Stereoselective synthesis of functionalized trisubstituted olefins via palladium(0)-catalyzed cross-coupling reaction.

Article abstract of DOI:10.1021/ol016486l

[reaction: see text]. A highly flexible and stereoselective protocol for the synthesis of branched (E)- and (Z)-trisubstituted alkenes has been developed. The key steps are hydrozirconation-iodination of (1-alkynyl)trimethylsilane followed by Negishi-type

Full text of DOI:10.1021/ol016486l

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3281-3284
Stereoselective Synthesis of
Functionalized Trisubstituted Olefins via
Palladium(0)-Catalyzed Cross-Coupling
Reaction
Alexander Arefolov, Neil F. Langille, and James S. Panek*
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for
Science and Engineering, 590 Commonwealth AVenue, Boston UniVersity,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received July 24, 2001
ABSTRACT
A highly flexible and stereoselective protocol for the synthesis of branched (E)- and (Z)-trisubstituted alkenes has been developed. The key
steps are hydrozirconation-iodination of (1-alkynyl)trimethylsilane followed by Negishi-type cross-coupling. The resultant (Z)-vinyl silane is
iododesilylated and subjected to a second cross-coupling reaction to give the trisubstituted olefin. Model studies aimed at the construction
of the C14−C15 (Z)-trisubstituted olefin of discodermolide and the C8−C9 (Z)-trisubstituted olefin of callystatin A and analogues are also
described.
Construction of trisubstituted olefins with a high degree of
stereocontrol remains a formidable challenge in organic
synthesis. Traditional phosphorus-based olefination methods
such as the venerable Wittig1 and Horner-Wadsworth-
Emmons2 protocols often give mixtures of (E)- and (Z)-
isomers. In many instances these reactions have limited
ability to vary substituents on the double bond. Recently,
ring-closing metathesis (RCM)3 and intermolecular cross-
metathesis4 have emerged as useful strategies for the
construction of unsaturated ring systems and substituted
olefins.
Palladium-catalyzed cross-coupling of vinyl halides with
organozinc reagents (Negishi reaction)5 represents a powerful
method for carbon-carbon bond formation. The ready
availability and functional group compatibility of organozinc6
reagents significantly enhance the utility of the cross-coupling
process. Hydrozirconation of silyl acetylenes has been shown
to proceed with useful levels of regio- and stereoselectivity
to give the R-silyl alkenyl zirconium complexes.7 Electro-
(1) (a) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953, 580,
44-57. (b) Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318-1330.
For reviews, see: (c) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89,
863-927. (d) Nicolaou, K. C.; Ha¨rtner, M. W.; Gunzner, J. L.; Nadin, A.
Liebigs Ann./Recl. 1997, 97, 1283-1301.
(2) (a) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber. 1958, 91,
61-63. (b) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961,
83, 1733-1738. For a review, see: (c) Wadsworth, W. S. Org. React. 1977,
25, 73-253.
(3) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b)
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(4) Arduango, A. J. Acc. Chem. Res. 1999, 32, 913-921.
(5) For a review, see: Negishi, E.-i. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998;
Chapter 1.
(6) (a) Organozinc Reagents, A Practical Approach; Knochel, P., Jones,
P., Eds.; Oxford: New York, 1999. (b) Erdik, E. In Organozinc Reagents
in Organic Synthesis; CRC Press: Boston, 1996.
10.1021/ol016486l CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/18/2001

philic iodination of vinyl zirconium species proceeds with
retention of double bond configuration to afford the corre-
sponding vinyl iodides.8 When taken collectively, these
individual reactions could be merged in the correct order to
afford a flexible sequence that gives stereochemically well
defined trisubstituted olefins. Herein we describe a flexible
reaction sequence that is useful for the stereoselective
synthesis of functionalized trisubstituted olefins. The se-
quence is based on the formation (and use) of geminally
substituted iodo-vinylsilanes, which are synthetic equivalents
to 1,1-diiodoalkenes, where each iodide can be cross-coupled
independently. The order in which one performs cross-
coupling reactions determines the configuration of the
resulting olefin.
This modular approach allows significant flexibility in
accessing olefin fragments of different stereochemistries, as
well as high functional group compatibility limited only by
the reactivity of Schwartz reagent.
The use of Pd(0)-mediated cross-coupling reactions of
1-iodo-1-(trimethylsilyl)-1-alkenes with organozinc and or-
ganotin reagents results in the synthesis of nearly configu-
rationally pure functionalized trisubstituted olefins.
We first examined hydrozirconation of the R-branched
alkynes 1a,b with zirconocene hydrochloride (Schwartz
reagent), Table 1.9 Maximum conversion and selectivity were
The use of 1-iodo-1-(trimethylsilyl)-1-alkenes as synthons
of 1,1-diodoalkenes was demonstrated by converting these
R-iodo vinyl silanes to (Z)-vinyl iodides via a two-step
procedure (Table 2). Initially, we investigated the palladium-
Table 2. Synthesis of (Z)-Vinyl Iodides
entry
2 (R1)
R2
product (yield)
1
2
3
4
5
6
7
8
9
2a (CH2Ph)
Me
Et
4a (95%)
5a (75%)
5b (77%)
5c (69%)a
5d (68%)a
4b (97%)
4c (80%)
4d (80%)
4e (95%)
4f (94%)
4g (95%)
4h (96%)
4l (86%)
4j (82%)
4k (93%)
4l (88%)
iPr
Bn
CHdCH2
CtCH
Me
Et
iPr
Bn
CHdCH2
CtCH
2b (TBDPS)
5g (74%)
5h (78%)
5i (68%)
5j (64%)
10
11
12
a (Z)-Configuration was assigned by NOE measurements.
(0)-catalyzed cross-coupling reactions with organozinc re-
agents generated from the commercially available Grignard
reagents. High yields and selectivities were obtained with
in situ generated n-alkyl, sec-alkyl, benzyl, vinyl, and
alkynylzinc chlorides. In general, the reactions were complete
within 0.5 h, affording isomerically pure vinyl silanes 4. The
resulting cross-coupled vinyl silanes 4 were converted to
vinyl iodides 5 by treatment with 1 equiv of I2 in methylene
chloride at room temperature. In agreement with literature
precedent,11 iododesilylation occurs with retention of con-
figuration at the double bond and with good yields for the
alkyl or benzyl substituents. However, attempts at iodo-
desilylation for the substrates with vinyl or alkynyl substit-
uents were unsuccessful.12
Since vinyl and alkynyl substituents on the vinylsilane are
incompatible with iododesilylation conditions, the trisubsti-
tuted olefin synthesis is limited to cases where trans-
substituent R2 is an alkyl or benzyl group.13 Having
established high yields and complete stereoselectivity for the
conversion of 1-iodo-1-(trimethylsilyl)-1-alkenes to (Z)-vinyl
iodides via a two-step sequence, we explored Pd(0)-catalyzed
cross-coupling reactions for the construction of the trisub-
stituted olefins.
Table 1. Hydrozirconation of Silylacetylenes
1
R
time (h)
T (°C)
2/3a
2 (yield)b
1a
CH2PH
0.5
1
1
rt
rt
55
rt
>30:1
>30:1
>30:1
2:1
2a (50%)
2a (65%)
2a (87%)
2b (74%)c
2b (71%)d
2b (82%)
1b
TBDPS
2
1
1
50
55
5:1
12:1
1
a Ratio determined by H NMR analysis. b Isolated yield of the desired
isomer. c Undesired isomer also present. d Two equivalents of the Schwartz
reagent was used.
obtained in the presence of stoichiometric amounts of Cp2-
Zr(H)Cl in THF at 55 °C with reaction times around 1 h.
The hydrozirconation reactions of substrate 1a (benzyl ether)
proceed with higher regioselectivity than for 1b (silyl ether),
which suggests that the reversible nature of the second
hydrozirconation is slower for 1b, producing the kinetic
product 3 in greater amounts.10
During our studies toward the synthesis of the marine
natural product discodermolide14,15 we became particularly
(10) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679-680.
(7) (a) Xu, X.-H.; Zheng, W.-X.; Huang, X. Synth. Commun. 1998, 78,
4165-4170. (b) Hyla-Kryspin, I.; Gleiter, R.; Kruger, C.; Zwettler, R.; Erker,
G. Organometallics 1990, 9, 517-523.
(8) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853-12910.
(9) (a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115-
8116. (b) Buchwald, S. L.; La Maire, S. J.; Nielsen, R. B.; Watson, B. T.;
King, S. M. Tetrahedron Lett. 1987, 28, 3895-3898.
(11) Chan, T. H.; Fleming, I. Synthesis 1979, 10, 761-786.
(12) Utilization of N-iodosuccinimide in iododesilylation results in
isomerization of olefin geometry.
(13) An alternative way to synthesize (Z)-vinyl halides with sp2 or sp
types of substituents in geminal position is direct coupling with vinyl
dibromide; see refs 16 and 17.
3282
Org. Lett., Vol. 3, No. 21, 2001

interested in the stereoselective construction of the C13-
C14 trisubstituted (Z)-olefin of the natural product.
and the second cross-coupling under modified Negishi
conditions afforded trisubstituted olefin fragments 10a and
10b in high yields in (Z)-configuration as required for the
synthesis of C13-C14 trisubstituted olefin of discoder-
molide. Flexibility of this procedure was further demonstrated
by the synthesis of (E)-isomers of compounds 10a,b by
reversing the order of cross-coupling reactions (Scheme 2).
Initially, we investigated the difference in the reactivity
between two halogen groups of 1,1-dihalo-1-alkenes in the
palladium(0)-catalyzed coupling reactions. Such differentia-
tion of the two halogen groups has been well documented
for sp2-sp2 and sp2-sp but not for the sp2-sp3 cross-
coupling reactions.16 Our attempts to selectively methylate
vinyl dibromide under Negishi, Stille, or Suzuki conditions
proved unsuccessful, yielding only dialkylated product.17 As
a result, we searched for a useful synthetic equivalent of 1,1-
dihalo-1-alkenes. In studies toward the synthesis of disco-
dermolide, we examined the use of iodo-vinylsilane 7 for
the construction of the C13-C14 (Z)-olefin of discoder-
molide (Scheme 1). The vinylsilane 7 was obtained from
Scheme 2
Scheme 1
Under modified Negishi conditions, the vinylsilane 7 was
cross-coupled with the organozinc intermediate derived from
alkyl iodide 11. The resulting vinyl silane 12 was iodo-
desilylated and subjected to the second cross-coupling with
methyl- and ethylzinc chlorides to afford (E)-olefin fragments
14a,b.
Additionally, this methodology has been applied to the
synthesis of the C6-C9 (E,Z)-diene of callystatin A18,19
(Scheme 3). Hydrozirconation of the (trimethylsilyl)acetylene
14 followed by iododemetalation afforded iodo-vinylsilane
(16) For Kumada-Tamao-Corriu coupling, see: (a) Minato, A.; Suzuki,
K.; Tamao, K. J. Am. Chem. Soc. 1987, 109, 1257-1258. (b) Minato, A.
J. Org. Chem. 1991, 56, 4052-4056. For Suzuki coupling, see: (c) Roush,
W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett. 1990, 31, 6509-
6512. (d) Roush, W. R.; Koyama, K.; Curtin, M. L.; Moriarty, K. J. J. Am.
Chem. Soc. 1996, 118, 7502-7512. For Stille coupling, see: (e) Shen, W.;
Wang, L. J. Org. Chem. 1999, 64, 8873-8879. For Negishi coupling, see:
(f) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912-4913. For Sonogashira
coupling, see: (g) Uenishi, J.; Matsui, K. Tetrahedron Lett. 2001, 42, 4353-
4355.
TMS-terminated alkyne 6 in 90% yield as a single regio-
isomer under optimized hydrozirconation conditions (2.5
equiv of Schwartz reagent, 55 °C in THF). Cross-coupling
with Grignard-derived methyl- and ethylzinc chlorides af-
forded (Z)-vinyl silanes 8a and 8b, respectively, in high
yields as single stereoisomers. Subsequent iododesilylation
(14) Isolation and structure: Gunasekara, S. P.; Gunasekara, M.; Longley,
R. E.; Schulte, G. K. J. Org. Chem. 1990, 55, 4912-4915. Correction: J.
Org. Chem. 1991, 56, 1346.
(17) Cross-coupling reactions of vinyl dibromide with vinyl and alkynyl
zinc species selectively afforded products of trans-bromo substitution in
high yields.
(15) Total synthesis: (a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.;
Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621-12622. (b) Smith,
A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995,
117, 12011-12012. (c) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J.
Am. Chem. Soc. 1996, 118, 11054-11080. (d) Haried, S. S.; Yang, G.;
Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62, 6098-6099. (e)
Marshall, J. A.; Lu, Z.-H.; Johns, B. A. J. Org. Chem. 1998, 63, 7885-
7892. (f) Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.; LaMarche,
M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823-1826. (g) Smith, A. B., III;
Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto,
H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654-8664.
(h) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem.,
Int. Ed. 2000, 39, 2, 377-380.
(18) Isolation and structure: (a) Kobayashi, M.; Higuchi, K.; Murakami,
N.; Tajima, H.; Amok, S. Tetrahedron Lett. 1997, 38, 2859-2862. (b)
Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Higuchi, K.; Aoki, S.;
Kobayashi, M. Tetrahedron Lett. 1997, 38, 5533-5536.
(19) Total synthesis: (a) Murakami, N.; Wang, W.; Aoki, M.; Tsutsui,
Y.; Sugimoto, M.; Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349-2352.
(b) Crimmins, M.; King, B. J. Am. Chem. Soc. 1998, 120, 9084-9085. (c)
Smith, A. B., III; Brandt, B. M. Org. Lett. 2001, 3, 1685-1688.
(20) For synthesis of callystatin A analogues, for the purpose of
substructure activity relationships, see: (a) Murakami, N.; Sugimoto, M.;
Nakajima, T.; Kawanishi, M.; Tsutsui, Y.; Kobayashi, M. Bioorg. Med.
Chem. 2000, 8, 2651-2661. (b) Murakami, N.; Sugimoto, M.; Kobayashi,
M. Bioorg. Med. Chem. 2001, 9, 57-67.
Org. Lett., Vol. 3, No. 21, 2001
3283

vinyl iodide 17a in high yield as a single stereoisomer. Stille
coupling with vinylstannane (E)-18 afforded the requisite
C6-C9 (E,Z)-diene 19a as a potential synthon for the C1-
C12 fragment of callystatin A.
Scheme 3
Substituting methyl zinc chloride in the Negishi coupling
of this protocol provides an efficient route to the methyl
analogue 19b. Utilization of (Z)-18 provides the synthetically
challenging (Z,Z)-isomer 19c, albeit in low yield.20
In conclusion, we have developed a highly flexible
protocol that allows synthesis of configurationally pure (E)-
and (Z)-functionalized trisubstituted olefins. We have de-
scribed the preparation of trisubstituted olefin fragments as
a part of our model studies in the syntheses of natural
products discodermolide and callystatin A. Application of
this methodology toward the syntheses of these natural
products is currently in progress and will be reported at a
later time.
Acknowledgment. This work has been financially sup-
ported by the National Institutes of Health (R01GM55740).
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization (IR, HRMS, and
1H and 13C NMR data) of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
15 in 89% yield as a single isomer after chromatography
(SiO2). Stereoselective cross-coupling with Grignard-derived
ethylzinc chloride followed by iododesilylation afforded (Z)-
OL016486L
3284
Org. Lett., Vol. 3, No. 21, 2001