Temporary silicon connection strategies in intramolecular allylation of aldehydes with allylsilanes

Article abstract of DOI:10.1021/jo800824x

(Chemical Equation Presented) Three γ-(amino)silyl-substituted allylsilanes 14a-c have been prepared in three steps from the corresponding dialkyldichlorosilane. The aminosilyl group has been used to link this allylsilane nucleophile to a series of β-hydroxy aldehydes through a silyl ether temporary connection. The size of the alkyl substituents at the silyl ether tether governs the outcome of the reaction on exposure to acid. Thus, treatment of aldehyde (E)-9aa, which contains a dimethylsilyl ether connection between the aldehyde and allylsilane, with a range of Lewis and Bronsted acid activators provides an (E)-diene product. The mechanism of formation of this undesired product is discussed. Systems containing a sterically more bulky diethylsilyl ether connection react differently: thus in the presence of TMSOTf and a Bronsted acid scavenger, intramolecular allylation proceeds smoothly to provide two out of the possible four diastereoisomeric oxasilacycles, 23 (major) and 21 (minor). A diene product again accounts for the remaining mass balance in the reaction. This side product can be completely suppressed by using a sterically even more bulky diisopropylsilyl ether connection in the cyclization precursor, although this is now at the expense of a slight erosion in the 1,3-stereoinduction in the allylation products. The sense of 1,3-stereoinduction observed in these intramolecular allylations has been rationalized by using an electrostatic argument, which can also explain the stereochemical outcome of a number of related reactions. Levels of 1,4-stereoinduction in the intramolecular allylation are more modest but can be significantly improved in some cases by using a tethered (Z)-allylsilane in place of its (E)-stereoisomer. Oxidation of the major diastereoisomeric allylation product 23 under Tamao-Kumada conditions provides an entry into stereodefined 1,2-anti-2,4-syn triols 28.

Full text of DOI:10.1021/jo800824x

Temporary Silicon Connection Strategies in Intramolecular
Allylation of Aldehydes with Allylsilanes
Julien Beignet, Peter J. Jervis, and Liam R. Cox*
School of Chemistry, The UniVersity of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
l.r.cox@bham.ac.uk
ReceiVed April 14, 2008
Three γ-(amino)silyl-substituted allylsilanes 14a-c have been prepared in three steps from the
corresponding dialkyldichlorosilane. The aminosilyl group has been used to link this allylsilane nucleophile
to a series of ꢀ-hydroxy aldehydes through a silyl ether temporary connection. The size of the alkyl
substituents at the silyl ether tether governs the outcome of the reaction on exposure to acid. Thus, treatment
of aldehyde (E)-9aa, which contains a dimethylsilyl ether connection between the aldehyde and allylsilane,
with a range of Lewis and Brønsted acid activators provides an (E)-diene product. The mechanism of
formation of this undesired product is discussed. Systems containing a sterically more bulky diethylsilyl
ether connection react differently: thus in the presence of TMSOTf and a Brønsted acid scavenger,
intramolecular allylation proceeds smoothly to provide two out of the possible four diastereoisomeric
oxasilacycles, 23 (major) and 21 (minor). A diene product again accounts for the remaining mass balance
in the reaction. This side product can be completely suppressed by using a sterically even more bulky
diisopropylsilyl ether connection in the cyclization precursor, although this is now at the expense of a
slight erosion in the 1,3-stereoinduction in the allylation products. The sense of 1,3-stereoinduction observed
in these intramolecular allylations has been rationalized by using an electrostatic argument, which can
also explain the stereochemical outcome of a number of related reactions. Levels of 1,4-stereoinduction
in the intramolecular allylation are more modest but can be significantly improved in some cases by
using a tethered (Z)-allylsilane in place of its (E)-stereoisomer. Oxidation of the major diastereoisomeric
allylation product 23 under Tamao-Kumada conditions provides an entry into stereodefined 1,2-anti-
2,4-syn triols 28.
Introduction
react with aldehydes in the presence of external activators such
as Lewis or Brønsted acids.4 By using this type of activation
method, allylation proceeds through an open transition state in
a stepwise, anti SE′ fashion in which there is no interaction
between the carbonyl oxygen and the silicon atom in the
nucleophile in the rate-determining addition step.5,6 For its useful
application in synthesis, the allylation of aldehydes needs to
proceed stereoselectively.1a,7 In the case of allyltrialkylsilanes,
The allylation of aldehydes to provide homoallylic alcohols
represents a powerful transformation in organic synthesis and
is a reaction that has been the focus of intense investigation.1
Allylsilanes are particularly attractive agents for effecting this
transformation owing to their low toxicity and relative ease of
preparation and stability.1d,2 Allyltrialkylsilanes generally exhibit
fairly low nucleophilicity,3 and as a consequence, usually only
(2) (a) Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed. 2003, 42, 4732–
4739. (b) Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063–
2192. (c) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293–1316. (d)
Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. 1989, 37, 57–575.
(3) (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938–957.
(b) Mayr, H.; Hagen, G. J. Chem. Soc., Chem. Commun. 1989, 91–92.
(4) Additives, such as fluoride, which activate the allylsilane, have occasion-
ally been used. In these cases, the nucleophile may be an allyl anion, see: (a)
Hosomi, A. Shirahata, A. Sakurai, H. Tetrahedron Lett. 1978, 3043-3046. (b)
Sarkar, T. K.; Andersen, N. H. Tetrahedron Lett. 1978, 3513–3516.
* Corresponding author. Phone: +44 (0)121 414 3524. Fax: +44 (0)121 414
4403.
(1) (a) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763–2794. (b)
Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207–2293. (c) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, UK, 1991; Vol. 2, Chapter 1.1, pp 1-53. (d) Fleming, I. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
UK, 1991; Vol. 2, Chapter 2.2, pp 563-593.
5462 J. Org. Chem. 2008, 73, 5462–5475
10.1021/jo800824x CCC: $40.75 2008 American Chemical Society
Published on Web 06/17/2008

Intramolecular Allylation of Aldehydes
allylating agents (crotylboranes11 and crotylboronates12 being
the most important examples), which react with aldehydes
through well-defined chair-like transition state conformations,
and offer a straightforward route to both syn and anti homoal-
lylic alcohol products through judicious choice of the appropriate
crotylmetal stereoisomer. That said, crotylsilanes have been used
successfully in enantio- and diastereoselective synthesis. Until
recently, crotylsilanes, which incorporate a stereogenic center
at the R-site,2c,13 have been the most successful,14 with the
reagents developed by Panek and co-workers2c,13a,b providing
the paradigm in this field (Scheme 1, eq 2). More recently,
Leighton and co-workers have introduced crotylsilane reagents,
which use chirality embedded in the silyl ligands to impart
stereoselectivity (Scheme 1, eq 3),15–17 while Denmark18 and
others19 have introduced chiral Lewis base activators for use
with allyltrichlorosilanes (Scheme 1, eq 4). These last two
strategies can both be used to effect highly enantio- and
diastereoselective allylation reactions; however, these classes
of crotylsilane react rather differently to the anti SE′ pathway
followed by standard crotyltrialkylsilanes.18a,b,20
SCHEME 1. Stereoselective Allylation of Aldehydes
Employing Allylsilanes
An alternative approach to controlling the stereoselectivity
of reactions employing γ-substituted allyltrialkylsilanes is to
incorporate the nucleophile into the same molecule as the
electrophile and carry out an intramolecular allylation. Providing
the number of atoms linking the two reacting functionalities is
not too small, such that geometrical constraints prevent the
nucleophile and electrophile from approaching sufficiently
closely to one another to react, nor too large, such that the
reaction resembles an intermolecular reaction or is disfavored
on entropic grounds, this type of intramolecular allylation
provides a powerful method for generating rings in a stereo-
controlled fashion.21 We have been interested in using a
temporary silicon connection22 to exploit the advantages as-
sociated with this type of intramolecularization strategy in
(11) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54, 1570–
1576.
the stereoselectivity of their reaction with aldehydes can be
controlled in a variety of ways. Carreira and co-workers
introduced a powerful chiral Lewis acid derived from TiF4 and
binol.8 With use of this activation system, allylsilanes, which
are unsubstituted at the γ-terminus, react with aldehydes with
excellent levels of enantioselectivity (Scheme 1, eq 1).8 This
type of reagent-controlled strategy has rarely been extended to
achiral crotylsilanes and other γ-substituted allylsilanes, where
both diastereoselectivity and enantioselectivity need to be
considered.9 This is probably a result of (i) the relatively poorly
defined open transition states through which allyltrialkylsilanes
(type II allyl metals10) react, making the control of relative
stereoselectivity difficult, and (ii) competition from type I
(12) (a) Roush, W. R.; Adam, M. A.; Walts, A. E.; Harris, D. J. J. Am. Chem.
Soc. 1986, 108, 3422–3434. (b) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am.
Chem. Soc. 1985, 107, 8186–8190.
(13) (a) Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999–1002. (b)
Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 6594–6600. (c) Suginome,
M.; Iwanami, T.; Ito, Y. J. Am. Chem. Soc. 2001, 123, 4356–4357. (d) Hayashi,
T.; Konishi, M.; Ito, H.; Kumada, M. J. Am. Chem. Soc. 1982, 104, 4962–4963.
(e) Hayashi, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1982, 104, 4963–
4965.
(14) Chiral allylsilanes, which incorporate stereochemical information into
the ꢀ- and γ-sites, have also been investigated: (a) Nativi, C.; Palio, G.; Taddei,
M. Tetrahedron Lett. 1991, 32, 1583–1586. (b) Nishigaichi, Y.; Takuwa, A.;
Jodai, A. Tetrahedron Lett. 1991, 32, 2383–2386.
(15) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6,
4375–4377.
(16) The use of allylsilanes containing chiral ligands had previously met with
little success: (a) Nativi, C.; Ravida, N.; Ricci, A.; Seconi, G.; Taddei, M. J.
Org. Chem. 1991, 56, 1951–1955. (b) Wei, Z. Y.; Wang, D.; Li, J. S.; Chan,
T. H. J. Org. Chem. 1989, 54, 5768–5774. (c) Chan, T. H.; Wang, D. Tetrahedron
Lett. 1989, 30, 3041–3044. (d) Coppi, L.; Mordini, A.; Taddei, M. Tetrahedron
Lett. 1987, 28, 969–972.
(5) (a) Buckle, M. J. C.; Fleming, I.; Gil, S.; Pang, K. L. C. Org. Biomol.
Chem. 2004, 2, 749–769. (b) Denmark, S. E.; Almstead, N. G. J. Org. Chem.
1994, 59, 5130–5132. (c) Denmark, S. E.; Weber, E. J. HelV. Chim. Acta 1983,
66, 1655–1660.
(17) Allylsilanes with Si-centered chirality have also been investigated: (a)
Hathaway, S. J.; Paquette, L. A. J. Org. Chem. 1983, 48, 3351-3353.
(18) (a) Denmark, S. E.; Fu, J. P.; Coe, D. M.; Su, X.; Pratt, N. E.; Griedel,
B. D. J. Org. Chem. 2006, 71, 1513–1522. (b) Denmark, S. E.; Fu, J. P.; Lawler,
M. J. J. Org. Chem. 2006, 71, 1523–1536. (c) Denmark, S. E.; Fu, J. P. Chem.
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123, 9488–9489. (e) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J.
Org. Chem. 1994, 59, 6161–6163.
(6) For computational investigations on the Lewis acid-mediated reaction of
allyltrialkylsilanes with aldehydes see: (a) Tietze, L. F. Kinzel, T. Schmatz, S.
J. Am. Chem. Soc. 2006, 128, 11483-11495. (b) Mayer, P. S.; Morton, T. H.
J. Am. Chem. Soc. 2002, 124, 12928–12929. (c) Bottoni, A.; Costa, A. L.; Di
Tommaso, D.; Rossi, I.; Tagliavini, E. J. Am. Chem. Soc. 1997, 119, 12131–
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(7) Yamamoto, Y. Acc. Chem. Res. 1987, 20, 243–249.
(8) Gauthier, D. R.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 1996, 35,
2363–2365.
(19) For recent reviews see: (a) Malkov, A. V.; Kocovsky, P. Eur. J. Org.
Chem. 2007, 29–36. (b) Orito, Y.; Nakajima, M. Synthesis 2006, 1391–1401,
and references cited therein.
(9) See also: (a) Ishihara, K. Mouri, M. Gao, Q. Maruyama, T. Furuta, K.
Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 11490-11495. (b) Aoki, S.;
Mikami, K.; Terada, M.; Nakai, T. Tetrahedron 1993, 49, 1783–1792.
(10) For the classification of allyl metals see: (a) Hoffmann, R. W. Angew.
Chem., Int. Ed. Engl. 198221555-566. (b) Reference 5c.
(20) Zhang, X.; Houk, K. N.; Leighton, J. L. Angew. Chem., Int. Ed. 2005,
44, 938–941.
(21) (a) Langkopf, E.; Schinzer, D. Chem. ReV. 1995, 95, 1385–1408. (b)
Schinzer, D. Synthesis 1988, 263–273.
J. Org. Chem. Vol. 73, No. 14, 2008 5463

Beignet et al.
SCHEME 2. Reetz’s Intramolecular Allylation Strategy
Using a Silyl Ether Connection
SCHEME 3. Relocating the Silyl Ether Connection to the
γ-Terminus of the Allylsilane Generates an Oxasilacycle
Containing Two New Stereogenic Centers, Ripe for
Elaboration
a 1,3-anti relationship between the existing and newly formed
stereogenic centers. The stereochemical outcome of this reaction
was rationalized by invoking intermolecular addition of the allyl
nucleophile on a chelated intermediate 2. In an alternative
approach, when aldehyde 5, in which the allylsilane nucleophile
is now tethered to the ꢀ-carbinol stereogenic center contained
within the aldehyde, was treated with TiCl4, the desired
homoallylic alcohol products, 7 and 8, were again obtained in
good yield; however, this time, the favored diol product 8 now
contained a 1,3-syn relationship between the two stereogenic
centers (Scheme 2).24g Through judicious choice of reagents
and reaction conditions, Reetz was able to access both 1,3-anti
and 1,3-syn homoallylic alcohol diastereoisomers in a selective
fashion.
In this pertinent example from Reetz, the temporary silicon
connection is cleaved during the reaction, which removes the
need to introduce a separate cleavage step into the synthetic
sequence. While this is an attractive feature of this strategy, we
reasoned that a more versatile product, ripe for chemical
diversification, could be obtained if the temporary silicon
connection were to remain in the allylation product. To achieve
this, we elected to relocate the silyl ether connection to the
γ-terminus of the allyl nucleophile (Scheme 3). This modifica-
tion would serve a number of advantages. Although we would
still be relying on the carbinol stereogenic center in 9 to control
the stereochemical outcome of the allylation, substitution at the
γ-terminus of the allylsilane nucleophile would necessarily
introduce a second stereogenic center into the allylation product
11 and provide an added level of structural complexity.
Retaining the silyl ether connection would also make available
a number of potential elaboration strategies for the product.
Moreover, since the allylsilane would now be reacting with the
tethered aldehyde in an exocyclic fashion (10) (with respect to
the ring being formed), the reaction would more closely
resemble an intermolecular allylation. Assuming the substituent
appended off the carbinol stereogenic center dictates the low-
energy chair conformation for the formation of the six-
membered ring, by analyzing the stereochemical relationship
between the two new stereogenic centers in the product, we
would be able to ascertain the relative orientation of the reacting
π-systems in the aldehyde electrophile and allylsilane nucleo-
stereoselective synthesis.23 More specifically, by employing a
silyl ether tethering group to connect an allylsilane to an
electrophile, we aim to use the potentially more defined
transition states associated with the formation of small rings to
install new stereogenic centers in a controlled fashion. Being
able to cleave the silyl ether connection post allylation then
allows us to access a product that can be considered the result
of a net intermolecular process.
At the outset of this project, allylsilanes had been previously
tethered through a transient silyl ether connection to a small
number of electrophile substrates.24 In all cases, the silicon atom
in the allylsilane had also served as the tethering unit connecting
the nucleophile to the electrophile. A seminal study from Reetz
and co-workers illustrates the concept and potential utility of
this strategy (Scheme 2).24g Reaction of 3-benzyloxybutanal 1
with allyltrimethylsilane in the presence of TiCl4 generated two
homoallylic alcohol products, 3 and 4. In this instance, excellent
diastereoselectivity was observed for alcohol 3, which contains
(22) (a) Cox, L. R.; Ley, S. V. In Templated Organic Synthesis; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Chapter 10, pp
275-375. (b) Bols, M.; Skrydstrup, T. Chem. ReV. 1995, 95, 1253–1277. (c)
Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthesis 1997, 813–854. (d)
Gauthier, D. R., Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54, 2289–
2338.
(23) (a) Ramalho, R.; Jervis, P. J.; Kariuki, B. M.; Humphries, A. C.; Cox,
L. R. J. Org. Chem. 2008, 73, 1631–1634. (b) Jervis, P. J.; Cox, L. R. Beilstein
J. Org. Chem. 2007, 3, 6. (c) Ramalho, R.; Beignet, J.; Humphries, A. C.; Cox,
L. R. Synthesis 2005, 3389–3397. (d) Simpkins, S. M. E.; Kariuki, B. M.; Arico´,
C. S.; Cox, L. R. Org. Lett. 2003, 5, 3971–3974. (e) Beignet, J.; Tiernan, J.;
Woo, C. H.; Kariuki, B. M.; Cox, L. R. J. Org. Chem. 2004, 69, 6341–6356. (f)
Beignet, J.; Cox, L. R. Org. Lett. 2003, 5, 4231–4234.
(24) (a) Robertson, J.; Hall, M. J.; Green, S. P. Org. Biomol. Chem. 2003, 1,
3635–3638. (b) Wipf, P.; Aslan, D. C. J. Org. Chem. 2001, 66, 337–343. (c)
Pilli, R. A.; Riatto, V. B. Tetrahedron: Asymmetry 2000, 11, 3675–3686. (d)
Fujita, K.; Inoue, A.; Shinokubo, H.; Oshima, K. Org. Lett. 1999, 1, 917–919.
(e) Frost, L. M.; Smith, J. D.; Berrisford, D. J. Tetrahedron Lett. 1999, 40, 2183–
2186. (f) Hioki, H.; Okuda, M.; Miyagi, W.; Itoˆ, S. Tetrahedron Lett. 1993, 34,
6131–6134. (g) Reetz, M. T.; Jung, A.; Bolm, C. Tetrahedron 1988, 44, 3889–
3898. (h) Martin, O. R.; Rao, S. P.; Kurz, K. G.; El-Shenawy, H. A. J. Am.
Chem. Soc. 1988, 110, 8698–8700.
(25) For related approaches used to probe this aspect of the allylation reaction
see: (a) Schlosser, M.; Franzini, L.; Bauer, C.; Leroux, F. Chem. Eur. J. 2001,
7, 1909-1914. (b) Keck, G. E.; Dougherty, S. M.; Savin, K. A. J. Am. Chem.
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5464 J. Org. Chem. Vol. 73, No. 14, 2008

Intramolecular Allylation of Aldehydes
SCHEME 4. Retrosynthetic Analysis of the Cyclization
Precursor
SCHEME 5. Synthesis of the First-Generation Cyclization
Precursor
phile.5c,6,25,26 This would then allow us to probe a mechanistic
detail of this type of reaction, specifically whether there is a
preference for the allylsilane and aldehyde π-systems to adopt
a synclinal orientation in a staggered transition state,5c,25b,c,27
rather than an antiperiplanar orientation, which has also been
proposed.28 We have previously reported our initial results in
this project23,29 and now report the outcome of this study in
full.
Results and Discussion
regioselectively with Me3SiCl to provide γ-aminosilyl-substi-
tuted allylsilane 14a as a single (E)-stereoisomer, as evidenced
by a vicinal coupling constant of 18.3 Hz for the olefinic
hydrogens. Although aminosilanes are nowadays only rarely
used to form silyl ethers,31–36 they are useful alternatives to
more commonly employed silyl chlorides and silyl triflates.
Moreover, since the byproduct from the reaction is an innocuous
and volatile secondary amine, the reaction does not require the
inclusion of acid scavengers. Thus the silyl ether in (E)-12aa
was prepared by simply mixing equimolar quantities of ami-
nosilane 14a with ꢀ-hydroxyester 13a. Since this silyletherifi-
cation did not generate a strong exotherm, the two reactants
could be combined in the absence of solvent, and after 3 h,
silyl ether (E)-12aa was obtained in excellent yield. Chemose-
lective reduction of the ester in (E)-12aa with DIBALH
proceeded uneventfully to provide the aldehyde cyclization
precursor (E)-9aa (Scheme 5).
Retrosynthesis of the allylation precursor (E)-9 was straight-
forward and is summarized in Scheme 4. Thus functional group
interconversion of the aldehyde (E)-9 to the corresponding ester
(E)-12, followed by disconnection of the silyl ether in (E)-12
provided us with our two reacting partners, namely a ꢀ-hydroxy
ester 13 and a γ-silyl-substituted allylsilane 14.
For our first generation of allylsilanes we chose to investigate
a dimethylsilyl ether connection. The desired allylsilane 14a
was prepared in three steps following a modified procedure
originally reported by Tamao and Ito (Scheme 5).30 Thus
addition of a THF solution of LiNEt2 over 3 h to a solution of
an equimolar quantity of Me2SiCl2 in Et2O provided the desired
aminochlorosilane 15a in 51% yield after purification by reduced
pressure distillation. In an effort to replace n-BuLi (used to
generate the LiNEt2) with a cheaper base, we also investigated
the reaction of Me2SiCl2 with HNEt2 in the presence of NaH.
The NaCl precipitate generated in this reaction was more readily
separated from the reaction mixture by Schlenk filtration than
the LiCl generated in the reaction with LiNEt2. While this
simplified the workup and isolation of the highly moisture-
sensitive aminochlorosilane product, at 40%, the isolated yield
of aminosilane offered no significant improvement on our
procedure employing LiNEt2. Next, the chloro substituent in
aminochlorosilane 15a was selectively displaced with allyl
magnesium bromide to afford allylsilane 16a in good yield.
Carrying out these two steps in a one-pot operation led to a
further improvement in reaction efficiency (59% over two steps)
probably owing to removing the need to handle the rather
moisture-sensitive aminochlorosilane intermediate. In the final
step, reaction of allylsilane 16a with a strong base derived from
equimolar quantities of n-BuLi and TMEDA in Et2O provided
the corresponding allyllithium species, which was trapped
Since allylsilanes are susceptible to protodesilylation in the
presence of Brønsted acids,37 we elected to investigate the
intramolecular allylation of (E)-9aa under Lewis acid activation.
A wide range of Lewis acids38 was screened with use of
dichloromethane, which is the most commonly employed solvent
for allylation reactions with allylsilanes, and MeCN as a
(31) TMS protection by using an aminosilane: (a) Tanabe, Y.; Murakami,
M.; Kitaichi, K.; Yoshida, Y. Tetrahedron Lett. 1994, 35, 8409–8412. (b)
Rychnovsky, S. D.; Griesgraber, G. J. Org. Chem. 1992, 57, 1559–1563. (c)
Kerwin, S. M.; Paul, A. G.; Heathcock, C. H. J. Org. Chem. 1987, 52, 1686–
1695. (d) Yankee, E. W.; Bundy, G. L. J. Am. Chem. Soc. 1972, 94, 3651–
3652. (e) Ruehlmann, K. Synthesis 1971, 236–253.
(32) TES protection using an aminosilane: (a) Holton, R. A.; Zhang, Z.;
Clarke, P. A.; Nadizadeh, H.; Procter, D. J. Tetrahedron Lett. 1998, 39, 2883–
2886.
(33) TBDMS protection using an aminosilane: reference 31c.
(34) TIPS protection with an aminosilane: (a) Firouzabadi, H.; Iranpoor, N.;
Shaterian, H. R. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 166, 71–82.
(35) PhMe2Si protection with an aminosilane: Liepin’sh, E. E.; Birgele, I. S.;
Zelchan, G. I.; Urtane, I. P.; Lukevits, E. J. Gen. Chem. USSR (Engl. Transl.)
1980, 50, 2212–2216.
(26) For experimental studies employing related allyltrialkylstannanes see:
Denmark, S. E.; Hosoi, S. J. Org. Chem. 1994, 59, 5133–5135.
(27) Mikami, K.; Kawamoto, K.; Loh, T.-P.; Nakai, T. J. Chem. Soc., Chem.
Commun. 1990, 1161–1163.
(36) (Allyl)Me2Si protection with an aminosilane: reference 24g.
(37) (a) Chan, T. H.; Fleming, I. Synthesis 1979, 761–786, and references
cited therein. (b) Fleming, I.; Terrett, N. K. Tetrahedron Lett. 1983, 24, 4153–
4156.
(28) Yamamoto, Y.; Yatagai, H.; Naruta, Y.; Maruyama, K. J. Am. Chem.
Soc. 1980, 102, 7107–7109.
(38) TiCl4, SnCl4, ZrCl4, MgBr2 · OEt2, Cu(OTf)2, BF3 · OEt2, Yb(OTf)3,
MeAlCl2, Me3SiOTf, t-BuMe2SiOTf, Me3SiOTf/DTBMP, and TfOH were
investigated.
(29) Part of this work was presented at the 2007 ACS meeting in Chicago.
(30) Tamao, K.; Nakajo, E.; Ito, Y. Tetrahedron 1988, 44, 3997–4007.
J. Org. Chem. Vol. 73, No. 14, 2008 5465

Beignet et al.
SCHEME 6. Aldehyde (E)-9aa Containing a Dimethylsilyl
Ether Temporary Connection Provides a Diene Product on
Treatment with Lewis Acid
SCHEME 8. Diene Formation Directly from the
Oxasilacycle Allylation Products Is Conceivable
SCHEME 7. Ring-Opening of the Oxasilacycle Allylation
Product Followed by Elimination Provides a Route to Diene
Products
resulting conformationally flexible acyclic intermediates, syn-
19aa and anti-19aa would then be susceptible to a further
olefination reaction under the Lewis acidic reaction conditions.
Since acid-mediated silicon olefination is a stereospecific
process,43 syn-19aa would be expected to collapse to diene (Z)-
17a and anti-19aa to diene (E)-17a (Scheme 7).
We also considered a mechanism in which elimination
proceeds directly on the oxasilacycle allylation products (Scheme
8). The requirement for an antiperiplanar arrangement between
the leaving group and the ꢀ-C-Si bond43 would mean that the
two diastereoisomers, 20aa and 22aa, in which the newly
formed carbinol stereogenic center occupies an equatorial
orientation, should eliminate readily in their low-energy chair
conformations to provide (Z)-17a and (E)-17a, respectively,
whereas elimination from the other two diastereoisomers, 21aa
and 23aa, which contain an axially oriented C-O bond, would
proceed after ring-flip to a boat-like conformation to afford (Z)-
17a and (E)-17a, respectively (Scheme 8).
Since there was no reason to expect the initial allylation to
be completely stereoselective (this was later borne out, see
below) and analysis of the crude reaction mixture by 1H NMR
spectroscopy revealed the presence of a single diene stereoiso-
mer, namely (E)-17a, we discounted these mechanisms and
considered an alternative, which is summarized in Scheme 9.
Not only does this mechanism rationalize the observed stereo-
selectivity of diene formation, more importantly it offered a
potential way forward. In this third elimination pathway, we
again proposed that the first step in the allylation of (E)-9aa
proceeds as desired, to provide the carbocationic intermediate
representative more polar solvent.39 In all cases, we were
disappointed to observe the desired oxasilacycle allylation
product in only trace quantities, even in the best case, which
employed Me3SiOTf in the presence of 2,6-di-tert-butyl-4-
methylpyridine (DTBMP) or 2,4,6-tri-tert-butylpyrimidine (TT-
BP),40 both of which act as scavengers for adventitious triflic
acid.41 The starting aldehyde was always consumed rapidly at
-78 °C to provide a diene (E)-17a as the major product (Scheme
6).
At this juncture, we felt it necessary to attempt to rationalize
the product outcome to identify whether or not it might be
possible to modify our system and redirect the course of reaction
along the desired pathway. A number of mechanisms for diene
formation were considered and are summarized in Schemes
7–9.42 These essentially differ in the order in which the two
silyl residues, namely the trimethylsilyl group and the silyl ether,
are lost. In the first mechanism (Scheme 7), we proposed that
allylation proceeds as desired to provide the oxasilacycle product
18aa, potentially as a mixture of up to four diastereoisomers.
Under the Lewis acidic conditions, we hypothesized that
cleavage of the silyl ether connection might be occurring. The
(39) Kampen, D.; List, B. Synlett 2006, 2589–2592.
(40) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323–326.
(41) The silyl ether tether decomposed rapidly in the presence of TfOH.
(42) No reaction was observed when (E)-γ-(i-PrO)Me2Si-substituted allyl-
trimethylsilane was treated with PhCHO in CH2Cl2 in the presence of TiCl4
at -78 °C for 24 h. The lack of product formation in this reaction, combined
with the generation of the desired oxasilacycles when tethered allylsilanes
containing bulkier groups at the silyl ether connection were employed, confirms
that the mechanism of diene formation involves an intramolecular allylation step.
(43) (a) Ager, D. J. Product Subclass 37: ꢀ-Silyl Alcohols and the Peterson
Reaction. In Science of Synthesis; Fleming, I., Ed.; Georg Thieme Verlag:
Stuttgart, Germany, 2002; Vol. 4, Chapter 4.4.37, pp 789-809. (b) Ager, D. J.
Org. React. 1990, 38, 1–223. (c) Hudrlik, P. F.; Peterson, D. J. Am. Chem. Soc.
1975, 97, 1464–1468. (d) Peterson, D. J. J. Org. Chem. 1968, 33, 780–784.
5466 J. Org. Chem. Vol. 73, No. 14, 2008

Intramolecular Allylation of Aldehydes
SCHEME 9. Preferential Collapse of the Carbocationic
Intermediate by Attack at the Silyl Tether Provides an
Acyclic Intermediate That Can Afford a Diene Product after
a Vinylogous Silicon-Mediated Olefination
FIGURE 1. Vinylogous silicon-mediated olefination on a conformation
that minimizes A1,3-interactions leads to an (E)-diene product.
SCHEME 10. Synthesis of Cyclization Precursors
Containing Bulkier Substituents at the Silyl Ether
Connection
24aa.44 While this cation will be stabilized by the exocyclic
silyl group through the ꢀ-Si effect,45 it only requires a 60° bond
rotation46 for the endocyclic silyl group to also adopt an
orientation for this group to stabilize the carbocation optimally.
If the presence of the oxygen substituent increases the elec-
trofugacity of the endocyclic silyl ether, and in the absence of
unfavorable steric effects, then collapse of this intermediate will
proceed through preferential nucleophilic attack on the silyl ether
silicon atom, to provide acyclic allylsilane intermediate 25aa,
potentially as an inconsequential (see below) mixture of olefin
stereoisomers. Under the Lewis acidic reaction conditions, this
intermediate would be susceptible to a vinylogous silicon-
mediated olefination, which would lead to the diene product
(E)-17a (Scheme 9).47,48
and of the olefin geometry in the acyclic allylsilane intermediate
25aa, all products will then converge on a single diene product,
(E)-17a.50
Vinylogous silicon-mediated reactions, when carried out
under acidic conditions, are known to be highly (E)-stereose-
lective.47 Elimination in allylsilane 25aa should proceed on a
reactive conformation in which the (smallest) hydrogen sub-
stituent at the stereogenic center R to the olefin sits in the plane
of the olefin thereby minimizing A1,3-interactions (Figure 1).49
Irrespective of the stereoselectivity of the initial allylation step,
Were the mechanisms outlined in Schemes 7 and 8 to be
operating, we reasoned that it would be difficult to stop the
reaction at the oxasilacycle stage; however, if the diene product
(E)-17 were being generated via the mechanism described in
Scheme 9, we postulated that using sterically more demanding
substituents at the silyl ether tether would encourage the initially
formed carbocationic intermediate 24aa to collapse by nucleo-
philic attack at the less sterically hindered trimethylsilyl group.
With this reasoning in mind, we prepared γ-aminosilyl-
substituted allylsilanes 14b and 14c, which would allow the
methyl substituents at the silyl ether connection in (E)-9aa to
be replaced with ethyl groups and even bulkier isopropyl groups,
respectively (Scheme 10). These compounds were prepared by
using a similar approach to that employed in the synthesis of
our first-generation silane (E)-9aa (Scheme 5); however, the
presence of bulkier groups in the starting dialkyldichlorosilane
required slight modifications to our previous methods (see the
Experimental Section in the Supporting Information for full
(44) Evidence for a stepwise reaction mechanism in the reaction of allylsilanes
with electrophiles: Fleming, I.; Langley, J. A. J. Chem. Soc., Perkin Trans. 1
1981, 1421–1423.
(45) Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu, X. Y.;
So, J. H.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 183–190.
(46) The energetic barrier to bond rotation will be very low.
(47) (a) Merten, J.; Hennig, A.; Schwab, P.; Fro¨hlich, R.; Tokalov, S. V.;
Gutzeit, H. O.; Metz, P. Eur. J. Org. Chem. 2006, 1144–1161. (b) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. Eur. J. 2002, 8, 1719–1729. (c) Stragies,
R.; Blechert, S. Tetrahedron 1999, 55, 8179–8188. (d) Qi, X.; Montgomery, J.
J. Org. Chem. 1999, 64, 9310–9313. (e) Yamashita, K.; Sato, F. Tetrahedron
Lett. 1996, 37, 7275–7278. (f) Angell, R.; Parsons, P. J.; Naylor, A.; Tyrrell, E.
Synlett 1992, 599–600. (g) Suzuki, K.; Hasegawa, T.; Imai, T.; Maeta, H.; Ohba,
S. Tetrahedron 1995, 51, 4483–4494. (h) Angoh, A. G.; Clive, D. L. J. J. Chem.
Soc., Chem. Commun. 1984, 534–536.
(50) We do not discount a non-concerted elimination pathway in which
ionization first generates an allyl carbocationic intermediate, which then collapses
to the diene through loss of the trimethylsilyl group. However, the carbocationic
intermediate would again be expected to give rise to an (E)-diene product for
similar reasons to those outlined in the text.
(48) In our work on the synthesis of ꢀ-allyl-C-mannosyl derivatives using a
related intramolecular allylation strategy, the isolation of intermediates along
this mechanistic pathway supports this proposed mechanism: see reference 23e.
(49) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841–1860.
J. Org. Chem. Vol. 73, No. 14, 2008 5467

Beignet et al.
SCHEME 11. Increasing the Steric Bulk of the Alkyl
details). First, it is noteworthy that the final allylsilane products
14b and 14c, and the intermediates 15b and 15c, and 16b and
16c, were all appreciably less hydrolytically labile than their
dimethylsilyl analogues, which made for more straightforward
workup and purification procedures and led to improved yields
of the products. In the case of diethylsilyl-substituted allylsilane
14b, tethering to ꢀ-hydroxy ester 13a was achieved in an
identical fashion to that used for dimethylsilyl derivative 14a;
however, for the diisopropylsilyl analogue 14c, the increased
steric bulk of the isopropyl substituents resulted in a very slow
reaction, which led to reduced yields of the silyl ether product
owing to slow decomposition of both the ester (dehydration to
the enoate) and amino silane (hydrolysis to the silanol) starting
materials. To improve matters, aminosilane 14c was therefore
converted to the corresponding chlorosilane 26c by treatment
with acetyl chloride;51 without isolation, addition of ꢀ-hydroxy
ester 13a and imidazole to the reaction mixture, provided the
desired silyl ether (E)-12ac in greatly improved yield. The
aldehyde precursors (E)-9ab and (E)-9ac were once again
obtained in excellent yield by treating the corresponding esters
with DIBALH (Scheme 10).
Groups at the Silyl Tether Suppressed Diene Formation
We were delighted to observe that treating aldehyde (E)-9ab
with Me3SiOTf,52 in the presence of DTBMP, which was again
necessary to avoid premature cleavage of the silyl ether by
adventitious triflic acid, provided two of the possible four
diastereoisomeric oxasilacycles, 21ab and 23ab, as the major
products,53 along with a small amount of the diene (E)-27ab54
(Scheme 11). When aldehyde (E)-9ac containing the bulkier
diisopropylsilyl tether was treated with Me3SiOTf/DTBMP
under the same reaction conditions, diene formation was
suppressed completely, although the 1,3-stereoinduction (see
below) was eroded slightly with all four possible diastereoiso-
mers 20ac, 21ac, 22ac, and 23ac now being observed in the
ratio 1:9:1:33 (Scheme 11). The relative stereochemistry in these
products was determined by extensive NMR experiments, and
in particular with NOE data (see the Supporting Information
for full details).
Preferring to sacrifice an improvement in chemoselectivity
for better stereoselectivity, we investigated a range of aldehydes
(E)-9ab-(E)-9hb, all containing a diethylsilyl ether connection,
to demonstrate the generality of the process. The cyclization
precursors were prepared as outlined in Scheme 10, from
aminosilane 14b and the corresponding ꢀ-hydroxy esters 13a-h,
which were accessed uneventfully by a Reformatski reaction
between ethyl bromoacetate and the corresponding aldehyde.55
In all cases, only two out of the possible four diastereoisomers,
21 and 23, were observed, owing to complete 1,3-stereoinduc-
tion in the cyclization. Levels of 1,4-induction were more modest
ranging from 2.7:1 to 9.7:1 in the best case (Table 1). Dienes
(E)-27 were again obtained as minor side products.
presence of an electronegative substituent on the diethylsilyl
group renders the C-Si bond in the oxasilacycle amenable to
oxidation by using the Tamao-Kumada protocol.56 Signifi-
cantly, since this transformation is a stereospecific process in
which the configuration at the carbon center, which is undergo-
ing oxidation, is retained,57 a single diastereoisomeric allylation
product should furnish a single stereodefined 1,2,4-triol product
on oxidation. In this way, a tether formation-allylation-oxidation
sequence would provide a route to a net hydroxyallylation of
an aldehyde.58 Moreover, while extensive NMR experiments,
in particular NOE measurements, had allowed us to assign the
relative stereochemistry in the two allylation products, we were
keen to use the triol oxidation products to confirm our
assignments. Owing to the very low polarity of the oxasilacycles,
which rendered separation of these products from the diene side
product and Brønsted acid scavenger difficult,59 the crude
As alluded to in the introductory paragraphs, retaining the
silyl ether connection in the allylation products provided us with
a compound that is ripe for elaboration. For our purposes, the
(56) (a) Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120–
2122. (b) Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1–64.
(51) Zechel, D. L.; Foucher, D. A.; Pudelski, J. K.; Yap, G. P. A.; Rheingold,
A. L.; Manners, I. J. Chem. Soc., Dalton Trans. 1995, 1893–1899.
(52) This Lewis acid had shown greatest promise in our early studies with
9aa.
(53) One could argue that the other two diastereoisomers, which both contain
an equatorially oriented OSiMe3 substituent, undergo elimination and provide
the source of diene; however, the exclusive formation of the (E)-diene would
point against this.
(54) Diene (E)-27 was not particularly stable; however, in some cases, small
amounts of this side product could be isolated by HPLC and at least partially
characterized (see the Supporting Information).
(55) Picotin, G.; Miginiac, P. J. Org. Chem. 1987, 52, 4796–4798.
(57) Tamao, K.; Kakui, T.; Akita, M.; Iwahara, T.; Kanatani, R.; Yoshida,
J.; Kumada, M. Tetrahedron 1983, 39, 983–990.
(58) For related approaches see: (a) Toshima, K.; Arita, T.; Kato, K.; Tanaka,
D.; Matsumura, S. Tetrahedron Lett. 2001, 42, 8873–8876. (b) Dankwardt, J. W.;
Dankwardt, S. M.; Schlessinger, R. H. Tetrahedron Lett. 1998, 39, 4979–4982.
(c) Shimura, T.; Komatsu, C.; Matsumura, M.; Shimada, Y.; Ohta, K.; Mitsunobu,
O. Tetrahedron Lett. 1997, 38, 8341–8344. (d) Roush, W. R.; Grover, P. T.
Tetrahedron 1992, 48, 1981–1998. (e) Barrett, A. G. M.; Malecha, J. W. J. Org.
Chem. 1991, 56, 5243–5245. (f) Keck, G. E.; Boden, E. P.; Wiley, M. R. J.
Org. Chem. 1989, 54, 896–906.
(59) Analytically pure samples of the allylation products were obtained by
HPLC (see the Supporting Information).
5468 J. Org. Chem. Vol. 73, No. 14, 2008

Intramolecular Allylation of Aldehydes
TABLE 1. An Intramolecular Allylation/Tamao-Kumada
Oxidation Sequence Provides a Route to Stereodefined 1,2,4-Triols
SCHEME 12. Different Behavior of the Two
Diastereoisomeric Allylation Products under the
Tamao-Kumada Oxidation Reaction Conditions
aldehyde
(E)-9
combined yielda 23:21 isolated yieldc
entry
R
of 21 + 23 (%) ratiob
of 28 (%)
1
2
3
4
5
6
7
8
9ab
9bb
9cb
9db
9eb
9fb
Ph
2-furyl
cyclohexyl
n-Bu
i-Bu
BnOCH2CH2
(E)-styryl
TIPS-alkynyl
88
86
83
76
55
75
82
92
3.9:1
4.0:1
4.9:1
8.5:1
2.7:1
9.7:1
3.5:1
6.7:1
73
61
51
65
60
63
85
34d
9gb
9hb
a Diene product accounted for the remaining material in the crude
reaction mixture. b Ratio calculated from analysis of the crude reaction
mixture by 1H NMR. c Isolated yields following column
chromatography. d The lower yield in this case can be attributed to
competing decomposition of the TIPS-alkynyl group under the reaction
conditions.
allylation product mixture was treated directly to the standard
Tamao-Kumada conditions. The reaction was rather slow,
requiring several days to reach completion. Notably, only the
major oxasilacycles, 23ab-hb, were converted efficiently to
the desired 1,2,4-triol products, 28a-h (Table 1); the minor
allylation products, 21ab-hb, were preferentially consumed in
a competing Peterson olefination under the mildly basic reaction
conditions.43 This accounted for the increased amount of diene
product, (E)-17, that was observed on 1H NMR analysis of the
crude reaction mixture.
That only the minor diastereoisomer, 21, underwent elimina-
tion in preference to oxidation can be rationalized by considering
the relative stability of the two conformers through which this
reaction has to proceed to provide an elimination product
(Scheme 12).43c In the case of the major diastereoisomer, 23,
adopting the synperiplanar alignment of the C-O and C-Si
bonds in the intermediate 29, required for the Peterson elimina-
tion, results in a build up of steric interactions (Scheme 12).
As a consequence, this diastereoisomer is channeled along the
oxidation pathway, leading to triol 28. In the case of the minor
diastereoisomer, 21, the bulky substituents in the synperiplanar
conformer 30, required for olefination, are anti to one another,
which allows this diastereoisomer to follow the competing
olefination pathway (Scheme 12).
from the minor triol 31 was observed in only two cases (34a,
R ) Ph, 4% and 34h, R ) TIPS-C≡C, 5%), and in these
isolated examples, only the major 1,3-dioxolane product could
be detected. All of the acetonide products were analyzed by
13C NMR spectroscopy. The acetal resonance for the 1,3-
dioxanes, 33a-h, generated from the major oxidation products,
28a-h, appeared in the region 98.4-99.1 ppm, which is
consistent with a 1,3-syn diol relationship in the starting triol
(Figure 2).61 This conclusion was supported by the large
difference in the chemical shifts (around 10 ppm) observed for
the resonances for the two methyl groups in the protecting group
(Figure 2).61 NOE experiments supported this stereochemical
assignment (Figure 2). A similar analysis of the 1,3-dioxolanes,
32a-h, generated from the major oxidation products, 28a-h,
revealed a 1,2-anti relationship between these two stereogenic
centers:62 the two methyl resonances for the 1,3-dioxolanes,
32a-h, appeared in two distinct regions at 25.0-25.7 and at
27.6-28.3 ppm, which is indicative of a 1,2-anti relationship
between the vicinal alcohols in the major triol products, 28a-h.
Extensive NOE experiments on the minor oxasilacycle 21 had
already allowed us to assign the relative stereochemistry in this
Acetonide protection of the crude triol oxidation products
furnished inseparable mixtures of the corresponding 1,3-
dioxolanes and 1,3-dioxanes, with the former predominating as
expected.60 Owing to the minor allylation product undergoing
elimination preferentially (Scheme 12), an acetonide derived
(60) (a) Kocienski, P. J.; Yeates, C.; Street, S. D. A.; Campbell, S. F. J. Chem.
Soc., Perkin Trans. 1 1987, 2183–2187. (b) Mori, K.; Iwasawa, H. Tetrahedron
1980, 36, 87–90.
(61) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511–
3515.
(62) Dana, G.; Danechpajouh, H. Bull. Soc. Chim. Fr. 1980, 395–399.
J. Org. Chem. Vol. 73, No. 14, 2008 5469

Beignet et al.
SCHEME 13. Keck Invoked Secondary Orbital Interactions
to Rationalize the Adoption of a syn-Synclinal Alignment of
π-Systems in the Formation of the Major Diastereoisomer
FIGURE 2. The relative stereochemistry in the products was deter-
mined by NMR spectroscopy.
product. However, the 1,2-syn relationship in the triol oxidation
product from this diastereoisomer was confirmed by a similar
analysis of the 13C NMR spectra of the 1,3-dioxolanes, 34a and
34h, generated from 31a and 31h, respectively (Figure 2).62 In
these cases, the two methyl resonances for 1,3-dioxolane 34a
appeared at 27.1 and 27.5 ppm, while the two methyl resonances
for 1,3-dioxolane 34h appeared at 26.5 and 26.8 ppm. In both
cases, similar chemical shifts for the two methyl resonances in
the acetal protecting group are indicative of a vicinal diol
displaying a 1,2-syn relationship.62
The Brønsted or Lewis acid-mediated reaction of crotylsi-
lanes,63 and their closely related stannane analogues28,64 with
aldehydes, has been shown to be syn-selective for both (E)-
and (Z)-stereoisomers. It is likely that in the relatively poorly
defined transition states through which this class of allylating
agent reacts with aldehydes, steric,28 stereoelectronic,5c,25b,c and
electronic25a,65 factors all play a role in governing the stereo-
chemical outcome of the reaction. Furthermore, it is possible
that this type of reaction proceeds through a number of low-
energy reactive conformations, which are rather substrate-
dependent. Mindful that gross generalizations need to be made
with care, the origins of the syn selectivity in this type of
crotylation reaction have been the subject of numerous studies,
which have successfully elucidated the favored reactive con-
formations of type II allyl metals reacting with aldehydes.5c,25
From these results, a range of factors that predispose the
adoption of such low-energy arrangements has been proposed.
One of the aims of our study was to examine whether in our
tethered system, there was any preference for the reacting
π-systems in the aldehyde and allylsilane to adopt a synclinal
or an antiperiplanar arrangement in the reactive conformation.
While an antiperiplanar alignment of π-systems had been
proposed originally for this type of allylation reaction,28
synclinal alignments of the π-systems have also been shown to
be important low-energy reactive arrangements that need to be
considered.5c,6,25 Keck has carried out a related study to ours
using aldehyde 35 containing an allylstannane in the alkyl side
chain (Scheme 13).25a,b Cyclization of (E)-35 was effected with
a variety of Lewis acid and Brønsted acid activators, and
provided the corresponding 2-vinylcyclohexanols as a mixture
of four diastereoisomers. In the case of allylstannane, (E)-35,
which most closely resembles our own allylsilane (E)-9, the
best stereoselectivity was obtained by using the Brønsted acid,
CF3CO2H, which afforded cyclohexanols 36, 37, 38, and 39 in
the ratio 81:6:1:8 (Scheme 13). The stereoselectivity for the
major diastereoisomer 36 was reduced when bulkier Lewis acids
were employed; for example, with BF3 ·OEt2, cyclohexanols 36,
37, 38, and 39 were now obtained in the ratio 60:24:6:6.66
Improved stereoselectivity (for a different diastereoisomer, 37)
was observed when the (Z)-allylstannane was employed; thus
(Z)-35 reacted in the presence of CF3CO2H to provide cyclo-
(63) Hayashi, T.; Kabeta, K.; Hamachi, I.; Kumada, M. Tetrahedron Lett.
1983, 24, 2865–2868.
(64) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J. Org.
Chem. 1994, 59, 7889–7896.
(66) The effect of size of the activator on the stereoselectivity of reactions
between aldehydes and allylsilanes has also been observed by Denmark, see
references 5b and 5c.
(65) Gevorgyan, V.; Kadota, I.; Yamamoto, Y. Tetrahedron Lett. 1993, 34,
1313–1316.
5470 J. Org. Chem. Vol. 73, No. 14, 2008

Intramolecular Allylation of Aldehydes
SCHEME 14. Evans Proposes an Electrostatic Model to
Rationalize the Diastereoselectivity
hexanols 36, 37, 38, and 39 in the ratio 4:96:0:0, while with
BF3 ·OEt2 the ratio of products was 15:85:<1:<1. To rationalize
the observed stereoselectivity, Keck invoked transition state
conformations in which the aldehyde and allylstannane assume
a syn-synclinal orientation and proposed that these can benefit
from a favorable interaction between the π* LUMO of the
aldehyde electrophile and the HOMO of the allylsilane nucleo-
phile. In the absence of steric and other interactions, this frontier
orbital effect could then account for the observed stereoselec-
tivity (Scheme 13).67
Were such secondary orbital interactions controlling the
stereochemical outcome of our cyclization, it would be the two
diastereoisomers, 20 and 22, which we do not observe (at least
with the diethylsilyl tether) that would be expected to predomi-
nate; in our case, it is those two diastereoisomers, 21 and 23,
which cannot benefit from the proposed secondary orbital
interaction that are observed. Keck’s cyclization precursors differ
principally in the atoms linking the electrophile and nucleophile.
In Keck’s substrates, an all-carbon chain connects the two
reacting groups, whereas in our cyclization precursors the
-CH2CH2- unit is substituted for a -OSiEt2- motif. To
rationalize the observed stereochemical outcome of our reac-
tions, we therefore need to consider other factors that might
affect the relative energies of the transition states leading to
the four diastereoisomeric cyclization products. The intramo-
lecular allylation reaction of aldehyde (E)-9 containing a
diethylsilyl ether tether exhibited complete 1,3-stereoinduction
while 1,4-induction was more modest (Table 1). To rationalize
the high 1,3-induction we propose that the reaction is governed
by electronic factors and proceeds through a chair-like transition
state in which the R substituent in the cyclization precursor
adopts a pseudoequatorial orientation; this is in analogy to
Keck’s substrates (Scheme 13). To provide the observed sense
of 1,3-induction, the aldehyde functionality must then adopt a
pseudoaxial orientation. The addition of nucleophiles into
aldehydes containing a ꢀ-carbinol stereogenic center has been
investigated previously. Evans has looked at this problem in
detail and proposed a model, which rationalizes the high
stereoselectivity that can sometimes be observed in this type of
addition reaction.68,69 For example, he showed that the BF3 ·OEt2-
mediated Mukaiyama aldol reaction of silyl enol ether 40 with
ꢀ-silyloxy aldehyde 41 generates the corresponding aldol
products with high stereoselectivity, favoring the diastereoisomer
42 in which there is a 1,3-anti relationship between the existing
and new carbinol stereogenic centers (Scheme 14).68 Under the
rather apolar reaction conditions in which this (and our own)
reaction is performed, Evans proposes a reactive conformation
for 41 outlined in Scheme 14. Looking along the carbonyl-
carbon-CR bond, the conformation is very similar to that
proposed by Felkin and Anh in which the bulky substituent lies
orthogonal to the carbonyl functionality.70 Next, considering
rotation along the CR-Cꢀ bond, Evans favors a staggered
conformation in which the dipole moments across the polar
CsO and CdO bonds are opposed and steric interactions
FIGURE 3. An electrostatic argument rationalizes the observed 1,3-
stereoinduction.
minimized. Approach of the nucleophile along a Bu¨rgi-Dunitz
trajectory opposite the large group on this conformer then gives
rise to the 1,3-anti diastereoisomer 42.68
Our proposed chair-like transition state in which the aldehyde
adopts a pseudoaxial position similarly minimizes electrostatic
interactions (Figure 3); the 1,3-syn stereochemistry observed
in our products, 21 and 23, which is opposite to that obtained
in Evans’ study, can be explained by the fact that tethering the
allylsilane to the aldehyde electrophile delivers the nucleophile
to the opposite diastereoface (cf. Reetz’s allylations in Scheme
2).
If electrostatic effects are responsible for the 1,3-stereoin-
duction in our allylation, one would expect that carrying out
the reaction in solvents with higher dielectric constants might
lead to an erosion in the level of 1,3-induction. Unfortunately,
attempted cyclization of (E)-9ab in more polar solvents (MeCN,
THF, acetone) led to a complex mixture of products, which was
difficult to analyze. However, support for our proposals comes
from some related work, which we have recently carried out
on the synthesis of 2,4,5-tetrahydropyrans (Table 2).71 In this
study, the diethylsilyl tether present in aldehyde (E)-9ab was
replaced with a methylene unit to provide 43. Removal of the
labile silyl ether linkage provided a more robust substrate that
now allowed us to investigate the cyclization in a variety of
(67) Frontier orbital-controlled allylations have also been proposed by
Denmark, see reference 25c.
(68) (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322–4343. (b) Evans, D. A.; Duffy, J. L.; Dart, M. J.
Tetrahedron Lett. 1994, 35, 8537–8540. (c) Evans, D. A.; Dart, M. J.; Duffy,
J. L. Tetrahedron Lett. 1994, 35, 8541–8544.
(69) This model has also been supported by computational calculations:
Bonini, C.; Esposito, V.; D’Auria, M.; Righi, G. Tetrahedron 1997, 53, 13419–
13426.
(70) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199–
2204. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61–70.
(71) Jervis, P. J.; Kariuki, B. M.; Cox, L. R. Org. Lett. 2006, 8, 4649–4652.
J. Org. Chem. Vol. 73, No. 14, 2008 5471

Beignet et al.
SCHEME 15. An Electrostatic Model Rationalizes the
Stereochemical Outcome of Other Intramolecular Allylation
and Allenylation Reactions
TABLE 2. Replacing the Diethylsilyl Tether with a Methylene
Bridge Provides a Route to 2,4,5-Tetrahydropyrans Where the
1,3-Stereoinduction Exhibits a Strong Solvent Dependency
solvent
activator
44:45 ratio
MeCN-CH2Cl2 1:1
CH2Cl2
CH2Cl2
Me3SiOTf
Me3SiOTf
TfOH
5:1
12:1
30:1
toluene
TfOH
>50:1
solvent systems. In the event, intramolecular allylation of 43 in
the presence of TfOH or Me3SiOTf afforded two out of the
possible four diastereoisomers, 44 and 45,71 in this instance as
a result of the cyclization proceeding with complete 1,4-
induction. The levels of 1,3-induction proved to be strongly
dependent on the dielectric constant of the solvent and on the
activator employed (Table 2). The best results (leading to the
same sense of 1,3-induction as observed in the present work,
i.e., to the production of 44) were observed when the reaction
was performed in the apolar solvent, toluene, as would be
predicted if the 1,3-stereoinduction was under electrostatic
control. The size of the activator also influenced the level of
1,3-induction, with the Brønsted acid, which would minimize
the size of the activated aldehyde functionality when it occupies
a sterically less favorable pseudoaxial orientation, providing the
best results.
Our proposed electrostatic model also rationalizes a number
of related reactions. For example, having demonstrated the
reaction was an intramolecular process, Reetz invoked chelation-
control to account for the 1,3-syn selectivity, which was
observed in the reaction of aldehyde 5 under TiCl4 activation
(Scheme 2).24g Ti(IV) Lewis acids are commonly used in
chelation-controlled processes, although it is relatively unusual
to invoke a silyl ether oxygen as a donor group, owing to their
relatively low Lewis basicity (compared with alkyl ethers).72
While it is not unreasonable to consider the allyldimethylsilyl
group sufficiently small to permit the formation of the chelate
intermediate 6 with the proximal carbonyl residue, intramo-
lecular delivery of the allyl nucleophile to the re face (as drawn
in Schemes 2 and 15) is stereoelectronically disfavored.73 The
electrostatic model, which rationalizes the sense of 1,3-stere-
oinduction in our system, also predicts the stereochemical
outcome observed by Reetz in his system without the need to
invoke chelation (Scheme 15). Results from a related study from
Hioki and co-workers can also be explained by using a similar
argument (Scheme 15),24f,74 as can the observed 1,3-stereoin-
duction in the intramolecular allenylation of propargylsilane 46,
carried out in our own laboratories (Scheme 15).23c
16).75 Davis used a steric argument to explain the observed anti
selectivity; thus reaction of ketone 47 proceeds through a chair-
like transition state in which the carbonyl group adopts a
pseudoaxial position, enabling the keto substituent to occupy a
pseudoequatorial orientation and thereby minimize 1,3-diaxial
interactions. However, it is not unreasonable to argue that the
Lewis acid-complexed carbonyl group in the favored transition
state is actually larger than the methyl substituent. If this is the
case, then the proposed electrostatic arguments would still
rationalize the high anti stereoselectivity that is observed in this
reaction (Scheme 16).
As mentioned earlier, the reaction of aldehyde (E)-9ac, which
contains a bulkier diisopropylsilyl ether tether, proceeded with
the same sense of 1,3-stereoinduction although in this case there
was a slight erosion in stereoselectivity (Scheme 11). We
tentatively propose that this slight drop in selectivity is a
consequence of increased 1,3-diaxial interactions between the
pseudoaxially oriented aldehyde and the pseudoaxial isopropyl
substituent (cf. Davis’ reduction in Scheme 16).
Davis’ reduction of ꢀ-hydroxy ketones using a tethered
diisopropylsilane to deliver the hydride nucleophile intramo-
lecularly to the proximal carbonyl group is one of the most
stereoselective methods for forming 1,3-anti diols (Scheme
(72) Certain aluminum Lewis acids have been proposed to form chelates
between carbonyl groups and a ꢀ-silyl ether functionality: Evans, D. A.; Allison,
B. D.; Yang, M. G.; Masse, C. E. J. Am. Chem. Soc. 2001, 123, 10840–10852.
(73) (a) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289–296. (b) Deslong-
champs, P. In Stereoelectronic Effects in Organic Chemistry; Baldwin, J. E.,
Ed.; Pergamon: Oxford, UK, 1983; Vol. 1, Chapter 6.
The 1,4-induction in the reaction of aldehydes (E)-9ab-(E)-
9hb (and aldehyde (E)-9ac) was modest, varying from 9.7:1 in
the best case to 2.7:1 in the worst (Table 1). While rationalizing
(74) A chelation-control argument cannot be used to rationalize the stereo-
chemical outcome in this example.
(75) Anwar, S.; Davis, A. P. Tetrahedron 1988, 44, 3761–3770.
5472 J. Org. Chem. Vol. 73, No. 14, 2008

Intramolecular Allylation of Aldehydes
SCHEME 16. An Electrostatic Model Rationalizes the
Observed 1,3-anti Selectivity in Davis’ Reduction of
ꢀ-Hydroxy Ketones
SCHEME 17. Synthesis of (Z)-Allylsilane Cyclization
Precursors
that if Keck’s frontier orbital interactions had any influence,
the (Z)-allylsilane might lead to the preferential formation of
the minor oxasilacycle 21 (cf. the reaction of (Z)-35 in Scheme
13).25b Thus, a change in the degree of 1,4-induction observed
in the cyclization of (Z)-9 would allow us to probe the relative
importance of steric and stereoelectronic effects in governing
the stereochemical outcome of this intramolecular allylation.
Synthesis of this modified aldehyde precursor (Z)-9 called
for a slight change in the synthetic strategy, which is outlined
in Scheme 17. γ-(Amino)silyl-substituted propargylsilane 48b
was prepared from the reaction of lithiated propargyltrimeth-
ylsilane with amino(chloro)silane 15b. Stirring aminosilane 48b
with ꢀ-hydroxy esters 13b-e in the absence of solvent at 40 °C
for 2 days provided the desired silyl ethers 50bb-eb in good
to excellent yield. For the phenyl substrate, 50ab, these
silyletherification conditions led to preferential elimination so
in this case, aminosilane 48b was first converted to the
corresponding chlorosilane 49b by treatment with acetyl chlo-
ride.51 Tether formation with alcohol 13a could then be achieved
by reaction with chlorosilane 49b under standard conditions.
Having formed the silyl ether tether in 50, a number of methods
was examined for effecting partial reduction of the alkyne
functionality. Lead-poisoned Pd on CaCO3 and quinoline-
poisoned Pd on BaSO4 under a hydrogen atmosphere led to a
complex mixture of products resulting from over-reduction,
translational isomerization of the olefin reduction product, and
mixtures of both the (Z)- and (E)-stereoisomers. Raney nickel
offered a more controlled hydrogenation, and with care, the
reaction could be stopped before over-reduction to the alkane
became a problem, to provide (Z)-12 in good yield; however,
even under these conditions we still observed varying amounts
of the corresponding (E)-stereoisomer and trace amounts of an
olefin product, which we tentatively suggest is an (E)-allylsilane
resulting from translational isomerization of the double bond.
DIBALH reduction of esters (Z)-12ab-(Z)-12eb once again
FIGURE 4. Steric interactions rationalize the observed 1,4-stereoin-
duction.
relatively small differences in selectivity needs to be made with
care, we considered the two chair-like transition states leading
to the observed products and propose that that leading to the
minor diastereoisomer, 21, is disfavored owing to steric interac-
tions between the vinylic hydrogen in the allylsilane and the
pseudoaxially oriented ethyl substituent in the silyl tether, and
the pseudoaxially oriented activated aldehyde (Figure 4). Placing
the allylsilane in a pseudoaxial orientation relieves these
interactions as in this conformation, the vinylic hydrogen is now
interacting with the axial lone pair on the silyl ether oxygen
and potentially also the pseudoequatorial substituent at the silyl
tether (Figure 4). The fact that the level of 1,4-stereoinduction
was similar for (E)-9ab (23ab:21ab, 3.9:1) and (E)-9ac (23ac:
21ac 3.5:1) could suggest that interactions between the vinylic
hydrogen in the pseudoequatorially oriented allylsilane and the
activated aldehyde are more significant than those with the
pseudoaxial ligand at the silyl tether. Indeed the slight reduction
in 1,4-induction on going from (E)-9ab to (E)-9ac might suggest
additional unfavorable interactions are introduced into the
transition state leading to 23 when the diisopropylsilyl tether is
employed.
If the proposed steric interactions were indeed differentiating
the two transition states leading to the oxasilacycles 21 and 23,
we postulated that changing the configuration of the double bond
in the cyclization precursor 9 from (E) to (Z) would better
differentiate these two transition states and lead to an increase
in 1,4-induction in favor of 23 while having a negligible effect
on the 1,3-induction. However, to counter this, we were mindful
J. Org. Chem. Vol. 73, No. 14, 2008 5473

Beignet et al.
TABLE 3. Intramolecular Allylation with Allylsilane (Z)-9 Led to
in the product oxasilacycles we would then be able to ascertain
the reactive conformation of the nucleophile and electrophile,
and in doing so, probe the factors that control the stereochemical
outcome of allylation reactions involving type II allyl metals.
To this end, we have described the synthesis of a series of
γ-aminosilyl-substituted allylsilanes and shown that these can
be tethered to a selection of ꢀ-hydroxy aldehyde electrophiles.
The size of the substituents in the silyl tether proved to be critical
for governing the chemoselectivity of the allylation reaction:
too small (SiMe2) and a diene is the end product, too large
(SiiPr2) and all four diastereoisomeric allylation products are
obtained. A tether of intermediate steric bulk (SiEt2) provides
the best compromise. By analyzing the relative stereochemistry
in the oxasilacycle products we have provided a rationale for
the observed levels and sense of 1,3-stereoinduction based on
Evans’ dipole minimization model; thus it seems that in our
case, the reaction is not controlled by frontier orbital interactions
but by electrostatic effects. A model to account for the 1,4-
stereoinduction based on minimization of steric interactions has
also been proposed and from this we were able to predictably
improve the 1,4-induction by using the stereoisomeric (Z)-
allylsilane. That there is not a universal increase in 1,4-induction
for all substrates suggests that our working transition state model
may require modification, at least in some cases.
As an added bonus, the oxasilacycle allylation products are
also ripe for elaboration. For example, we used an oxidative
cleavage of the temporary silicon connection to verify the
relative stereochemistry of the allylation products, and in the
best cases with use of a (Z)-allylsilane, this intramolecular
allylation/Tamao-Kumada oxidation sequence provides a highly
stereoselective route to 1,2-anti-2,4-syn triols.
This study once again highlights the complexity of such a
commonly used reaction as an allylation of an aldehyde. A
multitude of factors can influence the stereochemical outcome
of this reaction and steric, electronic, and stereoelectronic factors
should all be considered. The relative importance of each
depends on the reagents and reaction conditions; in the present
study we advance an electrostatic controlling factor to be
important and propose that this can be applied to a range of
other stereoselective reactions.
Improved 1,4-Stereoinduction in Some Cases
aldehyde
(Z)-9
combined yielda
of 21 + 23 (%)
23:21
entry
R
ratiob
1
2
3
4
5
(Z)-9ab
(Z)-9bb
(Z)-9cb
(Z)-9db
(Z)-9eb
Ph
92
95
50
79
55
15:1
21:1
14:1
9:1
2-furyl
cyclohexyl
n-Bu
i-Bu
7:1
a Diene product accounted for the remaining material in the crude
reaction mixture. b Ratio calculated from analysis of the crude reaction
1
mixture by H NMR.
proceeded uneventfully to provide the corresponding aldehyde
cyclization precursors (Z)-9ab-(Z)-9eb in excellent yield
(Scheme 17).
Aldehydes (Z)-9ab-eb were subjected to our standard
cyclization conditions and generated the corresponding allylation
products in good yield. Dienes, (E)-27, again accounted for the
mass balance in these reactions. In all cases, we were pleased
to observe the formation of just two diastereoisomers, 21 and
23. Furthermore, in the majority of cases, the level of 1,4-
stereoinduction was better, in some cases significantly so, than
that observed in the reaction employing the corresponding (E)-
stereoisomer, (E)-9; however, the increase in 1,4-induction was
not uniform for all examples (Table 3). Substrates (Z)-9ab and
(Z)-9bb containing an aryl substituent at the carbinol stereo-
center showed the most dramatic improvement in 1,4-induction;
the 1,4-induction in cyclohexyl derivative (Z)-9cb was also
significantly better although in this case, the diene side product,
(E)-27cb, was formed in higher amounts. Isobutyl derivative
(Z)-9eb afforded a small but significant improvement in 1,4-
induction, while perhaps most interestingly, the level of 1,4-
induction for the n-butyl derivative, (Z)-9db, which had been
one of the best substrates with use of the (E)-allylsilane (Table
1, entry 4), remained essentially unchanged when its (Z)-
stereoisomer was employed.
Experimental Section
It is difficult to account for these interesting observations and
here we simply offer a few comments for consideration. It
appears that the degree of improvement in 1,4-induction is a
function of the steric bulk of the substituent at the carbinol
stereogenic center, with the bulkiest groups (as measured by
their A values) affording the most significant improvements. It
would be expected that these groups provide the strongest
conformational anchor in a chair-like transition state. The
straight alkyl chain in (Z)-9db will provide a weaker anchoring
effect, which may allow the reactive conformation to deviate
significantly from a chair, in which case, additional factors that
we have not considered may be more important in determining
the 1,4-induction.
General Procedure for the Synthesis of Silyl Ether 12
from Alcohol 13 and Aminosilane 14. Alcohol 13 (50 mmol) and
aminosilane 14 (50 mmol) were stirred at 40 °C for 2 d. Evaporation
of the Et2NH byproduct and purification of the residue by flash
column chromatography (eluent Et2O in hexane) afforded silyl ether
12 as a colorless liquid.
General Procedure for the Synthesis of Aldehyde 9 from
Ester 12. DIBALH (31.7 mL, 1.5 M in toluene, 47.6 mmol) was
added dropwise over 30 min to a solution of ester 12 (47.0 mmol)
in CH2Cl2 (470 mL) at -78 °C. After 1 h, the reaction was
quenched with MeOH (1.93 mL, 47.6 mmol) and H2O (5.19 mL,
285.6 mmol) at -78 °C, and the resulting slurry was allowed to
warm to rt. It was then filtered through MgSO4 and Celite and the
solvent was evaporated under reduced pressure to leave a yellow
liquid, which was purified by flash column chromatography (eluent
Et2O in hexane) to afford aldehyde 9 as a colorless liquid.
General Procedure for Allylation Reaction: Synthesis of
Oxasilacycles 23aa-ha and 21aa-ha. TMSOTf (1.0 equiv) was
added dropwise (approximately one drop per second) via syringe
to a solution of aldehyde 9 (1.0 equiv) and 2,6-DTBMP or TTBP
(1.2 equiv) in CH2Cl2 (0.1 M reaction concentration) at -78 °C.
The reaction mixture was stirred at -78 °C. TLC indicated
Conclusions
In summary, we set out to investigate the stereoselectivity
of an intramolecular allylation reaction involving an allylsilane
that had been tethered through the γ-terminus of the allyl
nucleophile to a range of ꢀ-hydroxy aldehydes via a temporary
silyl ether connection. By studying the relative stereochemistry
5474 J. Org. Chem. Vol. 73, No. 14, 2008

Intramolecular Allylation of Aldehydes
consumption of starting material within 8-16 h. The reaction
mixture was then quenched by adding an equivalent volume of
NaHCO3 solution at -78 °C and allowed to warm to rt over 30
min. The two phases were separated and the aqueous phase was
extracted with CH2Cl2 (two times the volume of aqueous phase).
The combined organic extracts were successively washed with H2O
(one-third volume of organic phase) and brine (one-third volume
of organic phase) and dried over MgSO4. Filtration and evaporation
of the volatiles under reduced pressure provided a yellow oil
(quantitative mass recovery). This was used in the following
Tamao-Kumada oxidation without further purification. Analytically
pure samples of each oxasilacycle were obtained by preparative
HPLC.
General Procedure for Tamao-Kumada Oxidation: Forma-
tion of Triols 28a-h. H2O2 (20 equiv, 60% in H2O), KHCO3 (3.0
equiv), and KF (5.0 equiv) were added to a solution of the products
from the allylation of aldehyde 9 (1 equiv) in MeOH:THF (1:1)
(0.1 M reaction concentration) and the resulting mixture was stirred
at rt. The progress of the reaction was monitored by TLC and
consumption of the starting material occurred within 4 to 7 d (an
additional 5 equiv of H2O2 was sometimes added after a few days
to drive the reaction to completion). The mixture was then poured
into an equal volume of Na2S2O3 solution and stirred for 30 min.
The resulting mixture was extracted with EtOAc (3 × two volumes)
and the combined organic extracts were washed with brine (ca.
one-sixth volume of EtOAc) and dried (MgSO4). Filtration and
evaporation of the volatiles under reduced pressure afforded the
triol 28 as a yellow oil that was purified by flash column
chromatography.
Acknowledgment. We thank the Engineering and Physical
Sciences Research Council (grant no. GR/N32556) for a
studentship (to J.B.), the University of Birmingham and the
Engineering and Physical Sciences Research Council for a
studentship (to P.J.J.), and Astra Zeneca for an unrestricted
award (to L.R.C).
Supporting Information Available: General experimental
details, experimental procedures and complete compound
characterization data for all new compounds, scanned 1H NMR
spectra, and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO800824X
J. Org. Chem. Vol. 73, No. 14, 2008 5475