Complementary diastereoselective reduction of cyclic γ-keto acids: Efficient access to trisubsituted γ-lactones

Article abstract of DOI:10.1021/ol047821j

(Chemical Equation Presented) Complementary reduction conditions have been identified that provide ready access to each respective diastereomer of bi- and tricyclic, trisustituted γ-lactones starting from the corresponding cyclic γ-keto acids. Subjection

Full text of DOI:10.1021/ol047821j

ORGANIC
LETTERS
2005
Vol. 7, No. 1
107-110
Complementary Diastereoselective
Reduction of Cyclic -Keto Acids:
Efficient Access to Trisubsituted
-Lactones
γ
γ
Eric A. Bercot, David E. Kindrachuk, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
roVis@lamar.colostate.edu
Received October 23, 2004
ABSTRACT
Complementary reduction conditions have been identified that provide ready access to each respective diastereomer of bi- and tricyclic,
trisustituted -lactones starting from the corresponding cyclic -keto acids. Subjection of cyclic -keto acids to silane reagents in the presence
of trifluoroacetic acid provides all syn- -lactones, while reduction with trialkylborohydrides furnishes the syn,anti- -lactones. The conditions
are mild and provide the product lactones in good yields and modest to excellent selectivity.
γ
γ
γ
γ
γ
New methods for the synthesis of the lactone moiety continue
to be an area of intense investigation due to its synthetic
utility and its prevalence in biologically significant natural
products.1 In particular, γ-butyrolactones represent an equiva-
lent to 4-hydroxycarbonyl compounds, also known as ho-
moaldol products.2 Among the multitude of approaches
devised for the synthesis of γ-lactones,3,4 the synthesis of
trisubstituted derivatives still represents a formidable chal-
lenge.5 We have recently developed complementary ap-
proaches to γ-keto acid derivatives6 using alkylative anhy-
dride desymmetrization as well as asymmetric Stetter
reactions.7 Herein, we report the complementary diastereo-
selective reduction of γ-keto acids bearing a cyclic backbone
providing ready access to trisubstituted γ-lactones.
Substrate-directed reactions represent a powerful method
for the introduction of new stereochemical elements into
(4) For recent representative examples, see: (a) Sohn, S. S.; Rosen, E.
L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370-14371. (b) Burstein,
C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205-6208. (c) Quinn,
K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143-4145. (d)
Floreancig, P. E.; Wang, L. Org. Lett. 2004, 6, 4207-4210. (e) Fukuzawa,
S.; Miura, M.; Saitoh, T. J. Org. Chem. 2003, 68, 2042-2044. (f) Chhor,
R. B.; Nosse, B.; So¨rgel S.; Bo¨hm, C.; Seitz, M.; Reiser, O. Chem. Eur. J.
2003, 9, 260-270. (g) Buchwald, S. L.; Speilvogel, D. J. J. Am. Chem.
Soc. 2002, 124, 3500-3501. (h) Mandal, S. K.; Amin, S. R.; Crowe, W. E.
J. Am. Chem. Soc. 2001, 123, 6457-6458.
(5) For selected approaches, see: (a) Barros, M. T.; Burke, A. J.; Lou,
J.-D.; Maycock, C. D.; Wahnon, J. R. J. Org. Chem. 2004, 69, 7847-
7850. (b) Evans, D. A.; Wu, J.; Masse, C. E.; MacMillian, D. W. C. Org.
Lett. 2002, 4, 3379-3382. (c) Hong, S.-p.; McIntosh, M. C. Org. Lett. 2002,
4, 19-21. (d) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675-678.
(e) Miyabe, H.; Fujii, K.; Goto, T.; Naito, T. Org. Lett. 2000, 2, 4071-
4074. (f) Sibi, M. P.; Lu, J.; Talbacka, C. L. J. Org. Chem. 1996, 61, 7848-
7855.
(1) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985,
24, 94-110. (b) For a review on lignan natural products, see: Ward, R. S.
Nat. Prod. Rep. 1997, 14, 43-74. (c) Koch, S. S. C.; Chamberlin, A. R. J.
Org. Chem. 1993, 58, 2725-2737 and references therein.
(2) (a) O¨ zlu¨gedik, M.; Kristensen, J.; Wibbeling, B.; Fro¨hlich, R.; Hoppe,
D. Eur. J. Org. Chem. 2002, 414-427 and references therein. (b) Gaul,
C.; Seebach, D. HelV. Chim. Acta 2002, 85, 963-978 and references therein.
(3) For a review, see: Collins, I. J. Chem. Soc., Perkin Trans. 1 1999,
1377-1395.
(6) For a review on the synthetic utility of 1,4- and 1,5-keto acids, see:
Csende, F.; Stajer, G. Heterocycles 2000, 53, 1379-1419.
10.1021/ol047821j CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/14/2004

molecules containing preexisting stereocenters.8 Although
reductions of â-hydroxyacids are well developed, relatively
few examples applying this concept to the reduction of γ-keto
acids have appeared.9 Several reports have detailed the
diastereoselective reduction of cyclic10 and acyclic11 1,4-keto
acid derivatives providing the product lactones in good yield
and selectivity. We envisioned that treatment of the 4-oxo-
carboxylic acids with a particular reducing agent ([H-]A)
would potentially provide the syn-lactone A, while treatment
of the starting material with a separate hydride source ([H-]B)
may supply the paired anti-lactone B (Scheme 1).
Table 1. Reducing Agent Screen
entry
1
conditions
DIBAL-H
yield (%)
64
2:3a
25:75
THF, -78 °C
2
3
4
5
Et3SiH
TFA/CH2Cl2 (1:3), 0 °C
PhMe2SiH
TFA/CH2Cl2 (1:3), 0 °C
Et3BHLi
THF, -78-23 °C
s-Bu3BHLi
54
90
83
65
20:80
7:93
Scheme 1
85:15
75:25
THF, -78-23 °C
1
a Diastereomeric ratios determined by H NMR.
with Et3SiH under acidic conditions provided an isomeric
mixture of the desired lactones in modest yield but improved
selectivity favoring 3 in an 80:20 ratio (entry 2). Increasing
the steric demand of the silane source in the form of PhMe2-
SiH leads to a dramatic increase in both reaction efficiency
and selectivity, supplying 3 in a 93:7 ratio (entry 3).14
With efficient entry to the syn diastereomer, we turned
our attention to the search for conditions that would favor
the corresponding anti isomer. Lithium trialkylborohydrides
had been shown to provide the anti-lactones in similar
systems.10 Subjection of keto acid 1 to 2.4 equiv of Super-
Hydride (Et3BHLi) in THF provided the desired products
after cyclization in 83% yield and an 85:15 ratio favoring
anti-lactone 2 (entry 4). Increasing the steric bulk of the
reducing agent resulted in reduced selectivity (entry 5).
Having identified two discrete reducing agents that provide
complementary diastereomers of the product γ-butyrolac-
tones in synthetically useful selectivities, we sought to
examine the effects of backbone architecture (Table 2).
Unsaturation present in the cyclohexyl ring has little effect
on the selectivity or efficiency of the reaction. Super-Hydride
reduction of cyclohexenyl keto acid 4 provides the corre-
sponding anti product in a 79:21 ratio, while silane reduction
favors the syn product as a 90:10 mixture (entry 1).
Tetrasubstituted olefin-containing keto acid 5 and benzofused
oxoacid 6 undergo smooth reduction under both conditions,
supplying each respective isomeric lactone in slightly
elevated selectivity (entries 2 and 3). Keto acids bearing
bicyclic [2.2.1] and [2.2.2] backbones also efficiently
participate in the reaction manifold. Upon reduction with the
silane system, saturated and unsaturated bicyclic keto acids
7-10 afford the expected syn-lactones in uniformly high
yield and selectivity. When keto acids 7-10 are subjected
Our initial efforts to discover a set of conditions that
provide access to each diastereomer focused on reducing
agents known to participate in substrate-directed reduction
manifolds (Table 1). Alkyl aluminum hydrides have been
shown to reduce acyclic 1,4-keto acids with high levels of
stereocontrol.11 Reduction of cis-cyclohexyl keto acid 1 with
DIBAL-H at low temperature followed by cyclization
afforded the desired lactone in modest yield and selectivity
favoring syn-lactone 3 (entry 1).12 Silanes have seen ap-
plication as hydride sources usually under acidic conditions
and have been shown to be effective for the reduction of
R-hydroxyketones.13 In the event, treatment of keto acid 1
(7) (a) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 174-175.
(b) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 10248-10249.
(c) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. In press. (d) Kerr, M. S.;
Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298-10299.
(e) Kerr, M. S.; Rovis, T. Synlett 2003, 1934-1936. (f) Kerr, M. S.; Rovis,
T. J. Am. Chem. Soc. 2004, 126, 8876-8877. (g) Rovis, T. Chemtracts
2003, 16, 542-553.
(8) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307-1370. (b) Sailes, H.; Whiting, A. J. Chem. Soc., Perkin Trans. 1
2000, 1785-1805.
(9) (a) For enantioselective reduction of prochiral keto acids using
boranes, see: Ramachandran, P. V.; Brown, H. C.; Pitre, S. Org. Lett. 2001,
3, 17-18. Ramachandran, P. V.; Pitre, S.; Brown, H. C. J. Org. Chem.
2002, 67, 5315-5319. (b) For enzymatic methods, see: Forzato, C.;
Gandolfi, R.; Molinari, F.; Nitti, P.; Pitacco, G.; Valentin, E. Tetrahedron:
Asymmetry 2001, 12, 1039-1046 and references therein.
(10) (a) Fujiwara, Y.; Kimoto, S.; Okamoto, M. Chem. Pharm. Bull. 1975,
23, 1396-1403. (b) Miyano, S.; Abe, N.; Fujisaki, F.; Sumoto, K.
Heterocycles 1987, 26, 1813-1826. (c) Pourahmady, N.; Eisenbraun, E. J.
J. Org. Chem. 1983, 48, 3067-3070.
(11) (a) Frenette, R.; Kakushima, M.; Zamboni, R.; Young, R. N.;
Verhoeven, T. R. J. Org. Chem. 1987, 52, 304-307. (b) Frenette, R.;
Monette, M.; Bernstein, M. A.; Young, R. N.; Verhoeven, T. R. J. Org.
Chem. 1991, 56, 3083-3089. (c) Satoh, M.; Washida, S.; Takeuchi, S.;
Asaoka, M. Heterocycles 2000, 52, 227-236. (d) Fernandez, A.-M.;
Paquevent, J.-C.; Duhamel, L. J. Org. Chem. 1997, 62, 4007-4014.
(12) Relative stereochemistry was determined by NOE experiments.
(13) For an excellent review, see: Fleming, I.; Barbero, A.; Walter, D.
Chem. ReV. 1997, 97, 2063-2192.
(14) This effect has been observed in other reduction manifolds; see:
Fujita, M.; Hiyama, T. J. Org. Chem. 1988, 53, 5415-5421.
108
Org. Lett., Vol. 7, No. 1, 2005

Table 2. Substrate Scope
Table 3. Effect of Ketone Substituents
substrate
yield (%)b
anti:sync
Et3BHLia
Me (12)
Et (1)
iPr (13)
Ph (14)
Me (12)
Et (1)
75
83
85
83
82
90
78
91
86:14
85:15
95:5d
>95:5
5:>95
7:93
PhMe2SiH/TFAa
iPr (13)
Ph (14)
8:92d
50:50
a See Table 2. b Isolated yield. c Diastereomeric ratios determined by
NMR. d Diastereomeric ratio determined by GC.
the complementary syn-lactone in >95:5 selectivity (entry
1). The branched iso-propyl oxo acid 13 effciently affords
each respective lactone in excellent yield and high diaste-
reoselectivity (entry 3). Aromatic ketones also participate
in the reaction. Phenyl keto acid 14 undergoes a highly
selective reduction under Super-Hydride conditions, supply-
ing the anti-lactone in superb yield.10c Unfortunately, when
keto acid 14 is reduced with the PhMe2SiH/TFA system,
the product lactone is produced as a 1:1 mixture of
diastereomers. We attribute the low selectivity to an epimer-
ization event of the benzylic stereocenter under the acidic
reaction conditions that presumably proceeds via an SN1-
type ionization pathway.15
To this point, all of the reductions had been performed
on keto acid derivatives. Although we reasoned that the
carboxylic acid was acting as a directing or activating group
in light of the low selectivity and reactivity of acyclic keto
acids (vide infra), we could not rule out simple conforma-
tional effects being responsible for the observed results. To
delineate between these two possibilities, keto ester 15 was
subjected to each of the respective reaction conditions (eq
1). Super-Hydride reduction of methyl ester 15 provided an
85% yield of a 75:25 mixture of isomeric lactones favoring
syn-lactone 3. Subjection of keto ester 15 to standard reaction
conditions provides an 89:11 mixture of lactones favoring
syn 3, but in dramatically reduced yield.
a Reaction conducted in the presence of 2.4 equiv of Et3BHLi in THF
from -78 °C to ambient temperature for 4 h. b Reaction conducted in the
presence of 1.2 equiv of PhMe2SiH in 3:1 CH2Cl2/TFA from 0 °C to ambient
temperature for 14 h. c Isolated yield. d Diastereomeric ratios determined
1
by H NMR.
to lithium trialkylborohydride reduction, the product lactones
are isolated in good yields but the selectivity is eroded with
the exception of substrate 7 (entries 4-7). Finally, submis-
sion of the acyclic δ-keto acid 11 to silane reduction fails to
yield any reduced product, while Super-Hydride affords the
product δ-lactone in good yield slightly favoring the forma-
tion of the syn diastereomer (entry 8).
Next, we focused our attention on the effect the ketone
substituent may have on the course of the reaction (Table
3). Methyl keto acid 12 provides the corresponding anti-
lactone when subjected to Super-Hydride in modest yield
and selectivity. Silane reduction of 12 efficiently provides
The acid functionality plays a fundamental role in the
silane reduction process as that of an activator at least.
Org. Lett., Vol. 7, No. 1, 2005
109

We have performed some initial calculations16 that suggest
that the acid functionality participates in a hydrogen bond
to the ketone in the minimized structure. We suggest that
activation of this ketone by TFA protonation proceeds via
this conformer allowing hydride to attack from the sterically
more accessible front face (A in Figure 1). Correspondingly,
calculation suggests that structure B in Figure 1 is the lowest
energy conformer, which, upon addition of hydride to the
sterically more accessible distal face relative to the carboxy-
late, would afford the observed major diastereomer. How-
ever, we caution that this conclusion should be considered
tenuous at best since the minimized structure is only about
0.7 kcal/mol more stable than a structure involving rotation
about the cyclohexyl/ketone carbonyl bond, which exposes
the other diastereoface to attack. This small difference in
energy may be responsible for the modest selectivities we
observe in many of these reactions.
In conclusion, we have identified a set of complementary
reducing conditions to afford either diastereomer of trisub-
stituted lactone starting from the γ-keto acids bearing cyclic
backbones. We observe increased selectivity with increasing
steric bulk on the ketone. We further note that the carboxylic
acid functionality is a key element of this reaction, controlling
facial selectivity in Et3BHLi reductions and affecting reactiv-
ity in silane reductions.
Figure 1.
Acknowledgment. We thank Merck, GlaxoSmithKline,
Amgen, Johnson and Johnson, and Eli Lilly for unrestricted
support. We also thank Richard Frenette (Merck-Frosst) for
helpful discussions. E.A.B thanks Pharmacia for a graduate
fellowship.
the formation of the lithium carboxylate under the reaction
conditions plays a crucial role in the stereochemical course
of hydride delivery when using LiBHEt3, as evidenced by
the turnover in selectivity observed with ester substrates. A
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) (a) See ref 10c. (b) For similar observations in the context of
Mitsunobu displacements, see: Hillier, M. C.; Desrosiers, J.-N.; Marcoux,
J.-F.; Grabowski, E. J. J. Org. Lett. 2004, 6, 573-576.
(16) Geometry optimizations were performed at the PM3 level (Spartan,
Wavefunction, Inc., Irvine, CA).
OL047821J
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