A relay ring-closing metathesis synthesis of dihydrooxasilines, precursors of (Z)-lodo olefins

Article abstract of DOI:10.1021/ol802063h

(Chemical Equation Presented) A convenient Grubbs II metathesis provides dihydrooxasilines by relay RCM (RRCM). Dihydrooxasilines undergo ring opening to give Z-vinyl silanes. These can then be converted to Z-vinyl iodides. This sequence provides a short,

Full text of DOI:10.1021/ol802063h

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5345-5348
A Relay Ring-Closing Metathesis
Synthesis of Dihydrooxasilines,
Precursors of (Z)-Iodo Olefins
Qiuzhe Xie, Richard W. Denton, and Kathlyn A. Parker*
Department of Chemistry, SUNY Stony Brook, Stony Brook, New York 11794-3400
kparker@notes.cc.sunysb.edu
Received September 3, 2008
ABSTRACT
A convenient Grubbs II metathesis provides dihydrooxasilines by relay RCM (RRCM). Dihydrooxasilines undergo ring opening to give Z-vinyl
silanes. These can then be converted to Z-vinyl iodides. This sequence provides a short, high yield, and convenient route to trisubstituted
Z-vinyl iodides, useful intermediates for the preparation of polypropionate antibiotics.
Iodo olefins are important intermediates in organic synthesis.
As key reactants in the convergent steps of many total
syntheses, they are often the reagents of choice in Heck, Stille
and Suzuki, Sonogashira, and Negishi coupling methods1 as
well as in the popular Nozaki-Hiyama-Kishi (NHK)
addition reaction.2 Stereochemical homogeneity in the prod-
ucts of these transformations depends on the availability of
geometrically clean iodo olefins as starting materials.
We have been interested in the preparation of a 2-iodo
(Z)-olefin of general structure 1 (Figure 1) and, in particular,
the iodoolefinic alkyne 2,3 which we projected as a key
intermediate in the synthesis of discodermolide (3).4
(1) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
Figure 1. Functional group pattern in target intermediates and
relationship to the structure of discodermolide.
2005, 44, 4442.
(2) For a review, see: (a) Fuerstner, A. Chem. ReV. 1999, 99, 991. For
the asymmetric NHK reaction, see: (b) Choi, H.-w.; Nakajima, K.; Demeke,
D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.; Kishi, Y. Org. Lett. 2002, 4, 4435.
See also: (c) Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.l.;
Paterson, I. Angew. Chem., Int. Ed. 2003, 42, 1032.
(3) Parker, K. A.; Cao, H. US Patent Applications, Serial No. 11/421,290
and Serial No. 11/697,340. We had prepared alkyne 2 by a scheme that
employed the Stork-Zhao conversion, a transformation that is low-
yielding for the preparation of trisubstituted olefins. See: Arimoto, H.;
Kaufman, M. D.; Kobayashi, K.; Qiu, Y.; Smith, A. B., III. Synlett 1998,
7, 765.
Given the small number of approaches to vinyl iodides of
this substitution pattern,5 we considered the design of a new
method that might be high yielding and that would be easy
to implement.
10.1021/ol802063h CCC: $40.75
Published on Web 11/12/2008
2008 American Chemical Society

starting material. We repeated both the Grubbs II and
Schrock experiments under an atmosphere of ethylene,9
recovering silyl ether 7 in both cases.
In order to find conditions that would effect the desired
closure, we prepared the model substrate 10 and subjected
it to metathesis conditions (Scheme 3). Material recovered
Scheme 1. Desired Iodo Olefin-Containing Polyketide Building
Block, Readily Available Potential Precursor, and Possible
Intermediate
Scheme 3
.
Test of Metathesis Conditions with Model Silyl
Ether
We were especially motivated to prepare alcohol 4, an
obvious precursor to alkyne 2 and a generally useful
intermediate, from a precursor of general structure 5.
Alcohols 5 are readily available from a short scheme based
on asymmetric catalysis.6 Thus, we considered the possibility
that the dihydrooxasiline 6 might serve as an intermediate
in the desired conversion.
Imagining the silyl ether 6 to be the product of a ring-
closing metathesis (RCM) reaction, we set out to attempt
this cyclization.7 Silylation of the known alcohol 5 (R, R )
(CH2)5, Scheme 2) with isopropenyldimethylsilyl chloride
from the Grubbs II reaction showed two spots on tlc, one of
which represented the starting material 10 and the other a
new compound(s), which was clearly not the cyclized 11.10
This result was not particularly surprising. The literature
sports no examples of ruthenium catalyst-promoted ring
closing olefin metathesis to 1,2-dihydrooxasilines; both
Grubbs generation I catalyst11 and Grubbs generation II
catalyst (8)11c are reported to fail with the relevant sub-
strates.12 On the other hand, the Schrock catalyst converted
silyl ether 10 to the RCM product in 97% yield.
Scheme 2. Initial Plan for the Ring-Closing/Ring-Opening
Strategy for the Preparation of Alcohol 6
(4) (a) Florence, G. J.; Gardner, N. M.; Paterson, I. Nat. Prod. Rep.
2008, 25, 342. (b) Smith, A. B.; Freeze, B. S. Tetrahedron 2008, 64, 261.
(c) Mickel, S. J. Pure Appl. Chem. 2007, 79, 685, and references
therein.
(5) Those that are generally appropriate for introduction of the vinyl
iodide moiety into advanced intermediates include: (a) The Stork-Zhao
reaction: Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827.
(b) Iododemetalation: de Lemos, E.; Poree, F.-H.; Commercon, A.; Betzer,
J.-F.; Pancrazi, A.; Ardisson, J. Angew. Chem., Int. Ed. 2007, 46, 1917.
Arefolov, A.; Panek, J. S. J. Am. Chem. Soc. 2005, 127, 5596. (c) The
Tanino-Miyashita olefination: Tanino, K.; Arakawa, K.; Satoh, M.; Iwata,
Y.; Miyashita, M. Tetrahedron Lett. 2006, 47, 861.
(6) (a) Parker, K. A.; Cao, H. Org. Lett. 2006, 8, 3541. See also: (b)
Tsai, D. J. S.; Midland, M. M. J. Org. Chem. 1984, 49, 1842.
(7) All exploratory reactions were carried out with racemic materials.
Structures 14-20, 6, and 4 in Schemes 4 and 5 represent chiral
compounds.
(8) Denmark and Yang have shown that, in simple systems, dihydrooxa-
silines with di- and trisubstituted olefins were formed with the Schrock
catalyst. However, an attempt to effect closure to a tetrasubstituted olefin
was not successful. See: Denmark, S. E.; Yang, S.-M. Tetrahedron 2004,
60, 9695.
(9) Chen, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Org. Lett. 2004, 6,
4077.
(10) The NMR spectrum of the compound represented by the second
spot (approximately 10% of the recovered material) contained absorptions
in the silylmethyl, vinylmethyl, allyl, vinyl, and aromatic regions (as does
silyl ether 10); however, the integral of the aromatic region was enhanced.
Metathesis of the catalyst with the substrate is the likely origin of this minor
product.
(11) (a) Barrett, A. G. M.; Beall, J. C.; Braddock, D. C.; Flack, K.;
Gibson, V. C.; Salter, M. M. J. Org. Chem. 2000, 65, 6508. (b) Ahmed,
M.; Barrett, A. G. M.; Beall, J. C.; Braddock, D. C.; Flack, K.; Gibson,
V. C.; Procopiou, P. A.; Salter, M. M. Tetrahedron 1999, 55, 3219. (c)
Denmark, S. E.;Yang, S.-M.;Org. Lett. 2001, 3, 1749, and ref 8. See also
entry 2 in Table I in: (d) Kroell, R. M.; Schuler, N.; Lubbad, S.; Buchmeiser,
M. R. Chem. Commun. 2003, 2742.
provided the desired 7. In this metathesis substrate, the
functional group pattern should allow RCM to favor the
formation of a 6-membered ring containing a trisubstituted
olefin (not a cyclobutane and not a 5-membered ring
containing a tetrasubstituted olefin).8
Attempted RCM with Grubbs’s second-generation catalyst
(8) or with Schrock’s catalyst 9 resulted in the recovery of
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Org. Lett., Vol. 10, No. 23, 2008

supply the excisable tether, followed the strategy of Ashby15
(see the Supporting Information for details). Addition of the
chiral zinc reagent16 from cis-1-bromopropene17 and (-)-
N-methylephedrate afforded the (S)-alcohol 14, which was
converted to the methallyl ether 15. Treatment with the
n-BuLi/KO-t-Bu reagent effected the expected stereoselective
2,3-Wittig rearrangement. Silylation of the resulting (3S,4S)-
undecatrienol 16 afforded the relay metathesis susbstrate 17.
Scheme 4
.
Relay Metathesis-Based Synthesis of
Dihydooxasiline 6
When exposed to the Grubbs II catalyst 8, silyl ether 17
underwent the relay RCM (RRCM) reaction to provide the
desired cyclic silyl ether 6 in high yield. The surprising but
welcome success of this reaction provides another example18
of the power of the relay metathesis strategy.
With 6 in hand, we studied methods for effecting the
desired conversion to a linear vinyl iodide such as our target
4 (Scheme 5). Ring cleavage of silyl ether 6 with methyl-
Scheme 5. Ring Cleavage, Modification, and Iododesilylation
All of the above suggested that the Grubbs II catalyst
would not effect RCM to dihydrooxasilines (as is believed),
that the Schrock catalyst would effect such a closure, but
that the Schrock catalyst was not generating the critical metal
carbene by metathesis with our substrate 7, even when the
reaction was run under ethylene.
In an effort to drive the initiation of the metathesis reaction,
we resolved to prepare substrate 17, designed so that it would
participate in a Hoye-type “relay.”13 In our design, the tether
between the initiating terminal olefin and the site of desired
reactivity was to be three carbons long, setting up a cascade
in which the first ring formed would be a cyclopentene. Also,
the tether would contain, adjacent to the internal olefin, two
methyl substituents. This design would promote ring closure
in the first step of the metathesis reaction by the famous “gem
dimethyl effect.”14 Furthermore, substitution at this position
would be advantageous in the synthesis of the substrate
precursor 16, the product of a 2,3-Wittig rearrangement,6
by favoring the syn relationship of the adjacent methyl and
hydroxyl substituents.
lithium19 proved to be a high yield transformation, giving
vinyl silane 18. Then protection of the alcohol (18 f 19)
and hydroboration with 9-BBN gave silane 20.20 Iododesi-
lylation of silane 20 with recrystallized NIS in CH3CN/
CCl3CN21 gave a high yield of the known alcohol 4 as an
85:15 Z/E mixture.22
A small amount of a byproduct was also isolated. The
NMR spectrum of this compound showed the MOM and
(15) Ashby, E. C.; Park, B.; Patil, G. S.; Gadru, K.; Gurumurthy, R. J.
Org. Chem. 1993, 58, 424.
(16) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777.
(17) cis-1-Bromopropene is conveniently prepared in multigram quanti-
ties by the method of: Fuller, C. E.; Walker, D. G. J. Org. Chem. 1991, 56,
4066.
Synthesis of the “relay substrate” 17 relied on methods
already established. Preparation of aldehyde 13, which would
(18) Hoye’s original paper (ref 13a) describes several different cases in
which the relay strategy proved advantageous. For others, see: (a) Zakarian,
J. E.; El-Azizi, Y.; Collins, S. K. Org. Lett. 2008, 2027. (b) Cho, E. J.;
Lee, D. Org. Lett. 2008, 10, 257. (c) Dudley, G. B.; Engel, D. A.; Ghiviriga,
I.; Lam, H.; Poon, K. W. C.; Singletary, J. A. Org. Lett. 2007, 9, 2839. (d)
Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am. Chem. Soc. 2007, 129, 8960.
(e) Collins, S. K. J. Organomet. Chem. 2006, 691, 5122. (f) Crimmins,
M. T.; Zhang, Y.; Diaz, F. A. Org. Lett. 2006, 8, 2369. (g) For an example
of the use of relay strategy in macrocyclic enyne metathesis, see: Collins,
S. K.; El-Azizi, Y.; Schmitzer, A. R. J. Org. Chem. 2007, 72, 6397.
(19) For a cleavage of a related cyclic silyl ether with phenyllithium,
see Barrett’s synthesis of glycosphingolipids; see reference 11a.
(12) A related enyne RCM proceeds with catalyst 8. See Miller, R. L.;
Maifeld, S. V.; Lee, D. Org. Lett. 2004, 6, 2773.
(13) (a) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao,
H. J. Am. Chem. Soc. 2004, 126, 10210. (b) For a review, see: Wallace,
D. J. Angew. Chem., Int. Ed. 2005, 44, 1912.
(14) (a) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735. (b) For a
discussion of this effect in ring-closing enyne metathesis, see: Kim, Y. J.;
Grimm, J. B.; Lee, D. Tetrahedron Lett. 2007, 48, 7961.
Org. Lett., Vol. 10, No. 23, 2008
5347

TMS groups but no vinyl proton and its infrared spectrum
showed no absorption for a hydroxyl group.
Scheme 6. Protection and Stereoselective Iododesilylation
We attempted to improve the ratio of isomers in the
iododesilylation product of alcohol 20 by adopting hexafluoro
isopropanol (HFIP) as solvent.23 This experiment afforded
a crude product, which contained many compounds (as
indicated by tlc). Only minor amounts of the desired vinyl
iodide 4 (both E and Z, as judged by analysis of the NMR
spectrum) could be seen; furthermore, the aforementioned
byproduct appeared to be the major component of the product
mixture. We suspect that this byproduct results from an
iodoetherification reaction and that the use of HFIP in
iododesilylations may be limited to substrates that cannot
take part in this type of pathway.24
Improved results were obtained when TBS ether 21 was
subjected to the iododesilylation conditions in HFIP. This
reaction afforded an 88% yield of the known vinyl iodide
22 (a key intermediate in Smith’s fourth-generation disco-
dermolide synthesis)22 as a 92:8 mixture of (Z)- and (E)-
isomers.
Overall, the preparation depicted in Schemes 4-6 provides
the original target, iodo olefin 4, in 29% yield (corrected for
the presence of the E-isomer) and the vinyl iodide building
block 22 in 27% yield (likewise corrected for the presence
of E-isomer) from alcohol 12. Thus, the relay RCM prepara-
tion of dihydrooxasilines followed by ring opening and
iododesilylation provides efficient access to (Z)-vinyl iodides.
As it is generally accepted that the Schrock catalyst is
required for the closure of vinyl silane metathesis substrates,
the effectiveness of the Grubbs II catalyst in the relay RCM
reaction (17 f 6) is noteworthy and will be the subject of
further examination.
(20) The corresponding TBS ether is a known compound, prepared in
11 steps including a chiral resolution; see: (a) Arefolov, A.; Panek, J. S.
Org. Lett. 2002, 4, 2397. (b) Arefolov, A.; Panek, J. S. J. Am. Chem. Soc.
2005, 127, 5596. (c) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain,
N. F.; Panek, J. S. Org. Synth. 1998, 75, 78.
(21) (a) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996,
37, 8647. A detailed protocol for NIS iododesilylation in acetonitrile/
chloroacetonitrile can be found in the Supporting Information of reference
20a.
Acknowledgment. This work was supported by the Army
Breast Cancer Initiative (BC 051816), the National Institutes
of Health (GM 74776), and the National Science Foundation
(CHE-0131146, NMR instrumentation). We thank Professor
Richard Franck of Hunter College for valuable discussions.
(22) Smith, A. B., III.; Freeze, B. S.; Xian, M.; Hirose, T. Org. Lett.
2005, 7, 1825.
(23) (a) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003,
125, 7822. (b) lardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10,
1727.
(24) Iodoetherification by addition to vinyl silanes to form tetrahydro-
pyrans has not been reported. However, iodolactonization in vinyl silane
substrates is known; see: (a) Kira, K.; Hamajima, A.; Isobe, M. Tetrahedron
2002, 58, 1875. (b) Kobayashi, Y.; Yoshida, S.; Nakayama, Y. Eur. J. Org.
Chem. 2001, 1873. (c) Kira, K.; Isobe, M. Tetrahedron Lett. 2001, 42, 2821.
(d) Kitano, Y.; Okamoto, S.; Sato, F. Chem. Lett. 1989, 2163. Also, Zakarian
(ref 23b) noted the isolation of products derived from addition to a
vinylsilane of iodonium and the carbonyl of a benzoate by way of a
5-membered ring.
Supporting Information Available: Detailed descriptions
of the experimental procedures and complete analytical data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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