Trans-selective conversions of γ-hydroxy-α,β-alkynoic esters to γ-hydroxy-α,β-alkenoic esters

Article abstract of DOI:10.1021/ol0495366

Matrix presented. γ-Hydroxy-α,β-acetylenic esters are used as precursors to prepare γ-hydroxy-α,β-alkenoic esters by means of trans-selective additions of two hydrogen atoms or one hydrogen atom and one iodine atom across the triple bonds. These methods a

Full text of DOI:10.1021/ol0495366

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1785-1787
Trans-Selective Conversions of
γ-Hydroxy-r,â-Alkynoic Esters to
γ-Hydroxy-r,â-Alkenoic Esters
Christopher T. Meta and Kazunori Koide*
Department of Chemistry, UniVersity of Pittsburgh, 219 Parkman AVenue,
Pittsburgh, PennsylVania 15260
koide@pitt.edu
Received March 11, 2004
ABSTRACT
γ-Hydroxy-r,â-acetylenic esters are used as precursors to prepare γ-hydroxy-r,â-alkenoic esters by means of trans-selective additions of
two hydrogen atoms or one hydrogen atom and one iodine atom across the triple bonds. These methods allow for the preparation of â-substituted
and r,â-disubstituted alkenoic esters in highly stereoselective manners.
Stereoselective alkene synthesis is an important topic in
organic synthesis.1 Of particular interest are the preparation
of R,â-alkenoic esters because these compounds are versatile
synthetic intermediates2,3 and are contained in many natural
products.4 This class of compounds has been prepared by
several different methods,3,5,6 among which the most common
method is the Wittig approach. The shortcomings of the
Wittig approach are that R-alkoxy (or hydroxy) aldehydes
are prone to epimerization and that an R-alkoxy group often
influences the E:Z selectivity of the Wittig reactions, often
generating a mixture of stereoisomers.6,7
several steps from the corresponding aldehydes, have po-
tential to be excellent precursors for B (Scheme 1). However,
the conversion of A to B is extremely rare,9 presumably due
to the lack of a general method for achieving trans addition
of two hydrogen atoms across the triple bond in a kinetically
controlled manner. (E)-selective reductions of propargylic
(4) (a) Aldridge, D. C.; Armstrong, J. J.; Speake, R. N.; Turner, W. B.
Chem. Commun. 1967, 26-27. (b) Weber, H. P.; Hauser, D.; Sigg, H. P.
HelV. Chim. Acta 1971, 54, 2763-2766. (c) Bu¨chi, G.; Kitaura, Y.; Yuan,
S.-S.; Wright, H. E.; Clardy, J.; Demain, A. L.; Glinsukon, T.; Hunt, N.;
Wogan, G. N. J. Am. Chem. Soc. 1973, 95, 5423-5425. (d) Huneck, S.;
Schreiber, K.; Steglich, W. Tetrahedron 1973, 29, 3687-3693. (e)
Rodphaya, D.; Sekiguchi, J.; Yamada, Y. J. Antibiot. 1986, 39, 629-635.
(f) Takamatsu, S.; Kim, Y. P.; Hayashi, M.; Hiraoka, H.; Natori, M.;
Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95-98. (g) Hu, T.; Curtis,
J. M.; Walter, J. A.; Wright, J. L. C. Tetrahedron Lett. 1999, 40, 3977-
3980. (h) Smith, C. J.; Abbanat, D.; Bernan, V. S.; Maiese, W. M.;
Greenstein, M.; Jompa, J.; Tahir, A.; Ireland, C. M. J. Nat. Prod. 2000, 63,
142-145. (i) Yamada, T.; Iritani, M.; Doi, M.; Minoura, K.; Ito, T.; Numata,
A. J. Chem. Soc., Perkin Trans. 1 2001, 3046-3053. (j) Berg, A.; Notni,
J.; Do¨rfelt, H.; Gra¨fe, U. J. Antibiot. 2002, 55, 660-662.
(5) Tanikaga, R.; Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis 1983, 134-
135.
Alternatively, γ-hydroxy-R,â-acetylenic esters A, which
can be prepared enantioselectively by known methods8 in
(1) (a) Faulkner, D. J. Synthesis 1971, 175-189. (b) Maciagiewicz, I.;
Dybowski, P.; Skowronska, A. Tetrahedron 2003, 59, 6057-6066.
(2) (a) Gung, B. W.; Francis, M. B. J. Org. Chem. 1993, 58, 6177-
6179. (b) Ibuka, T.; Taga, T.; Habashita, H.; Nakai, K.; Tamamura, H.;
Fujii, N. J. Org. Chem. 1993, 58, 1207-1214. (c) Marshall, J. A.; Elliott,
L. M. J. Org. Chem. 1996, 61, 4611-4616. (d) McKinney, J. A.; Eppley,
D. F.; Keenan, R. M. Tetrahedron Lett. 1994, 35, 5985-5988. (e) Zheng,
W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.; Oinuma, H.;
Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946-7968. (f) Noda, M.; Ibuka,
T.; Habashita, H.; Fujii, N. Chem. Pharm. Bull. 1997, 45, 1259-1264. (g)
Lee, J. Y.; Chung, Y. J.; Bae, Y.-S.; Ryu, S. H.; Kim, B. H. J. Chem. Soc.,
Perkin Trans. 1 1998, 359-365. (h) Berts, W.; Luthman, K. Tetrahedron
1999, 55, 13819-13830. (i) Kiefelt, M. J.; Wilson, J. C.; Bennett, S.;
Gredley, M.; von Itzstein, M. Bioorg. Med. Chem. 2000, 8, 657-664. (j)
Ohba, M.; Izuta, R. Heterocycles 2001, 55, 823-826. (k) Hong, Z.; Xu, X.
Tetrahedron Lett. 2003, 44, 489-491.
(6) Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591-3593.
(7) Koenig, S. G.; Lo¨we, R. S.; Austin, D. J. Synth. Commun. 2002, 32,
1379-1383.
(8) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-
9688. (b) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806-1807. (c) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855-
1857. (d) Lu, G.; Li, X. S.; Chan, W. L.; Chan, A. S. C. Chem. Commun.
2002, 172-173.
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5387.
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9329.
10.1021/ol0495366 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/29/2004

not able to detect any other byproducts even when this
reaction was performed in an NMR tube in CD3OD (from
-72 to 20 °C) in an attempt to detect minor products.
Scheme 1. Trans-Selective Reduction of Acetylenic Esters
To gain insight into the mechanism of this stereoselective
reduction, this reaction was carried out in CD3OD (eq b).
Subsequently, the deuterated compound 6 was isolated as a
sole product, suggesting the conjugate addition of a hydride
at C-3 of 4. To address the role of the hydroxy group at the
γ-position in this stereoselective reduction of 4, the TBS-
protected derivative 7 was subjected to the same reaction
conditions (1.2 equiv of NaBH4 in MeOH at -30 °C), which
resulted in the recovery of the starting material in a
quantitative yield. When this reduction was carried out at 0
°C for 1 h, the NMR spectrum of the resulting crude mixture
showed the presence of approximately 15% enoates 8 (E:Z
) 1:2) together with 80% of the starting material (eq c).
We also treated acetylenic ester 9 with NaBH4 in methanol
at 0 °C, which resulted in the recovery of the starting material
in nearly quantitative yield (eq d). These results suggest that
the reduction of 4 to 5 is facilitated by the γ-hydroxy group,
and this hydroxy group is involved in E/Z stereocontrol. To
determine whether this reduction was a thermodynamic or a
kinetic process, NaBH4 was added to a solution of (Z)-enoate
10 in methanol at -34 °C. The olefin was reduced to the
saturated methyl ester 11, and no trace of (E)-olefin 5 was
detected (eq e). This result indicates that the reduction of 4
to 5 is kinetically controlled.
alcohols are known, calling for LiAlH4-NaOMe in THF at
reflux10 or NaAlH2(OCH2CH2OCH3)2 (Red-Al) at room
temperature.11 However, these reaction conditions are not
compatible with many functional groups. Herein, we report
a general method for preparing B from A by a simple
procedure using readily available sodium borohydride or
Red-Al at lower temperatures.
Recently, we reported the reduction of ketone 1 to form
(E)-enoate 3 (Scheme 2).12 We hypothesized that this
Scheme 2. Trans-Selective Reduction of γ-Keto-R,â-acetylenic
Ester 1
This (E)-selective reduction of acetylenic esters appears
to be general, as shown in Table 1. Upon treatment of the
acetylenic esters 2 and 4 with NaBH4 in methanol (condition
a), the corresponding (E)-enoates D were obtained in good
to excellent yields with little E. The base-sensitive N-Fmoc
group of alcohol 1213 was found to be compatible with this
method, providing the corresponding (E)-enoate in quantita-
tive yield with excellent (E)-selectivity ((Z)-isomer was not
detectable). Sterically more hindered alcohols 13 and 14 gave
somewhat compromised stereoselectivities.
unexpected stereoselective reduction of the ynoate proceeded
through intermediate 2.
To test this hypothesis, we treated alcohol 4 with NaBH4
at -34 °C in methanol and found that (E)-enoate 5 was
formed in 86% isolated yield (Scheme 3, eq a). We were
Scheme 3. Control Experiments to Elucidate the Mechanism of
the Trans-Selective Reduction of Acetylenic Esters
To further improve the (E)-selectivities of the sterically
hindered alcohols 13 and 14, we turned our attention to other
reducing agents. After screening various reducing agents,14
we found that Red-Al showed excellent (E)-selectivities in
the reduction of alcohols 13 and 14 to form the corresponding
R,â-alkenoic esters (Table 1, condition b). It is noteworthy
1
that the H NMR analyses of the crude mixtures of these
two reactions indicate that neither formations of the corre-
sponding (Z)-enoates or saturated compounds nor reduction
of the methyl esters occurred. To test the compatibility of
this Red-Al reduction with an epoxide, compound 1511 was
treated with Red-Al at -72 °C for 25 min to afford the
(10) Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem.
Soc. 1967, 89, 4245-4247.
(11) (a) Marshall, J. A.; DeHoff, B. S. J. Org. Chem. 1986, 51, 863-
872. (b) Kucera, D. J.; O’Connor, S. J.; Overman, L. E. J. Org. Chem.
1993, 58, 5304-5306. (c) Roulland, E.; Monneret, C.; Florent, J.-C. J. Org.
Chem. 2002, 67, 4399-4406.
(12) Naka, T.; Koide, K. Tetrahedron Lett. 2003, 44, 443-445.
(13) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525-
2527.
(14) Besides NaBH4 and Red-Al, we tested NaBH3CN, n-Bu4NBH4, and
BH3, none of which afforded the desired product.
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Org. Lett., Vol. 6, No. 11, 2004

to form allenolate G. We postulate two possible pathways
from this point. Either allenolate G reacts with MeOH or
H2O acidified by the Lewis acid formed at the bottom face
of the allenolate as shown in H (path a) or ate complex I
reacts with MeOH or H2O to form compound D. These
working hypotheses imply wide applications of this method
by using other electrophiles.
Table 1. Scope of NaBH4 and Red-Al Reductions of
Acetylenic Esters Ca
To extend the application of the trans-selective Red-Al-
promoted conjugate addition toward acetylenic esters, the
Red-Al reduction of 4 was quenched with I2 rather than water
(Scheme 5). Subsequently, we isolated vinyl iodide 16 in
Scheme 5. Preparations of Highly Functionalized,
R,â-Disubstituted Alkenoatesa
a Reagents and conditions: (a) Red-Al (1.5 equiv), -72 °C, 25
min; then I2 (5.0 equiv), -72 f -10 °C, THF, 2 h, 78%; (b)
1-hexyne (2.0 equiv), Pd(Ph3P)4 (10 mol %), CuI (5 mol %),
i-Pr2NH (excess), 23 °C, 6 h, 64%; (c) CH2dCHSnBu3 (1.2 equiv),
Pd(Ph3P)2Cl2 (2 mol %), DMF, 23 °C, 48 h, 45%.
a Reagents and conditions: (a) NaBH4 (1.2-4 equiv), MeOH, -34 to 0
°C, 15-50 min; (b) Red-Al (2 equiv), THF, -72 °C, 25 min.
corresponding (E)-alkenoate in 80% yield. Therefore, the
NaBH4- or Red-Al-mediated (E)-selective reductions of
acetylenic esters are compatible with both the base-sensitive
N-Fmoc group and the electrophilic epoxide.
We speculate that this unusual trans addition of two
hydrogen atoms across the C-C triple bond can be accounted
for by either of the following mechanisms (Scheme 4). First,
both Red-Al and NaBH4 react with alcohol C to form
intermediate F. Then, a hydride is delivered intramolecularly
78% yield.15 This vinyl iodide could be transformed into
disubstituted alkenoates 17 (64% yield; not optimized) and
18 (45% yield; not optimized) by means of Sonogashira
coupling and Stille coupling, respectively. These two-step
schemes have potential for the preparation of highly conju-
gated disubstituted alkenoates in a trans-selective manner.
In conclusion, we have developed a general method for
preparing synthetically versatile (E)-enoates D and (Z)-enoate
16 from acetylenic esters C under mild conditions. The
working hypothesis depicted in Scheme 4 indicates that it is
possible to further functionalize intermediate G or I with
other electrophiles.
Scheme 4. Plausible Mechanisms
Acknowledgment. Financial support was provided by the
University of Pittsburgh and CRDF. We thank Dr. Fu-Tian
Lin for assistance in NMR experiments and Dr. Kasi
Somayajulafor for assistance with mass spectroscopy.
1
Supporting Information Available: H NMR, 13C NMR,
IR, and HRMS data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0495366
(15) (Z)-geometry of vinyl iodide 16 was determined by means of a
NOESY experiment after the DIBALH reduction of a closely related
compound (see Supporting Information for details).
Org. Lett., Vol. 6, No. 11, 2004
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