Inter- and intramolecular reductive coupling reactions: an approach to the phorbol skeleton.

Article abstract of DOI:10.1021/ol006301v

[reaction: see text] An expeditious convergent route to the ABC-tricyclic core of the phorbol esters is described. The chemistry capitalizes upon both inter- and intramolecular reductive coupling processes promoted electrochemically and via the use of sam

Full text of DOI:10.1021/ol006301v

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2873-2876
Inter- and Intramolecular Reductive
Coupling Reactions: An Approach to
the Phorbol Skeleton
Georgia Law Carroll and R. Daniel Little*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara,
Santa Barbara, California 93106
little@chem.ucsb.edu
Received July 7, 2000
ABSTRACT
An expeditious convergent route to the ABC-tricyclic core of the phorbol esters is described. The chemistry capitalizes upon both inter- and
intramolecular reductive coupling processes promoted electrochemically and via the use of samarium diiodide.
The phorbol esters 1b are well-known for their tumor-
promoting properties.1 Studies have also established that the
closely related materials 2 and 3 display phorbol inhibitory
or anti-tumor properties.2 This fine line between two
extremes of biological activity for such similar materials adds
to their attractiveness as synthetic targets and potential
sources of new bioactive materials. Phorbol (1a) has been
synthesized, most recently in an enantiopure state, by Wender
and co-workers (Scheme 1).3 In addition to their pioneering
efforts, those of others have led to the development of a
number of ingenious routes to the tigliane, daphnane, and
ingenane class of naturally occurring substances.4
(Scheme 2) features the use of both inter- and intramolecular
reductive coupling strategies to form the C5-C6, C8-C9, and
C9-C10 bonds and provides an exceptionally rapid access
to the framework. We selected 4 as a target structure, and
compounds 5, 6, and 7 as key subgoals.
We first elected to synthesize 7 (as 10 and 11), and did
so in the following manner. In each case, an electroreductive
Scheme 1
In this paper we report our recent studies directed toward
construction of the tricyclic core of the phorbols. The route
(1) Naturally Occurring Phorbol Esters; Evans, F. J., Ed.; CRC Press:
Boca Raton, FL, 1986. (b) Berenblum, I. In Risk Factors and Multiple
Cancer; Stoll, B., Ed.; John Wiley and Sons: New York, 1984. (c) Wender,
P. A.; Koehler, K. F.; Sharkey, N. A.; Dell ’Aquila, M. L.; Blumberg, P.
M. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 4214.
(2) (a) Szallasii, Z.; Krsmanovic, L. Blumberg, P. M. Cancer Res. 1993,
53, 2507. (b) Yoshida, M.; Feng, W. J.; Saijo, N.; Ikekawa, T. Int. J. Cancer
1996, 66, 268.
(3) (a) Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112,
4956. (b) Wender, P. A.; Mascaren˜as, J. L. J. Org. Chem. 1991, 56, 6267.
(c) Wender, P. A.; Rice, K. D.; Schnute, M. J. Am. Chem. Soc. 1997, 119,
7897.
10.1021/ol006301v CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/12/2000

as it can more readily be removed by extraction into the
aqueous layer during workup.
Scheme 2
Keto nitrile 10 and ketone 11 were examined as candidates
for the proposed intermolecular reductive coupling with
enoate 6. For the hydroxynitrile 9a, produced from the
electroreductive cyclization of 8a, this simply required
oxidation with PCC. For 9b and 9c, reduction with LAH
converted each to a mixture of diols (Scheme 3). Although
Scheme 3
cyclization was used.5 Ester 9b and lactone 9c were
constructed from enoate 8b; nitrile 9a was derived from 8a.
Voltammetric studies (cyclic voltammetry [CV]) of 8a and
8b show an irreversible reduction wave indicative of the
existence of a rapid reaction on the time scale of the CV
scan, following the electron transfer step. Our previous
mechanistic studies have shown that process to be a rate-
determining protonation of the initially formed radical anion.6
This is followed by the addition of a second electron and
cyclization of the resulting carbanion. Reactions were carried
out at a controlled potential, in the presence of a variety of
proton donors, solvents, electrode materials, supporting
electrolytes, and additives. As illustrated in Table 1 (entry
1), the best results were obtained using a mercury cathode
with dimethyl malonate as the proton source. Recent studies
have shown that malononitrile is often preferable, however,
selective oxidation of the 2° alcohol to the desired keto-
alcohol could be accomplished with NaOCl, rapid formation
of the internal hemi-ketal made further transformations
problematic. Consequently, selective protection as the pri-
mary benzoate was required prior to oxidation. PCC oxida-
tion provided the R-substituted ketobenzoate 11 in high yield.
With 10 and 11 in hand, we were positioned to examine
the samarium diiodide promoted intermolecular reductive
coupling to enoate 6.7 The latter was conveniently synthe-
sized from vinyl bromide 12 via lithium-halogen exchange
and subsequent treatment with methyl chloroformate (Scheme
4).8 Coupling of 6 and ketobenzoate 11 occurred with modest
Table 1. Electroreductive Cyclization
Scheme 4
efficiency to afford hydroxy ester 15 as a single stereoisomer.
We presume the stereoselectivity reflects the role of sa-
marium in both complexing to and holding the coupling
(4) For example, see: (a) Lee, K.; Cha, J. K. Org. Lett. 1999, 1, 523.
(b) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A.
L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976. (c) Shigeno, K.; Sasai,
H.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 4937. (d) Sugita, K. Neville,
C.; Sodeoka, M.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1995, 36, 1067.
(e) Rigby, J.; Keirkus, P. Tetrahedron Lett. 1989, 30, 5073.
(5) (a) Little, R. D. Chem. ReV. 1996, 96, 93. (b) Little, R. D.; Schwaebe,
M. K. Reductive Cyclizations at the Cathode. In Electroorganic Synthesis:
Bond Formation at Anode and Cathode; Steckhan, E., Ed.; Topics in Current
Chemistry 185; Springer: Berlin, 1997; pp 1-48.
(6) Fry, A. J.; Little, R. D.; Leonetti, J. J. Org. Chem. 1994, 59, 5017.
2874
Org. Lett., Vol. 2, No. 18, 2000

partners in the manner portrayed by 13 (Scheme 5). While
it is more sterically demanding than the alternative formula-
enoate and also minimizes steric interactions. Unlike the
chemistry shown in Scheme 5 where the stereochemistry at
the pro C10 carbon is opposite to that needed to access the
natural products, the coupling between 10 and 6 leads to
the desired stereochemical outcome at the pro C8, C9, and
C10 carbons.9
Scheme 5
The preceding examples (Schemes 5 and 6) illustrate that
it is possible to obtain either stereochemical outcome at C10
simply by making the appropriate choice of substituents
appended to the coupling partners. That obtained in the case
of ketonitrile 10 is the outcome needed for natural product
synthesis. In the discussion that follows, we focus attention
upon 15, however, since the nitrile proved difficult to
manipulate in subsequent transformations.10 Furthermore, our
goal at this point was to determine whether the methodology
portrayed in Scheme 2 could be used to gain access to the
basic skeleton of the natural products.
In preparation for cyclization leading to the formation of
the pro C5-C6 bond and the assembly of the seven-
membered ring, we treated 15 with sodium methoxide in
methanol/THF. This led to removal of the benzoate, epimer-
ization R to the methyl ester, and lactonization, affording 5
in an 85% yield. Conversion of 5 to the iodide using I2, PPh3,
and imidazole in THF provided iodo lactone 18 in yields of
90% (Scheme 7).
tions 14a and b, the former maximizes the opportunity for
complexation between samarium and each of the oxophilic
sites located on both of the reacting partners.
Scheme 7
Interestingly, when the oxophilic benzoyloxyethyl side
chain of 11 is replaced by a cyanomethyl substituent (see
10), the stereochemical outcome at the pro-C10 carbon is
reVersed (Scheme 6). This is consistent with a picture where
Scheme 6
The best method for reductive cyclization of 18 used
samarium diiodide. The initial reaction was clean but required
5-7 h to reach completion and occurred with variable yields
(43-68%). Upon the addition of catalytic nickel(II) iodide,
the reaction reached completion within 1 h and yields
improved to 82-88%.11 A single isomer was isolated and
established to be the hemiketal 4; the presence of the
(7) (a) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (b)
Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99, 745. (c) Fukuzawa, S.;
Nakanishi, A.; Fujinami, T.; Sakai, Shizuyoshi, S. J. Chem. Soc., Perkin
Trans. 1 1988, 1669. (d) Fukuzawa, S.; Seki, K.; Tasuzawa, M.; Mutoh,
K. J. Am. Chem. Soc. 1997, 119, 1482. (e) Fukuzawa, S.; Iida, M.;
Nakanishi, A.; Fujinami, T.; Sakai, Shizuyoshi, S. J. Chem. Soc., Chem.
Commun. 1987, 920. (f) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai,
Shizuyoshi, S. J. Chem. Soc., Chem. Commun. 1986, 624.
(8) Smith, A. B., III.; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J.
Org. Chem. 1982, 47, 1855.
(9) Yields for this transformation ranged from 68 to 74%. The major
product, consistently isolated in a 56% yield, was compound 17. The
remainder of the mass consisted of a mixture of open hydroxy ester and
lactonized forms.
(10) Selective manipulation of the nitrile in the presence of the lactone
proved problematic. Thus, while the use of 1 equiv of DIBAL did result in
the formation of the desired lactol, further reductions proved unselective.
Acid or base hydrolysis procedures also proved problematic and require
further investigation before they can be used reliably.
the coupling partners, in this case 6 and 10, approach one
another in the sterically least demanding manner. Since
coordination of samarium to the nitrile is not expected to
occur, the trajectory portrayed by 16 allows optimal interac-
tion between the samarium ketyl and the ester unit of the
Org. Lett., Vol. 2, No. 18, 2000
2875

hemiketal was evident by the absence of a carbonyl signal
in both the IR and 13C NMR spectra (Scheme 8).
is opposite to that of the natural materials. It is important to
reiterate that we are able to control the stereochemistry,
thereby making the appropriate choice of the side chain
substituent appended to the ketone coupling partner (compare
Schemes 5 and 6).
Scheme 8
We have described a rapid and direct means to assemble
the basic skeleton of the phorbol esters. The chemistry more
clearly establishes the utility of both inter- and intramolecular
reductive coupling methods in synthesis. Efforts to use it to
synthesize functionally more elaborate bioactive phorbol
analogues are in progress.
Acknowledgment. We thank the National Science Foun-
dation for supporting this research and Dr. X. Bu for the
X-ray structural determination of 4 and 17.
This material provided a single crystal from which X-ray
data was acquired. The structure was solved and the
stereochemical outcome was determined unambiguously. The
pro C4, C8, and C9 stereocenters match those of the phorbol
skeleton. The stereochemistry at C10 is consistent with the
intermolecular coupling model portrayed in Scheme 5 but
Supporting Information Available: Spectral data for 6,
8a, 8b, 9a, 9b, 9c, 10, 11, 15, 17, 5, 18, and 4. This material
is available free-of-charge via the Internet at http://pubs.acs.org.
(11) (a) Machrouhi, F.; Hamann, B.; Namy, J.-L.; Kagan, H. B. Synlett
1996, 633. Molander, G. A.; Machrouhi, F. J. Org. Chem. 1999, 64, 4119.
(c) Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62, 7418.
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