Synthesis of optically active 4-substituted 2-cyclohexenones

Article abstract of DOI:10.1021/ol301874x

Recently, Nicolaou and Baran independently synthesized optically active 4-substituted 2-cyclohexenones via an efficient LiOH-mediated intramolecular aldol condensation. Thus far, application of their cyclization approach has been limited to ketoaldehydes where the R-group is branched. It is demonstrated that the LiOH-mediated cyclization, when applied to substrates containing unbranched R-groups, results in significant erosion of optical purity. A mechanistic justification is provided, and a set of neutral, organocatalyzed conditions is identified that enables cyclization with little loss in optical purity.

Full text of DOI:10.1021/ol301874x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Optically Active
4‑Substituted 2‑Cyclohexenones
Tania I. Houjeiry,† Sarah L. Poe,‡ and David T. McQuade*,†
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306, United States, and Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, New York 14853, United States
mcquade@chem.fsu.edu
Received July 8, 2012
ABSTRACT
Recently, Nicolaou and Baran independently synthesized optically active 4-substituted 2-cyclohexenones via an efficient LiOH-mediated
intramolecular aldol condensation. Thus far, application of their cyclization approach has been limited to ketoaldehydes where the R-group is
branched. It is demonstrated that the LiOH-mediated cyclization, when applied to substrates containing unbranched R-groups, results in
significant erosion of optical purity. A mechanistic justification is provided, and a set of neutral, organocatalyzed conditions is identified that
enables cyclization with little loss in optical purity.
Optically active 4-substituted-2-cyclohexenones are
both natural products and intermediates for the synthesis
of complex molecules. An example is (R)-cryptone, an
essential oil of Eucalyptus cneorifolia, that is used as a
starting material for the synthesis of dihydrojunenol,
faurinone, β-cadinene, and other natural products.1,2
Asymmetric routes into 4-substituted 2-cyclohexenones
including cryptone have been relatively limited considering
their wide use, although notable examples do exist.3 For
example, Koga et al. used optically active bases to depro-
tonate prochiral cyclohexanones followed by isomerizat-
ion of the silyl enol ether to provide optically active
cyclohexenones.4 Later, Fuchs et al. introduced a multistep
process starting with enantiopure epoxyvinyl sulfones5 and
Eloi et al. recently reported an approach using stoichiometric
† Florida State University.
‡ Cornell University.
(1) For cryptone in synthesis: (a) Chen, K.; Ishihara, Y.; Galan,
ꢀ
M. M.; Baran, P. S. Tetrahedron 2010, 66, 4738. (b) Findley, T.; Sucunza,
D.; Miller, L.; Davies, D.; Procter, D. Chem.;Eur. J. 2008, 14, 6862.
(c) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Ferreira, V.; Michelotti, E.;
Porter, B.; Wenkert, E. J. Org. Chem. 1985, 50, 890. (d) Becker, J.;
(3) (a) Elliot, M. L.; Urban, F. J. J. Org. Chem. 1985, 50, 1752.
(b) Itagaki, N.; Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005,
7, 4185. (c) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, H.;
Terrel, R. J. Am. Chem. Soc. 1963, 85, 207. (d) Rawal, V. H.; Kozmin,
S. A. J. Am. Chem. Soc. 1999, 121, 9562. (e) Asaoka, M.; Aida, T.;
Sonoda, S.; Takei, H. Tetrahedron Lett. 1989, 30, 7075.
(4) (a) Aoki, K.; Nakajima, M.; Tomioka, K.; Koga, K. Chem.
Pharm. Bull. 1993, 41, 994. (b) Shirai, R.; Tanaka, M.; Koga, K.
J. Am. Chem. Soc. 1986, 108, 543.
(5) Evarts, J.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc. 2002, 124,
11093.
(6) Eloi, A.; Rose-Munch, F.; Rose, E.; Pille, A.; Lesot, P.; Herson, P.
Organometallics 2010, 29, 3876.
€
Bergander, K.; Frohlich, R.; Hoppe, D. Angew. Chem., Int. Ed. 2008, 47,
1654. (e) Ley, S. V.; Dixon, D. J.; Rodrıguez, F.; Sheppard, T. D. Org.
´
Biomol. Chem. 2005, 3, 4095. (f) Mori, K. Tetrahedron: Asymmetry 2006,
17, 2133.
(2) (a) ApSimon, J. A., Ed. The Total Synthesis of Natural Products;
John Wiley & Sons: New York, 1973; Vol. 2. (b) Stevens, R. V.; Albizati,
K. F. J. Org. Chem. 1985, 50, 632. (c) Mizutani, R.; Nakashima, K.;
Saito, Y.; Sono, M.; Tori, M. Tetrahedron Lett. 2009, 50, 2225.
(d) Edwards, M.; Kenworthy, M. N.; Kitson, R. R. A.; Perry, A.; Scott,
M. S.; Whitwood, A. C.; Taylor, R. J. K. Eur. J. Org. Chem. 2008, 4769.
(e) Ishigami, K. Biosci. Biotechnol. Biochem. 2009, 73, 971.
r
10.1021/ol301874x
XXXX American Chemical Society

chiral manganese complexes.6 Despite these outstanding ap-
proaches, a simple catalytic method leading to 4-substituted
cyclohexenones remains elusive. An excellent step forward
was recently reported by both Baran and Nicolaou’s groups.
Nicolaou en route to ent-7-epizingiberene and Baran en
route to dihydrojunenol used Robinson annulations em-
ploying an asymmetric Michael addition followed by a
base-mediated ring closure (Figure 1).7
Figure 2. Plot of percent conversion and enantiomeric excess as
a function of time for the base catalyzed aldol condensation of
substrate 1a.
stereoselectivity of the chiral ketoaldehyde before under-
going the cyclization step. The second possible pathway is
the racemization of the product via conjugate enolization
ofthe enone. Herethe rate of epimerization of the aldehyde
R-hydrogen is slow compared to the methyl hydrogen
(Keq 1 , Keq 2), but the chiral cyclohexenone produced
undergoes an epimerization step at a faster or equal rate
(Keq 3 g Keq 2).
Figure 1. Baran’s and Nicolaou’s basic conditions for Robinson
annulations.
In both cases, the asymmetric Michael addition was
performed using an organocatalyst modeled after the
pioneering work of Barbas et al. and other groups.8 As
shown in Figure 1, both Nicolaou and Baran’s substrates
featured β-branched substituents proximal to the chiral
center. We wondered whether these conditions would
function for unbranched substrates, as many optically
active aldehydes are racemized under basic conditions.
We tested our curiosity by first preparing 1a using
Gellman’s catalyst combined with methyl vinyl ketone
and 3-phenylpropanal.8f The desired ketoaldehyde 1a re-
sulted in an 80% yield with 90% ee. Cyclization of 1a under
Baran’s conditions provided cyclohexenone 2a (Figure 2).
We observed a steep initial decrease in optical purity con-
comitant with formation of product, but once the reaction is
complete, the optical purity stays constant (Figure 2). We
speculated that loss of optical purity was most likely to
occur via two pathways as described in Scheme 1.
Scheme 1. Possible Epimerization Routes Leading to the Loss of
Enantioselectivity
The first pathway is the reversible enolization of alde-
hyde (Scheme 1; Keq 1 g Keq 2), leading to the loss of the
(7) (a) Chen, K.; Baran, P. S. Nature 2009, 459, 824. (b) Nicolaou,
K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem., Int. Ed. 2007, 46, 4708.
(c) Paquette, L. A.; Guevel, R.; Sakamoto, S.; Kim, I.-H.; Crawford, J.
J. Org. Chem. 2003, 68, 6069.
(8) (a) Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737.
(b) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org.
Lett. 2004, 6, 2527. (c) Betancort, J. M.; Sakthivel, K.; Thayumanavan,
R.; Barbas, C. F., III. Tetrahedon Lett. 2001, 42, 4441. (d) Betancort,
J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III.
Synthesis 2004, 1509. (f) Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am.
Chem. Soc. 2005, 127, 11598.
Based on the data presented in Figure 2, we predicted
that the aldehyde enolization was the dominant origin, as
optical purity stabilizes once the reaction is complete. To
support our model further, we synthesized 2a (83% ee) and
B
Org. Lett., Vol. XX, No. XX, XXXX

subjected the material to the LiOH reaction conditions of
Baran (Figure 3). If the aldehyde enolization step is the
main source of optical purity erosion, we expect to see little
change in optical purity. We observe that the optical purity
remains nearly constant over the 2 h period that we
monitored, indicating that racemization of the product is
too slow to explain the loss of optical purity.
Table 1. Condition Screening for the Model Reactiona
Based on these observations, we further hypothesized
that 1a must exhibit rapid loss of optical purity for our
ee smb
(%)
yieldc
(%)
ee pd
(%)
entry
cat.
Δ ee
1
2
3
4
5
6
ae
af
b
90
89
90
90
90
90
87
85
35
15
50
61
87
83
85
83
70
88
3
6
5
c
7
d
e
20
2
a Reaction conditions: 1a, catalyst (30 mol %), rt, hexane, 2 h. b See
Supporting Information. c Determined using GC analysis. d Determined
by HPLC analysis using IA chiral column. e Reaction time is 1 h.
f Opposite enantiomer of 1a is used.
Figure 3. Plot of change in enantioselectivity of 2a in presence of
LiOH/IPA.
model tobe valid. Wemeasuredthe ee of substrate 1awhile
the reaction was still at low conversion (20 min into the
reaction) (Figure 4) to test our hypothesis.
As shown in Figure 4, we observed that the ee of 1a
decreases from 89% to 35% in the first 20 min of reaction.
This indicates that 1a epimerizes faster than the rate of
cyclization, leading to the loss of enantiopurity (Keq
Keq 2). Taking the initial rates of epimerization of 2a from
>
1
plots of Figures 2 and 3 into consideration, we conclude
is 30-fold faster than Keq 3. For branched
that Keq
2
substrates such as those used by Baran and Nicolaou, we
predict that R-branched aldehydes have significantly
slower rates of aldehyde enolization.
With 1a speculated as an aberrant case, examination of
the loss of optical purity on cyclization of 1b (R = ethyl)
confirmed that nonbranched substrates exhibit erosion of
optical purity on cyclization. In the case of 1bf2b, we
observeda lossof opticalpurityfrom88%eeinthestarting
material to 64% ee in the product similar to 1af2a. This
led us to conclude that the base catalyzed conditions
provide unsatisfactory results for substituents that do not
Figure 4. Enantioselectivity of the starting material 1a as a
function of reaction progress. Description of the experiment:
enantiomeric excess was found using 1H NMR spectrum of the
acetal-protected product. Plot A represents the acetal doublets
of the two enantiomers of the racemic 1a. Plot B represents the
doublets of the two enantiomers of the enantioselective 1a. Plot
C represents the doublets of 1a after 20 min of the reaction with
LiOH. D is a residue from the crude sample at 20 min, which
contains the starting material, product, and the excess diol
added together with the pTSA catalyst.
(9) For reviews, see: (a) Jung, M. E. Tetrahedron 1976, 32, 3.
ꢀ
ꢀ
(b) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron Asymmetry
2007, 18, 2249. Other papers with cyclic ketoaldehydes: (c) Hayashi, Y.;
Sekizawa, H.; Yamaguchi, J.; Gotoh, H. J. Org. Chem. 2007, 72, 6493.
(d) Corey, E. J.; Tius, M. A.; Das, J. J. Am. Chem. Soc. 1980, 102, 7613.
(e) Burke, S. D.; Murtiashw, C. W.; Saunders, J. O.; Oplinger, J. A.;
Dike, M. S. J. Am. Chem. Soc. 1984, 106, 4558. (f) Diaba, F.; Bonjoch, J.
Org. Biomol. Chem. 2009, 7, 2517.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Substrate Scopea
Scheme 2. Enolization Routes for Acyclic Ketoaldehydes Re-
ported in Literature
(entry 6) afforded increased yields and ee, but the best
results were obtained using a catalyst containing a pendant
group with a pKa of ∼10 (entry 1). We propose that the
matched acidity between the pendant group and the
pyrrolidine amine is a critical attribute that promotes
enolization of the ketone over the aldehyde.
As Table 2 shows, the identified conditions catalyzed
cyclization of substrates containing both aromatic and
aliphatic R-groups. The most significant loss of optical
purity from starting material to product was observed with
simple aliphatic and aromatic groups with substitution in
the ortho position. Overall, the method appears to be
successful with a wide range of substrates.
a Reaction conditions: 30 mol % of catalyst a, hexane, rt, 1À1.5 h.
b See Supporting Information. c Determined by HPLC analysis using IA
column. d Isolated yield. e Determined by optical rotation. f Peaks were
not fully separated (see Supporting Information). g Peaks of acetals were
inseparable.
contain a β-branch. We sought a set of organocatalytic
conditions that could fill this method’s gap.
Identifying organocatalytic conditions to promote the
desired cyclization is confounded by the observation that
aldehyde enolization or internal ketone enolization is
faster than enolization of the terminal ketone in most cases
(Scheme 2).9,10 This mechanistic detail might be one reason
that asymmetric organocatalyzed 6-enol endo cyclizations
where the aldehyde R center is tertiary are yet to be
described.11 We selected a range of pyrrolidine catalysts
and screened them for capacity to enolize the ketone in
favor of the aldehyde with the goal of producing 4-
substituted-2-cyclohexenones without loss of optical purity
(Table 1).
From our broader screen (see Supporting Information),
it became clear that the acidity of the group pendant to the
pyrrolidine was critical. Proline and similar derivatives
containing carboxylic acid groups (entries 3 and 4) gave
low yields or low ee (entry 5) and a poorly acidic amide
In conclusion, we have demonstrated that base mediated
cyclization of 2-monosubstituted-5-oxohexanals requires
branching of the substituent to prevent loss of optical
purity. Weprovidedevidencethatthe aldehyde enolization
was responsible for this decrease in optical purity and not
epimerization of the product. Using this gap as inspira-
tion, we successfully identified organocatalyzed conditions
to accomplish the aldol condensation reaction on un-
branched substrates with minimal loss of optical purity.
The method is successful on both aliphatic and aro-
matic substrates, yielding a wide range of 4-substituted
2-cyclohexenones with high yields and ee.
Acknowledgment. The authors thank the NSF (CHE-
0809261, 1152020), Pfizer, Corning Glass, and FSU for
support and FSU VP of Research and Dean of A&S for
NMR upgrades.
(10) (a) Hammar, P.; Ghobril, C.; Antheaume, C.; Wagner, A.; Baati,
R.; Himo, F. J. Org. Chem. 2010, 75, 4728. (b) Ghobril, C.; Sabot, C.;
Mioskowski, C.; Baati, R. Eur. J. Org. Chem. 2008, 4104. (c) Pidathala,
C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003, 42,
2785. (d) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int.
Ed. 2008, 47, 7656.
(11) (a) Inokoishi, Y.; Sasakura, N.; Nakano, K.; Ichikawa, Y.;
Kotsuki, H. Org. Lett. 2010, 12, 1616. (b) Yang, H.; Carter, R. G.
Org. Lett. 2010, 12, 3108.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data of the reaction products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX