Synthesis of the hamigeran skeleton through an electro-oxidative coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2004.11.108

The tricyclic skeleton of the hamigerans has been prepared through an anodic coupling under alcohol-free conditions. The tricyclic core of the hamigerans has been prepared through the use of a two-step electrochemical benzannulation reaction. The annulation proceeds through an initial conjugate addition of a phenethyl cuprate to 3-methylcyclopentenone with in situ silylation of the resulting enolate. Anodic oxidation effectively couples the pendant arene and the silyl enolether to produce a key intermediate for the synthesis of the natural products. Careful optimization revealed that the use of 'alcohol-free' conditions during the electrolysis was critical to obtain high yields of the annulated product. This method allowed the preparation of the tricyclic core of hamigeran A and B in just four steps from commercially available starting materials.

Full text of DOI:10.1016/j.tetlet.2004.11.108

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 411–414
Synthesis of the hamigeran skeleton through an
electro-oxidative coupling reaction
Jeffrey B. Sperry and Dennis L. Wright*
Burke Laboratories, Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Received 27 September 2004; revised 11 October 2004; accepted 22 November 2004
Abstract—The tricyclic core of the hamigerans has been prepared through the use of a two-step electrochemical benzannulation
reaction. The annulation proceeds through an initial conjugate addition of a phenethyl cuprate to 3-methylcyclopentenone with
in situ silylation of the resulting enolate. Anodic oxidation effectively couples the pendant arene and the silyl enolether to produce
a key intermediate for the synthesis of the natural products. Careful optimization revealed that the use of Ôalcohol-freeÕ conditions
during the electrolysis was critical to obtain high yields of the annulated product. This method allowed the preparation of the tri-
cyclic core of hamigeran A and B in just four steps from commercially available starting materials.
ꢀ 2004 Published by Elsevier Ltd.
The hamigerans are unusual halogenated marine natural
products isolated by Cambie and co-workers1 in 2000
from a sponge harvested near New Zealand. Of particu-
lar note was the biological activity of hamigeran B,
which showed potent inhibition of both the polio and
herpes virus while displaying relatively little cytotoxi-
city. Hamigeran B has been synthesized by Nicolaou
and co-workers2 using a novel photochemical benzannul-
ation reaction, Clive and Wang3 who used a free radical
process to annulate the five membered A-ring onto a
tetralone derivative and Trost et al.4 through a palla-
dium catalyzed coupling strategy. Mehta and Shende5
has synthesized 6-epi-hamigeran B through the use of
a key Heck cyclization.
ing a pendant arene to an enone followed by anodic
oxidation to couple the two electron rich moieties. These
reactions proceed under kinetic control and lead exclu-
sively to the formation of cis-fused products. Although
the majority of our work has centered upon the use of
furan as the terminator, we have been interested in
extending this process to other aromatics, notably benz-
enoid systems. The structure and biological activity of
the hamigerans make them an appealing target for this
annulation methodology (Scheme 1).
We hoped to access both hamigeran A and B, as well as
analogs, from the tricyclic ketone 1, which would be
Over the past several years, we have been developing
methodology for the construction of annulated arenes
(most notably furans) through the electro-oxidative
coupling of silyl enolethers and pendant aromatic
nucleophiles.6 The pioneering work of Moeller and
co-workers7 and others8 has shown that electron-rich
aromatics and olefins can be oxidatively coupled under
electrochemical conditions. This type of reaction forms
the basis for our two-step annulation protocol, which
involves the silyl-promoted addition of a cuprate bear-
OH
O
OH
O
OR2
OH
CO2Me
11
Br
O
Br
R1O
H3C
10
C
B
9
H3C
H3C
A
5
6
6
O
1
hamigeran A
hamigeran B
OR2
CH3
R1O
R1O
R2O
CH3
O
2
3
4
Keywords: Electrochemistry; Anodic oxidation; Hamigeran;
Annulation.
TMSO
*
Scheme 1. Approach to the hamigerans based on an arene–enolether
coupling.
Corresponding author. Tel.: +1 603 646 6481; fax: +1 603 646 396;
e-mail: dwright@dartmouth.edu
0040-4039/$ - see front matter ꢀ 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.11.108

412
J. B. Sperry, D. L. Wright / Tetrahedron Letters 46 (2005) 411–414
OMe
OMe
carbon anode
69% overall
from cyclohexenone
MeO
CH3
MeO
CH3
OH
Br2
PPh3
87%
LiClO4 (.1M)
lutidine
MeCN:iPrOH
1) nBuLi then
O
O
O
TMSO
O
O
60%
5
6
12
OMe
13
carbon anode
LiClO4 (1M)
lutidine
MeCN:iPrOH
OMe
OMe
MeO
CH3
Br
MeO
CH3
Mg (0) then
TMSO
TMSO
O
CuI, TMSCl, Et3N
then
Y
X
OMe
9
7
8a, Y=H, X=OMe
8b, X=H, Y=OMe
38% overall
O
a:b=4:1
from cyclohexenone
14
15
TMSO
24%
Scheme 3. Synthesis of a cyclization precursor.
carbon anode
11a, Y=H, X=OMe
11b, X=H, Y=OMe
LiClO4 (1M)
lutidine
MeCN:iPrOH
a:b=4:1
OMe
O
10
Y
X
ylene oxide. Conversion of the phenethyl alcohol 13 to
the corresponding bromide 14 was accomplished under
standard conditions with bromine and triphenylphos-
phine. Preparation of the Grignard reagent from the
bromide and conversion to the corresponding cuprate
preceded trimethylsilyl chloride-accelerated addition to
3-methylcyclopentenone. The resultant silyl enolether
15 was isolated and used in the subsequent electrochemi-
cal reaction without the benefit of further purification
(Table 1).
from cyclohexenone
60% overall
Scheme 2. Model cyclizations.
available from the electro-oxidative annulation strategy.
A carbonyl group at C6 will allow introduction of the A-
ring isopropyl group while C10 and C11 will be retained
in reduced form. It is anticipated that sequential oxida-
tion of the benzylic C11 position followed by oxidation
at C10 can be used to introduce the remaining B-ring
functionality. The cis relationship at C4 and C9 of the
key intermediate will be a consequence of the kinetically
controlled electrochemical cyclization of 2, a direct pre-
cursor to the key tricyclic intermediate. This compound
is envisioned to arrive from simple A-ring and C-ring
subunits such as 3 and 4. Preliminary work on model
cyclizations of this type had shown that, despite the sim-
ilarities, the use of an aromatic terminator in this case
was distinctly different from the furanoid case (Scheme
2).
Disappointingly, attempts to close the B-ring of the
hamigerans under our previously optimized conditions
(entry 1) resulted only in poor yields of the cyclized
ketone 16. The major by-product identified was the
hydrolyzed ketone 17, a type of side reaction not previ-
ously observed in these closures. In previous optimiza-
tion studies, variables such as electrolyte composition
and concentration, current density and electrode mate-
rial were found to be critical for the facility of the elec-
trolysis. Returning to the original conditions reported
for the furan case showed again the importance of elec-
trolyte concentration (entry 2). Increasing the concen-
tration of LiClO4 to 2 M (the practical upper limit set
by the solubility of the salt in i-PrOH/MeCN) led to
an increase in yield, but the viscous nature of the solu-
tion made effective mixing and work-up difficult and
was not viewed as practical. The role of the higher elec-
trolyte concentration in this type of cyclization remains
unclear but it may relate to the ability of the more polar
solution to stabilize the radical-cation intermediate and
allow the slower cyclization reaction to be competitive
with other reactions. Changes in electrolyte, electrode
composition and current density had only deleterious
effects on the cyclization (entries 4–10).
The closure of the corresponding benzenoid substrate 7
under the conditions6c used successfully for the furan-
based closure (5!6) was a very poor process and pro-
duced only trace amounts of the cyclized ketones 8a/b.
The major product 9 was derived from the loss of a pro-
ton from the initially generated radical-cation. A methyl
group at the b-position eliminated this pathway,
although the yields of the ring closure were still signifi-
cantly lower than the furan case. We attributed this
rather poor cyclization reaction to the lower nucleophi-
licity of the anisyl group relative to the furyl appendage.
However, a significant improvement in yield was found
when the concentration of the supporting electrolyte
(LiClO4) was increased 10-fold to a concentration of
1 M. Under these conditions, a good ring closure could
be observed as long as the competing elimination was
blocked (10!11a/b). Referring back to the synthetic
plan for the hamigerans, we were optimistic that the
electrochemical ring closure would be a useful process
for constructing this system (Scheme 3).
The lower overall yields in this system as compared to 10
were surprising, as it was believed that the presence of
additional donors on the aromatic would accelerate
the cyclization reaction. In every case where cyclized
product was formed, significant quantities of the hydro-
lysis product 17 were observed as the major by-product.
Previous work in the furan series had shown that the
silyl enolethers were unstable toward methanol but that
the bulkier 2-propanol was compatible with this func-
tionality. A control experiment showed that silyl enol-
ether 15 was stable to the isopropanol/acetonitrile
solution for extended periods of time and that conver-
sion to ketone 17 only took place during the electrolysis
reaction. Alcohol additives have always been used in
Not only was a b-substituent present to block elimina-
tion, but this synthesis would call for the use of a cate-
chol-based nucleophile, which was expected to close at
a faster rate than the simple anisyl derivatives. The aro-
matic A-ring fragment was easily prepared from com-
mercially available 3-methylcatechol by directed ortho
metalation followed by a quench of the anion with eth-

J. B. Sperry, D. L. Wright / Tetrahedron Letters 46 (2005) 411–414
Table 1. Electrochemical cyclization studies
413
OMe
OMe
OMe
MeO
CH3
MeO
CH3
MeO
CH3
anode
TMSO
O
O
15
16
17
Entry
Anodea
Electrolyte
Electrolyte concn (M)
Current densityb
Yieldc (%) 16
Ratiod 16:17
1
2
3
4
5
6
7
8
9
10
Carbon
Carbon
Carbon
Carbon
Carbon
Carbon
RVC
LiClO4
LiClO4
LiClO4
n-Bu4ClO4
n-Bu4ClO4
LiNTf2
LiClO4
LiClO4
LiClO4
LiClO4
1
1
32
3.1:1
0:1
0.1
2
1
0
35
1
3.6:1
0:1
0.1
1
1
0
1
0
Trace
0:1
1
1
ꢀ0:1
5:95
N/A
0:1
1
N/A
N/A
0.1
0.5
<5
0
Pt
Carbon
Carbon
1
1
0
1
5
ꢀ0:1
a All reactions run at a concentration of 0.02 M in MeCN/i-PrOH (4:1).
b Reported in mA/cm2.
c Two-step yield from 3-methylcyclopentenone.
d Determined by GC–MS.
Table 2. Effect of alcohol concentration on electrochemical cyclization
OMe
OMe
OMe
MeO
CH3
MeO
CH3
MeO
CH3
anode
TMSO
O
O
15
16
17
Entrya
Ratio i-PrOH/MeCN
Current densityb
Yieldc (%) 16
Ratio 16:17d
1
2
3
4
1:4
0:1
0:1
0:1
1
32
57
67
44
3.1:1
5.8:1
6.5:1
4.4:1
1
0.5
0.3
a All reactions run at a concentration of 0.02 M with a carbon anode.
b Reported in mA/cm2.
c Two-step yield from 3-methylcyclopentenone.
d Ratio determined by GC–MS.
these types of reactions7 as both a cation scavenger and
as the cathodic component, where it is reduced to an
alkoxide that could likely be responsible for the forma-
tion of 17. We varied the amount of alcohol in an at-
tempt to suppress this unwanted side reaction (Table 2).
Acknowledgements
The authors gratefully acknowledge the National Sci-
ence Foundation and Dartmouth College for support.
Surprisingly, it was observed that the alcohol additive
could be eliminated from the reaction altogether (entry
2) and that significantly improved yields of the cyclized
product could be realized at the expense of hydrolysis. A
combination of a lower current density and alcohol-free
conditions gave a reliable 65–68% yield overall for two
steps from 3-methylcyclopentenone (entry 4); formed
exclusively as the desired cis-isomer.9
References and notes
1. (a) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.;
Bergquist, P. R. J. Nat. Prod. 2000, 63, 79; (b) Cambie, R.
C.; Rickard, C. E. F.; Rutledge, P. S.; Wellington, K. D.
Acta Cryst. C 2001, 57, 958.
2. (a) Nicolaou, K. C.; Gray, D.; Tae, J. S. Angew. Chem., Int.
Ed. 2001, 40, 3675; (b) Nicolaou, K. C.; Gray, D.; Tae, J. S.
Angew. Chem., Int. Ed. 2001, 40, 3679.
3. (a) Clive, D. L. J.; Wang, J. Tetrahedron Lett. 2003, 44,
7731; (b) Clive, D. L. J.; Wang, J. Angew. Chem., Int. Ed.
2003, 42, 3406.
4. Trost, B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder,
G. M. J. Am. Chem. Soc. 2004, 126, 4480.
5. Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2003, 44, 7049.
6. (a) Wright, D. L.; Whitehead, C. R.; Sessions, E. H.;
Ghiviriga, I.; Frey, D. A. Org. Lett. 1999, 1, 1535;
A key tricyclic intermediate en route to the synthesis of
hamigeran A and B has been prepared in four steps from
dimethoxytoluene. The route features a key electro-
chemical annulation reaction under alcohol-free condi-
tions and complements our methodology using furyl
terminators. The conversion of this intermediate to the
hamigerans will be reported in due course.

414
J. B. Sperry, D. L. Wright / Tetrahedron Letters 46 (2005) 411–414
(b) Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Wright,
precipitation of most of the LiClO4. The mother liquor was
decanted and the salt was washed with cold diethyl ether
(2 · 75 mL). The combined organic fractions were concen-
trated in vacuo and taken up in 100 mL of diethyl ether. The
ether layer was washed with 1 M HCl, water, satd NaHCO3,
and brine. After drying over Na2SO4, the organic layer was
concentrated and purified by flash chromatography (20:1
hexanes/EtOAc) to yield ketone (16) (263 mg, 67%) as a
viscous, colorless oil. IR (neat) 2931, 2856, 1741, 1606, 1573,
D. L. Org. Lett. 2002, 4, 3763; (c) Sperry, J. B.; Whitehead,
C. R.; Ghiviriga, I.; Walczak, R. M.; Wright, D. L. J. Org.
Chem. 2004, 3726.
7. (a) Moeller, K. D.; New, D. G. Tetrahedron Lett. 1994, 35,
2857; (b) New, D. G.; Tesfai, Z.; Moeller, K. D. J. Org.
Chem. 1996, 61, 1578.
8. For a comprehensive review see: Moeller, K. D. Tetrahe-
dron 2000, 56, 9527–9554.
9. To a 250 mL beaker charged with 70 mL of CH3CN, 7.62 g
of LiClO4, and 0.67 mL of 2,6-lutidine was placed the crude
silyl enol ether (500 mg, 1.43 mmol). The solution was
degassed by sonication prior to electrolysis. An electrode
consisting of alternating stainless steel and carbon plates
was submerged into the solution and 10 mA of current was
passed until 2.2 F/mol were consumed. The electrodes were
removed and the solution cooled to ꢁ5 ꢁC to facilitate the
1484, 1454 cmꢁ1 1H NMR (500 mHz, CDCl3): d 6.88 (s,
;
1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.85 (s, 1H), 2.80 (dd,
J = 5.6 Hz, 3.2 Hz, 1H), 2.61–2.68 (m, 1H), 2.37–2.45 (m,
2H), 2.28 (s, 3H), 1.93–1.98 (m, 1H), 1.83–1.88 (m, 1H),
1.56–1.62 (m, 1H), 1.50–1.58 (m, 1H), 1.19 (s, 3H); 13C d
217.1, 150.5, 150.0, 129.9, 128.2, 127.2, 126.5, 60.1, 59.4,
38.0, 37.0, 35.4, 34.2, 30.3, 25.2, 20.2, 16.1; HRMS m/z
calculated for C11H22O3 (M+): 274.1569, found: 274.1567.