Total synthesis of (-)-Jiadifenin

Article abstract of DOI:10.1002/anie.201203176

As easy as ABCD: (-)-Jiadifenin was synthesized in eighteen reaction steps from 1-[(E)-(4′-bromo-2′-butenyl)oxy]-4-methoxybenzene. Key features of this synthesis include: 1) Ireland-Claisen rearrangement to produce the two contiguous quaternary centers at

Full text of DOI:10.1002/anie.201203176

Angewandte
Chemie
DOI: 10.1002/anie.201203176
Natural Product Synthesis
Total Synthesis of (ꢀ)-Jiadifenin**
Yang Yang, Xingnian Fu, Jianwei Chen, and Hongbin Zhai*
Dedicated to Professor Matthew S. Platz on the occasion of his birthday
A growing number of the world population suffer from
neurodegenerative disorders, such as Alzheimerꢀs, Hunting-
tonꢀs, and Parkinsonꢀs diseases, as a result of the increased
[
1]
longevity of the population. Over the past few decades,
polypeptidyl neurotrophic factors have played an important
[1b,2]
role in mediating neuronal survival and outgrowth.
However, as a result of the intrinsic unfavorable pharmaco-
kinetic properties of polypeptidyl neurotrophic agents, non-
peptidyl CNS-permeable small-molecule neurotrophins are
emerging as attractive alternatives.
In 2002, jiadifenin (1, Scheme 1) was isolated from the
pericarps of Illicium jiadifengpi and characterized as a novel
nonpeptidyl neurotrophic modulator, which prominently
promoted neurite outgrowth in primary cultures of fetal rat
[
3]
cortical neuronal cells at concentrations of 0.1 ~ 10 mm. This
highly oxygenated sesquiterpene features a unique seco-
prezizaane-type skeleton (A and B rings) decorated with
a fused g-lactone (C ring) and a bridged cyclic hemiacetal
(
D ring). Densely imbedded in the framework of this compact
cage-shaped molecule are six stereocenters, including two
separate all-carbon quaternary centers (C5 and C9) and two
oxo-functionalized quaternary ones (C6 and C10). The
impressive structural complexity together with the potential
therapeutic value for neurodegenerative diseases has ren-
dered 1 as an attractive target for synthetic studies. Note-
worthy accomplishments include the total syntheses by the
Scheme 1. Retrosynthetic analysis for (ꢀ)-jiadifenin. SADH=Sharpless
asymmetric dihydroxylation, TBS=tert-butyldimethylsilyl.
[
4]
[5]
groups of Danishefsky and Theodorakis with a ring-
construction sequence of B!AB!ABC!ABCD and of
A!AB!ABC!ABCD, respectively. In addition, a syn-
thetic exploration was reported by Fukuyama and co-work-
including regio- and stereoselective [2+2] photo-cycloaddi-
[7]
tion of 4 with allene (4!3), ozonolysis and regioselective
[
7b,c]
1,3-dione b-fragmentation
(3!2), and A-ring dehydro-
[
6]
ers. Herein, we wish to describe a novel enantioselective
total synthesis of jiadifenin (1).
genation followed by oxidative D-ring formation (2!1),
while the 6/5 fused-ring system in 4 may be installed by
a strategic intramolecular Pauson–Khand reaction (IMPKR,
As outlined in Scheme 1, we envisioned that jiadifenin (1)
may be accessible through a series of transformations
[
8]
5!4). Enyne 5 may be generated from a stereoselective
[
9]
Ireland–Claisen rearrangement of (Z)-6 followed by desi-
lylation and lactonization, which may establish the two
contiguous quaternary centers (C5 and C6, referring to the
numbering system for 1). The (Z)-6 ester may be enantio-
selectively synthesized from readily accessible starting mate-
rials by the Sharpless asymmetric dihydroxylation
[
*] Dr. Y. Yang, Dr. X. Fu, Dr. J. Chen, Prof. Dr. H. Zhai
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
[
10]
Prof. Dr. H. Zhai
(SADH). Overall, the current strategy is characterized by
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
E-mail: zhaih@lzu.edu.cn
a new ring-construction sequence, that is, C!ABC!ABCD.
Our synthesis commenced with the coupling of allylic
[10c]
bromide 7
with lithiated propyne to give enyne 8 (74%).
[
**] We thank the National Basic Research Program of China (973
Program: 2010CB833200),the NSFC (21172100), the Program for
Changjiang Scholars and Innovative Research Team in University
[10a,c]
Asymmetric dihydroxylation
of 8 in the presence of AD-
mix-b provided diol 9 (95% yield, > 93% ee) with the desired
configuration at the C7-position (Scheme 2).
(
PCSIRT: IRT1138), and “111” Program of MOE for financial
support.
At this stage, the choice of an appropriate protecting
group of the two vicinal hydroxy groups of 9 proved to be
critical for the success of the Ireland–Claisen rearrangement
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203176.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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1
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Scheme 2. Synthesis of esters (Z)-6 and (E)-6: a) 1-bromo-1-propene,
nBuLi, CuI, THF, ꢀ788C to RT, 74%; b) AD-mix-b, MeSO NH ,
Scheme 3. Ireland–Claisen rearrangement of (Z)-6 and (E)-6 and the
2
2
subsequent lactonization: a) LDA, TMSCl, THF, ꢀ788C to RT to reflux;
tBuOH/H O (1:1), 08C, 95%, >93% ee; c) KOH, CH I , [18]-crown-6,
.
2
2
2
b) TsOH H O, MeOH, reflux. LDA=lithium diisopropylamide, R=2-
2
CH Cl , reflux, 80%; d) CAN, MeCN/H O (2.5:1), 90%; e) Jones
2
2
2
butynyl, TMS=trimethylsilyl.
reagent, acetone, ꢀ788C to RT; f) DCC, DMAP, (Z)-11, THF, RT, 70%
for 2 steps; g) DCC, DMAP, (E)-11, THF, RT, 56% for 2 steps.
DCC=dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine,
Jones reagent=CrO in diluted H SO , PMP=4-methoxyphenyl,
3
2
4
13a, as a major product via a preferred chair-like transition
state (TS-1), while the minor product (13b) arose from the
less-favored twist-boat-like transition state (TS-2) in the
rearrangement step. Note that intermediate 13a contains two
contiguous quaternary centers at C5 and C6 with correct
configurations, which were controlled by the stereochemistry
at C7 of (Z)-6. In comparison with the case of (Z)-6, enyne
TBS=tert-butyldimethylsilyl.
of an ester such as (Z)-6. Preliminary studies showed that
when subjected to a base such as LDA, ester 12a (having
a cyclic carbonate unit) underwent a b-elimination, followed
by loss of a molecule of CO rather than a [3,3] sigmatropic
[
14]
13b was produced as the sole product from (E)-6 upon the
Ireland–Claisen rearrangement (via chair-like transition state
TS-3) and the subsequent lactonization, thus indicating that
the twist-boat-like TS-4 essentially had no contribution to the
reaction outcome. Furthermore, the presence of a more
2
,
rearrangement. Prenyl esters 12b and 12c failed to undergo
the rearrangement upon exposure to LDA and TMSCl,
presumably because of the steric hindrance exerted by the
methyl group(s) on the dioxolane ring. We next scrutinized
1
,3
1
2d, a sterically less-demanding ester, which when subjected
severe A interaction in TS-1 than in TS-3 might account for
the fact that 13a was not the exclusive product for the same
reaction sequence starting from (Z)-6.
to the same reaction conditions delivered the Ireland–Claisen
rearrangement product. Therefore, the two vicinal hydroxy
groups in 9 were protected as a dioxolane. After the dioxolane
[15]
Upon dihydroxy deprotection and selective silylation of
the secondary hydroxy group at C7, the 13a/13b mixture
(derived from (Z)-6, as mentioned above) was converted into
enynes 14a/14b in 51% combined overall yield (Scheme 4).
Treatment of the 14a/14b mixture with [Co (CO) ] effected
[11a]
[11b]
formation
of the vicinal diol followed by PMP removal,
9
was converted into primary alchol 10 in 72% yield over two
[
12]
steps (Scheme 2). Jones oxidation
corresponding carboxylic acid, which was coupled
the known alcohols (Z)-11
of 10 afforded the
[
9d,e]
with
2
8
[13a]
[13b]
[8d]
and (E)-11
to deliver the
an IMPKR to produce tricyclic enone 4 (67%) and epi-4
corresponding esters (Z)-6 and (E)-6, respectively.
(6%) along with a trace amount of enyne/Co (CO) com-
2
6
Sequential treatment of (Z)-6 with LDA and TMSCl
plexes. Whereas 14a furnished 4 and epi-4, lactone 14b only
[
9d,e]
effected the expected Ireland–Claisen rearrangement
form a pair of inseparable diastereomers 13a/13b (7:1) in
4% combined yield after acid-promoted
to
resulted in the formation of the enyne/Co (CO) complex
2
6
without further cyclization. The structure of 4 was confirmed
by NOESY experiments. With significant quantities of 4 in
5
[
7b,c]
lactonization (Scheme 3). Good diaste-
reoselectivity was observed for the rear-
rangement. The a-hydroxy group of the
hand, irradiation
of 4 in the presence of a large excess of
allene in THF at ꢀ788C was carried out to furnish a mixture
of head-to-head photocycloadducts 3 (72%) and 15 (15%).
The structure of 3 was assigned by assuming that the allene
approached the enone from the b-face of 4 in the photo-
cycloaddition step.
[
9d]
ester is an effective chelator of lithium
ions that can ensure chelation control in
the deprotonation step leading to the
[7b,c]
(Z)-ketene acetal. The latter underwent
Ozonolysis
of 3 followed by ring opening with
thermal rearrangement to deliver the
desired carboxylic acid, the precursor of
methanolic NaOMe led to 2 (89%) as a fragmentation
product, the structure of which was confirmed by X-ray
[
7b]
2
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Chemie
[
4a,5b]
ysis, according to a known procedure.
The spectroscopic
1
13
data ( H and C NMR spectroscopy; HRMS) of both 17 and
our synthetic 1 were identical to those reported in the
2
5
literature;
ꢀ
the
optical
rotation
value
([a]
=
D
3
ꢀ1
ꢀ1
ꢀ3
126.6 cm g cm (c = 0.08 gcm , EtOH)) of 1 was similar
2
4
3
ꢀ1
ꢀ1
ꢀ1
to the literature data (Ref. [5b]: [a] = ꢀ123.8 cm g cm
D
ꢀ
3
22
3
ꢀ1
(
(
c = 0.17 gcm , EtOH); Ref. [3]: [a] = ꢀ152.9 cm g cm
D
ꢀ
3
c = 0.24 gcm , EtOH)).
In summary, we have accomplished a novel asymmetric
total synthesis of (ꢀ)-jiadifenin in eighteen reaction steps
from the known compound 7. Key features of the current
synthesis include: 1) the Ireland–Claisen rearrangement to
produce the two contiguous quaternary centers at C5 and C6
simultaneously, 2) the intramolecular Pauson–Khand reac-
tion (IMPKR) to concurrently construct the A and B rings,
and 3) the [2+2] photo-cycloaddition to generate the all-
carbon quaternary center at C9.
[10c]
.
Scheme 4. Synthesis of tetracycle 3: a) Ph C BF , CH Cl , reflux, 60%;
3
4
2
2
b) TBSOTf, Et N, CH Cl ,RT, 85%; c) [Co (CO) ], Bu PS, toluene, RT to
3
2
2
2
8
3
7
58C, 67%; d) hu, allene, THF, ꢀ788C, 3 (72%), 15 (15%). TBSOTf=
tert-butyldimethylsilyl trifluoromethanesulfonate.
[
16]
crystallographic analysis (Scheme 5). By applying the Ito–
[
17]
Saegusa oxidation protocol,
2 was regioselectively con-
Received: April 25, 2012
Published online: && &&, &&&&
verted into a,b-unsaturated ketone 16 in 92% yield over the
[
18]
two steps. Upon exposure to TBAF, tandem desilylation
and lactonization of enone 16 furnished dilactones 17 in 96%
yield, although partial epimerization was observed at C1.
Encouraged by the relevant findings by Theodorakis and co-
Keywords: cycloaddition · Pauson–Khand reaction ·
.
photochemistry · sesquiterpene · total synthesis
[
5b]
workers,
treatment of the diastereomeric mixture of 17
sequentially with NaHMDS (3 equiv) and Davis oxaziri-
dine (1 equiv) produced a-hydroxy lactone 18 as a single
[1] a) J. T. Coyle, D. L. Price, M. R. Delong, Science 1983, 219,
[
19]
1184 – 1190; b) R. M. Wilson, S. J. Danishefsky, Acc. Chem. Res.
2006, 39, 539 – 549; c) H. Hampel, D. Prvulovic, S. Teipel, F.
diastereomer in 55% (or 74%, based on recovered starting
[
20]
Jessen, C. Luckhaus, L. Froeliche, M. W. Riepe, R. Dodel, T.
Leyhe, L. Bertram, W. Hoffmann, F. Faltraco, Prog. Neurobiol.
material) yield.
Finally, 18 was transformed into (ꢀ)-
jiadifenin (1) by Jones oxidation and a subsequent methanol-
2
011, 95, 718 – 728.
2] a) S. D. Skaper, F. S. Walsh, Mol. Cell Neurosci. 1998, 12, 179 –
93; b) M. V. Sofroniew, C. L. Howe, W. C. Mobley, Annu. Rev.
[
1
Neurosci. 2001, 24, 1217 – 1281; c) M. R. Bennett, W. G. Gibson,
G. Lemon, Auton. Neurosci-Basic 2002, 95, 1 – 23; d) D. Daw-
barn, S. J. Allen, Neuropathol. Appl. Neurobiol. 2003, 29, 211 –
2
4
30; e) S. D. Skaper, CNS Neurol. Disord. Drug Targets 2008, 7,
6 – 62.
[
[
3] R. Yokoyama, J. M. Huang, C. S. Yang, Y. Fukuyama, J. Nat.
Prod. 2002, 65, 527 – 531.
4] a) Y. S. Cho, D. A. Carcache, Y. Tian, Y. M. Li, S. J. Danishefsky,
J. Am. Chem. Soc. 2004, 126, 14358 – 14359; b) D. A. Carcache,
Y. S. Cho, Z. H. Hua, Y. Tian, Y. M. Li, S. J. Danishefsky, J. Am.
Chem. Soc. 2006, 128, 1016 – 1022.
[
5] a) J. Xu, L. Trzoss, W. K. Chang, E. A. Theodorakis, Angew.
Chem. 2011, 123, 3756 – 3760; Angew. Chem. Int. Ed. 2011, 50,
3672 – 3676; b) L. Trzoss, J. Xu, M. H. Lacoske, W. C. Mobley,
E. A. Theodorakis, Org. Lett. 2011, 13, 4554 – 4557.
6] K. Harada, A. Imai, K. Uto, R. G. Carter, M. Kubo, H. Hioki, Y.
Fukuyama, Org. Lett. 2011, 13, 988 – 991.
[
[
7] For reviews, see: a) T. Bach, J. P. Hehn, Angew. Chem. 2011, 123,
1032 – 1077; Angew. Chem. Int. Ed. 2011, 50, 1000 – 1045; for
representative applications of this method in natural product
synthesis, see: b) E. Piers, B. F. Abeysekera, D. J. Herbert, I. D.
Suckling, Can. J. Chem. 1985, 63, 3418 – 3432; c) P. Magnus,
L. M. Principe, M. J. Slater, J. Org. Chem. 1987, 52, 1483 – 1486;
d) Y. Tobe, D. Yamashita, T. Takahashi, M. Inata, J. Sato, K.
Kakiuchi, K. Kobiro, Y. Odaira, J. Am. Chem. Soc. 1990, 112,
775 – 779.
Scheme 5. Synthesis of (ꢀ)-jiadifenin: a) (i) O , MeOH, CH Cl , then
3
2
2
Me S, ꢀ788C to RT; (ii) NaOMe, MeOH, 89%; b) LDA, TMSCl, Et N,
2
3
THF, ꢀ788C to ꢀ208C; c) Pd(OAc) , O , DMSO, 758C, 92% (2 steps);
2
2
d) TBAF, THF, RT, 96%; e) NaHMDS, (ꢀ)-trans-2-(phenylsulfonyl)-3-
phenyloxaziridine, THF, ꢀ788C, 55% (74%, brsm); f) Jones reagent,
acetone, 08C, then, MeOH, RT, 46%. The X-ray crystal structure of 2 is
shown with thermal ellipsoids at 30% probability. DMSO=dimethyl
sulfoxide, HMDS=hexamethyldisilazane, TBAF=tetrabutylammonium
fluoride.
[8] For reviews, see: a) J. Blanco-Urgoiti, L. Anorbe, L. Perez-
Serrano, G. Dominguez, J. Perez-Castells, Chem. Soc. Rev. 2004,
33, 32 – 42; for representative applications of this method in
natural product synthesis, see: b) L. A. Paquette, S. Borrelly, J.
Org. Chem. 1995, 60, 6912 – 6921; c) T. F. Jamison, S. Sham-
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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.
Angewandte
Communications
bayati, W. E. Crowe, S. L. Schreiber, J. Am. Chem. Soc. 1997,
19, 4353 – 4363; d) M. Hayashi, Y. Hashimoto, Y. Yamamoto, J.
Usuki, K. Saigo, Angew. Chem. 2000, 112, 645 – 647; Angew.
Chem. Int. Ed. 2000, 39, 631 – 633; e) S.-J. Min, S. J. Danishefsky,
Angew. Chem. 2007, 119, 2249 – 2252; Angew. Chem. Int. Ed.
crystallographic analysis. CCDC 881252 (A) contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1
2007, 46, 2199 – 2202; f) Q. Xiao, W.-W. Ren, Z.-X. Chen, T.-W.
Sun, Y. Li, Q.-D. Ye, J.-X. Gong, F.-K. Meng, L. You, Y.-F. Liu,
M.-Z. Zhao, L.-M. Xu, Z.-H. Shan, Y. Shi, Y.-F. Tang, J.-H. Chen,
Z. Yang, Angew. Chem. 2011, 123, 7511 – 7515; Angew. Chem.
Int. Ed. 2011, 50, 7373 – 7377.
[
9] a) R. E. Ireland, D. Habich, D. W. Norbeck, J. Am. Chem. Soc.
1985, 107, 3271 – 3278; b) R. E. Ireland, D. W. Norbeck, J. Am.
Chem. Soc. 1985, 107, 3279 – 3285; c) R. E. Ireland, D. W.
Norbeck, G. S. Mandel, N. S. Mandel, J. Am. Chem. Soc. 1985,
1
07, 3285 – 3294; d) J. C. Gilbert, R. D. Selliah, J. Org. Chem.
[15] H. Niwa, T. Ogawa, O. Okamoto, K. Yamada, Tetrahedron 1992,
48, 10531 – 10548.
1993, 58, 6255 – 6265; e) C. P. Dell, K. M. Khan, D. W. Knight, J.
Chem. Soc. Perkin Trans. 1 1994, 341 – 349; f) U. Kazmaier, J.
Org. Chem. 1996, 61, 3694 – 3699; g) Y. H. Chai, S. P. Hong,
H. A. Lindsay, C. McFarland, M. C. McIntosh, Tetrahedron 2002,
[16] CCDC 874982 (2) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
58, 2905 – 2928.
[
[
10] a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J.
Hartung, K. S. Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang,
D. Q. Xu, X. L. Zhang, J. Org. Chem. 1992, 57, 2768 – 2771; b) T.
Hashiyama, K. Morikawa, K. B. Sharpless, J. Org. Chem. 1992,
[17] a) M. Ihara, K. Makita, K. Takasu, J. Org. Chem. 1999, 64, 1259 –
1264; b) A. Nakayama, N. Kogure, M. Kitajima, H. Takayama,
Org. Lett. 2009, 11, 5554 – 5557.
[18] a) M. G. B. Drew, L. M. Harwood, A. J. Macꢁas-Sꢂnchez, R.
Scott, R. M. Thomas, D. Uguen, Angew. Chem. 2001, 113, 2373 –
2375; Angew. Chem. Int. Ed. 2001, 40, 2311 – 2313; b) D. M.
Hodgson, J. M. Galano, M. Christlieb, Tetrahedron 2003, 59,
9719 – 9728.
[19] a) F. A. Davis, B. C. Chen, Chem. Rev. 1992, 92, 919 – 934;
b) L. C. Vishwakarma, O. D. Stringer, F. A. Davis, Org. Synth.
1993, 8, 546.
[20] Compound 18 was obtained from (1R)-17 (with a-methyl at C1)
in three steps consisting of Luche reduction of ketone carbonyl,
a-hydroxylation of lactone, and Jones oxidation in the literature,
see Ref. [4a,b]. In contrast, both diastereomers of 17 were
converted into 18 in only one step in our case.
57, 5067 – 5068; c) L. L. He, H. S. Byun, J. Smit, J. Wilschut, R.
Bittman, J. Am. Chem. Soc. 1999, 121, 3897 – 3903.
11] a) A. L. Marlow, E. Mezzina, G. P. Spada, S. Masiero, J. T. Davis,
G. Gottarelli, J. Org. Chem. 1999, 64, 5116 – 5123; b) T.
Fujishima, K. Konno, K. Nakagawa, M. Kurobe, T. Okano, H.
Takayama, Bioorg. Med. Chem. 2000, 8, 123 – 134.
[
[
12] B. Xu, G. B. Hammond, J. Org. Chem. 2006, 71, 3518 – 3521.
13] For the synthesis of (Z)-11, see: a) A. T. Koppisch, B. S. J. Blagg,
C. D. Poulter, Org. Lett. 2000, 2, 215 – 217; for the synthesis of
(E)-11, see: b) A. Reichenberg, M. Hintz, Y. Kletschek, T. Kuhl,
C. Haug, R. Engel, J. Moll, D. N. Ostrovsky, H. Jomaa, M. Eberl,
Bioorg. Med. Chem. Lett. 2003, 13, 1257 – 1260.
[
15]
[
14] Dihydroxy deprotection of 13b followed by selective forma-
tion of p-nitrobenzoate at the secondary hydroxy group led to
ester A, the structure of which was confirmed by X-ray
4
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Chemie
Communications
Natural Product Synthesis
Y. Yang, X. Fu, J. Chen,
H. Zhai*
&&&& — &&&&
Total Synthesis of (ꢀ)-Jiadifenin
As easy as ABCD: (ꢀ)-Jiadifenin was
synthesized in eighteen reaction steps
from 1-[(E)-(4’-bromo-2’-butenyl)oxy]-4-
methoxybenzene. Key features of this
synthesis include: 1) Ireland–Claisen
rearrangement to produce the two con-
tiguous quaternary centers at C5 and C6
simultaneously, 2) intramolecular
Pauson–Khand reaction (IMPKR) to con-
currently construct the A and B rings, and
3) [2+2] photo-cycloaddition to generate
the all-carbon quaternary center at C9.
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!