Oxidation-initiated nazarov cyclization of vinyl alkoxyallenes

Article abstract of DOI:10.1021/ol1027255

A mild method for the diastereoselective formation of C₄, C ₅-disubstituted cyclopentenones has been developed, involving formation of a pentadienyl cation via diastereoselective oxidation of a vinyl alkoxyallene. Conrotatory electrocyclization provides the cyclopentenone product. The broad scope, mild conditions, and uncommon substitution pattern accessible through this transformation make it a useful addition to the existing repertoire of cyclopentenone synthetic methods.

Full text of DOI:10.1021/ol1027255

ORGANIC
LETTERS
2011
Vol. 13, No. 3
414-417
Oxidation-Initiated Nazarov Cyclization
of Vinyl Alkoxyallenes
William T. Spencer III, Mark D. Levin, and Alison J. Frontier*
Department of Chemistry, UniVersity of Rochester, Rochester,
New York 14627, United States
frontier@chem.rochester.edu
Received November 10, 2010
ABSTRACT
A mild method for the diastereoselective formation of C4, C5-disubstituted cyclopentenones has been developed, involving formation of a
pentadienyl cation via diastereoselective oxidation of a vinyl alkoxyallene. Conrotatory electrocyclization provides the cyclopentenone product.
The broad scope, mild conditions, and uncommon substitution pattern accessible through this transformation make it a useful addition to the
existing repertoire of cyclopentenone synthetic methods.
Cyclopentenones are an architectural underpinning of a wide
range of natural products and medicinal agents. Moreover,
their practical use as intermediates en route to these com-
pounds of interest makes the development of methods for
their synthesis of perennial importance.
commonly, access to the requisite pentadienyl cation is
gained via routes that do not conform to this conventional
rubric.2
Such an approach is exemplified in our laboratory’s recent
synthesis of (()-Rocaglamide,3 wherein the key step employs
a novel Nazarov cyclization triggered by the oxidation of a
vinyl alkoxyallene (Scheme 1). In this case, a pentadienyl
cation is generated upon oxidation, instead of via exposure
to an acidic promoter. Cyclization gives the cyclopentenone,
and both stereocenters created during the electrocyclization
are retained in the product.4
The Nazarov cyclization has, in recent times, played an
increasingly prominent role in this capacity.1 The prototypical
version employs the Lewis acid activation of a divinyl ketone
to generate a pentadienyl cation, which undergoes π4
a
conrotatory electrocyclization to form an oxyallyl cation.
Subsequent elimination forms the cyclopentenone. Less
(1) (a) Nazarov, I. N.; Zaretskaya, I. I. IzV. Akad. Nauk. SSSR, Ser. Khim.
1941, 211. (b) Santelli-Rouvier, C.; Santelli, M. Synthesis 1983, 429. (c)
Habermas, K. L.; Denmark, S. E.; Jones, T. K. In Organic Reactions;
Paquette, L. A., Ed.; John Wiley & Sons, Inc.: New York, 1994; Vol. 45,
pp 1-158. (d) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577. (e)
Pellissier, H. Tetrahedron 2005, 61, 6479. (f) Tius, M. A. Eur. J. Org.
Chem. 2005, 11, 2193. (g) Grant, T. N.; Rieder, C. J.; West, F. G. Chem.
Commun. 2009, 5676. (h) Nakanishi, W.; West, F. G. Curr. Opin. Drug
DiscoV. 2009, 12, 732.
Scheme 1
.
Oxidation-Initiated Nazarov Cyclization in the
Synthesis of (()-Rocaglamide
(2) (a) Iso-Nazarov example: Miller, A. K.; Banghart, M. R.; Beaudry,
C. M.; Suh, J. M.; Trauner, D. Tetrahedron 2003, 59, 8919. (b) Aza-Nazarov
example: Dieker, J.; Fröhlich, R.; Würthwein, E.-U. Eur. J. Org. Chem.
2006, 23, 5339. (c) Metallo-Nazarov example: Lemiere, G.; Gandon, V.;
Cariou, K.; Fukuyama, T.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M.
Org. Lett. 2007, 9, 2207. (d) Dichlorocyclopropane Nazarov example: Grant,
T. N.; West, F. G. J. Am. Chem. Soc. 2006, 128, 9348. (e) Vinylogous
Nazarov example: Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem.
Soc. 2009, 131, 7504. (f) Allenyl aryl carbinol Nazarov example: Cordier,
P.; Aubert, C.; Malacria, M.; Lacote, E.; Gandon, V. Angew. Chem., Int. Ed.
2009, 48, 8757.
This transformation is suspected to follow the same basic
mechanism as the metabolic conversion of polyunsaturated
(3) Malona, J. A.; Cariou, K.; Frontier, A. J. J. Am. Chem. Soc. 2009,
131, 7560.
10.1021/ol1027255  2011 American Chemical Society
Published on Web 12/14/2010

fatty acids to jasmonates in plants, wherein the enzymatic
conversion of a vinyl allene to a vinyl allene oxide is
followed by formation of a pentadienyl cation that cyclizes
to the cyclopentenone.5 Synthetic studies on the rearrange-
ments of simple vinyl allene oxides to cyclopentenones have
also been conducted.6 Observations included formation of
side products resulting from poor epoxidation selectivity6a
and undesired trapping of the pentadienyl cation intermediate
by nucleophiles present in the reaction mixture.6d
To expand the utility of the oxidation-initiated cyclization
utilized in the rocaglamide synthesis, we sought to explore
the oxidation/cyclization of type 2 allenes, which have an
alkoxy group on the internal allene terminus (Table 1).
Oxidation of these allenes should occur preferentially at the
electron-rich internal double bond. Our choice of substrates
exploits the cyclization’s full potential by enabling the
creation of adjacent stereocenters at C1 and C5 in high
diastereoselectivity.4b
istry shown (entry 1). Payne conditions (entry 2) and
vanadium peroxo-complex conditions (entry 3) each yielded
different unidentifiable products. Methyltrioxorhenium con-
ditions (entry 4) gave complex mixtures. Oxidation using
the Davis oxaziridine gave a reasonable yield of 50%.
However, the best results were obtained by using DMDO,
which furnished bicycle 3a in 63% yield.7
With use of these optimized conditions, a variety of vinyl
allenol ethers with variable substitution patterns were
surveyed (Table 2). Because of the instability of the allenes
to workup and chromatography conditions, we carried them
to the next step without purification. The crude allenes were
of estimated 75-95% purity. Nazarov cyclization yields
based on these estimations are reported alongside the yields
calculated over two steps from the propargylic ether.
Cyclohexenyl allene 2a cyclized to give bicycle 3a with
exclusively cis stereochemistry8 (entry 1). Prolonged expo-
sure to silica caused partial equilibration to the trans-
diastereomer 3b, presumably via keto-enol tautomerism.
Interestingly, chromatography on triethylamine-deactivated
silica allowed isolation of pure diastereomer 3b in the
same yield (entry 2). These results indicate that Nazarov
cyclization leads to the thermodynamically less stable
diastereomer. Cyclization of allene 2c, bearing a methyl
group on one of the cyclization termini, gave bicycle 3d
also as the cis-diastereomer (entry 4). Allene 2d yielded
3e as a single diastereomer, indicating that the methyl
stereocenter in 2d effects a completely torquoselective
cyclization (entry 5).9
Cyclization of 2f, bearing a methyl group on the allene
terminus, allowed formation of a quaternary center on carbon
5 (entry 7), and placement of methyl groups on both termini
(entry 8) cyclized to give bicycle 3h as a single diastereomer
containing adjacent quaternary centers. Cyclization of dihy-
dropyran 2h resulted in a lower yield, presumably due to
competing epoxidation of the two enol ether double bonds
(entry 9). With alkyl substitution on the allene terminus
(entries 10 and 11), a mixture of diastereomers was observed.
Table 1. Oxidant Screening
yield of 3a
entry
conditions
(% over 2 steps)b
1
2
m-CPBA (1 equiv), DMF, -20 to 0 °C
(i) PhCN, K2CO3, MeOH
43
-
c
(ii) H2O2 in H2O
c
3
4
5
6
VO(acac)2, t-BuOOH/decane, CH2Cl2
MTO, H2O2-urea complex, CH2Cl2
Davis oxaziridine, acetone, 0 °C
DMDO, acetone, 0 °C
-
d
-
50
63e
a Conditions for allene formation: t-BuLi, TMEDA, Et2O, -78 °C then
MeOH, -78 °C to rt. b Yields reported are for isolated material after
purification unless otherwise indicated. c Gave an unknown product. d Gave
e
1
a complex product mixture. On the basis of H NMR, using DMF as an
internal standard.
Cyclization of a siloxyethyl-substituted allene resulted in
bicycle 3m in 41% yield over 2 steps (from the vinyl
propargyl ether; Scheme 2). Deprotection of the allene and
subsequent cyclization of the free hydroxyl-containing allene
yielded bicyclic product 3n in 29% yield over 3 steps,
without workup or purification of the intermediates.
Optimization of the cyclization was carried out with
carbocyclic propargylic ether 1a (Table 1). Conversion to
allene 2a was achieved via base-induced isomerization.
m-CPBA oxidation in different solvents resulted in poor to
moderate conversions to bicycle 3a with cis-diastereochem-
(7) For examples of formation of allene diepoxides with DMDO, see:
(a) Lotesta, S. D.; Kiren, S.; Sauers, R. R.; Williams, L. J. Angew. Chem.,
Int. Ed. 2007, 46, 7108. (b) Zhang, Y.; Cusick, J. R.; Ghosh, P.; Shangguan,
N.; Katukojvala, S.; Inghrim, J.; Emge, T. J.; Williams, L. J. J. Org. Chem.
2009, 74, 7707. (c) Ghosh, P.; Cusick, J. R.; Inghrim, J.; Williams, L. J.
Org. Lett. 2009, 11, 4672.
(4) For an example of Nazarov cyclization triggered by protonation
(rather than oxidation) of an allene, see: (a) Wu, Y. K.; West, F. G. J. Org.
Chem. 2010, 75, 5410. For an example of a Nazarov cyclization that affords
products similar to those described here, see: (b) Basak, A. K.; Shimada,
N.; Bow, W. F.; Vicic, D. A.; Tius, M. A. J. Am. Chem. Soc. 2010, 132,
8266.
(8) Stereochemistry of Nazarov products was determined by NOE
analysis (see the Supporting Information).
(5) Recent reviews on the lipoxygenase pathway for jasmonate forma-
tion: (a) Schaller, A.; Stintzi, A. Phytochemistry 2009, 70, 1532. (b) Gfeller,
A.; Dubugnon, L.; Liechti, R.; Farmer, E. E. Sci. Signal. 2010, 3, cm3.
(6) (a) Grimaldi, J.; Bertrand, M. Tetrahedron Lett. 1969, 38, 3269. (b)
Bertrand, M.; Dulcere, J.-P.; Grimaldi, J. C. R. Seances Acad. Sci., Ser. C
1974, 279, 805. (c) Bertrand, M.; Dulcere, J.-P.; Gil, G.; Roumestant, M. L.
Tetrahedron Lett. 1979, 21, 1845. (d) Doutheau, A.; Gore, J.; Malacria, M.
Tetrahedron 1977, 33, 2393. (e) Dulcere, J.-P.; Grimaldi, J.; Santelli, M.
Tetrahedron Lett. 1981, 22, 3179. (f) Kim, S. J.; Cha, J. K. Tetrahedron
Lett. 1988, 29, 5613.
(9) This stereochemical assignment is based upon past observations,
which indicate that bond formation occurs on the least hindered face of the
pentadienyl cation: (a) Denmark, S. E.; Habermas, K. L.; Hite, G. A.; Jones,
T. K. Tetrahedron 1986, 42, 2821. (b) Denmark, S. E.; Habermas, K. L.;
Hite, G. A. HelV. Chim. Acta 1988, 71, 168. (c) Denmark, S. E.; Wallace,
M. A.; Walker, C. B., Jr. J. Org. Chem. 1990, 55, 5543. (d) Paquette, L. A.;
Kang, H.-J. J. Am. Chem. Soc. 1991, 113, 2610. (e) Occhiato, E. G.; Prandi,
C.; Ferrali, A.; Guarna, A.; Venturello, P. J. Org. Chem. 2003, 68, 9728.
(f) Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P.; Occhiato, E. G. J.
Org. Chem. 2004, 69, 7705.
Org. Lett., Vol. 13, No. 3, 2011
415

Table 2. Oxidation-Initiated Nazarov Cyclizations
a t-BuLi, TMEDA, Et2O, -78 °C then MeOH, -78 °C to rt. b DMDO, acetone, 0 °C to rt. c Yields of Nazarov cyclizations are estimated in cases when
allene formation was not quantitative. d Extremely fast silica gel chromatography yielded the cis diastereomer. e Allene estimated to be 85% pure.
f Et3N-deactivated silica gel chromatography yielded the trans diastereomer. g 2:1 mixture of diastereomers. h Allene estimated to be 75% pure.
i Diastereochemical assignment based on NOE analysis of carbonyl reduction product. j Isolated as a 4:1 mixture of diastereomers (major shown). k Isolated
as a 3:1 mixture of diastereomers (major shown).
In an attempted cyclization of triisopropylsiloxy allene 1o,
formation of ketone 5 was observed, presumably via transfer
of the TIPS group to the adjacent anionic oxygen (see 4,
Scheme 3).10 Its stereochemistry suggests that oxidation
occurs on the face of the internal allene double bond away
from the phenyl group, which is consistent with literature
precedent.7,11 However, in substrates with an alkyl group
on the allene terminus instead of a phenyl group, selectivity
was not as high (Table 2, entry 10; 4:1 mixture of
diastereomers). If 2i was treated with a bulky version of the
Scheme 2. Cyclization of Siloxy- and Hydroxyethyl-Substituted
Vinyl Alkoxyallenesa
a dr based on analogy to 3m.
(10) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319.
416
Org. Lett., Vol. 13, No. 3, 2011

Scheme 3. Rubottom Oxidation of O-Silylated Allenol Ethers
Scheme 5
.
Proposed Mechanistic Rationale for Observed
Diastereochemistry
Scheme 4. Cyclization of 2i with Use of a Bulky Oxaziridine
electron-rich internal allene double bond. This rearrangement
offers an attractive two-step conversion of vinyl propargylic
ethers to cyclopentenones with high diastereoselectivity, and
the ability to install adjacent quaternary carbons. Develop-
ment of an enantioselective version of this cyclization is
currently underway in our laboratory.
Davis oxaziridine12 instead of DMDO, an 8:1 mixture of
diastereomers was obtained (Scheme 4).
On the basis of these results and the stereochemistries
of the remaining cyclization products, we hypothesize that
in cases where there is a large difference between steric
bulk of the two substituents on the allene terminus (RL .
RS, Scheme 5), DMDO oxidation of the allene occurs on
the face opposite RL. This produces either allene oxide B
(as a single diastereomer) or generates C directly (with
control of enolate geometry). Pentadienyl cation C then
undergoes conrotatory electrocyclization to give cyclo-
pentenone D as a single diastereomer (products 3a, 3c,
3d, 3f, 3g, 3h, and 3i).
For reactions in which the steric difference between RL
and RS is smaller, our results suggest that the oxidation
does not occur exclusively opposite RL (see A to B′;
Scheme 5), and a mixture of diastereomers D′ is obtained
(products 3j, 3k, and 3m). Thus, the selectivity of the
oxidation is reflected in the product ratio, since we expect
the electrocyclization to occur stereospecifically.13 As
demonstrated in Scheme 4, selectivity was improved with
the use of a bulkier oxidant.
Acknowledgment. The authors thank Professor Barry
M. Trost (Stanford University) for helpful discussions. We
are also grateful to Dr. A. Bergmann (SUNY Buffalo)
and Dr. Furong Sun (University of Illinois at Urbana-
Champaign) for carrying out high-resolution mass spec-
trometry. This work was funded by the NIH (NIGMS R01
GM079364).
Note Added after ASAP Publication. Reviewer com-
ments, including text, references, and Scheme 5 changes,
are included in the version reposted January 11, 2011.
Supporting Information Available: Experimental pro-
cedures for the preparation of all compounds and char-
acterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1027255
(11) Crandall, J. K.; Batal, D. J.; Sebesta, D. P.; Lin, F. J. Org. Chem.
1991, 56, 1153.
In summary, we have developed a mild, oxidation-initiated
Nazarov cyclization. The use of vinyl alkoxyallenes controls
the regioselectivity of oxidation, which occurs on the more
(12) Sandrinelli, F.; Perrio, S.; Beslin, P. J. Org. Chem. 1997, 62, 8626.
(13) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. 1969, 8,
781.
Org. Lett., Vol. 13, No. 3, 2011
417