Preparation of alkylidene indane and related scaffolds and their further elaboration to novel chemotypes

Article abstract of DOI:10.1021/ol7023778

(Chemical Equation Presented) Alkylidene indane and ring-expanded scaffolds have been prepared using an enantioselective crotylation/Heck cyclization sequence. Further diversification using consecutive cyclopropanation-Cope rearrangement affords novel che

Full text of DOI:10.1021/ol7023778

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5203-5206
Preparation of Alkylidene Indane and
Related Scaffolds and Their Further
Elaboration to Novel Chemotypes
Sarathy Kesavan, James S. Panek,* and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment (CMLD-BU), Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@bu.edu; panek@bu.edu
Received September 29, 2007
ABSTRACT
Alkylidene indane and ring-expanded scaffolds have been prepared using an enantioselective crotylation/Heck cyclization sequence. Further
diversification using consecutive cyclopropanation Cope rearrangement affords novel chemotypes including spiroindane frameworks.
−
Diversity-oriented synthesis (DOS) has emerged as a power-
ful approach to obtain complex molecules for biological
studies.1 The utility of DOS relies ultimately on the develop-
ment of chemical methodologies for the synthesis of novel
structural types with high levels of skeletal and stereochem-
ical complexity.2 Polyketide natural products possess a broad
spectrum of biological activity and both stereochemical and
skeletal diversity and have served as an inspiration for
complex chemical library design.3 For instance, our labora-
tory reported the use of “tagged” organosilanes for enanti-
oselective synthesis of linear polypropionate arrays.4,5 We
anticipated that this methodology could be extended to
prepare constrained scaffolds via Heck cyclization of the
(1) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Burke, M. D.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (c) Spring, D. R.
Chem. Soc. ReV. 2005, 34, 472. (d) Tan, D. S. Nat. Chem. Biol. 2005, 1,
74. (e) Arya, P.; Joseph, R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163.
(2) (a) Wipf, P.; Stephenson, C. R. J.; Walczak, M. A. A. Org. Lett.
2004, 6, 3009. (b) Gan, Z.; Reddy, P. T.; Quevillon, S.; Couve-Bonnaire,
S.; Arya, P. Angew. Chem., Int. Ed. 2005, 44, 1366. (c) Beeler, A. B.;
Acquilano, D. E.; Su, Q.; Yan, F.; Roth, B. L.; Panek, J. S.; Porco, J. A.,
Jr. J. Comb. Chem. 2005, 7, 673. (d) Adriaenssens, L. V.; Austin, C. A.;
Gibson, M.; Smith, D.; Hartley, R. C. Eur. J. Org. Chem. 2006, 22, 4998.
(e) Dandapani, S.; Lan, P.; Beeler, A. B.; Beischel, S.; Abbas, A.; Roth, B.
L.; Porco, J. A., Jr.; Panek, J. S. J. Org. Chem. 2006, 71, 8934. (f)
Fitzmaurice, R. J.; Etheridge, Z. C.; Jumel, E.; Woolfson, D. N.; Caddick,
S. Chem. Commun. 2006, 46, 4814. (g) Freifeld, L.; Holtz, E.; Dahmann,
G.; Langer, P. Eur. J. Org. Chem. 2006, 14, 3251. (h) Beeler, A. B.; Su,
S.; Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 1413.
(i) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc. 2007,
129, 1020.
Figure 1. Sequential asymmetric crotylation-Heck cyclization to
access alkylidene indane and related scaffolds.
crotylation products (Figure 1). Herein, we report our initial
studies to prepare alkylidene indane and related scaffolds
(4) Kesavan, S.; Su, Q.; Shao, J.; Porco, J. A., Jr.; Panek, J. S. Org.
Lett. 2005, 7, 4435.
(3) Shang, S.; Tan, D. S. Curr. Opin. Chem. Biol. 2005, 9, 248.
10.1021/ol7023778 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/13/2007

and their further diversification to novel structural motifs
including spiroindane frameworks.
Our study began with enantioselective crotylation6 of
2-bromobenzaldehyde 5 using silane (R)-2 to afford the syn-
homoallylic ether 6 (dr >20:1, Scheme 1). Heck cyclization7
Table 1. Additional Bicyclic Scaffolds
Scheme 1. Preparation of Alkylidene Indane Scaffolds
of 6 (cat. Pd(OAc)2, Et3N, 120 °C) cleanly afforded alky-
lidene indane 7 (82%).8 The olefin geometry of 7 was
assigned through NOE analysis (inset). Alternatively, per-
forming the Heck cyclization at a lower temperature (80 °C)
afforded 7 and trisubstituted indane 8 in 35 and 38% yields,
respectively. NOE measurements (inset) indicated that the
benzylic vinyl group of 8 was established trans to the
adjacent methyl group. Subjection of the presumed kinetic
product 8 to the Heck reaction conditions (Pd(OAc)2, Et3N,
120 °C) led to complete isomerization to thermodynamic
product 7 where the olefin is conjugated with the aromatic ring.
Table 1 illustrates six bicyclic scaffolds prepared using
the diastereo- and enantioselective crotylation-Heck reaction
sequence. Various scaffolds bearing both electron-rich and
-poor aryl rings (Table 1, entries 2 and 3) and scaffolds with
functional handles for further diversification including hy-
droxyl and carbamate groups (Table 1, entries 1 and 4) were
prepared using the two-step sequence. Crotylation of acetal
199 yielded homoallylic ether 20 which was subjected to
Heck cyclization to afford tetrahydronaphthalene (21).
Finally, diethyl acetal 228 was efficiently converted to
crotylation product 23 en route to the alkylidene oxepine
derivative (24).10
a Isolated yield. b Reaction conditions: MeCO2NH2 (1.1 equiv), BF3‚Et2O
(1.0 equiv), 2 (1.1 equiv), CH2Cl2, -78 to -30 °C. c TMSOTf (1.0 equiv),
TMSOMe (1.1 equiv), 2 (1.1 equiv), CH2Cl2, -78 to -30 °C. d TMSOTf
(1.0 equiv), 2 (1.1 equiv), CH2Cl2, -78 to 30 °C. e Pd(OAc)2 (10 mol %),
Et3N (2 equiv), PPh3 (40 mol %), DMF, 120 °C, 2 h.
ization chemistry. As part of our studies, we considered
diazotization of the â,γ-unsaturated ester moiety to a vinyl
diazoester. The rich chemistry of diazo compounds provides
access to numerous C-C bond forming reactions to generate
a variety of functionalized scaffolds11 and renders them
reactive intermediates suitable for DOS.12 In the event,
diazotization of 13 with sulfonyl azide 2613 and DBU led to
clean formation of the stable vinyl diazoester 27 (Scheme
2). In order to evaluate intermolecular cyclopropanation, 27
was treated with cyclopentadiene in the presence of Rh2-
With access to a number of alkylidene indane and related
scaffolds, we turned our attention toward their functional-
(5) (a) Paterson, I.; Donghi, M.; Gerlach, K. Angew. Chem., Int. Ed.
2000, 39, 3315. (b) Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E. M.
Angew. Chem., Int. Ed. 2001, 40, 2082. (c) Smith, A. B., III; Walsh, S. P.;
Frohn, M.; Duffey, M. O. Org. Lett. 2005, 7, 139. (d) Shang, S.; Iwadare,
H.; Macks, D. E.; Ambrosini, L. M.; Tan, D. L. Org. Lett. 2007, 9, 1895.
(6) (a) Panek, J. S.; Xu, F. J. Am. Chem. Soc. 1995, 117, 10587. (b)
Jain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S. Tetrahedron Lett. 1995,
36, 8727. (c) Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc.
1996, 118, 12475. (d) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain, N.
F.; Panek, J. S. Org. Synth. 1997, 75, 78.
(11) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley-Inter-
science: New York, 1998; pp 112-162. (b) Mass, G. Topics in Current
Chemistry; Springer-Verlag: New York; 1987; Vol. 137, pp 75-254.
(12) For application of diazo compounds in DOS, see: (a) Oguri, H.;
Schreiber, S. L. Org. Lett. 2005, 7, 47. (b) Wyatt, E. E.; Fergus, S.;
Galloway, W. R. J. D.; Bender, A.; Fox, D. J.; Plowright, A. T.; Jessiman,
A. S.; Welch, M.; Spring, D. R. Chem. Commun. 2006, 3296. (c) Ni, A.;
France, J. E.; Davies, H. M. L. J. Org. Chem. 2006, 71, 5594.
(13) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
(7) Link, J. T. Org. React. 2002, 60, 157.
(8) See Supporting Information for complete experimental details.
(9) Garcia-Ruano, J. L.; Aleman, J.; Aranda, M. T.; Fernandez-Ibanez,
M. A.; Rodriguez-Fernandez, M. M.; Maestro, M. C. Tetrahedron 2004,
60, 10067.
(10) Martins, A.; Marquardt, U.; Kasrvi, N.; Alrerico, D.; Lautens, M.
J. Org. Chem. 2006, 71, 4937.
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Org. Lett., Vol. 9, No. 25, 2007

Scheme 2. Synthesis and Cyclopropanation of a Complex
Scheme 3. Diastereoselective Cyclopropanations
Vinyl Diazoester
dirhodium(II) dicarboxylate catalysts developed by Davies
and co workers.16 Treatment of 27 with cyclopentadiene and
the chiral catalyst Rh2(S-DOSP)4 (2 mol %) led to isolation
of cyclopropane 28a (65%, dr ) 7:1). To our delight, use of
the corresponding enantiomeric catalyst Rh2(R-DOSP)4 led
to isolation of cyclopropane 28b in excellent diastereose-
lectivity (dr > 10:1), indicating good catalyst control in a
double stereodifferentiating cyclopropanation reaction.
(OAc)4 (5 mol %) which afforded a mixture of complex
divinylcyclopropane products 28a and 28b (28a/28b ) 1:2)
in 63% yield (Scheme 2). The stereochemistries of both 28a/
28b were assigned using NOE measurements as depicted in
Figure 2.8 For both diastereoisomers, the cyclopentene and
Given our ability to access divinylcyclopropane products,
we were positioned to evaluate use of the Cope rearrange-
ment to access spiroindane frameworks (Scheme 4).17 Previ-
Scheme 4. Cope Rearrangement to a Spiroindane Framework
Figure 2. Ground state conformations for divinylcyclopropanes
obtained using MOE calculations and their corresponding NOE
correlations.
indene units are cis to each other14 and the cyclopropane
formed on the face opposite to the allylic methyl group.
Conformational search calculations15 (cf. Figure 2) support
the NOE measurements8 and indicate that, in the major
diastereoisomer (28b), the newly formed divinylcyclopropane
unit is situated in a twist boat-like conformation, while it is
forced into a boat-like conformation in the minor diastere-
oisomer (28a) (Scheme 3).
ous studies by Davies and others have demonstrated the facile
Cope rearrangement of cis-divinylcyclopropanes to yield
seven-membered carbocycles.13 However, for the present
cases, steric interactions in cyclopropanes 28a and 28b
prevent the Cope rearrangement and allow isolation of the
In light of the poor diastereoselection observed in cyclo-
propanation experiments, we next evaluated use of the chiral
(16) Davies, H. M. L.; Stafford, D. G.; Doan, B. D.; Houser, J. H. J.
Am. Chem. Soc. 1998, 120, 3326.
(17) For general reviews on the Cope rearrangement of divinylcyclo-
propanes, see: (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y. C.;
Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165. (b) Hudlicky, T.; Fan,
R.; Reed, J. W.; Gadamasetti, K. G. Org. React. 1992, 41, 1. (c) Piers, E.
In ComprehensiVe Organic Synthesis; Trost, B. M. ,Ed.; Pergamon Press:
Oxford, 1991; Vol. 5, p 971.
(14) Davies, H. M. L.; McAfee, M. J.; Oldenburg, C. E. M. J. Org. Chem.
1989, 54, 930.
(15) Conformational analysis was conducted using the Molecular Operat-
ing Environment (MOE) (version 2006.08) stochastic search.
Org. Lett., Vol. 9, No. 25, 2007
5205

cyclopropanes at ambient temperature.18 However, micro-
wave heating of compound 28a (100 °C, 200 W) led to an
efficient divinylcyclopropane rearrangement to yield spiroin-
dane 29a (92%). The stereochemistry of spiroindane 29a was
assigned using NOE experiments.8
Interestingly, subjection of 28b to the same microwave
heating conditions did not lead to the desired divinylcyclo-
propane rearrangement (Scheme 5) as only starting materials
Scheme 5. Steric Inhibition of the Cope Rearrangement
Figure 3. Additional divinylcyclopropane and spirocyclic scaffolds.
lective crotylation-intramolecular Heck reaction sequence.
Scaffolds have been further transformed to novel chemo-
types, including spiroindanes, utilizing cyclopropanation of
derived vinyl diazoesters and microwave-mediated Cope
rearrangement. The use of Davies’ chiral dirhodium(II)
dicarboxylate catalysts allows access to divinylcyclopropane
products with high levels of diastereoselection. Application
of the methodology described herein to library synthesis and
evaluation of the novel chemotypes described in biological
assays is currently in progress and will be reported in due
course.
and decomposition products were recovered. The difference
in reactivity of the two diastereoisomers may be explained
by destabilizing steric interactions present in the requisite
boat-like transition states. In compound 28a, the cyclopentene
unit approaches on the face opposite to the methyl group
leading to the formation of product 29a. On the other hand,
when compound 28b is subjected to thermal rearrangement,
the inherent stereochemistry forces the cyclopentene unit to
approach on the same face as the methyl group. This
unfavorable steric interaction likely inhibits the transforma-
tion; use of forcing conditions (up to 160 °C) led to
decomposition of starting material likely due to rupture of
the cyclopropane ring. A collection of four additional
scaffolds derived from the appropriate vinyl diazoesters
employing the cyclopropanation rearrangement protocol is
shown in Figure 3.
Acknowledgment. Financial support from the NIGMS
CMLD initiative (P50 GM067041) is gratefully acknowl-
edged. We thank Drs. Aaron Beeler and Sivaraman Danda-
pani (Boston University) for helpful discussions, Symyx, Inc.
(Santa Clara, CA) for assistance with chemical reaction
planning software, and CEM Corp. (Matthews, NC) for
assistance with microwave instrumentation.
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.
In conclusion, alkylidene indane scaffolds and their ring-
expanded variants have been prepared using an enantiose-
(18) Bykowski, D.; Wu, K.-H.; Doyle, M. P. J. Am. Chem. Soc. 2006,
128, 16038.
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