Iododesilylation of TIPS-, TBDPS-, and TBS-substituted alkenes in connection with the synthesis of amphidinolides B/D

Article abstract of DOI:10.1021/ol2020187

The C-Si bonds of triisopropylsilyl-substituted alkenes, 1,3-dienes, and related multifunctional substrates, as well as analogous C-TBDPS and C-TBS bonds, are readily and chemoselectively cleaved with NIS (or other sources of I⁺, such as N-iodo

Full text of DOI:10.1021/ol2020187

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4934–4937
Iododesilylation of TIPS-, TBDPS-, and
TBS-Substituted Alkenes in Connection
with the Synthesis of Amphidinolides B/D
Mireia Sidera, Anna M. Costa,* and Jaume Vilarrasa*
´
Departament de Quımica Organica, Facultat de Quımica, Universitat de Barcelona,
Diagonal 647, 08028 Barcelona, Catalonia, Spain
ꢀ
´
amcosta@ub.edu; jvilarrasa@ub.edu
Received July 26, 2011
ABSTRACT
The CꢀSi bonds of triisopropylsilyl-substituted alkenes, 1,3-dienes, and related multifunctional substrates, as well as analogous CꢀTBDPS and
CꢀTBS bonds, are readily and chemoselectively cleaved with NIS (or other sources of Iþ, such as N-iodosaccharin, 1,3-diodohydantoin, and
Ipy2BF4). The desired iodoalkenes are obtained stereospecifically without byproducts, provided that the reactions are carried out in CF3CHOHCF3
and, in general, with 30 mol % of Ag2CO3 (or AgOAc/2,6-lutidine) as an additive. Fragment C10ꢀC18 of cytotoxic amphidinolides B1ꢀB3 and D has
been synthesized using this improved procedure.
In a total synthesis1 of amphidinolides B1ꢀB3 and D,
26-membered macrolides with impressive cytotoxic activi-
ties (in the nanomolar range),2 we faced the problem of the
formation of the key C13ꢀC14 bond of the West Frag-
ment (see Iaꢀc, Scheme 1) by means of Negishi couplings
between IIaꢀc and bromoalkenes of type III. The total
syntheses reported to date of amphidinolides B/D/G/H
achieved similar fragments by other approaches.3
Scheme 1. Retrosynthetic Analysis of Amphidinolides B1ꢀB3/D
Fragments IIaꢀc could arise from the iododesilylation
of IVaꢀc (Scheme 1, bottom), which could come from
precursor V via a Suzuki C15ꢀC16 coupling. However,
(1) Sidera M. PhD Thesis, Universitat de Barcelona (2007ꢀ2011).
(2) (a) Kobayashi, J. J. Antibiot. 2008, 61, 271. (b) Kobayashi, J.;
Kubota, T. J. Nat. Prod. 2007, 70, 451.
(3) (a) Lu, L.; Zhang, W.; Carter, R. G. J. Am. Chem. Soc. 2008, 130,
7253 (B1 and B2, allyl silane addition to a methyl ketone, C14ꢀC15),
€
and references therein. (b) Furstner, A.; Bouchez, L. C.; Morency, L.;
after the remarkable work of Soderquist et al.,4 it is known
that the hydroboration of R03SiꢀCtCꢀR with 9-BBN
gives regioisomers of type V, only with the largest silyl
group examined (triisopropylsilyl, TIPS), whereas TMS,
TES, and TBS afforded the undesired regioisomers and
Funel, J.-A.; Liepins, V.; Poree, F.-H.; Gilmour, R.; Laurich, D.;
Beaufils, F.; Tamiya, M. Chem.ꢀEur. J. 2009, 15, 3983 (B1, B4, G1,
H1, and H2, Stille coupling). C16ꢀOH lacking amphidinolides H and G:
€
(c) Furstner, A.; Bouchez, L. C.; Funel, J.-A.; Liepins, V.; Poree, F.-H.;
Gilmour, R.; Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem., Int.
Ed. 2007, 46, 9265. Most recent reports of fragments: (d) Petri, A. F.;
Schneekloth, J. S.; Mandal, A. K.; Crews, C. M. Org. Lett. 2007, 9, 3001.
(e) Formentin, P.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron:
Asymmetry 2006, 17, 2938. (f) Gopalarathnam, A.; Nelson, S. G. Org.
Lett. 2006, 8, 7. For a very recent review on the synthesis of amphidino-
(4) Soderquist, J. A.; Colberg, J. C.; Valle, L. D. J. Am. Chem. Soc.
1989, 111, 4873.
€
lides, see: (g) Furstner, A. Isr. J. Chem. 2011, 51, 329.
r
10.1021/ol2020187
Published on Web 08/25/2011
2011 American Chemical Society

overaddition.4 The challenge was that, whereas there are
>360 reports on the substitution of I for TMS, there is
none, according to an exhaustive SciFinder search, on the
iododesilylation of TIPS alkenes,5 of tert-butyldiphenylsi-
lyl alkenes (CꢀTBDPS cleavage), or even of the less
sterically crowded TBS alkenes.6 In this connection, it is
worth noting a very recent report by Zakarian et al.7 on the
use of polar, non-nucleophilic (CF3)2CHOH (1,1,1,3,3,3-
hexafluoro-2-propanol, “hexafluoroisopropanol”, HFIP)
as the solvent of choice to iodinate TMS alkenes and
PhMe2Si alkenes with N-iodosuccinimide (NIS).8 Would
these iododesilylation conditions, the best reported to date,7
allow the conversion of IVaꢀc into IIaꢀc without affecting
other CꢀSiR3 bonds as well as standard functional groups?
We first examined the reactions of 4-phenyl-1-butene
and 4-phenyl-1-butyne derivatives shown in Scheme 2 with
NIS in HFIP/CDCl3, by NMR spectroscopy. For exam-
ple, when an equimolar mixture of 1, 2, and 3 in 1:1 HFIP/
CDCl3 was treated with NIS at 0 °C and its NMR
spectrum was registered at 20 °C, only the olefinic signals
of 1 decreased. A mixture of 1 and 4a, treated with a
substoichiometric amount of NIS, gave rise to the dis-
appearance of 4a to form vinyl iodide 5a, with retention of
the double-bond configuration; only when more NIS was
added, did 1 disappear. In another competition experiment
between 4a and 4b, no difference in the reaction rate of
4a (to give 5a) and 4b (to give 5b) was detected, even
at ꢀ20 °C. Thus, TIPS-substituted alkenes (Z and E) could
be transformed into vinyl iodides under these conditions,
with retention of the configuration, in the presence of
alkenes, alkynes, and silylated alkynes.
several byproducts began to appear while some starting
material still remained (long reaction times being
contraindicated). We hypothesized that radical reactions
affording HI by hydrogen abstraction and I2 (from the
dimerization of iodine atoms or from the reaction of HI
with remaining NIS) may promote the cleavage of some
OꢀPG bonds and the opening of the epoxide rings; be-
sides, I2 and HI may add to reactive double bonds. After a
series of experiments with different amounts of silver salts
and/or bases to trap these impurities, we found that in the
presence of 30 mol % of Ag2CO3 no pink color appeared
during the reactions in which we used 1.2 equiv of NIS. A
mixture of AgOAc (0.3ꢀ0.4 equiv) and 2,6-lutidine
(0.3ꢀ0.4 equiv)11 was similarly efficient. With either of
these two procedures, no byproducts were formed; the
conversions were 100%, with isolated yields around 90%
(see Table 1).
Table 1 shows that enyne 4c (entry 3 of Table 1), dienes
4d and 4e (entries 4 and 5), and compounds with OꢀSi
bonds (entries 4, 5, 7, and 8) only undergo the desired
C(sp2)ꢀTIPS bond cleavage. CꢀTBDPS and CꢀTBS
bonds can also be cleaved (entries 9ꢀ12).
Other iodinating reagents such as N-iodosaccharin
(NISac),12 1,3-diodo-5,5-dimethylhydantoin (DIH),13
and bis(pyridine)iodonium tetrafluoroborate (Ipy2BF4),
a reagent developed by Barluenga’s group,14 were exam-
ined (Table 1, last three columns). These reagents were
similarly efficient. As reactions with Ipy2BF4 were slower
but did not give rise to secondary reactions, they were
allowed to warm to rt;15 the advantage of this reagent is
that the addition of Ag2CO3 or AgOAc/2,6-lutidine is
unnecessary.
Scheme 2. Competition Experiments among 1ꢀ4, with NISa
(8) (a) In our group, this procedure had been applied to the cleavage
of a CꢀTMS bond arising from a Si-tethered RCM: Rodrı
´
guez-Escrich,
C.; Urpı, F.; Vilarrasa, J. Org. Lett. 2008, 10, 5191. For similar
´
applications: (b) Xie, Q.; Denton, R. W.; Parker, K. A. Org. Lett.
2008, 10, 5345. (c) Martin, D. B. C.; Vanderwal, C. D. J. Am. Chem. Soc.
2009, 131, 3472. For very recent I/TMS exchanges, see: (d) Herrmann,
A. T.; Martinez, S. R.; Zakarian, A. Org. Lett. 2011, 13, 3636. (e) Parker,
K. A.; Denton, R. W. Tetrahedron Lett. 2011, 52, 2115. Also see:
(f) Pawluc, P.; Franczyk, A.; Walkowiak, J.; Hreczycho, G.; Kubicki,
M.; Marciniec, B. Org. Lett. 2011, 13, 1976. (g) Denmark, S. E.; Muhuhi,
J. M. J. Am. Chem. Soc. 2010, 132, 11768. (h) Pawluc, P.; Madalska, M.;
Hreczycho, G.; Marciniec, B. Synthesis 2008, 3687.
a NMR chemical shifts are given in CDCl3 (the spectrawere registered
in CDCl3 and in 1:1 HFIP/CDCl3). The competition experiments were
carried out in 1:1 HFIP/CDCl3.
(9) In standard solvents such as CH3CN or in CH2Cl2, the outcomes
were worse.
(10) Commercial samples that were yellow or red were purified by
recrystallization from 1,4-dioxane/CCl4. See: Djerassi, C.; Lenk, C. T.
J. Am. Chem. Soc. 1953, 75, 3493.
However, with samples containing oxygen functional
groups and/or other double bonds conjugated with the
vinyl-TIPS group, the treatment with NIS gave moderate
yields and several byproducts, even in HFIP.9
Addition of 1 equiv of 2,6-lutidine7 did not prevent the
appearance of several spots on TLC. Even at 0 °C under
Ar, with pure NIS (white),10 protecting the vial from the
light, the solution turned pink after few minutes and
(11) For the most simple cases, the addition of Agþ was not crucial, as
mentioned (the reaction solutions turned pink, but very small amounts
of byproducts were formed).
(12) (a) Dolenc, D. Synlett 2000, 544. (b) Rai, A. Synlett 2008,
784 and references cited therein. NISac has not been used in
iododesilylations.
(13) Orazi, O. O.; Corral, R. A.; Bertorello, H. E. J. Org. Chem. 1965,
30, 1101. An exhaustive SciFinder search indicates that DIH has not
been used as a iododesilylating reagent (N-iodophthalimide either).
(14) (a) Creighton, J. A.; Haque, I.; Wood, J. L. Chem. Commun.
ꢁ
1966, 229. (b) Barluenga, J.; Gonzalez, J. M.; Campos, P. J.; Asensio, G.
Angew. Chem. 1985, 97, 341. (c) Barluenga, J.; Alvarez-Garcıa, L. J.;
Gonzalez, J. M. Tetrahedron Lett. 1995, 36, 2153. (d) Barluenga, J.;
´
(5) There is only one related example, the desilylation of 2-TIPS-2-
cyclopentenone with ICl. See: Davie, C. P.; Danheiser, R. L. Angew.
Chem., Int. Ed. 2005, 44, 5867.
ꢁ
ꢁ
a, L. J.; Gonzalez, J. M.; Campos, P. J.; Dıaz,
´ ´
Llorente, I.; Alvarez-Garcı
M. R.; Garcıa-Granda, S. J. Am. Chem. Soc. 1997, 119, 6933. (e) Also see
´
(6) The desilylation of ArSiR3 (ipso-SEAr) is well-known, however.
(7) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10, 1727.
For previous procedures, see references cited therein.
ref 8h and references cited therein.
(15) Also with Ipy2BF4, the use of HFIP was crucial to achieve high
yields of the desired iodo derivative in relatively short reaction times.
Org. Lett., Vol. 13, No. 18, 2011
4935

TBDPS. We attributed this signal to (CF3)2CHOTBDPS,
asitwas coincident withthe newsignal thatappearedwhen
we heated TBDPSCl and Ag2CO3 in neat HFIP. These
results suggest that the solvent, HFIP, acts as the main
silicon trap (at least at the beginning).
Table 1. Iododesilylation of Molecules Containing C(sp2)ꢀ
TIPS, C(sp2)ꢀTBDPS, or C(sp2)ꢀTBS Bondsa
With this information, the synthesis of fragment
C10ꢀC18 of amphidinolides B1ꢀB3/D was carried out
as summarized in Scheme 3.
Scheme 3. Synthesis of Fragment C10ꢀC18
Additionof9-BBN to1-(triisopropylsilyl)-1-propyne, as
reported by Soderquist et al.4 followed by a standard
SuzukiꢀMiyaura coupling,16 Sharpless’ asymmetric
epoxidation,17 and protection of the primary alcohol, gave
4g in excellent overall yield. Wesubjected4gtothe reaction
conditions of Table 1 to afford 5g. A Negishi coupling,
after previous conversion of a bromoalkene (see III in
Scheme 1)18 into the corresponding organozinc reagents
(with tBuLi, ZnCl2),19 gave the desired C10ꢀC18 moiety
(6) in 72% yield (with 15% recovery of 5g).
In summary, it is reported here for the first time that
TIPS groups (as well as TBDPS and TBS) linked to acyclic
doublebondscanbequickly, fully, and selectivelyremoved
by iodination with full retention of the double-bond con-
figuration, in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP).
This is consistent with the very recent report by the group
of Zakarian7 of the cleavage of alkeneꢀTMS bonds, but it
can also be applied to complex multifunctional substrates
in the presence of a small amount of Ag2CO3 (or, alter-
natively, of AgOAc/lutidine). Under these conditions,
N-iodosaccharin and 1,3-diiodo-5,5-dimethylhydantoin,
evaluated as iododesilylation reagents for the first time,
are also efficient and do not affect either OꢀSi bonds,
C(sp)ꢀSi bonds, epoxides, etc. Although Ipy2BF4 reacts
slowly, it does not require the addition of silver salts. Thus,
any of the four reagents examined in Table 1 can be used in
iododesilylation protocols of complex substrates; other N-
a With NIS, NISac, or DIH, substrates and reagents were stirred for
5ꢀ25 min at 0 °C, under Ar in the dark. With Ipy2BF4, the reactions were
slower (at 0 °C, >1 h was required for completion of several reactions);
substrates and reagents (without Agþ, which was not crucial with this
reagent) were mixed at 0 °C, and stirring was then maintained at rt for
15ꢀ45 min. Conversions were quantitative in all cases; isolated yields
after the workup are given (the yield differences are mainly due to
different operation scales and isolation procedures). b 60 mol % of DIH
was sufficient (both iodine atoms are reactive). c A drop of CH2Cl2 was
added to solubilize 4i.
The reaction rates of TIPS-substituted alkene 4c and
TBS-substituted alkene 4k were practically identical. On
the other hand, we observed by NMR that, when NIS was
added in small portions (up to 90 mol %) to an equimolar
mixture of 4a and 4i in HFIP/CDCl3, the CꢀTIPS bond of
4a was cleaved selectively with regard to the CꢀTBDPS
bond of 4i.
The fate of the silyl groups in these desilylation reactions
was also examined. When the reaction of 4i with NIS in
HFIP was followed by 1H NMR, a new signal appeared at
δ 1.33 corresponding to the methyl groups (of a tBu) of a
(16) (a) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New York, 2004; Chapter 2.
(b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
(c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(17) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I.; Ed.; Wiley-VCH: New York, 2000; Chapter 6A.
(18) Prepared from Aux*ꢀCOEt and BrCH2C(dCH2)Br. See:
Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 8, 2506.
(19) (a) Negishi, E..; Swanson, D. R.; Rousset, C. J. J. Org. Chem.
1990, 55, 5406. (b) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55,
5404.
4936
Org. Lett., Vol. 13, No. 18, 2011

iodoimides and iodonium ion sources, also commercially
available or of easy preparation, may work similarly. The
procedure has paved the way to our syntheses of 26-
membered ring amphidinolides, as their West Fragment,
synthetically the most complex and challenging, is now
readily achievable.
Dec. 2010. J.V. dedicates this article to his colleague and
old friend Rafael Suau, Organic Chemistry Full Prof. of
ꢁ
the Universidad de Malaga since 1982, president of the
Organic Chemistry Division of the RSEQ (2006-10), who
died of cancer on November 11, 2010.
Supporting Information Available. Experimental de-
tails and spectral data, including copies of the 1H and 13
C
NMR spectra of the new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Acknowledgment. The Spanish Government (MEC,
MICINN) is acknowledged for grants CTQ2006-15393
and CTQ2009-13590. M.S. held a studentship from
AGAUR (Generalitat de Catalunya) from Jan. 2007 to
Org. Lett., Vol. 13, No. 18, 2011
4937