Enantiocontrolled total syntheses of breviones A, B, and C

Article abstract of DOI:10.1021/ja202874d

Enantiocontrolled total syntheses of the breviones A, B, and C have been accomplished using a highly diastereoselective oxidative coupling of an α-pyrone with a tricyclic diene prepared from an optically pure Wieland-Miescher ketone derivative through the 7-endo-trig mode of acyl radical cyclization.

Full text of DOI:10.1021/ja202874d

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Enantiocontrolled Total Syntheses of Breviones A, B, and C
Hiromasa Yokoe, Chika Mitsuhashi, Yoko Matsuoka, Tomoyuki Yoshimura, Masahiro Yoshida, and
Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
S Supporting Information
b
ABSTRACT: Enantiocontrolled total syntheses of the
breviones A, B, and C have been accomplished using a
highly diastereoselective oxidative coupling of an R-pyrone
with a tricyclic diene prepared from an optically pure
WielandꢀMiescher ketone derivative through the 7-endo-
trig mode of acyl radical cyclization.
1
reviones AꢀE (1ꢀ5, Figure 1), the diterpene/polyketide
2
B
hybrid natural products also called meroterpenoids, were
first isolated from Penicillium brevicompactum Dierckx by Macías
1
et al. Their structures were elucidated by chemical transforma-
3
tions and extensive 2D NMR studies. Breviones FꢀH (6ꢀ8)
were recently isolated from the marine deep-sea fungus Penicil-
lium sp. (MCCC3A00005). These compounds contain unpre-
cedented penta- (1ꢀ4, 6, and 7), hexa- (5), and heptacyclic (8)
basic carbon frameworks, and in 1ꢀ4, 6, and 7, the framework
includes a characteristic oxygen-containing spiro CD ring. 1ꢀ5
Figure 1. Structures of the breviones.
Scheme 1. Retrosynthetic Analysis
1b
inhibit etiolated wheat coleoptile growth, while 6ꢀ8 exhibit
cytotoxic activity against HeLa cells and 6 has an inhibitory effect
3
on HIV-1 replication in C8166 cells. Because of their intriguing
structural features, biological profiles, and limited availability,
these natural products represent attractive targets for total synth-
4
,5
esis. To date, several synthetic studies have been reported,
5c
including the total synthesis of optically active brevione B (2), in
which the absolute structure was determined. Here we describe
the first enantioselective total synthesis of brevione C (3) and
highly efficient enantioselective total syntheses of breviones A
(
1) and B (2) employing a regioselective 7-endo acyl radical
6
cyclization to assemble the seven-membered A ring (for brevione
C) and a diastereoselective oxidative coupling of an exocyclic
olefin and an R-pyrone for the construction of the spiro ring
as the key steps. For the initial target, we chose brevione C,
reasoning that if a synthetic route to brevione C could be
established, it would then be easier to prepare breviones A and B.
Our strategies for the syntheses of breviones C (3), A (1), and B
7
8
9
1
0
(
2) are illustrated in Scheme 1. For the synthesis of 3, we chose as
the key intermediate the pentacyclic compound 9, which would be
converted to 3 by oxidation. It was thought that 9 could be
constructed by the oxidative coupling of tricyclic compound 10, a
diterpene moiety, with R-pyrone 11, a polyketide unit. The seven-
membered A ring of 10 would be assembled using a highly
regioselective 7-endo-trig mode of cyclization of the acyl radical
was thought that 14 could serve as the common intermediate; it
would be converted to diene 16, which would then be coupled
11
1
1
2, which was previously developed in our laboratory. Aldehyde
3, a precursor of the acyl radical, would in turn be prepared
12
from the optically active WielandꢀMiescher ketone derivative
Received: March 29, 2011
Published: May 11, 2011
1
3
1
5
via tricyclic compound 14. For the synthesis of 1 and 2, it
r 2011 American Chemical Society
8854
dx.doi.org/10.1021/ja202874d
|J. Am. Chem. Soc. 2011, 133, 8854–8857

Journal of the American Chemical Society
COMMUNICATION
a
Scheme 2. Synthesis of Aldehyde 13
Table 1. Acyl Radical Cyclization of 13
entry
equiv of V-40
equiv of t-C12
H25SH
time (h)
yield (%)
1
2
3
4
5
0.5
1
0.5
1
12
12
3
47
59
70
72
82
1.5
3
1.5
15
3
2
3
2
a
Scheme 3. Synthesis of the Diterpene Segment 10
a
Reagents and conditions: (a) 2 M HCl, THF, reflux, 50 min. (b) Pd/C,
AcOEt, rt, 57 h; 91% (two steps). (c) mCPBA, NaHCO , CH Cl , rt,
3
2
2
1
8
CH
8 h, 95%. (d) p-TsOH H O, MeOH, rt, 4 h, 98%. (e) IBX, DMSO,
3
2
5 °C, 12 h, 86%. (f) DIBAH, toluene, ꢀ78 °C, 10 min. (g) DMP,
Cl , rt, 2 h; quant (two steps).
2
2
with 11 to produce 2. Finally, 2 would be dehydrogenated
to give 1.
The WielandꢀMiescher ketone derivative 15 (>99% ee) was
converted to the optically pure tricyclic alcohol 14 via a four-step
1
4
sequence. Acidic hydrolysis followed by hydrogenation af-
forded keto alcohol 17, which was subjected to BaeyerꢀVilliger
oxidation to give lactone 18 (Scheme 2). The lactone was treated
a
Reagents and conditions: (a) Ethylene glycol, PPTS, benzene, reflux,
4
Pd
h, 98%. (b) I
2
, TMSN
3 4 3
, pyridine, rt, 12 h. (c) Me Sn, CuI, Ph As,
2
(dba) CHCl
3
3
3
, NMP, 80 °C, 3 h; 87% (two steps). (d) MeLi,
15
þ
3
with p-toluenesulfonic acid in MeOH to produce alkenyl ester
THF, ꢀ78 °C, 1 h, 98%, (e) Ac O, 270 °C then H O , 80%.
2
1
9 in excellent yield. IBX oxidation gave enone 20, which was
converted to aldehyde 13 by sequential treatment with DIBAH
and DessꢀMartin periodinane.
Scheme 4. Synthesis of r-Pyrone 11
With the acyl radical precursor in hand, we next investigated the
16
7
-endo-trig cyclization used to assemble the A ring of 21, a seven-
membered cyclic ketone. Treatment of aldehyde 13 with tert-
dodecanethiol (t-C H SH) (0.5 equiv) and the radical initiator
12 25
0
,1 -azobis(cyclohexane-1-carbonitrile) (V-40) (0.5 equiv) in re-
17
1
fluxing toluene produced 21 in 47% yield as a single product
through the 7-endo-trig cyclization of the acyl radical intermediate
resulted in low yields of the product and was not reproducible.
Consequently, we set out to develop a more general and effi-
cient method. After several attempts, we found that sequential
carbomethoxylation of the dianion generated from 3-methyl-
pentane-2,4-dione and cyclization of the resulting diketo ester
12. The configuration of the newly generated tertiary stereogenic
center in 21 was deduced to be S on the basis of the previous
11
19
results. Encouraged by these findings, we next proceeded to
examine more closely the reaction conditions (Table 1). The best
result was obtained when 13 was treated with t-C H SH (3 equiv)
25 using DBU in refluxing benzene efficiently provided 11
12 25
20
and V-40 (3 equiv) in refluxing toluene for 2 h, which afforded 21 in
2% yield (entry 6). It should be emphasized that the reaction
(Scheme 4).
8
Having made the two segments, we next examined the key
oxidative coupling. The results are shown in Table 2. Treatment
proceeded selectively even in the presence of an enone moiety.
After protection of the A-ring ketone in 21, an iodide was
of tricyclic diene 10 with R-pyrone 11 using ceric ammonium
18
7f
introduced at the R-carbon of the enone to give 22, which was
methylated by Stille coupling to provide 23 (Scheme 3). At-
tempts at direct methylenation of 23 using a variety of methods
failed to afford the carbonyl-protected analogue of 10. Therefore,
nitrate (CAN) in CH
3
CN at 0 °C gave the desired pentacyclic
compound 9 in 65% yield as a separable 10:1 diastereomeric
21
mixture. X-ray crystallographic analysis of the major diaster-
eoisomer revealed it to be the desired pentacycle, as shown
in Figure 2. To improve the chemical yield, we examined
7b
2
3 was treated with methyllithium, and the resulting tertiary
7a
alcohol 24 was dehydrated under thermal conditions to produce
in good yield tricyclic diene 10 containing an exocyclic olefin (the
diterpene segment).
many oxidizing agents [e.g., Mn(OAc)
3
(entry 2), Mn(pic)
CO /Celite, etc.] as well as the reaction conditions and
3
3
,
7e
Ag
found that using a 2:1 mixture of CAN and Cu(OAc)
2
2
2
resulted
2
Next we examined the synthesis of R-pyrone 11, a compound
in a dramatic improvement in the yield to 84% with the same
8
23
known in the literature. However, the literature procedure
diastereoselectivity of 10:1. As for the diastereoselectivity, the
8
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Journal of the American Chemical Society
COMMUNICATION
Table 2. Oxidative Coupling of 10 with 11
Scheme 6. Total Synthesis of Brevione C (3)
a
time
yield
Scheme 7. Synthesis of Diene 16
a
b
entry
conditions
(h)
(%)
dr
1
2
3
4
5
6
CAN, CH
3
CN, 0 °C
2H O, benzene, reflux
, CH CN, 0 °C
CAN, [bdmin]BF /CH Cl
(1:5), 0 °C∼rt
CAN, [bmin]BF /CH Cl
(1:5), 0 °C∼rt
CAN, Cu(OAc) [bmin]BF /CH Cl (1:5),
°C∼rt
1.2
21
1.3
4.8
3
65
dec
84
45
78
81
10:1
ꢀ
Mn(OAc)
3
2
3
CAN, Cu(OAc)
2
3
10:1
4
2
2
>20:1
>20:1
>20:1
4
2
2
2
4
2
2
4
0
a
b
1
Isolated yields. Determined by H NMR analysis of the crude product.
a
Reagents and conditions: (a) H
2
, Pd/C, EtOH, rt, 71 h, 95%. (b) Dessꢀ
Martin periodinane, CH Cl , rt, 30 min, 96%, (c) LDA, MeI, HMPA,
2
2
THF, 0 °C, 2 h, 91%, (d) LDA, TMSCl, THF, ꢀ20 to ꢀ10 °C, 2 h, 98%.
(
1
e) Pd(OAc)
h, 96%, (g) Ac
2
, O
2
, DMSO, 80 °C, 15 h, 75%, (f) MeLi, THF, ꢀ78 °C,
þ
2
O, 270 °C, sealed tube, then H
3
O ; 86% (two steps).
Scheme 8. Total Synthesis of Breviones A (1) and B (2)
Figure 2. ORTEP drawing of 9.
Scheme 5. Presumed Mechanism
The pentacyclic ketone 9 thus prepared was treated
24
with IBX in DMSO at 80 °C for 1.3 h to provide brevione
C (3) along with enone 28 in 44 and 54% yield, respectively
25
(
Scheme 6). The semioxidized enone 28 was converted to 3
in 37% yield by subsequent treatment with IBX. The spectral
properties and optical rotation of the synthetic material were
identical with those of natural brevione C.
addition of an ionic liquid, [bdmin]BF , as the solvent elicited
4
1b
a dramatic improvement in the annulation efficiency, afford-
ing 9 exclusively, but the yield remained at 45% (entry 4).
However, excellent results (exclusive formation of 9 in 81%
yield) were obtained when the reaction was conducted with
CAN/Cu(OAc) in a 1:5 mixture of the ionic liquid [bmin]BF
The syntheses of the breviones A (1) and B (2) started from
optically pure alcohol 14, which was used for the synthesis of
brevione C. Sequential hydrogenation, DessꢀMartin oxidation,
and methylation furnished ketone 29 (Scheme 7). Attempted
IBX oxidation gave unsatisfactory results, so 29 was converted
to the silyl enol ether, which was then exposed to oxidation
2
4
7
i
and CH Cl (entry 6). Comparable diastereoselectivities and
2
2
yields were obtained even using only CAN (entry 5).
The diastereoselective formation of the CD spiro ring can be
explained by considering the conformation of the intermediate
carbocation 27 that would be generated from the initially formed
allyl radical intermediate 26 by oxidation (Scheme 5). The
hydroxyl oxygen atom of the R-pyrone in 27 would attack
from the sterically less hindered bottom face of the molecule
to give 9 with the S configuration at the spiro stereogenic
center preferentially.
2
6
conditions using Pd(OAc) and O in DMSO at 80 °C to
2 2
5b,c
obtain enone 30. The enone was likewise transformed to the
1,3-diene 16 in two steps.
Oxidative coupling of diene 16 and R-pyrone 11 with CAN
and Cu(OAc) in CH CN at 0 °C for 2.5 h gave a mixture of
2 3
brevione B (2) and its diastereoisomer in a 10:1 ratio in 96% yield
(Scheme 8). When the reaction was conducted with CAN in a 1:5
27
mixture of [bmin]BF
/CH
Cl
at 0 °C ∼ rt for 0.5 h, 2 was
4
2
2
8
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dx.doi.org/10.1021/ja202874d |J. Am. Chem. Soc. 2011, 133, 8854–8857

Journal of the American Chemical Society
COMMUNICATION
obtained in 99% yield as a single product. The brevione B thus
obtained was treated with IBX in DMSO to give brevione A (1) in
1989, 2169. (c) Nair, V.; Mathew, J. J. Chem. Soc., Perkin Trans. 1
1995, 187. (d) Nair, V.; Mathew, J.; Alexander, S. Synth. Commun. 1995,
25, 3981. (e) Lee, Y. R.; Kim, B. S. Tetrahedron Lett. 1997, 38, 2095. (f)
8
4% yield. The spectral properties and optical rotations of both
1a 1b
Kobayashi, K.; Sakashita, K.; Akamatsu, H.; Tanaka, K.; Uchida, M;
Uneda, T.; Kitamura, T.; Morikawa, O.; Konishi, H. Heterocycles 1999,
compounds were identical to those for natural breviones A and B.
In summary, we have completed the first enantiocontrolled total
synthesis of brevione C using a highly diastereoselective oxidative
coupling of R-pyrone 11 with tricyclic diene 10, which was readily
prepared from an optically pure WielandꢀMiescher ketone deri-
vative via a regioselective 7-endo-trig mode of acyl radical cycliza-
tion as the key reaction step in a longest linear sequence of 14 steps
with an overall yield of 17%. Using a similar strategy, we have
completed efficient and enantiocontrolled total syntheses of bre-
viones A and B, in 42% yield and nine steps and 50% yield and
eight steps, respectively, starting from a compound known in the
51, 2881. (g) Lee, Y. R.; Kim, B. S.; Kim, D. H. Tetrahedron 2000,
56, 8845. (h) Muthusamy, S.; Gunanathan, C.; Babu, S. A. Synlett
2002, 787. (i) Bar, G.; Bini, F.; Persons, A. F. Synth. Commun. 2003,
33, 213. (j) Karade, N. N.; Shirodkar, S. G.; Patil, M. N.; Potrekar, R. A.;
Karade, H. N. Tetrahedron Lett. 2003, 44, 6729. (k) Wu, K.-L.; Mercado,
E. V.; Pettus, T. R. R. J. Am. Chem. Soc. 2011, 133, 6114.
(8) Hagiwara, H.; Fujimoto, N.; Suzuki, T.; Ando, M. Heterocycles
2000, 53, 549.
(9) Three examples of CAN-mediated oxidative coupling of exocyc-
lic alkenes with cyclic 1,3-diketones to construct spiro compounds have
been reported. In ref 7d, no diastereoselectivities were mentioned; on
the other hand, the spiro compound was obtained in 72% yield with a
diastereomeric ratio of 65:35 in ref 7h. In ref 7k, a mixture of the two
isomeric quinones was obtained.
13
literature, 14, which is an intermediate in the synthesis of brevione
C. The synthetic route developed here is general and efficient and
could also be applied to the syntheses of other breviones with more
complicated structures and interesting biological profiles.
(10) The early stages of the work were presented at the 48th
Symposium on the Chemistry of Terpenes, Essential Oils, and Aro-
matics (Yamaguchi, Japan, Oct 30, 2004; abstract paper pp 84ꢀ86) and
the 47th Symposium on the Chemistry of Natural Products (Tokushima,
Japan, Oct 9, 2005; abstract paper pp 595ꢀ600).
’
ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
(
11) Ohtsuka, M.; Takekawa, Y.; Shishido, K. Tetrahedron Lett.
acterization data, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
1
998, 39, 5803.
12) (a) Harris, E. F. P.; Waters, W. A. Nature 1952, 170, 212.
b) Barrett, K. E. J.; Waters, W. A. Discuss. Faraday Soc. 1953, 14, 221.
(
(
’
AUTHOR INFORMATION
(
(
13) Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
14) Honda, T.; Favaloro, F. G., Jr.; Janosik, T.; Honda, Y.; Suh, N.;
Corresponding Author
shishido@ph.tokushima-u.ac.jp
Sporn, M.; Gribble, G. W. Org. Biomol. Chem. 2003, 1, 4384.
15) Maitraie, D.; Hung, C.; Tu, H.; Liou, Y.; Wei, B.; Yang, S.;
Wang, J.; Lin, C. Bioorg. Med. Chem. 2009, 17, 2785.
16) Examples of competitive 7-endo/6-exo cyclization of acyl radicals
have been reported. See: (a) Crich, D.; Fortt, S. M. Tetrahedron 1989,
5, 6581. (b) Crich, D.; Eustace, K. A.; Fortt, S. M.; Ritchie, T. J. Tetrahedron
(
’
ACKNOWLEDGMENT
(
A Grant-in-Aid for JSPS Fellows (20-11673) to H.Y. from the JSPS
4
is gratefully acknowledged. This work was supported by a Grant-in-
Aid from the Program for the Promotion of Basic and Applied
Research for Innovations in the Bio-oriented Industry (BRAIN).
1
1
990, 46, 2135. (c) Batty, D.; Crich, D. J. Chem. Soc., Perkin Trans. 1
992, 3193. For a review, see:Yet, L. Tetrahedron 1999, 55, 9349.
(17) (a) Dang, H.-S.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 1
1
998, 67. (b) Yoshikai, K.; Hayama, T.; Nishimura, K.; Yamada, K.;
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(
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1
(
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(
(
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8
(
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/
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dx.doi.org/10.1021/ja202874d |J. Am. Chem. Soc. 2011, 133, 8854–8857