New conjunctive reagents as cross-coupling partners en route to retinoid-like polyenes

Article abstract of DOI:10.1021/ol051406p

(Chemical Equation Presented) New conjunctive reagents E-2 and Z-3 can be used, after transmetalation, in Negishi couplings with vinyl and aryl iodides. The subsequently unmasked terminal alkynes can be further manipulated to arrive at retinoid-like produ

Full text of DOI:10.1021/ol051406p

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4561-4564
New Conjunctive Reagents as
Cross-Coupling Partners En Route to
Retinoid-like Polyenes
Bruce H. Lipshutz,*,† Giuliano C. Clososki,† Will Chrisman,† David W. Chung,†
David B. Ball,‡ and Jennifer Howell‡
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara,
California 93106, and Department of Chemistry, California State UniVersity, Chico,
California 95929
lipshutz@chem.ucsb.edu
Received June 16, 2005
ABSTRACT
New conjunctive reagents E-2 and Z-3 can be used, after transmetalation, in Negishi couplings with vinyl and aryl iodides. The subsequently
unmasked terminal alkynes can be further manipulated to arrive at retinoid-like products.
Retinoids regulate a vast array of biological processes,
including cell differentiation and proliferation, control of
embryonic development, as well as apoptosis.1 They are
routinely used clinically both in dermatology (e.g., accutane)
and for treatment of select oncological diseases. Synthetic
studies abound in this field, with many potentially useful
routes to the highly conjugated polyenic core where the
accent is on analogue formation.2 Most of the disconnections
associated with the parent skeleton, all-trans-retinoic acid,
as well as the valued 9Z- and 13Z-isomers, have been
examined. Traditional Wittig/Horner-Emmons chemistry,3
Julia couplings,4 and more recent organometallic cross-
coupling methodology5 have been successfully utilized. In
this paper, we disclose two new linchpin or “conjunctive”
reagents that have been designed for rapid construction
of stereochemically controlled analogues of the parent
skeleton.
Disconnection of the basic retinoic acid array between C-8,
C-9, and C-14, C-15 in 1 leads to two isomeric seven carbon
subunits E-2 and Z-3 that allow for direct introduction of
C-9 in either the E- or Z-geometry via Negishi coupling of
the derived vinylzinc reagents (Scheme 1). Subsequent
Scheme 1
† University of California.
‡ California State University.
(1) (a) The Retinoids; Sporn, M. B., Roberts, A. B., Goodman, D. S.,
Eds.; Raven Press: New York, 1994. (b) Altucci, L.; Rossin, A.;
Raffelsberger, W.; Reitmair, A.; Chomienne, C.; Gronemeyer, H. Nature
Med. 2001, 7, 680. (c) Faul, M. M.; Grese, T. A. Curr. Opin. Drug DiscoV.
DeV. 2002, 5, 974.
(2) Dominquez, B.; Alvarez, R.; de Lera, A. R. Org. Prep. Proc. Int.
2003, 35, 239. Chemistry and Biology of Synthetic Retinoids; Dawson, M.
L., Okamura, W. H., Eds.; CRC Press: Boca Raton, FL, 1990.
(3) Pommer, H. Angew. Chem. 1977, 89, 437.
(4) Jeon, H.-S.; Yeo, J. E.; Jeong, Y. C.; Koo, S. Synthesis 2004, 2813.
(5) For representative examples, see Otero, M. P.; Torrado, A.; Pazos,
Y.; Sussman, F.; de Lera, A. R. J. Org. Chem. 2002, 67, 5876. Dominguez,
B.; Iglesias, B.; de Lera, A. R. Tetrahedron 1999, 55, 15071.
10.1021/ol051406p CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/10/2005

Scheme 2
desilylation to the corresponding terminal alkynes 4 and 5
then 5% Pd(Ph3P)4 with stirring overnight of the resulting
purple-red mixtures gave clean couplings by TLC. Moderate
to high yields of the desired products could be obtained after
flash chromatography. Little homocoupling of either partner
was observed. Several examples using E-2 or Z-3 are
illustrated in Tables 1 and 2, respectively. From these cases,
it appears that both linchpins couple with equal facility,
introducing the E- or Z- stereochemistry formally at the
retinoid C-9 or equivalent site. An acetylenic halide could
also be used to afford a diynic product (Table 1, entry G).
Desilyation of all polyenynes could be effected usually in
>90% yields using ethanolic carbonate at ambient temper-
atures (Scheme 4). The resulting terminal acetylenes 24 were
found to have limited shelf life even when maintained in a
frozen benzene matrix and protected from light.
Carboalumination/Acylation. Negishi carboalumination6
of the newly formed terminal alkynes required mildly forcing
conditions, as the extensive conjugation slows cis-addition
considerably related to isolated acetylenes. Premixing Cp2-
ZrCl2 (1 equiv) and either Me3Al or Et3Al (4 equiv) in
dichloroethane (DCE) at 0 °C followed by addition of the
alkyne and stirring for 1 h at rt led to complete consumption
of educt. Acylation with methyl chloroformate at rt gave
good isolated yields of stereodefined polyenes 25. Table 3
shows a number of representative examples demonstrating
insertion of formal C-13 E stereochemistry.
permit either acylation to a reactive ynoate subject to
stereocontrolled manipulation of the acetylenic moiety (e.g.,
cuprate additions to give 6 and 8) or a carboalumination/
acylation sequence that arrives at the isomeric product (e.g.,
7 and 9; Scheme 2).
Preparation of E-2 and Z-3. Starting with commercially
available 2-butynol (10) as educt for both conjunctive
reagents, stannylcupration at -78 °C affords allylic alcohol
E-11, which is smoothly oxidized with MnO2 at rt to enal
12 (Scheme 3). Wittig olefination with the Bu3P-derived ylide
13 formed from silylated propargyl bromide at -100 °C
leads to E-2 of >99% stereochemical purity. Treatment of
10 with Red-Al in THF at rt, on the other hand, followed by
quenching with Bu3SnCl leads to Z-allylic alcohol Z-11.
Identical processing as for E-11 ultimately gives predomi-
nantly Z-3 as a 90:10 mix of Z/E isomers (the outcome of
the Wittig reaction).
Cross-Couplings of E-2 and Z-3. Negishi reactions of
organozinc halides derived from vinylstannanes E-2 and Z-3
appeared to offer the best option for realizing the highly
conjugated polyenyne products. After lithiation at -78 °C
with n-BuLi, which produced deep green solutions in THF,
introduction of dry, fused ZnCl2 in THF (1 equiv) and
warming to rt gave a yellow-tan solution of the derived
organozinc chloride. Addition of a vinyl or aryl iodide and
Scheme 3
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Org. Lett., Vol. 7, No. 21, 2005

Table 1. Cross-Couplings with Conjunctive Reagent E-2a
Table 2. Cross-Couplings with Conjunctive Reagent Z-3a
a All yields refer to isolated, chromatographically purified materials.
a All yields refer to isolated, chromatographically purified materials.
Conjugate Additions. To generate the isomeric C-13 Z
series of polyenes, a representative trienynoate 26 was treated
with various organocopper reagents (Scheme 5). After
considerable experimentation aimed at minimizing un-
wanted E isomer,7 careful dropwise addition of Me2CuLi
to 26 in THF at -78 °C followed by the addition of MeOH
(7 equiv) reproducibly afforded the desired Z-adduct 27
exclusively judging from 1H NMR. Likewise, Bu2CuLi could
be added to form 28 in high isolated yield. Stannyl-
copper, Me3SnCu‚LiBr, added in a similar fashion, led to
the highly sensitive Z-â-stannyl tetraenoate 29 in modest
yield.
The alkyne moiety, e.g., in 30, provides alternative modes
of functionalization and/or substitution (Scheme 6). Thus,
carboalumination/iodination with I2 in THF at 0 °C to rt
afforded E-tetraene 31 (65% isolated). Other protocols (e.g.,
Scheme 4
(6) Negishi, E. Acc. Chem. Res. 1987, 20, 65.
(7) Krause, N.; Hoffmann-Roder, A. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Dortmund, 2002; pp 145-
165.
Org. Lett., Vol. 7, No. 21, 2005
4563

Scheme 5
Table 3.
NIS in THF or DCE) led to significant amounts of protio-
quenched product. Lindlar reduction of 26 using 1 equiv of
quinoline in EtOAc gave (in <1 h) the E,E,E,Z-tetraenoate
32 (77% isolated). Complete over-reduction was observed
in dry THF.
In summary, new conjunctive reagents, stannylated di-
enynes E-2 and Z-3, can be prepared in gram quantities and
used in a short sequence to arrive at highly conjugated
polyenic arrays characteristic of retinoids.
Scheme 6
Acknowledgment. We are pleased to warmly acknowl-
edge financial support of this work by the NSF (CHE 02-
13522). G.C.C. thanks CAPES (Brazil) for the fellowship.
We thank Drs. M. Scalone and R. Schmid (Roche, Basel)
for supplying trans-R,R-actinol.
Supporting Information Available: Procedures and
spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL051406P
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