Synthesis of seco-psymberin/irciniastatin A: the discovery of a novel PhI(OAc)2 mediated cascade cyclization reaction

Article abstract of DOI:10.1016/j.tetlet.2008.04.016

The psymberin unsaturated 'psymberate' side chain 7 was synthesized in 7 steps (36% yield) with good diastereoselectivity using commercially available starting material to control the stereochemistry at C₄ and C₅. The synthesis of se

Full text of DOI:10.1016/j.tetlet.2008.04.016

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Tetrahedron Letters 49 (2008) 3592–3595
Synthesis of seco-psymberin/irciniastatin A: the discovery
of a novel PhI(OAc)2 mediated cascade cyclization reaction
Xianhai Huang *, Ning Shao, Anandan Palani, Robert Aslanian,
Alexei Buevich, Cynthia Seidel-Dugan, Robert Huryk
Department of Chemical Research, Schering-Plough Research Institute, Kenilworth, NJ 07033, United States
Received 25 February 2008; revised 27 March 2008; accepted 2 April 2008
Available online 7 April 2008
Abstract
The psymberin unsaturated ‘psymberate’ side chain 7 was synthesized in 7 steps (36% yield) with good diastereoselectivity using com-
mercially available starting material to control the stereochemistry at C4 and C5. The synthesis of seco-psymberin was completed in an
efficient manner based on a CuI mediated coupling reaction between vinyl iodide 8 and ‘psymberamide’ 7. In an attempt to synthesize
natural psymberin from the seco-intermediate, a novel PhI(OAc)2 mediated cascade ring closing reaction was discovered. A possible
mechanistic pathway for the formation of the ring closing product was presented.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Total synthesis; seco-Psymberin; ‘Psymberate’ side chain; (Diacetoxyiodo)benzene; Oxidative cyclization
The structure of psymberin (1)/irciniastatin A was iden-
tified by two research groups1 independently in 2004 after
almost a decade of effort. This natural product is extremely
potent against various human cancer cell lines with unprec-
edented selectivity1a for its class. This compound is a new
member of the pederin family1a in that it shares the com-
mon pederin a-cyclic-oxy N-acyl aminal core (C6–C13,
Scheme 1). However, its structure is unique within this class
as this core is flanked by a novel dihydroisocoumarin unit
and an unusual unsaturated acyclic side chain. The total
synthesis of psymberin has drawn much attention from
the synthetic chemistry community2 including our recent
total synthesis.3 The key in our approach is the assembly
of the synthetically challenging pederin common core using
our recently reported4 novel PhI(OAc)2 mediated oxidative
cyclization to synthesize 2-(N-acylaminal) substituted tetra-
hydropyrans from enamides. The rational behind this is
that the natural product psymberin (1) may be synthesized
in nature from seco-psymberin 2 through a natural oxida-
OMe O
OMe O
OMe
5
9
11 OH
5
9
11 OH
1
1
8
8
4
N
H
4
N
H
OH
HO
OH
O
13
13
[O]
15
15
17
17
HO
21
HO
21
16
16
25 O
O
OH
25 O
O
OH
23
OH
23
OH
2
seco-psymberin
1 psymberin
Scheme 1. A possible ‘biomimic’ formation of psymberin from seco-
psymberin.
tion process in a ‘biomimic’ way. Based on this hypothesis,
we became interested in synthesizing and testing compound
2 for biological activity. Herein, we report our synthetic
effort toward seco-psymberin involving an efficient route
to synthesize the unsaturated ‘psymberate’ side chain, and
the discovery of a novel PhI(OAc)2 mediated cascade cycli-
zation reaction in this process.
According to our retrosynthetic analysis, N-acyl enam-
ine 2 (seco-psymberin) can be synthesized through a CuI-
mediated coupling reaction to form the N7–C8 bond and
a substrate controlled Mukaiyama aldol reaction to
*
Corresponding author. Tel.: +1 908 740 3487; fax: +1 908 740 7664.
E-mail address: xianhai.huang@spcorp.com (X. Huang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.016

X. Huang et al. / Tetrahedron Letters 49 (2008) 3592–3595
3593
OMe
This is a surprising but satisfactory result. We hypothesized
that the enrichment of the stereoselectivity might be an
equilibration process involving a six-membered intermedi-
ate (Scheme 3). After initial palladium mediated proton
transfer between 6 and acetamide to form intermediate
6a, 6a can isomerize to palladium chelated intermediate
6b (pathway A). Upon protonation, the favored intermedi-
ate 6c will prevail and further transform to the desired
major product 7. To this point, side chain 7 was prepared
in an overall 36% yield in 7 steps with good diastereoselec-
tivity. An alternative mechanistic pathway (Scheme 3,
pathway B) is also possible. This involves the initial con-
version of 6a to ketenimine 6e. Subsequent hydration of
6e followed by diastereoselective protonation would lead
to the major product 7.
OMe
H
a-b
c-d
O
OTBS
O
OTBS
4
3
5
e-f
OMe O
OMe
g
CN
OTPS
NH2
OTPS
6
7
Scheme 2. Synthesis of the acyclic ‘psymberate’ side chain. Reagents and
conditions: (a) 2-propenylMgBr, CuI, THF, ꢁ15 °C, 90%; (b) Me3OBF4,
proton sponge, CH2Cl2, 95%; (c) TBAF, THF, 90%; (d) DMP, CH2Cl2,
0 °C to rt, 80%; (e) (1) TMSCN, K2CO3, Et2O, 0 °C, rt, 91%; (2) TBAF,
THF, 95% dr = 1:1; (f) TPSCl, NEt3, DMAP, CH2Cl2, 95%; (g)
MeCONH2, PdCl2, H2O, THF, 71% (pure isomer).
With amide 7 in hand, we proceeded to complete the
synthesis (Scheme 4). Vinyl iodide 83 was coupled with
compound 7 using CuI7 under Buchwald conditions to give
protected N-acyl enamine 9, and the major product E-iso-
mer was separated at this stage. Upon treatment of E-9
with NaOMe/MeOH followed with TBAF at 50 °C, a glo-
bal deprotection was realized to give seco-psymberin 2.
With 2 in hand, we studied its antiproliferation activity in
a human lung cancer cell line (HOP62), and found that it
was weakly active (IC50 >1 ꢀ 104 nM). This result suggests
that the 2-(N-acylaminal) substituted tetrahydropyran por-
tion of psymberin is crucial for its potent cytotoxic activity.
Since we had compound 9 in hand, we also attempted to
complete the total synthesis of psymberin with this material
(Scheme 5). Cyclization precursor enamide 10 (E/Z = 5/1)
was synthesized from 9 (E/Z = 5/1) in two operations: (1)
removal of C13, C15 acetate, and O21 TIPS groups with
NaOMe/MeOH, (2) acetylation of O21. Surprisingly, when
we subjected compound 10 under the PhI(OAc)2 mediated
cyclization reaction, the reaction was rather complex. After
isolation of the products and careful NMR analysis, we
connect C14–C15. Our synthesis started with the prepara-
tion of unsaturated ‘psymberamide’ side chain 7 (C1–N7).
Although a few research groups have reported the synthesis
of the ‘psymberate’ side chain,5 we decided to employ a
commercially available chiral precursor (3) to set up the
C4 chiral center (Scheme 2).
Regioselective epoxide opening of 3 with isopropenyl-
magnesium bromide gave a secondary alcohol which was
protected as a methyl ether with Me3OBF4 to give 4. Ether
4 was converted to 5 in 2 steps via deprotection of the TBS
group and Dess–Martin oxidation. Aldehyde 5 underwent
basic cyanohydrin formation (dr = 1:1), deprotection of
the TMS group with TBAF, and protection of the free
alcohol as a TPS ether to give nitrile 6. At this point, we
did not attempt to improve the stereoselectivity at C5.
When the nitrile was subjected to hydrolysis under very
mild conditions,6 we successfully obtained amide 7 not only
in good yield but also in good diastereoselectivity (3:1 to
5:1 in favor of the desired product, isomers were easily sep-
arated at this step with silica gel column chromatography).
Pd(II)(H2O)
Pd(II)(H2O)
pathway
B
H
H
OMe N
O
NH
O
N
NH
NH
7 & 7'
O
O
OTPS
OTPS
OTPS
6
6a
6e
pathway A
Pd(II)(H2O)
Pd(II)(H2O)
Pd(II)(H2O)
Pd
O
NH
NH
O
NH
protonation
favored
NH
protonation
unfavored
O
NH
NH
O
OTPS
O
OTPS
O
OTPS
6b
6c
6d
minor product
Pd(II)(H2O)
major product
Pd(II)(H2O)
OMe NH2
OMe NH2
N
N
O
OTPS
O
OTPS
7'
7
Scheme 3. Possible mechanism for the stereochemistry enrichment at C5.

3594
X. Huang et al. / Tetrahedron Letters 49 (2008) 3592–3595
11 OTBS
noticed that the enamine double bond was still present in
I
all spectra and the terminal double bond was missing.
Among the products isolated, we identified two major
products 11 (40%) and 12 (20%). In both compounds, the
methoxy group at C4 disappeared. This surprising result
prompted us to wonder what the possible reaction pathway
is for the formation of these products. Although it is pos-
sible for DIB to complex with simple alkenes8a in aqueous
media, we did not think that the terminal double bond was
involved in the initial step in this case because only very
mild conditions were employed and a control reaction
showed that the terminal double bond was not affected.8b
Herein, we propose a possible reaction pathway for the
transformation (Scheme 6). Upon treatment of 10 with
DIB, the reagent first coordinates with the electron rich
enamide to form a weak iodine nitrogen bond to give 13
(which may dissociate to a tight iron pair).9 The conforma-
tionaly close methoxy group then attacks the terminal dou-
ble bond followed by ring formation to give intermediate
oxonium ion 14 (or 140). Intermediate 14 can undergo
two possible reactions: (1) the antiparallel proton elimi-
nates using methyloxonium ion as a leaving group (14) to
give the major product 11, or (2) external nucleophile
(MeOH) attacks the methyloxonium ion (140) to give prod-
uct 12. If this hypothesis is viable, we thought that product
11 would not form if the antiparallel proton was not pres-
ent. To confirm this, we prepared compound 15 in which
the stereochemistry at C5 was inverted. When we subjected
15 to the oxidative cyclization reaction conditions, indeed,
the only major product obtained is the bicyclic compound
16. In this case (Scheme 7), after the formation of interme-
diate 17, it undergoes ring closure to give intermediate 18.
There is no antiparallel proton to eliminate in 18, and the
only reaction that can happen is the external nucleophilic
attack to give product 16. At this point, we can not totally
rule out the possibility that the interaction between alkenes
and oxidants is reversible and the product would be
resulted from addition of the nucleophilic amide carbonyl
group to the tertiary carbon of the alkene.
AcO 13
15
OMe O
a
TIPSO
NH2
+
21
OAc
O
OTPS
7
TIPSO
O
8, E/Z = 5/1
OMe O
OH
OMe O
OH
OTBS
N
H
N
H
HO
OTPS AcO
b
HO
TIPSO
OH
OAc
O
O
TIPSO
O
OH
O
9
seco-symberin 2
Scheme 4. Completion of the synthesis of seco-psymberin. Reagents and
conditions: (a) CuI, MeNHCH2CH2NHMe, Cs2CO3, toluene, 70 °C, 86%;
(b) (1) NaOMe, MeOH; (2) TBAF, THF, rt to 50 °C, 70%.
OMe O
OMe O
OTBS
OTBS
N
H
N
H
OTPS AcO
OTPS
HO
a-b
TIPSO
AcO
OAc
= 5/1
OH
O
O
TIPSO
O
TIPSO
O
9,
E/
Z
10, E/Z = 5/1
c
OTBDPS
O
OTBDPS
O
N
MeO
AcO
O
N
OTBS
OTBS
HO
HO
+
AcO
O
OH
O
OH
TIPSO
O
TIPSO
O
12 20%
11 40%
In conclusion, we have synthesized the psymberin unsat-
urated ‘psymberate’ side chain using commercially avail-
able starting material to control the stereochemistry at C4
and C5. An unexpected stereochemistry enrichment was
Scheme 5. The discovery of a novel PhI(OAc)2 mediated cascade ring
closure reaction. Reagents and conditions: (a) NaOMe, MeOH; (b) Ac2O,
pyridine, DMAP, CH2Cl2, 0 °C, 90% over 2 steps; (c) PhI(OAc)2, MeOH,
HFIP, 60%.
10
11
12
major
~ 40%
minor
~ 20%
- H+
- Me+
Ph
I
AcO
N
H
N
H
O
N
TBDPSO
Me
O
O
TBDPSO
Me
TBDPSO
Me
O
Me
O
O
Me
Me
13
A possible reaction pathway
14
14'
ROH
+ PhI + AcO-
Scheme 6. A possible reaction pathway for the formation of 11 and 12.

X. Huang et al. / Tetrahedron Letters 49 (2008) 3592–3595
3595
N
OMeO
PhI(OAc)2 , HFI, MeOH
0 ºC, 1h
TBDPSO
OH
O
N
H
HO
65%
TBDPSO
O
15
16
Ph
I
O
TPSO
OAc
TPSO
H
N
N
O
H
Me
Me
- PhI - AcO-
O
O
Me
Me
ROH
18
17
Scheme 7. Further studies of the PhI(OAc)2 mediated ring formation reaction.
J. C.; Pettit, R. K.; Tackett, L. P.; Doubek, D. L.; Hooper, J. N. A.;
Schmidt, J. M. J. Med. Chem. 2004, 47, 1149.
observed at C5. Based on a CuI mediated coupling reaction
between vinyl iodide 8 and ‘psymberamide’ 7, the synthesis
of seco-psymberin 2 was completed in an efficient manner.
The preliminary biological data of compound 2 support
that the 2-(N-acylaminal) substituted tetrahydropyran por-
tion of psymberin is crucial for its potent cytotoxic activity.
In an attempt to synthesize natural psymberin from the
seco-intermediate, we discovered a novel PhI(OAc)2 medi-
ated cascade ring closing reaction. A possible mechanistic
pathway for the formation of the ring closing product
was presented. Further studies and potential synthetic
applications of this novel cyclization reaction are underway
and the result will be reported in due course.
2. Total synthesis, see: (a) Jiang, X.; Garcia-Fortanet, J.; De Brabander,
J. K. J. Am. Chem. Soc. 2005, 127, 11254 and references cited therein;
Formal total synthesis, see: (b) Ning, S.; Kiren, S.; Williams, L. J. Org.
Lett. 2007, 9, 1093; Fragment syntheses, see: (c) Rech, J. C.;
Floreancig, P. E. Org. Lett. 2005, 7, 5175; Analog synthesis, see: (d)
Jiang, X.; Williams, N.; De Brabander, J. K. Org. Lett. 2007, 9, 227.
3. Huang, X.; Shao, N.; Palani, A.; Aslanian, R.; Buevich, A. Org. Lett.
2007, 9, 2597.
4. Huang, X.; Shao, N.; Palani, A.; Aslanian, R. Tetrahedron Lett. 2007,
48, 1967.
5. (a) Green, M. E.; Rech, J. C.; Floreancig, P. E. Org. Lett. 2005, 7,
4117; (b) Kiren, S.; Williams, L. J. Org. Lett. 2005, 7, 2905; (c)
Henssen, B.; Kasparyan, E.; Marten, G.; Pietruszka, J. Heterocycles
2007, 74, 245.
6. Maffioli, S. I.; Marzorati, E.; Marazzi, A. Org. Lett. 2005, 7, 5237.
7. Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5,
3667.
Acknowledgments
8. (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123 and
references cited therein; (b) A control reaction with compound 19
under the same reaction condition resulted in no change of the terminal
double bond with majority of the starting material recovered. The only
side product observed was the small amount of aromatic ring oxidized
compound.
We thank Drs. Ismail Kola, John Piwinski, and Satwant
Narula for their strong support of the SPRI postdoctoral
program.
Supplementary data
MeO
Experimental details and spectral data for all new
compounds. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2008.04.016.
OMe
MeO
O
19
9. The interaction between bis(trifluoroacetoxy)iodobenzene and amides
was reported: Boutin, R. H.; Loudon, R. M. J. Org. Chem. 1984, 49,
4277.
References and notes
1. (a) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6,
1951 and references cited therein; (b) Pettit, G. R.; Xu, J. P.; Chapuis,