization of
Allenes
Jun Li and Scott R. Gilbertson*
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ABSTRACT: A diastereoselective [4 + 2] cycloisomerization of
asymmetric allenyl dienes is reported. The asymmetric dienyl allenes
are synthesized using the method reported by Ma. These substrates
readily undergo diastereoselective intramolecular rhodium catalyzed [4
+ 2] cycloisomerization analogous to thermal intramolecular Diels−
Alder reactions. Overall, 29 examples are presented with tethers
possessing nitrogen, oxygen, and carbon. Diastereoselectivities range
from 99:1 to 90:10 in most examples.
Scheme 1. Synthesis of Allenyl Diene Substrates
e have had an ongoing program developing the use of
transition metals, such as rhodium, in the catalysis of
W
cycloisomerization reactions. In particular [4 + 2] and [4 + 2 +
2] products have been studied.1−5 To date, there has been
minimal work in the cyclization of allenes with dienes in an
intramolecular fashion and even less with chiral substrates.6−8
Wender reported nickel and rhodium versions9 of this reaction
with achiral starting material, while Trost reported two
moderate rhodium examples.10 Most recently Ma has reported
select examples using chiral allenyl dienes.11,12 Using gold as
the catalyst, Toste has published select examples of
intermolecular allene diene [4 + 2] cycloisomerizations on
achiral allenes.13 To our knowledge there are no large studies
of the diastereoselective [4 + 2] cycloisomerizations of chiral
allenes with dienes. Given that there are now efficient routes to
chiral allenes, this should be a useful approach for the synthesis
of chiral bicyclic structures.14−17 A contrast from previous
work with the gold system of Toste is that their system
provides products with a trans ring juncture, while the rhodium
systems provide cis fused products.
The synthesis of the necessary starting allene containing
dienes is performed by the prolinol controlled copper catalyzed
asymmetric synthesis of the allenes from an alkyne and an
aldehyde.17,18 This provides optically active allenes in excellent
selectivity (Scheme 1 cpds 1 to 3). The allenyl sulfonamides
then undergo a Mitsunobu substitution with a dienyl alcohol
(6) to provide the substrates with a sulfonamide tether (7).
The substrates with a diester linker are accessed by reaction
between a 1,3-diesterdiene (8) with a methanesulfonate ester
allene. It is also possible to convert dienynes into the necessary
allenes directly with this reaction (Scheme 1 cpds 10 to 12).
A probe for the best rhodium system to catalyze this reaction
was carried out using substrate 13 (Table 1). The reaction
took place with rhodium cyclooctadiene dimer but in low yield
and with no diastereoselectivity. Reaction with the chiral
phosphine-phosphineoxide catalyst system (BozPHOS) re-
sulted in products that were matched and mismatched in terms
of the diastereoselectivity and the chiral induction provided by
the catalyst (entries 3 and 4). (S,S)BozPHOS provided the
product in a diastereomeric ratio of nearly 1 to 1, while
(R,R)BozPHOS gives the [4 + 2] product in a ratio of 85:15.
The system starting with rhodium cyclooctadiene dimer and
adding the monoxide of BINAP [BINAP(O)] provided the
Received: February 15, 2021
Published: March 30, 2021
https://doi.org/10.1021/acs.orglett.1c00554
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2911−2914
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Table 1. Catalyst Screening
Scheme 2. Substrate Scope
b
time yield
c
complex
ligand
(h)
(%)
er
1
2
[Rh(cod)Cl]2 (2.5 mol %)
24
12
7
37
50:50
54:46
[Rh(nbd){(S,S)-Me-
BozPHOS}9]SbF6 (5
mol %)
3
4
5
[Rh(nbd){(S,S)-Me-
BozPHOS}]SbF6 (5
mol %)
[Rh(nbd){(R,R)-Me-
BozPHOS}]SbF6 (5
mol %)
24
24
24
54
57
43
54:46
85:15
51:49
[Rh(cod)Cl]2 (2.5 mol %) BINAP(O)
(5%)
6
7
8
[Rh(cod)Cl]2 (2.5 mol %) BINAP (5%)
[Rh(cod)Cl]2 (2.5 mol %) dppe (5%)
[Rh(cod)Cl]2 (2.5 mol %) dppeO (5%)
24
24
24
18
57
83
95:5
92:8
97:3
a
Reaction conditions: 12 (0.1 mmol), catalyst (2.5 mol %), ligand (5
b
c
mol %), toluene (1.0 mL). Isolated yield. As determined by chiral
HPLC. The er value is the ratio of enantiomers obtained from a start
material with an er of 97:3. Within the limits of detection only one
diastereomer was observed.
product in moderate yield and nearly no selectivity. The same
system using BINAP proceeded to give the product in fair yield
and with better selectivity than BINAP(O). Testing dppe and
dppeO illustrated that the best ligand system appears to be
dppeO for substrate 12. The reaction proceeded in shorter
time, with the best selectivity and yield (6 h, 82% and 97:3 er).
Other phosphine-phosphine oxide systems with different
tether lengths between the phosphorus atoms were tested, as
were different reaction temperatures (Table 2). While dppeO
Table 2. Phosphine-Phosphineoxide Ligands Screen
b
c
entry
t
ligand
temp (°C)
yield (%)
er
1
2
3
4
5
6
12
6
6
6
6
dppeO
dppeO
dppmO
dpppO
dppeO
dppeO
80
80
80
80
55
rt
82
83
88
67
30
trace
97:3
97:3
97:3
96:4
97:3
6
a
b
Reaction conditions: 12 (0.1 mmol), toluene (1.0 mL). Isolated
c
yield. As determined by chiral HPLC.
is generally the best ligand, both dppeO and dppmO appear to
be viable, with our best temperature for the reaction being 80
°C, with 55 °C providing lower yield even with extended
reaction time. There was only a trace of product obtained at
room temperature. The longer tethered ligand dpppO provides
the product in lower yield but still good selectivity.
groups on the chiral allene are well tolerated with isopropyl
(12), ethyl (16), isobutyl (18), and phenethyl (22) providing
nearly complete control. Primary carbons attached to the
allene, such as methyl (14) and n-butyl (20), proceeded with
slightly lower selectivity. Substrates with cyclic rings attached
to the allene (26, 28, 32, 34) proceeded with good to excellent
Using the dppeO conditions, a number of different allenyl
diene structures were investigated (Scheme 2). In general alkyl
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er and good yield, with the exception of the allene with
cyclopropyl attached (30), where it was not possible to isolate
the product. Versions with groups other than methyl on the
diene (36, 38, 40) provided the products in good yield and
with diastereoselectivity comparable to the simpler versions.
Select examples where a different tether, a diester or ether,
was used to connect the allene and diene proceeded in good to
excellent yield (Scheme 3). These versions with secondary
purity of the substrate over time illustrated that it isomerizes
under the reaction conditions.
The formation and structure of the [Rh(COD)dppeO]SbF6
complex was validated by X-ray structure determination
(Figure 1). In the structure both the phosphine and the
Scheme 3. Reaction with Other Tethers
Figure 1. X-ray of [Rh[COD]dppeO]SbF6.
oxygen of the phosphine oxide are coordinated to rhodium
along with the cyclooctadiene. The reaction can be run under a
number of different conditions. Either the discrete [Rh-
(COD)dppeO]SbF6 complex can be used in the reaction or
2.5 mol %[Rh(cod)Cl]2 can be mixed with 5.0 mol % dppeO
to form the catalyst in situ. Both approaches provide systems
that give essentially the same result.
With this in mind, lower reaction temperatures were
investigated. Optimal conditions were found to be 5 mol %
[Rh(COD)dppeO]SbF6 at 40 °C, CH2Cl2 solvent in a sealed
tube. These conditions were later applied in the reaction of
other aromatic substrates (Table 3).
The stereochemistry of products were verified by X-ray
crystallography (Figure 2). Single crystal X-ray analysis of
carbons attached to the allene provide yields and selectivities
comparable to the examples in Scheme 2. Typically examples
with an aromatic group attached to the allene provided
products with lower selectivity and yield (Table 3). It appears
that over time substrates of this type isomerize as the reaction
proceeds. Examination of the reaction in terms of enantio-
Table 3. Aromatic Allene Substrates
Figure 2. X-ray of product 29.
product 29 illustrates that the stereochemistry at the ring
juncture between the 5- and 6-membered rings is cis. This is in
contrast to the trans ring fusions observed with gold catalyzed
reactions reported by Toste.13 Additionally the stereo-
chemistry of the exocyclic double bond was found to be as
drawn with the group on the allene positioned toward the five
member ring. The NMR spectra for this product correlated
with the other products reported here.
As of now the reaction does not proceed with 4 atom tethers
that would form a [4.4.0] bicyclic system. Other tether systems
are being examined, and chemistry to selectively carry the
products forward to other products is being developed. In
summary we have demonstrated that the chirality of the allene
in this type of substrate can be used to control the selectivity of
the of the subsequent cycloisomerizations. The unique
structures obtained in this reaction have applications in small
molecule library screening.
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(8) Trillo, B.; López, F.; Gulías, M.; Castedo, L.; Mascarenas, J. L.
̃
ASSOCIATED CONTENT
■
Platinum-catalyzed intramolecular [4C+3C] cycloaddition between
dienes and allenes. Angew. Chem., Int. Ed. 2008, 47 (5), 951−954.
(9) Wender, P. A.; Jenkins, T. E.; Suzuki, S. Transition Metal-
Catalyzed Intramolecular [4+ 2] Diene-Allene Cycloadditions: A
Convenient Synthesis of Angularly Substituted Ring Systems with
Provision for Catalyst-Controlled Chem- and Stereocomplementarity.
J. Am. Chem. Soc. 1995, 117 (6), 1843−1844.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00554.
Complete experimental procedures including general
considerations and characterization data and NMR
spectra (PDF)
(10) Trost, B. M.; Fandrick, D. R.; Dinh, D. C. Dynamic kinetic
asymmetric allylic alkylations of allenes. J. Am. Chem. Soc. 2005, 127
(41), 14186−14187.
(11) Han, Y.; Ma, S. Rhodium-catalyzed highly diastereoselective
intramolecular [4 + 2] cycloaddition of 1,3-disubstituted allene-1,3-
dienes. Org. Chem. Front. 2018, 5 (18), 2680−2684.
(12) Han, Y.; Qin, A.; Ma, S. One Stone for Three Birds-Rhodium-
Catalyzed Highly Diastereoselective Intramolecular [4 + 2] Cyclo-
addition of Optically Active Allene-1,3-dienes. Chin. J. Chem. 2019,
37, 486−496.
(13) González, A. Z.; Toste, F. D. Gold(I)-catalyzed enantioselective
[4 + 2]-cycloaddition of allene-dienes. Org. Lett. 2010, 12 (1), 200−
203.
Accession Codes
CCDC 2062291 and 2062293 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
(14) Ye, J.; Lu, R.; Fan, W.; Ma, S. Studies on ZnBr2-mediated
̈
synthesis of axially chiral aryl-substituted allenes from terminal
alkynes, aromatic aldehydes and (S)-α,α-diphenylprolinol. Tetrahe-
dron 2013, 69 (42), 8959−8963.
(15) Ye, J.; Fan, W.; Ma, S. tert-Butyldimethylsilyl-Directed Highly
Enantioselective Approach to Axially Chiral α-Allenols. Chem. - Eur. J.
2013, 19 (2), 716−720.
Scott R. Gilbertson − Department of Chemistry, University of
Houston, Houston, Texas 77204, United States;
orcid.org/0000-0003-3665-5693; Email: srgilbe2@
central.uh.edu
Author
(16) Periasamy, M.; Sanjeevakumar, N.; Dalai, M.; Gurubrahamam,
R.; Reddy, P. O. Highly Enantioselective Synthesis of Chiral Allenes
by Sequential Creation of Stereogenic Center and Chirality Transfer
in a Single Pot Operation. Org. Lett. 2012, 14 (12), 2932−2935.
(17) Ye, J.; Li, S.; Chen, B.; Fan, W.; Kuang, J.; Liu, J.; Liu, Y.; Miao,
B.; Wan, B.; Wang, Y.; Xie, X.; Yu, Q.; Yuan, W.; Ma, S. Catalytic
Asymmetric Synthesis of Optically Active Allenes from Terminal
Alkynes. Org. Lett. 2012, 14 (5), 1346−1349.
(18) Huang, X.; Cao, T.; Han, Y.; Jiang, X.; Lin, W.; Zhang, J.; Ma,
S. General CuBr2-catalyzed highly enantioselective approach for
optically active allenols from terminal alkynols. Chem. Commun. 2015,
51, 6956−6959.
Jun Li − Department of Chemistry, University of Houston,
Houston, Texas 77204, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00554
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the M.D. Anderson Foundation and
the University of Houston for supporting this work.
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