Divergent stereocontrol of acid catalyzed intramolecular aldol reactions of 2,3,7-triketoesters: Synthesis of highly functionalized cyclopentanones

Article abstract of DOI:10.1021/ol301317a

The intramolecular acid catalyzed aldol cyclization of 2,3,7-triketoesters formed from Χ-keto-α-diazo-β-ketoesters provides highly functionalized cyclopentanones with good diastereoselectivity in high overall yields via kinetically controlled and stereodivergent catalytic processes. Lewis acid catalysis gives high selectivity for the 1,2-anti tetrasubstituted cyclopentanones, whereas Bronsted acid catalysis produces the corresponding 1,2-syn diastereomer.

Full text of DOI:10.1021/ol301317a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Divergent Stereocontrol of Acid Catalyzed
Intramolecular Aldol Reactions of
2,3,7-Triketoesters: Synthesis of Highly
Functionalized Cyclopentanones
Phong Truong, Charles S. Shanahan, and Michael P. Doyle*
Department of Chemistry & Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
mdoyle3@umd.edu
Received May 16, 2012
ABSTRACT
The intramolecular acid catalyzed aldol cyclization of 2,3,7-triketoesters formed from ζ-keto-R-diazo-β-ketoesters provides highly functionalized
cyclopentanones with good diastereoselectivity in high overall yields via kinetically controlled and stereodivergent catalytic processes. Lewis
acid catalysis gives high selectivity for the 1,2-anti tetrasubstituted cyclopentanones, whereas Brønsted acid catalysis produces the
corresponding 1,2-syn diastereomer.
New strategies for the synthesis and application of
complex diazo compounds have proven fruitful in the
preparation of carbocyclic and heterocyclic ring systems
due to the proven utility of selective diazo decomposition
reactions in complex environments.1 A longstanding inter-
est in our research group has been the application of enol
diazoacetates of type 1 toward the synthesis of more
complex diazo compounds by developing methods that
take advantage of the remarkable stability of the diazo-β-
ketoester functional group (Scheme 1).2 To that end, we
have recently reported the Mukaiyamaꢀaldol reactions
of 1 to give δ-hydroxy diazo-β-ketoesters 22a as well as
a MukaiyamaꢀMichael variant with enones to provide
ζ-keto-R-diazo-β-ketoesters 3 (Scheme 1).2b These new
methods have provided access to highly functionalized
diazo compounds that have allowed us to study increasingly
complex materials by way of transition metal catalyzed
dinitrogen extrusion reactions.1
We have also been intrigued by the umpolung in reac-
tivity provided by the conversion of the diazo functional
group to the keto functional group that has been made
possible through the use of DMDO.5 In general, conver-
sion of a diazo functionality 4 to a carbonyl functionality 5
causes a reversal in the polarity of carbon (Scheme 2).
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From Cyclopro-
panes to Ylides; John Wiley & Sons: New York, 1998. Reviews: (b) Doyle,
M. P.; Duffy, R.; Ratnikov, M. O.; Zhou, L. Chem. Rev. 2010, 110, 704–724.
(c) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 1137–1156. (d) Davies,
H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2904. (e)
Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1–326. (f)
Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc. Rev.
2001, 30, 50–61.
(2) (a) Doyle, M. P.; Kundu, K.; Russell, A. E. Org. Lett. 2005, 7,
5171–5174. (b) Liu, Y.; Zhang, Y.; Jee, N.; Doyle, M. P. Org. Lett. 2008,
10, 1605–1608. (c) Truong, P.; Xu, X.; Doyle, M. P. Tetrahedron Lett.
2011, 52, 2093–2096. (d) Zhou, L; Doyle, M. P. Org. Lett. 2010, 12, 796–
799. (e) Xu, X.; Hu, W.; Doyle, M. P. Angew. Chem., Int. Ed. 2011, 50,
6392–6395. (f) Xu, X.; Ratnikov, M. O.; Zavalij, P. Y.; Doyle, M. P. Org.
Lett. 2011, 13, 6122–6125.
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Q. Org. Lett. 2007, 9, 291–293. (b) Zheng, J.; Xie, X.; Zhao, C.; He, Y.;
Zheng, H.; Yang, Z.; She, X. Org. Lett. 2011, 173–175. (c) Zhu, X.;
Xiang, K.; Zhang, F.; Tu, Y. J. Org. Chem. 2011, 76, 6918–6924.
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Trost, B.; Krische, M. J. J. Am. Chem. Soc. 1996, 118, 233–234.
(5) Saba, A. Synth. Commun. 1994, 24, 695–699.
r
10.1021/ol301317a
XXXX American Chemical Society

Scheme 1. Mukaiyama Reactions of Silyl Ketene Diazoacetates
Scheme 3. Diazo-umpolung Route to Cyclopentanones
Upon reaction of DMDO with δ-hydroxy-R-diazoacetoa-
cetate 2 (Scheme 2), the polarity inversion causes an
intramolecular nucleophilic attack from the remote hydro-
xyl group into the newly formed carbonyl unit to generate
hemiketal 6.2c Hemiketal 6 was then further manipulated
to provide 3-alkoxyfuran derivatives such as 7 by acid
catalyzed dehydration/methanolysis.
cases proceeded in virtually quantitative yields, and the
products were isolated as hydrates.6 Thus yields of 8 reflect
limitations in the MukaiyamaꢀMichael reaction.
Table 1. Synthesis of 2,3,7-Triketoestersa
Scheme 2. Oxidation of δ-Hydroxy-R-diazoacetoacetates as a
Route to Furanones and Furans
8
Ar
C6H5
R
R0
yield (%)b,c
a
b
c
d
e
f
H
H
H
H
H
H
H
H
Ph
Me
Me
Me
Me
Me
Me
Me
Bn
Me
80
83
92
83
71
69
81
73
90
2-naphthyl
4-MeOC6H4
4-ClC6H4
9-anthryl
mesityl
g
h
i
4-CF3C6H4
4-CF3C6H4
C6H5
With the success of these early studies, we directed our
attention to the application of this umpolung strategy to
the previously reported2b MukaiyamaꢀMichael adducts 3
(Scheme 3). Our hypothesis was that oxidation of this class
of diazo compounds would provide tetracarbonyl com-
pounds (8), which we envisioned as candidates for intra-
molecular aldol reactions for the construction of the highly
functionalized cyclopentanones 9. Our interest in this
strategy was piqued by the knowledge that a number of
biologically active natural products such as prezawlskin B
(10)3 and the picrotoxanes (e.g., 11ꢀ12)4 share a similarly
functionalized cyclopentanone system to which the pro-
posed methodology may allow access.
a See Supporting Information for procedural details. b Isolated yield
following purification via column chromatography. c Overall yields are
reported starting from 1 and the respective enone used.
The capabilities of Lewis acids to catalyze aldol con-
densation reactions with high stereocontrol is well-
known;7 however, application to vicinal tricarbonyl com-
pounds has not been reported. Copper(II), scandium(III),
and ytterbium(III) triflates are reported to be effective for
aldol condensation reactions,8 and tin(II) triflate has also
been described.9 These catalysts were evaluated for their
effectiveness in mediating carbocyclization of 8a in
Our investigation began by first preparing a family of
tetracarbonyl compounds, which were available via a two-
step sequence involving the intermolecular Mukaiyamaꢀ
Michael reaction of enol diazoacetate 1 followed by oxida-
tion of the diazoacetoacetate with DMDO (Table 1).2b
Yields from the two-step process ranged from 69 to
92%.5,2c It should be noted that the oxidation step in all
(7) (a) Kurteva, V. B.; Afonso, C. A. M. Chem. Rev. 2009, 109, 6809.
(b) Mahrwald, R. Chem. Rev. 1999, 99, 1095. (c) Shibasaki, M.;
Yoshikawa, N. Chem. Rev. 2002, 102, 2187–2210. (d) Kobayashi, S.;
Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102, 2227.
(8) (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325–
335. (b) Le, J.; Pagenkopf, B. Org. Lett. 2004, 6, 4097–4099. (c) Lefebvre,
O.; Brigaud, T.; Portella, C. J. Org. Chem. 2001, 66, 1941–1946. (d)
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209–217. (e)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. Chem. Rev. 2002,
102, 2227–2302. Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S.
J. Am. Chem. Soc. 2004, 126, 12236–12237.
(6) Typical product mixtures were ∼9:1 hydrate/ketone and were
used without dehydration for subsequent chemistry. If desired, however,
the products can be dehydrated by heating at 100 °C under a high
vacuum for 2 h. For other examples, see: (a) Rubin, M. B.; Gleiter, R.
Chem. Rev. 2000, 100, 1121–1164. (b) Wasserman, H. H.; Parr, J. Acc.
Chem. Res. 2004, 37, 687–701.
(9) (a) Kobayashi, S.; Hachiya, I. J. Org. Chem. 1992, 57, 1325–1327.
(b) Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T. Tetrahedron.
1993, 49, 1761–1772. (c) Evans, D.; MacMillan, D.; Campos, K. J. Am.
Chem. Soc. 1997, 119, 10859–10860.
B
Org. Lett., Vol. XX, No. XX, XXXX

refluxing dichloromethane (Table 2, entries 1ꢀ7). Each of
these catalysts exhibited a high degree of diastereocontrol,
but Yb(OTf)3 provided the highest level of diastereoselec-
tivity. Alternative catalysts such as La(OTf)3,9c,11
Zn(OTf)2,9a,3,4 Ni(OTf)2,12 and Mg(OTf)213 showed little
or no activity for this transformation under the reaction
conditions.
had simply discovered conditions for both the kinetically
and thermodynamically controlled processes; however
extensive investigations have revealed that the aldol ad-
ducts themselves are resistant to equilibration between
their syn- and anti-forms under any of the optimized
reaction conditions. When either purified 13a or 14a was
resubjected to the standard reaction conditions (Table 2,
entries 4 and 11), no interconversion of these products was
observed. Interconversion was only observed after 7 days
in refluxing CDCl3; however, interconversion under these
more forcing conditions was accompanied by a significant
amount of byproduct formation (>30% relative to 13a
Table 2. Optimization of the Intramolecular Aldol Reaction of
2,3,7-Triketoester 8a
1
and 14b based on H NMR). The absence of product
interconversion under the standard reaction conditions
suggests that this unique stereochemical divergence be-
tween Lewis and Brønsted acid catalysis is the result of a
kinetically controlled process. In this scenario Lewis acids
alter the course of the reaction to give the less common
anti-aldol product. We believe that the stereochemical
outcomes of the Brønsted and Lewis acid catalyzed aldol
reactions can be rationalized by analyzing the conforma-
tional intermediates en route to the respective products
(Scheme 4). Activation of the central carbonyl by a
Brønsted acid presumably results in the dipole minimized
orientation of the 1,2-diketo unit, which can then be
attacked by the tethered Z-enol via the lower energy
intermediate 16 thus providing 14a. Lewis acid activation,
however, has the ability to coordinate the 1,2-diketo unit
thus locking the carbonyls in a syn-orientation. The Z-enol
then reacts with the central carbonyl via intermediate 17 to
give 13a.
entrya
catalystb
anti/sync
% conversionc
d
1
Yb(OTf)3
N.D.
95:5
<5
e
2
Yb(OTf)3
65
f
3
Yb(OTf)3
95:5
>95
>95
93
4
Yb(OTf)3
Sn(OTf)2
Sc(OTf)3
Cu(OTf)2
95:5
5
85:15
87:13
89:11
25:75
32:68
30:70
30:70
93:7
6
>95
>95
75
7
g
8
H2PO4
9
p-TsOH
84
10
11
12i
Mes-SO3H
Mes-SO3Hh
Yb(OTf)3
90
>95
>95
a Reaction performed substrate 8a. b Reaction performed with
10 mol % catalyst. c Determined by 1H NMR spectroscopy (see Support-
ing Information). d 10 mol % catalyst at room temp for 24 h. e 5 mol %
catalyst. f 20 mol % catalyst. g 4 equiv of acid used. h 30 mol % of the acid
used. i The stereochemistry of the process was confirmed by a reaction
with 8c using 10 mol % Yb(OTf)3, and product 13c was analyzed by
X-ray (see Supporting Information).
Scheme 4. Stereochemical Rationale for the Diastereoselectivity
of Lewis and Brønsted Acids
We were surprised to find a significant divergence in
stereocontrol between Lewis acid and Brønsted acid cata-
lysts. The use of a Lewis acid gave the 1,2-anti product 13a
predominantly, whereas Brønsted acids greatly favored
formation of the 1,2-syn product 14a. Furthermore, given
the prevalence of syn-selective aldol reactions of 1,n-dicar-
bonyl compounds under both Brønsted and Lewis acid
catalyzed conditions,7 the fact that the anti-aldol product
13 is formed with high selectivity is notable. Our initial
thought regarding the observation that Lewis and
Brønsted acids provided divergent reactivity was that we
Expanding on these initial results, we applied the opti-
mized conditions for the Lewis and Brønsted acid cata-
lyzed processes to representative substrates (Table 3). Both
electron-withdrawing and -donating aromatic rings were
tolerated, as were sterically demanding aromatic substitu-
ents. In the case of the o,o-disubstitued substrates 13e and
13f (Table 3, entries 5 and 6), however, a significant
deterioration in anti/syn selectivity was observed under
Lewis acid catalyzed conditions. In fact, in the mesityl
example (Table 3, entry 6) selectivity was inverted, and the
syn-diastereomer was formed preferentially. This anomaly
seems to highlight the fact that the anti-transition state is
inherently more sterically demanding; thus, when the steric
(10) (a) Evans, D.; Downey, W. C.; Hubbs, J. J. Am. Chem. Soc.
2003, 125, 8706–8707. (b) Fossey, J.; Matsubara, R.; Kiyohara, H.;
Kobayashi, S. Inorg. Chem. 2008, 47, 781–783.
(11) (a) Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807–
6810. (b) Ji, J.; Barnes, D.; Zhang, J.; King, S.; Wittenberger, S.; Morton,
H. J. Am. Chem. Soc. 1999, 121, 10215–10216.
(12) (a) Jung, M. E.; Johnson, T. W. J. Am. Chem. Soc. 1997, 119,
12412–12413. (b) Bouillon, J. P.; Portella, C. Eur. J. Org. Chem. 1999,
1571–1580. (c) Bouillon, J. P.; Portella, C.; Bouquant, J.; Humbel, S.
J. Org. Chem. 2000, 65, 5823–5830. Baik, T. G.; Luis, A. L.; Wang, J. C.;
Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112–5113.
(13) The stereochemistry of 13i was determined by X-ray crystal-
lography (Supporting Information).
Org. Lett., Vol. XX, No. XX, XXXX
C

With the cyclopentanone system bearing two ketone
groups we next queried whether these carbonyl groups
could be orthogonally reacted, thus enhancing the syn-
thetic utility of these novel cyclopentanone products. We
found that reduction of the cyclic ketone could be per-
formed with high chemo- and stereoselectivity to give the
diol 18in 85% yield asonly one diastereomer (Scheme 5).14
The stereochemistry of 18 was confirmed by X-ray crystal-
lography to be the 1,2-anti diol resulting from a chelation
controlled delivery of the hydride.
Table 3. Scope and Limitations
Scheme 5. Chemo- and Stereoselective Reduction of Dione 13aa
a No trace of the aryl ketone reduction product under these
conditions.
In conclusion, the MukaiyamaꢀMichael reaction of
silyl enoldiazoacetates was exploited to prepare a series
of highly functionalized ζ-keto-R-diazo-β-ketoesters. The
diazo groups of these compounds were oxidized with
DMDO to generate 2,3,7-triketoesters in virtually quanti-
tative yields, which set up highly stereoselective intramo-
lecular aldol reactions to provide usefully functionalized
cyclopentanones. Lewis acid catalysts provided high de-
grees of 1,2-anti diastereoselectivity, while Brønsted acids
selectively provided the 1,2-syn diastereomer, a factthatwe
believe makes this methodology even more synthetically
attractive. The prospect of using chiral acid catalysts to
achieve an asymmetric variant of this reaction, and appli-
cation of the overall strategy toward natural product
synthesis are currently being explored.
a Isolated yield. b Diastereomeric ratios determined by 1H NMR
spectroscopy. c Method A: Reaction was performed with 10 mol %
Yb(OTf)3. d Method B: Reaction was performed with 30 mol % mesi-
tylenesulfonic acid (Mes-SO3H). e Method C: Reaction was performed
with 10 mol % Sn(OTf)2. f Method D: Reaction was performed with
10 mol % Sc(OTf)3.
Acknowledgment. Support for this research from the
National Institutes of Health (GM 46503) and the Na-
tional Science Foundation (CHE-0748121) is gratefully
acknowledged.
demand is too high, an alternative acid coordination such
as that in 16 is favored due to the fewer number of Gauche
interactions. We were also interested in studying the effect
of a δ-substituent on the stereochemical course of the
reaction (Table 3, entry 9). To that end, when 8i was
subjected to standard Lewis acid catalyzed conditions the
reaction provided 13i as the major product (dr = 93:7)
with the usual 1,2-anti geometry where the 3-phenyl
substituent is positioned syn to the aryl ketone moiety,
which further exemplifies the stereocontrol predicted
by 17.13
Supporting Information Available. General experimen-
tal procedures, the X-ray structures of 13c, 13i, and 18,
and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Tsubuki, M.; Matsuo, S.; Honda, T. Tetrahedron Lett. 2008, 49,
229–232.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX