Ga(IIl)-catalyzed cycloisomerization approach to (±)-icetexone and (±)-epi-icetexone

Article abstract of DOI:10.1021/ol902959v

"Chemical eqation presented" A Ga(III)-catalyzed cycloisomerization reaction provides expedient access to a benzannulated cycloheptadiene bearing a cyano group, which has been applied to the syntheses of several icetexane diterpenoids including icetexone

Full text of DOI:10.1021/ol902959v

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1428-1431
Ga(III)-Catalyzed Cycloisomerization
Approach to (()-Icetexone and
(()-epi-Icetexone
Felipe de Jesus Cortez and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
rsarpong@berkeley.edu
Received December 25, 2009
ABSTRACT
A Ga(III)-catalyzed cycloisomerization reaction provides expedient access to a benzannulated cycloheptadiene bearing a cyano group, which
has been applied to the syntheses of several icetexane diterpenoids including icetexone and epi-icetexone. Key to the synthesis is a novel
in situ generated diazene rearrangement.
The icetexane family of diterpenoids is a group of [6-7-
6] tricyclic natural products, which are believed to arise
in Nature from an oxidation-induced rearrangement of the
structurally related abietane diterpenoids.1 Biosynthetic
modification of the abietane skeleton has led to a wide
variety of icetexane natural products that possess unique
structures as well as biological activity.2 We became
interested in the synthesis of members of the icetexane
family as a prelude to a systematic investigation of their
biological activity. Previously, we reported the syntheses
of several members including salviasperanol (1, Figure
1), abrotanone (2), and 5,6-dihydro-6R-hydroxysalvi-
asperanol (3).3 In this paper, we report the extension of
these studies to the formal syntheses of icetexone (5) and
epi-icetexone (6).
Figure 1. Selected icetexane natural products.
against the trypomastigote form of Trypanosoma cruzi,
the parasite that causes Chagas’ disease.5 In 2009,
Majetich and Grove reported the first syntheses of 5 and
6,6 which exploited a cyclialkylation to forge the seven-
membered ring,7 as well as a late stage iodolactonization to
construct the bridging lactone.
Icetexone and epi-icetexone have been isolated from
several Mexican SalVia plants including SalVia ballotae-
flora and SalVia gillessi.4 Of these two natural products,
icetexone has been shown to possess trypanocidal activity
(1) Simmons, E. M.; Sarpong, R. Nat. Prod. Rep. 2009, 26, 1195–1217.
(2) For a review on abietane diterpenoids, see: (a) Uc¸ar, G.; Fengel, D.
Phytochemistry 1995, 38, 877–880. (b) Dev, S.; Misra, R. In CRC Handbook
of Terpenoids; Dev, S., Ed.; CRC: Boca Raton, FL, 1986.
(3) (a) Simmons, E. M.; Sarpong, R. Org. Lett. 2006, 8, 2883–2886.
(b) Simmons, E. M.; Yen, J. R.; Sarpong, R. Org. Lett. 2007, 9, 2705–
2708.
(4) The structural assignments of icetexone and epi-icetexone were
recently shown to be reversed (see ref 6). For isolation of icetexone and
epi-icetexone, see: (a) Watson, W. H.; Taira, Z. Tetrahedron Lett. 1976,
29, 2501–2502. (b) Nieto, M.; Garcia, E. E.; Gordano, D. S.; Tonn, C. E.
Phytochemistry 2000, 53, 911–915.
10.1021/ol902959v  2010 American Chemical Society
Published on Web 03/01/2010

In principle, the related natural products anastomosine (4),
icetexone (5), and epi-icetexone (6) could arise from hy-
droxyl-directed oxygenation of the ꢀ-methyl group at C-19
(see 3) followed by a series of oxidations and dehydrations.
However, the anticipated instability of potential alkoxy
radical intermediates,8 as well as uncertainties regarding the
stereoselectivity of the C-H functionalization process,
dissuaded us from this line of inquiry.
Scheme 2. Synthesis of Alkyl Iodide 17
Encouraged by our previous synthetic studies on the
icetexane diterpenoids, we were drawn to the use of
benzannulated cycloheptadienes (e.g., 8) as key precursors
to 5 and 6 (see Scheme 1). Importantly, a cyano group at
Scheme 1. Retrosynthetic Analysis of 5 and 6
by homologation of the resulting aldehyde with the
Ohira-Bestmann reagent (14) gave alkyne 15. Subsequent
transformation of 15 to iodide 17 proceeded via a sequence
involving silyl ether cleavage to yield 16, followed by
conversion of the hydroxy group to the corresponding
mesylate and displacement with sodium iodide.
At this stage, the synthesis of indanone 22 (Scheme 3), a
precursor to the other coupling partner required for the
construction of 9, was pursued.9
C-4 could serve as a masked carboxylic acid group that
would be unveiled at a late stage. Benzannulated cyclohep-
tadiene 8 could in turn be prepared from alkynyl indene 9
via a Ga(III)-catalyzed cycloisomerization.
Scheme 3. Synthesis of Indanone 22
The incorporation of a cyano group as a part of the alkynyl
indene substrate for the cycloisomerization reaction has not
been previously demonstrated. Thus, the present plan would
seek to advance the substrate scope of this seven-membered
ring forming cycloisomerization reaction.
In this paper, we present the realization of this synthetic
strategy, which has led to the formal syntheses of (()-
icetexone (5) and (()-epi-icetexone (6).
Our efforts commenced with the preparation of iodide 17
as outlined in Scheme 2. The sequence started with 3-bromo-
1-propanol (10), which was converted to TIPS ether 11 under
standard conditions. Bromide 11 served as an electrophile
for the alkylation of methyl cyanoacetate, the product of
which yielded 12 upon subsequent methylation. The ester
group of 12 was then selectively reduced to provide the
corresponding alcohol (13). Swern oxidation of 13 followed
The sequence began with known benzyl alcohol 18,6,7
which was oxidized under Parikh-Doering conditions10 to
afford aldehyde 19. Horner-Wadsworth-Emmons homolo-
gation of 19 afforded enoate 20, which following hydrogena-
tion and saponification gave acid 21. At this stage, the
carboxylic acid group was converted to the corresponding
acid chloride, and an ensuing Friedel-Crafts acylation gave
indanone 22.
(5) Sanchez, A. M.; Jimenez-Ortiz, V.; Tonn, C. E.; Garcia, E. E.; Nieto,
M.; Burgos, M. H.; Sosa, M. A. Acta Trop. 2006, 98, 118–124. This paper
reports studies on epi-icetexone. However, on the basis of the structural
reassignments by Majetich (ref 6), the biological studies were conducted
on icetexone.
(6) Majetich, G.; Grove, J. L. Org. Lett. 2009, 11, 2904–2907.
(7) Cyclialkylation reactions for the synthesis of icetexane diterpenoids
were pioneered by Majetich. For an early example, see: Majetich, G.; Zhang,
Y. J. Am. Chem. Soc. 1994, 116, 4979–4980.
(8) In preliminary studies conducted in these laboratories, fragmentation
of the seven-membered ring was observed upon generation of the presumed
alkoxy-radical intermediate. This is consistent with observations made by
Majetich and co-workers, see: Li, Y. Ph.D. Dissertation, University of
Georgia, Athens, GA, 2006 and ref 6.
(9) The synthesis of 22 reported herein was adapted from an earlier
synthesis in our laboratories, see: Simmons, E. M. Ph.D. Dissertation,
University of California, Berkeley, CA, 2009.
(10) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
Org. Lett., Vol. 12, No. 7, 2010
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With indanone 22 in hand, we next investigated its
conversion to indene substrate 9 as outlined in Scheme 4.
solvents, and temperatures, an optimal set of conditions
was identified (0.25 equiv of GaCl3, 100 °C, 48 h; entry
6), which gave 8 in 91% isolated yield. Interestingly, the
use of PtCl2 or InCl3, which had been previously estab-
lished as catalysts for enyne cycloisomerization,11 returned
only the starting material.
Scheme 4. Synthesis of Indene 9
With benzannulated cycloheptadiene 8 in hand, our
attention turned to the functionalization of the conjugated
diene moiety. We first investigated the hydrolysis of the
nitrile functional group. In this regard, we found that the
transformation was best effected using Ghaffar and
Parkins’ platinum catalyst (25, Scheme 5),12 which was
Scheme 5. Initial Iodolactonization Studies
Claisen condensation of 22 and dimethyl carbonate provided
a ꢀ-ketoester, which upon alkylation with 17 gave alkyne
23. A subsequent saponification/decarboxylation sequence
afforded indanone 24. Selective reduction of the carbonyl
group in the presence of the nitrile group was accomplished
with NaBH4 and was followed by elimination of the resulting
hydroxyl group to afford indene 9.
On the basis of our previous studies, we first investigated
the cycloisomerization of alkynyl indene 9 to cyclohep-
tadiene 8 using Ga(III) salts (entries 1-6, Table 1). We
Table 1. Cycloisomerization of 9
uniquely effective in giving primary amide 26 in 87%
yield. Subjecting 26 to standard iodolactonization condi-
tions, followed by IBX oxidation, led to the isolation of
lactone 27, the structure of which was confirmed by X-ray
crystallography (see ORTEP representation in Scheme 5).
Although 27 was undesired with respect to our efforts
toward icetexone and epi-icetexone, it provides a potential
entry to the synthesis of anastomosine (4) and related
natural products.
Following careful optimization studies, we established
a route, as outlined in Scheme 6, that leads to the late-
stage intermediates 7a and 7b for the synthesis of
icetexone and epi-icetexone, respectively. The sequence
begins with the diastereoselective epoxidation of cyclo-
heptadiene 26 to afford 28 in 81% yield. Treatment of 28
with camphorsulfonic acid and tosylhydrazide in benzene
at 80 °C gave a 2.5:1 mixture of 7a and 7b in a combined
42% yield. In this key reductive condensation event, the
permethylated hydroquinone precursors to icetexone and
epi-icetexone are formed in a single pot cascade trans-
formation.
entry catalyst equiv temp (°C) time (h) % conversiona
1
2
3
4
5
6
7
8
GaCl3
GaBr3
GaI3
GaI3
GaI3
GaCl3
PtCl2
InCl3
0.2
0.2
0.2
0.5
0.25
0.25
0.2
40
40
40
48
48
48
96
96
48
72
120
41
43
38
100
100
100
NR
NR
65
80
100b
40
0.2
40
a Conversion of 9 based on 1H NMR of crude reaction product following
standard workup. b Reaction was run in toluene.
found that GaCl3, GaBr3, or GaI3 worked comparably in
the cycloisomerization reaction with a 0.20 equiv of
catalyst loading at 40 °C in benzene (entries 1-3),
resulting in ca. 40% conversion to 8 over 48 h. In the
cases where GaI3 was used to mediate the cycloisomer-
ization, increasing the temperature to 65 (with 0.5 equiv
of GaI3; entry 4) or 80 °C (with 0.25 equiv of GaI3; entry
5) led to complete conversion after 96 h. After a systematic
investigation of various combinations of Ga(III) salts,
(11) For recent examples, see: (a) Simmons, E. M.; Hardin, A. R.; Guo,
X.; Sarpong, R. Angew. Chem., Int. Ed. 2008, 47, 6650–6653. (b)
Miyanohana, Y.; Chatani, N. Org. Lett. 2006, 8, 2155–2158.
(12) (a) Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657–
8660. (b) Ghaffar, T.; Parkins, A. W. J. Mol. Catal. A 2000, 160, 249–
261.
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Org. Lett., Vol. 12, No. 7, 2010

Scheme 6
.
Synthesis of Icetexone and epi-Icetexone Precursors
7a and 7b
Scheme 8. Synthesis of 7b
(>10:1 dr of 7b:7a). Presumably, attack of tosylhydrazide
occurs with high diastereocontrol from the convex face
of the rigid, polycyclic, allylic cation generated from 32
to give 33. Following the loss of p-toluenesulfinic acid,
stereospecific diazene rearrangement yields 7b as the
major product. Because Majetich and Grove have previ-
ously employed 7b in the synthesis of epi-icetexone, this
sequence completes a formal synthesis of this natural
product. Furthermore, because 7a was also applied in the
synthesis of icetexone by Majetich and Grove, we have
also achieved a formal synthesis of this natural product.
In conclusion, we have applied a Ga(III)-catalyzed cy-
cloisomerization reaction to the synthesis of a benzannulated
cycloheptadiene bearing a cyano group that serves as a key
intermediate in the synthesis of the icetexane diterpenoids
icetexone and epi-icetexone. The synthesis features a late-
stage cascade sequence that constructs the tetracyclic core
of these natural products.
Tetracycles 7a and 7b may arise via the postulated
sequence outlined in Scheme 7. The transformation com-
Scheme 7
.
Proposed Mechanism for the Formation of 7a and 7b
from 28
Because the syntheses of compounds closely related to
17 are known in enantioenriched form,16 the strategy
outlined here should be readily applied to the enantiose-
lective syntheses of 5 and 6. Our current efforts are
focused on this pursuit and the application of cyclohep-
tadiene intermediates such as 8 to the synthesis of other
natural products.
mences with protonation of the epoxide group of 28 and
subsequent opening to afford allylic cation 29, which is
trapped by tosylhydrazide to afford 30. This trapping step
ultimately determines the ratio of 7a to 7b that is obtained
(vide infra).13 From 30, the icetexone and epi-icetexone
precursors 7a and 7b may arise via a sequence involving
(A) cyclization with accompanying loss of a molecule of
NH3 to install the bridging lactone and (B) loss of p-
toluenesulfinic acid to afford diazene 31, which undergoes
a diazene decomposition14 with accompanying double bond
transposition and loss of dinitrogen. The stereospecific nature
of the diazene rearrangement leads to the observed mixture
of 7a and 7b.
Support for the proposed formation of 7a and 7b from
28 was gained from the observations detailed in Scheme
8. Treating epoxide 28 with camphorsulfonic acid in wet
CH2Cl2 yielded 32 as a single diastereomer.15 Subjection
of 32 to camphorsulfonic acid and tosylhydrazide in
benzene at 80 °C for 15 h gave 7b as the major product
Acknowledgment. The authors are thankful to Ms. Ariel
Yeh for assistance in the preparation of 17 and Dr. Eric
Simmons (University of Illinois Urbana-Champaign) for
numerous intellectual contributions. The authors are
gratefultoUCBerkeley, theNIH(NIGMSRO1GM086374-
01 and F31 GM089139-01), Johnson and Johnson, and
Eli Lilly for generous financial support. R.S. is an Alfred
P. Sloan Foundation Fellow and a Camille Dreyfus
Teacher-Scholar.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) On the basis of the observed ratio of 7a to 7b, this trapping step
likely proceeds with poor diastereocontrol.
OL902959V
(14) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841–4844.
(15) The relative stereochemistry for 32 at C-5, which is inconsequential,
was not established.
(16) Sawamura, M.; Hamashima, G.; Shinoto, H.; Ito, Y. Tetrahedron
Lett. 1995, 36, 6479–6482.
Org. Lett., Vol. 12, No. 7, 2010
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