Synthetic studies toward penitrem E: Enantiocontrolled construction of B-E rings

Article abstract of DOI:10.1039/c4cc08505a

Enantiocontrolled construction of B-E rings of penitrem E was accomplished from 4-iodoindole in 13 steps with an overall yield of 1.7%. Diastereoselective Tf₂NH-catalyzed (2+2)-cycloaddition between silyl enol ether and methyl acrylate furnishe

Full text of DOI:10.1039/c4cc08505a

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Synthetic studies toward penitrem E:
enantiocontrolled construction of B–E rings†
Cite this: Chem. Commun., 2015,
51, 1070
Yu Yoshii, Takanori Otsu, Norihiko Hosokawa, Kiyosei Takasu,‡ Kentaro Okano and
Received 28th October 2014,
Accepted 19th November 2014
Hidetoshi Tokuyama*
DOI: 10.1039/c4cc08505a
www.rsc.org/chemcomm
Enantiocontrolled construction of B–E rings of penitrem E was eight-membered cyclic ether (A ring). Due to its highly fused
accomplished from 4-iodoindole in 13 steps with an overall yield cyclic structure, only Smith et al. have so far achieved the
of 1.7%. Diastereoselective Tf2NH-catalyzed (2+2)-cycloaddition enantiocontrolled total synthesis of (À)-penitrem D (2) via
between silyl enol ether and methyl acrylate furnished a tetracyclic [2+2]-photo-cycloaddition for the formation of the B ring.5
product possessing the characteristic cyclobutane ring bearing a Curran et al. also reported the construction of B–D rings of
hydroxyl group.
penitrem D (2) using a SmI2-mediated intermolecular radical
cascade reaction.6 On the other hand, synthetic studies toward
A family of indole diterpene alkaloids has attracted a great deal penitrems A (1) and E (3) having a hydroxyl group at the bridge-
of interest from the synthetic community because of their head of the B and C rings have not yet been reported. Recently,
biological activity and unique structure. Penitrems, isolated we developed a bis(triflic imide) (Tf2NH)-catalyzed smooth (2+2)-
from Penicillium cyclopium and Penicillium crustosum by the cycloaddition reaction of silyl enol ether to provide a fused-
Wilson and Steyn groups, possess strong neurotoxicity1 cyclobutane ring bearing a silyloxy group at the bridgehead
(Fig. 1). Compared with the structurally related indole diter- position (Scheme 1).7 The major diastereomer of the bicyclic
penes, such as paspalicine,2 paspalinine,2c,d,3 and paspaline,2a,b,4 compounds has the opposite relative configuration at the a-posi-
penitrems have a characteristic cyclobutane ring (B ring) and an tion of the methyl ester to that of the B/C ring in penitrems A and E;
however, we anticipated that the stereochemistry of this position
could be isomerized and initiated synthetic studies toward peni-
trem E utilizing our (2+2)-cycloaddition. Herein, we describe a novel
strategy for an enantiocontrolled synthesis of the left segment 4
including B–E rings of penitrem E (3) featuring a palladium-
catalyzed Catellani reaction8 and Tf2NH-catalyzed (2+2)-cyclo-
addition reaction.7
The retrosynthetic sequence in Scheme 2 demonstrates a stereo-
controlled construction of the B and C rings, having a hydroxy group
at the bridgehead position. To control the facial selectivity in the
C–C bond formation of a silyl enol ether and methyl acrylate, we
planned to use the stereochemistry of a hydroxymethyl moiety,
which is a synthetic equivalent of exo-methylene according
to Smith’s synthesis5 utilizing Grieco–Nishizawa elimination.9
Fig. 1 Penitrems and related alkaloids.
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki,
Aoba-ku, Sendai 980-8578, Japan. E-mail: tokuyama@mail.pharm.tohoku.ac.jp
† Electronic supplementary information (ESI) available: Experimental proce-
dures, compound characterization data, and copies of 1H and 13C-NMR spectra
for all new compounds. CCDC 1026313. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4cc08505a
Scheme 1 Tf2NH-catalyzed (2+2)-cycloaddition of silyl enol ether and
methyl acrylate.7c
‡ Current address: Graduate School of Pharmaceutical Sciences, Kyoto
University.
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Scheme 2 Retrosynthetic analysis of the left segment 4.
Scheme 4 Synthesis of the C ring by Catellani reaction.
The tertiary alcohol attached to the B ring would be derived
from ester 6 and two equivalents of methyl Grignard reagent,
and the indole could be synthesized from the protected indoline
through deprotection and subsequent oxidation. The cyclobutane
ring bearing the hydroxyl group would be constructed by the
Tf2NH-catalyzed (2+2)-cycloaddition of silyl enol ether 7 and
methyl acrylate.7 In this reaction, we expected that the hydro-
xymethyl side chain in the C ring should control the facial
selectivity. Silyl enol ether 7 would be derived from the corre-
sponding ketone, which should be prepared from unsaturated
ester 8 through oxidative cleavage of CQC. We planned to
construct the C ring from 4-iodoindoline derivative 9 and opti-
cally active e-iodo-unsaturated ester 10 by Catellani reaction,8 a
one-pot palladium-catalyzed ring formation in the presence of
norbornene.
Manipulation of oxygen functionalities provided mono-TIPS ether
14 in 90% ee.12 Appel iodination13 of the alcohol and subsequent
olefin cross metathesis with ethyl acrylate yielded ester 16.
With the e-iodo-unsaturated ester 16 in hand, we then examined
Catellani reaction for the construction of the C ring14 (Scheme 4).
The known 4-iodoindole (17)15 was converted to the corresponding
N-mesyl-4-iodoindoline (18) in a two-step sequence. Gratifyingly,
subjection of the indoline 18 and the optically active ester 16 to
the standard Catellani conditions8 provided the desired tricyclic
compound 19 (ref. 16) in 96% yield. Oxidative cleavage of the
trisubstituted electron-deficient olefin was effected by the combi-
nation of OsO4 and NaIO4 (ref. 17) to give tetralone 20 in good
yield,18 which was converted to TBS enol ether 21a for the
construction of the cyclobutane ring.
Having synthesized the requisite silyl enol ether, we then
investigated the construction of the B ring using Tf2NH-
catalyzed (2+2)-cycloaddition (Table 1). An aliquot of 80 mM
solution of Tf2NH in toluene was added to a mixture of 21a and
excess methyl acrylate (5 equiv.) in CH2Cl2 at À78 1C. After 3 days,
First, we prepared optically active ester 16 from readily available
1,3-diol 11,10 a coupling partner for Catellani reaction (Scheme 3).
The synthesis commenced with lipase-mediated desymmetrization
of meso-1,3-diol 11 at À15 1C to give monoacetate 12.11
Table 1 Substituent effects on Tf2NH-catalyzed (2+2)-cycloaddition
Time
Entry R1 Substrate X (d)
22a (%) cis-22 : trans-22 21 (%) 20 (%)
1
2
3
4
TBS 21a
TBS 21a
TMS 21b
TES 21c
5 3
3 7
5 3
5 3
43 (22a) 2.1 : 1.0b
3b
—
27b
30b
53b
18b
c
54 (22a) 2.0 : 1.0 f
d
d
e
e
—
—
—
—
19b
65b
a
b
c
Combined yield of cis- and trans-isomers. Isolated yield. Not
detected. Not isolated. Not determined. Calculated by 1H NMR.
d
e
f
Scheme 3 Preparation of unsaturated ester 16.
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Table 2 Effects of the protective group on indoline nitrogen
Time
Entry R2 Substrate X (d)
22a (%) cis-22 : trans-22 21 (%) 20 (%)
c
1
2
Ts 21d
Cbz 21e
5 3
5 3
56 (22b) 1.1 : 1.0d
46 (22c) 2.4 : 1.0d
—
4b
20b
20b
a
b
c
Combined yield of cis- and trans-isomers. Isolated yield. Not
detected. Calculated by 1H NMR.
d
the reaction was quenched with Et3N, and the mixture was
concentrated in vacuo, which was then purified to provide a
mixture of cyclobutane cis-22a and trans-22a. Interestingly, unlike
the previous report using the simple substrate (Scheme 1), the
reaction of 21a gave the desired diastereomer cis-22a (ref. 19) as a
major product even under the previously established conditions7
(Table 1, entry 1). Reduction of the catalytic amount of the triflic
imide required a prolonged reaction time but gave 22a in better
yield with the concomitant generation of tetralone 20 (Table 1,
entry 2). TMS enol ether 21b was more prone to form tetralone 20,
and none of the desired cyclobutane was isolated (Table 1, entry
3). On the other hand, TES enol ether 21c was robust but less
reactive under the conditions, resulting in 65% recovery of the
starting material 21c (Table 1, entry 4). We also found that the
choice of a protecting group on the nitrogen was also important
for the diastereoselectivity. Thus, tosyl amide 21d and Cbz
carbamate 21e were converted to the corresponding products
22b (cis-22b :trans-22b = 1.1 :1.0) and 22c (cis-22c :trans-22c =
2.4 : 1.0) (Table 2, entries 1 and 2).20
Scheme 6 Synthesis of the left segment 4.
on the less hindered face.7,21 The possible conformers A and B
in the second aldol reaction provided the corresponding cyclo-
butanes trans-22a and cis-22a. Steric repulsion of the methyl
ester and the indoline moiety disfavored chair-like conformer
A, thus providing cis-22a (via the favored boat-like conformer B)
as a major product.22 We attempted epimerization of trans-22a
to obtain cis-22a; however, the treatment of the undesired trans-
22a with either DBU in refluxing toluene or NaOMe in refluxing
MeOH did not afford the desired cis-22a.
We then turned our attention toward the synthesis of the left
segment 4 (Scheme 6). Addition of excess methyl Grignard reagent
followed by protection of the resulting alcohol as its TMS ether
provided the trisilylated compound 23. Deprotection of the mesyl
group using LDA smoothly proceeded to give the desired unpro-
tected indoline 24 in high yields,23 which was then treated with
MnO2 to afford the indole 25. Synthesis of the left segment 4 was
completed in a three-step sequence through Grieco–Nishizawa
elimination.9 Thus, after removal of three silyl groups under basic
conditions,24 the resultant triol 5, whose structure was confirmed
by X-ray crystallographic analysis in Fig. 2,25 was subjected to
selenation followed by oxidative elimination to provide the left
segment 4 while leaving the unprotected indole intact.
A plausible mechanism depicted in Scheme 5 would explain
the observed diastereoselectivity, which was opposite to that of
the former (2+2)-cycloaddition.7 First, Tf2N–TBS, generated
from Tf2NH, reacted as a Lewis acid to promote Mukaiyama-
type Michael addition of the silyl enol ether to methyl acrylate
Scheme 5 A plausible mechanism for the diastereoselectivity in (2+2)-
cycloaddition.
Fig. 2 X-ray crystallographic structure of triol 5.
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6 A. Rivkin, F. G.-L. de Turiso, T. Nagashima and D. P. Curran, J. Org.
Chem., 2004, 69, 3719.
In conclusion, we have established an enantiocontrolled
construction of B–E rings in penitrem E (3). Catellani reaction
facilitated the one-step formation of the C ring. The B ring
bearing a hydroxyl group was successfully constructed by our
Tf2NH-catalyzed (2+2)-cycloaddition, in which the desired
diastereomer was obtained as a major product.
This work was financially supported by the Cabinet Office,
Government of Japan, through its ‘‘Funding Program for Next
Generation World-Leading Researchers’’ (LS008), the JSPS
KAKENHI, and a Grant-in-Aid for Scientific Research (A)
(26253001) for H.T., a Grant-in-Aid for Scientific Research (C)
(25460003) and a Grant-in-Aid for Scientific Research on Inno-
vative Areas ‘‘Molecular Activation Directed toward Straight-
forward Synthesis’’ (25105705) for K.O., and JSPS predoctoral
fellowship and Tohoku University Campus Asia Project for Y.Y.
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24 Acidic treatment caused ring opening of the cyclobutane.
25 CCDC 1026313 5.
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