Selective access to trisubstituted macrocyclic e - And Z-alkenes from the ring-closing metathesis of vinylsiloxanes

Article abstract of DOI:10.1021/ol400134d

Macrocyclic (E)-alkenylsiloxanes, obtained from E-selective ring-closing metathesis reactions, can be converted to the corresponding (Z)-alkenyl bromides and (E)-alkenyl iodides allowing access to both E- and Z-trisubstituted macrocyclic alkenes. The reac

Full text of DOI:10.1021/ol400134d

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Selective Access to Trisubstituted
Macrocyclic E- and Z‑Alkenes from the
Ring-Closing Metathesis of Vinylsiloxanes
Yikai Wang, Miguel Jimenez, Patrick Sheehan, Cheng Zhong, Alvin W. Hung,
Chun Pong Tam, and Damian W. Young*
Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge,
Massachusetts 02142, United States
dyoung@broadinstitute.org
Received January 16, 2013
ABSTRACT
Macrocyclic (E)-alkenylsiloxanes, obtained from E-selective ring-closing metathesis reactions, can be converted to the corresponding (Z)-alkenyl
bromides and (E)-alkenyl iodides allowing access to both E- and Z-trisubstituted macrocyclic alkenes. The reaction conditions and substrate
scope of these stereoselective transformations are explored.
Ring-closing metathesis (RCM) is a powerful transfor-
mation that can be used to construct macrocyclic mole-
cules. It has been extensively applied in the total synthesis
of natural products,1 diversity-oriented synthesis,2 and
medicinal chemistry.3 However, further elaboration of
the resulting macrocyclic alkene is usually limited to
symmetrical reactions (e.g., hydrogenation) that avoid
issues related to regioselectivity. Additionally, due to the
flexibility of macrocycles, RCM frequently results in mix-
tures of Z/E alkene isomers that may be undesirable or
difficult to separate.1b,4 Finally, in contrast to disubsti-
tuted macrocycles, the use of RCM to access trisubstituted
variants with control of olefin geometry has not been
rigorously explored.4b,5
Recently, several groups have made progress in achiev-
ing selective olefin geometry in macrocyclic RCM through
catalyst control.6 Nevertheless, these catalyst-controlled
approaches are limited to generating disubstituted alkene
products with Z geometry. Moreover, the problem of
(1) (a) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(b) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45,
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A.; Cho, Y. S.; Gabarda, A. E.; Yoshimura, F.; Danishefsky, S. J. J. Nat.
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(5) Macrocyclic RCM reactions to access trisubstituted alkenes were
largely limited to alkyl (Me or Et) substituted products with unpredict-
€
(3) (a) Tsantrizos, Y. S.; Ferland, J.-M.; McClory, A.; Poirier, M.;
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A. T.; Bickerstaffe, R. Angew. Chem., Int. Ed. 2009, 48, 1455. (c) Huber,
T.; Manzenrieder, F.; Kuttruff, C. A.; Dorner-Ciossek, C.; Kessler, H.
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able stereoselectivity. See: (a) Furstner, A.; Thiel, O. R.; Ackermann, L.
Org. Lett. 2001, 3, 449. (b) Jin, J.; Chen, Y. L.; Li, Y. N.; Wu, J. L.; Dai,
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10.1021/ol400134d
XXXX American Chemical Society

further transformation of the alkene in RCM products
remains unresolved. There is a need for a comprehensive
methodology that overcomes these limitations of macro-
cyclic RCM, allowing access to both geometric isomers of
the more demanding trisubstituted macrocyclic alkenes.7
Table 1. Influence of Reaction Conditions on the Stereoselec-
tivity of Converting Alkenylsiloxane 1 to Alkenyl Bromides
Scheme 1. General Concept
temp
entry
solventa
(°C)
conversionb
E/Zd
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
CS2
40
>90%
>90%
>90%
>90%
>90%
>90%
∼ 80%
>90%
>90%
>90%
f, mdc
f, md
i, mdc
i, md
>90%
>90%
∼ 30%
i, dc
15:85
8:92
2
0
3
À78
À100
23
3:97
4
2:98
5
17:83
13:87
8:92
6
0
7
À78
23
To address these issues, we focused on the introduction
of a removable 2-silyl substituent to one of the olefin
partners. We have shown previously that the RCM of
these vinylsiloxane substrates yields macrocyclic com-
pounds with high E selectivity, resulting in Z-disubstituted
alkenes after protodesilylation8 (Scheme 1A). Herein, we
report a strategy to selectively achieve both geometrical
isomers of trisubstituted macrocyclic alkenes from the
common (E)-alkenylsiloxane intermediate.
8
13:87
15:85
3:97
9
CS2
0
10
11
12
13
14
15
16
17
18
19
20
21
CS2
À78
23
THF
31:69
22:78
67:33
84:16
20:80
13:87
55:45
74:26
70:30
63:37
ndc
THF
0
THF
À78
À100
23
THF
Et2O
Et2O
0
Et2O
À78
23
DMF
DMF
DMF
MeOH
Noting early studies on the halogenation of acyclic
alkenylsilanes,9 we envisioned that macrocyclic (E)-alke-
nylsiloxanes could be transformed to the corresponding
alkenyl halides with either inversion or retention of stereo-
chemistry (Scheme 1B). Additionally, the resulting alkenyl
halides would serve as versatile synthetic intermediates
allowing access to trisubstituted alkenes. We first explored
conditions that yielded stereochemical inversion of the
starting (E)-alkenylsiloxanes.
Mild halogenating reagents such as pyridinium tribro-
mide and phenyltrimethylammonium tribromide were ex-
amined with substrate 1.10 Neither of these reagents led to
complete consumption of starting material, and decom-
position was also observed. Fortunately, treatment of
substrate 1 in DCM at À78 °C with dropwise addition of
0
i, d
À78
i, d
À78
d
a Br2 was added as a solution in the indicated solvent. b Conversion
was calculated based on 1H NMR analysis. c f: full conversion; md:
minor decomposition; i: incomplete conversion; d: decomposition; nd:
not determined. d E to Z ratio measured by 1H NMR analysis.
bromine solution gave complete consumption of starting
material and formation of a dibromide intermediate
along with a small amount of alkenyl bromide product
by LC-MS analysis. It was observed that the dibromide
intermediate was converting to the alkenyl bromide on
silica gel when conducting TLC analysis. Instead of iso-
lating the intermediate, a two-step one-pot procedure was
adopted. Accordingly, TBAF was chosen as the reagent
to promote bromodesilylation. Upon addition of up to
4 equiv of TBAF (1 M solution in THF, fresh, containing
water), the dibromide intermediate collapsed to the desired
alkenyl bromide after warming up to rt. The Z/E ratio was
determined to be 97:3 by 1H NMR analysis.
With this initial success, we next explored the influence
of solvent and temperature on the stereoselectivity of this
transformation (Table 1). It was found that nonpolar
solvents (DCM, toluene, and CS2, entries 1À10) generally
favored inversion of stereochemistry leading to the desired
(Z)-alkenyl bromide. Using these solvents and lowering
the temperature increased the selectivity toward the Z
isomer, and reactions reached complete conversion in
most cases. In contrast, polar nonprotic solvents such as
DMF favored the retention of stereochemistry yielding the
E isomer as the major product independent of reaction
(6) (a) Flook, M. M.; Jiang, A. J.; Schrock, R. R.; Muller, P.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 7962. (b) Vougioukalakis,
G. C.; Grubbs, R. H. J. Am. Chem. Soc. 2008, 130, 2234. (c) Yu, M.;
Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.;
Hoveyda, A. H. Nature 2011, 479, 88. (d) Marx, V. M.; Herbert, M. B.;
Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 94.
(7) For a method to construct disubstituted macrocycles using alkyne
€
ring-closing metathesis, see: (a) Furstner, A.; Guth, O.; Rumbo, A.;
€
Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108. (b) Furstner, A.; Grela, K.
€
Angew. Chem., Int. Ed. 2000, 39, 1234. (c) Furstner, A.; Radkowski, K.
Chem. Commun. 2002, 2182.
(8) Wang, Y. K.; Jimenez, M.; Hansen, A. S.; Raiber, E. A.; Schreiber,
S. L.; Young, D. W. J. Am. Chem. Soc. 2011, 133, 9196.
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Chem. 1976, 121, 293. (b) Chan, T. H.; Lau, P. W. K.; Mychajlowskij, W.
Tetrahedron Lett. 1977, 18, 3317. (c) Fisher, R. P.; On, H. P.; Snow, J. T.;
Zweifel, G. Synthesis 1982, 127. (d) Jarvie, A. W.; Holt, A.; Thompson,
J. J. Chem. Soc. B 1969, 852. (e) Koenig, K. E.; Weber, W. P. Tetra-
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(10) Synthesis of 1 involves hydrosilylation of the alkyne and sub-
sequent RCM of the vinylsiloxane. For details, see ref 8.
B
Org. Lett., Vol. XX, No. XX, XXXX

temperature, while decomposition became significant
(entries 18À20). Interestingly, when the reaction was per-
formed in THF or ether, the reaction proceeded more
slowly at lower temperatures (À100 and À78 °C, entries 13,
14, and 17) with higher E selectivity. As the temperature
was elevated, both the conversion and Z selectivity were
increased (entries 11, 12, 15, and 16). In MeOH (entry 21),
extensive decomposition occurred. Based on these results,
we selected DCM and À78 °C as the optimal reaction
conditions.
to the iodination pathway. However, we cannot exclude
the possibility of syn-dibrominationundertheseconditions
that also leads to the E product. Further mechanistic
studies are warranted to fully understand the factors
governing the selectivity of this reaction.
Scheme 3. Proposed Reaction Mechanisms
Scheme 2. Iodination of 1
We next explored reaction conditions that gave rise
to an alkenyl halide with retention of stereochemistry
(E isomer). Although bromination with retention of olefin
geometry has been reported,11 we chose to follow an
iodination procedure requiring a protic solvent and NIS
(Scheme 2).12 A singleE isomer E-1Iwas obtainedfromthe
reaction of 1 with 93% yield.
To explore the generality of both transformations
we applied the optimized reaction conditions to a variety
of substrates with ring sizes from 11 to 15 (Table 2). The
iodinations proceeded very efficiently to generate the
desired (E)-alkenyl iodide with high yield and selectivity
except for one case (compound 6). A moderate yield was
obtained even when the reaction was performed in reflux-
ing HFIP with the addition of 10 equiv of NIS. The
reluctance of this molecule may result from the position
of the silyl group (relative to compound 4) that limits the
flexibility of the macrocycle in undergoing rearrangement
leading to product.
In contrast, the bromination reactions were more com-
plex. As shown in Table 2, a general trend is that 11- or
12-membered rings tend to give retention of stereochemistry
while compounds with larger ring sizes successfully render
high Z selectivity. cis-Cyclohexanediol derived substrates
tend to have higher Z selectivity than their trans analogues
(compound 3 vs 2, 5 vs 4). The positions of the silyl group
have an influence on reaction outcomes for smaller rings
(compound 4, 87% yield with high E selectivity vs 6,
decomposition) but not for larger rings (compound
10 vs 11), and the positions of the double bond can slightly
affect the Z selectivity for larger rings (compound 1 vs 8).
The dependency on ring sizes, stereochemistry, and regio-
chemistry can be tentatively rationalized by two factors:
the ability of the substrates toundergo anti-dibromination,
which may be inaccessible in the smaller rings due to
transannular effects, and the flexibility of the macro-
cycle to accommodate the alkenyl bromide products
(especially the Z isomer). These results provide a basis
for further studies on the differences between macrocyclic
substrates that account for the differential outcomes.
Efforts to increase the Z selectivity of smaller macrocycles
are ongoing.
Based on literature precedent11,13 and our own results,
the reaction mechanisms leading to the products with
controlled olefin geometries are proposed in Scheme 3.
In the case of inversion, once the bromonium ion A is
formed, the bromide ion (BrÀ) undergoes backside attack
to generate the anti-dibromide (C and/or D). The issue of
which carbon the bromide attacks (C or D) is inconse-
quential as long as the relative stereochemistry of the
dibromide is anti. Upon treatment with TBAF, bromode-
silylation occurs more readily when the β-bromo group is
antiperiplanar to the silyl group via rotation about the
CÀC bond (transition state E and F) following an E2
mechanism. The product from both intermediates is the
same (Z)-alkenyl bromide. In contrast, formation of the
(E)-alkenyl iodide proceeds through a pseudo-E1 process in
which the iodonium ion B rearranges, accompanied by the
expulsion of the silicon (penta- or hexavalent silicate may
form initially11) yielding the E product. Retention is
favored because it requires the smallest angle of rotation
of the CÀC bond to achieve elimination.13 This mechan-
ism is in agreement with the observation that iodination
proceeds faster in polar protic solvents that stabilize the
iodonium ion and promote silicate formation. Similarly,
retention of stereochemistry with bromination in THF at
low temperatures (À78 °C and below) and DMF can be
rationalized by the fact that a longer-lived bromonium ion
exists and may allow formation of the E isomer, analogous
(11) Tamao, K.; Akita, M.; Maeda, K.; Kumada, M. J. Org. Chem.
1987, 52, 1100.
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Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Conversion of (E)-Alkenylsiloxane Substrates to the
Corresponding Alkenyl Bromide and Alkenyl Iodide
Scheme 4. Access to Both Stereoisomers of Trisubstituted
Alkene, and Macrocyclic Ketone
Tamao oxidation.18 Yields from all of these transforma-
tions are excellent.
In summary, we have demonstrated a methodology to
access trisubstituted macrocyclic (E)- and (Z)-alkenes
from ring-closing metathesis. The strategy employs a sub-
strate-controlled RCM reaction of linear vinylsiloxanes to
selectively generate macrocyclic (E)-alkenyl siloxanes.
Conditions were developed to convert the alkenyl siloxane
products into alkenyl halides with retention or inversion
of configuration of the alkene geometry. The E- and
Z-alkenyl halides in turn served as effective substrates for
palladium-mediated cross-coupling reactions to generate
trisubstituted alkenes. The application of this methodol-
ogy to the construction of biologically relevant macro-
cycles is currently underway.
a [Si] = Si(OEt)2Me. b Isolated yields for bromination reactions
(in blue) and iodination reactions (in black) including both isomers unless
otherwise noted. Selectivity (in parentheses) determined by 1H NMR
analysis of crude reaction mixtures. c Isolated yield for the major isomer.
The synthetic potential of this methodology is demon-
strated in Scheme 4. The macrocyclic (E)-alkenylsiloxane
1 can be converted to trisubstituted macrocyclic alkene
E-14 through a Suzuki coupling between alkenyl iodide
E-1I and 3-acetylphenyl-boronic acid.14 Compound E-14
can also be obtained directly through a Hiyama-type
reaction;15 however, for the majority of cross-coupling
reactions, alkenyl iodides serve as more effective inter-
mediates than the initial alkenylsiloxanes.16 Conversely,
the Z stereoisomer of 14 can be accessed from Z-1Br, the
product from the stereochemical inversion of 1.17 Finally,
since vinylsiloxane 1 contains a differentiated alkene it can
be regiospecifically oxidized to macrocyclic ketone 13 via
Acknowledgment. We gratefully acknowledge Profes-
sor Stuart L. Schreiber from the Broad Institute for his
mentorship and support of this work. We also acknowl-
edge Drs. Tuoping Luo, Drew Adams, Mingji Dai, Max
Majireck, Zarko Boskovic, Mahmud Hussain, and Partha
Nag from the Broad Institute for helpful discussions. This
work was funded by the NIGMS-sponsored Center of
Excellence in Chemical Methodology and Library Devel-
opment (Broad Institute CMLD; P50 GM069721).
(14) Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Deng, J. Z.; Nguyen,
D. N.; Potteiger, C. M.; Graham, S. L.; Vacca, J. P.; Williams, T. M.
Org. Lett. 2008, 10, 3235.
(15) (a) Denmark, S. E.; Pan, W. Org. Lett. 2003, 5, 1119. (b) Rooke,
D. A.; Ferreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3225. (c) Tamao,
K.; Kobayashi, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 6051.
(16) For the synthetic utility of vinylsilanes, see: Denmark, S. E.; Liu,
J. H. C. Angew. Chem., Int. Ed. 2010, 49, 2978.
Supporting Information Available. Experimental pro-
cedures, and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) Trost, B. M.; Pinkerton, A. B. J. Am. Chem. Soc. 2002, 124, 7376.
(18) Tamao,K.;Kumada,M.;Maeda,K.Tetrahedron Lett. 1984,25,321.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX