Total synthesis of (-)-13-oxyingenol and its natural derivative

Article abstract of DOI:10.1002/anie.201201383

Ring functionalization: The total synthesis of a natural derivative of (-)-13-oxyingenol, a potent anti-HIV diterpenoid, is reported. The key steps in this synthesis include a ring-closing olefin metathesis and a Mislow-Evans-type [2,3]-sigmatropic rearrangement. This synthesis provides access to (-)-13-oxyingenol and its natural derivative in 21 steps from a synthetic intermediate previously prepared by Kigoshi and co-workers. Copyright

Full text of DOI:10.1002/anie.201201383

Angewandte
Chemie
DOI: 10.1002/anie.201201383
Natural Product Synthesis
Total Synthesis of (ꢀ)-13-Oxyingenol and its Natural Derivative**
Takayuki Ohyoshi, Shota Funakubo, Yamato Miyazawa, Keisuke Niida, Ichiro Hayakawa, and
Hideo Kigoshi*
13-Oxyingenol derivative 1[1] and ingenol (4)[2] are diterpe-
noids isolated from the plants of Euphorbia sp. The main
structural features of ingenols are a bicyclo[4.4.1]undecane
skeleton with inside–outside intrabridgehead stereochemistry
and a high degree of oxygenation (Scheme 1). Ingenols and
Recently, we reported the construction of the fully
substituted tetracyclic inside–outside framework of 13-oxy-
ingenols.[10] We attempted the ring-opening reaction of an
epoxide to construct the allylic alcohol part of the B ring
under acidic, basic, or radical conditions (Scheme 2). How-
Scheme 2. Unsuccessful attempts to convert the epoxide into the
allylic alcohol in the previous synthetic studies. Bz=benzoyl,
TBS=tert-butyldimethylsilyl.
Scheme 1. Structures of 13-oxyingenols and ingenol.
ever, the desired ring-opened allylic alcohol could not be
obtained. Herein, we describe an improved synthetic route
and the first total synthesis of optically active (ꢀ)-13-oxy-
ingenol (3) and its natural derivative 1.
According to our retrosynthetic analysis of 13-oxyingenol
derivative 1 (Scheme 3), the B ring of 1 could be constructed
by a Mislow–Evans-type [2,3]-sigmatropic rearrangement of
a selenoxide that was generated from 5.[11,12] The A-ring part
at diol 5 can be established from tetracyclic ketone 6 by
a strategy similar to the one we used in our previous
their analogues show strong bioactivities, such as protein
kinase C activation.[3] Furthermore, related compounds, such
as RD4-2138 (2), have strong anti-HIV activity.[4] The unique
structures of ingenol derivatives along with their potent
biological activity have made them attractive targets for total
synthesis. Several synthetic studies, including total syntheses
of ingenol (4), have been reported.[5–8] However, the total
synthesis of 13-oxyingenols has not been reported to date,
despite the fact that 13-oxyingenol derivative 1 was isolated
over 30 years ago.[9]
[*] Dr. T. Ohyoshi,[+] S. Funakubo, Y. Miyazawa, K. Niida,
Dr. I. Hayakawa, Prof. Dr. H. Kigoshi
Department of Chemistry, Graduate School of
Pure and Applied Sciences, University of Tsukuba
1-1-1 Tennodai, Tsukuba 305-8571 (Japan)
E-mail: kigoshi@chem.tsukuba.ac.jp
[+] Research fellow of the Japan Society for the
Promotion of Science (JSPS).
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology (MEXT; Japan); by a grant from the Uehara Memorial
Foundation, and by a grant from the Suntory Institute for Bioorganic
Research (SUNBOR GRANT). We thank the Takasago International
Corp. for their gift of (S)-b-hydroxy g-butyrolactone. We would also
like to thank Prof. Daisuke Uemura (Kanagawa University) for
providing a sample of the 13-oxyingenol derivative and for his
helpful discussion.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201383.
Scheme 3. Retrosynthetic analysis of 13-oxyingenol derivative 1.
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synthesis.[10] Tetracyclic ketone 6 would be synthesized by
using an aldol reaction between spiro ketone 8 and aldehyde
9,[11] followed by the ring-closing olefin metathesis (RCM) of
7. In this work, we introduced two hydroxy groups at C2 and
C7, and used them to introduce the requisite functional
groups at the A- and B-ring parts.
Table 1: Ring-closing olefin metathesis of dienes 13–15.
The synthesis started with the preparation of the optically
active spiro ketone 8 (Scheme 4). We synthesized 8 in racemic
Entry
Precursor of RCM
Catalyst
Yield [%]
1
2
3
4
5
13
14
14
14
15
19
19
20
21
19
54 (16)
64 (17)
51 (17)
0 (17)
86 (18)
1
determined by H NMR analysis (see the Supporting Infor-
mation). Under these RCM conditions, a small amount of
spiro ketone 8 was obtained because a retro-aldol reaction
occurred. Thus, we next investigated the RCM of acetate 14
by screening an assortment of Ru catalysts (entries 2–4). The
reaction with the second-generation Hoveyda–Grubbs cata-
lyst (19) gave 7-acetoxy tetracyclic ketone 17 in 64% yield
(entry 2). Use of highly active Ru catalyst 20[15] in this reaction
afforded 7-acetoxy tetracyclic ketone 17 (entry 3). However,
the reaction was not as successful as expected and the yield of
product 17 was moderate. Treatment of acetate 14 with the
less hindered Ru catalyst 21[16] (Stewart–Grubbs catalyst) did
not result in the formation of 7-acetoxy tetracyclic ketone 17.
Next, we tried this cyclization with a,b-unsaturated ketone 15,
in which the reactivity of one olefin is different and the steric
hindrance of the cyclization is lowered. The reaction of a,b-
unsaturated ketone 15 with Hoveyda–Grubbs catalyst 19
proceeded smoothly to give the desired 7-keto tetracyclic
ketone 18 in 86% yield (entry 5). It is noteworthy that no
epimerization of b-diketone moiety in 15 and 18 was
observed.
Scheme 4. Syntheses of precursors of ring-closing olefin metathesis.
Reagents and conditions: a) 1) 11, Cs2CO3, DMSO, 508C; 2) chroma-
tographic separation, 12a: 45%, 12b: 46%; b) 9, NaHMDS, THF,
ꢀ788C; c) Ac2O, pyr, DMAP, 508C, 83% (2 steps); d) Dess–Martin
periodinane, CH2Cl2, RT, 81% (2 steps). Ac=acetyl, DMAP=4-dime-
thylaminopyridine, DMSO=dimethyl sulfoxide, MPM=p-methoxyphe-
nylmethyl, NaHMDS=sodium bis(trimethylsilyl)amide, pyr=pyridine,
THF=tetrahydrofuran.
form in our previous work, in which we found that alkylated
compounds 12a and 12b could be easily separated chromato-
graphically. Thus, the racemic keto ester 10 was alkylated with
optically active iodide 11[13] to give alkylated compounds 12a
and 12b as single stereoisomers that were separated by silica
gel chromatography. Optically active compound 12a was
converted into spiro ketone 8 in the same manner as in our
previous work.[10] With optically active spiro ketone 8 in hand,
we then prepared the precursors for the RCM. The aldol
reaction between spiro ketone 8 and unsaturated aldehyde 9
gave aldol 13 as a single diastereomer.[11] The stereochemistry
at C7 in 13 was determined by 1H NMR analysis of the
corresponding 7-hydroxy tetracyclic ketone 16 (see Table 1
and the Supporting Information). Aldol 13 was converted into
acetate 14 and a,b-unsaturated ketone 15 as the precursors of
RCM.
We next attempted the functionalization of the A and
B rings in 13-oxyingenol derivative 1 (Scheme 5). Reduction
of the carbonyl group at C7 in compound 18 gave allylic
alcohol 16 as a single diastereomer. Mesylation of alcohol 16
by the method described by Tanabe and co-workers[17]
afforded mesylate 22, and the introduction of a phenyl selenyl
group with a selenide anion generated from (PhSe)2 and
NaBH4 gave selenide 6. The stereochemistry of selenide 6 was
1
determined by H NMR analysis (see the Supporting Infor-
We next examined the crucial construction of the inside–
outside framework of 13-oxyingenol by RCM (Table 1). RCM
of 13 with the second-generation Hoveyda–Grubbs catalyst
(19)[14] gave 7-hydroxy tetracyclic ketone 16, but the yield was
moderate (54%; entry 1). The stereochemistry of 16 was
mation). The removal of both MPM groups in selenide 6 and
subsequent selective protection of the primary hydroxy group
afforded alcohol 24. The remaining secondary hydroxy group
at C2 in alcohol 24 was oxidized by Parikh–Doering
oxidation[18] to give diketone 25. Substrate 25 was trans-
2
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formed into enone 26 by using the Ito–Saegusa oxidation.[19]
Enone 26 was converted into enol triflate 27, which was
subjected to a Negishi coupling[20] to afford triene 28. Regio-
and stereoselective dihydroxylation of triene 28 with a stoi-
chiometric amount of OsO4 gave diol 5. The high regio- and
stereoselectivity could be explained by considering that steric
hindrance at the C11 methyl group shielded the olefin at C1/
C2, and that the strain and pyramidal distortion of the olefin
at C3/C4 enhance its reactivity (see the Supporting Informa-
tion). The phenyl selenyl group was not affected during the
conversion of selenide 6 into diol 5 under different oxidizing
conditions, including the use of DDQ, Parikh–Doering
oxidation, and OsO4. The introduction of the hydroxy group
at C5 by using a Mislow–Evans-type rearrangement was next
attempted. The oxidation of the aromatic selenide group in 5
with mCPBA and subsequent [2,3]-sigmatropic rearrange-
ment with P(OMe)3 afforded triol 29. The removal of both
TBS groups in 29 afforded 13-oxyingenol (3), a parent
compound of 13-oxyingenol derivatives, such as 1. 13-oxy-
ingenol (3) was protected as two acetonide groups to afford
compound 30. Acylation of the remaining tertiary hydroxy
group at C13 gave dodecanoyl ester 31. Hydrolysis of two
acetonides with aqueous HCl, followed by selective acylation
of the primary hydroxy group, led to the formation of 13-
oxyingenol derivative 1. The spectral data of synthetically
obtained 13-oxyingenol derivative 1 (1H NMR, 13C NMR,
HRMS) were in full agreement with those of the natural
23
product. The optical rotation of 1 (½aꢁD ¼ꢀ25.0 (c = 0.10,
CHCl3)) was in good agreement with that of the isolated
23
sample (½aꢁD ¼ꢀ24.6 (c = 0.17, CHCl3)).
In conclusion, we have achieved the first total synthesis of
(ꢀ)-13-oxyingenol (3) and its natural derivative 1 in 21 steps
from spiro ketone 8. The presence of the hydroxy groups at
C2 and C7 enables the efficient functionalization of the A and
B rings. The highlights of this approach are the use of an RCM
for the construction of an inside–outside framework and
a Mislow–Evans-type [2,3]-sigmatropic rearrangement for the
introduction of a hydroxy group at C5. This synthetic strategy
is also applicable to the synthesis of ingenol (4) and more
concise than the method we used in our previous work.[6]
Scheme 5. Total synthesis of 13-oxyingenol derivative 1. Reagents and
conditions: a) DIBAL, toluene, ꢀ788C, 96%; b) MsCl, Me2N-
(CH2)3NMe2, toluene, 08C; c) (PhSe)2, NaBH4, THF/EtOH, RT, quant.
(2 steps); d) DDQ, pH 6.6 phosphate buffer, tBuOH/CH2Cl2, RT,
quant.; e) TBSCl, Et3N, DMAP, CH2Cl2, RT, 97%; f) SO3·pyr, DMSO,
Et3N, CH2Cl2, RT, quant.; g) TMSCl, LHMDS, Et3N, THF, ꢀ788C;
h) Pd(OAc)2, DMSO, RT, 64% (2 steps); i) Tf2NPh, LHMDS, THF,
ꢀ408C; j) Me2Zn, Pd(PPh3)4, THF, RT; k) OsO4, THF/pyr, 08C, then
aq. NaHSO3, RT, 64% (3 steps); l) mCPBA, THF, ꢀ788C; m) P(OMe)3,
MeOH, 08C, 61% (2 steps) (borsm quant.); n) HF·pyr, THF/pyr, RT,
quant.; o) 2,2-dimethoxypropane, PPTS, CH2Cl2, RT; p) C11H23CO2H,
EDCI, DMAP, CH2Cl2, RT, 63% (2 steps); q) HCl (1m), THF, RT, 99%;
r) (C5H11CO)2O, Et3N, CH2Cl2, ꢀ208C, 85%. borsm=based on recov-
ered starting material, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none, DIBAL=diisobutylaluminum hydride, DMSO=dimethyl sulfox-
ide, EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlo-
ride, LHMDS=lithium bis(trimethylsilyl)amide, mCPBA=m-chloroper-
benzoic acid, Mes=2,4,6-trimethylphenyl, Ms=methanesulfonyl, o-
Tol = o-tolyl, PPTS=pyridinium p-toluenesulfonate, Tf=trifluorometha-
nesulfonyl, TMS=trimethylsilyl.
Received: February 20, 2012
Published online: && &&, &&&&
Keywords: 13-oxyingenol · inside–outside framework ·
.
metathesis · sigmatropic rearrangement · terpenoids
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[6] For a total synthesis of ingenol, see: a) J. D. Winkler, M. B.
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Communications
Natural Product Synthesis
T. Ohyoshi, S. Funakubo, Y. Miyazawa,
K. Niida, I. Hayakawa,
H. Kigoshi*
&&&& — &&&&
Total Synthesis of (ꢀ)-13-Oxyingenol and
its Natural Derivative
Ring functionalization: The total synthe-
sis of a natural derivative of (ꢀ)-13-
oxyingenol, a potent anti-HIV diterpe-
noid, is reported. The key steps in this
synthesis include a ring-closing olefin
metathesis and a Mislow–Evans-type
[2,3]-sigmatropic rearrangement. This
synthesis provides access to (ꢀ)-13-oxy-
ingenol and its natural derivative in 21
steps from a synthetic intermediate pre-
viously prepared by Kigoshi and co-
workers.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!