An approach to skeletal diversity using functional group pairing of multifunctional scaffolds

Article abstract of DOI:10.1021/ol070606t

Diversification of enantioenriched Michael adducts through functional group pairing to gain access to a range of five- to ten-membered complex fused and bridged ring systems is described.

Full text of DOI:10.1021/ol070606t

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2123-2126
An Approach to Skeletal Diversity
Using Functional Group Pairing of
Multifunctional Scaffolds
Eamon Comer,† Erin Rohan,† Li Deng,‡ and John A. Porco, Jr.*,†
Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215, and Department of Chemistry, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
porco@bu.edu
Received March 12, 2007
ABSTRACT
Diversification of enantioenriched Michael adducts through functional group pairing to gain access to a range of five- to ten-membered complex
fused and bridged ring systems is described.
Diversity-oriented synthesis (DOS) involves preparation of
structurally diverse collections of compounds with the aim
of discovering small molecule protein modulators.1a-e To
further develop this strategy, methodologies that allow for
the preparation of enantioenriched compounds with high
levels of skeletal diversity are needed.1b Synthetic approaches
toward this goal have successfully explored skeletal
rearrangement,1i convergent synthesis,1f,g “folding” processes,1h
and linear sequences.1j We sought to address this overall
objective through synthetic approaches involving selective
pairing of two functional groups of interest strategically
placed on multifunctional, enantioenriched scaffolds.2 Skel-
etal diversity may be achieved by chemoselective activation
of different pairs of functional groups in transformations of
interest. Similar use of multifunctional enyne scaffolds has
recently been reported by Schreiber and co-workers.2b
Our overall strategy is outlined in Figure 1. Deng and co-
workers recently demonstrated that readily available, modi-
fied Cinchona alkaloids are effective catalysts for enantio-
selective Michael addition of 2-substituted 1,3-ketoesters to
â-nitrostyrenes.3 We envisioned that expansion of this
methodology would permit access to highly functionalized
modular scaffolds4 (cf. 1, Figure 1) suitable for functional
group pairing studies and overall investigation of their
† Boston University.
‡ Brandeis University.
(1) For reviews and seminal papers on diversity-oriented synthesis see:
(a) Schreiber, S. L. Science 2000, 287, 1964-1969. (b) Burke, M. D.;
Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613-618. (c) Spring,
D. R. Org. Biomol. Chem. 2003, 1, 3867-3870. (d) Burke, M. D.; Schreiber,
S. L. Angew. Chem., Int. Ed. 2004, 43, 46-58. (e) Arya, P.; Joseph, R.;
Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163-180. For recent approaches
to diversity-oriented synthesis see: (f) Shun, S.; Acquilano, D. E.;
Arumugasamy, J.; Beeler, A. B.; Eastwood, E. L.; Giguere, J. R.; Lan, P.;
Lei, X.; Min, G. K.; Yeager, A. R.; Zhou, Y.; Panek, J. S.; Snyder, J. K.;
Schaus, S. E.; Porco, J. A., Jr. Org. Lett. 2005, 7, 2751-2754. (g) Chen,
C.; Li, X.; Neumann, C. S.; Lo, M. M.-C.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2005, 44, 2249-2252. (h) Spiegel, D. A.; Schroeder, F. C.; Duvall,
J. R.; Schreiber, S. L. J. Am. Chem. Soc. 2006, 128, 14766-14767. (i)
Yeager, A. R.; Min, G. K.; Porco, J. A., Jr.; Schaus, S. E. Org. Lett. 2006,
8, 5065-5068. (j) Mitchell, J. M.; Shaw, J. T. Angew. Chem., Int. Ed. 2006,
45, 1722-1726.
(2) (a) Couladouros, E. A.; Strongilos, A. T. Angew. Chem., Int. Ed.
2002, 41, 3677-3680. (b) Kumagai, N.; Muncipinto, G.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2006, 45, 3635-3638.
(3) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B.
M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105-108.
(4) For related chiral, racemic scaffolds, see: Guillaume, M.; Dumez,
E.; Rodriguez, J.; Dulce`re, J.-P. Synlett 2002, 11, 1883-1885.
10.1021/ol070606t CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/02/2007

Our initial results encouraged us to investigate the
unexplored, stereoselective Michael additions of ortho-
substituted â-nitrostyrenes using Cinchona alkaloid derivative
5c as catalyst. Deng and co-workers have shown that
catalysts 5 were tolerant of â-nitrostyrenes bearing halogens
in the para position.3 We considered that nitroarenes sub-
stituted in the ortho position with bromide (3c), allyl (3b),
and alkynyl (3d) substituents would permit the synthesis of
a number of diverse molecules through selective functional
group pairings with ortho-substituted aryl functionality. In
the event, we found that conjugate addition of nucleophiles
to ortho-substituted â-nitrostyrenes occurred with excellent
enantioselectivity (entries 6-9). However, substrates 3b-d
showed comparatively sluggish reactivity presumably due
to steric hindrance. The absolute configuration of adduct 4g
(entry 8) was determined by X-ray crystallography5 and is
consistent with the previously reported transition-state model.3
Figure 1. Skeletal diversity through functional group pairing.
synthetic utility to produce novel structural types. For
example, in generalized structure 1, the nitro group may be
paired in chemical reactions with the ester functional group
or with the alkyne. Likewise, incorporation of an o-allyl
moiety into nitrostyrene 1 (Figure 1, R2 ) allyl) enables
pairing between R2 and the alkyne/alkene. In this manner,
structurally distinct carbon skeletons may be produced
depending on the two functional groups paired. In this Letter,
we report the diversification of enantioenriched Michael
adducts through functional group pairing approaches to
access a range of five- to ten-membered complex fused and
bridged ring systems.
We began our study with preparation of the requisite
scaffolds (Table 1). Our initial efforts were focused on
expansion of the scope of the asymmetric conjugate addition
methodology to acyclic substituted malonates bearing pen-
dant alkenes and alkynes. Extensive reaction screening
identified phenanthrene derivative 5c as an optimal catalyst
for these reactions (entries 1 and 2). Significantly, it was
discovered that malonate derivatives with terminal alkynes
were also effective substrates in terms of stereoselectivity
(entry 4). Allyl-substituted malonate 2e (entry 5) performed
well in terms of stereoselectivity, but with a slower overall
reaction rate.
With access to a range of highly functionalized Michael
adducts established, we next turned our attention to examina-
tion of their synthetic utility in a range of functional group
pairings. Selective nitro reduction of 4b in the presence of
the alkyne, followed by cyclization to form the lactam,
required extensive optimization (Scheme 1, reaction a) and
provided reductive cyclization product 6 in good yield (dr
) 12:1). The absolute configuration of lactam 6 was
established through NOE analysis of the corresponding
alcohol derived through selective reduction with LiBH4.5 The
nitro group of 4c was also activated toward reaction with
the alkyne through intramolecular 1,3-cycloaddition of the
derived nitrile oxide6 (Scheme 1, reaction b) to provide
bicyclic isoxazole 7.7 Alternatively, nitrile oxide generation8
of 4d and subsequent cycloaddition afforded the corre-
sponding isoxazolines in good yield (dr ) 1.1:1 (25 °C), dr
) 2.6:1 (0 °C)). The stereochemistries of 8 and 9 were
assigned by comparison to spectral data reported for (() 8
and 9.9
Table 1. Enantioselective 1,4-Addition of Substituted Dicarbonyls to â-Nitrostyrenesa
entry
2: R1, R2
3: R3
cat.
T (°C)
time (h)
convb
yieldc (%)
eed,e (%)
product
1
2
3
4
5
6
7
8
9
2a: Me, CH2CtCH
2b: Me, CH2CtCH
2c: OMe, CH2CtCMe
2d: OMe, CH2CtCH
2e: OMe, CH2CdCH2
2d: OMe, CH2CtCH
2e: OMe, CH2CdCH2
2c: OMe, CH2CtCMe
2e: OMe, CH2CdCH2
3a: H
3a: H
3a: H
3a: H
3a: H
3b: CH2CdCH2
3b: CH2CdCH2
3c: Br
5a
5c
5a
5c
5c
5c
5c
5c
5c
-20
-20
-20
-40
-20
-20
-20
-20
-20
16
48
48
3 d
5 d
168
15 d
5 d
5 d
84
77
97
50
51
68
58
100
44
73
71
85
45
44
35
55
87
41
99f
98g
90
92
90
95
92
97
96
4a
4a
4b
4c
4d
4e
4f
4g
4h
3d: CtCCH2OMe
1
a Reactions were conducted (1 M in nitrostyrene) with 2 equiv of the nucleophile and 10 mol % of catalyst. b Determined by H NMR analysis of the
crude reaction mixture (ratio of nitro styrene to product). c Isolated yield of product after silica gel chromatography. d Determined by HPLC analysis. e ee
1
1
of the major diastereomer. f dr of 1.6:1 as determined by H NMR analysis. g dr of 2.4:1 as determined by H NMR analysis.
2124
Org. Lett., Vol. 9, No. 11, 2007

Scheme 1. Skeletal Diversity through the Pairing of (a)
Nitro-Ester, (b) Nitro-Alkyne, and (c) Nitro-Alkene Functional
Groups
Scheme 3
12 was highly stereoselective (dr ) 15:1), with the major
diastereomer resulting from endo approach of the dienophile
from the same face as the nitro group as determined by NOE
experiments.5 A derived molecular model of 1214 (Scheme
3) indicates that the nitro group is directed away from the â
face leaving it open to react with the dienophile, while the
R face is hindered by one ester group of the malonate moiety.
To access skeletal diversity using enyne RCM, we sought
to take advantage of the modularity of the multifunctional
scaffolds produced by enantioselective Michael addition and
chose to interchange the allyl and alkyne moieties. We
therefore subjected 4h to enyne metathesis conditions to
afford the complex diene 14 (Scheme 4), which is structurally
The ability to construct Michael adducts containing o-allyl
phenyl groups with high enantioselectivity (Table 1, entries
6 and 7) enabled evaluation of ring-closing metathesis (RCM)
(Scheme 2). Thus, when 4f was microwaved in the presence
Scheme 2
Scheme 4
of Grubbs’ second generation catalyst,10 cyclooctene deriva-
tive 10 was formed in high yield. Reductive cyclization of
10 (Scheme 2) provided tricyclic lactam 11 as a mixture of
diastereomers (dr ) 1.5:1).
We next investigated diversification of the multifunctional
scaffolds using enyne metathesis.2b We discovered that the
reaction (Scheme 3) was highly efficient in the presence of
ethylene gas (Mori’s condition11) and was compatible with
microwave heating. Diene 12 was utilized directly in [4+2]
cycloaddition with N-phenylmaleimide in a one-pot pro-
cess.12,13 Interestingly, Diels-Alder cycloaddition of diene
(5) See the Supporting Information for complete experimental details.
(6) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339-
5342.
distinct from 12. Cycloaddition of 14 with N-phenyltriazo-
linedione afforded the 7-membered fused cycloadduct 15
(7) (a) Pal, A.; Bhattacharjee, A.; Bhattacharjya, A. Synthesis 1999, 9,
1569. (b) Yip, C.; Handerson, S.; Tranmer, G. K.; Tam, W. J. Org. Chem.
2001, 66, 276-286.
(12) For improved yields with one-pot, enyne metathesis/Diels-Alder,
cycloaddition, see: Bentz, D.; Laschat, S. Synthesis 2000, 12, 1766-1773.
(13) Ruthenium catalyst byproducts were removed by using a literature
procedure, see: Cho, K. J. H.; Kim, B. M. Org. Lett. 2003, 5, 531-533.
(14) Conformational searches (Merck Molecular Mechanics Force Field
(MMFF)) were performed with Spartan ’04 Windows (Wavefunction:
Irvine, CA).
(8) Basel, Y.; Hassner, A. Synthesis 1997, 309-312.
(9) Tu, Z.; Jang, Y.; Lin, C.; Liu, J.-T.; Hsu, J.; Sastry, M. N. V.; Yao,
C.-F. Tetrahedron 2005, 61, 10541-10551.
(10) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140.
(11) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082-6083.
Org. Lett., Vol. 9, No. 11, 2007
2125

with complete stereoselectivity. Reductive cyclization of 15
afforded 16, the stereochemistry of which was established
by NOE analysis of the derived primary alcohol.5
Scheme 6
We next investigated adduct 4e as a substrate for skeletal
diversity via the Pauson-Khand reaction15 (PKR) (Scheme
5). The Co2(CO)6 complex derived from 4e was consumed
Scheme 5
22.5 The stereochemistry of lactam 22 was established by
NOE analysis of the corresponding alcohol.5 Products such
as 1,4-diene 21 are unusual in gold(I) chemistry as the normal
mode of reactivity generally involves attack of the carboca-
tion by the alkene in 20 to form a cyclopropane intermediate
that may rearrange to form a conjugated diene with an
exocyclic alkene.17a However, in the case at hand, elimination
likely competes effectively with cyclopropane formation due
to the presence of the aryl ring leading to the observed 10-
membered-ring product.
In summary, asymmetric Michael additions of substituted
1,3-dicarbonyls to â-nitrostyrenes employing Cinchona
alkaloids have been expanded in scope to prepare a series
of acyclic, multifunctional scaffolds. These scaffolds have
been utilized in chemical reaction sequences engaging two
specific functionalities of interest (functional group pairing)
to gain access to a range of five- to ten-membered complex
fused and bridged ring systems. The overall approach has
also enabled discovery of several interesting reaction types,
including an efficient Pauson-Khand cycloaddition leading
to a bridged nine-membered ring and a novel Au(I)-catalyzed
cycloisomerization to produce a ten-membered ring. Further
applications of this strategy as a means to access novel
reactions and chemotypes are in progress in our laboratories
and will be reported in due course.
upon heating to afford a single new product (67%). It was
apparent from NMR studies that the structure of the new
compound was not the expected fused eight-membered ring
18. X-ray structure analysis showed that the interesting
bridged nine-membered ring 17 had been formed.16 PKR
product 17 is an attractive substrate for diversification
through Michael addition as its X-ray structure shows the
cyclopentenone group stacked over the aromatic ring allow-
ing access to the enone from one face. An NOE was observed
between the vinyl proton of 17 and the methine â to the
nitro group demonstrating that the solution phase conforma-
tion of 17 was similar to the X-ray structure shown in
Scheme 5.5 When 17 was treated with thiophenol under basic
conditions, the Michael adduct 19 was formed with complete
selectivity. The expected stereochemistry of 19 was supported
by conformational and NOE analyses.5
Our emphasis on generating skeletal diversity also led us
to investigate cycloisomerization of enyne scaffolds2b using
homogeneous gold catalysis.17 Upon thermolysis of 4e with
a cationic gold(I) complex (Scheme 6), a major product was
obtained. This product was identified by NMR analysis5 as
the 10-membered cycloisomerization product 21. The mini-
mum-energy conformer derived from a conformational search
(MMFF)14 of 21 approximates to a chair-boat-chair con-
formation that is supported by a strong NOE between protons
on the two opposite methylene groups in the derived lactam
Acknowledgment. Financial support from the NIGMS
CMLD initiative (P50 GM067041) is gratefully acknowl-
edged. We thank Dr. Emil Lobkovsky, (Cornell University)
for X-ray crystal structure analyses and Prof. John Snyder,
Dr. Andreas Heutling, and Mr. Christopher Singleton (Boston
University) for helpful discussions.
(15) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263-3283.
(16) For production of bridged ring systems via PKR, see: (a) Lovely,
C. J.; Seshadri, H.; Wayland, B. R.; Cordes, A. W. Org. Lett. 2001, 3,
2607-2610. (b) Bonaga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 9795-
9833.
(17) (a) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200-
203. (b) Eloisa, J.-N.; Echavarren, A. M. Chem. Commun. 2007, 333-
346. (c) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395-403.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
materials. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL070606T
2126
Org. Lett., Vol. 9, No. 11, 2007