Intramolecular Diels-Alder Cycloaddition Approach toward the cis-Fused Δ5,6-Hexahydroisoindol-1-one Core of Cytochalasins

Article abstract of DOI:10.1021/acs.orglett.8b04129

Synthesis of the cis-fused Δ^5,6-hexahydroisoindol-1-one core of cytochalasins B₂-B₅, K, Z₈, Z₉, Z₁₂-Z₁₅, and Z₁₇ has been established starting from an intramolecular D

Full text of DOI:10.1021/acs.orglett.8b04129

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Intramolecular Diels−Alder Cycloaddition Approach toward the cis-
5
,6
Fused Δ -Hexahydroisoindol-1-one Core of Cytochalasins
†
,‡
†
†
†
,†
,†,§
Jingjing Xu,
Benguo Lin, Xiuqing Jiang, Zejun Jia, Jinlong Wu,* and Wei-Min Dai*
†
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
Department of Chemistry, Hangzhou Medical College, Hangzhou 310053, P. R. China
‡
§
Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong SAR, P. R. China
*
S Supporting Information
5,6
ABSTRACT: Synthesis of the cis-fused Δ -hexahydroisoindol-1-
one core of cytochalasins B −B , K, Z , Z , Z −Z , and Z has
2
5
8
9
12
15
17
been established starting from an intramolecular Diels−Alder
reaction of the amide-tethered (8E)-1,3,8-nonatriene. The trans-
fused 5/6-bicyclic adduct was then subjected to highly stereo-
selective C9-β-hydroxylation and epimerization of the C7-α-OH
group.
3
ytochalasans are a large family of fungal polyketide−amino
possessing open-chains (4−7 in Figure 1) and spirocyclic/
1c
C
acid hybrid metabolites possessing a common perhydroi-
polycyclic scaffolds have been reported. Additional structural
complexity has been observed in merocytochalasans arising
from incorporation of epicoccine molecule(s) through dimeri-
zation or oligomerization. Cytochalasans are best known as
microfilament-targeting molecules, exhibiting influence on
cellular processes such as cell adhesion, intracellular motility,
1
soindol-1-one core. The C3 group originates from amino acids
2
−4
and includes benzyl [cytochalasins 1−7 in Figure 1],
p-
1c,5
1b,c
signaling, and cytokinesis. Studies have revealed two groups
of cytochalasins, being cytotoxic and cytostatic. This finding
6
suggests potential use of cytostatic cytochalasins in cancer
treatment. Other biological activities have been recognized for
7
8
cytochalasans, including antibacterial, antitumor, immuno-
9
8e,10
12
modulatory, and phytotoxic activities,
glucose transport and HIV-1 protease.
and inhibition of
11
The established biosynthesis of cytochalasins E (13) and K
1
3
(
14) is illustrated in Scheme 1, featuring an intramolecular
14
Diels−Alder (IMDA) reaction of a 1,5-dihydropyrrol-2-one
6
,7
derivative 8 to form the adduct 9 in which a cis-Δ -
hexahydroisoindol-1-one core is fused with a carbocycle.
Further enzymatic oxidation of 9 results in the proposed
15
precytochalasin (11a) via ketocytochalasin (10). Oxidation of
11a to 12 takes place only for the C3-benzyl-substituted
cytochalasans. Epoxidation of the C6−C7 double bond in 12
gives 13, which is finally converted into 14. However, iso-
precytochalasin (11b) is transformed into cytochalasin Z (3)
5
,6
Figure 1. Cytochalasins possessing a Δ -hexahydroisoindol-1-one
core and a fused lactone (1−3) or a side chain (4−7).
13
16
17
1
7
methoxybenzyl [pyrichalasins], (indol-3-yl)methyl [chaetoglo-
bosins], 2-methylpropyl [aspochalasins], and methyl [alachala-
sins] groups. The perhydroisoindol-1-one core of cytochala-
sans is typically fused with a carbocycle (10 in Scheme 1),
lactone (1−3 in Figure 1), and cyclic carbonate (12−14 in
Scheme 1), respectively, in various ring sizes. Cytochalasans
via rosellichalasin (16) (see Scheme S1 in the Supporting
Information).
1
b
Received: December 26, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04129
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
2
3
Scheme 1. Biosynthesis of Cytochalasins E and K
The parent amide-tethered 1,3,8-nonatriene 17 (R = R = R
4
=
R = H) was reported to undergo IMDA reaction at 190 °C to
24,25b
form a 46:54 mixture of 18a and 18b.
From the C9-
2
3
4
substituted (E)-17 and (Z)-17 (R = R = H; R = CO Me,
2
CO H, Ar), 18a and 19a were obtained as the major products in
2
25
low to excellent diastereomeric ratios. With an additional
substituent at C1 or C5 position, high diastereoselectivity was
observed for 1,9- and 5,9-disubstituted (E)-17 and (Z)-17 (R =
H or R = H). However, a 1,5,9-trisubstituted (E)-17 afforded
a 1:1 ratio of 18a and 18b. Taking the adducts of (E)-17 as the
2
3
26
27
examples, inversion of stereochemistry at C7/C9 and C7/C8 of
1
8a and 18b, respectively, is required in order to synthesize 1−7
(
Figure 1).
We first examined the IMDA reaction of 23a,b derived from
the dienyl amine 21a,b and the acid 22 (Scheme 3). The Wittig
Scheme 3. IMDA Cycloaddition of Substrates 23a,b
Compounds 12−15 represent the four main types of the cis-
5
,6
fused perhydroisoindol-1-one cores. Except for the Δ -
hexahydroisoindol-1-one core in 14, total synthesis of
cytochalasan congeners with the perhydroisoindol-1-one cores
of 12, 13, and 15 has been reported by using both inter- and
intramolecular Diels−Alder reactions (similar to 8 → 9) as the
1
b,18−20
5,6
key steps.
We report here on a synthesis of the Δ -
hexahydroisoindol-1-one core, which would be derived from the
indicated retrosynthetic bond disconnections for Z (1), Z
2), Z −Z (4−7), and Z (3) (Figure 1) via an IMDA
reaction of the amide-tethered (8E)-1,3,8-nonatrienes (Scheme
). The same core structure is found in cytochalasins B −B
Figure S1 in the Supporting Information) and K (Scheme
). The key issues to be addressed are (a) installation of the
2
8
9
2
3
4
(
1
2
15
17
22
2
2
5
21
(
1
17
C9-β-OH group; and (b) epimerization of the C7-α-OH group
23
within the initially formed trans-fused 5/6-bicyclic adducts.
olefination of 20 (see Scheme S2 in the Supporting Information)
with excess Ph P = CHOMe gave a 69:31 inseparable mixture of
3
Scheme 2. IMDA Cycloaddition of 1,3,8-Nonatrienes 17
2
1a and 21b (87%); the latter were coupled with the acid 22
(
DCC, DMAP) to form the trienyl amide 23a,b. Spontaneous
IMDA reaction of 23a,b took place at room temperature to
furnish three adducts 24a−c in a ratio of 68:29:3 as estimated by
1
H NMR spectroscopy of the crude products. The compound
2
4a (63%) should be the major adduct of (E)-23a formed via
the trans-TS, while the minor adduct 24c of (E)-23a would be
24
formed via the cis-TS. An analogous trans-TS should be
considered for the formation of 24b (27%) from (Z)-23b. The
structures of 24a and 24b were assigned by comparison with a
similar compound whose stereochemistry was determined by X-
ray crystal structural analysis (vide infra).
The observed high diastereoselectivity of the IMDA reaction
of both (E)-23a and (Z)-23b is very encouraging. Unfortu-
nately, several attempted transformations (such as cleavage of
B
DOI: 10.1021/acs.orglett.8b04129
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the methyl ether and reduction of the ester) of 24a,b failed to
form the expected products or afforded the byproducts due to
elimination of the C7 methoxy group (see Scheme S4 in the
Supporting Information). Next, we decided to explore the
IMDA reaction of the N-unprotected substrates 28a,b (Scheme
4
). The Wittig olefination of 25 (see Scheme S3 in the
Scheme 4. Synthesis of trans-Fused Bicyclic Compounds
Figure 2. X-ray crystal structure of 32.
5,6
Scheme 5. Synthesis of Δ -Hexahydroisoindol-1-one
2
8
Supporting Information) using Ph PCHOTMSE gave a
3
5
6:44 inseparable mixture of (E)-26a and (Z)-26b, which were
labile in CDCl during NMR analysis and were prone to
3
decompose to the corresponding ketone. Upon refluxing in
29
THF in the presence of KOt-Bu, the Boc group of 26a,b was
removed to afford the dienyl amines 27a,b as a 76:24 E/Z
1
mixture as analyzed by H NMR spectroscopy, suggesting partial
decomposition of the (Z)-isomer during the deprotection. The
crude dienyl amines 27a,b were then coupled with the acid 22 to
give the amides 28a,b, among which only (E)-28a sponta-
neously underwent the IMDA reaction to furnish the adduct 29
as a single diastereoisomer in 40% overall isolated yield from the
mixed materials 26a,b (71% overall yield based on the
composition of 26a). Presumably, the conjugated diene (Z)-
2
8b did not prefer the s-cis conformation due to the bulky O-
Scheme S5 in the Supporting Information). The results could be
attributed to the nearly flat structure (analogous to 32 in Figure
2) of the trans-fused bicyclic skeleton of S14, which rendered the
tetrasubstituted double bond at C5/C6 less stable than the
trisubstituted one at C6/C7 due to higher ring strain. We
envisaged that the cis-fused bicyclic skeleton of 33 would
facilitate installation of the C7-OH group with the desired β
TMSE group, rendering its IMDA reaction difficult at room
temperature. Because (Z)-28b was not recovered, it was
assumed that decomposition of (Z)-28b occurred during the
reaction or product purification. The stereochemistry of 29 was
confirmed by X-ray crystal structural analysis of 32 (Figure 2);
the latter was obtained via DIBAL-H reduction of 29 (80%),
methylenation of 30 (90%), and N-Boc protection of 31 in
MeCN (rt, 40 h; 93%).
30
configuration (Scheme 5).
Thus, the C9-β-hydroxylation of 32 was carried out by
Attempted cleavage of the TMSE group in 31 using CsF in
HMPA at 120 °C or BF ·OEt at 0 °C was unsuccessful due to
exposing the lactam enolate to O at −50 °C to give 33 in 71%
2
yield. Removal of the Boc group in 33 using Mg(OMe) in
3
2
2
nonselective attack of H O at C5 from both α and β faces as well
MeOH or BF ·OEt at −30 °C gave 34. It was found that
2
3
2
as at C11−H of the allylic carbocation S14 (Scheme 5; also see
concurrent cleavage of the Boc group and the TMSE ether in 33
C
DOI: 10.1021/acs.orglett.8b04129
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
could be achieved by exposure to BF ·OEt at 0 °C for 3 h to
Remm, N.; Hertweck, C. Nat. Prod. Rep. 2010, 27, 869−886.
3
2
(c) Skellam, E. Nat. Prod. Rep. 2017, 34, 1252−1263.
afford 35 in 91% overall yield. It was pleasing that a trace amount
of the diol 36 was detected. We assumed that the diol 36 should
be formed from the cis-fused bicyclic allylic carbocation S18 via
(
2) For cytochalasin Z −Z , see: Liu, R.; Gu, Q.; Zhu, W.; Cui, C.;
7
9
Fan, G.; Fang, Y.; Zhu, T.; Liu, H. J. Nat. Prod. 2006, 69, 871−875.
(
3) For cytochalasin Z −Z , see: Liu, R.; Lin, Z.; Zhu, T.; Fang, Y.;
1
0
15
highly face- and regioselective attack of H O; the convex shape
2
Gu, Q.; Zhu, W. J. Nat. Prod. 2008, 71, 1127−1132.
(
of S18 assured attack of H O from the β-face, while the
2
4) For cytochalasin Z −Z , see: Lin, Z.-J.; Zhang, G.-J.; Zhu, T.-J.;
1
6
20
regioselectivity was originated from the stability of the
Liu, R.; Wei, H.-J.; Gu, Q.-Q. Helv. Chim. Acta 2009, 92, 1538−1544.
(
3
1
tetrasubstituted double bond at C5/C6. Finally, upon
treatment of 33 with BF ·OEt at 0 °C for 6 h, the desired
5) For merocytochalasans, see: Wei, G.; Chen, C.; Tong, Q.; Huang,
3
2
J.; Wang, W.; Wu, Z.; Yang, J.; Liu, J.; Xue, Y.; Luo, Z.; Wang, J.; Zhu,
product 36 was obtained in 72% yield (Scheme 5; also see
H.; Zhang, Y. Org. Lett. 2017, 19, 4399−4402.
13
Scheme S5 in the Supporting Information). The C NMR data
(6) Van Goietsenoven, G.; Mathieu, V.; Andolfi, A.; Cimmino, A.;
Lefranc, F.; Kiss, R.; Evidente, A. Planta Med. 2011, 77, 711−717.
3
of 36 are almost consistent with those of 4 except for C5 (see
(7) (a) Cunningham, D.; Schafer, D.; Tanenbaum, S. W.; Flashner, M.
Figure S2 in the Supporting Information).
J. Bacteriol. 1979, 137, 925−932. (b) Zheng, C.; Shao, C.; Wu, L.; Chen,
M.; Wang, K.; Zhao, D.; Sun, X.; Chen, G.; Wang, C. Mar. Drugs 2013,
In conclusion, we have established a concise synthesis of the
5,6
common cis-fused Δ -hexahydroisoindol-1-one core of cyto-
1
(
1, 2054−2068.
chalasin B −B , K, Z , Z , Z −Z , and Z via an IMDA
2
5
8
9
12
15
17
8) (a) Alvi, K. A.; Nair, B.; Pu, H.; Ursino, R.; Gallo, C.; Mocek, U. J.
cycloaddition of the amide-tethered (8E)-1,3,8-nonatriene
followed by highly stereoselective hydroxylation at C9 and
epimerization of the allyl alcohol at C7. This synthetic strategy
could be amended for synthesis of other cytochalasan congeners
by replacing C3-Bn with other substituents.
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ASSOCIATED CONTENT
Supporting Information
■
(
9) Hua, C.; Yang, Y.; Sun, L.; Dou, H.; Tan, R.; Hou, Y.
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*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b04129.
(
(
Experimental procedures, compound characterization
1
13
data, and copies of original H and C NMR spectra
PDF)
(
(
Meyer, R.; Ondeyka, J. G.; Giacobbe, R. A.; Monaghan, R. L.; Lingham,
R. B. J. Antibiot. 1992, 45, 671−678. (b) Ondeyka, J.; Hensens, O. D.;
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J. Antibiot. 1992, 45, 679−685. (c) Lingham, R. B.; Hsu, A.; Silverman,
K. C.; Bills, G. F.; Dombrowski, A.; Goldman, M. E.; Darke, P. L.;
Huang, L.; Koch, G.; Ondeyka, J. G. J. Antibiot. 1992, 45, 686−691.
Accession Codes
CCDC 1588694 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(13) For biosynthesis of cytochalasin E and K, see: (a) Qiao, K.;
Chooi, Y.-H.; Tang, Y. Metab. Eng. 2011, 13, 723−732. (b) Fujii, R.;
Minami, A.; Gomi, K.; Oikawa, H. Tetrahedron Lett. 2013, 54, 2999−
3002. (c) Hu, Y.; Dietrich, D.; Xu, W.; Patel, A.; Thuss, J. A. J.; Wang, J.;
AUTHOR INFORMATION
Corresponding Authors
Yin, W.-B.; Qiao, K.; Houk, K. N.; Vederas, J. C.; Tang, Y. Nat. Chem.
Biol. 2014, 10, 552−554. (d) For a review, see: Tang, M.-C.; Zou, Y.;
Watanabe, K.; Walsh, C. T.; Tang, Y. Chem. Rev. 2017, 117, 5226−
■
*
*
E-mail: wyz@zju.edu.cn.
E-mail: chdai@zju.edu.cn or chdai@ust.hk.
ORCID
5333.
(
14) For selected reviews, see: (a) Marsault, E.; Toro, A.; Nowak, P.;
́
Deslongchamps, P. Tetrahedron 2001, 57, 4243−4260. (b) Bear, B. R.;
Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820−849.
c) Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42,
Jingjing Xu: 0000-0002-6420-9060
Jinlong Wu: 0000-0003-1720-4758
Wei-Min Dai: 0000-0001-5688-7606
Notes
(
3
078−3115. (d) Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005,
105, 4779−4807.
15) For ketocytochalasin, see: Wang, J.; Wang, Z.; Ju, Z.; Wan, J.;
(
Liao, S.; Lin, X.; Zhang, T.; Zhou, X.; Chen, H.; Tu, Z.; Liu, Y. Planta
Med. 2015, 81, 160−166.
The authors declare no competing financial interest.
(
16) For cytochalasin E, see: Buchi, G.; Kitaura, Y.; Yuan, S.-S.;
̈
ACKNOWLEDGMENTS
■
Wright, H. E.; Clardy, J.; Demain, A. L.; Glinsukon, T.; Hunt, N.;
The Laboratory of Asymmetric Catalysis and Synthesis is
established under the Cheung Kong Scholars Program of The
Ministry of Education of China. This work is supported in part
by the National Natural Science Foundation of China (Grand
No. 21172191). Mr. Jianming Gu of the X-ray crystallography
facility of Zhejiang University is acknowledged for the assistance
on crystal structural analysis.
Wogan, G. N. J. Am. Chem. Soc. 1973, 95, 5423−5425.
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(
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(
1
2
̈
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31) One reviewer suggested an interesting possibility of a directing
(
(
1
(
effect of C9-OH during the epimerization of C7-OH in 35. However, at
this stage there is no experimental evidence to support this proposal.
E
DOI: 10.1021/acs.orglett.8b04129
Org. Lett. XXXX, XXX, XXX−XXX