An expeditious approach toward the total synthesis of CP-263,114

Article abstract of DOI:10.1021/ol015979n

matrix presented Assembly of the carbocyclic core of CP-263,114 has been accomplished efficiently and in high yield. Key steps include a phenolic oxidation/ intramolecular Diels-Alder sequence, tandem radical cyclization, and the late-stage fragmentation

Full text of DOI:10.1021/ol015979n

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2435-2438
An Expeditious Approach toward the
Total Synthesis of CP-263,114
Jo´n T. Njardarson, Ivar M. McDonald, David A. Spiegel, Munenori Inoue, and
John L. Wood*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity,
New HaVen, Connecticut 06520-8107
john.wood@yale.edu
Received April 12, 2001
ABSTRACT
Assembly of the carbocyclic core of CP-263,114 has been accomplished efficiently and in high yield. Key steps include a phenolic oxidation/
intramolecular Diels−Alder sequence, tandem radical cyclization, and the late-stage fragmentation of a densely functionalized isotwistane
skeleton.
In the preceding Letter,1 we described the evolution of a
synthetic approach to CP-263,114 (1). On the basis of these
efforts, our current retrosynthetic analysis focuses on the late-
stage fragmentation of a heavily functionalized isotwistane
ring system. Whereas our earlier efforts focused on a
Wharton fragmentation,1 in this series we hoped to achieve
the same result via a carbon-based fragmentation (2, Scheme
1). Although the bicyclo[2.2.2]octane construct offers a
variety of Diels-Alder disconnections, we were inspired by
reports from Yates and Wessely and began by focusing on
a tandem phenolic oxidation/intramolecular Diels-Alder
sequence.2,3
of 5 using lead(IV) acetate in acetic acid furnished only
minuscule quantities of the desired orthoquinol oxidation
product (6). However, after much experimentation, we found
that Quinkert’s modified Wessely conditions afforded an
improved yield of oxidation products.6 Thus, reaction of
phenol 5 under these conditions furnished two products (6
and 7) in a 1:3 ratio, respectively. Heating of triene 6 in
Scheme 1
To investigate the Yates chemistry, we prepared 5, via a
route that commenced with known ester 3.4 Alkylation of 3
with propargyl bromide set the stage for a Gabriele dicar-
bonylation reaction (Scheme 2)5 that, followed by removal
of the allyl group, furnished free phenol 5. Wessely oxidation
(1) Njardarson, J. T.; Wood, J. L. Org. Lett. 2001, 3, 2431 and references
therein.
(2) Wessely, F.; Sinwel, F. Monatsch. Chem. 1950, 81, 1053.
(3) Yates, P.; Maras, T. S. Can. J. Chem. 1988, 66, 1.
(4) Kunio, H.; Jun, A.; Kyoko, S.; Toshihiro, K. J. Org. Chem. 1994,
59, 203.
(5) Gabriele, B.; Costa, M.; Salerno, G.; Chiusoli, G. P. J. Chem. Soc.,
Perkin Trans. 1 1994, 83.
10.1021/ol015979n CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/10/2001

Our point of departure in the quinone monoketal approach
was the known catechol 138 (Scheme 4) which we desym-
Scheme 2
Scheme 4
metrized under Mitsunobu conditions with alcohol 149 to
furnish mono ether 15 in good yield. Our hope was that
aromatic oxidation of 15 would be followed by trapping and
intramolecular Diels-Alder reaction to furnish 17, a com-
pound poised for further advancement to the isotwistane and
possessing the desired stereochemical relationship between
the side chains.
In the event, we were pleased to find that exposure of 15
to iodobenzene diacetate (IBDA) in methanol at room
temperature resulted in the desired cascade reaction and
provided 18 in good yield (Scheme 5). In employing more
synthetically useful trapping reagents, we found that prop-
argyl alcohol in acetonitrile provided the desired cycloadduct
19 in excellent yield. Moreover, the acid oxidation state
found at C(27) in the natural product could be readily
incorporated simply by changing the oxidizing agent from
IBDA to lead(IV) acetate, to furnish 20 in high yield.
benzene yielded 8, thus completing construction of the
isotwistane skeleton in only five steps from 3.
Our inability to optimize the conversion of 5 to 6 beyond
20% isolated yield coupled with the inefficiencies associate
with transforming the Diels-Alder-derived olefin into the
trans-disposed side chains led us to explore alternative
phenolic oxidations. Specifically, attention was turned to
orthoquinone monoketals since the litereature suggests that
these systems often are superior to those used in the Wessely-
type oxidations.7 In addition to altering the oxidation
substrate, we focused on a different Diels-Alder discon-
nection (cf. 9 f 10 and 11 f 12). As illustrated in Scheme
3, the latter of these two allows efficient access to the trans-
Scheme 3
Scheme 5
orientated side chains (i.e., R1 and R2) found in the natural
product.
(6) Quinkert, G.; Billhardt, U.-M.; Jakob, H.; Fischer, G.; Glenneberg,
J.; Nagler, P.; Autze, V.; Heim, N.; Wacker, M.; Schwalbe, T.; Kurth, Y.;
Bats, J. W.; Durner, G.; Zimmerman, G.; Kessler, H. HelV. Chim. Acta
1987, 70, 771.
(7) Quideau, S.; Pouysegu, L. Org. Prep. Proc. Int. 1999, 617.
2436
Org. Lett., Vol. 3, No. 16, 2001

With these promising results in hand, we continued
construction of the isotwistane skeleton. Treatment of 19 with
triphenyltin hydride under the various reaction conditions
afforded the desired cyclization product 21 (Scheme 6), the
To our delight, treatment of bromoacetal 24 with tributyltin
hydride and triethylborane delivered 27 as a mixture of
diastereomers in excellent yield for the two steps. Mecha-
nistically, this transformation likely proceeds via initial
formation of primary radical 25 followed by 5-exo-trig
cyclization into the adjacent exocyclic olefin. A second
cyclization event into the maleate followed by trapping of
hydrogen from the less hindered face yields 27. The acetal
diastereomers (27a and 27b) were separated, and the
stereochemistry was confirmed via single-crystal X-ray
analysis of 27a.12
Scheme 6
Curious as to functional group tolerance in the cyclization
cascade, we explored preformation of the maleic anhydride
unit found in the natural product (Scheme 8). Thus, hydroly-
Scheme 8
highest yield being achieved with triethylborane in toluene.10
Stannane 21 was obtained in all cases as a single isomer,
the structure of which was confirmed by X-ray crystal-
lographic analysis.
To complete the isotwistane core, we turned to Stork’s
bromoacetal method in hope of advancing tertiary alcohol
21 via the intramolecular tandem/radical cyclization sequence
outlined in Scheme 7.11 To this end, stannane 21 was
protodestannylated with dry hydrochloric acid to furnish 22
which was efficiently converted to bromoacetal 24 by
exposure to dibromoethyl ether 23 and N,N-dimethylaniline.
Scheme 7
sis and dehydration of maleate 22 with acetic anhydride
provided maleic anhydride 28 in good yield. As before,
derivatization as the corresponding bromoacetal was followed
by exposure to Bu3SnH and Et3B. We were pleased to find
that the radical cascade sequence again delivered a cycliza-
tion product (29) in excellent yield.
Having established an extremely efficient method for
constructing the isotwistane core, we turned our attention to
the acid oxidation state at C27 (Scheme 1).13 Since we had
already successfully incorporated an acetate moiety into the
phenolic oxidation cascade by using Pb(OAc)4 (i.e., 15 f
20), our efforts focused on advancing the latter. In what
proved to be a remarkable one-pot procedure, we discovered
that simply exposing 20 to LiTMP and Eschenmoser’s salt
effects conversion to 30, thus setting the stage for the tandem
radical cascade.14 As before, bromoacetal formation furnished
(8) Anderson, D. R.; Koch, T. H. J. Org. Chem. 1978, 43, 2726.
(9) Fujisawa, T.; Kurita, Y.; Kawashima, M.; Sato, T. Chem. Lett. 1982,
1641.
(10) Nishida, A.; Takahashi, H.; Takeda, H.; Takada, N.; Yonemitsu,
O. J. Am. Chem. Soc. 1990, 112, 902.
(11) Stork, G.; Biller, S. A.; Rychnovsky, S. D.J. Am. Chem. Soc. 1983,
105, 3741.
(12) 27a and 27b were subjected separately to Jones conditions, in which
they both converged to the same lactone.
(13) Phomoidride numbering system as reported in the following:
Dabrah, T. T.; Kaneko, T.; Massefski, W., Jr.; Whipple, E. B. J. Am. Chem.
Soc. 1997, 119, 1594.
(14) Lansbury, P. T.; Zhi, B.-X. Tetrahedron Lett. 1988, 29, 5735.
Org. Lett., Vol. 3, No. 16, 2001
2437

Scheme 9
Scheme 10
In summary, we have devised a short and efficient
synthesis of an isotwistane core needed for the synthesis of
the phomoidrides. The approach employs a phenolic oxida-
tion/cycloaddition cascade followed by two substrate-
controlled radical cyclizations. Additionally, installations of
the anhydride moiety and the C(27) oxidation state have been
addressed in parallel studies. Importantly, preliminary results
show great promise for completing the phomoidride synthe-
ses via fragmentation of the isotwistane core.
31 (Scheme 9), and subsequent treatment of 31 with
tributyltin hydride effected the cascade event. In contrast to
previous substrates, the desired 5-exo-5-exo-trig product (32)
was accompanied by a 6-endo-4-exo-trig product (33)
(produced in a 7:3 ratio, respectively).
Having developed methods for installing both the anhy-
dride unit and the appropriate oxidation level at C27, our
attention turned to the critical fragmentation. Our initial
explorations began with acetal mixture 27, which was
converted to dithiolane 34 using standard protocols. To
facilitate analysis of the product mixture, the dithiolane was
removed using Raney Ni to furnish 35. Formation of
S-methyl dithiocarbonate 36 was accomplished using an
excess of potassium hydride in combination with carbon
disulfide and methyl iodide as described by Barton.15 To our
delight, reaction of 36 with samarium diiodide in the presence
of HMPA furnished the desired fragmentation 37 in 60%
yield (Scheme 10).16
Acknowledgment. We acknowledge the support of this
work by Bristol-Myers Squibb, Eli Lilly, Glaxo-Wellcome,
Yamanouchi, and Zeneca through their Faculty Awards
Programs and the Camille and Henry Dreyfus Foundation
for a Teacher-Scholar Award. We thank Susan DeGala for
securing the X-ray crystallographic analyses.
Supporting Information Available: Experimental details
and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL015979N
(15) Barton, D. H. R.; Parekh, S. I.; Tse, C.-L. Tetrahedron Lett. 1993,
34, 2733.
(16) Ananthanarayan, T. P.; Gallagher, T.; Magnus, P. Chem. Commun.
1982, 709.
2438
Org. Lett., Vol. 3, No. 16, 2001