Enantioselective rhodium-catalyzed [4+2+2] cycloaddition of dienyl isocyanates for the synthesis of bicyclic azocine rings

Article abstract of DOI:10.1021/ja906641d

(Chemical Equation Presented) A highly enantioselective rhodium-catalyzed [4+2+2] cycloaddition of terminal alkynes and dienyl isocyanates has been developed. The cycloaddition provides a rapid entry to highly functionalized and enantioenriched bicyclic a

Full text of DOI:10.1021/ja906641d

Published on Web 08/27/2009
Enantioselective Rhodium-Catalyzed [4+2+2] Cycloaddition of Dienyl
Isocyanates for the Synthesis of Bicyclic Azocine Rings
Robert T. Yu, Rebecca Keller Friedman, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received August 5, 2009; E-mail: rovis@lamar.colostate.edu
Table 1. Development of the Rh-Catalyzed [4+2+2] Cycloaddition
Transition metal catalyzed cycloadditions have proven to be
among the most attractive methods to construct medium-sized ring
systems.1 Although [4+4],2 [6+2],3 [5+2+1],4 and [4+2+2]5
cycloadditions have been elegantly demonstrated to assemble
various eight-membered carbocycles, formation of eight-membered
nitrogen-containing rings (azocines) has not been explored. In
addition, there are no reported examples of successful enantiose-
lective cycloadditions to construct eight-membered rings.6 We have
recently demonstrated that Rh(I) catalysts are capable of effecting
enantioselective [2+2+2] cycloadditions with the use of alkenyl
heterocumulenes.7 Herein we describe a highly asymmetric rhodium-
catalyzed [4+2+2] cycloaddition of terminal alkynes and dienyl
isocyanates to afford bicyclo[6.3.0] azocine derivatives (eq 1).
E/Z ratio
of 2
yield (%)
of 3c
ee (%)
of 3d
entrya
L*
3:4b
2:3b
1
2
3
4
1.4:1
g19:1
g19:1
g19:1
L1
L1
L2
L3
4:1
1:2.5
1:2.5
1:10
1:10
40e
47
74
67
n.d.
99
99
g19:1
g19:1
g19:1
99
a Conditions: 1 (1.5 equiv), 2 (0.18 mmol), Rh catalyst, L in PhMe
(0.02 M) at 110 °C. b Ratio determined by 1H NMR of the unpurified
reaction mixture. c Isolated yield. d Determined by HPLC using a chiral
stationary phase. e Combined yield of 3 and 4.
Chart 1. Enantioselective Synthesis of [6.3.0] Bicyclic Azocines
Bicyclo[6.3.0] azocine ring systems are unique architectures
found in several biologically active compounds. Wang and co-
workers have recently designed a potent XIAP antagonist, a small
molecule consisting of the bicyclic azocine as the basic template.8
A number of manzamine alkaloids such as nakadomarin A and
manzamine A, which exhibit potent antimalarial and antituberculosis
activity, are equipped with such ring systems.9 Previous approaches
to bicyclo[6.3.0] heterocycles have been stepwise including a ring-
closing metathesis to afford the eight-membered ring.10
Our initial efforts to effect the [4+2+2] cycloaddition focused
on 1-octyne 1a and the dienyl isocyanate 2 as a mixture of E/Z
isomers (Table 1, entry 1). Treatment of the substrates with
[Rh(C2H4)2Cl]2 modified with phosphoramidite L1 furnishes both
the [4+2+2] cycloadduct 3a and the [2+2+2] cycloadduct 4a in
40% yield as an inseparable 4:1 mixture.11 Further investigation
led to the isomerically pure diene (E)-2 as the optimal substrate to
provide 3a selectively (entry 2).12 Despite a significant amount of
unreacted isocyanate 2, the desired bicyclic azocine 3a is obtained
with an exceptional enantioselectivity (99% ee). Replacing the
pyrrolidinyl group on the phosphoramidite ligand with either the
piperidine (L2) or azepine (L3) dramatically increases reactivity
toward azocine ring formation while maintaining the high level of
enantioselectivity (entries 3-4).13
lectivities (Chart 1). Alkyl alkynes bearing a chloride, a methyl
ester, or an unprotected terminal alkyne (1b-1d) all participate
smoothly to provide the corresponding cycloadducts (3b-3d).
With optimal conditions in hand, a variety of substituted bicyclic
azocines can be synthesized in good yields and superb enantiose-
9
13250 J. AM. CHEM. SOC. 2009, 131, 13250–13251
10.1021/ja906641d CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Proposed Mechanism
dienyl isocyanates. The process provides access to highly func-
tionalized bicyclo[6.3.0] azocine ring systems with exceptional
enantioselectivities. Further studies on the full scope of this new
process are in progress.
Acknowledgment. We thank the NIGMS (GM080442) for
support. We gratefully acknowledge Johnson Matthey for a loan
of Rh salts.
Supporting Information Available: Experimental procedures,
characterization, 1H and 13C NMR spectra are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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Alkynes possessing functionalities such as silyl ether, phthalimide,
phenyl, and Boc-protected indole at the propargylic positions
(1e-1h) are well tolerated to furnish the [4+2+2] cycloadducts
(3e-3h) in good yields and identical enantioselectivities.14
Cycloaddition of isocyanates with substitution at the diene portion
is also feasible. For example, when 2-methyl dienyl isocyanate 5
is reacted under the standard conditions, [4+2+2] cycloadditions
with various alkynes all proceed uneventfully (6a, 6e, 6j).15
Reactions with aryl alkynes, however, proceed only in moderate
yield. With 1-bromo-4-ethynylbenzene (1i), cycloadduct 3i can only
be obtained in 35% isolated yield with the same high enantiose-
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(6) In their full paper, Gilbertson and coworkers reported a single example of
Several aspects of these findings suggest that there may be a
mechanistic divergence from our previously developed reaction.
Prime among these is the invariant enantioselectivity with regard
to alkyne structure as well as the failure to observe any vinylogous
amide adducts in this chemistry.7b To gain insight into the reaction
mechanism, we conducted a competition experiment between dienyl
isocyanates 2 and 5. If oxidative cycloaddition occurs between the
alkyne and isocyanate first (path a in Scheme 1), the ratio of
products 3 and 6 should be 1:1.7h In the event, 3 is formed with
2:1 selectivity over 6.16 We suggest that this is most consistent
with initial oxidative cyclization between the diene and isocyanate
following path b to form V. Coordination and insertion of alkyne
then provides the [4+2+2] adduct. With more reactive nucleophilic
alkynes, path a becomes competitive forming rhodacycle II. Diene
coordination and insertion are slow, presumably for steric reasons,
allowing competitive alkyne insertion to form pyridone. The diene
found in Z-2 is a poor ligand for Rh and thus prefers path a, leading
to increased amounts of both 4 and pyridone.17
41% ee as the highest selectivity observed. See: ref 5i.
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Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370. (c) Yu, R. T.; Rovis, T.
J. Am. Chem. Soc. 2008, 130, 3262. (d) Lee, E. E.; Rovis, T. Org. Lett.
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Chem., Int. Ed. 2009, 48, 2379. (f) Oberg, K. M.; Lee, E. E. Tetrahedron
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131, 10775. (h) Dalton, D. M.; Oberg, K. M.; Yu, R. T.; Lee, E. E.;
Perreault, S.; Oinen, M. E.; Pease, M. L.; Malik, G.; Rovis, T. Submitted.
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A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F.
J. Am. Chem. Soc. 2002, 124, 8584. (c) Nagata, T.; Nakagawa, M.; Nishida,
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2287.
(11) This reaction also forms ∼4% pyridone. Conducting this reaction at 0.06
M in 2 leads to 25% combined yield of 3 and 4 in a 3:1 ratio along with
∼10% pyridone.
The Rh-catalyzed cycloaddition protocol allows access to
synthetically useful bicyclic azocines. Dihydroxylation affords diol
7 in 72% yield for the major diastereomer (7:1 dr, eq 3a).
Alternately, an R,ꢀ-unsaturated aldehyde functionality can be readily
unmasked in two simple steps from 3e, eq 3b.
(12) Further studies on [2+2+2] cycloadditions with various 1,2-disubstituted
alkenyl isocyanates are ongoing.
(13) We observe symmetrical ureas derived from the isocyanate as the only
significant byproduct. No regioisomers have been observed.
(14) Larger scale reactions may be conducted with lower catalyst loading and
slightly higher concentration; with 3 mol % [Rh(C2H4) 2Cl]2 and 6 mol %
L3 at 0.073 M using 1.5 mmol of 2, 3e is formed in 68% yield and 99%
ee.
(15) Substitution at the terminus of the diene leads to only [2+2+2] adduct
under these conditions (E,E-octa-4,6-dienyl isocyanate and 1a afford 4a′
in 46% yield, 46% ee). Bicyclo[6.4.0] systems are not accessible under
these conditions.
(16) At higher catalyst loading (25 mol % [Rh(C2H4)2Cl]2), 3 and 6 are formed
quantitatively in a 4:1 ratio.
(17) At 0.02 M, no pyridone is observed with E-2. At 0.1 M, we see <5%
pyridone (75% yield of 3a). Also see entry 1, Table 1 and ref 11.
In conclusion, we have developed the first enantioselective
rhodium-catalyzed [4+2+2] cycloaddition of terminal alkynes and
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