The total synthesis of psymberin

Article abstract of DOI:10.1021/ol071068n

The total synthesis of a new member of the pederin family of natural products, psymberln 1, was accomplished. Using a recently reported novel and efficient Phl(OAc)₂ mediated oxldatlve entry to 2-(N-acylaminal)- substituted tetrahydropyrans as

Full text of DOI:10.1021/ol071068n

ORGANIC
LETTERS
2
007
Vol. 9, No. 13
597-2600
The Total Synthesis of Psymberin
2
Xianhai Huang,* Ning Shao, Anandan Palani, Robert Aslanian, and
Alexei Buevich
Department of Chemical Research, Schering-Plough Research Institute,
Kenilworth, New Jersey 07033
xianhai.huang@spcorp.com
Received May 11, 2007
ABSTRACT
The total synthesis of a new member of the pederin family of natural products, psymberin 1, was accomplished. Using a recently reported
novel and efficient PhI(OAc) mediated oxidative entry to 2-(N-acylaminal)-substituted tetrahydropyrans as the key step, this total synthesis
2
was executed in a convergent and efficient manner. The longest linear sequence of this synthesis was 22 steps starting from known 6.
After almost a decade of effort, two research groups1
independently reported in 2004 the isolation and structure
elucidation of a potent anticancer marine natural product. It
Scheme 1. Retrosynthetic Analysis of Psymberin with Use of
an Oxidative Cyclization as the Key Step
was named psymberin (1) and irciniastatin A by each group,
4
respectively. The C stereochemistry was undefined. This
1
a
compound is a new member of the pederin family in that
it shares the common pederin R-cyclic-oxy N-acyl aminal
core (C -C13, Scheme 1). However, its structure is unique
6
within this class as this core is flanked by a unique
dihydroisocoumarin unit and an unusual unsaturated acyclic
side chain. More importantly, psymberin is an extremely
potent and selective cytotoxin compared to other pederin
1a
natural products. Therefore, the total synthesis of psymberin
has drawn much attention from the synthetic chemistry
2
community. In 2005, an elegant total synthesis of this natural
(
1) (a) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6,
1
951 and references cited therein. (b) Pettit, G. R.; Xu, J. P.; Chapuis, J.
C.; Pettit, R. K.; Tackett, L. P.; Doubek, D. L.; Hooper, J. N. A.; Schmidt,
J. M. J. Med. Chem. 2004, 47, 1149.
2
a
(2) Total synthesis, see: (a) Jiang, X.; Garcia-Fortanet, J.; De Brabander,
product was reported by De Brabander’s group, leading to
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. (d) Green, M. E.; Rech, J. C.; Floreancig,
P. E. Org. Lett. 2005, 7, 4117. (e) Kiren, S.; Williams, L. J. Org. Lett.
a complete stereochemical assignment of psymberin with an
S-configuration at C and the conclusion that psymberin and
4
irciniastatin A were identical. To assemble the synthetically
3
challenging pederin common core, we recently reported a
2
005, 7, 2905. Analogue synthesis, see: (f) Jiang, X.; Williams, N.; De
Brabander, J. K. Org. Lett. 2007, 9, 227.
novel synthesis of 2-(N-acylaminal)-substituted tetrahydro-
1
0.1021/ol071068n CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/25/2007

2
pyrans from enamides using PhI(OAc) as an oxidant. Herein,
we present a convergent total synthesis of psymberin using
this new methodology.
Scheme 3. Synthesis of Ketone 4
According to our retrosynthetic analysis (Scheme 1), the
core R-cyclic-oxy N-acyl aminal portion would be obtained
from N-acyl enamine 2 through the use of the PhI(OAc) -
2
mediated oxidative cyclization reaction. Enamide 2 poten-
tially would be synthesized from 3, 4, and 5 through a CuI-
mediated coupling reaction to form the N
7 8
-C bond and a
substrate-controlled Mukaiyama aldol reaction to connect
C
14-C15.
Our synthesis started with the preparation of 5 (Scheme
4
2
). Compound 6 was converted to 7 through triflate
Scheme 2. Synthesis of the Dihydroisocoumarin Unit
7
of 11 with TMSCH
2
Li in pentane gave ketone 4 in a single
operation and was converted to enol ether 12 by treatment
with TMSOTf/Et N.
3
8
For the unsaturated acyclic side chain (Scheme 4), 3 was
initially designed to be used as the building block; how-
ever, we later found out that the alkene interfered with our
2
PhI(OAc) -mediated oxidative cyclization reaction. We then
9
proceeded with the synthesis of 17 in which the double bond
was temporarily masked. Regioselective epoxide opening of
1
4 with isopropenylmagnesium bromide gave a secondary
alcohol that was protected as a methyl ether with Me OBF
3
4
to give 15. Ether 15 was converted to 16 in 4 steps via
hydroboration, benzylation, deprotection of the TBS group,
and Swern oxidation. Aldehyde 16 underwent cyanohydrin
formation (dr ) 2:1), and the free alcohol was protected as
a TPS ether. The nitrile group was hydrolyzed under very
mild conditions to give amide 17 (isomers were easily
separated at this step). To this point, side chain 17 was
prepared in an overall 27% yield in 9 steps.
formation, allylation, deprotection of the phenolic methyl
groups, and protection of the diphenol with TIPS groups.
4 4
Alkene 7 was treated with OsO /NaIO followed by a
5
classical Brown crotylation reaction to provide syn-8 with
excellent diastereoselectivity (dr > 50:1) and 90% ee, which
was determined by chiral OD HPLC. Hydroxyester 8 was
converted to 5 through lactone formation in the presence of
acid and cleavage of the double bond. In this route, aldehyde
1
0
With all three subunits in hand, we proceeded to complete
the synthesis (Scheme 5). A substrate-controlled aldol
5
was synthesized from 6 in 8 steps (53% overall yield) with
1
1,2c
reaction
between 5 and 12 gave ketone 18 in good yield
excellent diastereoselectivity and good enantioselectivity.
The central linker 4 was quickly synthesized in 89%
overall yield in 3 steps from the commercially available
aldehyde 9 (Scheme 3). A highly enantioselective Masamune
aldol condensation between 9 and 10 gave the secondary
alcohol as a single enantiomer (er > 50:1) by Mosher ester
(
76% as pure isomer (for two isomers: 91%, dr ) 5:1)).
1
2
Chelation-controlled reduction of ketone 18 provided a
(
6) Parmee, E. R.; Tempkin, O.; Masamune, S. J. Am. Chem. Soc. 1991,
1
13, 9365.
(7) Mulzer, J.; Mantoulidis, A.; Ohler, E. J. Org. Chem. 2000, 65, 7456.
6
analysis with the desired R-configuration, which was sub-
(8) Although we did not proceed with compound 3 for the total synthesis,
it was prepared efficiently from 14 in 7 steps (Scheme 4) and served as a
vehicle to determine the correct sterochemistry at C5 by spectrum
comparison with the psymberin side chain.2
sequently protected with a TBS group to give 11. Treatment
d,e
(
3) Huang, X.; Shao, N.; Palani, A.; Aslanian, R. Tetrahedron Lett. 2007,
8, 1967.
4) 6 was prepared from commercially available 2,4,6-trimethoxytoluene
(9) All compounds containing this side chain were a 1:1 mixture of two
isomers (R, S) at C2 except when otherwise indicated.
(10) Maffioli, S. I.; Marzorati, E.; Marazzi, A. Org. Lett. 2005, 7, 5237.
(11) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840 and references cited therein.
4
(
in two steps in 46% yield according to literature procedure. Solladie, G.;
Gehrold, N.; Maignan, J. Tetrahedron: Asymmetry 1999, 10, 2739.
(5) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(12) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190.
2598
Org. Lett., Vol. 9, No. 13, 2007

Scheme 4. Synthesis of the Acyclic Side Chain
Scheme 5. Completion of the Total Synthesis
secondary alcohol at C13 with excellent diastereoselectivity
13
(
dr ) 15:1), which was transformed to 19 (E/Z ) 5/1) via
bis-acetylation at C13 and C15, de-benzylation, Dess-Martin
14
oxidation, and Takai vinyl iodide formation. Enamide 20
1
5
(
(
E/Z ) 5/1) was synthesized from 19 in three operations:
16
1) coupling of 19 with 17 by using CuI to give protected
N-acyl enamine, (2) removal of the C13, C15 acetate and O21
TIPS groups with NaOMe/MeOH, and (3) selective acety-
lation of O21. As expected, enamide 20 cyclized slowly but
smoothly with use of the PhI(OAc)
2
-mediated cyclization
reaction to give a total of 72% yield of isolated products
60% of two major pairs of diastereomers and 12% of other
possible isomers). The major two pairs of diastereomers (30%
3
(
1
7
isolated yield each, C
separately acetylated at C15 and debenzylated to give alcohols
1 and epi-21. The C terminal double bond was revealed
by converting 21 and epi-21 to the o-nitrophenyl selenide
8
, C
9
) S, S and C
8 9
, C ) R, R ) were
2
1
18
2 2
followed by treatment with H O at 50 °C. Upon treatment
with TBAF at 50 °C, a global deprotection was realized to
1
give the final products 1 and epi-1. The spectral data ( H,
13
C, optical rotation, MS) of synthetic 1 matched exactly with
(13) Relative stereochemistry at C11, C13, and C15 was determined by
1
,2a
preparing the C11, C13 acetonide and the C13, C15 acetonide from the
corresponding hydroxy derivatives of 18.
those reported of natural psymberin.
In conclusion, our novel PhI(OAc) -mediated oxidative
cyclization method was successfully applied to the total
synthesis of psymberin, and this further confirmed the
2
(
14) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
408.
15) It is not necessary to separate the E and Z isomers since they work
equally well in the oxidative cyclization reaction. See ref 3.
16) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003,
, 3667.
17) The R,R stereochemistry at C8, C9 was assigned by using COSY,
7
3
(
2
a
(
4
assignment of the configuration at C . The synthesis was
5
(
NOESY, HSQC, and HMBC experiments with the final product epi-1, see
the Supporting Information.
(18) Grieco, P. A.; Takigawa, T.; Schillinger, W. J. J. Org. Chem. 1980,
45, 2247.
Org. Lett., Vol. 9, No. 13, 2007
2599

executed in a convergent manner by preparing building
blocks 4, 5, and 17. The longest linear sequence of this
synthesis is 22 steps starting from the known phenol 6. This
practical oxidative cyclization can be applied to the synthesis
of other pederin family natural products as well as analogues
of psymberin, and will be reported in due course.
John Piwinski, and Satwant Narula at Schering-Plough
Research Institute (SPRI) for their strong support of the
postdoctoral program.
Supporting Information Available: Experimental details
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. Craig Boyle at SPRI
for proofreading our manuscript and Drs. Catherine Strader,
OL071068N
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Org. Lett., Vol. 9, No. 13, 2007