Anodic coupling reactions: probing the stereochemistry of tetrahydrofuran formation. A short, convenient synthesis of linalool oxide.

Article abstract of DOI:10.1021/ol0162670

[reaction: see text]. Intramolecular coupling reactions between enol ether radical cations and oxygen nucleophiles are primarily governed by stereoelectronics. By taking advantage of this observation, a tetrahydrofuran building block for use in constructing (+)-linalool oxide and rotundisine has been synthesized in four steps from a commercially available starting material. The synthesis of (+)-linalool oxide has been completed.

Full text of DOI:10.1021/ol0162670

ORGANIC
LETTERS
2
001
Vol. 3, No. 17
685-2688
Anodic Coupling Reactions: Probing
the Stereochemistry of Tetrahydrofuran
Formation. A Short, Convenient
Synthesis of Linalool Oxide
2
Shengquan Duan and Kevin D. Moeller*
Department of Chemistry, Washington UniVersity, St. Louis, Missouri 63130
moeller@wuchem.wustl.edu
Received June 12, 2001
ABSTRACT
Intramolecular coupling reactions between enol ether radical cations and oxygen nucleophiles are primarily governed by stereoelectronics. By
taking advantage of this observation, a tetrahydrofuran building block for use in constructing (+)-linalool oxide and rotundisine has been
synthesized in four steps from a commercially available starting material. The synthesis of (+)-linalool oxide has been completed.
By reversing the polarity of enol ethers in the presence of
alcohol nucleophiles, anodic oxidation reactions can provide
a unique method for forming substituted tetrahydropyran and
tetrahydrofuran ring systems (Scheme 1).1-3 Since these
cases, one can envision using the anodic cyclization reaction
to construct a common tetrahydrofuran building block 7.
Yet while this reaction is easy to propose, it is not clear what
factors determine the stereochemical outcome of such
cyclizations. Can the anodic cyclization reaction of 8 really
be used to synthesize 7 in a stereoselective fashion? We
report herein that reactions of this type are controlled by
stereoelectronic factors and that they can provide a con-
venient, stereoselective method for rapidly synthesizing both
aldehyde 7 and linalool oxide 5.
Scheme 1
(
1) For a recent review of anodic electrochemistry and its appli-
cations to organic synthesis, see: Moeller, K. D. Tetrahedron 2000, 56,
527.
9
(
(
2) Sutterer, A.; Moeller, K. D. J. Am. Chem. Soc. 2000, 122, 5636.
3) For an example initiated by the oxidation of a ketene dithioacetal
group, see: Sun, Y.; Liu, B.; Kao, J.; d’Avignon, D. A.; Moeller, K. D.
Org. Lett. 2001, 3, 1729.
(
4) For previous syntheses, see: (a) Fournier-Nguefack, C.; Lhoste, P.;
Sinou, D. Tetrahedron 1997, 53, 4353. (b) Mischitz, M.; Faber, K. Synlett
996, 978. (c) Corma, A.; Iglesias, M.; S a´ nchez, F. J. Chem. Soc., Chem.
Commun. 1995, 1635. (d) Garcia, M. A.; M e´ ou, A.; Brun, P. Synlett 1994,
11. (e) M e´ ou, A.; Bouanah, N.; Archelas, A.; Zhang, X. M.; Guglielmetti,
R.; Furstoss, R. Synthesis 1990, 91, 752. (f) Howell, A. R.; Pattenden, G.
J. Chem. Soc., Chem. Commun. 1990, 103. (g) Howell, A. R.; Pattenden,
G. J. Chem. Soc., Perkin Trans. 1 1990, 2715.
1
reactions form a bond between an oxygen nucleophile and
a carbon R to a carbonyl equivalent, they look ideal for
constructing tetrahydrofuran containing natural products such
9
4
5
as linalool oxide 5 and rotundisine 6 (Scheme 2). In both
(5) Gill, M. Nat. Prod. Rep. 1999, 16, 301.
1
0.1021/ol0162670 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/27/2001

“
product-like”, then either an equatorial enol ether radical
cation or an axial enol ether radical cation would have the
same relationship to the equatorial methyl group controlling
the coiling of the chain. Second, it was possible that
formation of the trans isomer 10a was favored by a
Scheme 2
7
stereoelectronic effect. If the alcohol attacked the π* orbital
of the radical cation, then the required overlap (attack along
8
the Dunitz angle) would be maximized for a transition state
like 11 relative to transition state 12 (Figure 1). No such
The possibility that the oxidative cyclization of 8 might
proceed in a stereoselective fashion was suggested by the
2
earlier oxidation of 9a (Scheme 3). In this experiment, the
Figure 1. Stereoelectronic approaches.
Scheme 3
difference would arise for the transition states leading to the
six-membered ring products (13 and 14). Understanding
which one of these two possibilities controlled the stereo-
selectivity of the reaction was critical for predicting the utility
of future cyclization reactions. If the stereoselectivity were
dependent on the neighboring methyl group, then the
oxidation of 8 would most likely be nonselective. If the
reaction were controlled by stereoelectronics, then a stereo-
selective cyclization of 8 was reasonable to suggest.
With this in mind, a series of substrates was synthesized
tetrahydrofuran product (10a) was obtained as a 3:1 mixture
of isomers favoring the trans product. It was found that this
selectivity was not dependent on the stereochemistry of the
3
that removed the methyl group from C and replaced it with
a sterically bulky group at C of the substrate (Scheme 4).
5
6
starting enol ether. Surprisingly, the analogous oxidation
9
b to form a six-membered ring product was not stereo-
Scheme 4
selective and afforded a 1:1 mixture of isomers. This result
suggested that the reactions were under kinetic control since
thermodynamics would have favored the formation of a six-
membered ring having the larger dimethoxyacetal group in
an equatorial position.
Two possible explanations for the observed stereoselec-
tivity appeared reasonable. First, it was possible that the
selectivity obtained in the case of the five-membered ring
resulted from a steric interaction between the developing
3
acetal group and the neighboring methyl substituent on C .
If the transition state were “product-like”, then this steric
interaction would favor the formation of a product where
the two groups were trans to each other. No such preference
would be observed for the oxidation originating from 9b. If
the transition state leading to the six-membered ring were
Six-membered ring substrates were made using the same
chemistry starting from δ-valerolactone. In these examples,
the alkyl group at C (C for a six-membered ring substrate)
5 6
was expected to occupy a pseudoequatorial position in the
(
6) When combined with evidence that the reactions are under kinetic
control, this observation is best explained by equilibration of the radical
cations prior to cyclization.
2686
Org. Lett., Vol. 3, No. 17, 2001

transition state and thus control coiling of the chain. The
substituent would exert little steric influence over the course
of the reaction and hence the stereoselectivity observed for
the reactions would be principally attributed to stereo-
electronic factors.
The earlier substrate leading to the formation of a quaternary
carbon with no substituent on C (9b) and substrates having
the substituent on C that did not require the formation of a
6
6
quaternary carbon (17e,f) all led to satisfactory yields of the
cyclized products. While the cyclization originating from 17d
did not lead to a high yield of the cyclized product, it was
informative in that it generated the cyclized products that
did form in an approximately 1:1 ratio. As in the earlier
cyclization of 9b there was no preference for the enol ether
radical cation to occupy a psuedoequatorial position. The
stereoselectivity of the cyclizations did not improve greatly
when the allylic methyl group (and hence the axial substituent
in a transition state like 13, Figure 1) was removed from the
substrate. Despite the absence of this methyl group, the
oxidation of both 17e and 17f still led to levels of selectivity
that were low relative to the selectivities obtained for the
oxidations leading to five-membered ring products (17e vs
Substrates 17a-c were electrolyzed using constant current
conditions (8 mA/2.0 F/mols), a reticulated vitreous carbon
9
(
RVC) anode, an undivided cell, a Pt cathode, and a 0.03
M tetraethylammonium tosylate in 30% MeOH/THF elec-
trolyte solution (Scheme 5).
Scheme 5
1
7a and 17f vs 17b). Clearly, the stereochemistry of the
reactions was not controlled by placing the enol ether radical
cation in the sterically less hindered psuedoequatorial posi-
tion, a situation that would have been favored by both the
more clearly defined equatorial and axial positions of a six-
membered ring transition state and the absence of the
pseudoaxial methyl group. The data supported the view that
the reactions were controlled by stereoelectronics.
With that backdrop, we turned our attention to the
synthesis of tetrahydrofuran building block 7. For this
cyclization it was hoped that the substituent at C of the
5
substrate would approximate the size of a tert-butyl group
and lead to a synthetically useful degree of stereoselectivity
The cyclization reactions leading to five-membered rings
17a-c) afforded selectivities that ranged from 5:1 and 4:1
when R was either a tert-butyl or an isopropyl group to 2.5:1
when R was a methyl group. The major products were
assigned as having trans stereochemistry because of the
(
(
Scheme 6). This effort began with an asymmetric cis-
1 5
presence of an NOE interaction between H and H (Scheme
5). The lower selectivity observed for the cyclization
originating from 17c was attributed to the inability of the
smaller methyl group to effectively control the conformation
of the coiling chain. The selectivities obtained for the
oxidations of 17a and 17b suggested that the stereochemistry
of the reactions was governed by stereoelectronic factors.
This suggestion was supported by the oxidations leading to
six-membered ring products.
Scheme 6
As in earlier intramolecular anodic coupling reactions,1,2
reactions leading to six-membered rings were not as efficient
as their five-membered ring counterparts. In the case of 17d
the cyclization led to only a 30% isolated yield of the
cyclized product. Similar reactions using isopropyl and tert-
butyl substituents in position R did not lead to any cyclized
material. These cyclizations were hindered by both the
6
formation of the quaternary center and the substituent at C .
(
7) Deslongchamps, P. Stereoelectronic Effects in Organic Synthesis;
Pergamon Press: Oxford, 1983. In particular note pages 32 and 33. For an
example involving the cyclization of an oxygen nucleophile onto an oxonium
ion, see: Pothier, N.; Goldstein, S.; Deslongchamps, P. HelV. Chim. Acta
1
992, 75, 604.
(
8) B u¨ rgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95,
065. B u¨ rgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153.
9) A 100 PPI electrode was used (available from The Electrosynthesis
5
(
Co., Inc.). The electrolyses were conducted utilizing a model 630 coulom-
eter, a model 410 potentiostatic controller, and a model 420A power supply
purchased from the Electrosynthesis Co., Inc. As an alternative the reactions
can be accomplished with a simple setup using a 6-V lantern battery as the
power supply. Frey, D. A.; Wu, N.; Moeller, K. D. Tetrahedron Lett. 1996,
3
7, 8317.
Org. Lett., Vol. 3, No. 17, 2001
2687

hydroxylation of the commercially available ketone 23 using
the previously reported procedure.10 The resulting product
was then transformed into the desired electrolysis substrate
with the use of a Wittig reaction. The anodic oxidation
reaction was conducted using the same conditions utilized
for the model systems. In this case, the reaction led to an
have larger steric differences between competing transition
states. When the conformation of the coiling chain was
effectively controlled, the reactions led to five-membered
rings with synthetically useful levels of stereoselectivity. This
information was used to develop an efficient, four-step
synthesis of a key tetrahydrofuran building block 7.
8
0% yield of the cyclized product. A 7:1 ratio of trans to
Acknowledgment. We thank the National Science Foun-
dation (CHE-9023698) for their generous support of this
work. We also gratefully acknowledge the Washington
University High Resolution NMR facility, partially supported
by NIH grants RR02004, RR05018, and RR07155, and the
Washington University Mass Spectrometry Resource Center,
partially supported by NIHRR00954, for their assistance.
cis isomers was obtained. A hydrolysis reaction then
completed the synthesis of 7 in just four steps. To confirm
the absolute stereochemistry of the product, aldehyde 7 was
converted into (+)-linalool oxide 5 with the use of a Wittig
reaction.
In conclusion, the intramolecular trapping of an enol ether
radical cation by an alcohol nucleophile appears to be
controlled by stereoelectronics. Reactions generating five-
membered ring products that would be expected to have
larger stereoelectronic differences between competing transi-
tion states consistently led to higher stereoselectivities than
their six-membered ring forming counterparts that would
Supporting Information Available: A sample for the
experimental electrochemical procedure is included along
with characterization data for the electrochemical substrates
and corresponding products. This material is available free
of charge via the Internet at http://pubs.acs.org.
(10) Brimble, M. A.; Rowan, D. D.; Spicer, J. A. Synthesis 1995, 1263.
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