Asymmetric synthesis of the fully functionalized six-membered ring of trigoxyphin A

Article abstract of DOI:10.1039/C8CC04351E

An asymmetric synthesis strategy of the fully functionalized six-membered ring of trigoxyphin A, a daphnane-type diterpenoid, has been accomplished concisely from a d-tartrate derivative. Key elements of this synthesis involve the tandem ozonization/intramolecular HWE reaction to construct the α,β-unsaturated cyclohexenone skeleton, the radical cyclization to introduce the C8 chirality and sequential Kumada cross-coupling/hydroboration-oxidation to introduce the C11 chirality. The target substructure could be synthetically achieved on a multi-gram scale.

Full text of DOI:10.1039/C8CC04351E

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COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
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/haaÜbL/!ÇLhb
!symmetric synthesis of the fully functionalized six-membered
ring of trigoxyphin !
Wing Ceng,a Çianzi òu,a ùhijiang ùhang,a Winpeng [i,a {haomin Cu,a Wuan /hen,b and .o [iu *a
weceived 00th Wanuary 20xx,
!ccepted 00th Wanuary 20xx
5hL: 10.1039/x0xx00000x
www.rsc.org/
!symmetric synthesis of the fully functionalized six-membered respectively.
ring of trigoxyphin !, a daphnane-type diterpenoid, has been
accomplished concisely from 5-tartrate derivative. Yey elements
of this synthesis involve the tandem ozonization/intramolecular
Ií9 reaction to construct the r,t-unsaturated cyclohexenone
skeleton, the radical cyclization to introduce the /8 chirality and
sequential Yumada cross-coupling/hydroboration-oxidation to
introduce the /11 chirality. Çhe target substructure could be
synthetically achieved in a multi-gram scale.
Çhe daphnane diterpene orthoesters (55hs) are a large family
of natural products isolated from the plant families of
Çhymelaeaceae and 9uphorbiaceae. .y the end of 2017, about
260 unique members had been identified.1,2 aany 55hs
exhibit remarkable biological activities, such as activation of
transient receptor potential vanilloid 1 (Çwtë1)3, anticancer4,
insecticidal5, and acaricidal6 activities. Çhese natural products
embrace a highly functionalized trans,trans-fused 5/7/6 (!./-
ring) skeleton containing the 9,13,14-orthoester motif at ring /.
Curther studies on the structure-activity relationship ({!w) of
biologically active 55hs have revealed that the orthoester
group may act as an essential pharmacohpore.1a Çrigoxyphin !
(1, Cig. 1), a representative member of the 55hs, was isolated
from twigs of Çrigonostemon xyphophylloides (9uphorbiaceae)
in 2010 by òue’s group.2a 5ifferent from other 55hs identified
before, trigoxyphin ! bears an r-oriented oxygen substitution
at /12. /ytotoxic experiments have demonstrated that
trigoxyphin ! exhibits high activity against I[60 human
leukemia cells and moderate activity against !549 human lung
Cig. 1 taquette’s protocol to 5/7/6 skeleton and our protocol
to trigoxyphin !
/aptivated by their complex molecular structure and diverse
biological activities, the synthetic community has devoted
numerous endeavors into developing creative approaches to
the 55hs. .esides a number of remarkable strategies to the
5/7/6 tricyclic skeleton documented,7 the first total synthesis
of resiniferatoxin8 was accomplished by íender’s group in
1997 via intramolecular 1,3-dipolar cycloaddition and
zirconium-mediated cyclization to forge the scaffold,9 and the
second total synthesis was achieved by Lnoue’s group in 201710
adenocarcinoma cells with L/50 values of 0.27
Àa and 7.5Àa
a. Yey [aboratory of Dreen /hemistry & Çechnology of ainistry of 9ducation,
/ollege of /hemistry, {ichuan Üniversity, /hengdu 610064, t. w. /hina.
b. !nalytical & Çesting /enter, {ichuan Üniversity, /hengdu 610064, t. w. /hina.
† 9lectronic {upplementary Lnformation (9{L) available: experimental details and
characterization data for all new compounds. {ee 5hL: 10.1039/x0xx00000x
Çhis journal is © Çhe woyal {ociety of /hemistry 2018
W. bame., 2013, 00, 1-3 | 1
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featuring radical-mediated three-component coupling and 7- centers, two of which are adjacent to the carbonyl and thus
endo cyclization. aoreover, /6, /7-epi-yuanhuapin, an epimer facile to experience isomerization. Çhus the synthesis of the
of yuanhuapin which is a natural analog of resiniferatoxin, was ring
synthetically conquered by íender and co-workers in 2011.11 functionalized and labile structure. Ience, compound
!s for the construction of the six-membered ring of fused 5/6 bicyclic scaffold stabilizing its all-cis configuration,
/
subunit is challenging on account of its highly
4
, with a
resiniferatoxin, Lnoue’s w/a/olefin isomerization strategy has was selected as the synthetic surrogate of compound 3 in
provided a practical access.7p,10 !ll these remarkable works accordance with both structural stability and synthetic
provide viable pathways to the 55hs or the related practicality. Ierein we present our synthetic endeavors toward
unexplored analogs.
compound
{ynthesis of
aukaiyama aldol reaction ({cheme 1).14 weaction of the known
compound 5 15
with crotonaldehyde, provided compound in
4.
4
commenced with the .C3-mediated
OH
O
O
LiHMDS, TMSCl,
ethyl vinyl
ether, NBS
O
O
,
6
OiPr then crotonaldehyde,
OiPr
OiPr
O
O
OiPr
BF3.Et2O
62% yield (dr 25:1). Çhe resultant hydroxy was then protected
as an acetal by ethyl vinyl ether and b.{ to result in compound
(90%)
(62%)
O
O
5
6
7
. Ço achieve r,t-unsaturated cyclohexenone from t-keto
phosphonates,16 we exposed
7
to an anion, generated from
n
Br
Br
OEt
OEt
O
dimethyl methylphosphonate and .u[i, delivering 8a in 85%
yield.17 Çhen we set about conducting the tandem
ozonization/intramolecular Ií9 reaction. íhile initial
optimization of a number of bases, solvents and [ewis
acid/[ewis base combinations18 gave no satisfactory results,
the weak base 9t3b afforded the desired compound 10 in 26%
yield, along with a number of unidentified compounds.
!lthough the combination of {c(hÇf)3 and 9t3b (1:2.5) made
the reaction much cleaner than 9t3b alone, compound 10
could only be delivered in 19% yield, along with the undesired
compound 1119 as the major product
O
O
O
O3,
OiPr
O
MePO(OMe)2
OiPr
O
O
nBuLi
(85%)
MeOH
OiPr
O
P(OMe)2
O
O
O
7
8a
O
Br
O
OEt
OiPr
O
O
O
O
O
O
Et3N
OEt
OiPr
P(OMe)2
O
(26% for 10)
Br
R
O
10 R = H;
11 R = PO(OMe)2;
O
O
9
Br
Br
19% for 10 with
11 as the major
product
OEt
OEt
Sc(OTf)3,
Et3N
O
O
O3,
MeOH,
then Et3N
O
O
MePO(OCH2CF3)2
OiPr
O
O
OiPr
OiPr
O
O
OiPr
RO
O
Sc
O
O
LiHMDS
(67%)
O
(80%)
OiPr
OR
H
O
O
P(OCH2CF3)2
14
O
O
Sc
O
O
P
OMe
OMe
O
7
8b
O
H
H
H
O
O
O
O
(R1O)2P
trans
O
favorable
O
nBuSnH,
AIBN
Sc
TS2
OiPr
O
OiPr
O
O
+
INT2
O
O
O
+
DBU
OEt
OiPr
RO
OEt
O
(81%)
O
O
O
O
OiPr
OR
H
Br
H
O
H
O
14
12 -EtO
13 -EtO
10
P
OMe
OMe
O
67% for 2 steps through
unpurified 8b
Sc
O
H
O
O
O
Substrate Lewis acid Product Yield
(R1O)2P
cis
Sc
nonea
noneb
14
14
14
15
15
15
33%
56%
74%
28%
54%
80%
O
12
12
12
13
13
13
unfavorable
TS1
INT1
O
O
{cheme 1. {ynthesis of compound 10
OiPr
O
b
Sc(OTf)3
nonea
noneb
O
OEt
Lnspired by taquette’s work (Cig. 1),12 which utilized a
nucleophilic addition/w/a strategy to forge the 5/7/6 skeleton,
we became fascinated by developing a convergent strategy
toward 55hs including trigoxyphin !. {ynthetically, selective
formation of 9,13,14-orthoester,13 epoxidation and inversion
O
b
Sc(OTf)3
14 -EtO
p-TsOH
a THF as the solvent; b MeCN as the solvent
15 -EtO
(66%)
Ph3PMeBr,
nBuLi
of the chirality of 5-hI from the !./ ring skeleton
2, a
(78%)
O
O
potential synthetic precursor of trigoxyphin !, would furnish
the target molecule (Cig. 1). Çhen we conceived a prudent
OiPr
O
O
protocol through w/a strategy to disassemble compound
2
OEt
into two highly functionalized segments, i.e. the ring !
substructure and the ring / substructure. {tructurally, the ring
X-ray crystal
structure of 13
16
{cheme 2. {ynthesis of compound 16
/ subunit (compound
3) bears five contiguous stereogenic
2 | W. bame., 2012, 00, 1-3
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through Ynoevenagel condensation. Çhe chelation of /14-hw, hindered site and further treatment with thbÇf2 furnished the
{c(hÇf)3 and the aldehyde made Ç{2 the favorable transient triflic enol ester 17 ({cheme 3). Lron-catalyzed Yumada-
state and delivered Ynoevenagel condensation product 11
.
coupling between 17 with and aeag.r in the presence of
which then underwent hydroboration-
íith these negative results, we inferred that modification of bat afforded 18 27
,
the t-keto phosphonate 8a into the bis(trifluoroethyl) oxidation to produce the alcohol 19 in 35% yield over 3 steps.
phosphonoketone 8b might prompt the elimination step in the botably, the degradative product of thbÇf228 made it tough for
desired Ií9 process ({cheme 2).20 !ccordingly, exposure of purification of 17 and 18 29
, so we could not calculate the exact
the aldehyde intermediate, obtained after ozonization, to 9t3b yields until formation of 19. {ubsequent Drignard addition and
boosted the desired r,t-unsaturated ketone 10 in 80% yield. 5ess-aartin oxidation provided compound 21 smoothly. Çhe
botably, synthetic access to compound 8b required quick stereochemistry of compound 21 was confirmed by ó-ray
transfer of [iIa5{ (keeping at -78o/) to the mixed solution of crystallography. Cinal elimination of the tertiary hydroxyl with
the bis(trifluoroethyl) methylphosphonate and compound
o
7
at .urgess reagent furnished compound 4 30
.
Çhe relative
-78 /.21 Curther treatment of the acetal 10 with tri-n-butyltin configuration of compound
4 was established by bh9{ò
hydride in the presence of azobisisobutyronitrile22 successfully correlations of I11/I12, I11/I14, I12/I17, I14/I17 and
afforded the bicycle 12 and 13 in the ratio of 1.2:1, as I8/I14.
1
determined by I baw. Çhe stereochemistry of compound 13
.ecause both the Yumada coupling from 17 to 18 and the
was confirmed by ó-ray crystallography.23 12 and 13 were Drignard addition from 19 to 20 utilized methylmagnesium
separated and then subjected to stereochemical inversion at bromide ({cheme 3), we envisioned the synthetic route from
/12 to achieve the thermodynamically more stable product 14 14 to 20 could be simplified. tleasingly, treatment of the crude
and 15 respectively. {ole utilization of 5.Ü24 in ÇIC only led to compound 17, generated from 14, with excess aeag.r and
14 and 15 in 33% and 28% yield respectively. {witching from subsequent addition of catalytic Ce(acac)3 led to the olefin 22
ÇIC to ae/b as the solvent resulted in higher yields (56% and in 66% yield over two steps ({cheme 4). Çhen hydroboration-
54% for 14 and 15 respectively). aore pleasingly, optimal oxidation reaction successfully gave rise to the alcohol 20 in 65%
combination of 5.Ü/{c(hÇf)3 (8:1) delivered compounds 14 yield.31
25
and 15 in 74% and 80% yield respectively. Çreating 15 under p-
ÇshI fulfilled its conversion into 14 in 66% yield.26 íittig
olefination of 14 afforded compound 16 in 78% yield.
.oth allylic oxidation and isomerization of the exo double
bond into the endo position in compound 16 failed, which
made us to resort to alternative tactics to access compound
Çhus, regioselective enolization of the ketone 14 at the less
4.
{cheme 4. !lternative synthesis of compound 20
Ln summary, we have reported a concise and asymmetric
synthesis toward the fully functionalized six-membered ring of
trigoxyphin !. trotections of dihydroxyl group (/12, /14) as
acetals were devised to minimize undesired t-elimination. Çhe
synthesis features direct introduction of the stereogenic
centers at /12 and /13 from the cheap starting material,
generation of the /14 stereogenic center via aukaiyama aldol
reaction, construction of r,t-unsaturated cyclohexenone
through tandem ozonization/intramolecular Ií9, and radical
cyclization and hydroboration-oxidation to introduce the /8
and /11 stereogenic centers. Curther synthetic extension to
trigoxyphin
! and other related daphnane diterpene
orthoesters (55hs) is on progress in our laboratory.
!cknowledgements
íe acknowledge financial support from the bational batural
{cience Coundation of /hina (21672153 and 21290180), and
the Cundamental wesearch Cunds for the /entral Üniversities
(2012017yjsy148). íe also thank the !nalytical & Çesting
/enter of {ichuan Üniversity for baw and ó-way recording.
/onflicts of interest
{cheme 3. {ynthesis of compound
4
Çhere are no conflicts to declare.
Çhis journal is © Çhe woyal {ociety of /hemistry 2018
W. bame., 2013, 00, 1-3 | 3
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Çetrahedron 2017, 73, 4172; (u) w. [iu, W. Ceng and .. [iu,
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1975, 16, 1595.
t. !. íender, /. 5. Wesudason, I. bakahira, b. Çamura, !. [.
Çebbe and ò. Üeno, W. !m. /hem. {oc., 1997, 119, 12976.
botes and references
1
2
Cor recent reviews on daphnane diterpene orthoesters, see:
(a) {.-D. [iao, I.-5. /hen and W.-a. òue, /hem. wev., 2009,
109, 1092; (b) I.-.. íang, [.-t. [iu and ó.-ò. íang, aagn.
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/hen, {.-t. òang, {. ùhang, a.-ò. Deng and W.-a. òue, W. bat.
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,
3
4
5
19 Çhe Ç[/ of the reaction showed only two products with
almost 100% conversion of intermediate 9. Çhe Ynoevenagel
condensation product (11) was failed to be purified, but the
high resolution mass spectrum (Iwa{) of the crude proved
this product.
20 !. !. 5avis, W. W. wosen and W. W. Yiddle, Çetrahedron [ett.,
1998, 39, 6263.
21 Y. aolnár, [. Çakács, a. Yádár, C. Caigl and ù. Yardos,
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6
7
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23 Çhe configuration of acetal of compound 12 could not be
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!m. /hem. {oc., 1989, 111, 8954; (b) t. !. íender and C. 9.
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.
24 w. aohanrao, !. !sokan and Y. a. {ureshan, /hem.
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,
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Y. /ha, hrg. [ett., 1999,
[ittle, hrg. [ett., 2000,
1
2
, 523; (k) D. [. /arroll and w. 5.
, 2873; (l) {. w. Wackson, a. D.
29 /omin’s reagent and Çf2h were also tested, but both
resulted in lower yields. /omin’s reagent condition, see:
{ubmitted by 5. [. /omins, !. 5ehghani, /. W. Coti and {. t.
Woseph. /hecked by a. !. /ichy and !. .. {mith, LLL. hrg.
{ynth., 1997, 74, 77. Çf2h condition, see: (a) w. W. Iargrove
and t. W. {tang, W. hrg. /hem., 1974, 39, 581; (b) {ubmitted by
t. W. {tang and Ç. 9. 5ueber. /hecked by í. Waeger and I. h.
Iouse, hrg. {ynth., 1974, 54, 79.
30 9. a. .urgess, I. w. tenton and 9. !. Çaylor, W. hrg. /hem.,
1973, 38, 26.
31 t//, another alternative oxidant in hydroboration-oxidation
reaction, was also explored to simplify the synthesis, but
failed. Cor related reference, see: 9. W. tarish, {. tarish and I.
Ionda, {ynth. /ommun., 1990. 20, 3265.
Wohnson, a. aikami, {. {hiokawa and 9. a. /arreira, !ngew.
/hem., Lnt. 9d. 2001, 40, 2694; (m) t. /. .. tage, /. a.
Iayman, I. [. acCarland, 5. W. íillock and b. a. Dalea,
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C. Dosselin, /. Yan, W.-a. Yee and I. hhmura, hrg. [ett., 2006,
8
, 5373; (o) /. {tewart, w. ac5onald and C. D. íest, hrg.
[ett., 2011, 13, 720; (p) Y. aurai, {. Yatoh, 5. Ürabe and a.
Lnoue, /hem. {ci., 2013, , 2364; (q) !. W. /atino, !. {herlock,
t. {hieh, W. {. ízorek and 5. !. 9vans, hrg. [ett., 2013, 15
4
,
3330; (r) D. Çong, ù. [iu, and t. [i, hrg. [ett., 2014, 16, 2288;
(s) !. I. 9. Iassan, W. Y. [ee, !. b. tae, {.-W. ain and ò. {. /ho,
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4 | W. bame., 2012, 00, 1-3
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DOI: 10.1039/C8CC04351E
BzO
O
Me
11 steps O
O
O
H
B
C
O
O
C
A
O
O
OiPr
OiPr
O
O
O
HO
HO
H
Ph
O
O
OEt
trigoxyphin A
D-tartrate derivative
five contiguous
chiral centers
background plant:
Trigonostemon xyphophylloides (Croiz.)
cheap material
Asymmetric synthesis of the fully functionalized six-membered ring of trigoxyphin A, a
daphnane-type diterpenoid, has been accomplished concisely from D-tartrate derivative. Key
elements of this synthesis involve the tandem ozonization/intramolecular HWE reaction to
construct the α,β-unsaturated cyclohexenone skeleton, the radical cyclization to introduce the C8
chirality and sequential Kumada cross-coupling/hydroboration-oxidation to introduce the C11
chirality. The target substructure could be synthetically achieved in a multi-gram scale.