Convergent cyclopentannelation process.

Article abstract of DOI:10.1021/ol034309+

[reaction: see text] A triply convergent synthesis of alpha-methylene cyclopentenones has been demonstrated in which an intermediate C,O-dianion is formed and trapped on carbon by electrophiles.

Full text of DOI:10.1021/ol034309+

ORGANIC
LETTERS
2
003
Vol. 5, No. 10
681-1684
Convergent Cyclopentannelation
Process
1
Cisco Bee and Marcus A. Tius*
Department of Chemistry, 2545 The Mall, UniVersity of Hawaii,
Honolulu, Hawaii 96822, and The Cancer Research Center of Hawaii,
1236 Lauhala Street, Honolulu, Hawaii 96813
tius@gold.chem.hawaii.edu
Received February 20, 2003
ABSTRACT
A triply convergent synthesis of r-methylene cyclopentenones has been demonstrated in which an intermediate C,O-dianion is formed and
trapped on carbon by electrophiles.
1
A variant of the Nazarov reaction in which one π electron
two approaches to 2b is completely satisfactory. Since
both terminal carbon atoms of the allene can be deproto-
nated, a more direct approach to 2b would be through R,γ-
allene dianion 4 (Scheme 1). Deprotonation of the γ-car-
bon atom would take place last; therefore, selective electro-
philic trapping at that site might be possible. Every attempt
to put this plan into practice failed. Although R,γ-dilithio-
allenes are known, it is apparently necessary to have
pair is supplied by an allenyl ether has been a research
interest of long standing in our group. We have prepared
the allenyl ethers according to Brandsma’s excellent proce-
dure (eq 1) by isomerizing propargyl ethers 1 under basic
conditions. In the case of 1a, the isomerization to 2a takes
place in the presence of potassium tert-butoxide in 90% yield.
In the case of 1b, the isomerization requires the use of
n-butyllithium as the base and inevitably leads to a mixture
of allene and acetylene.
2
3
stabilizing groups (e.g., R
3
Si, SPh, Ph) at both ends of the
5
allene.
Consideration of this problem suggested the simple solu-
tion that is summarized by Scheme 1. Lithiation of 2a leads
to 3, which adds to amide 5 to produce tetrahedral intermedi-
ate 6. The γ-allenic protons in 6 are acidic, and exposure to
(1) (a) Jacobi, P. A.; Armacost, L. M.; Kravitz, J. I.; Martinelli, M. J.;
Selnick, H. G. Tetrahedron Lett. 1988, 29, 6865. (b) Bender, J. A.; Arif,
A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 7443. (c) Hashmi, A. S.
K.; Bats, J. W.; Choi, J.-H.; Scharz, L. Tetrahedron Lett. 1998, 39, 7491.
(d) Schultz-Fademrecht, C.; Tius, M. A.; Grimme, S.; Wibbeling, B.; Hoppe,
D. Angew. Chem., Int. Ed. 2002, 41, 1532-1535. For a review of the
Nazarov reaction, see: Habermas, K. L.; Denmark, S.; Jones, T. K. In
Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New York,
An alternative approach that leads to allenes 2b exclusively
takes place in three steps from 2a. R-Lithiation of 2a is
followed by trapping of the resulting anion with trimethylsi-
lyl chloride. With the R-carbon atom blocked, exposure to
sec-butyllithium leads to the γ-lithiated allene ether that is
1
994; Vol. 45, pp 1-158.
(
2) For an overview of our work in this area, see: Tius, M. A. Acc.
Chem. Res. 2003, in press, and references cited therein.
(3) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. TraV. Chim. Pays-Bas 1968,
8
7, 916-924.
(4) Tius, M. A.; Busch-Petersen, J.; Yamashita, M. Tetrahedron Lett.
4
then alkylated. Desilylation leads to pure 2b. Neither of the
1998, 39, 4219-4222.
1
0.1021/ol034309+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/17/2003

Scheme 1a
Table 1. R-Hydroxy Cyclopentenonesa
a
Reaction conditions: (a) 1.2 equiv of n-BuLi, THF, -78 °C,
2
0 min; (b) 1.0 equiv of 5, -78 °C, 30 min; (c) 1.7 equiv of sec-
BuLi, -78 °C, 20 min; (d) 3.0 equiv of MeI, -78 °C for 30 min
and then -40 °C for 30 min; (e) aqueous HCl.
sec-butyllithium leads to O,C-dianion 7. Whereas the C,C-
dianion 4 apparently cannot be formed, 7 is a readily
accessible intermediate. Exposure of 7 to iodomethane,
followed by quenching the reaction with 5% HCl in ethanol
gave 9a in 75% overall yield.
a
Yields calculated from the corresponding amides.
The cyclization leading to 9a is a triply convergent process
involving an allene, a morpholino amide, and an electrophile.
As such, it may be useful for application to the synthesis of
diverse small-molecule libraries.6 At a minimum, this
modification to our method has the potential to simplify the
preparation of R-methylene cyclopentenones substituted at
C6. We had also postulated that the approach that is outlined
in Scheme 1 would lend itself to the preparation of
R-methylene cyclopentenones that incorporate functionality
at C6 that is not compatible with the conditions for
R-lithiation of allenyl ethers. This proved to be the case.
Table 1 summarizes the results that were obtained with
various electrophiles. Product yields varied from moderate
to good; in all cases, a negligible (<5%) amount of cyclic
product unsubstituted at C6 was isolated from the reaction
mixtures. In the case of allyl bromide and n-butyl iodide,
we found it necessary to add HMPA in order to accelerate
the alkylation reaction that was slow at -30 °C. The yield
of 9f through the triply convergent procedure (54%; see Table
1) is comparable to the yield of 9f from allene 2b (R ) n-Bu;
6
1%). When alkyl halides were used as electrophiles,
quenching the reaction with aqueous KH
cyclization and generally led to a mixture of the (E)- and
Z)-isomers at the exocyclic double bond. Treatment of this
mixture with aqueous HCl led to isomerization of the (E)-
and (Z)-isomer. The reaction could also be quenched with
aqueous HCl, in which case only the (E)-isomers were
isolated. When ketones were used as electrophiles, no
2 4
PO catalyzed the
(
5) (a) Leroux, Y.; Mantione, R. Tetrahedron Lett. 1971, 12, 591-592.
b) Eisch, J. J.; Behrooz, M.; Galle, J. E. Tetrahedron Lett. 1984, 25, 4851-
854. (c) Pang, Y.; Petrich, S. S.; Young, V. G., Jr.; Gordon, M. S.; Barton,
(
4
(
T. J. J. Am. Chem. Soc. 1993, 115, 2534-2536. (d) Seyferth, D.; Langer,
P.; D o¨ ring, M. Organometallics 1995, 14, 4457-4459. See also: Reich,
H. J.; Holladay, J. E.; Walker, T. G.; Thompson, J. L. J. Am. Chem. Soc.
1
999, 121, 9769-9780.
6) Jang, W. B.; Hu, H.; Lieberman, M. M.; Morgan, J. A.; Stergiades,
I. A.; Clark, D. S.; Tius, M. A. J. Comb. Chem. 2001, 3, 346-353.
(
1682
Org. Lett., Vol. 5, No. 10, 2003

isomerization of the exocyclic double bond was observed7
even when the reactions were quenched with HCl (see 9d
and 9e). This may be an indication that the rate of acid-
catalyzed isomerization of the exocyclic double bond is
diminished by electronic deactivation by the allylic hydroxyl
group. Alternatively, the sterically favored isomer may be
the (Z)-isomer in these cases. The (E)-isomer may be
disfavored by destabilizing interactions of the sterically
Table 2. R-Ethyl Cyclopentenonesa
8
demanding C6 substituent with the C4 phenyl group. When
trimethylsilyl chloride was used as the electrophile, it was
necessary to quench the reaction with KH PO since pro-
2 4
tiodesilylation of 9b took place rapidly in the presence of
HCl. Under these conditions, the (Z)-isomer 9b was isolated
as the sole reaction product.
There are three broad categories of the cyclopentannela-
tion, differing in the R,â-unsaturated electrophilic component.
The morpholino amides lead to R-hydroxy cyclopentenones,
9
whereas nitriles lead to R-amino cyclopentenones and
ketones to R-alkyl (or aryl) cyclopentenones. Our goal was
to determine whether what was successful in the case of
morpholino amides would also work in the other two
categories. When we used enone 10 as the electrophile, the
intermediate alcohol 11 was isolated and then cyclized in a
separate step (Scheme 2). The cyclization could be effected
Scheme 2a
a
Yields calculated from the corresponding amides.
a
Reaction conditions: (a) 1.2 equiv of n-BuLi, THF, -78 °C,
cyclic products to HCl led to isomerization of the exocyclic
double bond.
2
0 min; (b) 1.0 equiv of 10, -78 °C, 30 min; (c) 1.7 equiv of
+
sec-BuLi, -78 °C, 20 min; (d) E (see Table 2); (e) aqueous
NaHCO ; (f) FeCl , CH Cl
3
3
2
2
.
either by trifluoroacetic anhydride/2,6-lutidine or FeCl
3
. The
yields of products were in all cases moderate or good (Table
1
0
2
). As in the cases described in Table 1, exposure of the
(
7) Stereochemistry of the exocyclic double bond was assigned on the
1
basis of comparison of the H NMR chemical shift of the vinyl proton at
C6. The vinyl proton of the (E)-isomers appears up to 1.2 ppm downfield
of where it appears in the spectra of the (Z)-isomers. In cases in which a
single isomer was isolated, stereochemistry was assigned by analogy, or,
in the case of 9d and 12d, by NOE.
The triply convergent strategy also works in the case of
R,â-unsaturated nitriles (eq 2). Addition of 3 to R-methyl-
cinnamonitrile followed by γ-deprotonation of the intermedi-
ate, trapping of the dianion with either benzophenone or
trimethylsilyl chloride, and cyclization led to (Z)-products
(
(
8) In the case of 9d, this hypothesis is supported by an MM2 calculation.
9) Tius, M. A.; Chu, C. C.; Nieves-Colberg, R. Tetrahedron Lett. 2001,
1
1
4
2, 2419-2422.
1
2 4 3
3 (KH PO quench) or 14 (FeCl quench). The choice of
(10) Dr. Oliver Weichold was the first person in our research group to
electrophiles appears to be limited, since the deprotonated
imine function in the intermediate dianion is a reactive
prepare C6-substituted cyclopentenones through a variant of the process
that is summarized in Scheme 2.
Org. Lett., Vol. 5, No. 10, 2003
1683

nucleophile. All attempts to use alkyl halides as electrophilic
traps for the dianion led to complex mixtures of products.
We have recently described an asymmetric version of the
trap them with diverse electrophiles. The result is a triply
1
4
convergent process that combines R-lithioallene 3 with an
R,â-unsaturated morpholino amide, ketone, or nitrile and with
an electrophile. The respective products are R-hydroxy-,
R-alkyl-, or R-aminocyclopentenones. Structures that cannot
be prepared through our earlier method (9b, 9d, 9e, 12b,
12d, 13, and 14) are readily accessible. Significantly, this
protocol is also successful in the asymmetric version of the
cyclopentannelation (eq 4). These results extend the scope
of the cyclopentannelation reaction, add to its versatility, and
suggest applications to the synthesis of small-molecule
libraries.
1
2
cyclopentannelation reaction that makes use of allene 15.
We were particularly interested in learning whether the
asymmetric version of the cyclization would also be ame-
nable to this new approach. The three preliminary experi-
ments have led to gratifying results (eq 3). Cyclopentenone
(R)-9a was obtained in 70-75% yield and in 78% ee. This
represents a modest improvement over our earlier work that
12
had led to (R)-9a in 67% yield and 70% ee. Cyclopentenone
(
9
R)-9c was formed in 54% yield and 60% ee, whereas (R)-
e was formed in 53% yield and 60% ee.13
Acknowledgment. We thank the National Institutes of
Health (GM57873) for generous support. We acknowledge
Dr. Oliver Weichold for his early contribution to this project.
Supporting Information Available: General procedures
for the synthesis of 9a, 12a, 14, and (R)-9a; spectroscopic
1
data for 9b-g, 12a-f, 13, and 14; and reproductions of H
NMR spectra of 9a-g, 12a-f, 13, and 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL034309+
(
11) It is usually necessary to protect the R-amino function in this series
to prevent polymerization of the products from occurring. In the case of
3, the polymerization through Michael addition to C6 by the amino function
is sterically inhibited.
12) Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem
Soc. 2002, 124, 10091-10100.
13) Ee of (R)-9e was determined by Mosher analysis of the H NMR
spectrum because we were unable to resolve the enantiomers by chiral HPLC
Chiralcel OD column). To validate the Mosher method for our system,
1
(
1
(
(
we measured the ee of (R)-9a by chiral HPLC (78%) and by Mosher’s
method (76%). (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512-519. (b) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
In conclusion, we have been successful in developing a
very convenient procedure that leads to C6-substituted
R-methylene cyclopentenones. The success of the method
depends on being able to generate dianions such as 7 and to
3
4, 2543-2549.
(
14) Tius, M. A.; Gomez-Galeno, J.; Gu, X.-Q.; Zaidi, J. H. J. Am. Chem.
Soc. 1991, 113, 5775-5783.
1684
Org. Lett., Vol. 5, No. 10, 2003