Oxidative cyclizations: The asymmetric synthesis of (-)-alliacol A

Article abstract of DOI:10.1021/ja048085h

A tandem anodic coupling-Friedel-Crafts alkylation strategy has been used to rapidly complete the asymmetric synthesis of alliacol A. The anodic oxidation reaction allowed for the generation of a new bond between two nucleophiles. In the synthesis, the ab

Full text of DOI:10.1021/ja048085h

Published on Web 07/03/2004
Oxidative Cyclizations: The Asymmetric Synthesis of
(-)-Alliacol A
John Mihelcic and Kevin D. Moeller*
Contribution from the Department of Chemistry, Washington UniVersity,
St. Louis, Missouri 63130
Received April 2, 2004; E-mail: moeller@wuchem.wustl.edu
Abstract: A tandem anodic coupling-Friedel-Crafts alkylation strategy has been used to rapidly complete
the asymmetric synthesis of alliacol A. The anodic oxidation reaction allowed for the generation of a new
bond between two nucleophiles. In the synthesis, the absolute stereochemistry of the final natural product
is set relative to a methyl group that is incorporated early in the sequence using an asymmetric Michael
reaction.
Our interest in determining the synthetic utility of oxidative
Scheme 1
1
cyclization reactions led us to explore new, potentially efficient
2
routes to (+)-alliacol A (1). Alliacol A is a sesquiterpene that
was first isolated in Europe from the culture broth of the fungus
3
Marasmius alliaceus. The molecule displays moderate anti-
microbial activity and inhibits DNA synthesis in the ascetic form
4
of Ehrlich carcinoma at concentrations less than 10 µg/mL.
Studies indicate that the R,â-unsaturated lactone present in the
C-ring serves as a Michael acceptor for sulfur-containing
residues present in enzymes.4 The molecule’s angulary fused
tricyclic skeleton, five contiguous stereogenic atoms, and three
contiguous tetrasubstituted carbons make it a challenging and
attractive target for synthesis. It has previously been made in
,5
6
racemic form by the Lansbury group. This very nice approach
to the molecule utilized an intramolecular SN2 displacement to
construct the C-ring late in the synthesis. For our part, we hoped
to demonstrate that an anodic cyclization reaction could lead
to a unique, very direct synthesis of the natural product in a
manner that would readily allow for the asymmetric synthesis
of the molecule.
cyclization reaction would then be used to construct the
tetrasubstituted carbon at the core of the natural product and a
tricyclic ring system (5) that would be converted into the natural
product. This pathway was intriguing because it offered the
opportunity to probe the ability of the intramolecular cyclizations
to overcome the barriers associated with a formal 5-endo-type
cyclization. However, from a synthetic perspective, the second
approach (path b) appeared much more attractive. In this
scenario, a more complex initial substrate having all of the
carbons needed to complete the synthesis would be synthesized
and then oxidized to afford bicyclic intermediate 6. The alcohol
functional group in 6 would then be used to set up either an
intramolecular Friedel-Crafts cyclization, a radical cyclization
reaction, or a second anodic cyclization. The approach selected
would be the one that allowed for construction of the tetrasub-
stituted carbon at the core of alliacol A while enabling the most
efficient pathway for completing the synthesis of the natural
Two such strategies appeared feasible (Scheme 1). Both
strategies would originate from an intramolecular cyclization
substrate having the overall form of 2. In the first (path a), the
intramolecular cyclization of a simple substrate (X ) H) would
afford a bicyclic product7 that would then be converted to a
second oxidative cyclization substrate (4). A second oxidative
,8
(
(
(
(
1) For reviews, see: (a) Moeller, K. D. Tetrahedron 2000, 56, 9527-9554.
(
b) Moeller, K. D. Top. Curr. Chem. 1997, 185, 50-86.
2) For a preliminary report on the racemic synthesis, see: Mihelcic, J. M.;
Moeller, K. D. J. Am. Chem. Soc. 2003, 125, 36-37.
3) King, T.; Farrell, K.; Halsall, T.; Thaller, V. J. Chem. Soc., Chem. Commun.
1
977, 20, 727-728.
4) Anke, T.; Watson, W.; Giannetti, B.; Steglich, W. J. Antibiot. 1981, 34,
1
271-1277.
(
5) Hoffman, H.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94-110.
6) (a) Lansbury P.; Zhi, B. Tetrahedron Lett. 1988, 29, 5735-5738. (b)
Lansbury, P.; La Clair, J. Tetrahedron Lett. 1993, 34, 4431-4434. (c) La
Clair, J.; Lansbury, P.; Zhi, B.; Hoogsteen, K. J. Org. Chem. 1995, 60,
(
4
822-4833. For a related synthesis of (()-alliacolide, see: (d) Ladlow,
M.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1988, 1107-1118.
7) (a) For a general discussion of enol ether/furan coupling reactions, see:
New, D. G.; Tesfai, Z.; Moeller, K. D. J. Org. Chem. 1996, 61, 1578-
(
(8) For a very nice example of anodic cyclizations using furans, see:
Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Wright, D. L. Org. Lett.
2002, 4, 3763-3765.
1
598. (b) For a review, see ref 1a.
9106
9
J. AM. CHEM. SOC. 2004, 126, 9106-9111
10.1021/ja048085h CCC: $27.50 © 2004 American Chemical Society

Asymmetric Synthesis of (−)-Alliacol A
A R T I C L E S
Scheme 2
Scheme 4
Scheme 5
Scheme 3
product. In each of the pathways, the initial oxidative cyclization
reaction would be used to construct an advanced intermediate
with all of the functionality needed to complete the synthesis.
Initial Model Studies. With this in mind, we set out to
determine if this approach to the key tetrasubstituted center and
the tricyclic ring skeleton of alliacol A was feasible. Because
regeneration of the furan from the initially formed product 11.
The reaction typically afforded the cyclized product in an 85-
9
0% yield as a 1.5:1 to 2.5:1 ratio of deprotected alcohol to
silyl ether products. Clearly, the electrochemical reaction was
compatible with the full side chain needed for the synthesis.
With the formation of the bicyclic molecule complete,
attention was turned toward finishing the tricyclic core of the
natural product. To this end, the alcohol in 12a was converted
to the corresponding iodide (Scheme 4), which would in turn
be used for either the planned Friedel-Crafts alkylation or
radical cyclization approach to construction of the A-ring. For
the Friedel-Crafts approach, treatment of the iodide with silver
nitrate in methanol then afforded a 71% yield of the desired
tricyclic product 14 (along with 16% of recovered starting
material). Interestingly, attempts to form the tricyclic product
7
9
of the ready availability of known starting materials 7 and 8,
this work commenced with the construction of model substrate
0 (Scheme 2). To this end, compound 7 was converted into
1
10
the corresponding iodide, compound 8 deprotonated to gener-
ate an enolate, and then the two molecules combined to form
ketone 9. In this reaction, the yield of the product was optimized
by slowly adding the iodide to 5 equiv of the enolate. This
minimized the formation of overalkylated enolate. Finally,
conversion of the ketone into a silyl enol ether provided substrate
1
0 for the initial electrolysis reaction.
The electrolysis reaction was performed in a three neck flask
11
using a radical cyclization reaction failed. These reactions led
to either the recovery starting material or reduction of the iodide.
The failure of the radical reaction was interesting because the
anodic cyclization pathway to formation of the A-ring using a
radical cation intermediate was successful (Scheme 5). In this
approach, the alcohol in 12a was converted into an enol ether,
forming the anodic oxidation substrate 15. Oxidation of 15 using
the same conditions employed in the first cyclization led to a
74% isolated yield of the tricyclic product 16. The success of
the anodic cyclization suggested that the radical cation inter-
using constant current conditions of 12.9 mA, a reticulated
vitreous carbon (RVC) anode, a carbon rod cathode, a 0.4 M
lithium perchlorate in 20% methanol/dichloromethane electrolyte
solution, and 2,6-lutidine as a proton scavenger. The electrolysis
was continued until 2.1 F/mol of charge had been passed
(Scheme 3). When complete, the crude reaction mixture was
treated with 5 equiv of p-toluenesulfonic acid, and the reaction
was stirred at room temperature for 17 h. As in previous
7
cyclizations using furans, this final acid step was done to ensure
(
9) Boeykens, M.; Di Kimpe, N.; Tehrani, K. J. Org. Chem. 1994, 59, 6973-
6
985.
(11) For radical cyclization reactions involving furan rings, see: (a) Parsons,
P. J.; Penverne, M.; Pinto, I. L. Synlett 1994, 721-722. (b) Demircan, A.;
Parsons, P. J. Eur. J. Org. Chem. 2003, 1729-1732.
(
10) Cebula, R.; Blanchard, J.; Boisclair, M.; Pal, K.; Bockovich, N. Bioorg.
Med. Chem. Lett. 1997, 7, 2015-2020.
J. AM. CHEM. SOC.
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A R T I C L E S
Mihelcic and Moeller
Scheme 6
Scheme 7
mediate was more reactive toward cyclization than the radical,
an observation that was consistent with earlier studies by
Newcomb and co-workers demonstrating that enol ether radical
cation intermediates are more reactive participants in cyclizations
with olefin trapping groups than are the corresponding radical
1
2
intermediates.
While the second electrochemical cyclization was successful,
it was clear that it would not be the method of choice for
completing the synthesis of alliacol A because it led to the
presence of a formyl group equivalent on the A-ring. This group
would need to be removed in a subsequent reaction. Since the
Friedel-Crafts cyclization led to formation of both the A-ring
and the tetrasubstituted carbon without this added complication,
the tandem electrochemical cyclization-Friedel-Crafts ap-
proach was chosen for the natural product synthesis.
Scheme 8
Developing a Racemic Synthesis.2 With a strategy for
making the ring skeleton in place, attention was turned toward
assembling substrate 2 having the B ring methyl group of alliacol
A in place. Initial plans for this synthesis called for construction
of enone 17 from an aldol condensation involving 8 and the
aldehyde generated from 7. A Michael reaction would then be
used to introduce the B-ring methyl group. Accordingly, alcohol
could also be performed using a 6 V lantern battery as a power
13
7
was oxidized using the Dess-Martin reagent and then treated
supply. Everything other than the power supply for the reaction
remained exactly as described above. The reaction was moni-
tored by TLC until complete and then worked up with acid as
described previously to afford an 82% isolated yield of product.
With the bicyclic product in hand, the alcohol was converted
into an iodide and the Friedel-Crafts cyclization was completed
using the same conditions employed in the initial model study.
A 92% isolated yield of the tricyclic product 21 was obtained
from the Friedel-Crafts reaction. The structure of the tricyclic
compound was assigned with the use of COSY and HMQC
NMR spectra. In addition, the stereochemistry of the two
methine protons on the B-ring was assigned with the use of
coupling constants. The J value for the coupling of these two
protons was 13 Hz, indicating a dihedral angle approaching 180°
for the two C-H bonds and a trans-diaxial relationship between
the protons. At this point, the Friedel-Crafts annulation was
assumed to provide a cis-product with respect to the A,B-ring
juncture.
Initial efforts to complete the racemic synthesis of alliacol A
focused on strategies that would preserve the protected lactol
while converting the A-ring ketone in 21 into the double bond
needed for introducing the epoxide found in the natural product.
All such efforts met with failure for two main reasons. First,
the protected lactol was sensitive to a variety of reaction
conditions. Even when the C-ring lactol ether was deprotected
and oxidized to the unsaturated lactone, all efforts to manipulate
with the enolate derived from 8 (Scheme 6). The aldol reaction
led to a mixture of the desired enone 17 and aldol product 18.
Treatment of 18 with DBU effected the elimination and
generated the enone in a 74% yield. However, the yield of the
aldol reaction was inconsistent. For this reason, a Horner-
Emmons-Wadsworth strategy was undertaken by first convert-
ing keto alcohol 19 to a phosphonate and then performing the
net condensation reaction. Using this method, we could generate
an 83% yield of enone 17 (two steps from alcohol 7) in a
consistent fashion (Scheme 7). For larger scale applications of
this sequence, it proved useful to employ a Swern oxidation
for the oxidation of 7 in place of the initial Dess-Martin
oxidation (Scheme 6). This avoided the need for purification
of the aldehyde prior to the Horner-Emmons-Wadsworth
reaction. Once the enone was in hand, the Michael reaction was
accomplished using a higher order cuprate reagent in the
presence of TBSCl to directly afford substrate 2 in a 91%
isolated yield.
Electrolysis substrate 2 was then oxidized using conditions
that were again directly analogous to those described above for
the electrolysis of substrate 10. In this manner, an 88% isolated
yield of the bicyclic product 6 was generated (Scheme 8).
As in other anodic cyclization reactions, specialized electro-
chemical equipment was not needed for generating good yields
of the desired product. For example, the electrolysis reaction
(
12) Horner, J.; Taxil, E.; Newcomb, M. J. Am. Chem. Soc. 2002, 124, 5402-
(13) Frey, D. A.; Wu, N.; Moeller, K. D. Tetrahedron Lett. 1996, 37, 8317-
5
410.
8320.
9108 J. AM. CHEM. SOC.
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Asymmetric Synthesis of (−)-Alliacol A
A R T I C L E S
Scheme 9
Scheme 11
Scheme 10
least hindered convex face of the molecule. Some support for
1
this assignment was gathered by comparing the H NMR of 24
to the earlier synthesized lactone analogues 25a and 25b. In
this case, the stereochemistry of 25b had been assigned as
having the alcohol cis to the bridgehead proton at C9 because
of the lack of a coupling interaction between the methine protons
at C9 and C8 in the COSY spectrum. The absence of this
coupling interaction suggested that the methine protons had a
dihedral angle of 90°. Once the two stereochemical isomers were
assigned, they could be readily distinguished because the
8
the A-ring functionality of the intermediate led to a complex
mixture of products. With this in mind, it was decided that the
lactol ether in the C-ring ether of 21 should be removed and
then reintroduced later. Such an approach would not lengthen
the overall synthesis since reintroduction of the lactone carbonyl
could be accomplished in a single oxidation step. Even in an
approach that retained the C-ring functionality from the
electrolysis, an oxidation reaction would eventually be required
to generate the lactone group needed for the final product.
Second, all attempts to effect the elimination reaction needed
to introduce the A-ring double bond failed as long as the C-ring
double bond was present. Presumably, the increase in ring strain
associated with placing a second double bond into the tricyclic
ring skeleton was simply too large. With this in mind, the
alternative strategy outlined in Scheme 9 was undertaken. In
this approach, a simultaneous reduction of the carbonyl and
removal of the lactol functionality in 21 would be followed by
conversion of the C-ring double bond into the bridgehead
alcohol needed for the total synthesis. At this point, a double
bond could be introduced into the A-ring. In this way, there
would be no need to introduce a second double bond and the
associated additional ring strain into the tricyclic skeleton. Such
a sequence would afford an intermediate (23) that had been
previously converted into (()-alliacol A.6
chemical shift of the C methine proton was at 4.5 ppm in 25a
and 3.8 ppm in 25b. For 24, the C methine had a chemical
8
shift of 4.34 ppm. On the basis of this comparison, the hydroxyl
group 24 appeared to have the same relationship to the ring
skeleton as the hydroxyl group in 25a. On the basis of the
tentative assignment of stereochemistry in 24, plans were made
to set up an anti-elimination of the hydroxyl group, knowing
that if the assignment was wrong an alternative syn-elimination
could be used.
Initially, the reduced product 24 was protected as a TBS ether,
and then the C-ring olefin epoxidized with m-CPBA. However,
the epoxidation reaction in this sequence led to a 1.3:1 mixture
of stereoisomers. While the isomers could be separated, clearly
a strategy that avoided such a mixture was preferred.
To this end, we found that treatment of alcohol olefin 24
with DMDO led to a single epoxide product that could be
reductively opened to form diol 26 (Scheme 11). On the basis
of NMR chemical shift data and molecular models of the
intermediate epoxide, the stereochemistry of 26 was tentatively
assigned as shown. However, the proof of stereochemistry was
only accomplished after converting the diol into the known
intermediate 23. To effect this transformation, the diol was first
converted into the monotosylate using p-toluenesulfonyl chloride
and pyridine. This reaction could not be forced to completion.
When the temperature was raised above 5 °C or excess TsCl
was employed, the reaction led to tosylation and elimination of
the tertiary alcohol. For this reason, the reaction was run to
partial conversion, the product and starting material were
separated, and then the recovered starting material was recycled.
After four such cycles, an 83% isolated yield of the desired
monotosylated product was obtained. This material was then
treated with DBU in DMF at 130 °C to form 23 in an 85%
c
The overall transformation started by treating 21 with Dibal-H
to reduce the ketone and remove the C-ring lactol functionality
(Scheme 10). The reduction led to a single alcohol product 24.
Assignment of the stereochemistry in 24 was difficult because
of the overlap of the resonances for the protons at C2, C1, and
C9. For this reason, the stereochemistry of the alcohol was
tentatively assigned as anti to the bridgehead proton since it
was thought that the Dibal-H reagent would approach from the
J. AM. CHEM. SOC.
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A R T I C L E S
Mihelcic and Moeller
Scheme 12
Scheme 13
yield and complete the formal racemic synthesis of alliacol A.
The success of the elimination reaction suggested that the earlier
tentative assignment of stereochemistry in 24 had been correct.
the reaction afforded a 79% yield of product with an 81% ee.
The magnitude of the asymmetric induction was established with
the use of a chiral HPLC column in comparison with the racemic
material. As for the direction of the asymmetric induction, it
was determined that the easiest method for making the assign-
ment was to convert the material into the natural product (the
enantiomer illustrated in Scheme 12 is the correct one based
on the assignment made below). Hence, the ketone was treated
with TBSOTf and triethylamine to form the silyl enol ether
substrate 2*, which was then transformed into the mono-alcohol
olefin product 23* using the exact same procedure described
above for the racemic material.
Once in hand, 23* was converted into alliacol A using the
procedure developed by Landsbury (Scheme 13).6c This se-
quence started with the m-CPBA epoxidation of 23* and the
subsequent oxidation of the C-ring to reintroduce the lactone
carbonyl with ruthenium tetraoxide. In the final step, the
exocyclic methylene of the natural product was introduced using
Eschenmoser’s salt.
Overall, the yield for the formal synthesis (()-alliacol A was
8% over 13 steps (88% per step) starting from the known
1
compounds.
Completing the Asymmetric Synthesis. In the synthesis
described above, the stereocenters in the final product are all
set relative to the initial methyl group in intermediate 2. Hence,
it appeared that if the methyl group in 2 could be introduced in
an asymmetric fashion, then the route developed would provide
a convenient means for completing the asymmetric synthesis
of alliacol A. With this in mind, attention was focused on
asymmetric variants of the Michael reaction used to introduce
the methyl group into substrate 2. Of immediate concern in these
deliberations was the observation that the direction and mag-
nitude of the asymmetric induction in such reactions were
1
4
difficult to predict. In fact, changes in a substrate for such a
reaction can completely change the direction of asymmetric
induction for even a single catalyst system. How would the use
of a more complex enone such as 17 alter the reaction, and
would a commercially available ligand lead to a high degree of
asymmetric induction? If so, then what enantiomer of the
product would be formed?
Analysis of the synthesized alliacol A by optical rotation
(
[R]23D -9.6 °C) indicated that the material was the opposite
23
5,16
enantiomer relative to the natural product ([R] D +10.2 °C).
Hence, (-)-alliacol A was synthesized. For construction of the
natural (+)-enantiomer, the R-(+)-monophos ligand would be
required for the Michael reaction.
To address these questions, substrate 17 was treated with
dimethylzinc in the presence of copper triflate and the com-
mercially available asymmetric ligand S-(+)-monophos (Scheme
15
1
2). Initial trials were conducted using 1 to 1.5 equiv of
dimethylzinc at 5-10% catalyst loading at low temperature
-20 to -10 °C). Under these conditions, none of the desired
Conclusion
The anodic coupling of two nucleophiles has been used as
the key step in an efficient synthesis of alliacol A. The
electrochemical reaction proceeds in high yield and can be
accomplished using a simple battery power supply. No special-
ized equipment is needed. The overall synthetic route utilizes a
single stereocenter established early in the synthesis to control
the relative stereochemistry of all the stereogenic atoms in the
final natural product. In this way, construction of the initial
stereocenter with control over absolute stereochemistry has
enabled the first asymmetric synthesis of alliacol A. The overall
strategy taken would appear to provide a general route to
(
product was formed. Raising the temperature of the reaction
did lead to some product, but it was only after dramatically
increasing the amount of catalyst used that the reaction afforded
synthetically useful amounts of material. To this end, 3 equiv
of dimethylzinc were employed along with 30 mol % of the
copper catalyst at the start of the reaction. Initially, the reagents
were added at -20 °C. The reaction was allowed to warm to
room temperature over a period of 5 h, and then an additional
2
5 mol % of the Cu(OTf)2 was added. Using these conditions,
(
14) Alexakis, A.; Benhaim, C.; Fournioux, X.; Van den Heuvel, A.; Leveque,
J.; March, S.; Rosset, S. Synlett 1999, 11, 1811-1813.
(16) The absolute stereochemistry of (+)-alliacol A was assigned by chemical
correlation to the structure of alliacolide. For the assignment of alliacolides
absolute stereochemistry by CD, see: Bradshaw, A. P. W.; Hanson, J. R.;
Kirk, D. N.; Scopes, P. M. J. Chem. Soc., Perkin Trans. 1 1981, 6, 1794-
1795.
(15) The conditions developed by Feringa and co-workers were used. Feringa,
B.; de Vries, A.; Meetsma, A. Angew. Chem., Int. Ed. Engl. 1996, 35,
2
374-2376. R- and S-monophos are available from Strem Chemicals.
9
110 J. AM. CHEM. SOC. VOL. 126, NO. 29, 2004
9

Asymmetric Synthesis of (−)-Alliacol A
A R T I C L E S
angularly fused tricyclic natural products. Efforts to establish
the scope of this approach are currently underway.
University Mass Spectrometry Resource Center, partially sup-
ported by NIHRR00954, for their assistance.
Supporting Information Available: Full experimental details
are included for the asymmetric synthesis along with both proton
and carbon spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Science Foundation
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
(
JA048085H
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