Sakurai reaction of 3,3-bis(silyl) silyl enol ethers with acetals involving selective desilylation of the geminal bis(silane). Concise synthesis of nematocidal oxylipid

Article abstract of DOI:10.1021/ol400069p

3,3-Bis(silyl) silyl enol ethers have been shown to exhibit predominantly Sakurai reactivity, rather than Mukaiyama aldol reactivity, in their Lewis acid promoted reactions with acetals. Starting from a geminal bis(silyl) moiety consisting of two differen

Full text of DOI:10.1021/ol400069p

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1068–1071
Sakurai Reaction of 3,3-Bis(silyl) Silyl Enol
Ethers with Acetals Involving Selective
Desilylation of the Geminal Bis(silane).
Concise Synthesis of Nematocidal Oxylipid
Linjie Li,† Xincui Ye,† Ya Wu,† Lu Gao,† Zhenlei Song,*,†,‡ Zhiping Yin,† and Yongjin Xu†
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal
Chemistry, West China School of Pharmacy, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu 610041, P. R. China
zhenleisong@scu.edu.cn
Received January 10, 2013
ABSTRACT
3,3-Bis(silyl) silyl enol ethers have been shown to exhibit predominantly Sakurai reactivity, rather than Mukaiyama aldol reactivity, in their Lewis
acid promoted reactions with acetals. Starting from a geminal bis(silyl) moiety consisting of two different silyl groups, such as SiMe3 and SiMe2Ph,
the SiMe3 is selectively eliminated to give monoprotected E- vinylsilyl diols with good to excellent syn-diastereoselectivity. This reaction also
underpinned a synthesis of the nematocidal oxylipid from Notheia anomala, demonstrating the attractive bifunctionality of geminal bis(silanes).
Organosilanes1 are extremely useful inorganicsynthesis.
Organosilanes with diverse structural features usually
possess quite different reactivities, and research into this
diverse reactivity has led to many significant achievements
in both the areas of synthetic methodology and natural
product synthesis. Therefore, the discovery of structurally
unique organosilanes could provide important break-
throughs in the development of novel reactions. With this
goal in mind, we recently launched a series of studies on
geminal bis(silanes) 12,3 that contain two bulky silyl groups
attached to a single carbon center (Scheme 1, left).4 Our
recent work, however, has shown that these compounds
exhibit unusual behavior that makes them particularly useful
as bifunctional synthons,2 suggesting that they can contri-
bute to a much broader range of reactions than previously
thought.
Among the various geminal bis(silanes) that have been
described, 3,3-bis(silyl) silyl enol ethers of general structure
2 appear to be particularly interesting (Scheme 1, right).
(3) For studies on geminal bis(silanes), see: (a) Fleming, I.; Floyd,
C. D. J. Chem. Soc., Perkin Trans. 1 1981, 969. (b) Brook, A. G.;
Chrusciel, J. J. Organometallics 1984, 3, 1317. (c) Klumpp, G. W.;
Mierop, A. J. C.; Vrielink, J. J.; Brugman, A.; Schakel, M. J. Am. Chem.
Soc. 1985, 107, 6740. (d) Bellasoued, M.; Majidi, A. J. Org. Chem. 1993,
58, 2517. (e) Lautens, M.; Delanghe, P. H. M.; Goh, J. B.; Zhang, C. H.
J. Org. Chem. 1995, 60, 4213. (f) Princet, B.; Gariglio, H. G.; Pornet, J.
J. Organomet. Chem. 2000, 604, 186. (g) Hodgson, D. M.; Barker, S. F.;
Mace, L. H.; Moran, J. R. Chem. Commun. 2001, 153. (h) Inoue, A.;
Kondo, J.; Shinokubo, H.; Oshima, K. Chem.;Eur. J. 2002, 8, 1370.
† Key Laboratory of Drug-Targeting of Education Ministry and Depart-
ment of Medicinal Chemistry.
‡ State Key Laboratory of Biotherapy.
(1) For selected reviews on organosilanes, see: (a) Overman, L. E.;
Blumenkopf, T. A. Chem. Rev. 1986, 86, 857. (b) Panek, M.; Masse, C. E.
Chem. Rev. 1995, 95, 1293. (c) Fleming, I.; Barbero, A.; Walter, D.
Chem. Rev. 1997, 97, 2063. (d) Denmark, S. E.; Regens, C. S. Acc. Chem.
Res. 2008, 41, 1486.
(2) (a) Song, Z. L.; Lei, Z.; Gao, L.; Wu, X.; Li, L. J. Org. Lett. 2010,
12, 5298. (b) Gao, L.; Lin, X. L.; Lei, J.; Song, Z. L.; Lin, Z. Org. Lett.
2012, 14, 158. (c) Sun, X. W.; Lei, J.; Sun, C. Z.; Song, Z. L.; Yan, L. J.
Org. Lett. 2012, 14, 1094. (d) Gan, Z. B.; Wu, Y.; Gao, L.; Sun, X. W.;
Lei, J.; Song, Z. L.; Li, L. J. Tetrahedron 2012, 68, 6928. (e) Lu, J.; Song,
Z. L.; Zhang, Y. B.; Gan, Z. B.; Li, H. Z. Angew. Chem., Int. Ed. 2012, 51,
5367.
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(i) Williams, D. R.; Morales-Ramos, A. I.; Williams, C. M. Org. Lett.
2006, 8, 4393.
(4) (a) Althaus, H.; Breunig, H. J.; Rosler, R.; Lork, E. Organometallics
€
1999, 18, 328. (b) Saito, M.; Tokitoh, N.; Okazaki, R. J. Am. Chem. Soc.
2004, 126, 15572. (c) Agou, T.; Sugiyama, Y.; Sasamori, T.; Sakai, H.;
Furukawa, Y.; Takagi, N.; Guo, J. D.; Nagase, S.; Hashizume, D.;
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r
10.1021/ol400069p
Published on Web 02/11/2013
2013 American Chemical Society

With concomitant removal of the SiMe3 group on oxygen,
monoprotected E-syn-diol 3a was generated in 70% yield
and g95:5 dr, and Mukaiyama aldol product 4a was
produced in 23% yield. The substrate shows selectivity
for Sakurai reactivity probably because the bulky bis(silyl)
moiety shields both sides of the β-position in 2, making the
competitive Mukaiyama aldol reaction unfavorable.
Switching the R group from SiMe3 to the larger SiEt3 or
smaller Me group dramatically reduced the yield, and
switching to Me also reduced the diastereoselectivity
(entries 4 and 5). Switching R to an electron-withdrawing
benzoyl group completely suppressed the Mukaiyama
aldol pathway, but 3c formed with only a moderate yield
and diastereoselectivity (entry 6). More interesting results
were obtained when we examined the effect of geminal
bis(silane) on the reaction. When both Si1 and Si2 were an
SiMe2t-Bu group, neither the Sakurai nor Mukaiyama
aldolreactionoccurred(entry 7). Thisled us tohypothesize
that if the geminal bis(silyl) moiety consisted of a SiMe3
group and a bulkier SiMe2t-Bu or SiMe2Ph group, the more
reactive SiMe3 might be selectively eliminated. To the best of
our knowledge, few studies have addressed this interesting
selectivity issue.8 As expected, the reaction of 2f provided 3e
in 80% yield, with only the SiMe3 eliminated (entry 8).
Moreover, the ratio of 3 to 4, in this case, was higher than
that in entry 1 due to increased hindrance around the
β-position in 2f. Thus, four different selectivities were real-
ized in a single transformation: Sakurai over Mukaiyama
aldol reaction, elimination of SiMe3 over SiMe2Ph, E- over
Z-configuration, and syn- over anti-diastereoselectivity.
The scope of this reaction was then tested using 2f and
various acetals derived from aryl, alkyl, and alkynyl
aldehydes. All reactions proceeded predominantly via the
Sakurai pathway and gave the monoprotected E-syn-diol
(()-3 in acceptable-to-good yields (Table 2), even though
Mukaiyama aldol products were still obtained in some cases
in yields around 10%. In all cases, the SiMe3 was reliably
eliminated, generating SiMe2Ph-substituted E-vinylsilanes
selectively. The diastereoselectivity was excellent in most
reactions, except for the dr of 86:14 for the sterically less
Scheme 1. General Structure of Geminal Bis(silane) (left);
Sakurai vs Mukaiyama Adol Reaction of 3,3-Bis(silyl)
Silyl Enol Ether with Acetal (right)
In previous work, we proposed the most favorable confor-
mation of 22a is that which minimizes allylic strain and non-
bonded interactions, and which also benefits from a double-
hyperconjugation effect between the two CꢀSi bonds and
the enol double bond. Since both the silyl enol ether and
allyl bis(silane) groups in 2 share the same Z-CdC double
bond, the compound was expected to participate in two
competing pathways in a Lewis acid promoted reaction
with an acetal. Such a reaction could either proceed by a
Mukaiyama5 aldol pathway at the β-position to give
aldehyde 4 or undergo umpolung6 and proceed by a
Sakurai7 pathway at the R-position to give monoprotected
diol 3. Here we report detailed studies of this reaction and
observe that up to four different selectivities can be
achieved in a single transformation.
Table 1. Screening of Sakurai Reaction Conditionsa
(5) (a) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc.
1974, 96, 7503. For selected reviews on Mukaiyama aldol and its
variants, see: (b) Mukaiyama, T. Org. React. 1982, 28, 203. (c) Casiraghi,
G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929.
(d) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65.
(6) For studies on the umpolung of silyl enol ethers, see: (a) Keck,
G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron Lett. 1978, 28, 139.
(b) Marshall, J. A.; Jablonowski, J. A.; Elliott, L. M. J. Org. Chem. 1995,
a Reaction conditions: 0.15 mmol of 2, 0.18 mmol of p-Cl-PhCH-
(OMe)2, and 0.22 mmol of Lewis acid in CH2Cl2 (3.0 mL) at ꢀ78 °C for
30 min. b R = H in 3a and 3e. c The E-configuration was assigned based
on J3HꢀH vinylic coupling constants ranging from 18 to 20 Hz in 3. The
syn-stereochemistry was determined by NOE experiments on the acet-
onide of desilylated 3a. d Stereochemistry was not determined. e Isolated
yields after purification by silica gel column chromatography. f Ratios
were determined by 1H NMR spectroscopy.
ꢀ ꢀ
60, 2662. (c) Madec, D.; Ferezou, J. P. Tetrahedron Lett. 1997, 38, 6661.
ꢀ
(d) Marko, I. E.; Dumeunier, R.; Leclercq, C.; Leroy, B.; Plancher,
J. M.; Mekhalfia, A.; Bayston, D. J. Synthesis 2002, 7, 958. (e) Roush,
ꢀ
W. R.; Newcom, J. S. Org. Lett. 2002, 4, 4739. (f) Greene, M. A.; Prevost,
M.; Tolopilo, J.; Woerpel, K. A. J. Am. Chem. Soc. 2012, 134, 12482. (g)
Linclau, B.; Cini, E.; Oakes, C. S.; Josse, S.; Light, M.; Ironmonger, V.
Angew. Chem., Int. Ed. 2012, 51, 1232.
(7) (a) Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976, 941. For
selected reviews on Sakurai allylation, see: (b) Fleming, I. Allylsilanes,
allylstannanes and related systems. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6,
pp 563ꢀ593. (c) Fleming, I.; Dunogues, J.; Smithers, R. Org. React 1989,
37, 57.
(8) (a) Lautens, M.; Ben, R. N.; Delanghe, P. H. M. Angew. Chem.,
Int. Ed. 1994, 33, 2448. (b) Lautens, M.; Ben, R. N.; Delanghe, P. H. M.
Tetrahedron 1996, 52, 7221.
The reaction was initially examined using global SiMe3-
substituted 2a and p-Cl-PhCH(OMe)2 in CH2Cl2 at
ꢀ78 °C. SnCl4 appeared to be a better Lewis acid than
both TiCl4 and BF3 OEt2 for leading the reaction pre-
3
dominantly along the Sakurai pathway (Table 1, entries 1ꢀ3).
Org. Lett., Vol. 15, No. 5, 2013
1069

Table 2. Scope of Sakurai Reaction of 2f with Acetalsa
Scheme 2. Model Analysis to Explain the Observed
E-syn-Selectivity during Sakurai Reaction of 2f with Acetal
Scheme 3. Synthesis of Nematocidal Oxylipid 10
competitive Mukaiyama aldol reaction. Moreover, mono-
protected E-syn-diol 3 was obtained as the major or only
product in all cases, indicating that introduction of a
β-substituent had no impact on stereoselectivity. Reaction
of 2g with a cyclic acetal provided an even more attractive
result, given the widespread existence of substituted tetra-
hydropyrans in natural products (entry 3).9
The observed E-syn-selectivity can be rationalized using
non-β-substituted 2f to simplify the discussion (Scheme 2).
The E-selectivity can be easily explained as a result of
SiMe3 elimination in the most favorable conformation of
2f. Based on the classical antiperiplanar and synclinal
a Reaction conditions: 0.15 mmol of 2f, 0.18 mmol of acetal, and
0.22 mmol of SnCl4 in CH2Cl2 (3.0 mL) at ꢀ78 °C for 30 min. b Mukaiyama
aldol products were observed in yields around 10%. c Isolated yields after
purification by silica gel column chromatography. d Ratios were determined
by 1H NMR spectroscopy.
1b,10
0
orientations applied to SE additions of allylic silanes,
the “open” transition states AꢀF can be proposed, in
which the CꢀSiMe3 bond to be eliminated is positioned
demanding diol 3n (entry 9). This approach is also suitable
for acetals derived from benzyl alcohol to provide 3o, in
which the benzyl group would be much easier to remove
than the methyl group (entry 10).
We next examined reactions of various 3,3-bis(trimethylsilyl)
silyl enol ethers bearing methyl, phenyl, or allyl substitu-
ents at the β-position (Table 3). In all cases, the additional
steric hindrance at the β-position completely inhibited the
(9) For a recent review, see: Fuwa, H. Heterocycle 2012, 85, 1255.
(10) (a) Yamamoto, Y.; Yatagai, H.; Naruta, Y.; Marutama, K.
J. Am. Chem. Soc. 1980, 102, 7107. (b) Paddon-Row, M. N.; Rondan,
N. G.; Houk, K. N. J. Am. Chem. Soc. 1982, 104, 7162. (c) Denmark,
S. E.; Almstead, N. G. J. Org. Chem. 1994, 59, 5130.
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Org. Lett., Vol. 15, No. 5, 2013

severe gauche interaction between bis(silyl) and R groups can
be ruled out, as can transition states C, E, and F involving
general gauche interactions between bis(silyl) and OMe
groups, as well as between OSiMe3 and R groups. The
remaining transition state, antiperiplanar A, appears to be
the most favorable for selective syn-addition.
Table 3. Scope of Sakurai Reaction of β-Substituted
3,3-Bis(silyl) Silyl Enol Ethers 2 with Acetalsa
We used this methodology to achieve a concise synthesis
of nematocidal oxylipid 10 (Scheme 3), which was isolated
from Notheia anomala and has shown nematocidal activity
comparable to that of commercially available nematocides.11
The Sakurai reaction of 512 with 2.0 equiv of 2a proceeded
smoothly and gave rise to the desired allylated product 6 in
66% yield, with complete E-syn-stereochemical control and a
cis/trans ratio of 80:20.13 Thus, the C9/C10-syn-stereochem-
istry and the entirely cis-stereochemistry on the tetrahydro-
furan ring was established in a single transformation. The
resulting E-vinylsilane moiety in 6, as the second functionality
of geminal bis(silane), was then transformed into Z-vinyl
bromide 7 in 63% yield.14 Vinyl bromide 7, in turn, under-
went Sonogashira coupling with terminal alkyne 8 to provide
9 in 96% yield. In this way, the long chain was efficiently
incorporated on the right side in the target. The final steps of
hydrogenation, reduction, Wittig olefination, and deprotec-
tion then furnished oxylipid 10 successfully.
To summarize, we have described a Lewis acid promoted
reaction of 3,3-bis(silyl) silyl enol ethers with acetals,
in which a predominant Sakurai reactivity rather than
Mukaiyama aldol reactivity, as well as a selective desilyla-
tion of geminal bis(silane), was observed. This reaction also
served as a key step in a concise synthesis of nematocidal
oxylipid 10 from Notheia anomala, demonstrating the
attractive bifunctionality of geminal bis(silane). More
extensive studies on other applications of this reaction are
underway.
a Reaction conditions: 0.17 mmol of 2,0.21mmolofacetal, and0.26mmol
of SnCl4 in CH2Cl2 (3.0 mL) at ꢀ78 °C for 30 min. b The E-configuration
was assigned based on NOE experiments on 3p. The syn-stereochemistry
was determined by NOE experiments on the acetonide of desilylated 3p.
c Isolated yields after purification by silica gel column chromatography.
d Ratios were determined by 1H NMR spectroscopy. e Z/E = 63:37.
anti to the CꢀC bond to be formed. While the observed
stereochemical control may arise from a number of effects,
our model assumes that the steric effect predominates.
Based on this assumption, transition states Band Dinvolving
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(21172150, 21021001, 21290180), the National Basic Re-
search Program of China (973 Program, 2010CB833200),
and Sichuan University 985 Project.
(11) Capon, R. J.; Barrow, R. A.; Rochfort, S.; Jobling, M.; Skene, C.
Tetrahedron 1998, 54, 2227. For the latest enantioselective syntheses of
10, see: Roy, S.; Spilling, C. D. Org. Lett. 2012, 14, 2230 and references
therein.
(12) Acetal 5 was prepared from the known (S, S)-lactone by two
steps and in 85% overall yield. See Supporting Information for details.
(13) The cis-facial selectivity on tetrahydrofuran can be explained
based on Woerpel’s “inside attack” model shown as TS-A. For the
related references, see: Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel,
K. A. J. Am. Chem. Soc. 1999, 121, 12208. In addtion, the reaction of 2f
with 5 led to selective elimination of the SiMe3 group to generate
the allylated product in 70% yield, with complete E-syn-selectivity and a
cis/trans ratio of 75:25.
Supporting Information Available. Experimental proce-
dures and spectra data for products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(14) Kobayashi, Y.; Asano, M.; Yoshida, S.; Takeuchi, A. Org. Lett.
2005, 7, 1533.
The authors declare no competing financial interest.
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