Asymmetric [2,3]-Wittig Rearrangement: Synthesis of Homoallylic, Allenylic, and Enynyl α-Benzyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.8b03659

A highly stereoselective [2,3]-Wittig rearrangement of allylic and propargylic ethers controlled by a chiral sulfoxide moiety is presented. The activation provided by the sulfoxide at the remote ortho position allows the rearrangement of less-activated and unexplored benzylic carbanions. Thus, this general methodology gives access to the asymmetric synthesis of homoallylic, enynyl, and allenylic α-benzyl alcohol derivatives.

Full text of DOI:10.1021/acs.orglett.8b03659

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Asymmetric [2,3]-Wittig Rearrangement: Synthesis of Homoallylic,
Allenylic, and Enynyl α‑Benzyl Alcohols
†
‡
†
Ricardo I. Rodríguez,†,‡ Elsie Ramírez, Jose A. Fernandez-Salas, Ruben Sanchez-Obregon,
́
́
́
́
́
,†
,‡,§
́
́
Francisco Yuste,* and Jose Aleman*
†
́
́
́
́
Instituto de Química, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Cd. Universitaria, Coyoacan 04510, Mexico
́
City, Mexico
‡
́
́
́
Departamento de Química Organica (modulo-1), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
§
́
Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autonoma de Madrid, 28049 Madrid, Spain
S
* Supporting Information
ABSTRACT: A highly stereoselective [2,3]-Wittig rearrangement of allylic and propargylic ethers controlled by a chiral
sulfoxide moiety is presented. The activation provided by the sulfoxide at the remote ortho position allows the rearrangement of
less-activated and unexplored benzylic carbanions. Thus, this general methodology gives access to the asymmetric synthesis of
homoallylic, enynyl, and allenylic α-benzyl alcohol derivatives.
Scheme 1. Previous Related Approaches and the Present
Work
[2,3]-Sigmatropic rearrangements hold a preferred position in
the synthetic chemist’s arsenal, as they represent a powerful
tool for the rapid installation of molecular complexity in
organic chemistry.1 Recently, the enantioselective version has
experienced an important development,2 mainly via onium
ylides3 generated from diazo compounds.2b,4 More specifically,
advances in the development of the asymmetric anionic Wittig
reaction, which involves the formation of α-oxycarbanion, are
less prevalent, because of the need for strong bases.
Nevertheless, methods based on the use of (i) strong Brønsted
bases, such as n-BuLi or t-BuLi, in the presence of a
stoichiometric ligand,5 and (ii) stoichiometric amounts of a
chiral boron reagent have been reported.6 Moreover, stereo-
selective [2,3]-rearrangements with substrates bearing either
existing stereocenters5b,7 or chiral auxiliaries5b,8 (Scheme 1a)
to control the configuration of the newly formed σ-bond have
been studied. Although rare, more recently, different
groups9−12 have described interesting organocatalyzed asym-
metric [2,3]-rearrangement methodologies of allyloxy deriva-
tives for the asymmetric synthesis of allylic alcohols. The
asymmetric [2,3]-Wittig rearrangement of propargylic ethers,
which lead to enantio-enriched functionalized allenes, has also
been explored. Regardless of the great interest in developing
such methods for the enantioselective preparation of syntheti-
cally valuable allenes,13 very few examples have been reported
for that purpose, following the deprotonation strategy.14 The
low reactivity shown by propargylic ethers is the main
shortcoming that these methodologies need to overcome.
Despite the great advances made in this field, prerequisite high
catalyst loadings, low diastereoselectivities and enantioselectiv-
ities, and the restricted array of suitable substratesin which
the presence of an electron-withdrawing group (EWG) is
required in order to promote the deprotonation stepstill
remain as the primary drawbacks and limitations of pre-existing
methods (Scheme 1a).
Chiral sulfoxides have been widely used to induce
stereocontrol in a variety of organic transformations.15 Despite
the well-known ability of sulfoxides to direct reactions in
Received: November 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03659
Org. Lett. XXXX, XXX, XXX−XXX

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a
Table 1. Remote [2,3]-Wittig Rearrangement of 1a
c
b
base (equiv)
additive
temperature, T (°C)
yield (%)
diastereomeric ratio, dr
1
2
3
4
5
6
7
8
9
KHMDS (1.5)
KHMDS (1.5)
s-BuLi (1.5)
LDA (1.5)
LDA (1.5)
LDA (4)
LDA (1.5)
LDA (1.5)
LDA (1.5)
−
−
−78
0
−78
−78
0
0
0
−78
-78
n.r.
n.r.
−
−
−
−
85:15
85:15
85:15
−
d
TMEDA
−
−
−
d
35
35
54
TMEDA
HMPA (1:6)
TMEDA
e
−
56
90:10
a
b
c
All the reactions were performed on 0.273 mmol scale of 1a in 4 mL of THF and the corresponding additive. Determined by 1H NMR. Isolated
d
e
yield of compound 2a after flash chromatography. Aldehyde 3a was obtained as major product. Complex mixture. Legend: KHMDS = potassium
hexamethyldisilazane, s-BuLi = sec-butyllithium, TMEDA= tetramethylethylenediamine, LDA = lithium diisopropylamide, and HMPA =
hexamethylphosphoramide.
strong basic media,16 to the best of our knowledge, chiral
sulfoxides have never been employed to induct a [2,3]-Wittig
rearrangement. The presence of a chiral sulfoxide in the ortho
position of an aromatic ring promotes the formation of stable
chiral lithium carbanions. Therefore, laterally lithiated
sulfoxides have been reported to react with a variety of
electrophiles.16 Thus, we envisioned that this strategy could
lead to a [2,3]-sigmatropic rearrangement upon deprotonation
of the benzylic position (Scheme 1b) without the need of
EWGs to enhance the acidity, as in all previous works. The
easy installation and removal (without racemization of the
synthesized stereogenic center) of the sulfoxide moiety in the
ortho position of the aromatic ring and the limitations of
previously reported methods would make this approach a
highly attractive and efficient alternative for the preparation of
synthetically useful and enantio-enriched homoallylic alcohols.
Moreover, by subjecting the corresponding propargylic ether
derivatives to the [2,3]-Wittig rearrangement, enantiopure
allenyl alcohol derivatives, which are otherwise difficult to
access, could be efficiently obtained. In this work, we report
the development of a general [2,3]-sigmatropic rearrangement
method that hinges on the presence of the ortho sulfoxide,
giving access to a variety of enantio-enriched homoallyl and
allenyl α-benzyl secondary and tertiary alcohols.
was isolated in diastereomerically pure fashion in 54% yield
(see Table 1, entry 7). When other additives were employed,
such as HMPA (Table 1, entry 8), a complex mixture was
obtained, whereas TMEDA at −78 °C allowed us to isolate
alcohol 2a in 56% yield and with very good diastereoselectivity
(Table 1, entry 9).
After optimizing the reaction conditions, we studied the
scope of the reaction using differently substituted allylic ethers
1 as starting materials (see Table 2). Terminal allylic ether
Table 2. Remote Asymmetric [2,3]-Wittig Rearrangement
a
of Sulfoxides 1
We began our studies by investigating the [2,3]-Wittig
rearrangement of sulfoxide 1a, which was easily prepared in
two steps (see the Supporting Information (SI)) from
commercially available starting materials (see Table 1). The
reaction did not proceed when a bulky base, such as potassium
hexamethyldisilazane, was used (Table 1, entries 1 and 2),
recovering the unaffected starting material. Other bases, such
as s-BuLi or LDA at −78 °C did not conduct to the desired
homoallylic alcohol, while aldehyde 3a, which is formed via
elimination of the stabilized allyl anion, followed by the
oxidation of the benzylic position, was observed as the major
product (Table 1, entries 3 and 4). Interestingly, LDA (1.5 or
4 equiv) at higher temperature (0 °C) led to the desired
alcohol (2a) in moderate yield and good diastereomeric ratio
(85:15), detecting aldehyde 3a again as side product (Table 1,
entries 5 and 6). The presence of TMEDA as an additive at the
same temperature (0 °C) clearly improved the reaction and 2a
a
All the reactions were performed on 0.273 mmol scale of 1a in 4 mL
b
c
of THF at −78 °C. Reactions performed at 0 °C. 1.1 mmol scale
reaction. Diastereomeric ratios were determined using H NMR.
1
derivatives were well-tolerated and gave the rearranged
products with high diastereoselectivities (2a and 2b). In
addition, the reaction was scaled up to 1.1 mmol with similar
results. The [2,3]-Wittig rearrangement efficiently proceeded
with α-branched terminal allylic ether (2d), leading to similar
levels of diastereoselectivity. Substrates bearing β-substituted
double bonds were then tested in the reaction. While aliphatic
B
DOI: 10.1021/acs.orglett.8b03659
Org. Lett. XXXX, XXX, XXX−XXX

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substitution on the double bond (2c) led to very good
diastereoselectivity, the aryl-substituted double bond (2e)
proceeded with lower stereoinduction. With a β-disubstituted
double bond derivative, a slight erosion in the stereoselectivity
was observed (2f). To our delight, the very challenging allylic
substrate bearing a tetrasubstituted double bond rearranged to
the homoallylic product with high diastereoselectivity and 58%
isolated yield (2g).
Table 3. Remote [2,3]-Wittig Rearrangement of Propargylic
Ethers for the Synthesis of α-Allenyl Alcohols
a
Encouraged by the good results obtained in the [2,3]-Wittig
rearrangement for the synthesis of secondary homoallylic
alcohols and with the aim of synthesizing enantio-enriched
tertiary alcohols, we studied the behavior of the corresponding
reaction with secondary ether derivatives 4 (Scheme 2). For
Scheme 2. Sulfinyl Double Induction: Synthesis and [2,3]-
Wittig Rearrangement of Tertiary Allylic Alcohols
a
All the reactions were performed on 0.273 mmol scale of 6 in 4 mL
of THF. The diastereomeric ratio (dr) has been determined using 1H
NMR.
of the formed allene (7d), and only one diastereomer was
obtained.18 The absolute configuration of the asymmetric
centers of 7a were unequivocally assigned as (S, R) by X-ray
crystallographic analysis (see the SI). The same stereochemical
outcome was assumed for all of the compounds of the series.
Apart from the high stereoinduction provided, the ortho-
sulfinyl group is an easily removable chiral auxiliary (Scheme
3). Direct treatment of allylic alcohols 2a, 2b, and 2c with t-
BuLi conducted to the desulfinylated products in good yields
without erosion in the enantiomeric purity.
Scheme 3. Desulfinylation of the Allylic Alcohols 2
the construction of the chiral scaffold required for the
rearrangement, we have taken advantage of the presence of
the ortho-sulfinyl group. The addition of lithium acetylides to
the aldehyde 3a gives rise to the propargylic alcohols with
excellent diastereoselectivities in all cases.17 Simple allylation
leads to the aforementioned chiral platforms (4a−4c) (eq a in
Scheme 2). TMS, as well as alkyl- and aryl-substituted alkyne
derivatives, were very well-tolerated in the [2,3]-sigmatropic
rearrangement, leading to the desired tertiary alcohols with
excellent diastereoselectivities (eq b in Scheme 2). Con-
sequently, the presence of the chiral ortho-sulfinyl inductor is
able to orchestrate the entire synthetic process.
Considering the limitations reported in the literature, where
only few reports have described [2,3]-Wittig rearrangements
for the asymmetric synthesis of allenyl alcohols,14a,b and to
further extend the applicability of the sulfinyl-promoted
asymmetric [2,3]-Wittig rearrangement, the reaction of
propargylic alcohol derivatives was then considered. With
that purpose, differently substituted propargylic ethers 6 were
tested under the optimized reaction conditions (Table 3). Both
methyl and bulky tert-butyl substituted alkynes efficiently led
to the allenyl alcohols with complete diastereoselectivity (7a
and 7b). In the presence of a tertiary propargylic ether (6c),
the reaction occurred in a highly stereoselective manner,
observing only one diastereomer (7c). When an enantiopure
(S)-oct-3-yn-2-ol derivative (6d) was used, the sulfoxide was
able to control the stereoselectivity, including the axial chirality
The absolute configuration of the asymmetric centers of
minor diastereomer 2e′ was unequivocally assigned as (S, 1R,
2R) by X-ray crystallographic analysis (see the SI), whereas the
major diastereomers were correlated with known compounds
in the literature (8a, 8b, and 8c; see Scheme 3 and the SI). The
same stereochemical outcome was assumed for all of the
compounds of the series (2a−2g, 5a−5c). With all this
information in hand, it is clear that the rearranged products
featuring two new stereocenters (2c and 2e) are epimers in the
carbon that bears the hydroxyl group. A plausible explanation
for the exclusive formation of two diastereomers in the
reactions presented in Table 2 is depicted in Scheme 4. We
propose, based on previous DFT calculations,16e,f the
formation of two plausible carbanions, that are capable of
reacting in a completely stereoselective way, which would
C
DOI: 10.1021/acs.orglett.8b03659
Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters
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Scheme 4. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yustef@unam.mx (F. Yuste).
*E-mail: jose.aleman@uam.es; URL: www.uam.es/jose.aleman
́
(J. Aleman).
ORCID
́
́
Jose A. Fernandez-Salas: 0000-0003-3158-9607
́
́
Jose Aleman: 0000-0003-0164-1777
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank DGAPA-UNAM (Project No. UNAM-PAPIIT-
IN205319) for financial support. R.I.R. thanks CONACYT for
■
establish the opposite configuration at the benzylic center. The
results obtained can be rationalized with the formation of a free
carbanion, which adopts a planar C(sp2) structure (TS-I). This
is in accordance with the observed better outcome at higher
temperatures (0 °C) and in the presence of TMEDA, which
would preferably avoid interactions between Li+ and the
carbanionic center. Therefore, the sulfinyl group assumes an
anti-arrangement (S−O bond versus the carbanionic C−O
bond), with respect to the benzyl carbanion center, in order to
avoid unfavorable electrostatic interactions. The reaction is
then controlled by sterics, the upper face being clearly favored
for the approach of the alkene as the p-tolyl group is blocking
the opposite face (TS-I). A five-membered envelope-type
transition state2b and the defined E configuration of the double
bond leads to the formation of the anti-isomer. A similar
approach would explain the configuration obtained in the
synthesis of enantio-enriched allenyl alcohols. In order to
explain the observed minor diastereomers, we propose the
formation of a “chelated” carbanion (TS-II), where the anion
is formed and the top face is blocked. Therefore, the alkene
reacts from the bottom face, establishing the opposite
confirmation at the benzylic center (R).
́
a graduate fellowship (Grant No. 663631) and Fundacion
Carolina. E.R. thanks DGAPA-UNAM for a postdoctoral
́
́
́
́
fellowship. We also thank E. Garcıa Rıos, C. Garcıa Gonzalez,
́ ́
̃ ̃
R. Gavino, L. C. Marquez, M. A. Pena, and L. M. Rıos
(UNAM) for their technical assistance. We are also grateful to
the Spanish Government (No. CTQ2015-64561-R) and J.A.F.-
S. thanks the Spanish Government for a Juan de la Cierva
contract.
REFERENCES
■
(1) (a) Isobe, M.; Ploysuk, C. Molecular Rearrangements in Organic
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In conclusion, the involvement of the key chiral auxiliary
ortho-sulfinyl group has led to an asymmetric [2,3]-Wittig
rearrangement in a nonactivated benzylic position. A wide
range of ethers have been studied, wherein allylic and
propargylic ethers efficiently rearranged to the corresponding
homoallylic and allenyl alcohols with very high diastereose-
lectivities. Finally, the auxiliary can be easily removed, leading
to the desired enantiomerically pure homoallylic alcohols.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03659.
(5) For a review, see: (a) Nakai, T.; Tomooka, K. Pure Appl. Chem.
1997, 69, 595−600. (b) Hodgson, D. M.; Tomooka, K.; Gras, E. Top.
Organomet. Chem. 2003, 5, 217−250. For selected examples, see:
(c) Kitamura, M.; Hirokawa, Y.; Maezaki, N. Chem. - Eur. J. 2009, 15,
9911−9917. (d) Hirokawa, Y.; Kitamura, M.; Mizubayashi, M.;
Nakatsuka, R.; Kobori, Y.; Kato, C.; Kurata, Y.; Maezaki, N. Eur. J.
Org. Chem. 2013, 2013, 721−727. (e) Kitamura, M.; Hirokawa, Y.;
Yoshioka, Y.; Maezaki, N. Tetrahedron 2012, 68, 4280−4285.
(f) Blackburn, T. J.; Kilner, M. J.; Thomas, E. J. Tetrahedron 2015,
71, 7293−7309. (g) Hirokawa, Y.; Kitamura, M.; Maezaki, N.
Tetrahedron: Asymmetry 2008, 19, 1167−1170. (h) Tomooka, K.;
Komine, N.; Nakai, T. Chirality 2000, 12, 505−509. (i) Kawasaki, T.;
1H and 13C spectra for all new compounds and X-ray
data for 2e′ and 7a (PDF)
Accession Codes
CCDC 1875997 and 1875998 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
D
DOI: 10.1021/acs.orglett.8b03659
Org. Lett. XXXX, XXX, XXX−XXX