Total synthesis of (±)-clavilactones A, B, and proposed D through iron-catalyzed carbonylation-peroxidation of olefin

Article abstract of DOI:10.1002/anie.201400326

Biologically significant clavilactones A, B, and the previously proposed D have been synthesized through iron-catalyzed carbonylation-peroxidation of a 1,5-diene. Three steps from aldehydes, alkenes, and tert-butylhydroperoxide build up α,β-epoxy-γ-butyrolactone skeleton as a key building block for synthesis of clavilactone family and its derivatives. Based on our results, the structure of the proposed clavilactone D is not correct and requires revision. A general, concise, and efficient approach for synthesis of clavilactones A, B, and D has been established. Three steps from aldehydes, 1,5-dienes, and tBuOOH build up α,β-epoxy-γ-butyrolactones (see scheme, left) as the key building blocks for synthesis of clavilactone family and its derivatives. From these results, the previously proposed clavilactone D structure requires revision.

Full text of DOI:10.1002/anie.201400326

Angewandte
Chemie
DOI: 10.1002/anie.201400326
Natural Product Synthesis
Total Synthesis of (Æ)-Clavilactones A, B, and Proposed D through
Iron-Catalyzed Carbonylation–Peroxidation of Olefin**
Leiyang Lv, Baojian Shen, and Zhiping Li*
Abstract: Biologically significant clavilactones A, B, and the
previously proposed D have been synthesized through iron-
catalyzed carbonylation–peroxidation of a 1,5-diene. Three
steps from aldehydes, alkenes, and tert-butylhydroperoxide
build up a,b-epoxy-g-butyrolactone skeleton as a key building
block for synthesis of clavilactone family and its derivatives.
Based on our results, the structure of the proposed clavilac-
tone D is not correct and requires revision.
achieved the total synthesis (Scheme 1), and several groups
have made great efforts in semisynthesis of clavilactones.[8]
The macrocycle of clavilactones were realized by ring-closing
metathesis (RCM),[6,7,9] and the major difference is how to
build the a,b-epoxy-g-butyrolactone skeleton.[10] It is worth
noting that clavilactone D (4, R = OH) is difficult to synthe-
size by strategy I owing to the selectivity of benzyne
coupling,[11] and five synthetic steps were used to transform
furan-2(5H)-one into a,b-epoxy-g-butyrolactone unit in strat-
egy II.
Clavilactones A–E (1–5), isolated from cultures of the
Basidiomycetous fungus Clitocybe clavipes,[1,2] are endowed
with an intriguing structure based on a ten-membered ring
fused to a a,b-epoxy-g-butyrolactone and a benzoquinone or
hydroquinone (Figure 1). Clavilactones A, B, and C (1, 2, and
Figure 1. The clavilactone family.
Scheme 1. The developed strategies for clavilactones A and B.
3) exhibit antifungal and antibacterial activities[3] and inhibit
the germination of Lepidium sativum. Clavilactone A, B, and
D (1, 2, and 4) are potent kinase inhibitors against Ret/ptc1
and epidermal growth factor receptor (EGF-R) tyrosine
kinases,[3] which might serve as potent molecularly targeted
anticancer agents.[4,5]
The significant biological properties of clavilactones have
attracted the endeavors from synthetic community and, to
date, the groups of Barrett[6] and Takao[7] have successfully
Recently we reported a novel iron-catalyzed carbonyla-
tion–peroxidation of olefin, which provides a general and
concise way to synthesize a,b-epoxy-g-butyrolactones
through base-catalyzed epoxidation followed by reductive
lactonization (Scheme 2).[12] Considering the efficiency and
high selectivity of the construction of the a,b-epoxy-g-
butyrolactone skeleton from simple alkenes, aldehydes, and
hydroperoxides, we then decided to use the developed
synthetic method to synthesize clavilactones.
Scheme 3 gives our retrosynthetic analysis to clavilac-
[*] L. Lv, Prof. Dr. Z. Li
À
tones. The tri-substituted alkene C11 C12 of clavilactones
Department of Chemistry, Renmin University of China
Beijing 100872 (China)
E-mail: zhipingli@ruc.edu.cn
Homepage: http://chem.ruc.edu.cn/ligroup/index.html
Prof. Dr. B. Shen, Prof. Dr. Z. Li
State Key Laboratory of Heavy Oil Processing
China University of Petroleum, Beijing 102249 (China)
[**] Financial support by the National Science Foundation of China
(Nos. 21072223, 21272267) and State Key Laboratory of Heavy Oil
Processing (2012-1-06). We are grateful to Prof. L. Merlini and Dr. L.
Scaglioni for providing the original spectra and helpful discussions
on the structure of clavilactone D.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400326.
Scheme 2. Our developed methodologies.
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The Stille coupling[14] of highly hindered 8 with tributyl(2-
methylallyl)stannane proved to be challenging. When 1,4-
dioxane was employed as the solvent,[7] the yield of the diene
7a was very poor and the debromination product was also
present. The desired products 7b and 7c were not observed if
1,2-dichloroethane was applied as the solvent.[8b] Gratifyingly,
MeCN was found as effective solvent for the present Stille
coupling, and the expected dienes 7 were obtained in
excellent yields (Scheme 5).[15] Finally, RCM reactions suc-
cessfully generated the ten-membered products 14 by
Grubbsꢀs second-generation catalyst.
Scheme 3. The retrosynthetic analysis for clavilactones.
can be constructed through RCM of diene 7, which might be
accessed by the cross-coupling reaction.[13] We envisioned that
8 can be constructed by a sequential steps of amine-catalyzed
epoxidation of a-ester-b-keto peroxide 9 followed by reduc-
tive lactonization. The designed key intermediate 9 can be
assembled by iron-catalyzed carbonylation–peroxidation of
alkene 10 with aldehyde 12 and tert-butyl hydroperoxide
(TBHP) 11. Herein, we report our efforts for synthesis of
clavilactones A, B, and D. The salient feature of our synthesis
is a highly convergent, general, and concise strategy to
accomplish the synthesis of diverse members of clavilactone
family as well as its analogues.
Scheme 5. Reagents and conditions: a) tributyl(2-methyl-allyl)stannane,
[Pd(PPh3)4], CsF, MeCN, 1008C, 12 h, R=H (7a, 87%), OMe (7b,
=
82%), OBn (7c, 88%); b) [Cl2(Cy3P)(sIMes)Ru CHPh], tetrafluoroben-
zoquinone, toluene, 808C, 18 h, R=H (14a, 65%), OMe (14b, 43%),
OBn (14c, 42%).
With the key precursor 14 in hand, we subsequently
investigated synthesis of diverse members of clavilactone
family (Scheme 6). Clavilactone B (2) was obtained by the
oxidative demethylation[6,16] of 14a in 70% yield. The
reduction of clavilactone B by NaBH4 afforded clavilacto-
ne A (1) in a quantitative yield. Initially, we expected that
clavilactone D could be generated by the deprotection of 6a
or 6b, which were obtained by the oxidation of 14b or 14c,
respectively. However, removal of the methyl group in 6a and
the benzyl group in 6b turned out to be more difficult than
anticipated, which is mainly due to the frangible structure of
a,b-epoxy-g-butyrolactone skeleton and the feasible reduc-
The synthesis began with three-component reactions of
10, 11, and 12 by the use of FeCl2 as catalyst (Scheme 4). The
desired transformation underwent smoothly by using
Scheme 4. Reagents and conditions: a) FeCl2, MeCN, 858C, 3 h, R=H
(9a, 60%), OMe (9b, 74%), OBn (9c, 70%); b) pyrrolidine, MeCN,
08C, 3 h, R=H (13a, 87%, d.r. 5:1), OMe (13b, 90%, d.r. 4:1), OBn
(13c, 91%, d.r. 4:1); c) NaBH4, EtOH, 08C, 3 h, R=H (8a, 73%),
OMe (8b, 71%), OBn (8c, 78%).
2.5 mol% FeCl2 for syntheses of 9a and 9b. However,
a reduced amount of catalyst (0.1 mol%) had to be used for
synthesis of 9c to avoid some unknown side reactions.
Subsequently, pyrrolidine-catalyzed epoxidation of 9 fol-
lowed by NaBH4-mediated reductive lactonization of 13
furnished a,b-epoxy-g-butyrolactones 8. The chelation
between the carbonyl and epoxy group with boron atom
allows hydride to attack the less hindered side of the
carbonyl.[12a]
Scheme 6. Reagents and conditions: a) CAN, MeCN/H2O (2:1), 08C,
R=H (2, 70%), OMe (6a, 65%), (6b, 60%); b) NaBH4, EtOH, 08C,
5 min, (1, 99%); c) 10 wt% Pd/C, 1,4-cyclohexadiene, EtOH, 258C,
1 h, (15, 99%); d) CAN, MeCN/H2O (2/1), 08C, 10 min (4, 85%);
e) K2CO3, Me2SO4, 258C,3 h, (6a, 70%). CAN=ceric ammonium
nitrate.
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tion of 2-hydroxyquinone to 2-hydroxyhydroquinone simul-
taneously. With extensive efforts, we found that benzyl
protecting group of 14c could be first removed in the
presence of 10 wt% Pd/C and 1,4-cyclohexadiene as the
hydrogen donor.[17] Followed by oxidative demethylation of
15, clavilactone D (4) was successfully achieved for the first
time. To verify the structure of our synthesized clavilactone D
(4), the methylation of the obtained 4 gave 6a, which is
identical to that synthesized from 14b.
methods failed to give the desired 3-hydroxy clavilactone D
(22) directly, while an ortho-quinone intermediate 21 was
generated. Fortunately, 21 could be transformed into the
desired product 22 through acid-catalyzed isomerization.[19]
Furthermore, the methylation of 22 led to the corresponding
methylated product 23.
Unfortunately, NMR spectroscopic data of 3-hydroxycla-
vilactone D (22) is still not identical with the data of
clavilactone D (4). To exclude the possibility of an ortho-
quinone skeleton for clavilactone D, 29 was synthesized by
our strategy (Scheme 8). Based on the chemical shift of two
carbonyl groups on the quinine ring by 13C NMR spectrum,[20]
the possibility of an ortho-quinone structure of clavilactone D
could be ruled out.
Surprisingly, it turned out that NMR spectroscopic data of
synthesized 4 is not identical with the data of clavilactone D
published by Merlini et al.[18] The only difference (Dd =
1
0.25 ppm) in the H NMR chemical shifts was observed for
3-H, which appears at 6.15 ppm for our synthesized 4, while
5.90 ppm for the naturally isolated clavilactone D. Moreover,
significant deviations (Dd > 5.5 ppm) were also detected in
the 13C NMR chemical shifts for C2, C3, and C5. On the basis
of NMR spectroscopic data analysis, we rationalized that:
1) the proposed structure for the natural clavilactone D does
not concur with NMR spectroscopic data; and 2) one of
possible structures for the natural clavilactone D is most
likely the other regioisomer of the proposed structure of
clavilactone D, in which the OH group is on 3-position of the
quinone ring instead of 2-position.
Guided by our established synthetic strategy, the newly
proposed structure of clavilactone D (22) was synthesized
(Scheme 7). The iron-catalyzed carbonylation–peroxidation
of alkene 10 with aldehyde 16 and tert-butyl hydroperoxide 11
gave the corresponding peroxide intermediate, which was
smoothly converted into the desired epoxide 17 by pyrroli-
dine. NaBH4-mediated reduction delivered the lactone 18.
The Stille coupling and RCM offered the macrolide 19. The
debenzylation of 19 by 10 wt% Pd/C gave 3-hydroxy inter-
mediate 20. Unexpectedly, various oxidative demethylation
Scheme 8. Reagents and conditions: a) FeCl2, MeCN, 858C, 3 h;
b) pyrrolidine, MeCN, 08C, 3 h, (25, 32%, over 2 steps); c) NaBH4,
EtOH, 08C, 3 h, (26, 76%); d) tributyl(2-methyl-allyl)stannane, [Pd-
=
(PPh3)4], CsF, MeCN, 1008C, 12 h; e) [Cl2(Cy3P)(sIMes)Ru CHPh],
tetrafluorobenzoquinone, toluene, 808C,18 h, (27, 47%, over 2 steps);
f) 10 wt% Pd/C, cyclohexene, EtOH/THF (3:1), 508C, 1 h, (28, 81%);
g) PIFA, MeCN/acetone/H2O (30:10:1), À108C, 30 min, (29, 78%).
PIFA=phenyliodonium bis(trifluoroacetate).
If the details of the NMR spectroscopic data of the natural
clavilactone D are considered, the current spectral differ-
ences with our synthesized products might plausibly arise
from the different stereoconfiguration of a,b-epoxy-g-butyr-
olactone skeleton. To accomplish the structure elucidation
and synthesis of the natural clavilactone D, new methods for
the construction of other diastereomers of a,b-epoxy-g-
butyrolactone skeleton are needed.
In conclusion, we established a general, concise, and
efficient approach for synthesis of clavilactone family and its
derivatives. For examples, the total synthesis of (Æ) clavilac-
tone B was completed in 6 steps with 15.1% yield, 7 steps with
14.9% yield for (Æ) clavilactone A, and 7 steps with 15.5%
yield for (Æ) the proposed clavilactone D. This step-econom-
ical approach features a key iron-catalyzed carbonylation–
peroxidation of olefin leading to a-ester-b-carbonyl perox-
ides, which can be transformed efficiently and selectively into
a,b-epoxy-g-butyrolactone skeleton as the key building block.
Scheme 7. Reagents and conditions: a) FeCl2, MeCN, 858C, 3 h; b) pyr-
rolidine, MeCN, 08C, 6 h, (17, 51%, over 2 steps); c) NaBH4, EtOH,
08C, 4.5 h, (18, 72%); d) tributyl(2-methyl-allyl)stannane, [Pd(PPh3)4],
Received: January 12, 2014
Published online: && &&, &&&&
=
CsF, MeCN, 1008C, 9 h; e) [Cl2(Cy3P)(sIMes)Ru CHPh], tetrafluoro-
benzoquinone, toluene, 808C, 18 h, (19, 58%, over 2 steps);
f) 10 wt% Pd/C, cyclohexene, EtOH/THF (3:1), 508C, 1 h,(20, 90%);
g) CAN, MeCN/H2O (2:1), 08C, 10 min, (21, 81%); h) MeCN, H2SO4
(10% aqueous), RT, 9 h, (22, 99%); i) K2CO3, Me2SO4, 258C, 3 h, (23,
82%).
Keywords: carbonylation–peroxidation · clavilactone · epoxides ·
iron catalysis · natural product synthesis
.
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Natural Product Synthesis
L. Lv, B. Shen, Z. Li*
&&&& — &&&&
Total Synthesis of (Æ)-Clavilactones A, B,
and Proposed D through Iron-Catalyzed
Carbonylation–Peroxidation of Olefin
A general, concise, and efficient approach
for synthesis of clavilactones A, B, and D
has been established. Three steps from
aldehydes, 1,5-dienes, and tBuOOH build
up a,b-epoxy-g-butyrolactones (see
scheme, left) as the key building blocks
for synthesis of clavilactone family and its
derivatives. From these results, the pre-
viously proposed clavilactone D structure
requires revision.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!