Decarboxylative alkenylation

Article abstract of DOI:10.1038/nature22307

Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.

Full text of DOI:10.1038/nature22307

LETTER
doi:10.1038/nature22307
Decarboxylative alkenylation
Jacob T. Edwards1*, Rohan R. Merchant1*, Kyle S. McClymont1, Kyle W. Knouse1, Tian Qin1, Lara R. Malins1, Benjamin Vokits2,
Scott A. Shaw2, Deng-Hui Bao3, Fu-Liang Wei3, Ting Zhou3, Martin D. Eastgate4 & Phil S. Baran1
Olefin chemistry, through pericyclic reactions, polymerizations, when using the tetrachloro-N-hydroxyphthalimide (TCNHPI, com-
oxidations, or reductions, has an essential role in the manipulation mercially available) esters, an inexpensive Ni(ii) source, and the
of organic matter1. Despite its importance, olefin synthesis still abundant ligand 2,2′-bipyridine (bipy, L1). Using the piperidine-
relies largely on chemistry introduced more than three decades ago, derived redox-active ester (RAE) 6, cyclohexenylation could be
with metathesis2 being the most recent addition. Here we describe a achieved at room temperature with 10 mol% of Ni(acac)2•xH2O,
simple method of accessing olefins with any substitution pattern or 10 mol% bipy, and 2.0 equivalents (equiv.) of alkenylzinc reagent
geometry from one of the most ubiquitous and variegated building 7 to furnish olefin 8 in 75% isolated yield. As has been demonstrated
blocks of chemistry: alkyl carboxylic acids. The activating principles in previous work5–7, the RAE could also be generated in situ (entry 1
used in amide-bond synthesis can therefore be used, with nickel- or in the table of Fig. 1d) without any purification or even solvent
iron-based catalysis, to extract carbon dioxide from a carboxylic removal. TCNHPI appears to be the optimal RAE (entries 2 and 3),
acid and economically replace it with an organozinc-derived olefin and Ni(acac)2•xH2O proved superior to the more air- and moisture-
on a molar scale. We prepare more than 60 olefins across a range of sensitive NiCl2•glyme (entry 4). In general, most common solvents
substrate classes, and the ability to simplify retrosynthetic analysis were tolerated in this reaction (see Supplementary Information for
is exemplified with the preparation of 16 different natural products details). Alternative ligands were also screened, and L1 was chosen as
across 10 different families.
it is the least expensive (entries 5 and 6). Finally, as will be shown in
An analysis of available routes to olefin-containing sterol acetate 2a several cases, the Fe-based catalytic system developed previously for
points to retrosynthetic deficiencies that still exist (Fig. 1a). Seven con- RAE cross-coupling7,12,13 could be used as well (entry 7).
ventional steps are required to convert steroid derivative 1 to 2a (ref. 3),
The scope of this new decarboxylative alkenylation reaction is
only one of which forms a strategic C–C bond. The entire strategy is striking because all possible classes of olefin coupling partners could
built around the Wittig transform4, which requires redox-adjustment be employed with exquisite control of olefin geometry. The scope of
of the free carboxylate to the aldehyde, necessitating protecting-group alkenylzinc reagents that can be used in this coupling are exempli-
manipulations. By this route only steroid 2a is accessible, because fied in Fig. 2a, b. Simple mono-, di-, tri-, and tetra-substituted olefins
related methyl- and ethyl-containing sterol acetates (2b, 2c) would are easily accessible (9–12, 16, 17). From a strategic perspective, the
require more complex designs. The inefficiency of this sequence is a cycloalkenyl products (8, 13, 14) would be challenging to make in a
well known problem that has yet to be solved despite the attraction of more direct way from either the same starting material or even from
a hypothetical method that would directly convert acylated 1 to 2a.
a piperidone. The selection of which method to use when construct-
Although olefins have the most richly developed reactivity and ing an olefin (for example, Wittig or metathesis) is usually linked to
highest abundance (via the petrochemical industry), the diversity the underlying mechanism of the process to enable production of the
of alkyl carboxylic acid building blocks available is unmatched. If desired stereochemistry of the newly formed olefin. Decarboxylative
the aforementioned versatile olefin-based cross-coupling partners alkenylation divorces the C–C bond-forming event from such stere-
could be used in decarboxylative cross-coupling5–10, novel synthetic ochemical concerns. As such, conventional techniques can be used
pathways could be accessed. For example (Fig. 1b), one could envis- to produce the precise E or Z geometry of an alkenyl-organometallic,
age the total synthesis of diol-containing natural products such as which can then be used without any isomerization. For example, olefin
3 and 4 as arising from tartaric acid, perhaps the most inexpensive 12 is produced as a 1:1.5 mixture of E/Z isomers because the starting
chiral building block available. This new disconnection could only commercial Grignard reagent from which it was derived exists as a
be conceived in a decarboxylative fashion as the corresponding tar- mixture. Similarly, styrenyl derivative 15 could be procured with high
trate halides do not exist, and if they did, would most certainly not geometrical purity (>20:1 E/Z) as controlled by the starting alkenylzinc
be stable.
species (derived from lithium–halogen exchange of the corresponding
Here we present the invention of a general, scalable, chemoselective styrenyl iodide). The power of stereocontrolled alkyne carbometallation14
method for decarboxylative alkenylation that exhibits broad scope can be coupled with this method to produce geometrically pure alke-
across a range of both olefin (from mono-substituted to fully substituted) nyl iodides. Alkenylzinc reagents derived therefrom (lithium–halogen
and carboxylic acid (primary, secondary and tertiary) coupling partners exchange/transmetallation) afford tri-substituted olefin products such
(>60 examples, Fig. 1c). Decarboxylative alkenylation dramatically as 18 and 24 that would be otherwise challenging to make in a single
simplifies retrosynthetic analysis11. To demonstrate this, total syn- step (in situ RAE) with complete stereopurity. One-pot alkyne hydro-
theses of sixteen natural products across ten different natural product zirconation/transmetallation15 can also be used to access stereodefined
families spanning a range of steroids, polyketides, vitamins, terpenes, E-olefins such as 20, 25 and 26. Despite the presence of low-valent
fragrances and prostaglandins are reported and directly compared to Ni-species, butadiene-containing products such as 21 do not inhibit the
prior syntheses (see Methods for more information).
reaction, and the E/Z ratio of the starting dienyl species is maintained.
The optimization of decarboxylative alkenylation is briefly sum- Experience from this laboratory has taught that cross-couplings at the
marized in Fig. 1d. In general, the reaction proceeded smoothly D-ring of a steroid can be challenging16; therefore the formation of
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. 2Discovery Chemistry, Bristol-Myers Squibb, 350 Carter Road,
Hopewell, New Jersey 08540, USA. 3Asymchem Life Science (Tianjin), Tianjin Economic-technological Development Zone, Tianjin 300457, China. 4Chemical Development, Bristol-Myers Squibb,
One Squibb Drive, New Brunswick, New Jersey 08903, USA.
*These authors contributed equally to this work.
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© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

RESEARCH LETTER
a
Decarboxylative alkenylation: strategic simpliꢀcation
Previous approach, 7 steps
c
Decarboxylative alkenylation: invention
O
R1
R6
R2
R3
Methylation
Reduction
Wittig
Acylation
R1
R2
This work
R5
OH
R6
Protection
Oxidation
Multiple steps
Deprotection
R = H
R3
R4
Oleꢀn
• Medicines
Activation;
Protecting groups
Redox-inefꢀcient
O
XZn
Alkyl acid
R5
• Catalyst [Ni] or [Fe]
• Direct-coupling
• One step
R
• Ubiquitous
• Inexpensive
• Building blocks
R4
Organometallic
Me
Me
Me
Me
• Natural products
• >60 examples
OH
Acylation
Me
Me
d
Optimization: cross-coupling of redox-active esters with alkenylzinc reagentsa
H
[Cross-coupling]
H
Me
Me
10 mol% Ni(acac)2•xH2O,
H
H
O
ZnCl
• 2 steps
•Redox-economic
• PG-free
2a: R = H
2b: R = Me
2c: R = Et
H
H
10 mol% L1,
THF:DMF, RT
+
OA*
Target
1
HO
AcO
TsN
6: A* from TCNHPI
TsN
8: 80%b (75%)c
7 (2 equiv.)
b
Stereo-enriched diol natural products from tartaric acid
Me Me
X
Yield (%)b
O
Entry
Deviation from above
X
X
O
O
In situ activationd
A* from NHPI
63c
42e
38e
66e
74e
66e
70f
1
2
3
4
5
6
7
HO
HO
N
Me
O
OH
A* = –At, in situ from HATU
NiCl2•glyme, L1
CO2R
[M]
EtO2C
CO2A*
Ni(acac)2•xH2O, L2
Ni(acac)2•xH2O, L3
Fe(acac)3, dppBz
O
Me Me
5a
O
X
3
Redox-active ester
from tartaric acid
(–)-cladospolide B
X = H, NHPI
X = Cl, TCNHPI
O
O
Catalyst [Ni]
[Cross-coupling]
R
R
Ph
Ph
Me
N+
Me
N
R
Me
O
Me Me
Me
Me
N
N
N
N
N
O
OH
O
O
X = Cl, Br,
I, OTs, and so on
PPh2
PPh2
N
L3
–PF6
R = H, L1
R = tBu, L2
OH
N+
O–
4
EtO2C
X
(+)-cladospolide C
N
5b
Unsuitable for cross-coupling
dppBz
HATU
Figure 1 | Development of Ni- and Fe-catalysed decarboxylative
alkenylation. a, Conventional route to sterol acetates (2a–2c). Red text
highlights inefficiencies in the traditional approach. Green text refers to the
carbon–carbon bond forming step in the synthetic sequence. b, Utilization
of previously unavailable electrophiles in cross-coupling reactions.
c, Decarboxylative alkenylation presents a potential solution. R1, R2 and
R3 from the carboxylic acid are coloured blue, and R4, R5 and R6 from
alkenylzinc reagent are coloured green. d, Optimization of decarboxylative
alkenylation. a0.1 mmol. bYield by 1H nuclear magnetic resonance (NMR)
analysis with CH2Br2 internal standard. c0.25 mmol scale, isolated.
d1.1 equiv. TCNHPI, 1.1 equiv. DIC, CH2Cl2 (0.2 M). e20 mol% [Ni] and
L (L1, L2, or L3), 3.0 equiv. alkenylzinc. f10 mol% [Fe], 12 mol% dppBz,
1.5 equiv. dialkenylzinc. See Supplementary Information for additional
details. PG, protecting group; [Fe], [Ni], general nickel or iron precatalyst;
CO2Et, ethyl ester; Ts, tosyl; X, halide; DIC, N,N′-diisopropylcarbodiimide;
acac, acetylacetonate; L, ligand; dppBz, 1,2-bis(diphenylphosphino)
benzene; THF, tetrahydrofuran; DMF, N,N-dimethylformamide;
RT, room temperature; tBu, tert-butyl; A*, activating group; NHPI,
N-hydroxyphthalimide; TCNHPI, N-hydroxytetrachlorophthalimide;
HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]
pyridinium 3-oxide hexafluorophosphate; glyme, 1,2-dimethoxyethane.
19 from the easily obtained alkenylzinc species bodes well for future commercially available (41, 52/53, 54, 56, 57 and 58/59) but very easily
applications in such contexts. prepared. In contrast, substantially fewer of these electrophiles are
Pioneering work from the Knochel group17 has provided robust available as a halide or an alcohol (from which a tosylate or halide
methods for generating vinylogous zinc reagents for use in cross- could be made), whereas some substrates would be unstable if they
coupling chemistry. These species could also be used in the decarboxyl- were obtainable (43–46, 49 and 51). This points again to the undeniable
ative sense (Fig. 2b) to furnish a range of functionalized building convenience of a cross-coupling that employs readily available starting
blocks that may be otherwise challenging to access. Both cis and trans materials. Amino-acid-derived (38, 42), α-oxy (43–46), benzylic (48,
alkenylzinc reagents can be prepared with high geometric purity, lead- 50, 51), fusidane-based (52, 53), and heterocycle-containing (55) acids
ing smoothly to 27 and 28. This method provides a complementary could be successfully transformed into olefins of various types. Even
strategy to olefin cross-metathesis18 to access such structures. It is also peptides (58, 59) with unprotected residues are competent coupling
worth noting that the alkenylzinc reagent for butenolide (29) has never partners under the reaction conditions. Efficient synthesis of naftifine
been prepared before. Cross-coupling using butenolides, a motif often (57), an antifungal pharmaceutical, was accomplished in high yield
found in natural products, as a nucleophile has only been accomplished with excellent selectivity. Amino-acid-containing substrates showed no
through a Stille-coupling of the corresponding stannylated species16. base-mediated erosion of enantiomeric excess (38, 42) or epimerization
The adducts with dimedone (30–37) represent an orthogonal pathway (58, 59), and benzylic acid 50 showed no loss of the aromatic bromide.
to Stork–Danheiser type adducts19 that, in some cases, would not easily Similarly, other known coupling partners in low-valent Ni-chemistry20,
be accessed (31, 32, 35). The magnesium bromide diethyl ether com- such as aromatic C–O (48, 51) and C–Cl (45) bonds, and hydrolytically
plex (MgBr2•OEt2) was found to be an essential additive for reactions sensitive phenol acetate esters (54), remained untouched. Lewis-basic
with alkenylzinc reagents derived from alkenyl iodides via lithium– heteroatoms are tolerated (55, 57), and a formal synthesis of
halogen exchange, direct zinc insertion of electron-withdrawn α,β- (β)-santalene could be accomplished in short order (addition of MeLi
unsaturated alkenyl iodides, and hydrozirconation/transmetallation to ketone 56 and elimination leads to the natural product)21.
of terminal alkynes. All alkenylzinc reagents were prepared as docu-
mented in Supplementary Information.
Secondary (60–69) and tertiary bridgehead (70) RAEs can be
easily alkenylated, as well, as shown in Fig. 2d. Of note here is that
Figure 2c outlines decarboxylative alkenylations using eighteen diastereoselective alkenylations can be predictably incorporated into
different primary carboxylic acids, only six of which were not synthesis plans, as demonstrated with substrates 64, 65, 68 and 69.
2
| N A T U R E | V O L 0 0 0 | 0 0 M O N T H 2 0 1 7
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LETTER RESEARCH
Cl
Cl
N
• α,β-unsaturated alkenylzinc
10 mol% Ni(acac)2•xH2O,
10 mol% L1,
reagents
R6
R1
R6
Cl
O
TCNHPI
R2
R3
• Stereoselective oleꢀnation
• No erosion of enantiomeric excess
• In situ activation
THF:DMF, RT
DIC, DCM
R1
R2
O
ClZn
+
O
R5
R5
OH
Cl
Cross-coupling
Activation
R1
R2
R3
R4
R4
Oleꢀn
• Solution phase peptides
• [Ni] and [Fe] catalysis
• Mole scale
O
O
(2.0 equiv.)
R3
Alkyl acid
1º, 2º and 3º acids
>60 examples
• Natural products and drugs
Alkenylzinc reagent
Redox-active ester
Isolated or in situ
Mono-, di- and tri-substituted
Me
a Alkenylzinc reagents
c
Primary acids
NHBoc
Me
Me
Me
Me
Me
OMe
R
TsN
TsN
TsN
Ph
BnO2C
38: (62%b)
10: (71%, 67%a,b, 49%d)
11: (90%, 82%a,b, 57%d)
9: (60%)
R
Me
39: R = Me (40%)
41: (53%a,b
)
1 mol (620 g) : 63%b,l
40: R = H (62%, 57%d)
Cl
Me
Me
Me
Ph
NHCbz
O
n
O
Me
TsN
TsN
TsN
BnO2C
12: (63%, 63%a,b
1:1.5 E:Zc
)
13: n = 1 (70%, 68%a,b, 62%d)
8: n = 2 (75%, 63%a,b, 66%d)
14: n = 4 (93%, 81%a,b
15: (55%e)
>20:1 E:Z
Me
Cl
O
Me
iPr
44: (61%)
45: (62%)
from 2,4-D (herbicide)
)
Ts
N
42: (53%a,m
)
43: (48%)
R
Me
nC6H13
OMe
OTBS
Me
Me
BnO
Me
TsN
Me
TsN
Me
O
Me
O
Me
46: (59%)
47: (61%a,n) >20:1 Z:E
Me
H
18: (80%e)
>20:1 E:Z
16: R = Me (74%f)
17: R = Et (48%f,g
)
Me
Me
H
H
MeO2C
O
48: (96%f,o
Me
Me
Me
TBSO
49: (62%e, 56%a,k
>20:1 E:Z
)
Me
Me
)
19: (92%f)
from isoxepac
R
Me
from
fusidic acid
TsN
20: (50%g,h
TsN
CO2Me
Me
Me
OMe
MeO
H
Br
AcO
Me
50: (42%f,o
)
)
21: (51%h, 49%a,g,i), >20:1 E:Z
52: (52%a,b
)
Me
>20:1 E:Z
Me
Me
OAc
Me
Me
Me
O
OH
Me
H
53: (61%a,b
)
51: (47%f,o
)
Me
AcO
TsN
TsN
TsN
Me
H
Me
Me
Me
24: (72%e, 68%a,k
>20:1 E:Z
)
Me
22: (86%e)
>20:1 Z:E
23: (85%e,j
>20:1 Z:E
)
54: (54%a,b
from α-CEHC
)
AcO
CO2Me
OTBS
Me
O
Me
56: (47%a,b
)
(β)-santalene
(formal synthesis)
TsN
25: (50%g,h), >20:1 E:Z
TsN
Me
55: (57%a,b
)
O
Me
Me
Ph
26: (61%g,h), >20:1 E:Z
N
Me
N
R
b α,β-unsaturated alkenylzinc reagents
O
O
Naftiꢀne
O
Me
O
H
N
(antifungal drug)
57: (70%e)
EtO2C
CO2Et
N
NH2
Et
N
H
O
>20:1 E:Z
Me
Me
O
NHAc
O
TsN
TsN
TsN
TsN
Ph
Secondary and
tertiary acids
d
Me
OH
27: (80%g,h
>10:1 Z:E
)
28: (65%g,h
>10:1 E:Z
)
29: (40%g,i
)
30: (41%f)
58: (47%p)
59: (28%p), >20:1 E:Z
O
O
O
O
65: (59%a,b
,
O
Me Me
Me
MeO
O
>20:1 d.r.)
60: (57%a,b
)
O
Me
R
R
O
O
O
Me
Me
Me
Me
Me
CO2tBu
Me
Me
31: (57%f)
Me
32: (45%f)
33: R = Ph (52%f)
34: R = Cl (78%f)
TsN
63: (71%)
N
Ts
O
Me
64: (43%a,b, 3:1 d.r.)
OR
61: (60%)
62: (69%)
R = 4-PhC5H4CO
O
O
O
O
CO2Me
Me Me
68: (52%a,b
>20:1 d.r.)
,
Me
iPr
Me
Me
O
O
Me
Me
Me
Me
O
Me
Me
Me
69: (52%a,b
>20:1 d.r.)
,
Me
CbzN
CbzN
MeO2C
R
Me
Me
35: (49%f)
36: (43%f)
37: (60%f)
66: (74%)
67: (41%)
70: (42%q)
e Radical ring-opening
OTBS
COTCNHPI
Cross-coupling
Cross-coupling
OTBS
Me
HO2C
41%e, >20:1 E:Z
56%a,e, >20:1 E:Z,
10:1 exo/endo
H
Me
71
72
73
74
O
O
Figure 2 | Substrate scope of decarboxylative alkenylation. The
MgBr2•OEt2. i20 mol% Ni/L, 5 equiv. alkenylzinc, 5 equiv. MgBr2•OEt2.
jAlkenylzinc derived from OBO-ester; see Supplementary Information
for the work-up details. k3 equiv. alkenylzinc, 3 equiv. MgBr2•OEt2. lSee
Supplementary Information for details regarding mole-scale reaction.
m4 equiv. alkenylzinc. n4 equiv. alkenylzinc, 4 equiv. MgBr2•OEt2. o10 mol%
NiCl2•glyme/4,4′-di-tBuBipy. pSee Supplementary Information for details
regarding peptide substrates. q20 mol% Ni/L, 5 equiv. alkenylzinc, NMP.
DCM, dichloromethane; OBO, 4-methyl-2,6,7-trioxa-bicyclo[2.2.2]
octan-1-yl; TBS, tert-butyldimethylsilyl; CEHC, carboxyethyl-
carboxylic acid component is shown in blue and the alkenylzinc reagent is
shown in green. a–d, Cross-coupling using various alkenylzinc reagents
(a, b) and different primary (c), secondary and tertiary (d) acids is
evaluated. Yields refer to isolated yields of products after chromatography
on SiO2. e, Probing the presence of intermediate radical species in the
decarboxylative alkenylation reaction. aIn situ activation. b3 equiv.
alkenylzinc. cAlkenylzinc derived from commercial Grignard, which
exists as a mixture of olefin isomers. d10 mol% Fe(acac)3, 12 mol% dppBz,
1.5 equiv. dialkenylzinc. e2 equiv. alkenylzinc, 2 equiv. MgBr2•OEt2.
fMeCN as solvent. g60 °C. h20 mol% Ni/L, 3 equiv. alkenylzinc, 3 equiv.
hydroxychroman; d.r.; diastereomeric ratio; 4,4′-di-tBuBipy,
4,4′-di-tert-butyl-2,2′-dipyridyl; NMP, 1-methylpyrrolidin-2-one.
0 0 M O N T H 2 0 1 7
| V O L 0 0 0 | N A T U R E | 3
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

RESEARCH LETTER
a Steroids
c
Chrysanthemates
Me Me
Previous route; 7 steps
Me
Me
1. CH2N2
4. CrO3
R
Me
Me
2. THP
3. LAH
5. Wittig
6. Deprotect
H
H
CO2H
Me
7. Ac2O (R = H)
Me
H
Me
O
O
Me
H
O
77
H
H
1. Ac2O, pyridine
H
H
caronic anhydride
(commercial)
2. Cross-coupling
AcO
2a: R = H, 54%
HO
2b: R = Me, 55%
2c: R = Et, 38%
1
Radical cross-coupling
2 steps
(–)-desmosterol acetate
Methanolysis;
31%
4 steps from hyodeoxycholic acid
>20:1 d.r. [Cross-coupling]
b Clerodane diterpenes
R
O
O
CO2H
Me
Me
Me
O
Me
Cross-
coupling
HO
H
H
Me
Me
Me
RO2C
76b: 42%
(–)-solidagolactone
76a: 51%, >20:1 E:Z
76c: 53%
(–)-annonene
78
(–)-kolavenol
Me
Me
trans-chrysanthemate
6 steps from
(–)-5-methyl Wieland
Miescher ketone
21 steps
Previous route
Radical
cross-coupling
8 steps
9 steps
Previous route; 6 steps (R = Et)
Radical cross-coupling
1 step (R = Me)
Me
Me
9 steps
9 steps
9 steps
Me
Me
75
Macrocyclic polyketides
d
OTBS
XZn
CO2Et
Me
HO
Zn
4 steps
4
2
Me
O
OH
81
Cross-
coupling
80
Me Me
Cross-
coupling
Me Me
3
O
HO
OH
O
O
2 steps
(–)-cladospolide B
O
O
TBSO
CO2Et
OH
OH
>20:1 d.r.
Hydrolysis
20% (3 steps)
>10:1 Z:E,
>20:1 d.r.
EtO2C
CO2Et
5
HO2C
CO2Et
L-(+)-diethyl tartrate
Me
82
Me
79
O
1 step
83
Previous route; 14 steps (Wittig; 1:5 Z:E)
(–)-iso-cladospolide B
O
Enantiomers
Iterative radical cross-coupling; 5 steps (6 steps LLS)
EtO2C
D-(–)-diethyl tartrate
20% (3 steps)
Me
EtO2C
CO2H
>10:1 E:Z,
>20:1 d.r.
EtO2C
CO2Et
Hydrolysis
Me
>20:1 d.r.
O
5
4 steps
OTBS
O
O
2 steps
O
O
O
OH
HO
OH
Cross-
Cross-
Me Me
coupling
coupling
OH
4
(+)-cladospolide C
Me Me
86
84
CO2Et
Me
Zn
XZn
4
OTBS
80
85
Phoracantholide
CO2Me
2
CO2Me
Cross-coupling
Me
e
Prostaglandins
O
nC5H11
O
OTBS
Me
ClZn
76%
>20:1 Z:E
O
Iterative radical cross-coupling
CO2H
4 steps from 90 (R = 4-PhC6H4CO)
ClZn
O
87
91
92
OTBS
O
Previous route
10–12 steps
(+)-PGF2α
HO
88
Cross-
Cross-
coupling
coupling
CO2H
Me
O
OH
2 steps
Oxidation
Hydrolysis
protection
>20:1 E:Z
>20:1 d.r.
>20:1 Z:E
O
RO
90
89
HO
35% (4 steps)
Corey lactone
93
OH
Radical
cross-coupling
3 steps (8 LLS)
Me
(commercial)
Previous route; (R = Ac) 8 steps (Wittig, HWE)
(–)-phoracantholide J
1. Asymmetric [H]
2. Methylation
3. Hydrolysis
f Aureonitol
h Lyngbic acid
(–)-aureonitol
Me
Me
O
O
[Cross-coupling];
deprotection
7 steps from
(+)-xylose
O
8
52%, 98%
ee
(3 steps)
O
O
OMe
9
32%, >20:1 E:Z
OH
HO2C
Me
Me
OTBDPS
Previous route; 14 steps (Julia–Kocienski; 2:1 E:Z)
g Tocotrienols
94
95
MeO
OH
Previous route; 3 steps
(Cross-metathesis; 9:1 E:Z)
100
(commercial)
101
Radical cross-coupling; 8 steps
[Cross-
coupling];
hydrolysis
51%
> 20:1 E:Z
Previous route; 9 steps
97: R = MOM, R′ = CHO
3 steps
6 steps
Me
α-tocotrienol
(Wittig, SN2)
Me
Me
(–)-lyngbic acid
Me
Me
RO
HO
Me
Me
HO
Me
CO2H
Me
Me
OMe
Me
O
R′
OH
Me
[Cross-coupling];
hydrolysis
O
Me
102
Me
Me
2 steps
96 (commercial)
Me
99
98: R = Ac, R′ = CO2H
Radical cross-coupling
4 steps
50%, > 20:1 E:Z
Radical cross-coupling; 3 steps (4 steps LLS)
Figure 3 | Total synthesis enabled by decarboxylative alkenylation.
a–h All decarboxylative alkenylations were performed with in situ
activation of the carboxylic acid. See Supplementary Information for
full synthetic details and schemes. LLS, longest linear sequence. HWE,
Horner–Wadsworth–Emmons; THP, tetrahydropyran; LAH, lithium
aluminium hydride; MOM, methoxymethyl; [H], reduction.
Spirocyclic substrates 66 and 67 are of interest to a medicinal chemis- alkenylation reaction, radical ring-opening experiments (Fig. 2e) were
try programme (Bristol-Myers Squibb); 67 highlights how ethylvinyl performed with 71 and 73, affording the corresponding ring-opened
ether (zincated) can be used in this coupling as an alternative to products 72 and 74, respectively.
Grignard/organolithium addition to an ester or Weinreb amide (see
Of the 65 substrates depicted in Fig. 2, several were also performed
Supplementary Information for further details and comparison). To with an in situ protocol (especially in cases where the RAE was not
probe for the intermediacy of radical species in the decarboxylative stable) or using an Fe-based system. Supplementary Information
4
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LETTER RESEARCH
contains a detailed troubleshooting guide and a graphical user tuto- new methodologies (Fig. 3e)23. The commercially available Corey
rial. The reaction has been field-tested at Bristol-Myers Squibb in many lactone (90) could be used in a four-step sequence wherein two steps
different contexts, and the robustness was demonstrated by conduct- are non-strategic (oxidation and one-pot hydrolysis/protection)
ing the reaction of 38 on the mole scale (63% yield, >600 g, >99% and two install the key C–C bonds with the proper olefin geometry.
enantiomeric excess, carried out at Asymchem). As a testament to the Thus, sequential decarboxylative cross-coupling of E-(91) and Z-
robustness of this reaction, no substantial modifications to the general (92) alkenylzinc species to the requisite carboxylic acids provides a
procedure were necessary when scaling this reaction up from the simple route not only to 93 but is also conceivably sufficiently flexi-
millimole to the mole scale. At present, there are not many obvious ble to access many new prostaglandin analogues in a combinatorial
limitations for this method given that one can generally expect a fashion.
serviceable yield across a range of substrates; there are relatively more
limitations in the chemistry of preparing the alkenylzinc species.
Aureonitol (95) is a tetrahydrofuran-containing natural product
discovered in 1979 from Helichrysum aureonitens (Fig. 3f)24. A stra-
To illustrate a few of the vast number of ways to apply this new tegic decarboxylative dienylation of 94 delivers 95 in 32% yield with
transformation, Fig. 3 summarizes the total synthesis of fifteen dif- complete selectivity (>20:1 E/Z) as controlled by the chemistry used to
ferent natural products (full details of these sequences can be found in fashion the diene nucleophile. Application of this transformation sim-
Supplementary Information). As mentioned above (Fig. 1a), steroidal plifies the synthesis because 94 can be made in seven simple steps from
substrate 2a exemplifies the inefficiency of previous approaches to inexpensive (+)-xylose25,26. Tocotrienols, members of the vitamin E
olefin synthesis as a consequence of chemoselectivity issues sur- family, are dietary supplements and have been reported to have an array
rounding the Wittig reaction and the incorrect oxidation state of the of beneficial health effects (Fig. 3g)27. Current extraction methods from
starting material (1). With decarboxylative alkenylation (Fig. 3a), the plant materials provide these compounds as a mixture, which is both
same starting material can be used and the desired product 2a can difficult and costly to separate. Synthesis offers direct access to specific
be accessed in two steps. Of note is that the current method can be members of the tocotrienol family but contemporary efforts lack
used to make not only 2a but also related sterol acetates that would be selectivity in olefin formation or require concessionary redox manip-
otherwise inaccessible (in a direct fashion) such as 2b and 2c.
ulations. Trimethylhydroquinone (96) can be employed to furnish
The clerodane diterpene family consists of over 650 members that 99 with high selectivity (>20:1 E/Z) and in only four steps overall since
are broadly characterized as having a decalin framework appended to the farnesyl group can be directly coupled as a single fragment. Lyngbic
side chains with variegated substituents22. From a strategic perspective, acid (102), an inhibitor of quorum sensing in cyanobacteria, was pre-
it would be ideal if a single starting material could be used and diver- pared by Noyori asymmetric hydrogenation28 of the commercial β-keto
gently converted to multiple family members using a single reaction ester 100 followed by decarboxylative cross-coupling delivers 102 with
type. Decarboxylative alkenylation enables the synthesis of the same complete selectivity (>20:1 E/Z) in 51% isolated yield (about 98% enan-
three natural isolates from 75, a material that is made in six steps from tiomeric excess).
readily available (−)-5-methyl Wieland–Miescher ketone. Thus, in only
Olefins are ever-present functional groups that are found naturally
nine steps from commercially available materials, a simple alkyne, an and in every sector of chemical science. Their rich and robust chemistry
iodobutenolide and a bromofuran served as organozinc precursors that make them integral to the planning, logic and reliable execution of
when coupled with 75, enabled access to (−)-kolavenol (76a), (−)- soli- multistep synthesis. This operationally simple method harnesses
dagolactone (76b), and (−)-annonene (76c), respectively.
the reliable and programmable synthesis of olefin-containing zinc
With decarboxylative alkenylation, one can access methyl trans- species and the unparalleled commercial availability and stability
chrysanthemate (78, Fig. 2c) from commercially available caronic anhy- of alkyl carboxylic acids to access olefins in a powerful new way.
dride (77), which after one-pot methanolysis and radical cross-coupling Numerous applications can be anticipated of both this method and
delivers 78 in 31% yield with excellent diastereoselectivity (>20:1).
the strategy it enables in the contexts of chemoselective fragment
Many applications of this methodology to polyketide synthesis can coupling (convergent synthesis), homologation (as an alternative to
be envisaged where the decarboxylative approach allows for innovative Wittig olefination and related transforms), and stereospecific olefin
uses of classic chiral building blocks in highly convergent ways. For installation.
example, tartaric acid is perhaps the cheapest enantiopure chemical
Online Content Methods, along with any additional Extended Data display items and
Source Data, are available in the online version of the paper; references unique to
these sections appear only in the online paper.
that can be purchased (about US$1 per mole) and represents an ideal
source of the 1,2-diol motif. The total syntheses of (−)-cladospolide
B (3), (−)-iso-cladospolide B (83), and (+)-cladospolide C (4) illus-
Received 23 December 2016; accepted 20 March 2017.
trate how both enantiomers of tartaric acid can be used like simple
Published online 19 April 2017.
‘cassettes’, modularly incorporated to complete syntheses that are not
only dramatically shorter than prior approaches but also more selective
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Acknowledgements Financial support for this work was provided by Bristol-
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Author Contributions J.T.E., R.R.M. and P.S.B. conceived the work. J.T.E.,
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assisted in writing and editing the manuscript.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial
interests. Readers are welcome to comment on the online version of the paper.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations. Correspondence and
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reagent (Fig. 3h)53
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Data availability. Data generated in this study is available in Supplementary
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