Synthetic study of phomoidride B (CP-263,114); utilization of the oxidopyrylium [5 + 2] cycloaddition

Article abstract of DOI:10.1039/b104268h

The highly functionalized core structure of phomoidride B (CP-263,114) was pursued by using intermolecular oxidopyrylium-alkene cyclization as one of the key steps.

Full text of DOI:10.1039/b104268h

Synthetic study of phomoidride B (CP-263,114); utilization of the
oxidopyrylium [5 + 2] cycloaddition
Naoki Ohmori
Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan. E-mail: d1174001@hiroshima.u.ac.jp
Received (in Cambridge, UK) 15th May 2001, Accepted 28th June 2001
First published as an Advance Article on the web 1st August 2001
The highly functionalized core structure of phomoidride B
followed by the removal of the silyl protecting group and
(
CP-263,114) was pursued by using intermolecular oxido-
iodination gave 12 (Scheme 3). Of several attempts to cleave the
ether bridge in reductive fashion, Zn proved to be the most
suitable, yielding exo-enone 13 in 96% yield. Homologation of
the exo olefin seemed reasonable for introducing the lacking
two carbon unit required for construction of the bicyclo-
[4.3.1]decene core. To this end, 13 was treated with TBSOTf in
the presence of 2,6-lutidine to give a separable mixture of TBS-
protected acetal 14 (49%) and enone 15 (5%). Acetal 14 was
next converted to 16† in two steps by allylation in the presence
pyrylium–alkene cyclization as one of the key steps.
In 1997, the group of Kaneko reported the structure of
phomoidride B (1) and its hydrolysed derivatives, both showing
1
inhibitory activity towards farnesyl transferase with IC50
values in the micromolar range.2 A great many synthetic
organic chemists have been attracted by its fascinating struc-
tural features and so far four groups have achieved elegant
3
complete total syntheses. Retrosynthetic analysis suggested
4
of TiCl followed by reprotection of the liberated alcohol with
that 1 could be accessed from 2 by introducing side chains
followed by minimal functional group manipulations. Bicyclic
TBSOTf. Ketone 16 was subjected to ozonolysis to yield a keto-
aldehyde, which was subsequently treated with DBU to
6
2
in turn could be constructed from modestly functionalized
promote the intramolecular aldol reaction. The crude aldol
seven-membered ring 3, which could easily be obtained by
treating the oxidopyrylium ylide 4 with fumarate ester or its
variants thus providing easy access to the maleic anhydride
moiety of the CP-core (Scheme 1).
adduct was oxidized with PCC to deliver diketones 17a and 17b
(4+1, 82% yield over 2 steps). Oxidation of 17a to enone 18
4
7
under Saegusa’s conditions proceeded in 35% yield. Improved
yields were obtained using the recently reported Nicolaou
8
method using IBX (IBX = 2-iodylbenzoic acid), giving enone
1
8 in 30% yield along with recovery of the starting material
(
42%). Repeated oxidation of recovered 17a resulted in a
combined yield of 42% (52%, based on recovered 17a). Lewis
acid catalyzed allylation of 18 gave a 1,4-adduct as a single
stereoisomer. Further allylation utilizing palladium chemistry
Scheme 1 Strategy for the total synthesis of phomoidride B (1).
The synthesis began with the protection of but-2-ene-1,4-diol
with TBSCl (Scheme 2). Oxidopyrylium precursor 8 was easily
prepared in 5 steps (39% from but-2-ene-1,4-diol). When using
dimethyl fumarate as the alkene, cyclization took place quite
efficiently in the presence of Et
3
N to deliver oxabicycles 9a and
9b (13+1) in 77% combined yield. Hydrogenation of 9a
Scheme 3 Reagents and conditions: (a) H
c) I , PPh , imidazole, benzene, reflux, 64% (3 steps); (d) Zn, MeOH,
reflux, 96%; (e) TBSOTf, 2,6-lutidine, CH Cl , 278 °C, 54% (14+15,
Cl , 278 °C; (g) TBSOTf,
, rt, 66% (2 steps); (h) O , MeOH, then NaHCO
S, 278 °C ? rt, 81%; (i) DBU, CH Cl ; (j) PCC, CH Cl , 4 Å MS, rt,
82% (2 steps, 17a+17b, 4+1); (k) IBX, DMSO–PhMe (1+2), 80 °C, 52%; (l)
allyltrimethylsilane, TiCl , CH Cl
2
, Pd/C, MeOH, rt; (b) aq. HCl, rt;
(
2
3
2
2
1
2
Me
0+1); (f) allyltrimethylsilane, TiCl
,6-lutidine, CH Cl
4
, CH
2
2
2
2
3
3
,
Scheme 2 Reagents and conditions: (a) TBSCl, Et
, MeOH, 278 °C, then NaHCO , Me S, 278 °C ? rt, quant. (2 steps);
c) 2-lithiofuran, Et O, 278 °C ? rt; (d) MCPBA, CH Cl , 0 °C ? rt; (e)
Ac O, pyridine, rt, 39% (3 steps); (f) dimethyl fumarate, Et N, CH CN,
reflux, 77% (9a+9b, 13+1).
3
N, DMAP, THF, rt; (b)
2
2
2
2
2
O
(
3
3
2
2
2
2
4
2
2
, 278 °C, 57%; (m) KHMDS, allyl
2
3
3
2 3 3 3
chloroformate, THF, 278 °C, 63%; (n) Pd (dba) ·CHCl , PPh , THF, rt,
81% (19+20, 2+1).
1552
Chem. Commun., 2001, 1552–1553
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104268h

delivering effect of the hydroxy group in the intermediate silyl enol ether
during work-up (ref. 5).
‡
Although the C8 stereochemistry of 19 is not certain, 19 was obtained as
the sole stereoisomer.
§
2
Although SmI has previously been used for cyclopropane opening (ref.
1
0), to our knowledge, regioselective opening of cyclopropane bearing
electron stabilizing groups on all three carbons with SmI
2
is unprece-
dented.
¶
(
(
Data for 9a: R
CH Cl ); nmax(neat)/cm 2955, 1740, 1695; d
dd, J 9.8, 4.6, 1H, H-6), 6.02 (d, J 9.8, 1H, H-7), 5.19 (d, J 4.6, 1H, H-5),
.25 (d, J 11.9, 1H, H-8), 4.22 (d, J 4.3, 1H, CHCO Me), 4.01 (d, J 11.9, 1H,
H-8), 3.76 (s, 3H, CO CH ), 3.66 (s, 3H, CO CH ), 3.61 (d, J 4.3, 1H,
CHCO Me), 0.90 (s, 9H, Si-t-Bu), 0.11 (s, 3H, Si-Me) 0.70 (s, 3H, Si-Me);
(125 MHz, CDCl ) 193.6, 171.0, 170.3, 150.7, 127.3, 91.7, 75.9, 60.3,
52.6, 52.4, 50.6, 46.6, 25.6, 18.1, 25.5, 25.7. HRMS (EI): calc. for
f
= 0.39 (silica gel, EtOAc–hexane 1+2); mp 92–94 °C
21
2
2
H 3
(500 MHz, CDCl ) 7.34
4
2
2
3
2
3
2
d
C
3
Scheme 4 Reagents and conditions: (a) Br
NI, CH
Me, THF, 0 °C ? rt, 61%; (d) SmI
9%; (e) aq. HCl, 0 °C ? rt; (f) I , PPh , imidazole, benzene, reflux, 64%
O, 50 °C, 25%.
2
, CH
2
Cl
—H
2
, 240 °C, then Et
O, rt, then Et N, rt,
, THF, 278 °C,
3
N,
+
2
40 °C ? rt; 99%; (b) NaCN, Bu
4
2
Cl
2
2
3
C
18
H
28
O
7
Si (M ): 384.1604. Found: 384.1588. Anal calc: C 56.23, H 7.34.
Found: C 56.13, H 7.43%. For 26: R = 0.53 (silica gel, EtOAc–hexane
1+1); nmax(neat)/cm 2955, 1740, 1440; d (500 MHz, CDCl ) 5.59 (br s,
1H, exo-CH N), 5.09 (s, 1H, exo-CH N), 4.99 (s, 1H, H-5), 4.23 (d, J 7.0, 1H,
CHCO Me), 3.81 (s, 3H, CO CH ), 3.79 (s, 3H, CO CH ), 3.77 (s, 3H,
), 3.66 (dd, J 7.0, 1.8, 1H, CHCO Me), 3.08 (d, J 17.4, 1H,
Me), 3.00 (d, J 17.4, 1H, CH CO Me), 2.89 (d, J 13.7, 1H, H-7),
(125 MHz, CDCl ) 171.8,
71.5, 169.4, 167.6, 141.4, 119.8, 113.3, 104.9, 80.9, 53.1, 52.8, 52.3, 45.9,
9
7
7%; (c) Me SNCHCO
2
2
2
f
21
2
3
H
3
(
2 steps); (g) Zn, Ac
2
2
2
2
2
3
2
3
CO
CH
2
1
4
3
2
CH
3
2
2
CO
2
2
2
delivered 19‡ (19% yield from 18) a highly advanced bicyclic
intermediate with the required relative stereochemistry between
the bridging carbonyl group and the hydrophobic side-chain at
C9 along with 20 (10% yield from 18).
.62 (d, J 13.7, 1H, H-7), 2.11 (s, 3H, acetyl); d
C
3
+
5.5, 44.6, 43.1, 40.9, 21.6. HRMS (EI) calc. for C18
21 9
H O Si (M ):
95.1216. Found: 395.1212.
Having established a method for the construction of the
bicyclic framework, we then focussed upon the quaternary
carbon centre adjacent to the bridgehead. To this end 9a was
first converted to 21 in 2 steps (96%) (Scheme 4). Various
attempts to produce directly the desired quaternary centre with
organometal reagents were unsuccessful, probably due to the
highly functionalized nature of 21. Only by using a sulfonium
ylide did the reaction take place without any problems,
furnishing a cyclopropane product 22. Reductive cleavage of 22
1
Review: D. M. Leonard, J. Med. Chem., 1997, 40, 2971; K. Hinterding,
D. Alonso-Díaz and H. Waldmann, Angew. Chem., Int. Ed., 1998, 37,
688.
2 T. T. Dabrah, T. Kaneko, W. Massefski, Jr. and E. B. Whipple, J. Am.
Chem. Soc., 1997, 119, 1594; T. T. Dabrah, H. J. Harwood, Jr., L. H.
Huang, N. D. Jankovich, T. Kaneko, J.-C. Li, S. Lindsey, P. M. Moshier,
T. A. Subashi, M. Therrien and P. C. Watts, J. Antibiot., 1997, 50, 1.
3
K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, H.-S. Choi, W. H. Yoon, Y.
He and K. C. Fong, Angew. Chem., Int. Ed., 1999, 38, 1669; K. C.
Nicolaou, P. S. Baran, Y.-L. Zhong, K. C. Fong, Y. He, W. H. Yoon and
H.-S. Choi, Angew. Chem., Int. Ed., 1999, 38, 1676; K. C. Nicolaou,
J. K. Jung, W. H. Yoon, Y. He, Y.-L. Zhong and P. S. Baran, Angew.
Chem., Int. Ed., 2000, 39, 1829; C. Chen, M. E. Layton, S. M. Sheehan
and M. D. Shair, J. Am. Chem. Soc., 2000, 122, 7424; N. Waizumi, T.
Itoh and T. Fukuyama, J. Am. Chem. Soc., 2000, 122, 7825; Q. Tan and
S. J. Danishefsky, Angew. Chem., Int. Ed., 2000, 39, 4509.
2
with SmI proceeded with complete regioselectivity to generate
the required quaternary centre.§ Compound 23 was next
deprotected under acidic conditions followed by iodination to
give 25. Zinc reduction and protection of the resultant hydroxy
group with an acetyl group gave 26.¶
We are currently exploring methods to complete the fully
functionalized core and modify the side chains en route to
phomoidride B.
I am grateful to Professor K. Ohkata for his valuable advice
and to Dr S. Kojima for prereading of the manuscript. I am also
grateful to Drs Y. Hiraga and R. Takagi for assistance in
NMR.
4
5
J. B. Hendrickson and J. S. Farina, J. Org. Chem., 1980, 45, 3359; P. A.
Wender, K. D. Rice and M. E. Schnute, J. Am. Chem. Soc., 1997, 119,
7
897.
R. Hara, T. Furukawa, Y. Horiguchi and I. Kuwajima, J. Am. Chem.
Soc., 1996, 118, 9186.
6 J. R. Tagat, M. S. Puar and S. W. McCombie, Tetrahedron Lett., 1996,
7, 8463.
3
7
8
Y. Ito, T. Hirato and T. Saegusa, J. Org. Chem., 1978, 43, 1011.
K. C. Nicolaou, Y.-L. Zhong and P. S. Baran, J. Am. Chem. Soc., 2000,
1
22, 7596.
Notes and references
9
J. Tsuji, I. Minami and I. Shimizu, Tetrahedron Lett., 1983, 24, 1793.
†
In this reaction 16 was obtained stereoselectively at the C2 centre. While
10 R. A. Batey and W. B. Motherwell, Tetrahedron Lett., 1991, 32,
the reason for this selectivity is unclear, it may be due to the proton
6211.
Chem. Commun., 2001, 1552–1553
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