Anodic cyclization reactions and the synthesis of (-)-crobarbatic acid

Article abstract of DOI:10.1016/j.tetlet.2008.04.075

A synthesis of (-)-crobarbatic acid is reported along with the first use of a vinyl-substituted ketene dithioacetal as a coupling partner for an anodic cyclization reaction. The use of the vinyl-substituted ketene dithioacetal enables the construction of a cyclic product having a tetrasubstituted carbon with a relative stereochemistry opposite to that originally obtained from the cyclization.

Full text of DOI:10.1016/j.tetlet.2008.04.075

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Tetrahedron Letters 49 (2008) 3868–3871
Anodic cyclization reactions and the synthesis of (À)-crobarbatic acid
Hai-Chao Xu, John D. Brandt, Kevin D. Moeller *
Department of Chemistry, Washington University, St. Louis, MO 63130, USA
Received 13 March 2008; accepted 10 April 2008
Available online 15 April 2008
Abstract
A synthesis of (À)-crobarbatic acid is reported along with the first use of a vinyl-substituted ketene dithioacetal as a coupling partner
for an anodic cyclization reaction. The use of the vinyl-substituted ketene dithioacetal enables the construction of a cyclic product having
a tetrasubstituted carbon with a relative stereochemistry opposite to that originally obtained from the cyclization.
Ó 2008 Elsevier Ltd. All rights reserved.
Anodic olefin coupling reactions convert electron-rich
double bonds that normally serve as nucleophiles into
highly reactive radical cation intermediates that are in turn
trapped by other nucleophiles.1–3 The reactivity of the rad-
ical cation enables the reactions to generate a variety of
quaternary and tetrasubstituted carbons.4 For example,
an anodic olefin coupling reaction between a ketene dithio-
acetal and an oxygen nucleophile was used in the synthesis
of (+)-nemorensic acid (3) in order to generate the tetra-
substituted carbon at C2 of the natural product (Scheme
1).4d In this reaction, the stereochemistry of the tetrasubsti-
tuted carbon was controlled by sterics with the large dithio-
orthoester group winding up trans to the methyl
substituent at C3. While the electrolysis reaction illustrated
was ideal for synthesizing nemorensic acid, the natural pro-
pensity for the reaction to place the dithioorthoester trans
to the methyl group at C3 meant that an alternative
synthetic route was needed to synthesize molecules like
crobarbatic acid 4 that have the opposite relative stereo-
chemistry at C2.5,6
One method for solving this problem would be to incor-
porate functional groups into the electrolysis substrate that
would allow for manipulation of product stereochemistry
following the cyclization. For example, consider the chem-
istry outlined in Scheme 2. In this case, a vinyl-substituted
ketene dithioacetal would be employed in the electrolysis
reaction in order to afford product 6. A net oxidation of
Me
Me
Me
3
anodic
S
S
Me
Me
2
S
oxidation4d
O
Me
OH
MeO
S
2 Me
1
Me
1
2. 71%
S
S
anodic
( )n
O
S
S
( )n
O
.
+
oxidation
Me
Me
Me
O
Me
H
H
HO
O
Me
Me
5
OH
OH
O
O
O
Me
O
Me
Me
CO2H
3. (+)-Nemorensic Acid
Me
4. (-)-Crobarbatic Acid
( )n
O
( )n
O
S
Scheme 1.
Me
MeO
S
6
7
*
Corresponding author. Tel.: +1 314 935 4270; fax: +1 314 935 4481.
Scheme 2.
E-mail address: moeller@wuchem.wustl.edu (K. D. Moeller).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.075

H.-C. Xu et al. / Tetrahedron Letters 49 (2008) 3868–3871
3869
the olefin in 6 to a carboxylic acid and reduction of the
RVC anode
Pt cathode
2 Me
Me
orthoester to a methyl group would afford a product (7)
with a tetrasubstituted carbon stereochemically opposite
to that obtained in the nemorensic acid synthesis and ideal
for synthesizing crobarbatic acid.
Me
0.1 M Et4NOTs
S
S
1
S
O
OH
Me
30% MeOH/ THF
50 mole % n-BuLi
6.0 mA, 2.0 F/mole
72% (5:1 ratio
(of diastereomers)
MeO
S
The choice of the vinyl-substituted ketene dithioacetal in
this route appeared ideal because the vinyl group would be
compatible with the synthesis of the ketene dithioacetal in
5, would aid the subsequent anodic oxidation reaction by
stabilizing the radical cation generated, and would nicely
mask the carbonyl needed in the final product. Addition-
ally, there was the attractive possibility that the vinyl group
could be cleaved to form an acid in the same step used to
convert a tetrahydrofuran product like 6 or 7 into the lac-
tone needed for crobarbatic acid. However, it was also pos-
sible that the vinyl substituent on the radical cation
intermediate might significantly alter the reactivity of the
radical cation and prevent the cyclization. Certainly, earlier
cyclization reactions were dramatically altered by the nat-
ure of a substituent bound to the radical cation.4a
5
6
Scheme 4.
passed through the cell using a reticulated vitreous carbon
(RVC) anode and Pt cathode until 1.6–1.8 F/mol of charge
had been passed. The reaction used a 0.1 M tetraethylamo-
nium tosylate in 30% methanol/THF electrolyte solution
and 2,6-lutidine as an acid scavenger. Using these condi-
tions, a 57% isolated yield of product 6 was obtained as
a 5:1 ratio of diastereomers (the major product is shown
in Scheme 4). The yield of the reaction could not be raised
by passing more current through the cell even though a
stoichiometric amount of current (2 F/mol) was not con-
sumed and some starting material was recovered. Addi-
tional current led to the consumption of the remaining
starting material, but not increase in the amount of product
isolated.
Fortunately, both the yield and cleanliness of the reac-
tion could be improved by changing the base used as the
acid scavenger in the reaction. While the electrolysis reac-
tion as a whole is neutral, acid is generated at the anode
and base at the cathode (the cathodic reaction involves
the reduction of methanol). Conducting the reaction in a
basic medium accelerates the rate at which the acid gener-
ated at the anode is neutralized. This serves to protect acid-
sensitive oxidation substrates as they approach the anode.
In the present reaction, replacing the 2,6-lutidine previ-
ously used with LiOMe (generated by adding 50 mol %
of n-BuLi to the solution prior to the electrolysis) increased
the effectiveness of this process and led to the generation of
a 72% isolated yield of 6 (Scheme 4).
In order to address this question, the electrolysis sub-
strate 5 was synthesized as outlined in Scheme 3.
The synthesis began with an alkylation of the known
psuedoephedrine amide 8.7 Following the alkylation reac-
tion, amide 9 was treated with one equivalent of t-BuLi
to deprotonate the alcohol followed by 1-lithio-1-propene
in order to form ketone 10. The ketone was then converted
into the ketene dithioacetal moiety needed for the electrol-
ysis reaction using a Peterson olefination. In addition to the
66% yield of product obtained for the reaction, the Peter-
son olefination also led to a 31% yield of a 1,4-addition
product. Finally, the silyl ether was deprotected using tet-
rabutylammonium fluoride.
With electrolysis substrate 5 in hand, we set out to deter-
mine if the vinyl substituent would interfere with the ano-
dic cyclization reaction. Initially, reaction conditions
identical to those used for oxidizing substrate 1 were
employed.4d To this end, a constant current of 8 mA was
In analogy to earlier cyclization reactions (Scheme 1),
the major stereoisomer obtained from the anodic oxidation
had the large orthoester group in a position trans to the
methyl at C2. This stereochemical assignment was made
using a NOESY experiment following the reduction of
the electrolysis product to a dithioacetal with Dibal-H
(Scheme 5).8 The conversion of 6 to 11 was done in order
to simplify the separation of the two stereoisomers.
In addition to assigning the relative stereochemistry of
the product, a check was made to determine if the molecule
Me
2 Me
1) 2 eq. LDA, 6 eq. LiCl,
THF, -78ºC
1
O
OH
Ph
O
N
OH
Ph
TBSO
Me
N
Me
2) I-(CH2)2-OTBS, 90%
Me
Me
9
8
3 a) t-BuLi, Et2O
b) t-CH3CH=CHLi
4 a)
Et2O, 4 h, 0 ºC, 98%
S
S
2 Me
2 Me
TMS
nBuLi, THF,
S
S
1
1
O
Me
Me
OH
Me
TBSO
Me
Me
Dibal-H
-78 to 0 ºC, 5 h
b) -78ºC to RT,
overnight, 66%
5) TBAF, THF
3 h, RT, 90%
S
S
O
Me
O
MeO
THF, r.t.
62%
H
10
5
S
S
11
6
Scheme 3.
Scheme 5.

3870
H.-C. Xu et al. / Tetrahedron Letters 49 (2008) 3868–3871
had racemized the stereogenic atom at C2 during either the
reaction to form the ketene dithioacetal or the electrolysis
reaction. This was accomplished by comparing the major
isomer of 11 with racemic material that was independently
synthesized. HPLC analysis using a chiral stationary phase
(CHIRALPAKÒADH) showed product 11 to have a enan-
tiomeric excess greater that 97%, a value consistent with
the alkylation reaction to form 9.7 No racemization had
occurred.
While it was clear that the vinyl substituent had not
interfered with the cyclization, the question remained as
to whether its use would enable the synthesis of a product
having the relative stereochemistry found in crobarbatic
acid. Initial attempts to address this issue focused on the
earlier reports that dithianes can be selectively reduced in
the presence of an olefin.9 Such a reduction would allow
for conversion of the ortho ester into a methyl group fol-
lowed by oxidative cleavage of the olefin and formation
of a product with the correct C2 stereochemistry for cro-
barbatic acid. However, with 11 this approach failed.
Attempts to reduce the dithioacetal led to either incom-
plete reduction and the formation of thioethers or compet-
itive reduction of the double bond.
For this reason, a different tact was taken (Scheme 6).
An N-chlorosuccinimide-assisted hydrolysis of the dithiane
moiety in 6 led to the formation of a methyl ester that was
subsequently reduced with LiAlH4 to afford an alcohol.
Conversion of the alcohol to the isopropylsulfonyl ether
(12, 84% over three steps) followed by superhydride reduc-
tion led to the desired methyl substituent on C1. The iso-
propylsulfonyl group was used in this sequence instead of
a mesylate because reduction of the mesylate led to only
a small amount of the desired product 13 along with recov-
ered alcohol.10 No such problem occurred with the isopro-
pyl sulfonyl ether. Due to its volatility, compound 13 was
difficult to isolate. Therefore, it was carried forward with
the use of cat. RuO4 and NaIO4 in order to generate (À)-
crobarbatic acid (4) in a 55% yield (from 12).5e During
the course of the synthesis, the minor diastereomer from
the electrochemical cyclization was ‘lost’ and only one
diastereomer of the product was obtained. The absolute
stereochemistry of 4 was established by comparing its
optical rotation to the known literature values.5e
From a synthetic standpoint, the final oxidation step
was very satisfying in that it did allow for both the cleavage
of the olefin to the acid and the oxidation of the tetrahy-
drofuran ring in a single step. Interesting, this transforma-
tion did not proceed well unless both oxidations were
conducted at the same time. The use of either a substrate
having the lactone already in place or a substrate having
the olefin already oxidized to the acid led to a reaction that
failed to oxidize the group remaining in the reduced form.
In conclusion, we have developed a flexible synthetic
approach to substituted anodic cyclization substrates.
The route was used to study an anodic cyclization involv-
ing a vinyl-substituted radical cation intermediate. The
electrolysis reaction proceeded nicely, and the product
was converted into (À)-crobarbatic acid thereby illustrat-
ing the utility of the overall strategy for synthesizing prod-
ucts having relative stereochemistries opposite to that
originally afforded by the cyclization. The route to the elec-
trolysis substrate should allow us to probe the generality of
anodic cyclization reactions for assembling a variety of
functionalized molecules containing highly hindered tetra-
substituted carbons. While the approach was illustrated
here using an oxygen trapping group for the radical cation,
it should be compatible with a variety of carbon-based
nucleophiles and the construction of new quaternary
carbons.4 Work along these lines is underway.
Acknowledgments
We thank the National Science Foundation (CHE-
9023698) for their generous support of our work. We also
gratefully acknowledge the Washington University High
Resolution NMR facility, partially supported by NIH
Grants RR02004, RR05018, and RR07155, and the Wash-
ington University Mass Spectrometry Resource Center,
partially supported by NIHRR00954, for their assistance.
1. NCS, acetone/ H2O
(9/1), rt
2. LiAlH4, Et2O,
0 ºC - rt
References and notes
Me
Me
Me
Me
O O
1. For reviews of early efforts see: (a) Moeller, K. D. Tetrahedron 2000,
56, 9527; (b) Moeller, K. D. In Topics in Current Chemistry;
Steckhan, E., Ed.; Springer: Berlin, 1996; Vol. 185, pp 49–86.
2. For recent work see: (a) Tang, F.; Chen, C.; Moeller, K. D. Synthesis
2007, 3411; (b) Huang, Y.; Moeller, K. D. Tetrahedron 2006, 62, 6536;
(c) Brandt, J. D.; Moeller, K. D. Org. Lett. 2005, 7, 3553 and
references cited therein.
3. For a recent review of the use of electrochemistry in synthesis see:
Sperry, J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605.
4. For selected examples see Ref. 2a and c as well as: (a) Tang, F.;
Moeller, K. D. J. Am. Chem. Soc. 2007, 129, 12414; (b) Wu, H.;
Moeller, K. D. Org. Lett. 2007, 9, 4599; (c) Mihelcic, J.; Moeller, K.
D. J. Am. Chem. Soc. 2004, 126, 9106–9111; (d) Liu, B.; Duan, S.;
Sutterer, A. C.; Moeller, K. D. J. Am. Chem. Soc. 2002, 124, 10101;
(e) Reddy, S. H. K.; Chiba, K.; Sun, Y.; Moeller, K. D. Tetrahedron
2001, 57, 5183; (f) Frey, D. A.; Reddy, S. H. K.; Wu, N.; Moeller, K.
S
O
O
3. Isopropylsulfonyl chloride
Et3N, CH2Cl2, 0ºC - rt
84% (3 steps)
MeO
S
S
O
12
6
LiEt3BH, THF
65 ºC
Me
Me
Me
CO2H
.
RuO2 X H2O, NaIO4
O
O
O
Me
55% (2 steps)
Me
4
13
Scheme 6.

H.-C. Xu et al. / Tetrahedron Letters 49 (2008) 3868–3871
3871
D. J. Org. Chem. 1999, 64, 2805–2813; (g) Tinao-Wooldridge, L. V.;
Moeller, K. D.; Hudson, C. M. J. Org. Chem. 1994, 59, 2381.
5. For previous syntheses of crobarbatic acid see: (a) Huang, J.;
Meinwald, J. J. Am. Chem. Soc. 1981, 103, 861; (b) Donohoe, T. J.;
Stevenson, C. A.; Helliwell, M.; Irshad, R.; Ladduwahetty, T. Tetra-
hedron: Asymmetry 1999, 10, 1315; Chen, M.-Y. (c) Fang, J. –M. J.-
M. J. Org. Chem. 1992, 57, 2937; (d) Honda, T.; Ishikawa, F.;
Tamane, S. –I. S.-I. J. Chem. Soc. Perkin Trans. 1 1996, 1125; (e)
Jang, D.-P.; Chang, J.-W.; Uang, B.-J. Org. Lett. 2001, 3, 983.
6. For a related synthesis of epi-crobarbatic acid see: Brandt, J. D.;
Moeller, K. D. Heterocycles 2006, 67, 621.
7. Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.
8. Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V. Synthesis
1996, 285.
9. Troin, Y.; Diez, A.; Bettiol, J.-L.; Rubiralta, M. Heterocycles 1991,
32, 663.
10. Hua, D. H.; Venkataraman, S.; Ostrander, R. A.; Sinai, G.-Z.;
McCann, P. J.; Coulter, M. J.; Xu, M. R. J. Org. Chem. 1988, 53, 507.