One-Carbon bridge stereocontrol in robinson annulations leading to bicyclo[3.3.1]nonanes

Article abstract of DOI:10.1021/ol1000878

Chemical Equation Presented The one-carbon bridge stereochemistry of bicyclo[3.3,1]nonane products formed in the Robinson annulation reactions of 2-substituted cyclohex2-enones was investigated. In contrast to previous reports, it was found that the major diastereomer formed places the one-carbon bridge substituent anti to the β-Keto ester/amide unit introduced in the Robinson annulation. This stereoselectivity appears to be kinetically controlled. In the case of a β Keto amide product derived from carvone, it was demonstrated, through base-catalyzed epimerization, that thermodynamic control favors the syn isomer.

Full text of DOI:10.1021/ol1000878

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1232-1235
One-Carbon Bridge Stereocontrol in
Robinson Annulations Leading to
Bicyclo[3.3.1]nonanes
Dong Wang and William E. Crowe*
Department of Chemistry, Louisiana State UniVersity, Baton Rouge, Louisiana 70803
wcrowe1@lsu.edu
Received January 13, 2010
ABSTRACT
The one-carbon bridge stereochemistry of bicyclo[3.3.1]nonane products formed in the Robinson annulation reactions of 2-substituted cyclohex-
2-enones was investigated. In contrast to previous reports, it was found that the major diastereomer formed places the one-carbon bridge
substituent anti to the ꢀ-keto ester/amide unit introduced in the Robinson annulation. This stereoselectivity appears to be kinetically controlled.
In the case of a ꢀ-keto amide product derived from carvone, it was demonstrated, through base-catalyzed epimerization, that thermodynamic
control favors the syn isomer.
The framework of bicyclo[3.3.1]nonane is quite common in
biologically active natural products,1 and many synthetic and
biosynthetic pathways involve formation and transformation
of this framework.2 Due to the importance of this structural
feature, a number of efficient and highly stereoselective
synthetic methods have been established.3 However, intro-
duction of a stereocenter at the one-carbon bridge has rarely
been reported and remains an unsolved problem.
Interest in ring system 1, present in the natural product
vinigrol,4 prompted us to investigate the two-carbon ring
expansion of the tricyclic precursor 2, which we envi-
sioned could be prepared from appropriately substituted
bicyclo[3.3.1]nonane 3a (Scheme 1). Thus we explored
the Robinson annulation depicted schematically in struc-
ture 4 as a route to bicyclo[3.3.1]nonane 3a paying special
attention to the stereochemistry of the allyl group attached
to the one-carbon bridge. Herein we report the results of
this exploration.
(1) (a) Taschner, M. J.; Shahripour, A. J. Am. Chem. Soc. 1985, 107,
5570. (b) Paquette, L.; Schaefer, A. G.; Springer, J. P. Tetrahedron 1987,
43, 5567. (c) Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943. (d)
Marques, F. A.; Lenz, C. A.; Simonelli, F.; Maia, B. H. L. N. S.; Vellasco,
A. P.; Eberlin, M. N. J. Nat. Prod. 2004, 67, 1939. (e) Amagata, T.;
Minoura, K.; Numata, A. J. Nat. Prod. 2006, 69, 1384. (f) Moosophon, P.;
Kanokmedhakul, S.; Kanokmedhakul, K.; Soytong, K. J. Nat. Prod. 2009,
72, 1442.
(3) (a) Chakraborti, R.; Ranu, B. C.; Ghatak, U. R. J. Org. Chem. 1985,
50, 5268. (b) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G. Q.; Kim, S.;
Kessabi, J. Org. Lett. 1999, 1, 807. (c) Aoyagi, K.; Nakamura, H.;
Yamamoto, Y. J. Org. Chem. 1999, 64, 4148. (d) Geirsson, J. K. F.; Jonsson,
S.; Valgeirsson, J. Biorg. Med. Chem. 2004, 12, 5563. (e) Bertelsen, S.;
Johansen, R. L.; Jørgensen, K. A. Chem. Commun. 2008, 3016. (f)
Kuninobu, Y.; Morita, J.; Nishi, M.; Kawata, A.; Takai, K. Org. Lett. 2009,
11, 2535. (g) Zhao, Y. L.; Chen, L.; Yang, S. C.; Tian, C.; Liu, Q. J. Org.
Chem. 2009, 74, 5622. For reviews, see: (h) Peters, J. A. Synthesis 1979,
5, 321. (i) Butkus, E. Synlett 2001, 12, 1827.
(2) (a) Gambacorta, A.; Fabrizi, G.; Bovicelli, P. Tetrahedron 1992, 48,
4459. (b) Yamawaki, I.; Bukovac, S. W.; Sunami, A. Chem. Pharm. Bull.
1994, 42, 2365. (c) Srikrishna, A.; Vijaykumar, D. J. Chem. Soc., Perkin
Trans. 1 1999, 1265. (d) Aleu, J.; Hernandez-Galan, R.; Hanson, J. R.;
Hitchcock, P. B.; Collado, I. G. J. Chem. Soc., Perkin Trans. 1 1999, 727.
(e) Mach, R. H.; Yang, B.; Wu, L.; Kuhner, R. J.; Whirrett, B. R.; West,
T. Med. Chem. Res. 2001, 10, 339. (f) Chu, W. H.; Xu, J. B.; Zhou, D.;
Zhang, F.; Jones, L. A.; Wheeler, K. T.; Mach, R. H. Bioorg. Med. Chem.
2009, 17, 1222. (g) Ronco, C.; Sorin, G.; Nachon, F.; Foucault, R.; Jean,
L.; Romieu, A.; Renard, P. Y. Bioorg. Med. Chem. 2009, 17, 4523.
(4) For the isolation and biological activities of vinigrol, see: (a) Uchida,
I.; Ando, T.; Fukami, N.; Yoshida, K.; Hashimoto, M.; Tada, T.; Koda, S.;
Morimoto, Y. J. Org. Chem. 1987, 52, 5292. (b) Ando, T.; Tsurumi, Y.;
Ohata, N.; Uchida, I.; Yoshida, K.; Okuhara, M. J. Antibiot. 1988, 41, 25.
(c) Ando, T.; Yoshida, K.; Okuhara, M. J. Antibiot. 1988, 41, 31.
10.1021/ol1000878  2010 American Chemical Society
Published on Web 02/24/2010

Scheme 1
.
Stereoselective Robinson Annulation Reaction
Table 1. Stereochemical Outcome of Robinson Annulation
Reactions Leading to Bicyclo[3.3.1]nonanes
Required To Develop a Ring-Expansion Approach to Vinigrol
Stereochemistry at the one-carbon bridge will be
governed by the competition of aldol ring-closure reactions
of diastereomeric intermediates 6a and 6b formed from
Michael adduct 5 (Scheme 2). There are several lines of
starting
material
ratio
(syn/anti)a
entry
total yield (%)
1
2
3
4
5
11b
10c
13d
15e
8f
1:4.3
1:3.5
1:4.9
1:5
54
42
31
43
56
Scheme 2. Stereochemistry at the One-Carbon Bridge Is Governed
by the Competing Aldol Reactions 6a f 3a and 6b f 3b
1:4
a The ratio is based upon the 1H NMR of the crude product. b The
compound is prepared according to the literature.7 c The compound is
prepared according to the literature.8 d The compound is prepared by
methylation of compound 11.9 e The compound is prepared by
hydroboration-oxidation of compound 11 using Cy2BH·THF according
to a known procedure.10 f Carvone (8) is commercially available.
and 9b (anti) rather than 9a (syn) as the major product.
Compound 14b (anti) was the major diastereomer obtained
in the reaction of ethyl acetoacetate with 2-allyl-6-methyl-
2-cyclohexenone, 13 (entry 3). Neither the substituent on
the cyclohexane ring (entries 1-3) nor the substituent at the
one-carbon bridge (entries 4 and 5) significantly influence
stereoselectivity. In the reaction of ethyl acetoacetate with
15 (3-hydroxypropyl is the substituent at the one-carbon
bridge) and carvone (8), the anti diastereomers 16b and 17b
are the major products formed. The configuration of the one-
carbon bridge center has been unambiguously assigned
according to the X-ray crystal analysis of compounds 12b,
14b, and17b (Figure 1).
It is worth mentioning that, for a mixture of diastereomers
formed in a Robinson annulation reaction, we can quickly
assign the configuration of the one-carbon bridge stereocenter
on the basis of the relative positions of NMR signals for the
enolic protons and carbons (O2-H and C3; see Scheme 3).
In each case that we’ve examined, both the O2-H and C3
chemical shifts of the minor diastereomer (syn, a series) are
downfield to those of the major diastereomer (anti, b series).
Another trend that we have observed is that the minor
diastereomers are consistently less polar (higher Rf on TLC,
shorter retention time in column chromatography) than the
major diastereomers. Collectively, this data is consistent with
conformational equilibria where the relative stability of
reasoning that might lead one to expect that the aldol ring
closure of 6a, leading to the desired stereochemistry
present in 3a, might be the favored pathway. First, the
reactive conformer of 6a (equatorial allyl) should be lower
in energy than 6b (axial allyl). Second, Robinson annu-
lation product 3a (derived from 6a) is lower in energy
than its epimer 3b (derived from 6b) as a result of the
enolization of the ꢀ-keto ester, which removes a 1,3-
diaxial involving the allyl group. Indeed, two similar
Robinson annulations previously reported provide prece-
dent for the major product possessing the desired stere-
ochemistry 3a. Theobald reported that 7a is the major
product formed by annulation of carvone (8) with ethyl
acetoacetate, followed by saponification and decarboxy-
lation.5 Kraus reported that 9a was the major product
(>20:1 diastereoselectivity) formed from the analogous
annulation/decarboxylation sequence utilizing 2-allyl-5-
methyl-2-cyclohexenone (10).6
To our surprise, the Robinson annulation reaction of ethyl
acetoacetate with 2-allyl-2-cyclohexenone (11) gave 3b (anti)
rather than 3a (syn) as the major product (Table 1, entry 1).
Repeating the Robinson annulation originally reported by
Kraus, we were also surprised to find that 12b (anti) was
the major diastereomer obtained in the reaction of ethyl
acetoacetate with 2-allyl-5-methyl-2-cyclohexenone, 10 (en-
try 2). In order to directly compare our selectivity to the
Kraus result, the 12b/12a mixture was decarboxylated to
produce a 9b/9a mixture with the same diastereomer ratio
(5) Theobald, D. W. Tetrahedron 1969, 25, 3139.
(6) (a) Kraus, G. A.; Hon, Y. S. J. Am. Chem. Soc. 1985, 107, 4341.
(b) Kraus, G. A.; Hon, Y. S. Heterocycles 1987, 25, 377.
(7) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Zanirato, V.
Tetrahedron Lett. 1984, 25, 4291.
Org. Lett., Vol. 12, No. 6, 2010
1233

Figure 1. Crystal structures of compounds 12b, 14b, and 17b.
hydrogen-bonded conformers is greater for the minor dia-
stereomers. The one-carbon bridge substituent could influ-
ence such an equilibrium by sterically destabilizing non-
hydrogen-bonded conformers.
(3 equiv, 24 h) produced a 1:1 mixture of decarboxylation
products 19a and 19b (Scheme 4).13 Subjection of diaste-
reomerically pure 19a or 19b to the same reaction conditions
leads to the same 1:1 mixture, suggesting that the final
product ratio represents thermodynamic control. We propose
that this isomerization takes place via a retro-aldol reaction
followed by base-catalyzed epimerization of the ring-opened
diketones.
Scheme 3. Comparative Features Allowing Stereochemical
Assignment of Diastereomers Formed in the Robinson
Annulation
Scheme 4
.
Base-Catalyzed Epimerization of the One-Carbon
Bridge Stereocenter
The unanticipated stereoselectivity appears to be kinetically
controlled since major anti products (3b, 12b, 14b, 16b, and
17b) are higher in energy than diastereomeric minor syn
products (3a, 12a, 14a, 16a, and 17a). Stereoselectivity also
correlates with the expected rate of the aldol ring closure
where the major products result from reactions that place
the substituent R to the reacting ketone anti to the approach-
ing enolate (e.g., 6b f 3b in Scheme 2).11
While exploring the reaction chemistry of Robinson
annulation products, we discovered an interesting epimer-
ization reaction that might provide an alternative stereocon-
trol motif that can influence the stereochemistry of the
substituent at the one-carbon bridge. Treatment of a 1:4.3
mixture of 18a and 18b12 with refluxing methanolic KOH
A similar base-catalyzed epimerization conducted on a
mixture of 3b and 3a might change the 4.3:1 3b/3a kinetic
ratio to a thermodynamic ratio favoring the lower energy
isomer 3a. Unfortunately, the base-mediated decarboxylation
reaction that takes place under these conditions prevents such
an epimerization from being realized. We reasoned that there
may be other base-stable electron-withdrawing groups still
capable of promoting the enolization that stabilizes the
desired diastereomer of the Robinson annulation reaction.
Thus, we looked at the Robinson annulation of carvone with
acetone derivative possessing an R carbon substituted with
either a carboxamide or cyano group. We obtained kinetic
product ratios similar to those obtained using ꢀ-keto esters
(Table 2).
(8) Chong, B.-D.; Ji, Y.-I.; Oh, S.-S.; Yang, J.-D.; Baik, W.; Koo, S. J.
Org. Chem. 1997, 62, 9323.
(9) Marques, F. A.; Lenz, C. A.; Simonelli, F.; Maia, B. H. L. N. S.;
Vellasco, A. P.; Eberlin, M. N. J. Nat. Prod. 2004, 67, 1939.
(10) Kabalka, G. W.; Yu, S.; Li, N. S. Tetrahedron Lett. 1997, 38, 5455.
(11) An attractive explanation, suggested by a reviewer, is that observed
stereoselectivity could be accounted for by intramolecular proton transfer.
A similar stereochemical argument was presented in Grossman, R. B.; Ley,
S. V. Tetrahedron 1994, 50, 11553.
Base-catalyzed epimerization (6 equiv of KOH, refluxing
MeOH, 48 h) converted the 2.5:1 20b:20a ꢀ-keto amide
(12) A mixture of 18a and 18b was prepared by methylation of the
corresponding mixture of 3a and 3b.
(13) With less than
3
equiv of base, decarboxylation without
epimerization is observed.
1234
Org. Lett., Vol. 12, No. 6, 2010

under previously reported reaction conditions, we found that
the major diastereomer formed places the one-carbon bridge
substituent anti to the ꢀ-keto ester/amide unit introduced in
the reaction and stereoselectivity appears to be kinetically
controlled. Thermodynamically controlled stereoselectivity
can be realized under more forcing conditions in the presence
of a large excess of base through an interesting epimerization
reaction. In the case of one ꢀ-keto amide system that we
have investigated, it appears that it may be possible to use
base-catalyzed epimerization as a means to reverse the kinetic
selectivity obtained in these Robinson annulation reactions
thus obtaining the syn diastereomer as the major product.
Finally, it should be emphasized that the results presented
herein differ from literature precedent in both the sense and
the degree of diastereoselectivity, although the reaction
conditions employed appear to be identical to those previ-
ously reported.15,16
Table 2. Robinson Annulation Reactions Aimed at Producing
Bicyclo[3.3.1]nonane Products Resistant to Base-Mediated
Decarboxylation
product
ratio (a/b)a
total yield (%)
Acknowledgment. We thank Dr. Dale Treleaven (LSU)
and Thomas Weldeghiorghis (LSU) for assistance with 2D
NMR experiments and Frank Fronczek (LSU) for assistance
with X-ray crystallography.
20
21
1:2.5
1:2.7
1
80
74
a
The ratio is based upon the H NMR of the crude products
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
mixture obtained from Robinson annulation to a 3:1 20a:
20b mixture (Scheme 5). Base-catalyzed epimerization of
pure 20b produced the same 3:1 mixture where 20a was the
major component.14
OL1000878
(14) Since the keto form predominated for cyano-substituted Robinson
annulation products 21a and 21b, an epimerization reaction favoring 21a
was not considered a promising prospect. When the initially attempted
epimerization of 21a:21b led to an complex mixture of decomposition
products, this reaction was not pursued further.
Scheme 5
.
Stereoselectivity Reversal via Base-Catalyzed
Epimerization
(15) It is possible that the previously assigned one-carbon bridge
configuration5,6 is incorrect, since product stereochemistry was not confirmed
by X-ray crystallography.
(16) Reaction of dimethyl 1,3-acetonedicarboxylate with enals to form
bicyclo[3.3.1]nonanes proceeds by sequential Robinson annulations.3c-e The
second Robinson annulation of this sequence exhibits diastereoselectivity
analogous to those described herein, favoring the diastereomer that places
the one-carbon bridge substituent anti to the ꢀ-keto ester unit introduced
in the reaction:
In summary, the one-carbon bridge stereochemistry of
bicyclo[3.3.1]nonane systems formed by Robinson annulation
has been established, and factors influencing stereoselectivity
have been examined. For base-catalyzed reactions conducted
Org. Lett., Vol. 12, No. 6, 2010
1235