A scalable route to trisubstituted (E)-vinyl bromides

Article abstract of DOI:10.1021/ol051376q

(Chemical Equation Presented) An effective, readily scalable two-step synthesis of trisubstituted (E)-vinyl bromides involving bromination of α,β-unsaturated lactones followed by hydrolytic fragmentation has been developed. Several trisubstituted (E)-viny

Full text of DOI:10.1021/ol051376q

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3569-3572
A Scalable Route to Trisubstituted
(E)-Vinyl Bromides
Cheon-Gyu Cho,*,† Won-Suk Kim, and Amos B. Smith, III*
Department of Chemistry, Hanyang UniVersity, Seoul, Korea 133-791, and Department
of Chemistry, UniVersity of PennsylVania, Philadephia, PennsylVania 19104
ccho@hanyang.ac.kr; absmith@sas.upenn.edu
Received June 13, 2005
ABSTRACT
An effective, readily scalable two-step synthesis of trisubstituted (E)-vinyl bromides involving bromination of
r,â-unsaturated lactones followed
by hydrolytic fragmentation has been developed. Several trisubstituted (E)-vinyl bromides, including multigram quantities of (
+
)-(E)-4-bromo-
2-methyl-3-pentenol, a synthetic intermediate required for the C(8)−C(11) moieties of (+)-tedanolide (1) and (+)-13-deoxytedanolide (2), illustrate
the utility of this protocol.
Trisubstituted (E)-halo alkenes comprise important synthetic
intermediates often employed in natural product total syn-
theses, in particular for macrolides such as scyphostatin,1
octalactin,2 phomactin,3 borrelidin,4 apoptolidin,5 FK901464,6
phorboxazole A,7 fostriecin,8 taxifolial A,9 and kendomycin,10
tedanolide (1), and deoxytedanolide (2).11
In connection with our continuing interest in defining the
biochemical mode of action of architectually complex
macrolides, we recently initiated preparative-scale syntheses
of both (+)-tedanolide (1) and (+)-13-deoxytedanolide (2),
based on our now successful first-generation synthesis of
13-deoxytedanolide (2). For this venture we required mul-
tigram quantities of (E)-vinyl iodide 3 to serve as the C(8)-
C(11) fragment (Scheme 1). Although our first generation
† Sebbatical Leave from the Department of Chemistry, Hanyang Uni-
versity, Seoul, Korea 133-791.
(1) Inoue, M.; Yokota, W.; Murugeshi, M. G.; Izuhara, T.; Katoh, T.
Angew. Chem., Int. Ed. 2004, 43, 4207.
(2) O’Sullivan, P. T.; Buhr, W.; Fuhry, M. A. M.; Harrison, J. R.; Davies,
J. E.; Feeder, N.; Marshall, D. R.; Burton, J. W.; Holmes, A. B. J. Am.
Chem. Soc. 2004, 126, 2194.
Scheme 1
(3) Mohr, P. T.; Halcomb, R. L. J. Am. Chem. Soc. 2003, 125, 1712.
(4) Duffey, M. O.; LeTiran, A.; Morken, J. P. J. Am. Chem. Soc. 2003,
125, 1458.
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P.; Mitchell, H. J.; Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2003, 125, 15443.
(6) Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc.
2001, 123, 9974.
(7) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M.; J.
Am. Chem. Soc. 2001, 123, 4834.
(8) Esumi, T.; Okamoto, N.; Hatakeyama, S. Chem. Commun. 2002,
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(11) (a) Smith, A. B., III; Adams, C. M.; Lodise-Barbosa, S. A.; Degnan,
A. P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12042. (b) Smith, A. B., III;
Adams, C. M.; Lodise-Barbosa, S. A.; Degnan, A. P. J. Am. Chem. Soc.
2003, 125, 350. (c) Smith, A. B., III; Lodise-Barbosa, S. A. Org. Lett. 1999,
1, 1249.
route to (-)-5, employing the Pd-catalyzed hydrostannylation
of alkyne (-)-4 followed by iodination, proved effective, a
somewhat difficult to separate mixture (ca. 6:1) of the E-
and Z-isomers resulted (eq 1, Scheme 2).
We reasoned that hydrozirconation might be more effective
given the anticipated efficiency and higher E-selectivity after
the iodination (eq 2).1-6 This reaction sequence, however,
10.1021/ol051376q CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/15/2005

Scheme 2
Scheme 3. Bromination of Enoic Acid and Enoate
drolysis of unsaturated ester 14 to acid 15 for the fragmenta-
tion protocol (Scheme 3).
For example, with 15a or 15b bearing an acid-labile group,
bromination not surprisingly produced tetrahydrofuran 18
instead of dibromide 17. Apparently, trace HBr generated
during the bromination unmasked the protected hydroxyl,
which in turn intercepted the bromonium intermediate to
provide bromoether 18. Attempts to remove trace acid from
the reaction mixture by adding NaHCO3, Na2CO3, or Et3N
did not improve the reaction; only complex product mixtures
resulted. In case of 15c bearing a PMB group, aromatic
bromination occurred before that of the olefin. Alternatively,
bromination of ethyl ester 14a cleanly afforded dibromide
16a. However, subsequent hydrolysis of 16a resulted in
concomitant â-elimination of HBr. A similar result was
obtained with the methyl ester.
requires the use of excess Schwartz reagent, rendering large-
scale application both expensive and possibly cumbersome.
Additional concerns include the large-scale use of PPh3 and
CBr4 in the Corey-Fuchs protocol12 en route to the requisite
2-alkyne. Alternative methods based on stannocupration7-10,13
and/or silanocupration14 would also require 3-5 equiv of
expensive reagents and as such did not appear attractive for
large-scale synthesis.
A careful survey of the literature revealed few alternatives.
Roush and co-workers, in their elegant work directed at the
total syntheses of kijanolide and tetronolide,15 prepared (E)-
3-bromo-2-butenol 9 from erythro-2,3-dibromobutanol 8 in
50% yield, upon treatment with LDA (eq 3). Their approach,
however, was not immediately applicable to our system,
given the regioselectivity issue upon HBr elimination. An
innovative two-step sequence to (E)-vinyl bromide 11 was
reported by Cha et al. (eq 4).16 A similar fragmentation was
observed by Khim and co-workers to furnish 13 as a
byproduct from iodolactone 12 (eq 5).17
Ester 19 possessing the more readily removable TBS group
was prepared next from 15b (Scheme 4). Although bromi-
Scheme 4
Direct application of the Cha sequence in our system,
however, did not prove straightforward because of the
incompatibility of various hydroxyl protecting groups during
the bromination step, in conjuction with the required hy-
nation furnished the dibromide 20 in excellent yield (ca.
97%), 20 proved too unstable to be easily manipulated. For
example, pure 20 loses the trityl group to provide alcohol
21 upon standing overnight at room temperature.
Taken together, these results suggest the use of an R,â-
unsaturated lactone, comprising internal protection of the
hydroxyl group and at the same time imposing at most
modest steric hindrance for the hydrolysis step compared
with the acyclic counterpart.
(12) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(13) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet, J. J.
Org. Chem. 1997, 62, 7768.
(14) (a) Archibald, S. C.; Barden, D. J.; Bazin, J. F. Y.; Fleming, I.;
Foster, C. F.; Mandal, A. K.; Mandal, A. K.; Parker, D.; Takaki, K.; Ware,
A. C.; Williams, A. R. B.; Zwicky, A. B. Org. Biomol. Chem. 2004, 2,
1051. (b) Fleming, I.; Newton, T. W.; Roessler, J. Chem. Soc., Perkin Trans.
1 1981, 2527.
(15) Roush, W. R.; Brown, B. B. J. Am. Chem. Soc. 1993, 115, 2268.
(16) (a) Jeffery, D. W.; Perkins, M. V.; White, J. M. Org. Lett. 2005, 7,
1581. (b) Kim, H.; Lee, S.-K.; Lee, D.; Cha, J. K. Synth. Commun. 1998,
28, 729. (c) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662.
(17) Khim, S.-K.; Dai, M.; Zhang, X.; Chen, L.; Pettus, L.; Thakkar,
K.; Schultz, A. G. J. Org. Chem. 2004, 69, 7728.
We first focused on unsaturated lactone 22.18 Surprisingly,
bromination furnished all four possible diastereomers, two
3570
Org. Lett., Vol. 7, No. 16, 2005

Scheme 5. Bromination of Lactone (+)-22
Table 1. Tandem Hydrolysis-Fragmentation of (-)-23a
trans- (23a and 23b) and two cis-isomers (23c and 23d) as
depicted in Scheme 5. The ratio determined by 1H NNR was
50:25:5:1, respectively. The relative stereochemistries of
1
23a-c, initially assigned via H NMR coupling constants
of the adjacent methine protons, were in each case confirmed
by X-ray crystallography. Presumably formation of the cis-
dibromides (23c and 23d) arises via the intermediacy of the
C(3) carbocation rather than the conventional bromonium
ion, with possible stabilization by the lactone ether oxygen
atom.19
25. With additional H2O, the reaction did not go to
completion, thereby diminishing the yield. Elevation of the
reaction temperature resulted in the increased formation of
the elimination products 25 and 26. For the base, lithium
hydroxide proved uniformly superior to NaOH or Ba(OH)2
in terms of yield. Direct subjection of the bromination
mixture to the hydrolytic fragmentation conditions, without
chromatographic removal of the cis-dibromides, improved
the overall yield (52% f 67% from 22), albeit with modest
sacrifice of the stereochemical purity of 24 (ca. E/Z, 10:1).
To demonstrate the scalability of the two-step bromination-
hydrolytic fragmentation sequence, multigram quantities (ca.
13 g) of bromide 24 were prepared from (+)-22 (Scheme
6).20 Both relative and absolute stereochemical integrity of
The cis-dibromide was, of course, a significant issue, as
only the trans-isomers were expected to furnish the desired
trisubstituted (E)-vinyl bromide upon hydrolysis and subse-
quent fragmentation.16b Fortunately separation of the dibro-
mide isomers, and in particular removal of the cis-bromides,
proved readily achievable by flash chromatography.
Best selectivity in the bromination was obtained when the
reaction was conducted in CH2Cl2 with 3 equiv of Br2 over
a temperature range of -10 to 0 °C (cf. total isolated yield,
78%; trans/cis ratio > 10:1). Methylene chloride furnished
slighly higher yields than than CCl4, CHCl3, or ether.
Reaction temperatures higher than 0 °C increased formation
of the undesired cis-isomers, whereas temperatures below
-10 °C provided no advantage in terms of yield or the trans/
cis ratio. The minor trans-dibromide 23b proved quite
unstable upon silica gel column chromatography.
Scheme 6. Preparation of (+)-23
The hydrolytic fragmentations proceeded under somewhat
different conditions for 23a and 23b. For example, treatment
of 23b with lithium hydroxide in DMF readily led to (E)-
vinyl bromide 24 in near quantitative yield, whereas similar
treatment of 23a, possessing the C(3)Br and C(4)H oriented
anti-coplanar, required significant optimization, as not only
the desired vinyl bromide 24 but also elimination products
25 and 26 resulted, depending on the exact reaction condi-
tions employed (cf. Table 1).
Best results for the hydrolytic fragmentation involved
DMF/H2O as a 4:1 mixture (entry 6). Under these conditions,
the desired trisubstituted (E)-vinyl bromide 24 (>99:1 E to
Z by NMR) was obtained in 73% yield from 23a. Without
H2O, the reaction gave predominantly elimination product
(-)-24 were confirmed by conversion to (E)-vinyl iodide
5.21
(18) (a) Yoneda, E.; Zhang, S.-W.; Zhou, D.-Y.; Onitsuka, K.; Takahashi,
S. J. Org. Chem. 2003, 68, 8571. (b) Andrus, M. B.; Li, W.; Keyes, R. F.
J. Org. Chem. 1997, 62, 5542. (c) Collum, D. B.; McDonald, J. H., III;
Still, W. C. J. Am. Chem. Soc. 1980, 102, 2118.
(19) Bromination of 2-methyl-2-cyclohexenone provided a single dibro-
mide (e.g., trans-2,3-dibromo-2-methyl cyclohexanone).
(20) The vinyl iodide (-)-3 can be prepared from (R)-(-)-Roche’s ester
via the route in eq 2 in eight steps with 30% overall yield. Also see: Organ,
M. G.; Wang, J. J. Org. Chem. 2003, 68, 5568.
Org. Lett., Vol. 7, No. 16, 2005
3571

Scheme 7. Preparation of (-)-36
Table 2.
Application of the two-step bromination decarboxylation-
debromination sequence to lactone (-)-35 (Scheme 7),
readily available either by ring-closing metathesis (RCM)
from 32 or by aldol reaction of 34 followed by lactonization,
furnished bromide (-)-36, a key subunit in our on going
program to construct the potent cytotoxic agent, irciniastatin
A.22 Importantly, this sequence could be carried out on a
gram scale.
forward. Subsequent hydrolytic fragmentation afforded vinyl
bromides 44 and 4524 in 80% and 62% isolation yield,
respectively.
In summary, an effective, scalable sequence for the
synthesis of trisubstituted (E)-vinyl bromides from the
corresponding R,â-unsaturated lactone involving a bromi-
nation/hydrolytic fragmentation protocol has been developed.
In similar fashion, commercially available 3-methyl buteno-
lide 37 provided 2-bromo-2-butenol 43 in 55% overall yield
(Table 2). For 38 and 39,23 formation of the undesired cis-
dibromides became a more significant problem, reducing the
yields of the trans-dibromide 41 and 42. Separation of the
cis-bromides from the trans-isomers again proved straight-
Acknowledgment. Financial support was provided by the
National Instituted of Health (Institute of General Medical
Science) through grant GM 29028. C.-G.C. is grateful for
financial support from Hanyang University (HY-2004-I).
Supporting Information Available: Details of experi-
mental procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Smith, A. B., III; Gallagher, W. P. Unpublished results.
(22) Pettit, G. R.; Xu, J.-P.; Chapuis, J.-C.; Pettit, R. K.; Tackett, L. P.;
Doubek, D. L.; Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47,
1149.
(23) Prepared from δ-valerolactone (55%, 2 steps); see: Slouggi, N.;
Rousseau, G. Tetrahedron 1985, 41, 2643. Both 38 and 39 are also available
via the RCM or aldol route used for (-)-35 in Scheme 7.
OL051376Q
(24) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron 1999, 55, 7145.
3572
Org. Lett., Vol. 7, No. 16, 2005