An Expeditious Nazarov Cyclization Strategy toward the Hydroazulene Core of Guanacastepene A

Article abstract of DOI:10.1021/ol036433z

(Matrix presented) The hydroazulene core of guanacastepene A has been synthesized in five steps from commercially available starting materials using a classical Nazarov cyclization to install the stereochemistry in the cyclopentanone diastereoselectively.

Full text of DOI:10.1021/ol036433z

ORGANIC
LETTERS
2004
Vol. 6, No. 4
613-616
An Expeditious Nazarov Cyclization
Strategy toward the Hydroazulene Core
of Guanacastepene A
Pauline Chiu* and Shuoliang Li
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road,
Hong Kong, P. R. China
pchiu@hku.hk
Received December 14, 2003
ABSTRACT
The hydroazulene core of guanacastepene A has been synthesized in five steps from commercially available starting materials using a classical
Nazarov cyclization to install the stereochemistry in the cyclopentanone diastereoselectively. In the presence or absence of Lewis bases, a
hydroazulenone or a spirocyclic ketone generated via a novel Wagner−Meerwein rearrangement is obtained with excellent selectivity and
yield.
Guanacastepene A (1) has generated immense interest in the
scientific community since its isolation and the discovery
of its potency against methicillin-resistant and vancomycin-
resistant pathogens.1 The family of guanacastepene diterpe-
noids is exciting also because they represent a structurally
unique carboskeleton never before found in nature. The
synthetic organic community responded enthusiastically in
efforts toward the total synthesis of these compounds. The
first racemic total synthesis of 1 was completed by Dan-
ishefsky,2 followed by a formal total synthesis by Snider.3
The synthesis of the guanacastepenes has been the subject
of many distinct research efforts within the span of three
years,4 all representing unique entries to this interesting
system and fully demonstrating the diversity of strategies
originating from creative disconnections in total synthesis.
We are also engaged in a study of the total synthesis of
the guanacastepenes in which we envisioned a tandem
carbene cyclization-cycloaddition cascade reaction to furnish
the BC-ring system;5 the assembly of the cyclopentanone
(4) (a) Magnus, P.; Waring, M. J.; Ollivier, C.; Lynch, V. Tetrahedron
Lett. 2001, 42, 4947. (b) Magnus, P.; Ollivier, C. Tetrahedron Lett. 2002,
43, 9605. (c) Mehta, G.; Umarye, J. D. Org. Lett. 2002, 4, 1063. (d) Mehta,
G.; Umarye, J. D.; Gagliardini, V. Tetrahedron Lett. 2002, 43, 6975. (e)
Mehta, G.; Umarye, J. D.; Srinivas, K. Tetrahedron Lett. 2003, 44, 4233.
(f) Gradl, S. N.; Kennedy-Smith, J. J.; Kim, J.; Trauner, D. Synlett 2002,
411. (g) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett. 2003,
5, 4113. (h) Shipe, W. D.; Sorensen, E. J. Org. Lett. 2002, 4, 2063. (i)
Nguyen, T. M.; Seifert, R. J.; Mowrey, D. R.; Lee, D. Org. Lett. 2002, 4,
3959. (j) Nguyen, T. M.; Lee, D. Tetrahedron Lett. 2002, 43, 4033. (k)
Nakazaki, A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363. (l) Boyer,
F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469. (m) Du, X.; Chu, H. V.;
Kwon, O. Org. Lett. 2003, 5, 1923. (n) Brummond, K. M.; Gao, D. Org.
Lett. 2003, 5, 3491. (o) Sarpong, R.; Su. J. T.; Stoltz, B. M. J. Am. Chem.
Soc. 2003, 125, 13624.
(1) (a) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am. Chem.
Soc. 2000, 122, 2116. (b) Brady, S. F.; Bondi, S. M.; Clardy, J. J. Am.
Chem. Soc. 2001, 123, 9900. (c) Singh, M. P.; Janso, J. E.; Luckman, S.
W.; Brady, S. F.; Clardy, J.; Greenstein, M.; Maiese, W. M. J. Antibiot.
2000, 53, 256.
(2) (a) Dudley, G. B.; Danishefsky, S. J. Org. Lett. 2001, 3, 2399. (b)
Dudley, G. B.; Tan, D. S.; Kim, G.; Tanski, J. M. Danishefsky, S. J.
Tetrahedron Lett. 2001, 42, 6789. (c) Tan, D. S.; Dudley, G. B.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 2185. (d) Lin, S.;
Dudley, G. B.; Tan, D. S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002,
41, 2188.
(3) (a) Snider, B. B.; Shi, B. Tetrahedron Lett. 2001, 42, 9123. (b) Snider,
B. B.; Hawryluk, N. A. Org. Lett. 2001, 3, 569. (c) Shi, B.; Hawryluk, N.
A.; Snider, B. B. J. Org. Chem. 2003, 68, 1030.
10.1021/ol036433z CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/27/2004

Scheme 1. Retrosynthesis of Guanacastepene A 1
Scheme 2. Synthetic Plan
ring A with concomitant functionalization of ring B would
both be achieved by a classical Nazarov cyclization.6 Related
efforts reported recently in the synthetic studies of this
compound prompted us to disclose our results thus far
following this strategy, through which hydroazulenic ketones
6a and 10 resembling the AB rings of guanacastepene A 1
have been synthesized (Scheme 1).
The Nazarov reaction is an electrocyclic conrotatory ring
closure under thermal conditions.7 Deprotonation typically
favors the formation of the product bearing the most
substituted double bond; however, unless they are directed
by silicon or tin substituents, mixtures of isomeric olefinic
products are common.8 Due to the carbocationic nature of
the intermediates, Wagner-Meerwein rearrangements some-
times further complicate the product mixture.9 However, it
is clear that the facility of this reaction for the efficient and
stereospecific construction of cyclopentenones has tremen-
dous application in total synthesis.
substituted precursors such as 5 have been examined. In
particular, the hydroazulenone core of guanacastepene A
implied retrosynthetically a Nazarov cyclization of dienone
substrate 5a (n ) 2, R ) i-Pr).
The assembly of dienone 5a began with commercially
available ketoester 7, which was converted sequentially to
the enol phosphate and then to the â-methylated ester to give
8 by Weiler’s protocol (Scheme 3).11 The Horner-Emmons
reagent, 9, synthesized by treatment of 8 with lithio dim-
ethylmethylphosphonate, was poised to react with an alde-
hyde to install a trans-olefin. In the event, reaction of 9 with
isobutyraldehyde gave dienone 5a exclusively in good yield.
Scheme 3. Synthesis of Hydroazulenedione 10a
Previous studies of the cyclopentannulation reaction by
Hiyama on systems such as 2 demonstrated the thermal
conrotatory electrocyclic ring closure, resulting in cyclopen-
tanones 3 with both methyl groups on the same face, although
other products such as 4 are also obtained (Scheme 2).10 We
used dienone substrates 5 to examine the Nazarov reaction,
to separate the dehydration and electrocyclization events and
better appreciate the effects of acid on the induction of the
cyclization. Although many divinyl ketones and dienone
substrates have been studied in the context of the Nazarov
cyclization, there are few examples where monocyclic â,â,â′-
a Reaction conditions: (a) NaH, (MeO)2P(O)Cl, THF; (b)
Me2CuLi, 91% over two steps. (c) LiCH2P(O)(OMe)2, 96%. (d)
Me2CHCHO, LiCl, i-Pr2NEt, MeCN, 88%. (e) BF3‚Et2O, CH2Cl2,
98%. (f) Pd(OH)2/C, t-BuOOH, CH2Cl2, 48 h, 65%.
(5) (a) Chiu, P. C., B.; Cheng, K. F. Org. Lett. 2001, 3, 1721. (b) Chen,
B. K. R. Y. Y.; Yuen, M. S. M.; Cheng, K. F.; Chiu, P. J. Org. Chem.
2003, 68, 4195.
(6) Notably, Tius synthesized the hydroazulene portion of guanacastepene
A via a cyclopentannelation reaction, see ref 2k. For studies of the
cyclopentannelation of allenyl vinyl ketones, see: (a) Leclerc, E.; Tius, M.
A. Org. Lett. 2003, 5, 1171. (b) Bee, C.; Tius, M. A. Org. Lett. 2003, 5,
1681. (c) Tius, M. A. Acc. Chem. Res. 2003, 36, 284 and references therein.
(7) For reviews on the Nazarov reaction: (a) Habermas, K. L.; Denmark
S. E.; Jones, T. K. Org. React. 1994, 45, 1. (b) Denmark, S. E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: New York, 1991; Vol. 5, Chapter 6.3, p 751. (c) Santelli-Rouvier,
C.; Santelli, M. Synthesis 1983, 429. Recent studies: (d) He, W.: Sun, X.;
Frontier, A. J. J. Am. Chem. Soc. 2003, 125, 14278. (e) Liang, G.; Gradl,
S. N.; Trauner, D. Org. Lett. 2003, 5, 4931. (f) Giese, S.; Kastrup, L.; Stiens,
D.; West, F. G. Angew. Chem., Int. Ed. 2000, 39, 1970. (g) Wang, Y.;
Schill, B. D.; Arif, A. M.; West, F. G. Org. Lett. 2003, 5, 2747.
(8) (a) Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982, 104, 2642.
(b) Jones, T. K.; Denmark, S. E. HelV. Chim. Acta 1983, 66, 2377. (c)
Peel, M. R.; Johnson, C. R. Tetrahedron Lett. 1986, 27, 5947.
(9) Ohloff, G.; Schulte-Elte, K. H.; Demole, E. HelV. Chim. Acta 1971,
54, 2913.
Treatment of dienone 5a with various acids to induce
electrocyclic ring closure was examined next (Table 1).
Substrate 5a, with a 1:1 mixture of concentrated sulfuric acid
and methanol, underwent a remarkably clean Nazarov
cyclization to give hydroazulenone 6a in 91% yield (entry
1). NOESY spectra of 6a confirmed the syn relative
stereochemistry of the methyl and isopropyl groups. To
further demonstrate that the cycloheptene nucleus destined
to be ring B could be functionalized for appending ring C,
allylic oxidation of 6a using Corey’s conditions furnished
enedione 10 (Scheme 3).12 Compound 10 is an intermediate
prepared previously by Snider in his synthetic studies of 1.3
(10) (a) Hiyama, T.; Shinoda, M.; Siamoto, H.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1981, 54, 2747. (b) Hiyama, T.; Shinoda, M.; Nozaki, H. J. Am.
Chem. Soc. 1979, 101, 1599.
(11) Alderice, M.; Sum, F. W.; Weiler, L. Organic Syntheses; Wiley:
New York, 1993; Collect. Vol. VIII, p 351.
614
Org. Lett., Vol. 6, No. 4, 2004

Table 1. Nazarov Cyclization of Divinyl Ketone 5a
Table 2. Nazarov Cyclization of Divinyl Ketone 5b
ratio of
solvent T/t (h) 6a :11a b yieldc
entry
acida
solvent
MeOH
T/t (h) ratio of 6b:11bb yieldc
entry
acida
1
2
3
4
5
H2SO4
H2SO4
0°C/1
0°C/1
>95:5
84:16
>95:5
>95:5
87:13
86%
83%
95%
86%
74%
1
2
3
4
5
6
7
8
9
H2SO4/MeOH (1:1)
H2SO4
CF3SO3H
0°C /1 >95:5
91%
90%
90%
96%
86%
98%
92%
87%
90%
95%
0°C/1
17:83
BF3‚Et2O CH2Cl2 rt/1
CF3SO3H CH2Cl2 rt/1
0°C/1
7:93
CF3SO3H
CH2Cl2 0°C/1
7:93
CF3SO3H
60°C/1
CF3SO3H/DMSO (2:3) CH2Cl2 rt/4
91:9
a Performed with 3.0 equiv of acid. b Ratio determined by integration
of proton signals of the crude product mixture. c Combined isolated yield
of products after silica gel column chromatography.
BF3‚Et2O
CH2Cl2 0°C/1
CH2Cl2 0°C/1
CH2Cl2 0°C/1
rt/2
>95:5
5:95
39:61
87:13
>95:5
BCl3
SnCl4
70% HClO4
70% HClO4/H2O (1:1)
10
rt/2
The reaction of divinyl ketone substrate 5b, which differed
from 5a only in that both vinyl substituents were methyl
groups, generated fused bicyclic 6b without ring contraction
as the major product under all conditions examined, even
those that previously favored the formation of the rearranged
product (Table 2). Only in the case of sulfuric acid was some
of 11b generated (entry 2). Heating to encourage rearrange-
ments also generated more of 11b, although 6b remained
the major product (entry 5).
a Performed with 3.0 equiv of acid. b Ratio determined by integration
of proton signals of the crude product mixture. c Combined isolated yield
of products after silica gel column chromatography.
Surprisingly, the treatment of 5a with sulfuric acid in the
absence of methanol selectively afforded another bicyclic
product (Table 1, entry 2). Examination of this new
compound revealed that it was not the precedented secondary
hydroazulenone product related to 4, but that it was spiro-
[4.5]decenone 11a. The use of triflic acid generated 11a
almost exclusively, irrespective of the concentration of acid
in the reaction (entries 3, 4). Spirocyclic ketone 11a did not
arise from a subsequent transformation of 6a under the
reaction conditions, because resubjecting 6a to treatment with
triflic acid failed to convert it to 11a. Thus, 11a was
generated in the course of the electrocyclic ring closure by
a ring contraction via a Wagner-Meerwein shift. Although
carbocationic shifts in the course of the Nazarov cyclization
are known, the generation of such spirocyclic products under
these reaction conditions has never been reported.
Cyclohexadienone substrate 5c had the same vinyl sub-
stituents as 5a. Treatment of 5c with various acids in Lewis
basic solvents was highly selective for 6c (Table 3, entries
Table 3. Nazarov Cyclization of Divinyl Ketone 5c
We examined the reaction in greater detail and found
conditions that could selectively produce either cyclization
product 6a or 11a in excellent yield. It was found that the
use of boron trifluoride etherate generated 6a as the sole
product in quantitative yield (entry 6), while the use of boron
trichloride in dichloromethane favored the formation of 11a
with a selectivity of >95:5, also in nearly quantitative yield
(entry 4). The overall trend appears to be that both Brønsted
and Lewis acids in noncoordinating solvents favored car-
bocationic rearrangement leading to 11a, while acids in the
presence of Lewis basic solvents such as ether and methanol
induced deprotonation rapidly before rearrangement, generat-
ing 6a. The effect of Lewis basic solvents was particularly
apparent in the experiments using sulfuric acid (entries 1,
2), triflic acid (entries 4, 5), BF3‚Et2O vs BCl3 (entries 6,
7), and perchloric acid (entries 9, 10).
ratio of
entry
acida
H2SO4
solvent
MeOH
T/t (h) 6c:11c:12cb yieldc
1
2
3
4
5
0°C/1
0°C/1
>90:5:5
1:13:86
>90:5:5
0:58:42
11:30:59
86%
85%
93%
86%
81%
H2SO4
BF3‚Et2O
CF3SO3H
70% HClO4
CH2Cl2 rt/2
CH2Cl2 rt/1
rt/2
a Performed with 3.0 equiv of acid. b Ratio determined by integration
of proton signals of the crude product mixture. c Combined isolated yield
of products after silica gel column chromatography.
1, 3). Otherwise, carbocationic rearrangements predominated,
generating products 11c and 12c. Wagner-Meerwein shifts
in the Nazarov intermediate leading to products such as 12c
have been previously observed.10
We examined the Nazarov reaction of other dienone
substrates to see if reaction conditions could be manipulated
to selectively generate either cyclization product 6 or 11.
Scheme 4 summarizes the mechanistic pathways that
account for the formation of cyclization products 6, 11, and
12. Treatment of divinyl ketone 5 with acid induced a
Org. Lett., Vol. 6, No. 4, 2004
615

Scheme 4. Mechanistic Pathways Leading to 6, 11, and 12
conrotatory electrocyclization, leading to the carbocationic
We have shown herein that hydroazulenones 6a and 10
have been synthesized in good yield and selectivity to
demonstrate a Nazarov cyclization strategy for the construc-
tion of ring A in 1. The success of this reaction as applied
to the final synthesis of guanacastepene A will depend on
the sense and degree of torquoselectivity of the Nazarov
reaction with respect to the stereochemistry defined by the
proposed tandem carbene cyclization-cycloaddition cascade
to generate the BC nucleus, an aspect that is currently under
investigation. Furthermore, it has been demonstrated that
post-cyclization carbocationic rearrangement to afford spi-
rocyclic [4.5]decenones can be high yielding and selective,
and this tandem cyclization-ring contraction reaction could
potentially also be exploited for natural product synthesis.
intermediate 13. In the presence of proton acceptors (e.g.,
methanol, ether), fused bicyclic products with structure 6
are favored (Pathway A). In the absence of Lewis bases,
Wagner-Meerwein shifts predominate. These experiments
showed that ring contraction to give 11 is a favored
carbocationic rearrangement for certain ring sizes, for
example, n ) 2, leading to [4.5]spirocyclic compounds
(Pathway B). Otherwise, the strain in spirocyclic compound
11 (e.g., n ) 1) would give way to other kinds of
rearrangements, generating products like 12 (Pathway B′).13
Besides the unavailability of bases, the steric strain of the
cis substituents in 13 may also result in a propensity toward
rearrangement. This may explain the divergent fates of
intermediates 13a and 13b derived from 5a and 5b, which
differ only in R being an isopropyl or a methyl group.
Whereas the less-congested 13b underwent deprotonation
both in the presence or absence of Lewis bases (Pathway
A), 13a preferred ring contraction, as steric strain is relieved
by rearrangement but not by deprotonation (Pathway B).13
Acknowledgment. Financial support from the University
of Hong Kong is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures for all reactions; full characterization and H and
13C NMR spectra for compounds 5a-c, 6a-c, 9, 10, 11a-
c, and 12c. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Yu, J. Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232.
(13) Contrathermodynamic carbocationic rearrangements in Pathways B
and B′ could be driven by the ultimate formation of stable products 11 and
12. We thank the referee for input concerning aspects of the mechanism.
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Org. Lett., Vol. 6, No. 4, 2004