SYNTHESIS0039-78 1 437-210X
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–N
A
short review
en
Syn thesis
Short Review
R. J. Armstrong, V. K. Aggarwal
50 Years of Zweifel Olefination: A Transition-Metal-Free Coupling
Roly J. Armstrong 0-237590-61X
Varinder K. Aggarwal* 0-3046-30
School of Chemistry, University of Bristol, Cantock’s Close,
Bristol, BS8 1TS, UK
[email protected]
Dedicated to Professor Herbert Mayr on the occasion of his
70th birthday
Received: 15.05.2017
Accepted after revision: 16.05.2017
Published online: 11.07.2017
DOI: 10.1055/s-0036-1589046; Art ID: ss-2017-z0328-sr
License terms:
Abstract The Zweifel olefination is a powerful method for the stereoselective synthesis of alkenes. The reaction proceeds in the absence of a
transition-metal catalyst, instead taking place by iodination of vinyl boronate complexes. Pioneering studies into this reaction were reported
in 1967 and this short review summarizes developments in the field
over the past 50 years. An account of how the Zweifel olefination was
modified to enable the coupling of robust and air-stable boronic esters
is presented followed by a summary of current state of the art developments in the field, including stereodivergent olefination and alkynylation. Finally, selected applications of the Zweifel olefination in targetoriented synthesis are reviewed.
1
Introduction
2.1 Zweifel Olefination of Vinyl Boranes
2.2 Zweifel Olefination of Vinyl Borinic Esters
2.3 Extension to Boronic Esters
3.1 Introduction of an Unsubstituted Vinyl Group
3.2 Coupling of α-Substituted Vinyl Partners
3.3 Syn Elimination
4
Zweifel Olefination in Natural Product Synthesis
5
Conclusions and Outlook
Key words Zweifel olefination, coupling, boronic esters, alkenes,
transition-metal-free, enantiospecific
1
Introduction
The stereocontrolled synthesis of alkenes is a topic that
has attracted a great deal of attention owing to the prevalence of this motif in natural products, pharmaceutical
agents and materials.1 Of the many olefination methods
that exist, the Suzuki–Miyaura coupling represents a highly
convergent method to assemble alkenes (Scheme 1, a).2
However, although the coupling of vinyl halides with primary and sp2 boronates takes place effectively, the coupling
Varinder K. Aggarwal (right) studied chemistry at Cambridge University and received his Ph.D. in 1986 under the guidance of Dr Stuart
Warren. After postdoctoral studies (1986–1988) under Professor Gilbert Stork, Columbia University, he returned to the UK as a Lecturer at
Bath University. In 1991, he moved to Sheffield University, where he
was promoted to Professor in 1997. In 2000, he moved to Bristol University where he holds the Chair in Synthetic Chemistry. He was elected
Fellow of the Royal Society in 2012.
Roly J. Armstrong (left) graduated with an MSci in Natural Sciences
from Pembroke College, Cambridge (2011) spending his final year
working in the laboratory of Professor Steven Ley. He subsequently
moved to Merton College, Oxford to carry out a DPhil under the supervision of Professor Martin Smith (2011–2015) working on asymmetric
counterion-directed catalysis. In October 2015, he joined the group of
Professor Varinder Aggarwal at the University of Bristol as a postdoctoral research associate.
of secondary and tertiary (chiral) boronates remains problematic.3 Furthermore, the high cost and toxicity of the palladium complexes required to catalyze these processes also
detract from the appeal of this methodology.4
The Zweifel olefination represents a powerful alternative to the Suzuki–Miyaura reaction, enabling the coupling
of vinyl metals with enantioenriched secondary and tertiary boronic esters with complete enantiospecificity (Scheme
1, b).5 The reaction is mediated by iodine and base and proceeds with no requirement for a transition-metal catalyst.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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Short Review
R. J. Armstrong, V. K. Aggarwal
This process is based upon pioneering studies reported in
1967 by Zweifel and co-workers on the iodination of vinyl
boranes. This short review summarizes the key contributions made over the last 50 years that have enabled this
transformation to evolve into an efficient and atom-economical method for the coupling of boronic esters. Recent
contributions to the field are described including the development of Grignard-based vinylation, stereodivergent olefination and alkynylation processes. Finally, selected examples of Zweifel olefination in target-oriented synthesis are
reviewed to highlight the utility of this methodology.
R'
B
R'2BH
R
R
THF
I2, NaOH
1
OH
B R'
R'
I
R
R3 B(pin)
cat. Pd(0)
R2
R1
R3
M
+
R2
I
OH
B
R'
R
R'
4
Me
selected products:
Cy
Cy
Cy
Cy
2b; 75 % yield
99:1 Z/E
Me
2c; 77 % yield
92:8 Z/E
2d; 70 % yield
85:15 Z/E
Scheme 2 Zweifel olefination: iodination of vinyl boranes
R3 B(pin)
I2
R1
R3
Transition-Metal Free
Stereospecific
NaOMe
R2
with very high levels of E-selectivity. Chiral non-racemic
boranes could be transformed with complete stereospecificity.
Enantiospecific
Scheme 1 Olefination of boronic esters
R'
B
R'2BH
R
2.1
1,2-metallate
rearrangement
R2
(b) Zweifel Olefination
R1
anti
NaOH elimination
3
(a) Suzuki–Miyaura Coupling
+
2
iodination
Me
X
R
THF/H2O
I2
2a; 83 % yield
R1
R'
R'
THF
Zweifel Olefination of Vinyl Boranes
In 1967, Zweifel and co-workers reported that vinyl
boranes 1, obtained by hydroboration of the corresponding
alkynes, could be treated with sodium hydroxide and
iodine, resulting in the formation of alkene products 2
(Scheme 2).6 Intriguingly, although the intermediate vinyl
boranes were formed with high E-selectivity, after addition
of iodine, Z-alkenes were produced. A reaction with a diastereomerically pure secondary borane afforded the coupled product, 2d, as a single anti diastereoisomer, indicating
that the process proceeds with retention of configuration.7
Mechanistically, this reaction is thought to proceed by activation of the π bond with iodine along with complexation
of sodium hydroxide to form a zwitterionic iodonium intermediate 3. This species is poised to undergo a stereospecific
1,2-metalate rearrangement resulting in the formation of a
β-iodoborinic acid 4. In the presence of sodium hydroxide,
this intermediate then undergoes anti elimination to afford
the resulting Z-alkene product.8
Because vinyl borane intermediates could only be accessed by hydroboration of alkynes, the iodine-mediated
Zweifel coupling was initially limited to the synthesis of Zalkenes.9 However, Zweifel and co-workers subsequently
reported an elegant strategy for the complementary synthesis of E-alkenes (Scheme 3).10 This transformation was
achieved by reacting dialkyl vinyl borane 5 with cyanogen
bromide under base-free conditions. Following stereospecific bromination, a boranecarbonitrile intermediate 8, was
formed, a species that was sufficiently electrophilic to undergo syn elimination. A variety of boranes underwent this
transformation, forming alkenes 6a–c in high yields and
R
BrCN, CH2Cl2
R'
5
R
then workup
with aq. NaOH
R'
6
syn
elimination
BrCN bromination
Br
R
CN
B R'
R'
7
1,2-metallate
rearrangement
R
R'
8
Me
Me
selected products:
nBu
CN
B R'
Br
nBu
Cy
6a; 69 % yield
96:4 E/Z
6b; 68 % yield
93:7 E/Z
nBu
Me
6c; 75 % yield Me
98:2 E/Z
Scheme 3 Synthesis of E-alkenes using cyanogen bromide
A related syn elimination process was reported by Levy
and co-workers (Scheme 4).11 In this case, a vinyl lithium
reagent was prepared by lithium–halogen exchange and
then combined with a symmetrical trialkylborane resulting
in formation of boronate complex 9. Treatment of this intermediate with iodine resulted in stereospecific iodination to
produce β-iodoborane 10. The enhanced electrophilicity of
this species (compared to β-iodoborinic acids such as 4) enabled a syn elimination to occur, generating the corresponding trisubstituted alkene 11 with high levels of stereocontrol. Although the substrate scope of the process is
wide, the method was limited to the use of symmetrical trialkyl boranes.
Brown and co-workers demonstrated that the Zweifel
olefination can also be applied to the synthesis of alkynes
(Scheme 5).12 In this case, monosubstituted alkynes were
deprotonated to form lithium acetylides, which were reacted with trialkylboranes to form alkynylboronate complexes
12. Addition of iodine triggered a 1,2-metallate rearrangement to generate β-iodoboranes 13, which spontaneously
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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Short Review
R. J. Armstrong, V. K. Aggarwal
R2
i. nBuLi, THF
I
R3
ii. R3B
R
R2 R R
R2
I2, THF
I
B R
B
R
3
2
R
R
R 3
syn
R3
R
then workup
Li
R
elimination
with NaOH/H2O2
9
10
11
selected products:
Et Me
n
Hex
nPr
Et
Et
Et
11b; 80 % yield
>95:5 Z/E
Et
11a
66 % yield
Et
Et
Ph
11d; 38 % yield
>97:3 E/Z
Et
nPr
11c; 87 % yield
>95:5 E/Z
Scheme 4 Olefination of symmetrical trialkylboranes
underwent elimination to form alkyne products. This process represents a convenient alternative to the alkylation of
lithium acetylides with alkyl halides and has been successfully employed in total synthesis.13
2.2
ful when the borane is challenging to access or expensive.
One solution to this problem would be to employ a mixed
borane in which one (or two) of the boron-bound groups
demonstrates a low migratory aptitude (e.g., thexyl).14
However, in practice, determining which group will migrate
has proved to be non-trivial and highly substrate-dependent. For example, Zweifel and co-workers showed that
treatment of divinylalkylborane 15 (obtained by double hydroboration of 1-hexyne with thexylborane) with iodine
resulted in competitive migration of both the sp2 and thexyl
groups leading to a mixture of the desired product 16 along
with 17 (Scheme 6).15 They overcame this problem by treating the intermediate divinylalkylborane 15 with trimethylamine oxide, resulting in selective oxidation of the B–Cthexyl
bond to afford borinic ester 18. Due to the low migratory
aptitude of an alkoxy ligand on boron,16 addition of iodine
and sodium hydroxide now led to selective formation of
Z,E-diene 16. Although this allowed control over which
group migrated, the method was limited to the synthesis of
symmetrical dienes.
Zweifel Olefination of Vinyl Borinic Esters
The transformations described in the previous section
suffer from an inherent limitation in that only one of the alkyl groups present in the borane starting materials is incorporated into the alkene product. This is particularly wastei. nBuLi, THF
R'
R'
ii. R3B
Li R
B R
R
12
I2
R
B R
I
R'
R'
THF/Et2O
R
R
13
14
selected products:
nBu
nBu
14a; 96 % yield
nBu
nBu
Cy
14b; 99 % yield
Ph
Ph
14c; 98 % yield
Ph
14d; 95 % yield
Scheme 5 Alkynylation of boranes
(a) Problem: competitive thexyl group migration
nBu
Me Me
Me
Me
BH2
I2, NaOH
nBu
B
Me
nBu
Me
nBu
(2 eq.)
THF
Me Me
THF/H2O
15
nBu
nBu
B
Me
Me3N O
THF
nBu
I2, NaOH
Me Me
B
nBu
Me Me
15
Me
16
17
ratio 16/17 = 52:48
(b) Solution: selective oxidation to a borinic ester
nBu
nBu
Me
Me
Me
Me
+ n
Bu
Me
O
nBu
THF/H2O
Me
16; 65 % yield
98:2 Z,E:isomers
18
I2
iodination
nBu
nBu
I
B
OThex
OH
anti
elimination
NaOH
1,2-metallate
rearrangement
I
nBu
OThex
B
OH
nBu
Scheme 6 Diene synthesis by Zweifel olefination of boranes or borinic esters
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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Short Review
R. J. Armstrong, V. K. Aggarwal
Br
B
R2BHBr·SMe2
R1
R1
Et2O
NaOMe
R2
1
Et2O/MeOH
19
R
20
OMe I2, NaOMe
R
B 2
R
MeOH
R2
21
selected products:
n
Pr
Cy
nPr
nPr
21a; 74 % yield
>99:1 Z/E
nHex
nPr
Et
21b; 69 % yield
>99:1 Z/E
nHex
21c; 62 % yield
>99:1 Z/E
21d; 68 % yield
>99:1 Z/E
Scheme 7 Synthesis of Z-alkenes from vinyl borinic esters
A more general approach to the iodination of vinyl
borinic esters was later reported by Brown and co-workers
(Scheme 7).17 In this case, non-symmetrical vinyl borinic
esters 20 were obtained by hydroboration of alkynes with
alkylbromoboranes followed by methanolysis of the resulting bromoborane intermediates 19. Addition of sodium
methoxide and iodine led to alkene products 21a–d in good
yields and very high levels of Z-selectivity.
2.3
O
B
R1
R2Li
O
Et2O
22
Li
R1
O
B O
R2
23
I2
selected products:
R
Et
I2, NaOMe
TBSO
THF/MeOH
C5H11
TBSO
C5H11
27a
B(OMe)2
28a; 75 % yield
>96:4 Z/E
Et
I2, NaOMe
25
THF
Li
OTHP
24b; 65 % yield
Evans and co-workers’ strategy also began with formation of a vinyl boronate complex (Scheme 9).20 In contrast
to Matteson’s approach, this intermediate was accessed by
reacting E-vinyl lithium reagent 26a (prepared by lithium–
halogen exchange) with secondary alkyl boronic ester 25.
Treatment of the resulting vinyl boronate complex 27a with
iodine and sodium methoxide resulted in formation of
alkene 28a in 75 % yield (>96:4 Z/E). When a Z-vinyl lithium
precursor 26b was employed, alkene 28b was obtained in
58 % yield with very high E-selectivity. The flexibility derived from the ability to form identical vinyl boronate complexes by either reacting a vinyl boronic ester with an organolithium or a vinyl lithium with a boronic ester is a particularly appealing feature of the Zweifel olefination.
Brown and co-workers subsequently extended this
methodology to enable the synthesis of trisubstituted
alkenes (Scheme 10).17c,21 By reacting various trisubstituted
THF
26b
O
R2
Scheme 8 Zweifel olefination of vinyl boronic esters
B(OMe)2
OTHP
C5H11
O
B
Ph
Et
Et
I
1
Ph
C5H11
26a OTBS
anti
NaOH elimination
1,2-metallate
rearrangement
Me
24a; 30 % yield
Li
R2
24
iodination
nBu
Although the use of borinic esters significantly expanded the potential of the Zweifel olefination, there were still
significant problems with this approach, most notably associated with the high air sensitivity of the borane starting
materials. In contrast to boranes, boronic esters are air- and
moisture-stable materials which can be readily prepared
via a wide range of methods.18 Evans and Matteson independently recognized the potential of boronic esters as substrates for Zweifel olefination communicating independent
studies almost simultaneously.19,20
Matteson’s coupling process began with the synthesis of
a vinyl boronate complex 23 by addition of an organolithium reagent to a vinyl boronic ester 22 (Scheme 8).19 This intermediate was treated with iodine and sodium hydroxide,
resulting in iodination followed by 1,2-metallate rearrangement to form a β-iodoboronic ester which underwent anti
elimination to form the corresponding Z-alkene. This reaction could be carried out with alkyl or aryl lithium reagents
and the coupled products 24a and 24b were formed in
moderate to good yields.
R1
THF/H2O
IO
B O
R2
R1
Extension to Boronic Esters
I2, NaOH
B(OMe)2
Et
C5H11
THF/MeOH
OTHP
H11C5
27b
28b; 58 % yield
>99:1 E/Z
Scheme 9 Zweifel olefination of vinyl lithiums with boronic esters
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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R1
O
B
R1
R3Li
O
Li
Et2O
R2
29
selected products:
Ph
nBu
n
Bu
31a; 80 % yield
>97:3 E/Z
Short Review
R. J. Armstrong, V. K. Aggarwal
O
B
R2
30
O
R3
I2, MeOH
R1
then aq. NaOH
R2
31
Me
S
Cl
nBu
Ph
n
Bu
31b; 81 % yield
>97:3 E/Z
stereocontrolled synthesis of (+)-faranal (Scheme 11).23 In
this process, vinyl lithium was prepared in situ from tetravinyltin by tin–lithium exchange and was then reacted with
enantioenriched secondary boronic ester 32. The resulting
vinyl boronate complex was treated with iodine and sodium methoxide, thus promoting 1,2-metallate rearrangement and elimination affording alkene 33. This key intermediate was directly subjected to hydroboration and oxidation to provide alcohol 34 in 69 % yield with very high
diastereoselectivity. Oxidation with PCC completed the synthesis of (+)-faranal in 76 % yield.
It was subsequently shown that the vinyl lithium approach could be also be applied to the enantiospecific coupling of trialkyl tertiary boronic esters (Scheme 12, a)24 and
benzylic tertiary boronic esters25 (Scheme 12, b). It is noteworthy that in these cases despite the sterically congested
nature of the boronic ester starting materials, the coupled
products were obtained in excellent yields. The double vinylation of primary–tertiary 1,2-bis(boronic esters) has also
been achieved using this approach (Scheme 12, c).26 Using
four equivalents of vinyl lithium, diene 37 was obtained in
77 % yield.
R3
nBu
Me
n
Me
Bu
31c; 76 % yield
31d; 64 % yield
>97:3 E/Z
(with i PrMgCl); >97:3 E/Z
Scheme 10 Zweifel olefination of trisubstituted vinyl boronic esters
vinyl boronic esters (29) with organolithium nucleophiles,
a range of products was prepared in good to excellent
yields. Notably, heteroaromatic groups could be introduced
(in 31b) and alkyl Grignard reagents could be used in place
of organolithium reagents (in 31d).
The methods shown in Schemes 8–10 represented a significant advance upon the early work on the Zweifel olefination of boranes and borinic esters. However, at the time
the potential of the method was not fully realized owing to
the paucity of methods available for the preparation of boronic esters. Consequently, only a handful of studies involving Zweifel olefination were published over the following
three decades.22 In recent years, the huge increase in methods available for the enantioselective synthesis of boronic
esters has led to a renaissance in chemistry based upon the
Zweifel olefination. Several new studies into the process
have been reported along with elegant reports employing
Zweifel olefination in total synthesis. These results are described in the following sections.
3.1
(a) Synthesis of α-(tertiary trialkyl) alkenes
nBu
Et
PMP
Me
ii. I2, NaOMe, THF/MeOH
Me
PMP
Ph
PMP
Me
37; 77 % yield
Me
B(pin)
32
Me
PCC
Me
Me
Me
Me
R
Me
(+)-faranal; 76 % yield
Li THF
B(pin)
i.
Li Et2O/THF
B(pin)
ii. I2
iii. NaOMe, Et2O/THF/MeOH
THF/Et2O
ii. I2, THF/Et2O/MeOH
iii. NaOMe
Me O
i.
Ph
Scheme 12 Applications of Zweifel olefination with vinyl lithium (prepared from tetravinyltin); PMP = p-methoxyphenyl; e.s. = enantiospecificity
Li
Me
Me
35; 72 % yield
100 % e.s.
(c) Synthesis of dienes
Me
Me
nPr
36; 92 % yield
100 % e.s.
i. R
hexanes
nBu
Li Et2O/THF
ii. I2
iii. NaOMe, Et2O/THF/MeOH
Me B(pin)
PMP
The introduction of a vinyl group into a target molecule
is commonly required in synthesis owing to the prevalence
of this motif in natural products and as a valuable handle
for further functionalization. The first report describing the
introduction of an unsubstituted vinyl group by Zweifel olefination was published by Aggarwal and co-workers in their
nBuLi
Me
(b) Synthesis of α-(tertiary benzylic) alkenes
Introduction of an Unsubstituted Vinyl Group
Sn
i.
B(pin)
nPr
OH
R
Me
33
i. 9-BBN
ii. H2O2/NaOH
Me
34; 69 % yield
94:6 d.r.
Scheme 11 Introduction of an unsubstituted vinyl group with vinyl lithium: stereoselective synthesis of (+)-faranal; R = (CH2)2CHCMeEt; pin = pinacolato
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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Syn thesis
Vinylation under Zweifel conditions represents a powerful strategy for the synthesis of alkenes. However, the necessity of preparing vinyl lithium in situ from the corresponding toxic stannane or volatile vinyl bromide detracts
from the appeal of the process. In contrast, stable THF solutions of vinylmagnesium chloride or bromide are commercially available.27 Aggarwal and co-workers have studied
the Zweifel olefination of tertiary boronic ester 38 with vinylmagnesium bromide in THF.25 Monitoring the reaction
by 11B NMR spectroscopy revealed that with one equivalent
of vinylmagnesium bromide, the expected vinyl boronate
complex 39 was not observed and instead a mixture of unreacted boronic ester 38 and trivinyl boronate complex 40
was formed (Scheme 13). The latter species originates from
over-addition of vinylmagnesium bromide promoted by the
high Lewis acidity of the Mg2+ counterion. Upon addition of
an excess of vinylmagnesium bromide (4 eq.), trivinyl boronate complex 40 was obtained exclusively, and after addition of I2 followed by NaOMe, the coupled product 41a was
obtained in good yield. These conditions were successfully
applied to the synthesis of a series of benzylic tertiary substrates 41a–d. The reaction is ineffective at forming very
hindered alkenes such as 36, although this product could be
synthesized efficiently with vinyl lithium.
MgBr
B(pin)
(1.0–4.0 eq.)
Et
Ph
THF
Me
O
B O
Et
Ph
Me
39
δ B = 5–8 ppm
not observed
38
δ B = 32 ppm
MgBr
B
Et
Me
40
δB = –13 ppm
Ph
O
O
Mg
I2, THF/MeOH
then NaOMe
eq. RMgBr
ratio 38/40
yield 41a
1.0
70:30
26 %
4.0
0:100
66 %
Ph
Et
Me
41a
selected examples:
Ph
Et
Me
Short Review
R. J. Armstrong, V. K. Aggarwal
Ph
Me
41a; 66 % yield 41b; 79 % yield
100 % e.s.
100 % e.s.
PMP
Et
Me
Et
Me
Cl
41c; 62 % yield
100 % e.s.
41d; 79 % yield
100 % e.s.
PMP
Ph
Me
36
not observed
PMP
Me
R
solvent
42
δ B = 35 ppm
ratio 42/43/44
yield 45a
1.0
THF
>67:0:<33
37 %
4.0
THF
0:0:100
96 %
1.2
1:1 THF/DMSO
0:100:0
89 %
B
or
Me
R
43
δ B = 8 ppm
solvent
eq. RMgCl
Me
44
δ B = –13 ppm
I2, NaOMe
THF/MeOH
R
Me
45a
selected examples:
Me
NBoc
PMP
OTBS
Me
45a; 89 % yield
100 % e.s.
45b
78 % yield
45c
95 % yield
CO2Et
45d
74 % yield
45e
68 % yield
Scheme 14 Zweifel olefination of boronic esters with vinylmagnesium
chloride in THF/DMSO; R = (CH2)2PMP
ceeds effectively with a range of primary, secondary and aromatic boronic esters. Notably, the use of the mild Grignard
reagent allows chemoselective coupling to occur in the
presence of reactive functional groups such as carbamates
(in 45b) and ethyl esters (in 45d). Although good yields of
product were obtained with unhindered tertiary boronic
esters (in 45e), in general, the Zweifel vinylation of tertiary
boronic esters is best achieved either with four equivalents
of vinylmagnesium halide in THF or with vinyl lithium.
In summary, there are currently three methods available to introduce an unsubstituted vinyl group by Zweifel
olefination (Scheme 15). For aromatic, primary and unhindered secondary boronic esters, the desired boronate complex can be formed efficiently using 1.2 equivalents of vinylmagnesium halide in 1:1 THF/DMSO. For the majority of
tertiary boronic esters it is recommended to employ four
equivalents of vinylmagnesium halide in THF (to form the
trivinyl boronate complex), although with extremely hindered tertiary boronic esters, the best results are obtained
with vinyl lithium.
increasing steric hindrance
Scheme 13 Zweifel olefination of tertiary boronic esters with vinylmagnesium bromide in THF
R
B(pin)
B(pin)
B(pin)
ArB(pin)
Very recently, an improved procedure for coupling unhindered boronic esters with vinylmagnesium chloride has
been reported (Scheme 14).28 As with tertiary boronic esters, it was observed that addition of vinylmagnesium chloride to a THF solution of secondary boronic ester 42 resulted in over-addition to form trivinyl boronate complex 44.
However, if the reaction was carried out in a 1:1 THF/DMSO
mixture,29 over-addition was completely suppressed and
only mono-vinyl boronate complex 43 was obtained. After
addition of iodine and sodium methoxide, the coupled
product 45a was obtained in 89 % yield. This process pro-
O
B O
MgCl (1.0-4.0 eq.)
B(pin)
R
Me
MgX
(1.2 eq.)
1:1 THF/DMSO
R
R
R
B(pin)
B(pin)
R
R
Ar
R
R
MgX
(4.0 eq.)
THF
Ar
B(pin)
R
Ar
Li
(2 eq.)
THF
Scheme 15 Summary of the best methods for boronate complex formation for the Zweifel vinylation of various boronic esters; R = alkyl
group
3.2
Coupling of α-Substituted Vinyl Partners
In addition to the synthesis of alkyl-substituted alkenes,
the Zweifel olefination has also been applied to the cou-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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R. J. Armstrong, V. K. Aggarwal
the corresponding alkynes 50. Coupling of a wide range of
secondary and tertiary boronic esters was achieved in excellent yields with complete enantiospecificity.
In 2014, an interesting intramolecular variant of the
Zweifel olefination for the construction of four-membered
ring products was reported (Scheme 18).32 In this process,
51, which possesses both a boronic ester and a vinyl bromide, was treated with tert-butyllithium resulting in chemoselective lithium–halogen exchange followed by spontaneous cyclization to form cyclic vinyl boronate complex 52.
Upon treatment with iodine and methanol this species underwent stereospecific ring contraction to provide β-iodoboronic ester 53. Elimination of this intermediate gave exocyclic alkene 54 in 63 % yield. It is particularly noteworthy
that this challenging Zweifel olefination occurs in good
yield despite the highly strained nature of the exomethylene cyclobutene product.
pling of vinyl partners α-substituted with a heteroatom.
The coupling of lithiated ethyl vinyl ether 46 (readily prepared by deprotonation of ethoxyethene with tBuLi) with a
tertiary boronic ester proceeded smoothly to provide enol
ether 47, which was hydrolyzed under mild conditions to
form 48 (Scheme 16, a).25,30 This process represents a novel
method for the conversion of boronic esters into ketones.
This methodology has also been extended to the enantiospecific synthesis of vinyl sulfides (Scheme 16, b).28
A related strategy for the alkynylation of boronic esters
has recently been reported by Aggarwal and co-workers
(Scheme 17).31 In contrast to the successful alkynylation reactions of trialkyl boranes discussed previously (Scheme
5),12,13 boronic esters undergo reversible boronate complex
formation with lithium acetylides. This means that addition
of electrophiles does not result in coupling, but instead
leads to direct trapping of the acetylide and recovery of the
boronic ester. A solution to this problem was developed in
which vinyl bromides or carbamates were lithiated at the
α-position with LDA and then reacted with boronic esters
in a Zweifel olefination. Treatment of the resulting vinyl
bromides or carbamates with base (TBAF for bromides and
t
BuLi or LDA for carbamates) triggered elimination to form
3.3
Syn Elimination
Aggarwal and co-workers have reported a method for
the synthesis of allylsilanes through a lithiation–
borylation–Zweifel olefination strategy (Scheme 19).33 In
this process, silaboronate 56 was homologated with configurationally stable lithium carbenoids 55 to provide α-silyl-
(a) Synthesis of ketones from boronic esters
Et Me
i.
tBuLi
EtO
EtO
Li
(pin)B
46
Me
i.
n
BuLi·TMEDA
Ph
47
(b) Synthesis of vinyl sulfides
PhS
EtO
ii. I2
iii. NaOMe
THF/MeOH
THF
PhS
(pin)B
Li
aq.
NH4Cl
Et Me
Ph
Ph
Me
48; 66 % yield
100 % e.s.
Me
PMP
PhS
ii. I2, NaOMe
THF/MeOH
THF
Et Me
O
PMP
49; 91 % yield
100 % e.s.
Scheme 16 Synthesis of ketones and vinyl sulfides by Zweifel olefination
Br
R
B O
O
X
X
Li
or
R'
R'
O
B O
R
boronate complex
formation
direct
iodination
I2, MeOH
R'
TBAF for X = Br
for X = OCb
tBuLi
R
selected examples with X = OCb:
Me
Me
50a; 81 % yield
100 % e.s.
I + R–B(pin)
50
selected examples with X = Br:
Me Ph
I2
R
elimination
Ph
Li
R–B(pin)
X = Br, OCb
Zweifel
olefination
Li CbO
CO2tBu
2
50b; 68 % yield
100 % e.s.
Ph
Me
Me
50c; 89 % yield
100 % e.s.
Ph
Me
Cl
50d; 87 % yield
100 % e.s.
Scheme 17 Alkynylation of enantioenriched boronic esters; Cb = C(O)NiPr2
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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Short Review
R. J. Armstrong, V. K. Aggarwal
boronic esters 57, which were then subjected to Zweifel
olefination to obtain allylsilane products 58. Notably, it was
necessary to carry out the Zweifel olefination without sodium methoxide owing to the instability of the allylsilane
products under basic conditions. The substrate scope of the
process was wide and a range of allylsilanes was prepared
in high yields and with excellent levels of enantioselectivity.
Interestingly, with a hindered α-silylboronic ester, E-crotylsilane 58d was obtained as a single geometrical isomer, but
Z-crotylsilane 58c was formed in slightly reduced selectivity (95:5 Z/E).
To rationalize the reduced selectivity observed in the
formation of Z-crotylsilane 58c, it was postulated that as
the boronic ester becomes more hindered, the transition
state for anti elimination becomes disfavored due to a steric
clash between the bulky R1 and R2 substituents (Scheme
20). This allows the usually less favorable syn elimination
pathway to compete, resulting in the formation of small
amounts of the E-isomer.
Similar behavior has been observed in the Zweifel olefination of hindered secondary boronic esters with alkenyllithiums (Scheme 21).34 As the boronic ester becomes more
sterically encumbered (for example, benzylic or β-
anti
elimination
R1
B(pin)
H
2
R
R1
H
R2
I
I
Z-alkene
B(pin)
R1
R2
I B(pin)
syn
elimination
R2
H
R1
H
R2
R1
E-alkene
Scheme 20 Rationalization for reduced Z/E selectivity with bulky
boronic esters
branched), increasing formation of the E-isomer was observed, up to 90:10 Z/E in the case of menthol-derived
alkene 60c.
Bn
B(pin)
R1
R2
Li
(pin)B
R1
THF
R2
59
Me
Me
Ph
H
60a; 81 % yield
TBSO
100 % e.s.; 96:4 Z/E
Bn
H
R1
THF/MeOH
selected examples:
Bn
Me
Bn
I2, NaOMe
Bn
H
H
Me
R2
60
Me
3
iPr
Me
H
60b; 67 % yield
>95:5 d.r.; 92:8 Z/E
Bn
Me
60c; 64 % yield
>95:5 d.r.; 90:10 Z/E
Scheme 21 Reduced Z/E selectivity with bulky boronic esters
MeO
Me
Br
B(pin)
Me
boronate complex
formation
Me
tBuLi
Li
THF
Me
Ar
51
52
iodination
MeO Me
elimination
1,2-metallate
rearrangement Me
Ar
Me
I
Ar
(pin)B
Me
54; 63 % yield
100 % e.s.
In these cases, Aggarwal and co-workers have shown
that iodine can be replaced with PhSeCl resulting in the formation of β-selenoboronic esters (Scheme 22).35 Because
the selenide is a poorer leaving group than the corresponding iodide, treatment of these intermediates with sodium
methoxide led exclusively to anti elimination providing the
coupled products 60a–c as a single Z-isomer in all cases.34
It was also demonstrated that β-selenoboronic esters
(obtained by selenation of vinyl boronate complexes) could
be directly treated with m-CPBA resulting in chemoselective oxidation of the selenide to give the corresponding
selenoxide (Scheme 23, a).34 A novel syn elimination then
occurred in which the selenoxide oxygen atom attacked a
boron atom instead of a hydrogen atom, providing E-
B
(pin)
Ar
B(pin)
I2
THF/MeOH
I
B
(pin)
53
Scheme 18 Construction of an exomethylene cyclobutene by an intramolecular Zweifel olefination; Ar = 2-MeO-4-MeC6H3
R1
sBuLi·(–)-sp
Li·(–)-sp Si–B(pin), 56
Et2O
R
OCb
lithiation
selected examples:
R
OCb
55
borylation
B(pin)
R2
R
THF, then
I2, THF/MeOH
Si
57
68-69 % yield
Me
R2
Li
R1
R
Si
58
Me
Me
Me
Si
Ph
58a; 84 % yield
97:3 e.r.; >96:4 Z/E
Si
Ph
58b; 94 % yield
97:3 e.r.; >96:4 E/Z
Si
iPr
58c; 80 % yield
96:4 e.r.; 95:5 Z/E
Si
iPr
58d; 80 % yield
96:4 e.r.; >96:4 E/Z
Scheme 19 Synthesis of allyl- and crotylsilanes via a lithiation–borylation–Zweifel olefination strategy; Si = SiPhMe2; (–)-sp = (–)-sparteine
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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Short Review
R. J. Armstrong, V. K. Aggarwal
Bn
B(pin)
R1
R2
Li
(pin)B
R1
THF
R2
ii. NaOMe
THF/MeOH
59
1,2-metallate
rearrangement
anti
elimination
R1
Bn
R1
R2
60
NaOMe
SePh
(pin)B
R2
(pin)B
Bn
R2
SePh
selected examples:
H
Me
Bn
Me
Me
R1
selenation
PhSeCl
Bn
i. PhSeCl, THF
Bn
Ph
Me
3
H
iPr
Me
60c; 55 % yield
>95:5 d.r.; >98:2 Z/E
60b; 70 % yield
>95:5 d.r.; >98:2 Z/E
H
Bn
Me
H
H
TBSO
60a; 63 % yield
100 % e.s.; >98:2 Z/E
Bn
Me
Scheme 22 Highly Z-selective olefination of sterically hindered boronic esters
(a) Syn elimination of β-selenoboronic esters
Li
R2
R1—Bpin)
R2
(pin)B
i. PhSeCl, THF
R1
THF
R1
R2
ii. m-CPBA, THF
syn
elimination
selenation;
1,2-migration
PhSeCl
R1
R1
R2
m-CPBA
SePh
oxidation
(pin)B
R2
(pin)B
O
SePh
(b) Stereodivergent olefination
R2
R1
61
Bn
R3
i. tBuLi
ii. R3–B(pin)
R2
iii. I2, NaOMe
or PhSeCl, NaOMe
Me
Me
PMP
Br
R1
Bn
i. tBuLi
ii. R3–B(pin)
iii. PhSeCl
iv. m-CPBA
Me
Me
PMP
2
R2
Me
PMP
2
R3
R1
62
2
Me
PMP
2
Me
Me
61a; 80 % yield
62a; 74 % yield
61b; 95 % yield
62b; 83 % yield
>98:2 Z/E; 100 % e.s. >98:2 E/Z; 100 % e.s. >98:2 Z/E; 100 % e.s. 96:4 E/Z; 100 % e.s.
OTBS
TBDPSO
Me Me
61c; 48 % yield
98:2 Z/E; >95:5 d.r.
OTBS
Me
TBDPSO
OPMB
Me
OPMB
Me Me Me Me
62c; 52 % yield
98:2 E/Z; >95:5 d.r.
Scheme 23 Stereodivergent olefination of boronic esters
alkenes with high selectivity. In conjunction with the
Zweifel olefination (or its PhSeCl-mediated analogue) this
represents a stereodivergent method where either isomer
of a coupled product can be obtained from a single isomer
of vinyl bromide starting material (Scheme 23, b). The substrate scope of both processes is broad and a range of diand trisubstituted alkenes was prepared including 61c
which represents the C9–C17 fragment of the natural product discodermolide.
In some cases, the ability to carry out syn elimination of
β-iodoboronic esters is also desirable. For example, very recently Aggarwal and co-workers reported a coupling of cy-
clic vinyl lithium reagents with boronic esters (Scheme
24).28 In this case, the cyclic β-iodoboronic ester intermediates 63 cannot undergo bond rotation and therefore must
undergo a challenging syn elimination. It was found that
this elimination could be promoted by adding an excess of
sodium methoxide (up to 20 eq.). Using this methodology, a
range of five- and six-membered cycloalkene products 64
were prepared in high yields and with complete stereospecificity, including glycal 64b and abiraterone derivatives
such as 64c.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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Short Review
R. J. Armstrong, V. K. Aggarwal
Since the pioneering studies on Zweifel olefination reported by Evans and Matteson, the method has been significantly developed such that a wide range of functionalized
alkene products can now be obtained. The final section of
this short review showcases selected examples where
Zweifel olefination has been used in complex molecule synthesis.36
sis was the vinylation of the bridgehead tertiary boronic ester in 68. Formation of the trivinyl boronate complex with
excess vinylmagnesium bromide in THF followed by addition of iodine and sodium methoxide produced alkene 69,
which was employed without purification in a subsequent
sequence of oxidative cleavage and Horner–Wadsworth–
Emmons olefination to form 70 in a yield of 67 % over four
steps.
Morken and Blaisdell have reported an elegant stereoselective synthesis of debromohamigeran E that employs a
Zweifel coupling of an α-substituted vinyl lithium (Scheme
27).39 Cyclopentyl boronic ester 72 was prepared from 1,2bis(boronic ester) 71 in 42% yield by a highly selective hydroxy-directed Suzuki–Miyaura coupling. This intermediate was then subjected to Zweifel coupling with isopropenyllithium (synthesized by Li–Br exchange) to form 73 in
93 % yield. Completion of the synthesis of debromohamigeran
E required four further steps including hydrogenation of the
alkene to an isopropyl group.
A short enantioselective total synthesis tatanan A was
reported by Aggarwal and co-workers, which employs a
stereospecific alkynylation reaction (Scheme 28).40 Boronic
ester 74 (synthesized by a diastereoselective Matteson homologation) was subjected to Zweifel olefination with lithiated vinyl carbamate. Treatment of the resulting vinyl carbamate 75 with LDA resulted in elimination to form alkyne
4 Zweifel Olefination in Natural Product
Synthesis
Aggarwal and co-workers recently reported an 11-step
total synthesis of the alkaloid (–)-stemaphylline employing
a tandem lithiation–borylation–Zweifel olefination strategy
(Scheme 25).37 Pyrrolidine-derived boronic ester 65 was
homologated with a lithium carbenoid to afford boronic ester 66 in 58 % yield and 96:4 d.r. A subsequent Zweifel olefination with vinyl lithium (synthesized in situ from tetravinyltin) gave alkene 67 in 71 % yield. Notably, these two
steps could be combined into a one-pot operation, directly
providing 67 in 70 % yield. The alkene was later employed in
a ring-closing-metathesis–reduction sequence to form the
core 5-7 ring system of (–)-stemaphylline.
A recent formal synthesis of the complex terpenoid natural product solanoeclepin A has been reported by Hiemstra and co-workers (Scheme 26).38 A key step in this synthei. R—B(pin), THF
Li
X
ii. NaOMe (3-20 eq.)
I2, THF/MeOH
n
n = 0,1
selected examples:
Me
OTIPS
O
B(pin)
X
I
n
R
n
63
64
Me
PMP
64b
TIPSO
49 % yield
TIPSO >95:5 d.r.
64a
98 % yield
100 % e.s.
syn
elimination
R
X
Me
PMP
O
PMP
H
H
TBSO
64d
79 % yield
100 % e.s.
H
64c
86 % yield
Scheme 24 Synthesis of cycloalkenes via a challenging syn elimination
one-pot tandem lithiation–borylation–Zweifel olefination; 70 % yield
SiO
Me
OTIB
SiO
i.
Li
Et2O/THF
Me H
Li·(–)-sp
(pin)B
N
Boc
65
Et2O then
CHCl3, reflux
(pin)B
N
Boc
66; 58 % yield
96:4 d.r.
ii. I2
iii. NaOMe
THF/Et2O/MeOH
SiO
Me H
N
Boc
67; 71 % yield
O
O
Me
Me
steps
H
N
(–)-stemaphylline
Scheme 25 Stereocontrolled synthesis of (–)-stemaphylline; Si = TBDPS; TIB = 2,4,6-triisoproylbenzoyl
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
K
Syn thesis
Short Review
R. J. Armstrong, V. K. Aggarwal
MgBr
(4 eq.)
Me
B(pin)
H
O
O
TBSO
i. I2
THF/MeOH
Me
B
H
O
THF
O
TBSO
OBn
Me
O
H
O
TBSO
69
ii. NaOMe
OBn
68
OBn
i. cat. OsO4, NMO
ii. NaIO4
CO2Et
iii. (EtO)2OP
NaH
OH
O
H
Me
O
CO2H
CO2Et
Me
steps
H
Me Me
O
H
O
TBSO
OMe O HO O
solanoeclepin A
OBn
70; 67 % (4 steps)
Scheme 26 Formal synthesis of solanoeclepin A
O
Me
(pin)B
(pin)B
Me
Me
OH
Me
Me
O
O
Me
O
OTf
Me
OTBS
Pd(OAc)2 (2.5 mol %)
RuPhos (3 mol %)
aq. KOH, THF/PhMe
then TBSCl
71
76 in 97 % yield with complete diastereospecificity. This
alkyne was converted into the trisubstituted alkene of
tatanan A in two further steps.
A collaborative study on the synthesis of ladderane natural products was recently published by the groups of Boxer,
Gonzalez-Martinez and Burns (Scheme 29).41 A key intermediate in these studies was the unusual lipid tail [5]-ladderanoic acid. This compound was prepared from mesoalkene 77 by a sequence involving copper-catalyzed desymmetrizing hydroboration (95 % yield, 90 % ee) followed
by Zweifel olefination with vinyl lithium reagent 79 (3:1
E/Z). It was found that carrying out the Zweifel olefination
with N-bromosuccinimide rather than iodine was critical to
achieve efficient coupling. Following silyl deprotection, the
coupled product 80 was obtained in 88 % yield as an inconsequential mixture of Z/E isomers. Hydrogenation of the
alkene followed by Jones oxidation of the primary alcohol
completed the first catalytic enantioselective synthesis of
[5]-ladderanoic acid.
(pin)B
Me
72; 42 % yield
Me
i.
Et2O
Li
ii. I2, Et2O/MeOH
iii. NaOMe
Me
Me
Me
Me
OH
CO2H
CO2H
steps
Me
Me
O
O
Me
OTBS
Me
Me
73; 93 % yield (2.1 g)
debromohamigeran E
Scheme 27 Enantioselective synthesis of debromohamigeran E
OMe
MeO
Li
OMe Et
OCb
Et
THF
OMe
Ar
B(pin)
MeO
OMe
Me
74
Et
OCb LDA
Ar
then I2
THF/MeOH
THF
Me
75
Ar
Ar
Me
76; 97 % yield
100 % d.s.
OMe
MeO
MeO
Et
Me
MeO
OMe
steps
OMe OMe
Me
tatanan A
OMe
OMe
Scheme 28 Total synthesis of tatanan A; Ar = 2,4,5-trimethoxyphenyl; d.s. = diastereospecifity
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
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Syn thesis
H H H H
Cu(MeCN)4PF6 (10 mol %) (pin)B
(R)-DM-SEGPHOS (11 mol %)
H H H H
B2(pin)2, NaOtBu,
MeOH/THF
H H H H
H H H H
78; 95 % yield; 90 % e.e.
77
i. 79, Et2O/THF
ii. NBS
iii. NaOMe
THF/Et2O/MeOH
iv. HF·pyr, THF
OTBS
Li
5
79 (3:1 E/Z)
O
OH
H H H H H
HO
Short Review
R. J. Armstrong, V. K. Aggarwal
i. H2, Ra-Ni
H H H H H
5
5
ii. CrO3/H2SO4
H H H H
[5]-ladderanoic acid
H H H H
80; 88 % yield
Scheme 29 Zweifel olefination in the synthesis of [5]-ladderanoic acid
Negishi and co-workers have employed a Zweifel olefination in the synthesis of the side chain of (+)-scyphostatin
(Scheme 30).42 In this case, a boronate complex was formed
between vinyl boronic ester 81 (prepared in 7 steps from allyl alcohol) and methyllithium. After addition of iodine and
NaOH followed by silyl deprotection, trisubstituted alkene
82 was obtained in 76 % yield. The very high stereoselectivity obtained in this reaction (>98:2 E/Z) is particularly noteworthy and represents a significant improvement upon
previous synthetic approaches toward this fragment.
Me
i. MeLi, Et2O,
ii. I2, MeOH
Me
Me
Me
OTBS
B(pin)
81
Me
Me
Me
Me
OH
Me
iii. aq. NaOH
iv. TBAF
82; 76 % yield
>98:2 E/Z
OH O
Me
Me
Me
Me
steps
HO
Me
NH
(+)-scyphostatin
O
O
Scheme 30 Construction of the side chain of (+)-scyphostatin
(EtO)2OPO
OMe
OBOM
HO
Me
O
Me
Fifty years have passed since the first report by Zweifel
and co-workers on the iodine-mediated olefination of vinyl
boranes. Since then, this process has evolved into a robust
and practical method for the enantiospecific coupling of
boronic esters with vinyl metals. Recent contributions have
significantly expanded the generality of the process, enabling the efficient coupling of a wide range of different
alkenyl partners and allowing increasingly precise control
over the stereochemical outcome of the transformation.
Rapid progress in enantioselective boronic ester synthesis
combined with the extensive applications of chiral alkenes
bode well for the continued development and application of
the Zweifel olefination in synthesis.
Me
CuCl (5 mol %)
Et
N
N
(5 mol %)
PF6
Et
Ph
O
CO2H
5 Conclusions and Outlook
B2(pin)2, KOtBu, THF
Me
Me
Hoveyda and co-workers have employed a similar strategy to synthesize the antitumor agent herboxidiene
(Scheme 31).43 In this case, Z-vinyl boronic ester 83 was
prepared as a single stereoisomer by a Cu-catalyzed borylation–allylic substitution reaction. Boronic ester 83 was then
converted into trisubstituted alkene 84 in a Zweifel olefination with methyllithium. The resulting alkene was obtained
as a single E-isomer in 70 % yield and could be converted
into herboxidiene in five steps.
A stereocontrolled synthesis of (–)-filiformin has been
reported by Aggarwal and co-workers involving an intramolecular Zweifel olefination (Scheme 32).32 Intermediate
85 (synthesized in high stereoselectivity by lithiation–
borylation) was converted into cyclic boronate complex 86
by in situ lithium–halogen exchange. Addition of iodine and
methanol brought about the desired ring contraction to
provide exocyclic alkene 87 in 97 % yield. Deprotection of
the phenolic ether followed by acid-promoted cyclization
and bromination completed the synthesis of (–)-filiformin.
Me
Me
OMe
Me
Me
herboxidiene
OH
OMe
(pin)B
Me
Me
Me
OBOM
83; 76 % yield
>98:2 d.r.; >98:2 Z/E
i. MeLi, THF
ii. I2, THF/MeOH
OMe
steps
Me
Me
Me
Me
OBOM
84; 70 % yield
>98:2 E/Z
Scheme 31 Total synthesis of herboxidiene; BOM = benzyloxymethyl
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N
M
Syn thesis
Short Review
R. J. Armstrong, V. K. Aggarwal
MeO
Me
Br
B(pin)
Me
Me
tBuLi
MeO
Me
MeO
Me
Li
B(pin)
B(pin)
THF
Me
Me
Me
Me
85
86
Me
Br
Me
Me
O
I2
THF/MeOH
i. NaSEt
ii. TFA
iii. Br2
Me
MeO
Me
(-)-filiformin
Me
Me
87; 97 % yield
Scheme 32 Synthesis of (–)-filiformin via an intramolecular Zweifel olefination
Funding Information
We thank EPSRC (EP/I038071/1) and the European Research Council
(advanced grant 670668) for financial support.EPSRC
E(P0I/3871E)uropean
Resarch
Counlci
6(708)
Acknowledgment
We are grateful to Dr Eddie Myers and Dr Adam Noble for helpful discussions and suggestions during the preparation of this manuscript.
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