Oxidative heck vinylation for the synthesis of complex dienes and polyenes

Article abstract of DOI:10.1021/ja402891m

We introduce an oxidative Heck reaction for selective complex diene and polyene formation. The reaction proceeds via oxidative Pd(II)/sulfoxide catalysis that retards palladium-hydride isomerizations which previously limited the Heck manifold's capacity f

Full text of DOI:10.1021/ja402891m

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Communication
Oxidative Heck Vinylation for the Synthesis of Complex Dienes and Polyenes
Jared Heath Delcamp, Paul E Gormisky, and M. Christina White
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja402891m • Publication Date (Web): 23 May 2013
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Oxidative Heck Vinylation for the Synthesis
of Complex Dienes and Polyenes
Jared H. Delcamp,† Paul E. Gormisky‡ and M. Christina White*, ‡
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‡University of Illinois Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL 61801
†University of Mississippi, University, MS 38677
Supporting Information Placeholder
Table 1. Optimization of the Oxidative Heck Vinylation
ABSTRACT: We introduce an oxidative Heck reaction for selec-
O
S
Pd(OAc)2
1 (10 mol%)
O
tive complex diene and polyene formation. The reaction proceeds
via oxidative Pd(II)/sulfoxide catalysis that retards palladium-
hydride isomerizations which previously limited the Heck mani-
fold’s capacity for furnishing stereodefined conjugated dienes.
Limiting quantities of non-activated terminal olefins (1 equiv.)
and slight excesses of vinyl boronic esters (1.5 equiv.) that feature
diverse functionality can be used to furnish complex dienes and
polyenes in good yields and excellent selectivities (generally E:Z
= >20:1; internal:terminal = >20:1). Because this reaction only
requires prior activation of a single vinylic carbon, improvements
in efficiency are observed for synthetic sequences relative to ones
featuring reactions that require activation of both coupling part-
ners.
S
Ph
Ph
OMe
OMe
Bpin
+
Pent
R
Me2BQ (1.1 equiv)
AcOH (4 equiv)
DMF (2.0 M), 40 ˚C, 72 h
Pent
R
(1.5 equiv.)
(1.0 equiv.)
quinone
(equiv)
isolated
yielda,b
entry
R
solvent
1
2
3
4
5
6
7
8
9
16%
43%
49%
55%
40%
<5%
41%
9%
Bu 2
Bu
Bu
Bu
Bu
Bu
BQ (2.0)
THF (0.33 M)
THF (0.33 M)
THF (2.0 M)
DMF (2.0 M)
DMF (2.0 M)
DMF (2.0 M)
DMF (2.0 M)
DMF (2.0 M)
DMF (2.0 M)
2,6-Me2BQ (2.0)
2,6-Me2BQ (2.0)
2,6-Me2BQ (1.1)c
2,5-Me2BQ (1.1)
duroquinone (1.1)
2,6-Me2BQ (1.1)d
2,6-Me2BQ (1.1)e
2,6-Me2BQ (1.1)
Bu
Bu
Pentf
0%
a Average of 2 runs at 0.5 mmol. b >20:1 E:Z and >20:1 internal:terminal selectivities
determined by crude 1H NMR for all entries. For definition of selectivities, see SI.
cO2 atmosphere gave identical yield. d 1 µL H2O added.
No sulfoxide ligand.
e
f
Boronic acid in place of boronic ester.
Dienes and polyenes are of high synthetic interest due to their
frequent presence in medicinally relevant molecules and natural
products. Current synthetic strategies for accessing such motifs in
complex molecule synthesis involve carbonyl olefination reac-
tions or transition metal catalyzed cross-coupling reactions.1-3 All
of these methods share in common the requirement for using pre-
activated coupling partners. Such oxidized materials require sev-
eral steps for their installation and are often challenging to main-
tain throughout a synthetic sequence.4 Alternatively, the Heck
vinylation reaction enables direct formation of dienes from the
vinylic C—H bonds of abundant and relatively inert terminal
olefin substrates.5-8 Despite this potential, the Heck vinylation has
had limited cross-coupling applications in synthesis because the
scope is often limited to resonance activated olefins (e.g. α,β-
unsaturated car bonyls, stryenes, and enol ethers)8a,9 that are used
in excess (typically 3-5 equiv) and Pd-H isomerization limits its
applicability for the selective synthesis of stereodefined conjugat-
ed polyenes.10 Herein we report an oxidative Heck vinylation
under Pd(II)/sulfoxide catalysis that proceeds with limiting
amounts of non-resonance stabilized olefins in good yields and
excellent regio- and stereoselectivities to furnish complex diene
and polyene products. The streamlining potential4 of this reaction
in complex molecule synthesis is evaluated.
In 2004, our lab introduced electrophilic Pd(II)/sulfoxide
catalysis that has since proven itself to be a general reaction
manifold for allylic C—H esterifications, aminations, alkylations,
and dehydrogenations of terminal olefins.11 In 2006, we also dis-
covered Pd(II)/sulfoxide catalysis can alternatively promote oxi-
dative Heck arylations of non-resonance biased olefins with or-
ganometallic reagents, such as aryl boronic acids and aryl tri-
fluoroborate salts,12 under uniform and preparatively useful condi-
tions of fragment coupling quantities of valuable olefin (1.0
equiv.) and organoboron reagent (1.5 equiv.) required for efficient
application in complex molecule synthesis.13 Although styrenyl
boronic esters were effective coupling partners under these condi-
tions, attempts to utilize non-arylated vinyl boronic esters resulted
in modest yields (Table 1, entry 1). We hypothesized side reac-
tions with the benzoquinone oxidant could be problematic since
we have seen that insertion of the Pd-vinyl intermediate is favora-
ble with sterically accessible activated olefins. Accordingly,
changing the oxidant to the more sterically hindered 2,6-
dimethylbenzoquinone gave a significant increase in yield of
diene product (entry 2, 43%). Increasing both the molarity (0.33M
 2.0M, entry 2 to 3) of the limiting reactant and polarity (THF
 DMF, entry 3 to 4) of the solvent and lowering the equivalents
of oxidant (entry 4) led to an improvement in yield to 55%. Other
sterically hindered quinones (2,5-dimethylbenzoquinone or du-
roquinone, entries 5 and 6) provided lower or no reactivity, even
under these optimized conditions. Although reaction yields were
adversely affected by water, an oxygen atmosphere had no effect
(entries 7 and 4). Despite the known role of DMF as a ligand for
Previous work:
Oxidative Heck
O
O
R'
S
Pd(OAc)2 1
S
Ph
Ph
R
Ar
(HO)2B
(10 mol%)
or
or
X
(1)
Ar
R
H
+
BQ
R"
R
X
BPin
aryl or styrenyl
organoboranes
X
This work:
Oxidative Heck
O
O
S
Pd(OAc)2
(10 mol%)
S
Ph
Ph
1
R
H
R
alkyl
+
(2)
X
(
R'
)
m
2,6-DMBQ
alkyl
BPin
X
R'
m = 0-2
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Journal of the American Chemical Society
Page 2 of 5
oxidative Pd(II)-catalysis,6b,7b catalytic bis-sulfoxide ligand was
genic centers in the allylic position undergo vinylation with no
1
2
3
4
5
6
7
8
crucial for this reaction as Pd(OAc)2 under otherwise identical
conditions gave only 9% yield of diene (entry 8). Consistent with
our previous observations, less stable vinyl boronic acids were
unsuitable coupling partners for this reaction (entry 9). Notably,
in all cases, (E,E)-diene products were furnished as one regioiso-
mer (internal:terminal olefin ratios >20:1) in outstanding E:Z
selectivities (>20:1).
erosion in optical purity (entry 4). Although not a requirement for
high selectivities, resonance activated α-olefins also undergo
vinylation using only one equivalent of substrate (entries 5 and 6).
In addition to trans-disubstituted reagents, trisubstituted-vinyl
boronic esters couple smoothly (entries 7 and 8).14 Excitingly,
triene products are synthetically accessible in excellent selectivi-
ties and good yields by coupling dienyl boronic esters with simple
α-olefins (entry 9).
Table 2. Scope of the Oxidative Heck Vinylation
Examination of the olefin coupling partner showed that sub-
strates with allylic oxygen or nitrogen functionality, capable of
chelating to the palladium, provide excellent regio- and stereose-
lectivities (>20:1 internal:terminal and >20:1 E:Z) that are not
highly sensitive to the vinyl boron reagent (entries 1-10). Signifi-
cantly, as the functionality is transposed to the homoallylic or bis-
homoallylic positions, the regioselectivity of insertion (internal
versus terminal olefin products) remains >20:1; however, the
stereoselectivity (E:Z selectivity) decreases to 6:1 (entries 11 and
12). Previously, we had observed that Pd(II)/bis-sulfoxide cata-
lyzed oxidative Heck arylations provide uniformly high (>20:1)
stereoselectivity, irrespective of allylic substitution. This variance
may be due to the smaller size of the vinyl versus aryl group re-
sulting in higher rotational freedom prior to β-hydride elimina-
tion. Consistent with our previous observations, olefinic alcohols
do not give carbonyl compounds via palladium hydride mediated
migration of the double bond, a common feature of many other
1 (10 mol%)
Me2BQ (1.1 equiv)
AcOH (4 equiv.), 72hrs
R''
9
R''
BPin
+
R
R'
(1.5 equiv.)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
(1. 0 equiv.)
R'
% isolated
E:Zb
yieldc,d
producta
entry
OMe
79e
1
2
3
4
>20:1
>20:1
R = Pr
Bu
Pent
Pent
62
OAc
R
OMe
OMe
62f
50
3
4
>20:1
>20:1
5
TIPS
(+)-6
(-)-7
TBSO
OBz
( )n = 2
O
C11H23
5
>20:1
53
O
N
NBoc
Heck systems (entry 12).10e, Finally, unsubstituted aliphatic sub-
15
strates undergo oxidative Heck arylation with diminished regio-
and stereoselectivities (5:1 internal:terminal; 6:1 E:Z), poor direc-
tionality in β-hydride elimination (2:1 conjugated versus allylic
diene products) and low yields due to a loss in reactivity (entry
13).
O
O
O
6
7
>20:1
>20:1
66
71
8
9
OMe
Scheme 1. Streamlined Synthesis of the Macrolactin A C12-
C24 Segment
Pent
O
O
O
MeO
OBn
S
Pd(OAc)2
S
8
10:1
14:1
72
O
10
11
Ph
Ph
1
(10 mol%)
3.
1. (S,S)-Co(salen),
H2O, 44%
2. cyclohexanone,
PTSA, 86%
OMe
OMe
p-NO2PhCO2H;
K2CO3, MeOH
54%, 1.4:1 d.r.
H
O
9
52
54
O
O
Pent
Ph
Oct
4. PMBCl, NaH, 99%
H
16
17
NHBoc
Branched allylic
C—H oxidation
10
(-)-12 >20:1
(+)-13 6:1
O
O
Pent
S
Pd(OAc)2
S
Ph
Ph
1
(10 mol%)
O
OPMB
15
O
OPMB
O
O
11
51
5. Oxidative Heck,
51%
HO
HO
Bu
Bu
O
H
12
NHBoc
(+)-18
1 equiv.
6. K2CO3, MeOH;
TBDPSCl, 82%
(+)-20
54g
12
13
14
15
6:1
6:1
OAc
+
OTBDPS
42h,i
Bpin
Oct
Pent
(+)-19, 1.5 equiv.
aInternal:terminal and conjugated:allylic olefin isomer ratios are >20:1 unless
otherwise noted. See the SI for definition of selectivities. bSelectivities based on
crude 1H NMR unless otherwise noted. cAverage of 2 runs at 0.5 mmol scale.
dGenerally 20-30% olefin starting material remained by crude 1H NMR leading to
overall reaction mass balances of 80-90%. The boron coupling partner was
generally completely consumed, possibly due to protodeboronation under the
acidic reaction conditions. e20:1 internal:terminal. f17:1 internal:terminal. g1.75
equiv BPin used. h2:1 conjugated:allylic and 5:1 internal:terminal. i40%
recovered starting material (81% mass balance).
This route: 9 steps, 5% yield
Previous route: 22 steps, 1% yield
(3 steps, 15:1 E:Z,
62% yield)
The ability of the Pd(II)/sulfoxide-catalyzed Heck vinylation to
operate stereoselectively with broad scope using fragment cou-
pling levels of substrates enables the streamlining potential of this
powerful cross-coupling reaction to be explored in the synthesis
of medicinally relevant complex diene targets. Macrolactin A, a
scarce marine macrolide with potent antiviral properties, has three
diene moieties embedded in its 24-membered macrocyclic ring.16
The synthesis of the C16,C18 (E,E)-diene segment, has been pre-
viously achieved via Stille and Sonogashira cross-couping17
methods as well as Julia olefination/elimination sequences.18 We
envisioned that an oxidative Heck vinylation approach would be
highly efficient, in part because of the relative ease of accessing
functionalized, optically enriched α-olefin building blocks. Utiliz-
ing the HKR reaction,19 the C12-C13 diol was readily accessed
from epoxy hexene 16 in high enantiomeric purity (99% ee). Ex-
Examination of the boron component indicated a wide range of
aliphatic vinyl boron reagents couple under these optimized con-
ditions. Vinyl boronic esters substituted in the allylic position
with both alkyl and oxygen moieties are excellent coupling part-
ners (Table 2, entries 1 and 2). Interestingly, bulkier vinyl boron
reagents afford diene products in higher yields than unsubstituted
reagents, presumably by slowing homo-coupling pathways. Eth-
ylene triisopropylsilyl (TIPS) boronic ester coupled in synthetical-
ly useful yields to give the ethylene homologated TIPS product 5,
which is amenable to further cross-couplings upon activation
(entry 3). Optically enriched compounds substituted with stereo-
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ploiting the allylic C—H bond, the C15 alcohol was directly in-
olefin (+)-24 and the pinacol boronate (E,E,Z)-triene 25 using the
stalled via Pd/sulfoxide-catalyzed allylic esterification.11b Synthe-
Pd(II)/sulfoxide-catalyzed oxidative Heck transform (Scheme 3).
Members of the retinoid family of natural products are routinely
synthesized via coupling of pre-oxidized fragments: classically
via olefination/isomerization reactions and more recently through
stereoselective Suzuki and Stille cross-couplings.25 Because of
poor E:Z selectivities, the Heck vinylation has sparsely been used,
and only to assemble diene fragments. Excitingly, (+)-24 and 25
were coupled using the Pd(II)/sulfoxide-catalyzed oxidative Heck
to furnish the desired (E,E,E,Z)-tetraene DHR (+)-26 in a good
1
2
3
4
5
6
7
8
sis of the optically enriched olefin coupling partner (+)-18 pro-
ceeded in just 4 steps from commercial material. In contrast, syn-
thesis of the analogous alkyne coupling partner for the Sonaga-
shira route started with fully oxygenated chiral pool material that
required 9 steps for elaboration (see SI).17d The vinyl boronic
ester coupling partner (+)-19 was also generated efficiently (three
steps) via cuprate alkylation of (R)-propylene oxide followed by
cross-metathesis20 with commercial 1-propenylboronic ester. Oxi-
dative Heck coupling of (+)-18 and (+)-19 proceeded in 51%
yield and afforded the complex (E,E)-diene (+)-20 as one regio-
and stereoisomer. In total, the oxidative Heck route to reported
C12-C24 segment (+)-20 of macrolactin A proceeded in only 9
steps and 5% overall yield. This compares favorably to the previ-
ously reported Sonagashira route that proceeded in 22 steps and
1% overall yield.
1
9
yield and as a single stereoisomer (no Z-isomer detected by H
NMR). The excellent stereoselectivities, preservation of optical
purity for proximal stereogenic centers, and tolerance for unpro-
tected alcohols supports a mechanism where a Pd-H intermediate
is very short-lived. To the best of our knowledge, this example
represents the longest polyene synthesized highly stereoselective-
ly via the Heck vinylation.10a
The Pd(II)/sulfoxide-catalyzed oxidative Heck vinylation reac-
tion offers an alternative cross-coupling strategy for the genera-
tion of dienes and polyenes that requires pre-activation of only
one vinylic partner. The ability to use fragment coupling quanti-
ties of olefin (1 equiv) and vinyl borane (1.5-2 equiv) and the
suppression of Pd-H isomerization pathways are novel features of
this method that make it amenable to furnishing E-dienes and
polyenes in complex molecule settings.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Streamlined Synthesis of the Amphidinolide C C17-
C29 Segment
Oxidative Heck
O
O
S
S
Ph
Ph
1
Pd(OAc)2
OSEM
OSEM
H
H
(10 mol%)
H
H
O
O
H
Bpin
PMBO
PMBO
(-)-22
(-)-21
19 (2 equiv.)
69% yield
>20:1 E:Z
1.0 equiv.
>20:1 int.:term.
ASSOCIATED CONTENT
OH
H
H
O
Supporting Information. Experimental procedures and charac-
terization of compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
O
(+)-23
Amphidinolide C
C-17 - C-29 segment
AUTHOR INFORMATION
Amphidinolide C is a cytotoxic 25-membered macrolide with
two diene units embedded within the structure.21 We envisioned
that our oxidative Heck methodology would allow an efficient
synthesis of (E,E)-trisubstituted diene (+)-23, a precursor to the
amphidinolide B C17-C29 fragment. Starting from an α-olefin
intermediate (-)-21 and a commercial vinyl boronic ester, the
Pd(II)/sulfoxide-catalyzed oxidative Heck furnished (E,E)-
trisubstituted diene (-)-22, a precursor to the C17-C29, in a single
step with 69% yield as one regio- and stereoisomer. The previous-
ly reported route to a similar fragment proceeded via a traditional
Julia olefination/sodium amalgam elimination sequence. An anal-
ogous α-olefin precursor was used; however, the Julia olefination
route required 7 steps, including oxidation state and functional
group manipulations, for installation of the (E,E)-trisubstituted
diene (See SI).22
Corresponding Author
white@scs.uiuc.edu
ACKNOWLEDGMENT
M.C.W. acknowledges the NIH/NIGMS (2R01 GM076153B) and
generous gifts from Boehringer Ingelheim and Bristol-Myers
Squibb for financial support. The ACS division of organic chem-
istry is thanked for providing J.H.D. with an ACS Graduate Stu-
dent Fellowship. P.E.G. is the recipient of an NSF Graduate Re-
search Fellowship. We thank Dr. A. Young for checking the ex-
perimental procedure in Table 2, Entry 4.
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1, 999.
(2) Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am.
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Scheme 3. Synthesis of a Highly Conjugated Retinoid
OH
Oxidative Heck
RO
H
O
O
OH
11
S
S
OH
(+)-24
1 equiv
Ph
Ph
1
(3) (a) Bräse, S.; de Meijere, A. Metal-Catalyzed Cross-
Coupling Reactions; de Meijere, A.; Diederich, F., Ed; Wiley-
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kin Trans. 1 1991, 8, 1941.
Pd(OAc)2
(10 mol%)
RO
10
OH
+
Me2BQ, AcOH,
DMF, 40oC
51% yield
>20:1 E:Z
Bpin
>20:1 int.:term.
R = 4-MeOBz
25
1.5 equiv.
13R,14R-dihydroxyretinol
derivative (+)-26
From the outset, we anticipated that higher order polyene prod-
ucts like (+)-26 would be synthetically accessible in excellent
selectivities using the Pd(II)/sulfoxide catalyzed oxidative Heck
vinylation (Table 2, entry 9). Palladium-H isomerization, which
generally limits the stereochemical integrity of Heck vinylations,
is retarded under these mild, oxidative conditions.10,23 We envi-
sioned that the complex tetraene fragment of 13,14-
dihydroxyretinol (DHR), a biologically active metabolite of vita-
min A,24 could be retro-synthesized into optically enriched α-
(4) (a) Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C.
Org. Lett. 2005, 7, 223. (b) Covell, D. J.; Vermeulen, N. A.;
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1
2
3
4
5
6
7
8
8217. (c) Stang, E. M.; White, M. C. Nat. Chem. 2009, 1, 547.
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son, P.; von Schenck, H.; Larhead, M. J. Org. Chem. 2004, 69,
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M. J. Org. Chem. 2007, 72, 7957. (f) Cho, C. S.; Uemura, S. J.
Orgmet. Chem. 1994, 465, 85.
(7) For examples of oxidative Heck vinylations see: (a) Yoo, K.
S.; Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384.
For a limited examples with simple olefins see: (b) Du, X.; Sugu-
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(9) Gürtler, C.; Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107.
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9
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13
14
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31
32
33
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39
40
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(23) The LPdH(OAc) intermediate should be short-lived under
these highly oxidative conditions [LPdH(OAc) + AcOH ⇌
LPd(0) + 2AcOH + BQ → LPd(II)(OAc)2 + DHQ]. For an im-
portant study on Pd-H in Heck reactions, see ref. 10d.
(24) Retinoids: The Biochemical and Molecular Basis of Vita-
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Springer-Verlag: Heidelberg, Germany, 1999; Chapter 3.
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de Lera, A. R. Tetrahedron 1995, 51, 2435. Stille Coupling: (b)
Alvarez, S.; Alvarez, R.; de Lera, A. R. Tetrahedron: Asym. 2004,
15, 839. Hiyama Coupling: (c) Montenegro, J.; Bergueiro, J.; Saá,
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Graphic Entry for the Table of Contents (TOC)
1
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5
Oxidative
Heck reaction
O
O
S
Pd(OAc)2
S
OH
·
Ph
Ph
OR
OH
RO
6
1 equiv
OH
7
8
9
OH
+
>20:1 E:Z
>20:1 int.:term.
R = 4-MeOBz
pinB
13R,14R-dihyroxyretinol
derivative
10
11
12
13
14
15
16
17
18
19
20
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27
28
29
30
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41
42
43
44
45
46
47
48
49
50
51
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53
54
55
56
57
58
59
60
1.5 equiv
5
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