Synthesis of ent-kaurane and beyerane diterpenoids by controlled fragmentations of overbred intermediates

Article abstract of DOI:10.1002/anie.201304609

Efficient access to minimally oxidized members of the ent-kaurane and beyerane class of terpenes has been achieved by using a polyene cyclization precursor designed to directly yield oxidation at the axial C19-methyl group. Construction of the [3.2.1]bicyclic system found in the ent-kaurane skeleton was realized with two overbred intermediates. Wagner-Meerwein rearrangement of the [3.2.1]bicyclic system yields the beyerane skeleton of isosteviol. Copyright

Full text of DOI:10.1002/anie.201304609

Angewandte
Chemie
Communications
Total Synthesis
E. C. Cherney, J. C. Green,
P. S. Baran*
&&&& — &&&&
Synthesis of ent-Kaurane and Beyerane
Diterpenoids by Controlled
Fragmentations of Overbred
Intermediates
Efficient access to minimally oxidized
members of the ent-kaurane and beyer-
ane class of terpenes has been achieved
by using a polyene cyclization precursor
designed to directly yield oxidation at the
axial C19-methyl group. Construction of
the [3.2.1]bicyclic system found in the ent-
kaurane skeleton was realized with two
overbred intermediates. Wagner–Meer-
wein rearrangement of the [3.2.1]bicyclic
system yields the beyerane skeleton of
isosteviol.
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DOI: 10.1002/anie.201304609
Total Synthesis
Synthesis of ent-Kaurane and Beyerane Diterpenoids by Controlled
Fragmentations of Overbred Intermediates**
Emily C. Cherney, Jason C. Green, and Phil S. Baran*
Dedicated to R. W. Hoffmann on the occasion of his 80th birthday
The ent-kauranes present highly varied oxidation patterns (3,
4; Figure 1A), undergo intriguing skeletal rearrangements,
and possess antibacterial, antitumor, and antimalarial activ-
ity.[1] These attributes make ent-kauranes interesting candi-
dates for two-phase terpene total synthesis.[2] Steviol (1) was
chosen as the lowest oxidized logical target due to the known
conversion of such structures into beyeranes[3] (isosteviol, 2)
and the useful functionality present for an “oxidase phase.”
The first total synthesis reported by Mori et al. provides
steviol (1) in 35 steps and 0.013% overall yield.[4a,b,c] A 19-step
synthesis of steviol methyl ester was reported subsequently by
Ziegler and Kloek, but it relied on a key step that gave only
a 3% yield of the [3.2.1]bicyclic system and 0.015% overall
yield.[4d] An elegant approach to isosteviol (2) was reported by
Snider et al. in 13–18 steps, 0.37–1.2% overall yield.[5] Con-
version of isosteviol (2) into steviol (1), however, is unknown.
Herein, an efficient synthesis of (Æ)-steviol (1) is presented.
In 2009, Hoffmann formalized the concept of “overbred
intermediates” in synthesis design as intermediates having
are not adequately addressed by known approaches (Fig-
ure 1C). Radical-mediated methods give the undesired ortho-
methoxy product.[10] C H activation reactions directed from
À
C3 preferentially oxidize the C18-methyl group.[11,12] Cycliza-
tions initiated from a terminal epoxide (i.e. 10, Scheme 1)
À
one or more excess C C bonds that must be subsequently
cleaved.[6] The route to the [3.2.1]bicyclic system of steviol (1)
relies on the controlled fragmentation of two overbred
intermediates. Cyclopropane 5 (Figure 1B) would require
À
À
preferential cleavage of the C12 C16 bond over the C12 C13
bond. Such a fragmentation would be ambitious because
these two bonds appear to be nearly indistinguishable.[7]
Indeed, a similar system fragmented with only modest
diastereoselectivity (2:1).[4c] Cyclobutane 6 would then arise
from a [2+2] photocycloaddition with allene. This strategy
should install a very hindered quaternary center with high
diastereoselectivity.[8] It is known that strained cyclobuta-
nones in similar systems will open upon nucleophilic attack to
[9]
À
break the analogous C13 C14 bond.
Tricyclic system 7 presents a challenge when the issues of
stereo- and regioselectivity are considered. In particular, the
required axial C19-methyl oxidation and para regioselectivity
[*] E. C. Cherney,[+] Dr. J. C. Green,[+] Prof. Dr. P. S. Baran
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: pbaran@scripps.edu
[+] These authors contributed equally to this work.
[**] Financial support for this work was provided by an unrestricted
grant from TEVA, the NIH (GM097444-03), and NSF (a predoctoral
fellowship to E.C.C). We are grateful to Prof. A. Rheingold and Dr.
C. E. Moore (UCSD) for X-ray crystallographic analysis.
Figure 1. A) Truncated oxidation pyramid for ent-kauranes and beyer-
anes. B) Cyclase-phase retrosynthetic strategy. C) Polycyclization meth-
ods for installation of C18 or C19-methyl group oxidation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304609.
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Scheme 1. Total synthesis of (Æ)-steviol (1). Reagents and conditions: a) LiNEt2 (3 equiv), THF, 608C, 2 h (92%); b) [VO(acac)2] (0.25 equiv),
tBuOOH (5m in decane) (1.6 equiv), benzene, 68C, 2 h (74% or 83% BRSM); c) CBr4 (3 equiv), PPh3 (2.9 equiv), iPr2NEt (3.3 equiv), CH2Cl2,
À108C, 12 h (81%); d) NaOtBu (2.4 equiv) benzyl alcohol (solvent), 1008C, 3 h (92%); e) FeCl3 (2 equiv), CH2Cl2, RT, 3 h (52%); f) Li0
(50 equiv), NH3, THF; tBuOH, À788C to À458C, 2 h; 4m HCl in dioxane, RT, 30 min (79%); g) DEAD (5 equiv), PPh3 (5 equiv), THF, 708C, 5 h
(91%); h) H2, Pd/C (10 wt%; 10 mol%), EtOAc, RT, 7 h (93%); i) allene, CH2Cl2, RT, 450 W Hg lamp, pyrex, 12 h (82%); j) O3, MeOH, À788C,
5 min; Me2S, RT, 30 min; AcOH/PPA (9:1), 1108C, 12 h (62%); k) HCl(g), Ac2O (solvent), act. Zn0 (60 equiv), 08C, 45 min; l) AcCl (3m in
MeOH), 0–68C, 12 h (79% 18 and 11% 17); m) PPh3 (6.6 equiv), [RhCl(PPh3)3] (5 mol%), THF, iPrOH; TMSCHN2 (20 equiv), 48 h (63%);
n) PDC (5 equiv), DMF, RT, 18 h, (92%); o) NaClO2 (6 equiv), NaH2PO4 (10 equiv), 2-methyl-2-butene (10 equiv), THF/tBuOH, 08C to RT, 16 h
(85%). acac=acetylacetonate, BRSM=based on recovered starting material, DEAD=diethyl azodicarboxylate, PPA=polyphosphoric acid,
PDC=pyridinium dichromate, DMF=N,N-dimethylformamide, TMS=trimethylsilyl.
provide oxidation on the equatorial C18-methyl group.[13]
Consequentially, a unique cyclization precursor (8) was
designed with the following considerations: 1) the polycycli-
zation should be Lewis acid initiated (rather than radically
initiated) to give the correct para regioselectivity; 2) the
epoxide should be internal (rather than terminal) to give the
required C19 oxidation;[13] and 3) the Z stereochemistry of
this internal epoxide is imperative to give C19 oxidation.[14]
The pursuit of cyclization precursor 8 began from epoxide
9 (see Scheme 1). Elimination to open epoxide 9 followed by
vanadium-directed epoxidation gave the erythro product 10 in
68% overall yield (5.3 gram scale). The secondary alcohol in
10 was inverted to give the threo bromide 11 in 81% yield
(7.2 gram scale). Nucleophilic addition of benzyloxide to
open the epoxide followed by closure of the bromohydrin
provided the cyclization precursor 8 (7.1 gram scale). The
polycyclization was most efficiently effected by iron trichlor-
ide to give tricyclic system 12 (1.1 gram scale). Compound 12
was converted into crystalline enone 13 by Birch reduction/
deprotection and isomerization. X-ray analysis confirmed the
para regiochemistry, the crucial C19 axial methyl group
oxidation, and the correct stereochemistry at the C9-methine
group.
formed the hindered C8 quaternary center in overbred
cyclobutane 6 (1.1 gram scale).[8] The formation of this
overbred intermediate was strategic because all other
attempts to form this quaternary center failed, including:
copper-, indium-, and tin-mediated 1,4-additions, Sakurai and
Keck allylations, as well as intramolecular bond formations
through sigmatropic rearrangements. Cyclobutane 6 was
transformed to 15 in a one-pot sequence (1.0 gram scale):
ozonolysis, selective fragmentation with methanol to give the
methyl ester, and finally acid-mediated condensation to forge
the [2.2.2]bicyclic system.[9]
Reductive cyclopropanation of 15 would generate an
overbred cyclopropanediol (16), which could undergo diver-
À
À
gent fragmentation pathways: C12 C13 cleavage or C12 C16
cleavage to give 17 or 18, respectively. Mori et al. treated
a similar system with Zn(Hg) amalgam in 6m HCl/toluene at
1108C for 1 h to get a 2:1 ratio in favor of the analogous
desired isomer in 41% yield.[4c] Treatment of diketone 15 with
these conditions for 45 min gave only the undesired isomer 17
in 26% yield (see Table 1, entry 1). Encouragingly, when the
reaction was stopped after 5 min, a 2.2:1 ratio in favor of the
desired isomer 18 was observed (entry 3). Moreover, the
desired product 18 was found to rearrange to the undesired
isomer 17 under acidic conditions (Scheme 2A). It seemed
that Moriꢀs conditions were unsuitable due to the high
temperatures, which caused the desired kinetic isomer (18)
to rearrange to the thermodynamic isomer (17). Under the
Next, the neopentyl alcohol was eliminated, followed by
hydrogenation to furnish compound 7 (2.1 gram scale). Birch
reduction and isomerization proceeded to give enone 14
(1.3 gram scale). Allene [2+2] photocycloaddition with 14
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Table 1: Attempts at conversion of 15 or 5 into 18.
rearranged material or gave no reaction, respectively. A
modified Wittig procedure proceeded to give olefin 19,[16]
which was oxidized to give (Æ)-steviol (1) in 17 steps from
geranyl acetate.[17] Acid-induced rearrangement of steviol (1)
provided isosteviol (2; Scheme 2C). Alternatively, compound
19 could first be rearranged to the beyerane skeleton followed
by Jones oxidation to provide isosteviol (2) in 17 steps
(Scheme 2D).
To summarize, a synthetic route that offers efficient access
to minimally oxidized members of the ent-kaurane and
beyerane class of terpenes has been developed. This route
could conceptually be rendered enantioselective.[18] The
challenging axial C19 oxidation and [3.2.1]bicyclic motifs
prompted a reevaluation and strategic modification of
literature precedent. The first challenge was addressed with
a unique polycyclization precursor (8) while the second
necessitated the use of overbred intermediates (6 and 5) and
their controlled fragmentations. Such strained intermediates
enabled and simplified the overall synthetic route. The
completion of this cyclase phase sets the stage for an in-
depth study of the oxidation chemistry of these complex
terpenes.
Entry Conditions
Yield Yield
Ratio 18/
17
18
17
1
2
3
15, Zn(Hg), 6m HCl, PhMe, 1108C, 0%
45 min
15, Zn(Hg), 6m HCl, PhMe, 1108C, 13%
30 min
26%
0:1
9%
1.4:1
2.2:1
15, Zn(Hg), 6m HCl, PhMe, 1108C, 24%
11%
5 min
4
5
15, act. Zn0, HCl in Et2O, 08C, 15 m
5, AcCl, MeOH, 0–68C, 12 h
–
79%
trace
11%
–
7.2:1
reaction conditions, the ketones in products 17 and 18 likely
undergo further reduction. Attempts to run this reaction at
lower temperature with activated zinc led to decomposition,
with trace formation of 17 (entry 4).
To overcome these issues, cyclopropane diol 16 was
trapped as diacetate 5.[15] This would allow for fragmentation
at low temperatures, thereby avoiding isomerization of
kinetic product 18 to thermodynamic product 17. It would
also avoid over-reduction. Treatment of 5 with methanolic
HCl at 0–68C gave 18 and 17 in 79% and 11% yield,
respectively (greater than 7:1 ratio; entry 5). Undesired
isomer 17 can also be recycled to 15 (Scheme 2B).
Received: May 28, 2013
Revised: June 20, 2013
Published online: && &&, &&&&
Keywords: beyerane · diterpenes · ent-kaurane ·
.
overbred intermediates · total synthesis
With suitable quantities of 18 in hand, installation of the
methylene group was attempted (Scheme 1). While the Wittig
olefination of a similar substrate has been reported,[4a,c] this
procedure as well as salt-free variations either yielded
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Scheme 2. Reagents and conditions: a) 12m HCl, PhMe, 1108C,
30 min (79%); b) CAN (3 equiv), MeCN, 08C, 10 min; c) PPA, AcOH,
1108C, 12 h (72% over 2 steps); d) HBr (48% aq) Et2O, RT, 15 h
(90%); e) HBr (48% aq) Et2O, RT, 18 h (87%); f) CrO3 (10 equiv),
acetone, 08C to RT, 3 h (81%). CAN=cerium ammonium nitrate.
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