Unique reactivity of anti - and syn-acetoxypyranones en route to oxidopyrylium intermediates leading to a cascade process

Article abstract of DOI:10.1021/ol4012986

Unique reactivity of anti- and syn-acetoxypyranones was observed in oxidopyrylium-alkene [5 + 2] cycloadditions. The subtle interplay between the corresponding acetoxypyranone conformation and steric bulk of tertiary amine bases causes syn-acetoxypyranones to undergo [5 + 2] cycloaddition appreciably faster than anti-acetoxypyranones. Additionally, the efficiency of a cascade process that afforded a novel tetracyclic lactol was determined to be dependent on the relative stereochemistry of each diastereomer, the amine base utilized, and the addition of water.

Full text of DOI:10.1021/ol4012986

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Unique Reactivity of anti- and
syn-Acetoxypyranones en Route
to Oxidopyrylium Intermediates
Leading to a Cascade Process
000–000
†
†
Erica L. Woodall, Justin A. Simanis, Christopher G. Hamaker, John R. Goodell, and
T. Andrew Mitchell*
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160,
United States
tmitche@ilstu.edu
Received May 9, 2013
ABSTRACT
Unique reactivity of anti- and syn-acetoxypyranones was observed in oxidopyrylium-alkene [5 þ 2] cycloadditions. The subtle interplay between
the corresponding acetoxypyranone conformation and steric bulk of tertiary amine bases causes syn-acetoxypyranones to undergo [5 þ 2]
cycloaddition appreciably faster than anti-acetoxypyranones. Additionally, the efficiency of a cascade process that afforded a novel tetracyclic
lactol was determined to be dependent on the relative stereochemistry of each diastereomer, the amine base utilized, and the addition of water.
Cycloadditions constitute an efficient avenue toward the
1
synthesis of seven-membered ring systems. Oxidopyrylium-
Herein, we report the unique reactivity of anti- and syn-
acetoxypyranones 1 toward oxidopyrylium-alkene [5 þ 2]
cycloadditions (Scheme 1b). Investigation of various amine
base-mediated [5 þ 2] cycloadditions revealed a general
trend of syn-1 reacting faster than anti-1.
alkene [5 þ 2] cycloadditions give bridged, polycyclic ethers
which are common to many biologically active natural
2
products. Although many routes toward oxidopyrylium
intermediates have been disclosed, base-mediated or ther-
3
mal conversion of acetoxypyranones derived from Achma-
towicz rearrangement of readily available furfuryl alcohols
4
remains one of the most practical and versatile pathways.
Intramolecular variants were first reported by Sammes to
Scheme 1. Acetoxypyranone Conversion to Oxidopyrylium
Intermediates toward Intramolecular [5 þ 2] Cycloadditions
5
deliver bridged, tricyclic ethers (Scheme 1a). More recently,
Jacobsen disclosed an elegant approach toward enantio-
selective, intramolecular [5 þ 2] cycloadditions of similar
6
substrates.
†
E.L.W. and J.A.S. contributed equally.
(
1) Pellissier, H. Adv. Synth. Catal. 2011, 353, 189.
(2) Singh, V.; Krishna, U. M.; Vikrant; Trivedi, G. K. Tetrahedron
2008, 64, 3405.
(
3) Hendrickson, J. B.; Farina, J. S. J. Org. Chem. 1980, 45, 3359.
(4) (a) Achmatowicz, O.; Szechner, P. B. B.; Zwierzchowska, Z.;
Zamojski, A. Tetrahedron 1971, 27, 1973. (b) Georgiadis, M. P.; Albizati,
K. F.; Georgiadis, T. M. Org. Prep. Proc. Int. 1992, 24, 95.
(5) Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1982,
1056.
(
6) Burns, N. Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc.
2011, 133, 14578.
1
0.1021/ol4012986 r XXXX American Chemical Society

Upon preparation of the known acetoxypyranone 1a
emerged. First, from the pairwise comparison of structurally
similar bases such as N-methylmorpholine and N-methylpi-
peridine (entries 4,7), it is apparent that the electronic effects
of sterically comparable bases play an important role.
Second, the decreased steric hindrance of bases with similar
(
tricylic ether 2a (75% yield), the mixture was separated via
dr ∼2:1) previously utilized directly by Sammes en route to
5
SiO flash column chromatography to deliver diastereo-
2
1
merically pure (>19:1 as determined by H NMR analysis)
acetoxypyranones anti- and syn-1a (Scheme 2). The rela-
tive stereochemistry of each diastereomer was confirmed
by NOE analysis of syn-1a and X-ray crytallographic
pK values also plays a significant role, which is best
a
illustrated by the increasing conversion trend observed from
N,N-diisopropylethyl amine, triethylamine, N-methylpi-
peridine, NMP, and QUIN (entries 5ꢀ9). Lastly, these
results demonstrate that syn-acetoxypyranone 1a consis-
tently undergoes conversion to tricyclic ether 2a at a
qualitatively faster rate than anti-acetoxypyranone 1a.
7
analysis of the corresponding p-bromobenzoate analog.
For the purposes of this study, the reactivity of each
acetoxypyranone diastereomer was evaluated separately.
Our initial investigation focused on the attempted intra-
molecular cycloaddition of anti- and syn-acetoxypyranone-
enals 1b, which were prepared separately from anti-
and syn-1a via GrubbsꢀHoveyda cross-metathesis with
Table 1. Initial Screening of Amine Bases
8
crotonaldehyde. Although a complex mixture was ob-
9
tained and tricyclic ether 2b could not be isolated, we were
intrigued by the differing rates and product distributions
for each diastereomer. As a result of these initial studies, we
chose to investigate the reactivity of each acetoxypyranone
diastereomer anti- and syn-1a more thoroughly.
anti-1a/2a syn-1a/2a
a
a
entry
base
(% yield) (% yield)
1
2
4
5
6
7
8
9
none
99/0
88/0
89/5
86/5
62/36
59/41
0/88
0/90
0/81
0/34
93/0
90/2
68/14
68/14
6/80
7/89
0/91
0/95
0/88
0/37
Scheme 2. Attempted Cyclization of Acetoxypyranone-Enals 1b
pyridine
N-methylmorpholine
N,N-diisopropylethyl amine
triethylamine
N-methylpiperidine
N-methylpyrrolidine
quinuclidine
1
0
1,4-diazabicyclo[2.2.2]octane
1,8-diazabicyclo[5.4.0]undec-7-ene
11
a
1
Determined by H NMR analysis utilizing 1,3,5-trimethoxybenzene
as the internal standard.
To probe the base dependency, four effective bases
NMP, DABCO, QUIN, and DBU) were subjected to
(
various solvents at ambient temperature (Table 2). It was
determined that QUIN and DBU are the most efficient
bases and that CH Cl and CH CN are the most efficient
2
2
3
solvents (entries 11,12 and 15,16). With these conditions,
both the steric and electronic phenomena were further
validated since QUIN is less hindered than NMP and
DABCO is inductively deactivated compared to QUIN.
Perhaps indicative of the unique reactivity patterns of
1
0
Screening of amine bases at 60 °C in acetonitrile revealed
varying degrees of conversion with N-methylpyrrolidine
DBU, utilizing a single equivalent led to the increased
yield of ether 2a (i.e., Table 1, entry 11vs Table 2, entry 16).
Excess DBU and use of other bases such as imidazole
afforded complex mixtures of unidentified products.
In order to confirm the generality of this qualitative rate
(
(
NMP), quinuclidine (QUIN), 1,4-diazabicyclo[2.2.2]octane
DABCO), and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU)
all providing complete consumption of starting acetoxypyr-
anone (Table 1). From this base screen, three clear trends
difference, the same bases were tested in CH CN with an
3
electron-donating alkene (1c) and an electron-withdraw-
7
ing alkene (1d) (Table 3). Although some variation was
(
(
7) See Supporting Information for further details.
8) (a) Movassaghi, M.; Tjandra, M.; Qi, J. J. Am. Chem. Soc. 2009,
exhibited, these conversion results further validate the
general rate enhancement for the syn-acetoxypyranones
1c,d toward cycloadducts 2c,d and the aforementioned
1
31, 9648. (b) Chatterjee, A.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360. (c) Cossy, J.; BouzBouz, S.;
Hoveyda, A. H. J. Organomet. Chem. 2001, 624, 327. (d) Garber,
S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168.
(
quantity of aldehyde 2b with multiple byproducts.
6
steric and electronic trends (vide supra).
1
9) H NMR analysis of the crude reaction mixtures indicated a trace
(10) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311.
Org. Lett., Vol. XX, No. XX, XXXX
B

1
transition states that resemble low energy conformations
2
of anti-1a and syn-1a, respectively (vide infra).
Table 2. Solvent Screening of Selected Amine Bases
2
Scheme 3. KIE Studies of H-Labeled Acetoxypyranones 1e
anti-1a/2a
syn-1a/2a
a
a
entry
solvent
base
(% yield)
(% yield)
b
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
tol.
NMP
92/3
68/6
c
c
c
c
DABCO
91/8
69/12
42/32
5/80
7
,13
d
QUIN
44/22
7/68
From the calculated
ground-state conformation of
e
DBU
anti-1a (Figure 1), it was observed that the acetate group
adopts an anomeric configuration (pseudoaxial) which
puts the R-proton in an ideal orientation for extraction.
In the case of syn-1a, the calculated ground state con-
b
NMP
71/2
44/5
tol.
DABCO
69/6
28/7
d
tol.
QUIN
58/18
5/48
39/32
0/27
e
tol.
DBU
7
b
formation (not shown) also reveals an anomeric acetate
resulting in a presumably unproductive pseudoequatorial
DCM
DCM
DCM
DCM
NMP
79/13
86/18
30/39
3/68
35/26
62/23
14/63
0/77
1
0
DABCO
d
11
QUIN
orientation of the R-proton. CurtinꢀHammitt/Winsteinꢀ
e
14
Holness kinetic principles likely are operative, as a con-
1
1
1
1
1
2
3
4
5
6
DBU
b
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
NMP
68/25
48/39
0/69
38/42
31/61
0/83
formational ring flip of syn-1a (<1 kcal higher in energy)
would induce the R-proton to reside in the pseudoaxial
position which is perpendicular to the adjacent ketone and
thus serve as the reactive species (Figure 1). Whereas the
acetate group of anti-1a is pseudoaxial resulting in greater
steric hindrance around the acidic proton, the acetate of
the proposed reactive conformation of syn-1a is pseudo-
equatorial and projects away from the acidic proton. The
steric hindrance present in the ground-state conformation
of anti-1a sheds light on corresponding steric interactions
in the proposed early transition state which lead to slower
reactivity.
DABCO
d
QUIN
e
DBU
0/78
0/58
a
1
Determined by H NMR analysis utilizing 1,3,5-trimethoxybenzene
b
as the internal standard. N-Methylpyrrolidine. 1,4-Diazabicyclo[2.2.2]-
octane. Quinuclidine. 1,8-Diazabicyclo[5.4.0]undec-7-ene (only 1 equiv
was utilized).
c
d
e
Table 3. Conversion of Substituted Acetoxypyranones 1cꢀd
Based on these data, a proposed reaction pathway can
be envisioned (Scheme 4). Both anti- and syn-I likely adopt
conformations in which the R-proton is coplanar with the
π-system of the ketone. Rate-determining deprotonation
delivers dienolates III and ent-III that likely have very
short lifetimes due to the impending aromaticity. The
enantiomeric relationship between these dienolates III
and ent-III gives further creedance to the proposed rate-
determining deprotonation since they would rapidly coa-
lesce, thus essentially destroying the inherent difference
and bias between acetoxypyranone diastereomers anti-
and syn-I. However, it is also important to consider the
possibility of slightly different reaction pathways. For
example, it is conceivable that formation of oxidopyrylium
IV via anti-I, although slower, is more concerted due to the
anomeric orientation of the acetate moiety. In either case,
elimination of the acetoxy would deliver the oxidopyry-
lium IV, which undergoes endo [5 þ 2] cycloaddition
anti-1/2
syn-1/2
a
a
entry
R (a/b)
base
(% yield)
(% yield)
b
1
2
3
4
5
6
7
8
CH
CH
CH
CH
3
3
3
3
(c)
NMP
60/16
43/33
2/47
20/48
27/43
0/47
c
c
(c)
DABCO
d
(c)
QUIN
e
(c)
DBU
0/18
0/14
b
CO
CO
CO
CO
2
Et (d)
2
Et (d)
2
Et (d)
2
Et (d)
NMP
42/39
28/51
0/76
12/69
12/72
0/87
DABCO
d
QUIN
e
DBU
0/68
0/70
a
1
Determined by H NMR analysis utilizing 1,3,5-trimethoxyben-
b
zene as the internalstandard. N-Methylpyrrolidine. 1,4-Diazabicyclo-
c
d
2.2.2]octane. Quinuclidine. 1,8-Diazabicyclo[5.4.0]undec-7-ene (only
e
[
2
,6
1
equiv was utilized).
(i.e., endo-V).
We proposed that deprotonation was involved in the
rate-determing step, and thus studies were undertaken that
(11) Melander, L.; Saunders, W. H., Jr. Reaction Rates of Isotopic
Molecules; Wiley and Sons: New York, 1980.
(
12) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334.
2
revealed primary kinetic isotope effects (KIE) for both H-
(
13) Conformational analysis (Spartan ’02, Wavefunction, Inc.)
1
1
using MMFF94 force field, optimization (Gaussian ‘03), and B3LYP,
-31g**, Gaussian, Inc.: Wallingford CT, 2004.
14) (a) Seeman, J. I. Chem. Rev. 1983, 83, 83–134. (b) Seeman, J. I.
J. Chem. Educ. 1986, 63, 42.
labeled acetoxypyranones anti-1e and syn-1e (Scheme 3).
This provided evidence that abstraction of H(D) is in-
volved in the rate-determining step suggestive of early
6
(
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Cascade Process toward Lactol 3
in reasonable yields. Although [5 þ 2] cycloaddition is
believed to occur first, the corresponding bridged, tricyclic
ether 2b is not isolable. Water presumably attacks the
1
6
aldehyde in concert with the conjugate addition in a
facile process delivering the novel caged lactol 3. It is note-
worthy that increased efficiency was observed with quinu-
clidine as compared to alternative amine bases, especially
in the case of acetoxypyranone anti-1b. DBU, for example,
afforded complex mixtures of lactol 3 even with 1 equiv.
The diminished efficiency toward lactol 3 with acetoxypyr-
anone anti-1b is attributed to additional byproducts not
observed with syn-1b that have proven difficult to isolate
and characterize, but are still under investigation. In any
event, this unique oxidopyrylium-alkene [5 þ 2] cycloaddi-
Figure 1. Representations of proposed reactive conformers
anti- and syn-1a with pseudoaxial hydrogens perpendicular to
the ketone (hydrogens removed from tether for clarity).
Scheme 4. Proposed Pathway toward Oxidopyrylium IV
1
7
tion conjugate addition cascade sequence constructs
bonds, 3 rings, and 5 stereocenters to afford a novel
3
tetracyclic lactol 3 from readily accessible acetoxypyra-
none-enals 1b.
The unique reactivity of anti- and syn-acetoxypyranone
diastereomers was demonstrated in oxidopyrylium-alkene
[
5 þ 2] cycloadditions. Due to the subtle interplay be-
tween acetoxypyranone conformations and steric bulk of
tertiary amine bases, syn-acetoxypyranones consistently
undergo cycloaddition faster than the corresponding
anti-acetoxypyranones. Additionally, the efficiency of an
oxidopyrylium-alkene [5 þ 2] cycloaddition conjugate
addition cascade process that afforded a novel tetracyclic
lactol was determined to be dependent upon the relative
stereochemistry of the acetoxypyranone, the amine base
utilized, and the addition of water. Further studies directed
at a deeper understanding of this process and synthetic
applications will be reported in due course.
In the process of investigating reactivity differences of
acetoxypyranone diastereomers, it was previously ob-
served that acetoxypyranone-enals anti- and syn-1b were
unproductive (cf., Scheme 2), which is attributed to further
reaction of the presumed cycloadduct 2b with adventitious
Acknowledgment. Acknowledgment is made to the
Donors of the American Chemical Society Petroleum
Research Fund (PRF #52391-UNI1) for support of this
research. Funding from the College of Arts & Sciences and
Department of Chemistry (ISU) are gratefully acknowledged.
1
5
water (Scheme 5). Continued investigation of acetoxy-
pyranone-enals anti- and syn-1b based upon the optimized
quinuclidine conditions in CH CN/H O delivered lactol 3
3
2
Supporting Information Available. Full experimental
data. This material is available free of charge via the
Internet http://pubs.acs.org.
(
15) Trace lactol 3 was observed without intentional addition of H
2
O.
(16) For a similar, stepwise conjugate addition, see: Snider, B. B.;
Wu, X.; Nakamura, S.; Hashimoto, S. Org. Lett. 2007, 9, 873.
17) (a) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int.
(
Ed. 2007, 46, 1570. (b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A.
Chem. Commun. 2003, 551. (c) Tietze, L. Chem. Rev. 1996, 96, 115.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX