Aza-piancatelli rearrangement initiated by ring opening of donor-acceptor cyclopropanes

Article abstract of DOI:10.1021/ol401248p

The development of a new platform to initiate the cascade rearrangement of furans for the formation of functionalized cyclopentenone building blocks is reported. This methodology allows the creation of congested vicinal stereogenic centers with high diastereoselectivity through a 4π-electrocyclization process.

Full text of DOI:10.1021/ol401248p

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Aza-Piancatelli Rearrangement Initiated
by Ring Opening of DonorÀAcceptor
Cyclopropanes
Donald R. Wenz and Javier Read de Alaniz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
California 93106-9510, United States
javier@chem.ucsb.edu
Received May 3, 2013
ABSTRACT
The development of a new platform to initiate the cascade rearrangement of furans for the formation of functionalized cyclopentenone building
blocks is reported. This methodology allows the creation of congested vicinal stereogenic centers with high diastereoselectivity through a
4π-electrocyclization process.
Functionalized cyclopentenones are an important struc-
tural motif frequently found in natural products and
pharmaceutical drugs.1 The 4π-electrocyclization of
pentadienyl cation intermediates represents one of the
most powerful methods available for constructing cyclo-
pentenones. The quintessential example is the Nazarov
cyclization, which relies on a divinyl ketone as the pre-
cursor to the requisite pentadienyl cation intermediate.2
Limitations associated with the dienone substitution pat-
tern in the Nazarov cyclization have inspired the search for
new approaches to access the requisite pentadienyl cation,
and progress in this area has been demonstrated in several
elegant reports.3
We were drawn to a conceptually distinct strategy to
gain access to the required pentadienyl cation intermediate
that is based on the cascade molecular rearrangement of
R-furylcarbinols (Scheme 1).4 The overall transformation is
highly diastereoselective and believed to proceed through a
cascade sequence that terminates in a 4π-electrocyclic ring
closure of a pentadienyl cation intermediate D.5
Since the pioneering work by Piancatelli et al. in 1976,
the synthesis of functionalized 4-hydroxy- and 4-amino-
cyclopentenones through a molecular rearrangement has
almost exclusively relied on R-furylcarbinols.6 The classic
Piancatelli rearrangement is initiated by activation of
(4) (a) Veits, G. K.; Wenz, D. R.; Read de Alaniz, J. Angew. Chem.,
Int. Ed. 2010, 49, 9484. (b) Palmer, L. I.; Read de Alaniz, J. Angew.
Chem., Int. Ed. 2011, 50, 7167. (c) Palmer, L. I.; Read de Alaniz, J. Org.
Lett. 2013, 15, 476.
(5) For computational studies on the proposed mechanism, see: (a)
Faza, A. N.; Lopez, C. S.; Alvarez, R.; de Lera, I. R. Chem.;Eur. J.
2004, 10, 4324. (b) Davis, L. D.; Tantillo, D. J. Curr. Org. Chem. 2010,
14, 1561.
(6) (a) Piancatelli, G.; Scettri, A.; Barbadoro, S. Tetrahedron Lett.
1976, 17, 3555. (b) Piancatelli, G.; Dauria, M.; Donofrio, F. Synthesis
1994, 867. (c) Yin, B.-L.; Wu, Y.-L.; Lai, J.-Q. Eur. J. Org. Chem. 2009,
2695. (d) Ulbrich, K.; Kreitmeier, P.; Reiser, O. Synlett 2010, 2037. (e)
Reddy, B.V. S.; Narasimhulu, G.; Lakshumma, P. S.; Reddy, Y. V.;
Yadav, J. S. Tetrahedron Lett. 2012, 53, 1776. (f) Reddy, B. V. S.; Reddy,
Y. V.; Lakshumma, P. S.; Narasimhulu, G.; Yadav, J. S.; Sridhar, B.;
Reddy, P. P.; Kunwar, A. C. RSC Adv. 2012, 2, 10661.
(1) For representative reviews, see: (a) Gibson, S. E.; Lewis, S. E.;
Mainolfi, N. J. Organomet. Chem. 2004, 689, 3873. (b) Kurteva, V. B.;
Afonso, C. A. M. Chem. Rev. 2009, 109, 6809. (c) Roche, S. P.; Aitken,
D. J. Eur. J. Org. Chem. 2010, 5339.
(2) For reviews on the Nazarov reaction, see: (a) Frontier, A. J.;
Collison, C. Tetrahedron 2005, 61, 7577. (b) Pellissier, H. Tetrahedron
2005, 61, 6479. (c) Tius, M. A. Eur. J. Org. Chem. 2005, 2193. (d) Grant,
T. N.; Rieder, C. J.; West, F. G. Chem. Commun. 2009, 5676. (e) Vaidya,
T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3, 1531.
(3) For representative examples, see: (a) Prandi, C.; Deagostino, A.;
Venturello, P.; Occhiato, E. G. Org. Lett. 2005, 7, 4345. (b) Grant, T. N.;
West, F. G. J. Am. Chem. Soc. 2006, 128, 9348. (c) Spencer, W. T.; Levin,
M. D.; Frontier, A. J. Org. Lett. 2010, 13, 414. (d) Wu, Y.-K.; West,
F. G. J. Org. Chem. 2010, 75, 5410. (e) Brooks, J. L.; Caruana, P. A.;
Frontier, A. J. J. Am. Chem. Soc. 2011, 133, 12454.
r
10.1021/ol401248p
XXXX American Chemical Society

Table 1. Lewis Acid Screen for the Rearrangement
Scheme 1. Proposed Mechanism of the Molecular
Rearrangement
entry
cat.
time
yield (%)a
ratiob 4:5
1
Cu(OTf)2
Dy(OTf)3
La(OTf)3
Sc(OTf)3
Sn(OTf)2
Yb(OTf)3
YbCl3
48 h
5 min
5 min
5 min
48 h
5 min
24 h
24 h
2 h
<5
57
77
50
<5
58
80
84
83
58
58
<5
n.d.
6:1
1:1
5:1
n.d.
2:1
1:1
1:1
2:1
2:1
3:1
n.d.
2
3
4
5
6
R-furylcarbinols with a Brønsted or Lewis acid. Despite the
success of this strategy, this mode of activation has its
limitations. For example, when furylcarbinols bearing a ter-
tiary carbinol side chain are employed, a competitive dehy-
dration pathway severely decreases the yield of the molecular
rearrangement (Scheme 2, eq 1).7 To permit greater func-
tional group compatibility and to open a new direction for the
Piancatelli rearrangement, alternative methods for triggering
the reaction are necessary. Here, we describe a novel strategy
to initiate the cascade sequence by reporting the first highly
stereoselective aza-Piancatelli rearrangement to assemble
R-quaternary carbon stereocenters (Scheme 2, eq 2).
7
8c
9c,d
10e
11e
12e
ZnBr2
ZnBr2
Dy(OTf)3
Sc(OTf)3
Sn(OTf)2
24 h
3 h
48 h
1
a Determined by H NMR spectroscopy using dimethyl terephtha-
late as the internal standard. b Determined by H NMR spectroscopy.
1
c 1 equiv of ZnBr2 was used. d Reaction conducted at 80 °C. e Reaction
conducted in CH2Cl2. n.d = not determined.
ring strain (27.5 kcal/mol)9 and polarization of substituted
DÀA cyclopropanes make them latent carbocation
equivalents upon Lewis acid activation.10 This work pro-
vides a new mode of activation for the molecular rearran-
gement of a range of furans that complements the
traditional Piancatelli rearrangement.
Scheme 2. Cascade Rearrangements of Activated Furans
Substituted cyclopropane 3 was selected as a model
substrate to test the feasibility of using a DÀA cyclopro-
panetotrigger the cascaderearrangement. Lewis acids that
were previously known to facilitate ring-opening of DÀA
cyclopropanes were initially evaluated using p-methoxy-
aniline as the nucleophile component.8 Several Lewis acids
were found to promote the desired cascade reaction, al-
beit in a range of conversions and diastereoselectivities
(Table 1). To our gratification, the reactions are facile and
often complete in <10 min at rt in reagent grade aceto-
nitrile. From the initial screen, Lewis acidic salts of rare
earth, Dy(OTf)3, and Sc(OTf)3 were identified to be super-
ior catalysts with respect to diastereoselectivity and con-
version. Although less selective, fewer decomposition
byproducts were observed by 1H NMR spectroscopy when
YbCl3 and ZnBr2 catalysts were used. Interestingly, an
increase in both the rate and diastereoselectivity was
observed with ZnBr2 at 80 °C compared to ZnBr2 at rt
(cf. entries 8 and 9). There was no noticeable improvement
Our pursuit of a new trigger for the aza-Piancatelli
reaction started by investigating the use of donorÀ
acceptor (DÀA) cyclopropanes, as they are proven to be
extremely versatile synthetic intermediates.8 The inherent
(9) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.;
Hudlicky, T. Chem. Rev. 1989, 89, 165.
(10) For representative examples using cyclopropanes in the homo-
(7) D’Auria, M.; D’Onofrio, F.; Piancatelli, G.; Scettri, A. Gazz.
Chim. Ital. 1986, 116, 173.
(8) For representative reviews on DÀA cyclopropanes, see: (a)
Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (b) Yu, M.;
Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (c) Carson, C. A.; Kerr,
M. A. Chem. Soc. Rev. 2009, 38, 3051. (d) Campbell, M. J.; Johnson,
J. S.; Parsons, A. T.; Pohlhaus, P. D.; Sanders, S. D. J. Org. Chem. 2010,
75, 6317.
Nazarov cyclization, see: (a) Yadav, V. K.; Kumar, N. V. Chem.
ꢀ
R.; Waser, J. Org. Lett. 2009, 11, 1023. (c) De Simone, F.; Gertsch, J.;
Waser, J. Angew. Chem., Int. Ed. 2010, 49, 5767. (d) Patil, D. V.; Phun,
L. H.; France, S. Org. Lett. 2010, 12, 5684. (e) Phun, L. H.; Patil, D. V.;
Cavitt, M. A.; France, S. Org. Lett. 2011, 13, 195.
Commun. 2008, 0, 3774. (b) De Simone, F.; Andres, J.; Torosantucci,
B
Org. Lett., Vol. XX, No. XX, XXXX

using dichloromethane as the solvent, which is often used
in ring-opening reactions of DÀA cyclopropanes (entries
10À12). We chose to investigate the scope of this transfor-
mation with dysprosium triflate because it gave the best
diastereoselectivity and because of our long-term interest
in this intriguing Lewis acid.11 It is important to note that
water plays a role in the selectivity of the rearrangement;
see Supporting Information for more details.
Scheme 3. Substrate Scope for the Cascade Rearrangementa
Under the optimized reaction conditions (10 mol %
Dy(OTf)3, MeCN, rt), we investigated the scope of this trans-
formation with various aniline nucleophiles (Scheme 3). A
variety of cyclopentenones were synthesized in excellent yield
with diastereoselectivities that range from 6:1 to 60:1. Nucle-
ar Overhauser effect spectroscopy (NOESY) of the major
diastereomer and X-ray crystal structure analysis of 10
indicated a cis-relationship between the C4 hydrogen atom
and C5 tethered dimethyl malonate group.12 In general, the
use of anilines substituted with an electron-withdrawing
group resulted in the highest diastereoselectivity (11À13).
Secondary anilines were also well tolerated, but a drop in
diastereoselectivity was observed for tetrahydroquinoline 15
compared to N-methylaniline 14.
Encouraged by these results, we subsequently investi-
gated a series of reactions to evaluate if other aryl sub-
stitutedDÀA cyclopropanes would be compatible withthe
new mode of activation. Specifically, we studied the elec-
troniceffects by varying the R1 substituentsonthe arylring
attached to cyclopropane starting material 6 (Scheme 3).
The reaction proceeded exceptionally well when R1 was an
electron rich p-methoxyphenyl group (16À18). In these cases,
excellent diastereoselectivities were obtained with anilines
possessing either an electron-donating group (16) or an
electron-withdrawing group (18). This is a notable distinction
compared to cascade rearrangements with 3 (Ar = Ph; com-
pare substrates 4and 16 to 11 and 18, respectively). It appears
that the electron-rich aryl substituent plays a more signifi-
cant role in controlling the diastereoselectivity compared
to anilines and can override the wide variations previously
observed.
To our surprise, we discovered that it was difficult
to study the cascade rearrangement when an electron-
deficient group was placed at the R1 position because the
products derived from these substrates were less stable and
frequently underwent an intramolecular Michael addition
to afford a bicyclic compound.13 X-ray crystal structure
analysis of bicycle 22 helped establish the configuration of
the three contiguous stereocenters and confirmed that only
the cyclopentenone derived from the major diastereomer
led to bicycle formation (Figure 1).14 Unfortunately, all
attempts to suppress bicycle formation were unsuccessful
and isolation of the desired cyclopentenone product was
further complicated by bicycle formation during column
chromatography. Although cyclopentenone product isola-
tion was difficult, 1H NMR spectroscopy was successfully
utilized to study the diastereoselectivity resulting from
a Diastereoselectivity and yield determined by 1H NMR spectroscopy
using dimethyl terephthalate as the internal standard. bSee Supporting
Information for details.
the cascade rearrangement. Treatment of a cyclopropane
bearing an electron-withdrawing benzonitrile group with a
variety of anilines resulted in products with low diastereo-
selectivity, ranging from 1:1 to 5:1 (19À21). Under the
current reaction conditions, the incorporation of an elec-
tron-deficient aryl ring decreases product stability and
erodes diastereoselectivity. Despite this, we were pleased
to find that all reactions in Table 2 could be initiated at
ambient temperature and pressure, regardless of the elec-
tronic nature of the aryl ring attached to the DÀA
(11) Veits, G. K.; Read de Alaniz, J. Tetrahedron 2012, 68, 2015.
(12) See Supporting Information. CCDC 916408.
(13) p-Benzonitrile and p-trifluoromethyl benzene were tested.
(14) See Supporting Information. CCDC 901791.
Org. Lett., Vol. XX, No. XX, XXXX
C

cyclopropane starting material. High temperatures or pres-
sures are often required to help facilitate the Piancatelli
reaction when furylcarbinols are employed.6b
Scheme 4. Diastereoselectivity Shows an Inverse Temperature
Dependencea
Figure 1. ORTEP drawing of bicyclic compound 22 (left) shown
with 50% thermal ellipsoids. Hydrogen atoms have been
omitted for clarity.
We next turned our attention toward increasing the
diastereoselectivity of reactions that proceeded with mod-
erate levels of selectivity (below 12:1). Early experiments
indicated that temperature influenced the diastereoselec-
tivity of the cascade rearrangement (Table 1, entry 9).
Generally, increasing the reaction temperature leads to
decreased levels of stereocontrol; however, there have been
reports in the literature illustrating an inverse relationship
between temperature and stereoselectivity.15 To our de-
light, increasing the reaction temperature to 80 °C lead to a
significant increase in the levels of diastereoselectivity
(Scheme 4). The diastereoselectivity increased from 6:1 to
16:1 (4) when p-methoxyaniline was employed and from
13:1 to 30:1 (9) when aniline was used. Importantly, the
efficiency of these reactions also improved. We observed a
similar pattern of higher temperatures leading to increased
levels of diastereoselectivity for the series of cyclopropane
starting materials bearing an electron-withdrawing aryl
group (19, 20, and 21).16 The most notable example was
with p-trifluoromethylaniline where the selectivity went
from 5:1 to 22:1
The results in Schemes 3 and 4 revealed that both the
temperature and electronic nature of the substituents at the
termini of the pentadienyl cation intermediate, either C1 or
C5, influence the diastereoselectivity of the transforma-
tion. To gain insight into the mechanistic implications of
the increased diastereoselectivity with heat, we carried out
reversibility studies. Resubjection of 4, 11, 12, and 19 tothe
reaction conditions at 80 °C did not provide any support
for a reversible reaction. The minor diastereomer remained
unchanged, and some of the major diastereomer was
converted into a bicyclic compound via an intramolecular
a Diastereoselectivity and yield determined by 1H NMR spectroscopy
using dimethyl terephthalate as the internal standard.
Michael addition, analogous to the formation of 22. These
results suggest that the 4π-electrocyclization is not rever-
sible under the reaction conditions and that there is an
inverse temperature dependence on the diastereoselec-
tivity.15 Further studies are underway to help elucidate
the mechanism and the diastereodetermining event of this
cascade transformation.
In conclusion, we have developed a method for the
construction of densely functionalized cyclopentenones
based on a new cascade rearrangement. Electron-donating
groups at the C5 position, electron-withdrawing groups on
the aniline, and heat all increase the diastereoselectivity of
the transformation. Utilizing uniquely reactive donorÀ
acceptor cyclopropanes as a trigger for the aza-Piancatelli
provides efficient access to all-carbon quaternary stereo-
genic centers and provides a novel platform to initiate the
cascade rearrangement. We believe this new approach holds
promise to develop other novel transformations.
Acknowledgment. This work was supported by the
UCSB and National Science Foundation (CAREER
Award CHE-1057180). We also thank Dr. Guang Wu
(UCSB) for X-ray analysis.
(15) (a) Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746.
ꢁ
(b) Marko, I. E.; Chesney, A.; Hollinshead, D. M. Tetrahedron: Asym-
metry 1994, 5, 569. (c) Stone, G. B. Tetrahedron: Asymmetry 1994, 5, 465.
(d) Muzart, J.; Henin, F.; Aboulhoda, S. J. Tetrahedron: Asymmetry
Supporting Information Available. Full experimental
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢁ
1997, 8, 381. (e) Sibi, M. P.; Rheault, T. R. J. Am. Chem. Soc. 2000, 122,
8873.
(16) As observed previously with substrates bearing an electron-
deficient aryl ring, the same difficulties in product isolation were
encountered.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX