Syn-β-hydroxyallylic silanes from terminal epoxide α-lithiation-silylation and alkenylation: Application to the tetrahydrofuran portion of the lytophilippines

Article abstract of DOI:10.1021/ol3018853

Lithiation-in situ silylation of terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide in combination with phenyldimethyl(or diethyl)silyl chloride provides a direct process for the synthesis of trans-α,β-epoxysilanes, which undergo α-ring opening with alkenylcoppers to give syn-β-hydroxyallylic silanes. The chemistry is applied in an annulation approach to the C₁₀-C₁₉ tetrahydrofuran-containing portion of the lytophilippines.

Full text of DOI:10.1021/ol3018853

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4402–4405
syn-β-Hydroxyallylic Silanes from
Terminal Epoxide r‑LithiationꢀSilylation
and Alkenylation: Application to the
Tetrahydrofuran Portion of the
Lytophilippines
David M. Hodgson* and Saifullah Salik
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA, U.K.
david.hodgson@chem.ox.ac.uk
Received July 9, 2012
ABSTRACT
Lithiationꢀin situ silylation of terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide in combination with phenyldimethyl(or diethyl)silyl
chloride provides a direct process for the synthesis of trans-r,β-epoxysilanes, which undergo r-ring opening with alkenylcoppers to give syn-β-
hydroxyallylic silanes. The chemistry is applied in an annulation approach to the C10ꢀC19 tetrahydrofuran-containing portion of the lytophilippines.
ꢀ
In 2004, Rezanka and co-workers reported the isolation
of lytophilippines AꢀC (Figure 1) from the Red Sea
hydroid Lytocarpus philippinus, along with their antitumor
activities and structures, the latter proposed on the basis of
extensive NMR studies.1 Gille and Hiersemann synthe-
sized a protected C1ꢀC18 lytophilippine building block in
2010,2 and in 2011 Lee and co-workers disclosed a synth-
esis of the originally proposed structure of lytophilippine
A; however, the physical data did not match those of
the natural product and correction of the lytophilippine
structure will be necessary.3 In the present work, we have
focused on the challenge of assembling the C10ꢀC19 frag-
ment and report a convenient method for the synthesis of
syn-β-hydroxyallylic silanes and its application to assem-
bling the tetrahydrofuran portion of the lytophilippines in
a stereocontrolled manner.
Figure 1. Lytophilippines AꢀC.
efficient construction remain the focus of much synthetic
endeavor.4 While cyclizations have been previously used to
create THFswiththe desiredC11ꢀC15 stereochemistry,2,3,5
we were attracted to a different approach based on
allylsilaneꢀaldehyde annulation followed by Flemingꢀ
Tamao oxidation (Scheme 1). This type of annulation
chemistry has been extensively investigated.6 The require-
ment for cis-2,5-THF disubstitution and C14ꢀC15 erythro
Substituted tetrahydrofurans are found in a wide array
of natural and unnatural products, and methods for their
ꢀ
ꢀ
(1) Rezanka, T.; Hanus, L. O.; Dembitsky, V. M. Tetrahedron 2004,
60, 12191–12199.
(2) Gille, A.; Hiersemann, M. Org. Lett. 2010, 12, 5258–5261.
(3) Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Org. Lett. 2011, 13,
2476–2479.
(4) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290.
(5) Bradley, G. W.; Thomas, E. J. Synlett 1997, 629–631.
r
10.1021/ol3018853
Published on Web 08/16/2012
2012 American Chemical Society

stereochemistry indicated that reaction under nonchelate
control of a syn-β-hydroxyallylsilane 3 would be needed.7
Despite all the previous studies, to the best of our knowl-
edge such an annulation has not been previously reported.
anti-β-Hydroxyallylsilanes are relatively straightforward
to access from aldehydes and (E)-γ-silylallylmetal re-
agents.7a,8 syn-β-Hydroxyallylic silanes, where the allylic silyl
group facilitates annulation chemistry and can subsequently
be oxidized to alcohol functionality (e.g., PhMe2Siꢀ), are
also useful intermediates in organic synthesis9 but are not
so easy to synthesize, particularly with good control of
stereochemistry. One valuable approach, which however is
restricted to installation of the unsubstituted allyl group
only, involves aldehyde allylation with (Z)-γ-silylallyl-
boronate7b,9c or (allenylsilane-derived) -boron10 reagents.
We considered that more flexible access might be concisely
achieved by alkenyl metal-induced R-ring opening of trans-
R,β-epoxysilanes 4.11
group suitable for the annulation chemistry used PhMe2-
SiCl as the electrophile but gave trans-R,β-epoxysilane 5a
in only 15% yield. However, using t-BuOMe as solvent13
gave 5a in 63% yield,14 and this chemistry proved viable
with a range of terminal epoxides (59ꢀ65% yields, Table 1).
Table 1. Synthesis of trans-R-Phenyldimethylsilyl-Substituted
Epoxides 5 from Terminal Epoxides
Scheme 1. Synthetic Analysis of THF 1
An essential feature on which the conciseness of our
above approach relies on is direct access to the requisite
trans-R,β-epoxysilanes 4. In 2002, we reported a straight-
forward synthesis of trans-R,β-epoxysilanes 4 ([Si] =
SiMe3) by lithium 2,2,6,6-tetramethylpiperidide (LTMP)-
induced R-deprotonation of terminal epoxides and in situ
silylation with Me3SiCl in THF.12 An initial attempt to
extend this chemistry to incorporate an oxidizable silyl
With concise access to suitable trans-R,β-epoxysilanes 5
established, the propensity of 5a to undergo R-ring-open-
ing to give syn-β-hydroxyallylic silanes was investigated.
Three isolated examples exist of alkenyl metal-induced
R-ring-opening of phenyldimethylsilyl-substituted epoxides,
using isopropenyl- and vinyl-magnesium bromide under
copper catalysis.9a,b,d In these examples, the substrates
were the TMS and methyl ethers of the epoxide of trans-
3-(PhMe2Si)-prop-2-enol - where the presence of the ether
oxygen might ease ring-opening.15 In the current chemis-
try, ring-opening of R,β-epoxysilane 5a was initially ex-
amined using vinylmagnesium bromide (3 equiv) in the
presence of CuI (10 mol %) in Et2O at ꢀ60 °C for 2 h;9b,15
however, syn-β-hydroxyallylsilane 610 was isolated in
only 30% yield. An improved yield of allylsilane 6 (68%)
was obtained on increasing the temperature from ꢀ60
to ꢀ20 °C over a period of 1 h, then stirring the reaction
(6) (a) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868–
9870. (b) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293–1316.
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3199. (d) Bates, R. H.; Chen, M.; Roush, W. R. Curr. Opin. Drug
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T. R.; Beignet, J.; Beutler, J. A.; Panek, J. S. J. Org. Chem. 2009, 74,
1897–1916.
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Chem. Soc. 2009, 131, 14174–14175. (b) Chen, M.; Roush, W. R. Org.
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2004, 126, 8664–8665.
(11) Hudrlik, P. F.; Hudrlik, A. M. In Advances in Silicon Chemistry;
Larson, G. L., Ed.; JAI Press: Greenwich, 1993; Vol. 2, pp 1ꢀ89.
(12) Hodgson, D. M.; Reynolds, N. J.; Coote, S. J. Tetrahedron Lett.
2002, 43, 7895–7897.
(14) Changing other reaction parameters (equiv or ratio of LTMP
and PhMe2SiCl, temperature) led to lower yields of 5a.
(15) Chauret, D. C.; Chong, J. M.; Ye, Q. Tetrahedron: Asymmetry
1999, 10, 3601–3614.
Org. Lett., Vol. 14, No. 17, 2012
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mixture at ꢀ20 °C for a further 2 h (Scheme 2).16
To examine the scope of this methodology for accessing
more substituted syn-β-hydroxyallylic silanes, mono-,9a di-
or trialkyl-substituted alkenylmagnesium bromides were
also explored under the above conditions, but only starting
epoxysilane 5a was observed. More substituted syn-β-hy-
droxyallylic silanes 7ꢀ9 could be successfully obtained from
epoxysilane 5a by adopting Alexakis and Jachiet’s method
for BF3-assisted ring opening of (less-hindered) TMS-sub-
stituted epoxides with higher-order Z-alkenylcuprates17
(Scheme 2).
Scheme 3. Synthesis and Oxidation of THF 12
Scheme 2. Alkenylcopper Ring Opening of R,β-Epoxysilane 5a
Scheme 4. Synthesis of THF 22 from R-Citronellol-Derived
Aldehyde 14
Prior to examining a synthesis of the THF-containing
C10ꢀC19 fragment of the lytophilippines, the viability of
annulation with a syn-β-hydroxyallylsilane to give the
stereochemical array indicated in THF 1 was studied. In
the event, reaction of silyloxyallylsilane 11 with R-benzy-
loxyacetaldehyde in the presence of BF3OEt2 gave the
THF 12 in 70% yield with complete diastereoselectivity
(Scheme 3). Oxidation of the PhMe2Siꢀ substituent using
Hg(OAc)2 and peracetic acid7a,18 gavediol 13in 66% yield.
The stereochemistry of THFs 12 and 13 were determined
by NOE studies19 to be the same as that assigned for the
lytophilippines. As summarized in Scheme 1, this stereo-
chemicaloutcomeisconsistentwith annulationproceeding
by stepwise anti SE0 addition of the allylsilane to the Lewis
acid complexed aldehyde (through a syn-synclinal transi-
tion state), followed by suprafacial 1,2-silyl migration
and intramolecular ether formation, with inversion at the
original CꢀSi stereocenter.6,7a
The synthesis of the C10ꢀC19 fragment of the lytophi-
lippines (Scheme 4) used terminal epoxide 15, which was
obtained in 71% yield and 92:8 dr through asymmetric
organocatalytic R-chlorination20 of aldehyde 14 (two
steps from R-citronellol21). With epoxide 15, R-lithiationꢀ
silylation using PhMe2SiCl gave the corresponding trans-
R,β-epoxysilane (∼60%) together with a minor, but in-
separable, disilylated byproduct;22 this problem was
avoided by using PhEt2SiCl as the electrophile, which gave
epoxysilane 16 in 63% yield. Epoxysilane 16was converted
(16) The putative β-(magnesio-oxy)allylsilane intermediate appeared
stable at ꢀ20 °C and did not undergo Peterson olefination.
(17) Alexakis, A.; Jachiet, D. Tetrahedron 1989, 45, 381–389.
(18) (a) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28,
4229–4232. (b) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.;
Sanderson, P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317–337.
(19) See the Supporting Information for details.
(20) Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2009, 48, 5121–5124.
(21) Chandrasekhar, S.; Yaragorla, S. R.; Sreelakshmi, L.; Reddy,
Ch. R. Tetrahedron 2008, 64, 5174–5183.
4404
Org. Lett., Vol. 14, No. 17, 2012

in three steps to terminal olefin-containing epoxysilane 18
using standard conditions.23 This epoxysilane 18 was ring
opened to give alcohol 19, where the modest yield (38%)
likely reflects the greater steric encumbrance of the PhEt2Si
group compared with the PhMe2Si group used earlier.22
The presence of the alkene in the derived THF 21 (68%
from silyloxyallylsilane 20) necessitated18 different oxida-
tion conditions from those used earlier in Scheme 3. While
THF 21 proved inert to KH/t-BuOOH, TBAF, and NMP
(70 °C, 4 h),24 successful oxidation to THF 22 (64%)25 was
In summary, trans-R,β-epoxysilanes bearing an oxidiz-
able silyl group, PhMe2Siꢀ or PhEt2Siꢀ, are accessible by
direct lithiationꢀsilylation of terminal epoxides, and the
epoxysilanes can be regioselectively and stereospecifically
R-ring opened by using vinylmagnesium bromide under
copper catalysis or by various alkenyl cuprates in the pre-
sence of BF3 to give synthetically useful syn-β-hydroxyallylic
silanes. The utility of the methodology has been demon-
strated in a stereocontrolled asymmetric synthesis of the
THF portion (C10ꢀC19) of the lytophilippines involving
annulation of a syn-β-hydroxyallylsilane with an aldehyde.
achieved with TBAF in the presence of 4 A MS,26 followed
˚
by addition of further TBAF27 and H2O2.
Acknowledgment. We thank the Higher Education
Commission of Pakistan for studentship support (to S.S.).
(22) This ∼80% pure epoxysilane was also carried through to THF 22
(with the corresponding epoxide ring opening occurring in ∼55% yield),
but a disilylated component persisted until oxidation. The disilylated
byproduct was tentatively assigned (13C NMR spectra showed a CH2
signal at 0 ppm) as arising from SiMe lithiationꢀsilylation of the initially
formed epoxysilane (Hodgson, D. M.; Comina, P. J.; Drew, M. G. B.
J. Chem. Soc., Perkin Trans. 1 1997, 2279–2289). Disilylation was not a
significant side reaction with the racemic terminal epoxides studied earlier.
(23) Chandrasekhar, S.; Mahipal, B.; Kavitha, M. J. Org. Chem.
2009, 74, 9531–9534. Ring opening of epoxysilane 16 was compromised
by subsequent facile Peterson-like elimination to diene, likely assisted by
coordination to the TBDPSO-group; this necessitated introduction of
the terminal olefin prior to ring opening.
Supporting Information Available. Full experimental
procedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
€
(26) (a) Merten, J.; Hennig, A.; Schwab, P.; Frohlich, R.; Tokalov,
S. V.; Gutzeit, H. O.; Metz, P. Eur. J. Org. Chem. 2006, 1144–1161.
(b) Nelson, B.; Hiller, W.; Pollex, A.; Hiersemann, M. Org. Lett. 2011,
13, 4438–4441.
(27) Akiyama, T.; Hoshi, E.; Fujiyoshi, S. J. Chem. Soc., Perkin
Trans. 1 1998, 2121–2122.
(24) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044–
6046.
(25) THF 22 was isolated as an 89:11 mixture of diastereomers
(reflecting the diastereoselectivity in the formation of terminal epoxide 15).
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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