Diastereoselective formal total synthesis of the DNA polymerase alpha inhibitor, aphidicolin, using palladium-catalyzed cycloalkenylation and intramolecular Diels-Alder reactions.

Article abstract of DOI:10.1021/ol034027+

[structure: see text] A novel diastereoselective formal synthesis of aphidicolin has been achieved by exploiting a unique characteristic of a bicyclo[3.2.1]octane prepared by employing a palladium-catalyzed cycloalkenylation process.

Full text of DOI:10.1021/ol034027+

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1193-1195
Diastereoselective Formal Total
Synthesis of the DNA Polymerase r
Inhibitor, Aphidicolin, Using
Palladium-Catalyzed Cycloalkenylation
and Intramolecular Diels−Alder
Reactions
Masahiro Toyota,* Masato Sasaki, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Science,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp
Received January 7, 2003
ABSTRACT
A novel diastereoselective formal synthesis of aphidicolin has been achieved by exploiting a unique characteristic of a bicyclo[3.2.1]octane
prepared by employing a palladium-catalyzed cycloalkenylation process.
Palladium-promoted cycloalkenylation reactions of silyl enol
ethers with olefins are key C-C bond-forming reactions
utilized in organic synthesis.1 The catalytic version of this
process, developed in our laboratory, which produces bicyclic
compounds, including bicyclo[3.2.1]octanes,2 perhydro-pen-
talenes,3 hydrindanes,3 and benzo-fused bicyclo[3.3.0]-
octanes,3 has been applied to the construction of bioactive
natural products, e.g., C20 gibberellins4 and methyl atis-16-
en-19-oate.2,5 As part of an effort to demonstrate the
versatility of the palladium-catalyzed cycloalkenylation, we
have recently used this process in a novel approach to the
synthesis of the molecularly complex and biologically
significant target aphidicolin (1).
Aphidicolin (1)6 is a tetracyclic terpenoid that exhibits
significant antiviral and antitumor activity.7 Following its
isolation and the demonstration of its potential pharmaco-
logical uses, numerous synthetic approaches to 1 have been
developed.8 Aphidicolin (1) contains (1) a spiro-fused
bicyclo[3.2.1]octane CD ring architecture, (2) eight stereo-
(1) (a) Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa, T. J.
Am. Chem. Soc. 1979, 101, 494-496. (b) Kende, A. S.; Roth, B.; Sanfilippo,
P. J.; Blacklock, T. J. J. Am. Chem. Soc. 1982, 104, 5808-5810. (c)
Shibasaki, M.; Mase, T.; Ikegami, S. J. Am. Chem. Soc. 1986, 108, 2090-
2091.
(4) Toyota, M.; Odashima, T.; Wada, T.; Ihara, M. J. Am. Chem. Soc.
2000, 122, 9036-9037.
(5) Toyota, M.; Wada, T.; Ihara, M. J. Org. Chem. 2000, 65, 4565-
4570.
(2) (a) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am. Chem.
Soc. 1998, 120, 4916-4925. (b) Recent review: Toyota, M.; Ihara, M.
Synlett 2002, 1211-1222.
(3) Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.; Arakawa, M.;
Ihara, M. Org. Lett. 2002, 4, 4293-4296.
(6) Brundret, K. M.; Daliziel, W.; Hesp, B.; Jarvis, J. A. J.; Neidle, S.
J. Chem. Soc., Chem. Commun. 1972, 1027-1028.
(7) (a) Buchnall, R. A.; Moores, H.; Simms, R.; Hesp, B. Antimicrob.
Agents Chemother. 1973, 4, 294-298. (b) Ikegami, S.; Taguchi, T.; Ohashi,
M.; Oguro, M.; Mano, Y. Nature 1978, 275, 458-460.
10.1021/ol034027+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003

genic centers, of which five are associated with ring junc-
tions, and (3) a sterically crowded array of two adjacent
quaternary centers at C-9 and C-10. Critical problems that
need to be addressed in any synthesis of aphidicolin (1) are
(1) the construction of the tetracyclic ring system with
appropriate control of stereochemistry in the CD ring system
and (2) stereoselective introduction of four hydroxy groups.
Previous studies in this laboratory led to the development
of two formal syntheses of aphidicolin (1), one employing
palladium-catalyzed Heck reaction8a and the other a cycloi-
somerization process8c in key steps. However, both ap-
proaches are problematic due to difficulties with effective
functionalization of the AB ring system and the D ring.
Herein, we describe an improved synthesis of aphidicolin
(1) that features a palladium-catalyzed cycloalkenylation
process, stereoselective oxirane formation to install D ring
functionality, and intramolecular Diels-Alder reaction of a
silyloxydiene grouping to simplify introduction of A-ring
functionality.
Scheme 2 a
a Reagents: (a) LDA, HMPA, THF, -78 °C; NCCO2Me, 93%.
(b) LiAH4, THF; 10% HClO4, THF; MOMCl, i-Pr2NEt, CH2Cl2,
76%. (c) LDA, HMPA, THF, -78 °C; TBDMSCl, 91%. (d)
Pd(OAc)2 (5 mol %), DMSO, O2 (1 atm), 45 °C, 89%. (e)
L-Selectride, THF, -78 °C, 93%. (f) Me2S+ (O)CH2-, THF, 89%.
(g) 1 M KOH, dioxane, 100 °C. (h) Me2CdO, PPTS, reflux, 91%
for two steps.
The retrosynthetic plan guiding this synthetic approach to
aphidicolin (1) is outlined in Scheme 1. We anticipated that
to the corresponding cross-conjugated silyl enol ether,
cycloalkenylation10 is performed in the presence of 5 mol
% Pd(OAc)2 to furnish the bicyclo[3.2.1]octenone 9 in 89%
yield. Selective reduction of the conjugated double bond of
9 is then achieved by using L-Selectride. To introduce the
oxirane moiety stereoselectively, we used the Corey-
Chaykovsky protocol.11 The desired oxirane 10 is obtained
as the major product and is readily separated from the minor
isomer by silica gel column chromatography. The proton and
carbon resonances in the NMR spectra of 10 were assigned
by using 1H-1H COSY and 1H-13C COSY techniques. The
relative stereochemistry of 10 is established by employing
NOESY correlations between the olefinic and methylene
protons, as depicted in Scheme 2. Importantly, the stereo-
selectivity of the oxirane-forming reaction is in full ac-
cordance with Corey’s suggestion that equatorial addition
of dimethylsulfoxonium methylide to the carbonyl group of
cyclohexanone derivatives is favored. Basic treatment of 10
followed by protection of the resulting diol provides the
acetonide 11.
Triene 19, required for the intramolecular Diels-Alder
reaction, is synthesized by the pathway shown in Scheme 3.
Allylation of the ketone, resulting from ozonolysis of olefin
11, affords olefin 12 as a single diastereomer. This substance
is stereoselectively transformed to R-alcohol 13 by hydrobo-
ration-oxidation, followed by protection and hydride reduc-
tion. Direct dehydration of 13, by using either the Martin or
Burgess reagent, is not successful. However, 13 can be
converted to the corresponding olefin 14 by syn elimination
of its thioimidazolide derivative.
Scheme 1. Retrosynthetic Analysis of Aphidicolin
intramolecular Diels-Alder reaction of triene 3 would
proceed stereoselectively to form the pentacyclic ring system
in 2, a precursor of aphidicolin (1). We believed that stereo-
selective introduction of the diene and dienophile moieties
in 3 and the oxirane group in 4 could be achieved by
exploiting the characteristics of the bicyclo[3.2.1]octane ring
system. Finally, in a sequence based on this plan, intermedi-
ate 5 would be constructed by using palladium-catalyzed
cycloalkenylation of the cross-conjugated silyl enol ether 6.2
Our approach begins with the preparation of acetonide 11
by the route shown in Scheme 2. Carbomethoxylation of
6-allyl-3-isobutoxy-2-cyclohexen-1-one (7)9 affords the ester,
which is subjected to sequential reduction, acid treatment,
and etherification. After conversion of the resulting enone 8
We anticipated that hydrogenation of the resulting olefin
would occur preferentially from the convex face. In the event,
catalytic hydrogenation of the olefinic alcohol, obtained by
(8) Recent review: Toyota, M.; Ihara, M. Tetrahedron 1999, 55, 5641-
5679. Our previous work: (a) Toyota, M.; Nishikawa, Y.; Fukumoto, K.
Tetrahedron Lett. 1994, 35, 6495-6498. (b) Toyota, M.; Nishikawa, Y.;
Seishi, T.; Fukumoto, K. Tetrahedron 1994, 50, 10183-10192. (c) Toyota,
M.; Nishikawa, Y.; Fukumoto, K. Tetrahedron Lett. 1995, 36, 5379-5382.
(d) Toyota, M.; Nishikawa, Y.; Fukumoto, K. Tetrahedron 1996, 52,
10347-10362.
(10) Toyota, M.; Rudyanto, M.; Ihara, M. J. Org. Chem. 2002, 67, 3374-
3386.
(11) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-
1364.
(9) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775-1776.
1194
Org. Lett., Vol. 5, No. 8, 2003

Finally, the requisite C-4 hydroxymethyl group is introduced
by reaction with formaldehyde in the presence of anhydrous
tetrabutylammonium fluoride in THF. The NMR spectro-
scopic data of 21, the key synthetic intermediate formed in
this process, were identical to those previously reported.12
Scheme 3 a
The high degree of stereoselectivity observed in the intra-
molecular Diels-Alder reaction of 19 is attributed to the
strong conformational bias favoring transition state A, in
which 1,3-allylic strain between the olefinic hydrogen of the
isopropenyl group and a ring proton is minimized, and the
absence of a nonbonded interaction between the equatorial
hydrogen and the methyl group on the diene portion that is
present in transition state B (Figure 1). The conversion of
21 to aphidicolin (1) was reported earlier by Ireland.12
a Reagents: (a) O3, MeOH, -78 °C; Me2S, 96%. (b) LDA,
HMPA, THF, -78 °C; CH2dCHCH2I, -78 to rt, 92%. (c)
Dicyclohexylborane, THF; NaOH, H2O2, 0 °C. (d) TBDMSCl,
imidazole, DMF, 0 °C. (e) NaBH4, MeOH, 86%. (f) (Imid)2CdS,
CH2Cl2, reflux, 96%. (g) 250 °C, toluene, in stainless autoclave,
77%. (h) Bu4NF, THF, 100%. (i) H2, PtO2, MeOH, 100%. (j) NaH,
BnBr, DMF, 75%. (k) 10% HClO4, THF, 45 °C; Me2CO, p-TsOH,
53%. (l) SO3‚Py, DMSO, Et3N; MeLi, Et2O, -78 °C. (m) TPAP,
NMO, 4 Å molecular sieves, CH2Cl2, 50% for three steps. (n)
Ph3P+MeBr-, BuLi, toluene, 85%. (o) Li, liquid NH3; NH4Cl, 96%.
(p) SO3‚Py, DMSO, Et3N, 83%; (EtO)2P(O)CH(Me)COMe, NaH,
THF, 95%. (q) TBDMSOTf, i-Pr2NEt, CH2Cl2, 93%. (r) 230 °C,
toluene, in stainless autoclave, 75%. (s) CH2O, anhydrous Bu4NF,
THF, 44%.
Figure 1. Plausible conformations for the intramolecular Diels-
Alder reaction.
In conclusion, a novel and improved diastereoselective
formal total synthesis of aphidicolin has been achieved by
exploiting the characteristics of a bicyclo[3.2.1]octane ring
system that was poduced by employment of a palladium-
catalyzed cycloalkenylation process. In this sequence, highly
diastereoselective oxirane formation was employed to install
C-16 functionality. The strategy used in this aphidicolin syn-
thesis, relying on the combined use of palladium-catalyzed
cycloalkenylation and intramolecular Diels-Alder reactions
for diastereoselective polycyclic ring system formation,
should be broadly applicable to the preparation of targets
with related structural features.
removal of the TBDMS group from 14, produces the
corresponding alcohol 15 as a single stereoisomer. Sequential
benzylation of 15, acid treatment, and reprotection of the
partially generated 1,2-diol results in the formation of alcohol
16. Formation of the dienophile moiety is achieved by
successive functional group manipulations of 16. Accord-
ingly, Parikh oxidation of 16 followed by methyllithium
addition and TPAP oxidation provides methyl ketone 17,
which is converted to 18 by Wittig olefination and reductive
debenzylation. Assembly of the diene part of the alcohol 18
involves Parikh oxidation followed by Emmons olefination
and silyl enol ether formation.
Acknowledgment. This work is supported by a Grant-
in-Aid (No. 14571994) from the Ministry of Education,
Science, Sports and Culture, Japan.
Supporting Information Available: Full experimental
details and spectral data for 8-17. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL034027+
Intramolecular Diels-Alder reaction of 19, conducted in
toluene at 230 °C in a stainless steel autoclave, yields the
desired cycloadduct 20 (75%) as a single stereoisomer.
(12) Ireland, R. E.; Dow, W. C.; Godfrey, J. D.; Thaisrivongs, S. J. Org.
Chem. 1984, 49, 1001-1013.
Org. Lett., Vol. 5, No. 8, 2003
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