Stereocontrolled Total Syntheses of (?)-Rotenone and (?)-Dalpanol by 1,2-Rearrangement and SNAr Oxycyclizations

Article abstract of DOI:10.1002/anie.201609253

The total syntheses of (?)-rotenone and (?)-dalpanol have been achieved by a group-selective, stereospecific 1,2-shift of an epoxy alcohol and S_NAr cyclizations. Three oxacycles are constructed, thus illustrating a versatile synthetic route to various rotenoids.

Full text of DOI:10.1002/anie.201609253

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609253
German Edition: DOI: 10.1002/ange.201609253
Natural Products
Stereocontrolled Total Syntheses of (ꢀ)-Rotenone and (ꢀ)-Dalpanol
by 1,2-Rearrangement and S Ar Oxycyclizations
N
Kayo Nakamura, Ken Ohmori,* and Keisuke Suzuki*
In memory of Sankichi Takei
Abstract: The total syntheses of (ꢀ)-rotenone and
(
ꢀ)-dalpanol have been achieved by a group-selective, stereo-
specific 1,2-shift of an epoxy alcohol and S Ar cyclizations.
N
Three oxacycles are constructed, thus illustrating a versatile
synthetic route to various rotenoids.
R
otenoids constitute a class of isoflavonoids isolated from
various leguminous species. The generic name came from
[1]
rotenone (1), a historical natural product isolated as
a poisonous ingredient from Derris and Lonchocarpus
plants, traditionally used as a fish poison and insecticide
[
2]
(
Figure 1). The structure of 1 was determined in 1932 by
[3]
three independent groups, and synthetic endeavors culmi-
nated in the total syntheses, in racemic form, by Matsui in
[
4]
1
960, and in chiral, non-racemic form, by Yamashita in
[
5]
1
979. After a hiatus, synthetic interest has recently resurged
[6]
because of the discovery of novel bioactivities in rotenoids,
Scheme 1. Synthetic planning of rotenoids.
[7a,b]
including (ꢀ)-1 as well as (ꢀ)-dalpanol [(ꢀ)2]
and (ꢀ)-
[7c,8]
deguelin [(ꢀ)-3].
an aryl group, and stereoselective delivery of an aluminum
[
9]
ligand (R) gives the trans-product B. This strategy, however,
was not suitable for rotenoid synthesis (C), as a synthetic
ꢀ
equivalent to an umpoled synthon ( CH OH) is required and
2
must be installed from a cis direction.
To settle these issues, an idea surfaced from our previous
study of the 1,2-rearrangement-based strategy in natural
[11]
product synthesis. The reaction in Scheme 1b exemplifies
stereospecific conversion of the trans-epoxy alcohol D into
[
12]
the anti-aldol E (vice versa, cis!syn, not shown). Impor-
tantly, although D is a diastereomeric mixture at the
stereogenic center marked with an asterisk, exclusive 1,2-
migration of the vinyl group occurs, while the octyl group
remains intact, thus reflecting a large difference in their
migratory aptitudes (vinyl @ octyl). The conformational flex-
ibility allows both diastereomers of D to adopt their
respective reactive conformers, thus placing the vinyl group
antiperiplanar to the epoxide CꢀO bond to be cleaved upon
Figure 1. Natural rotenoids.
Herein, we describe the stereocontrolled total syntheses
of (ꢀ)-1 and (ꢀ)-2 by the selective 1,2-rearrangement of an
epoxy alcohol derivative and a threefold S Ar oxycyclization.
N
Scheme 1 shows how our synthetic plan has evolved, starting
with our recent synthetic access to isoflavonoids (Sche-
[
9]
me 1a), which was inspired by the biosynthetic flavo-
[10]
noid!isoflavonoid isomerization, including a 1,2-shift.
Lewis-acid activation to manifest a typical Curtin–Hammett
[13]
Activation of the catechin-derived mesylate A with an
system.
In addition, subsequent reduction of E allows
[
11c]
organoaluminum reagent effects stereospecific 1,2-shift of
control of three contiguous chiral centers in F,
which also
turned out to be relevant to the present project as discussed
below.
We envisioned a plan for the synthesis of rotenoids
starting from the cis-epoxy alcohol G which already has
[
*] Dr. K. Nakamura, Prof. Dr. K. Ohmori, Prof. Dr. K. Suzuki
Department of Chemistry, Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
a hydroxymethyl (CH OH) group installed (Scheme 1).
E-mail: kohmori@chem.titech.ac.jp
ksuzuki@chem.titech.ac.jp
2
Assuming stereospecificity, the 1,2-shift of a fluorophenyl
group in G would give the syn-aldol H, possessing a structural
feature ideally suited for constructing two tetrahydropyran
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609253.
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[
11]
rings by dual S Ar oxycyclizations to give the tetracycle I. In
the synthesis of catechin-class polyphenols, we had many
in the migratory aptitude (MA), where the stereochemistry
at the migrating origin (asterisked) is not consequential. In
the present case, however, both aryl groups share a similar
substitution pattern including an o-fluoro group, and thus,
their intrinsic MAs also appeared to be similar. Accordingly,
we had a premise that the conformational effect would play
an important role, and the identity of the tertiary alcohol
center, marked with an asterisk, would influence the reaction
course, although to an unknown extent.
N
[14]
successes with such S Ar cyclizations, which proved viable for
N
aryl fluorides without the aid of electron-withdrawing group-
(
s), such as the nitro. The key challenge was how to
discriminate between two similar aryl groups: the scenario
was that the blue one undergoes 1,2-shift to become the
A ring, while the red one the D ring, and not vice versa.
Scheme 2 shows the retrosynthesis of (ꢀ)-1. Assuming the
B- and C-pyran rings would be constructed by the S Ar
With these points in mind, our study began with the
preparation of the benzofuran 8, the DE-ring unit
(Scheme 4). Regioselective lithiation of 1,3-difluorobenzene
(4) followed by the addition of prenyl bromide gave the
isoprene 5 in 94% yield. The asymmetric Sharpless dihy-
droxylation, using (DHQD) PHAL as the ligand, gave the
(R)-diol 6 in 97% enantiomeric excess (97% yield). The
next stage was the first S Ar oxycyclization: Upon treatment
of 6 with NaH, cyclization to the five-membered ring, rather
than the six-membered ring, proceeded smoothly to give the
benzofuran 7 in quantitative yield. The tertiary alcohol in 7
was protected with a MOM group, giving 8 in 93% yield.
N
[
14]
oxycyclizations, the diol I, having two fluorophenyl units
corresponding to the A and D rings, was chosen as the
precursor. The aldol I could be traced back to the epoxy
[17]
[11]
alcohol II, assuming the 1,2-rearrangement.
The key
[18]
intermediate II would be assembled from the chiral, non-
racemic epoxy amide III, derived from diethyl l-(+)-tar-
2
[
19]
[
15]
[16]
trate, to which the A-ring unit IV and the DE-ring unit V
would be added. The furan ring (E-ring) in V would also be
N
cyclized by the S Ar reaction of the diol VI.
N
Scheme 4. Synthesis of the DE-ring fragment 8. Reagents and condi-
tions: a) nBuLi (1 equiv), HMPA (1 equiv), THF, ꢀ788C, 1 h; Me C=
2
CHCH
2
Br (1.1 equiv), ꢀ788C!RT, 2 h (94%). b) (DHQD)
2
PHAL
(
(
2 mol%), K OsO (OH) (1 mol%), K Fe(CN) (3 equiv), K CO
2 2 4 3 6 2 3
3 equiv), MeSO NH (2 equiv), tBuOH, H O, 08C, 120 h (97%, 97%
2
2
2
ee). c) NaH (3 equiv), DMF, RT, 5 h (quant.). d) MOMCl (10 equiv),
iPr NEt (20 equiv), nBu NI (20 mol%), CH Cl , RT, 24 h (93%).
2
4
2
2
(
DHQD) PHAL=1,4-bis-dihydroquinidine phthalazine, DMF=
2
dimethylformamide, HMPA=hexamethyl-phosphoric triamide,
MOM=methoxymethyl, THF=tetrahydrofuran.
With 8 in hand, we set out to prepare substrates for the
,2-rearrangement (Scheme 5). We arbitrarily installed the
Scheme 2. Retrosynthesis of (ꢀ)-1.
1
DE ring first, followed by the A ring, which led us to several
A critical question of this plan was the group selectivity in
interesting findings. The fluorobenzene 8 was lithiated and
[
20]
the 1,2-rearrangement, II !I (Scheme 3). The desired prod-
combined with the chiral, non-racemic epoxy amide 9, thus
a
a
[
16]
uct I is obtained by the 1,2-shift of the A ring (blue), whereas
giving epoxy ketone 10 in 72% yield. The bromide 11 was
subjected to bromine–lithium exchange and combined with
the ketone 10. The stereoselectivity at this stage was greater
than expected, thus giving the epoxy alcohol 12 (84% yield)
as a single product, whose stereochemistry was assigned as
a
the competing shift of the D ring (red) gives the isomeric
product I . As discussed previously, we had many examples to
b
show that such group selectivity is dictated by the difference
1
shown by H NMR analysis. The NOE correlation was
diagnostic, thanks to the restricted conformation resulting
[
21]
from the presence of hydrogen bonding.
The chelation
model A accounts for the stereochemical course of the
addition, where the access of the nucleophile from the right
side is blocked by the cis-substituent, thus leading to excep-
[
22]
tionally high selectivity.
The stage was set to examine the key 1,2-rearrangement
Scheme 3. Two competing 1,2-shifts.
of the epoxy alcohol 12 (Scheme 6). Upon treatment with
2
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Scheme 5. Synthesis of the epoxy alcohol 12. Reagents and conditions:
a) 8 (2 equiv), sBuLi (2 equiv), Et O, TMEDA (9:1), ꢀ788C, 1 h; 9
2
(
1 equiv), ꢀ788C, 30 min (72%). b) 11 (1 equiv), nBuLi (1 equiv),
Et O, ꢀ788C, 1 h; 10 (1 equiv), ꢀ78!ꢀ308C, 1 h (84%).
2
Scheme 6. 1,2-Shift-reduction sequence. Reagents and conditions:
a) BF ·OEt (20 mol%), CH Cl , 08C, 20 min. b) NaBH , MeOH, RT,
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
3
2
2
2
4
3
0 min (50%, 2 steps). c) p-MeOC H CH(OMe) (3 equiv), PPTS
6 4 2
(
30 mol%), CH Cl , RT, 3 h (51%). PPTS=pyridinium para-toluene-
2 2
BF ·OEt , 12 was consumed within 20 minutes (TLC analy-
sis). Since the aldol product 13 proved labile, as it decom-
3
2
sulfonate.
posed and/or epimerized, so the crude material was reduced
with NaBH to give the diol 14 as a single product (50%
Assuming 12a to be essentially the sole conformer
present, the D-ring (red) undergoes 1,2-migration, since it is
antiperiplanar to the CꢀO bond (green) which is cleaved
4
yield). Importantly, extensive NMR studies proved that 14
resulted from the 1,2-shift of the DE-ring unit (red), which
was unfortunately the wrong group selectivity.
Of additional importance, the above-stated process gave
us a hint for establishing the requisite stereochemical triad in
a single step. The stereochemistry of the three contiguous
chiral centers in 14 was assigned. By careful analysis of the
anisylidene acetal 15, derived from 14, it was proven that:
[
24]
upon Lewis-acid activation. Note that this interpretation
does not contradict the Curtin–Hammett principle, and just
corresponds to one of the prototypical categories, where both
conformers react at a similar rate (i.e., similar migratory
aptitudes), and the conformer ratio, virtually 100/0 in this
[25]
case, is reflected in the product distribution.
1
2
) the 1,2-shift occurred stereospecifically with inversion, and
) the reduction of the aldol product was stereoselective, as
This insight clearly guided us to change the order of
installing the A- and D-ring units in the preparation of the
substrate (Scheme 7). A bromine–lithium exchange reaction
of 11, followed by treatment with 9 gave the epoxy ketone 16
in 90% yield. The DE-ring unit 8 was lithiated as before, and
was reacted with 16 to give the epoxy alcohol 17 in 89% yield
as a single diastereomer. As expected, the stereochemistry of
17 proved to be epimeric to that of 12 by the NOE study.
Pleasingly, the key step proceeded perfectly: the reaction of
17 with BF ·OEt , followed by the reaction with NaBH , gave
[
11c,23]
rationalized by model B (Scheme 6).
Even though we obtained the undesired isomer, the
perfect group selectivity gave us significant insight. Figure 2
shows two hydrogen-bonded conformers of 12, where the
conformer 12b is disfavored by steric hindrance posed by the
cis-substituent R (= CH OTBS). The conformer 12a would
be highly populated, a hypothesis which was supported by
2
calculation on a simple model substrate (R = CH , and aryls =
C H ), showing an energy difference as large as 5.4 kcalmol .
3
3
2
4
ꢀ1
the diol 18 as a single isomer in 71% yield. Extensive NMR
studies ascertained that 18 was derived from the migration of
the A ring (blue). Further conversion of 18 into 19 (single
diastereomer, 89% yield) allowed the stereochemical assign-
6
5
1
ment by H NMR analysis.
To complete the synthesis, the acetal 19 was converted
into the pentacyclic rotenoid skeleton by two S Ar oxy-
N
cyclizations (Scheme 8). Upon treatment of 19 with nBu NF,
4
the TBS group was removed to give the alcohol 20 in 92%
yield, thus making it ready for the S Ar reaction. The initial
N
Figure 2. Rationale for the group selectivity.
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desired product 21 in 46% yield (run 1 in Table). The low
material balance was due to the competing benzylic depro-
tonation, thus inducing cleavage of the THF ring (C). Use of
a milder base, tBuOK, led to poor conversion with recovery of
a sizable amount of 20 (run 2). However, we were pleased to
find that the S Ar reaction was nicely facilitated by the
N
[
26]
addition of a catalytic amount of a nickel species, giving the
desired tetrahydropyran 21 in 86% yield (run 3). This
catalytic effect in the CꢀO bond formation will also be
[
27]
useful in the broader context of organic synthesis.
[
28]
Treatment of 21 with AlH3
allowed regioselective
reductive cleavage of the anisylidene acetal, giving the
alcohol 22 as a single isomer (79% yield). The last S Ar
N
oxy-cyclization of 22 proceeded smoothly under simple basic
conditions (NaH, 15-crown-5, toluene, DMPU, 808C) to give
the pentacycle 23 in 91% yield. The MPM group in 23 was
removed by hydrogenation to give the alcohol 24 in 64%
yield. Dess–Martin oxidation of 24 followed by removal of
the MOM group gave (ꢀ)-dalpanol [(ꢀ)-2] as colorless
needles in good yield {mp 199–2008C (benzene),
2
D
0
2
20
D
½
aꢁ ¼ꢀ1.1 ꢀ 10 (c = 0.52, CHCl ), [lit. 1968C, ½aꢁ ¼ꢀ136.3
3
[
7a]
(
c = 0.62, CHCl )]}. All the physical data of the synthetic
3
1
13
sample of (ꢀ)-2 ( H and C NMR, IR, high-resolution MS)
[
7a,b,29]
coincided with the reported data.
Finally, the conversion of (ꢀ)-2 into (ꢀ)-rotenone [(ꢀ)-1]
was examined. Treatment of (ꢀ)-2 with SOCl gave a mixture
2
of exo/endo olefins, from which (ꢀ)-rotenone [(ꢀ)-1] was
[30]
[31]
isolated in 40% yield.
By contrast, Burgessꢁ reagent
selectively gave (ꢀ)-1 in 50% yield. In this case, an
unexpected side product, the benzofuran derivative, was
obtained in 13% yield (see the Supporting Information),
presumably arising from a cation generated at the tertiary
carbon center followed by a 1,2-hydride shift. Recrystalliza-
tion afforded (ꢀ)-1 as colorless crystals {mp 153–1548C
Scheme 7. Isomeric-series conversions. Reagents and conditions:
a) 11 (1 equiv), nBuLi (1 equiv), Et O, ꢀ788C, 1 h; 10 (1 equiv),
2
ꢀ
788C, 1 h (90%). b) 8 (2 equiv), sBuLi (2 equiv), Et O, TMEDA (9:1),
2
ꢀ
788C, 1 h; 16 (1 equiv), ꢀ78!ꢀ308C, 1.5 h (89%). c) BF ·OEt
3
2
(
20 mol%), CH Cl , 08C, 15 min. d) NaBH , MeOH, RT (71%, 2
2
2
4
steps). e) p-MeOC H CH(OMe) (3 equiv), PPTS (20 mol%), CH Cl ,
6
4
2
2
2
RT, 4 h (89%).
Scheme 8. Endgame. Reagents and conditions: a) nBu NF (3 equiv), THF, RT, 1 h (92%). b) AlCl (3 equiv), LiAlH (2 equiv), CH Cl , Et O, 08C,
4
3
4
2
2
2
2
1
1
0 min (79%). c) NaH (3 equiv), 15-crown-5 (2 equiv), toluene, DMPU (9:1), 808C, 2 h (91%). d) H , 10% Pd/C (10 mol%), tBuOH, H O, RT,
2
2
5 h (64%). e) Dess–Martin periodinane (2 equiv), CH Cl , RT, 15 min. f) HCl aq., MeOH, 508C, 1.5 h (52–60%, 2 steps). g) SOCl , pyridine, 08C,
2
2
2
5 min (40%). h) Burgess’ reagent, toluene, reflux, 30 min (50%). Burgess’ reagent=methyl N-(triethylammoniumsulphonyl)carbamate,
DMPU=N,N’-dimethylpropyleneurea.
4
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2
D
3
2
(
1
benzene), ½aꢁ ¼ꢀ1.5 ꢀ 10 (c = 0.070, CHCl ), [lit. 165–
3829; b) K. Suzuki, T. Matsumoto, K. Tomooka, K. Matsumoto,
3
2
D
3
[5]
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Miyazawa, M. Shimazaki, G. Tsuchihashi, Tetrahedron 1988, 44,
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Am. Chem. Soc. 1996, 118, 8949 – 8950, and references therein.
12] If a TMS group was present on the vinyl group, the reduction
stereoselectivity was reversed, and was exploited in the stereo-
divergent syntheses of avenaciolide and isoavenaciolide (see
Ref [11c]).
668C, ½aꢁ ¼ꢀ177 (c = 2, CHCl )]}. All the physical data
3
1 13
of the synthetic sample of (ꢀ)-1 ( H and C NMR, IR, high-
resolution MS) also coincided with the reported data and
the synthetic material was identical to that of an authentic
[
5,32]
[
[33]
sample by direct comparison.
In conclusion, an effective synthetic approach to rotenoids
has been developed, and will be useful for the synthesis of
other congeners. Further studies are in progress in our
laboratory.
[
13] For Curtin – Hammett principle, see J. I. Seeman, Chem. Rev.
1
983, 83, 83 – 134.
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[
2
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Acknowledgements
10, 7685 – 7688; d) Y. Ito, K. Ohmori, K. Suzuki, Angew. Chem.
This work was supported by Grant-in-Aid for Specially
Promoted Research (No. 23000006, 16H06351, 16H01137
and 16H04107) from JSPS. We thank Mr. Seiya Matsuoka for
experimental assistance.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: cyclizations · heterocycles · natural products ·
rearrangements · total synthesis
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and subsequent direct condensation of the resulting potassium
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[
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Angew. Chem. Int. Ed. 2016, 55, 1 – 7
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Angewandte
Communications
Chemie
1
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intermolecular reactions: Unpublished results of Kayo Naka-
mura.
[
[
[
[
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to silica gel chromatography, thus leading to an impure material
contaminated by some degradation products.
Manuscript received: September 21, 2016
Revised: November 1, 2016
Final Article published: && &&, &&&&
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Natural Products
K. Nakamura, K. Ohmori,*
K. Suzuki*
&&&& — &&&&
Stereocontrolled Total Syntheses of (ꢀ)-
Rotenone and (ꢀ)-Dalpanol by 1,2-
Rearrangement and S Ar Oxycyclizations
N
Shifty approach: An approach to the
rotenoids is reported based on a stereo-
specific 1,2-shift of an epoxy alcohol
syntheses of the natural rotenoids, (ꢀ)-
rotenone and (ꢀ)-dalpanol, have been
achieved.
followed by S Ar oxycyclizations. The
N
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!