Convergent formal syntheses of (±)-brussonol and (±)-abrotanone via an intramolecular Marson-type cyclization

Article abstract of DOI:10.1021/ol802375g

The formal convergent syntheses of both (±)-brussonol and (±)-abrotanone are reported. The key step involved the diastereoselective capture of an in situ generated oxocarbenium cation via an intramolecular Friedel-Crafts/Marson-type cyclization.

Full text of DOI:10.1021/ol802375g

ORGANIC
LETTERS
2009
Vol. 11, No. 1
189-192
Convergent Formal Syntheses of
(()-Brussonol and (()-Abrotanone via
an Intramolecular Marson-Type
Cyclization
Dionicio Martinez-Solorio and Michael P. Jennings*
Department of Chemistry, The UniVersity of Alabama,
Tuscaloosa, Alabama 35487-0336
jenningm@bama.ua.edu
Received October 14, 2008
ABSTRACT
The formal convergent syntheses of both (()-brussonol and (()-abrotanone are reported. The key step involved the diastereoselective capture
of an in situ generated oxocarbenium cation via an intramolecular Friedel-Crafts/Marson-type cyclization.
Virtually every culture has utilized biologically relevant
extracts from plants and animals for specific medicinal
indications ranging from anti-inflammation to hepatitis.1
Currently, plants continue to provide biologically active
compounds as well as synthetically challenging targets.
Along this line, the icetexane diterpenoids are representative
of these types of medicinally relevant and architecturally
intriguing compounds.2 Members within this family of
natural products, as depicted in Scheme 1, include brussonol
(1), salviasperanol (2), and abrotanone (3). Isolated from the
root cultures of SalVia broussoneti, brussonol (1) was
reported by Fraga and co-workers in 2005 and was shown
to be cytotoxic toward insect and mammalian cell lines.3 In
addition to the initial biological investigation of 1, it has
recently been shown that 1 was found to exhibit moderate
cytotoxicity against the P388 murine leukemia cell line with
an IC50 value of 1.9 µg/mL.4
Scheme 1. Icetexane Natural Products
(1) Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003,
66, 1022.
(2) Esquivel, B.; Flores, M.; Hernandez-Ortega, S.; Toscano, R. A.;
Ramamoorthy, T. P. Phytochemistry 1995, 39, 139.
(3) Fraga, B. M.; Diaz, C. E.; Guadano, A.; Gonzalez-Coloma, A. J.
Agric. Food Chem. 2005, 53, 5200.
Due to the novel and intriguing structures, coupled with
the limited biological profiles of such icetexane natural
products, brussonol (1) and abrotanone (3) are attractive
targets for chemical synthesis. Recently, Sarpong and co-
workers achieved the first total syntheses of (()-brussonol
(4) Aoyagi, Y.; Takahashi, Y.; Fukaya, H.; Takeya, K.; Aiyama, R.;
Matsuzaki, T.; Hashimoto, S.; Kurihara, T. Chem. Pharm. Bull. 2006, 54,
1602.
10.1021/ol802375g CCC: $40.75
Published on Web 12/03/2008
2009 American Chemical Society

and (()-abrotanone by utilizing an innovative Ga(III)-
catalyzed cycloisomerization strategy.5 This work led to the
structural revisions of abrotanone and abrotandiol; the latter
was found to be identical to brussonol (1). Subsequently,
Majetich identified and reported conditions that lead to the
production of (-)-brussonol starting from (+)-demethyl-
salvicanol.6
Scheme 2. First-Generation Retrosynthetic Analysis of 1
We became attracted to the synthesis of 1 due to our long-
standing interest in constructing highly substituted ꢀ-C-
glycoside moieties via oxocarbenium cation intermediates
and the limited knowledge of its biological profile.7 Our
previous synthesis of bruguierol C featured a diastereose-
lective capture of an in situ generated oxocarbenium ion via
an intramolecular Marson-type Friedel-Crafts cyclization as
the key step that readily delivered the natural product.8 We
were hopeful that a similar strategy would allow for the for-
mal syntheses of both (()-brussonol and (()-abrotanone in
a very rapid and efficient manner utilizing inexpensive staring
materials and reagents.
Our synthetic plan, if realized, would not only be a
prime example of a step-economical synthesis but its
convergency would ensure that it could be amenable to
the practical synthesis of analogues in the search of more
potent cytotoxic therapeutic leads. Herein, we wish to
report the formal syntheses of both (()-brussonol and (()-
abrotanone via an intramolecular Friedel-Crafts/Marson-
type cyclization.9,10
As delineated in Scheme 2, our initial approach was
based on the successful union of epoxide 8 and isopro-
pylveratrol 7 via an ortho-directed metalation reaction.11
Synthons 8 and 7 should be both readily obtained starting
from commercially available 3-methyl-2-cyclohexen-1-one
10 and veratrol 12. Once this coupling was completed, it
could be envisioned that acetal 5 would arise in a single
step from an oxidation of the terminal alkene moiety of 6
via the aldehyde intermediate in the presence of MeOH.
Similar to bruguierol C, oxocarbenium formation under
Lewis acidic conditions followed by an intramolecular
Friedel-Crafts capture of the oxocarbenium cation inter-
mediate should provide 4, thus constituting a formal
synthesis of (()-brussonol. Subsequent cleavage of the
methoxy phenyl ethers should provide 1 and an ensuing
oxidation under Sarpong’s conditions should ultimately
afford 3.6
7 and 8. As shown in Scheme 3, the preparation of epoxide
8 commenced with a classical Kharasch-type reaction with
the R,ꢀ-unsaturated ketone 10.12 Under the conditions de-
scribed by Reetz,13 copper-catalyzed (5 mol % of CuI·2LiCl)
conjugate addition of MeMgCl to ketone 10 in the presence
of TMSCl provided silyl enol ether 11 in 91% yield which
was used without further purification.
Scheme 3. Synthesis of Epoxide 8
With our initial retrosynthetic plan in mind, focus was
placed on the synthesis of the required coupling fragments,
Subsequent treatment of 11 with n-BuLi in the presence
of HMPA followed by electrophilic quench of the corre-
sponding lithium enolate with allyl iodide provided a
mixture of ketone 9 and the O-alkyated allylic ether, which
was then transformed into the desired product 9 by means
of a Claisen rearrangement at elevated temperature in an
overall yield of 63% from enol ether 11. An ensuing
Corey-Chaykovsky epoxidation14 of 9 with the standard
reagents (trimethylsulfonium iodide and the Na salt of the
DMSO anion) delivered the desired coupling partner 8
with an overall yield of 44% over three steps from 10.
Much to our delight, nucleophilic addition of the corre-
sponding trimethyl sulfonium anion to ketone 9 led to
(5) Simmons, E. M.; Yen, J. R.; Sarpong, R. Org. Lett. 2007, 9, 2705.
(6) Majetich, G.; Zou, G. Org. Lett. 2008, 10, 81.
(7) (a) Jennings, M. P.; Clemens, R. T. Tetrahedron Lett. 2005, 46, 2021.
(b) Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321. (c) Clemens, R. T.;
Jennings, M. P. Chem. Commun. 2006, 2720. (d) Sawant, K. B.; Jennings,
M. P. J. Org. Chem. 2006, 71, 7911. (e) Sawant, K. B.; Ding, F.; Jennings,
M. P. Tetrahedron Lett. 2006, 47, 939. (f) Sawant, K. B.; Ding, F.; Jennings,
M. P. Tetrahedron Lett. 2007, 48, 5177. (g) Ding, F.; Jennings, M. P. J.
Org. Chem. 2008, 73, 5965.
(8) Solorio, D. M.; Jennings, M. P. J. Org. Chem. 2007, 72, 6621.
(9) Marson, C. M.; Campbell, J.; Hursthouse, M. B.; Abdul Mailk, K. M.
Angew. Chem., Int. Ed. 1998, 37, 1122
.
(10) (a) Fan, J.-F.; Wu, Y.; Wu, Y.-L. J. Chem. Soc., Perkin Trans. 1
1999, 1189. (b) Wu, Y.; Li, Y.; Wu, Y.-L. HelV. Chim. Acta 2001, 84,
163
.
(11) Snieckus, V. Chem. ReV. 1990, 90, 879.
190
Org. Lett., Vol. 11, No. 1, 2009

exclusive formation of the desired epoxide as a single
diastereomer.
Table 1. Attempted ortho-Lithiation of 7 Followed by
Electrophilic Quench with Epoxide 8
With epoxide 8 in hand, we next turned our attention
to the completion of 3-isopropylveratrol (7) using a short
and practical two-step sequence as first reported by
Majetich and is depicted in Scheme 4.15 Thus, treatment
of 12 with 1.05 equiv of n-BuLi at -78 °C afforded the
intermediate ortho-metalated anion which was subse-
quently trapped with acetone to provide the tertiary benzyl
alcohol 13 in 42% yield. An ensuing acid promoted
dehydration and hydrogenation under atmospheric pressure
using 10% Pd/C delivered 7 conveniently in a one-flask
operation, presumably through intermediate 14, in an
overall yield of 91% from 13. It is worth noting that we
modified the original Majetich procedure to circumvent
the usage of a high-pressure one-pot dehydration/hydro-
genation protocol from 13 to 7.
no.
solvent
T (°C)
time (h)
additive
yield (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
Et2O
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
12
24
24
24
12
48
48
48
48
none
trace
∼10a
∼15a
trace
trace
∼10a
∼10a
trace
trace
HMPA
TMEDA
BF3·OEt2
none
HMPA
TMEDA
BF3·OEt2
BF3·OEt2
b
a The quoted yields are a mixture of products (which includes 6) that
coelute from a silicia gel column. b reaction ran also with TMEDA as a
second additive.
Scheme 4
.
Attempted Coupling of 7 and 8 via Directed
Lithiation
Scheme 5. Second-Generation Retrosynthetic Analysis of 5
moiety of 17 should provide the stabilized organometallic
reagent followed by electrophilic quench of our previously
synthesized ketone 9 should afford the elusive tertiary
alcohol 6. In turn, 17 could be readily obtained from the
previously prepared isopropylveratrol 7 via a directed
aromatic lithiation/ alkylation protocol.
Armed with our revised strategy, we focused our
attention to the formation of 6 via the proposed coupling
of 17 and 9. Thus, a second ortho-directed metalation
followed by electrophilic quench with iodomethane pro-
vided 17 in a 83% yield. Once again, the stage was set
for the attempted coupling of fragments 17 and 9.
Gratifyingly, fragment union was achieved by a chemose-
lective directed benzylic lithiation of 17 in Et2O and in
the presence of TMEDA at -78 °C, which presumably
generated the stabilized five-membered chelate intermedi-
With our two fragments, 7 and 8, in hand we were ready
to explore conditions which would lead to the formation of
the highly desired tertiary alcohol 6. Unfortunately, as
highlighted in Table 1, all attempts failed to provide the
coupled product 6 in workable yields and purity. Attempted
ortho-lithiation of 7 under a variety of conditions, solvents,
and additives was quite successful (vide infra); however,
quenching of the lithiated arene with epoxide 8 generally
led to little or no desired product 6.
With the failure of the initial synthetic blueprint to 4, we
reformulated our synthetic plan. As depicted in Scheme 5,
our end-game strategy remained identical to that of our first-
generation retrosynthetic analysis. The major difference
between the two strategies lies in the formation of tertiary
alcohol 6.
(12) Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308.
(13) Reetz, M. T.; Kindler, A. J. Organomet. Chem. 1995, 502, C5.
(14) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
In the second-generation approach, we envisaged that
a chemoselective directed benzylic lithiation of the methyl
Org. Lett., Vol. 11, No. 1, 2009
191

Much to our delight, the nucleophilic addition of the
lithiated intermediate 16 to 9 provided 6 as a single
diastereomer via selective axial attack. With our fragments
successfully coupled, we next turned our attention to the
rapid completion of 4. Thus, terminal olefin oxidation of
6 via ozonolysis in MeOH presumably formed intermedi-
ate aldehyde 18, followed by creation of the methoxy
oxonium cation which subsequently cyclized to deliver
the methoxy ketal 5 in 89% yield. Much to our delight,
final treatment of 5 with 2 equiv of BF3·OEt2 at -20 °C
for 1 h provided the cyclized product 4 in 91% yield
apparently via the proposed intermediate 19. The spectral
data (1H NMR, 600 MHz; 13C NMR, 125 MHz) and
HRMS data of synthetic 4 were in complete agreement
with those previously reported.6 Finally, 4 could be con-
verted to (()-brussonol (1) by cleavage of the two
methoxy ethers by means of treatment of 4 with the
thiolate anion in DMF.6 In addition, it has been reported
by Sarpong that 1 can be readily converted into (()-
abrotanone (3) via a copper-mediated oxidation sequence
in a solution of NaOMe-MeOH.6
Scheme 6. Completion of 5 via a Marson Cyclization
In conclusion, we have completed a highly practical and
convergent formal synthesis of both (()-brussonol and (()-
abrotanone (in seven steps, longest linear sequence, from
veratrol for brussonol and nine steps for abrotanone) by
featuring a diasteroselective capture of an in situ generated
oxocarbenium ion via an intramolecular Friedel-Crafts/
Marson-type cyclization.
Acknowledgment. Support for this project was provided
by the University of Alabama.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL802375G
ate 16, followed by electrophilic quench with ketone 9 to
furnish 6 in 42% yield.
(15) Majetich, G.; Liu, S. Synth. Commun. 1993, 23, 2331.
192
Org. Lett., Vol. 11, No. 1, 2009