An approach for rapid increase in molecular complexity: Atom economic routes to fused polycyclic ring systems

Article abstract of DOI:10.1021/ol5009872

A protocol for the asymmetric trimethylenemethane (TMM) [3 + 2] cycloaddition reaction of alkynyl-substituted TMM donors and unsaturated N-acyl pyrroles employing a chiral bisdiamidophosphite ligand has been developed. This process generates alkynyl-substituted cyclopentanes in high yields and diastereo- and enantioselectivities. These chiral precursors are employed for the atom economic assembly of fused polycyclic hydrocarbons with hydroindene, hydroazulene, and hydrocyclopentanaphthalene scaffolds by consecutive cycloaddition reactions.

Full text of DOI:10.1021/ol5009872

Letter
pubs.acs.org/OrgLett
An Approach for Rapid Increase in Molecular Complexity: Atom
Economic Routes to Fused Polycyclic Ring Systems
Barry M. Trost* and Veronika Ehmke
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S
* Supporting Information
ABSTRACT: A protocol for the asymmetric trimethylenemethane (TMM) [3 + 2] cycloaddition reaction of alkynyl-substituted
TMM donors and unsaturated N-acyl pyrroles employing a chiral bisdiamidophosphite ligand has been developed. This process
generates alkynyl-substituted cyclopentanes in high yields and diastereo- and enantioselectivities. These chiral precursors are
employed for the atom economic assembly of fused polycyclic hydrocarbons with hydroindene, hydroazulene, and
hydrocyclopentanaphthalene scaffolds by consecutive cycloaddition reactions.
he most atom economic processes to increase molecular
the application of an alkynyl-substituted TMM donor family in
Tcomplexity, a constant need in the pharmaceutical and the asymmetric TMM [3 + 2] cycloaddition reaction, and we
show that the obtained alkynyl-derived cycloadducts serve as
chiral precursors for the atom economic assembly of fused
polycyclic hydrocarbons with hydroindene, hydroazulene, and
hydrocyclopentanaphthalene scaffolds by consecutive cyclo-
addition reactions.
At the outset of our investigations, we focused on the
reaction of suitable alkyne TMM donors 1 with electron-
deficient olefins 2 (EWG = electron-withdrawing group) to
obtain alkynyl-substituted cyclopentanes 3 bearing three
contiguous stereocenters (Scheme 1). We were particularly
chemical industry, are those forming more than one bond at a
time, as it is the case for cycloaddition reactions.1 The
performance of consecutive cycloaddition steps would thus
open up new routes to rapidly assemble complex fused
polycyclic ring systems. The scarcity of efficient methods for
the construction of these polycondensed hydrocarbons
prompted us to elaborate our palladium-catalyzed trimethylene-
methane (TMM) [3 + 2] cycloaddition approach further.2 The
use of chiral phosphoramidite3 and bisdiamidophosphite
ligands4 led to the development of enantioselective variants
and of substituted TMM donors to selectively access cyano-,3b,5
vinyl-,4 and vinylidene-substituted6 cyclopentanes and pyrroli-
dines. Despite this progress, however, the use of synthetically
more valuable TMM donors has not yet been disclosed,
preventing a broader application. We envisioned that the
implication of an alkyne substituent on the TMM donor would
represent a major advancement of this methodology for several
reasons. First, an alkyne functionality is able to chemo-
selectively participate in metal-catalyzed processes, offering a
broad scope of subsequent transformations. Second, the
variation of the substituent on the alkyne group itself would,
for the first time, provide access to a whole TMM donor family,
whereas previous efforts concentrated only on the development
of protocols for the use of one specific TMM donor. And last,
alkynyl-derived TMM donors represent a highly versatile donor
class, since alkynes serve as functional equivalents of alkene,
saturated alkyl, or functionalized alkyl groups.
Scheme 1. Palladium-Catalyzed TMM [3 + 2] Cycloaddition
Reaction with Alkynyl-Substituted TMM Donors 1
interested in the use of α,β-unsaturated N-acyl pyrroles as
substrates, as these ester surrogates can be directly transformed
into a wide range of carbonyl compounds at both the ketone
and ester oxidation level.7
Initial experiments with alkyne donor 1a (2.0 equiv) and α,β-
unsaturated N-acyl pyrrole 2 in toluene were unsuccessful in
the presence of Pd(dba)2 and phosphoramidite ligand L13b
(Table 1, entry 1, and Figure 1). The use of trans-stilbene
bisdiamidophosphite ligand L2,6 however, afforded cycloadduct
3a in 50% yield and moderate diastereo- and enantioselectivity
(5:1 dr, 79% ee, entry 2).8 Gratifyingly, upon changing the
Since the beginning of our program, alkynyl-substituted
TMM donors constantly failed as substrates in TMM
cycloadditions. The possible interference with the active
palladium species represents a major issue, and the extension
of this methodology toward alkyne donors is therefore not a
trivial extrapolation of our previous studies. We describe here
Received: April 3, 2014
Published: May 2, 2014
© 2014 American Chemical Society
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Letter
a
yields and excellent diastereo- and enantioselectivities (>70%
yield, >12:1 dr, >95% ee).
Table 1. Selected Optimization Studies
These results encouraged us to explore the scope of the
cycloaddition reaction with TMS-alkyne donor 1a (Scheme 3).
Scheme 3. Substrate Scope of the Palladium-Catalyzed TMM
[3 + 2] Reaction with Alkyne TMM Donor 1a
a
entry
precatalyst
Pd(dba)2
L
solvent
yield
dr
ee
1
2
3
L1
L2
L3
L3
L3
L3
toluene
toluene
toluene
toluene
toluene
dioxane
NR
b
Pd(dba)2
50%
83%
70%
85%
91%
5:1
6:1
79%
95%
94%
94%
99%
Pd(dba)2
c
4
Pd(dba)2
10:1
9:1
c
5
CpPd(η3-C3H5)
CpPd(η3-C3H5)
c
6
12:1
a
Reactions were performed with 2.0 equiv of 1a at 0.5 M
b
concentration with 0.1 mmol of substrate 2. Opposite enantiomer
obtained. 1.4 equiv of 1a. Yields are combined isolated values; ee’s
c
were determined by chiral HPLC with a chiral stationary phase. NR =
no reaction.
a
Reactions were performed at 0.5 M concentration with 0.1 mmol of
substrate 2. Yields are combined isolated values; ee’s were determined
c
by chiral HPLC with a chiral stationary phase. b Reaction time 15 h.
Figure 1. Chiral phosphoramidite (L1) and bisdiamidophosphite
ligands (L2 and L3) used for the optimization of reaction conditions.
Scale 0.9 mmol.
In general, good to excellent yields and diastereo- and
enantioselectivities were achieved with a large variety of α,β-
unsaturated N-acyl pyrroles 2. The reaction is tolerant toward
different aromatic groups regardless of the substitution pattern
and the nature of the substituent. Methoxy-, methyl-, and
chloro-substituted cycloadducts 4a−g were obtained in good
yields and selectivities (>84% yield, >8:1 dr, >90% ee).
Heterocycles, such as pyridine and furan, are well tolerated and
provided the respective products 4h and 4i with excellent
enantioselectivities. The reaction is highly chemoselective with
respect to the more electron-deficient double bond, and styryl
derivative 4j was isolated as a single isomer (84% yield, 10:1 dr,
93% ee). We were furthermore pleased to find that reactions
with various alkyl-substituted α,β-unsaturated N-acyl pyrroles
proceeded with excellent yields and selectivities as well (4k−
4n). Only cyclopropyl derivative 4m showed a somewhat
reduced enantioselectivity (82% ee). Notably, substrates with a
free alkyne group or increased steric bulk next to the reaction
center drastically affected the reaction and led to a complex
mixture (for 4o) or low conversion (for 4p). Nuclear
Overhauser experiments for 4c and X-ray crystal structure
analysis of a functionalization product (vide infra) were used to
determine the relative and absolute stereochemistry of the
cycloadducts.8 The stereochemistry of all other cycloadducts
was assigned by analogy.
ligand to the cyclohexyldiamine bisdiamidophosphite L3, we
observed significant improvement in both yield and selectivity
(83% yield, 6:1 dr, 95% ee, entry 3). Reduction of the TMM
donor equivalents gave the desired product in lower yield, but
proved to be beneficial in terms of diastereoselectivity (70%
yield, 10:1 dr, 94% ee, entry 4). Replacement of Pd(dba)2 with
CpPd(η3-C3H5) provided the product in high yield and
diastereo- and enantioselectivity (85% yield, 9:1 dr, 94% ee,
entry 5). Finally, an additional increase in yield and selectivities
was achieved by switching solvents from toluene to 1,4-dioxane
(91% yield, 12:1 dr, 99% ee, entry 6).
With these optimized conditions in hand, we wanted to
examine other TMM donors featuring different alkyne
substituents to determine whether the alkyne substituent is a
generally tolerated motif (Scheme 2). Indeed, donors with a
TBS-protected methyl alcohol, an acetal group, or a cyclopropyl
substituent afforded the respective cycloadducts 3b−d in good
Scheme 2. Scope of the Palladium-Catalyzed TMM [3 + 2]
Cycloaddition Reaction with Different Alkyne TMM Donors
a
1
With a reliable protocol in hand, we wanted to illustrate the
versatility of the accessible cycloadducts. We were intrigued by
the possibility of intramolecular cyclization reactions of the
alkyne group with proximal functionalities to efficiently
construct fused polycondensed ring systems. The ruthenium-
catalyzed [2 + 2 + 2] cyclotrimerization of alkynes is a
convenient approach for the synthesis of benzene systems,
especially since the development of catalytic and chemo- and
regioselective methods.9 To apply this strategy to our diyne
a
Reactions were performed at 0.5 M concentration with 0.1 mmol of
substrate 2. Yields are combined isolated values; ee’s were determined
by chiral HPLC with a chiral stationary phase.
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cycloadduct 4n, the TMS-alkynes were first deprotected using
potassium fluoride in dimethyl sulfoxide to quantitatively
provide the free 1,7-diyne 5 (Scheme 4). Subsequent exposure
of 5 to dimethyl acetylenedicarboxylate in 1,2-dichloroethane in
the presence of [Cp*Ru(MeCN)3]PF6 furnished tricyclic
diester 6 in 53% yield.
substrates for ring-closing enyne metatheses10 and palladium-
catalyzed enyne cyclizations.11 The TMM [3 + 2] cycloaddition
reaction of alkyne donor 1b and the respective α,β-unsaturated
N-acyl pyrroles afforded enynes 7a and 7b in satisfying yields
and excellent selectivities (>67% yield, >12:1 dr, >94% ee).
Treatment of 7a and 7b with Grubbs’ second-generation
catalyst in benzene under an ethylene atmosphere gave the
desired hexahydroindene 8a (98% yield) and octahydroazulene
8b (88% yield), respectively. The subsequent Diels−Alder
reaction of 8a with maleic anhydride in benzene afforded the
tetracyclic anhydride 9 in 61% yield as a single isomer. Crystals
of 9 suitable for X-ray crystal structure analysis unambiguously
confirmed its proposed structure and the relative and absolute
stereochemistry (Scheme 5).
Scheme 4. Functionalization of Cycloadduct 4n
The intramolecular palladium-catalyzed enyne cyclization11
of cycloadduct 7a should give rise to an isomeric dialkylidene
system (Scheme 6). To avoid undesired side reactions of the N-
acyl pyrrole substituent, cycloadduct 7a was first treated with
sodium methoxide in methanol to give the corresponding
methyl ester in 97% yield. The subsequent enyne cyclization
reaction proceeded with Pd2(dba)3·CHCl3 and acetic acid
furnishing 1,3-diene 10 in 65% yield. Careful control of the
reaction time was essential in order to avoid migration of the
exocyclic double bond. The TBS-group was quantitatively
cleaved upon treatment with HF·pyridine to allow for a
directed intermolecular Diels−Alder reaction.12 Exposure of
alcohol 11 to methyl acrylate in the presence of MgBr2·OEt2 as
a Lewis acid afforded the desired tetracylic lactone 12 in 63%
yield.
In addition, we sought to apply cyclization strategies leading
to conjugated 1,3-dienes with hydroindene or hydroazulene
skeletons suitable for subsequent Diels−Alder reactions
(Schemes 5 and 6). Enynes 7a and 7b were envisaged as
Scheme 5. Functionalizations of Cycloadducts 7a and 7b and
a
ORTEP Plot of the X-ray Crystal Structure of Anhydride 9
To conclude, we have developed an asymmetric palladium-
catalyzed [3 + 2] cycloaddition reaction with alkynyl-
substituted TMM donors to furnish highly functionalized
cyclopentane systems with three contiguous stereocenters in
good yields and high diastereo- and enantioselectivity. This
methodology allowed the employment of a TMM donor family
consisting of different alkynyl-substituted donors for the first
time, in contrast to our previous studies where mostly only one
TMM donor could be used. Moreover, the alkynyl-substituted
cycloaddition reaction was found to have the broadest substrate
tolerance as compared to any other substituted TMM donor
class. The proximity of the alkyne substituent to other
functional groups makes the obtained cycloadducts unique
chiral precursors for the rapid synthesis of fused polycyclic ring
systems with diverse hydrocarbon skeletons. The synthetic
utility of this TMM donor family is the key aspect of these
studies, and this new strategy allows access to structural
complexity in an overall atom economic and convergent
fashion.
a
Atomic displacement parameters obtained at 120 K are shown at the
50% probability level.
Scheme 6. Functionalization of Cycloadduct 7a
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and spectral data for all unknown
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bmtrost@stanford.edu.
Notes
The authors declare no competing financial interest.
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Letter
ACKNOWLEDGMENTS
■
Financial support by the NSF (CHE-1145236) and the
Alexander von Humboldt Foundation (Feodor Lynen Research
Fellowship for V.E.) is gratefully acknowledged. We thank Tom
M. Lam (Stanford University, USA) for helpful discussions, Dr.
Allen Oliver (University of Notre Dame, USA) for X-ray crystal
structure analysis, and Johnson-Matthey for generous gifts of
palladium salts.
REFERENCES
■
(1) (a) Trost, B. M. Angew. Chem. 1995, 107, 285−307; Angew.
Chem., Int. Ed. 1995, 34, 259−281. (b) Huisgens, R. W., III; Morrison,
K. C.; Hicklin, R. W.; Flood, T. A., Jr.; Richter, M. F.; Hergenrother, P.
J. Nat. Chem. 2013, 5, 195−202. (c) Trost, B. M. Science 1991, 254,
1471−1477.
(2) (a) Chan, D. M. T. Recent Advances in Palladium-catalyzed
Cycloadditions involving Trimethylenemethane and its Analogs. In
Cycloaddition Reactions in Organic Synthesis, 1st ed.; Kobayashi, S.,
Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002; pp
57−83. (b) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49−
92. (c) Trost, B. M. Pure Appl. Chem. 1988, 60, 1615−1626. (d) Trost,
B. M.; Nanninga, T. N.; Satoh, T. J. Am. Chem. Soc. 1985, 107, 721−
723.
(3) (a) Teichert, J. F.; Feringa, B. L. Angew. Chem. 2010, 122, 2538−
2582; Angew. Chem., Int. Ed. 2010, 49, 2486−2528. (b) Trost, B. M.;
Silverman, S. M.; Stambuli, J. P. J. Am. Chem. Soc. 2011, 133, 19483−
19497. (c) Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schworer, U.
̈
J. Am. Chem. Soc. 2006, 128, 13328−13329.
(4) Trost, B. M.; Lam, T. M. J. Am. Chem. Soc. 2012, 134, 11319−
11321.
(5) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc.
2007, 129, 12396−12397.
(6) Trost, B. M.; Maruniak, A. Angew. Chem. 2013, 125, 6382−6384;
Angew. Chem., Int. Ed. 2013, 52, 6262−6264.
(7) (a) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem. 2002,
114, 3320−3323; Angew. Chem., Int. Ed. 2002, 41, 3188−3191.
(b) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J.
Am. Chem. Soc. 2004, 126, 7559−7570.
(8) All products were isolated as single diastereoisomers. The relative
and absolute stereochemistry of the cycloadducts were assigned by
nuclear Overhauser effect experiments (for 4c) and X-ray crystal
structure analysis (for 9). The stereochemistry of all other cyclo-
adducts was assigned by analogy. For details see the Supporting
Information.
(9) (a) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901−2915.
(b) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc.
2003, 125, 12143−12160.
(10) Mori, M. Adv. Synth. Catal. 2007, 349, 121−135 and references
therein.
(11) (a) Trost, B. M.; Chung, C. K.; Pinkerton, A. B. Angew. Chem.
2004, 116, 4427−4429; Angew. Chem., Int. Ed. 2004, 43, 4327−4329.
(b) Trost, B. M.; Krische, M. J. Synlett 1998, 1, 1−16. (c) Trost, B. M.;
Lee, D. C.; Rise, F. Tetrahedron Lett. 1989, 30, 651−654.
(12) (a) Ward, D. E.; Abaee, M. S. Org. Lett. 2000, 2, 3937−3940 and
references therein. (b) Zografos, A. L.; Yiotakis, A.; Georgiadis, D. Org.
Lett. 2005, 7, 4515−4518.
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