Ni-Catalyzed Cross-Electrophile Coupling for the Synthesis of Skipped Polyenes

Article abstract of DOI:10.1021/acs.orglett.9b01019

Skipped polyenes featuring high (E)-selectivity and varying methyl substitution patterns are synthesized using a nickel-catalyzed cross-coupling reaction between allyl trifluoroacetates and vinyl bromides. The utility of this cross-electrophile coupling i

Full text of DOI:10.1021/acs.orglett.9b01019

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ni-Catalyzed Cross-Electrophile Coupling for the Synthesis of
Skipped Polyenes
Catherine P. McGeough,† Alexandra E. Strom,†,‡ and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
S
* Supporting Information
ABSTRACT: Skipped polyenes featuring high (E)-selectivity
and varying methyl substitution patterns are synthesized using
a nickel-catalyzed cross-coupling reaction between allyl
trifluoroacetates and vinyl bromides. The utility of this
cross-electrophile coupling is showcased in part by the
synthesis of the RST fragment of the marine ladder polyether, maitotoxin. Construction of this fragment is particularly
challenging due to the alternating methyl substitution pattern.
kipped polyenes featuring various methyl substitution
patterns are commonly found in biologically active natural
S
products with anticancer, antibacterial, and antiviral proper-
ties.1 These molecules can also provide efficient entry to the
fused cyclic ether skeletons of marine ladder polyether natural
products by way of epoxide ring opening cascade reactions.2a
Given their significance, researchers have developed a
number of individualized syntheses2 of skipped polyenes as
well as more generalized methods, but those are limited by
particular substitution and unsaturation patterns. The Trost
group, for example, recently reported the ruthenium-catalyzed
synthesis of 1,3,6-trienes via the coupling of propene with two
alkyl-substituted alkynes (Figure 1a).3a The Micalizio lab,
alternatively, demonstrated a titanium-mediated coupling
reaction of vinylcyclopropanes and alkynes to generate 1,4-
dienes and 1,4,7-trienes (Figure 1b).3b
Herein, we describe a more flexible approach to polyene
synthesis that proceeds via the Ni-catalyzed cross-electrophile
coupling of activated allyl alcohol 3 with vinyl bromide 4
(Figure 1c). Linear polyenes, including those that display a
variety of methyl substitution patterns, are readily accessed
with high (E)-selectivity while tolerating a free alcohol group.
Among the polyenes synthesized using this strategy is the all-
linear (E)-pentaene 7, which we use to prepare the RST
fragment of the ladder polyether natural product, maitotoxin,
via an epoxide opening cascade reaction (Figure 1d).2,4
Few examples of Ni-catalyzed cross-electrophile reductive
couplings between allyl and sp2 electrophiles are described in
the literature, and those that are described provide mixtures of
branched products, linear (E)-products, and linear (Z)-
products.5 To achieve high linear (E)-selectivity, our aim was
to limit alkene isomerization by choosing coupling partners
that react quickly under mild conditions and have excellent
cross-selectivity. While there are other metals that catalyze allyl
vinyl couplings,6 we were inspired by the Gong group5b who
reported the Ni-catalyzed coupling of aryl halides and allyl
acetates (Figure 2a). We thus began our investigations by
applying similar reaction conditions to the coupling of vinyl
Figure 1. Skipped polyene syntheses by the (a) Trost and (b)
Micalizio groups. (c) Proposed polyene synthesis described herein.
(d) Synthetic plan for the RST fragment of maitotoxin via pentaene 7.
bromide 9 and compound 8 featuring allyl acetate (8a), allyl
pivalate (8b), and allyl trifluoroacetate (8c) activating groups
(Figure 2b). Nickel(II) bromide (10 mol %) and 2,2-
bipyridine (10 mol %) served as the catalyst and ligand,
respectively, while zinc acted as the metal reductant. The
addition of magnesium chloride and pyridine to the reaction
mixture was found to be essential as similarly noted by the
Gong group.5b While each of the three Ni-catalyzed reactions
examined provided only the desired linear coupled products
10/11 (i.e., no branch product), the highly reactive 8c
Received: March 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01019
Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters
Letter
additional improvement in product yield (∼63%) without
affecting the (E)-selectivity. Notably, decreasing the equiv-
alents of manganese from 4.0 to 2.0 had little impact (Table 1,
entries 7 and 8). Although we observed near exclusive (E)-
selectivity, the yield of this transformation was not improved
beyond 63% until we noted the dramatic impact of the reaction
stir rate as a result of the heterogeneity of the manganese
reductant. Reaction stir rates of ∼600 rpm, for example,
consistently provided product yields of approximately 50−
60%, whereas a stir rate of 945 rpm led to an 86% product
yield (Table 1, entry 9). Increasing the stir rate beyond 945
rpm had no additional effect.
As shown in Table 2, we then examined the scope of the
vinyl halide coupling partners using the optimized conditions
Table 2. Coupling of 8c with Vinyl Halides 12−20 under
a
Optimized Conditions
Figure 2. (a) Allyl−aryl coupling conditions developed by the Gong
group. (b) Effect of the activating groups of 8 on product (E)-
selectivity.
provided the best (E)-selectivity (10:11, E:Z, 95:5).
1
Examination of the H NMR spectrum of the crude reaction
mixture revealed complete consumption of 8c but the
formation of homocoupled and hydrolyzed side products,
thereby accounting for the low yield of 10/11 (20%).7
Accordingly, we next conducted optimization studies to
further improve the reaction outcome. Because we observed a
slight increase in the yield of 10/11 (23%) upon doubling the
equivalents of nickel(II) bromide and 2,2-bipyridine (i.e., from
10 to 20 mol %) under otherwise identical conditions shown in
Figure 2b, we maintained the use of this higher catalyst and
ligand loading throughout our optimization studies. As shown
in entries 1−4 of Table 1, decreasing the reaction time from 6
to 1 h and the reaction temperature from 60 to 40 °C
significantly enhanced the product (E)-selectivity (>99:1) and
yield (40%). Utilizing manganese rather than zinc as the
reductant (entries 5 and 6) and increasing the equivalents of
vinyl bromide 9 from 2.0 to 3.0 (entries 6 and 7) provided an
a
Table 1. Optimization of the Coupling between 8c and 9
9
reductant
(equiv)
T
t
stirring rate
(rpm)
yield (%)
(10:11)
entry (equiv)
(°C) (h)
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
Zn(s) (2.0)
Zn(s) (2.0)
Zn(s) (2.0)
Zn(s) (2.0)
Zn(s) (4.0)
Mn(s) (4.0)
Mn(s) (4.0)
Mn(s) (2.0)
Mn(s) (2.0)
60
60
60
40
40
40
40
40
40
6
3
1
1
1
1
1
1
1
600
600
600
600
600
600
600
600
945
23% (96:4)
32% (97:3)
30% (97:3)
40% (>99:1)
41% (>99:1)
52% (>99:1)
63% (>99:1)
62% (>99:1)
86% (>99:1)
a
Yields are determined via NMR using 1,3,5-trimethoxybenzene as an
b
internal standard. Reaction time of 30 min.
established in entry 9 of Table 1. We found that vinyl bromides
substituted at the α position (entries 1, 2, and 6−8) resulted in
moderate to good yields of the corresponding products (56−
87%). Vinyl halides with α,β-substitution (entries 3 and 4), β-
substitution (entry 5), and β,β-substitution (entry 9) provided
a similar product yield range (48−72%).
a
Yields are determined via NMR using 1,3,5-trimethoxybenzene as an
internal standard.
B
DOI: 10.1021/acs.orglett.9b01019
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Next, we explored a range of allyl trifluoroacetate coupling
partners (Table 3). Both di- and trisubstituted allyl
marine biotoxin class of natural products and has been
reported to exhibit anticancer activity.8 The synthesis of the
RST fragment is particularly challenging due to its alternating
methyl substitution pattern and 6−7−6 ring structure. While a
previous synthesis of the QRSTU ring fragment of maitotoxin
was reported by the Nicolaou group in 2010, they found the
installation of the alternating methyl substituents to be
cumbersome and challenging.9
Table 3. Coupling of Vinyl Bromide 16 or 9 with Allyl
a
Electrophiles 29−34 under Optimized Conditions
As presented in Scheme 1, we commenced the synthesis of
pentaene 7 by activating known compound 41 with trifluoro-
Scheme 1. Synthesis of Pentaene 7
acetic anhydride. After aqueous workup, 42 was immediately
coupled with vinyl bromide 43 to furnish the desired product
44 in 46% yield. Notably, the use of 4,4′-dimethoxy-2,2-
bipyridine in this coupling reaction minimized hydrolysis of
the trifluoroacetate electrophile. Alcohol 44 was then trans-
formed to alkyl bromide 45 and coupled to vinyl bromide 46
using a Negishi cross-coupling reaction.10 Although we
attempted to synthesize 48 from alcohol 44 using a nickel-
catalyzed cross-electrophile coupling methodology, we could
obtain only inseparable E/Z mixtures of the desired product.
Following the formation of 47, the primary alcohol was then
deprotected and activated to generate 49. A final coupling
reaction under our developed nickel-catalyzed conditions
provided the desired pentene 7.
a
Yields are determined via NMR using 1,3,5-trimethoxybenzene as an
internal standard.
As illustrated in Scheme 2, a Sharpless epoxidation followed
by Shi epoxidation was next implemented to chemoselectively
and enantioselectively oxidize four of the five alkenes of
trifluoroacetates (entries 1−3) were coupled with vinyl
bromide 16 without observing isomerization in low to
moderate yields (12−46%). In addition to the desired product,
we observed both homocoupling and hydrolysis of the
trifluoroacetate starting materials, which accounted for the
lower yields in some of these reactions. Trisubstituted allyl
trifluoroacetates 32 and 29 coupled with vinyl bromide 9 in
good yields (entries 4 and 5, 52−61%). Interestingly, nerol 32
isomerized when coupled with vinyl bromide 9 to give linear
(E)-product 10 (entry 4). Due to the incomplete isomerization
of 33 and 34 during the coupling to 9, we observed E/Z
product mixtures as shown in entries 6 and 7.
Scheme 2. Epoxidation of Pentaene 7 Followed by a
Tetraepoxide Opening Cascade for the Formation of the
RST Fragment of Maitotoxin 1
To further demonstrate the utility of this cross-electrophile
coupling reaction, we implemented it in the construction of
pentaene 7. This intermediate was then used to synthesize the
RST fragment of maitotoxin via an epoxide opening cascade
reaction (Figure 1d). Maitotoxin is a member of the polyether
C
DOI: 10.1021/acs.orglett.9b01019
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L.; Bernhardt, P.; Nam, S.; Loesgen, S.; Ruby, J.; Skewes-Cox, P.;
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subsequently activated by forming the corresponding tert-butyl
carbonate 6. The final tetraepoxide opening cascade reaction
was then initiated in the presence of the BF3·OEt2 catalyst at
−40 °C.4 Following acetylation of the secondary alcohol, RST
fragment 1 of maitotoxin was obtained. To the best of our
knowledge, this is the first tetraepoxide opening cascade that
has been performed to synthesize a natural product fragment
containing both six- and seven-membered rings.
In conclusion, we have demonstrated the Ni-catalyzed cross-
electrophile coupling of activated allyl alcohols with vinyl
bromides as a general strategy for constructing skipped
polyenes displaying high (E)-selectivity. This method has
been applied to the synthesis of the all-(E), all-linear pentaene
7, which we have further shown is a viable precursor for the
synthesis of the challenging RST fragment of maitotoxin 1.
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ASSOCIATED CONTENT
* Supporting Information
1045.
■
(6) Seomoon, D.; Lee, K.; Kim, H.; Lee, P. Chem. - Eur. J. 2007, 13,
5197−5206.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01019.
(7) The use of dried versus nondried DMA did not affect the
amount of hydrolysis observed, so we suspect that the hydrolysis of
the starting material is catalyzed by reagents in the reaction.
(8) (a) Nicolaou, K.; Aversa, R. Isr. J. Chem. 2011, 51, 359−177.
(b) Nicolaou, K. C.; Heretsch, P.; Nakamura, T.; Rudo, A.; Murata,
M.; Konoki, K. J. Am. Chem. Soc. 2014, 136, 16444−16451.
(9) Nicolaou, K. C.; Gelin, C. F.; Seo, J. H.; Huang, Z.; Umezawa, T.
J. Am. Chem. Soc. 2010, 132, 9900−9907.
Experimental procedures and spectral data for polyenes
10, 21−28, and 35−40 and compounds 42−51, 7, 6,
and 1 (PDF)
AUTHOR INFORMATION
(10) Li, J.; Ballmer, S.; Gillis, E.; Fujii, S.; Schmidt, M.; Palazzolo, A.;
Lehmann, J.; Morehouse, G.; Burke, M. Science 2015, 347, 1221−
1226.
■
Corresponding Author
*E-mail: tfj@mit.edu.
ORCID
Timothy F. Jamison: 0000-0002-8601-7799
Present Address
‡A.E.S.: Department of Chemistry, Smith College, 100 Green
St., Northampton, MA 01063.
Author Contributions
†C.P.M. and A.E.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Institute of General Medical
Sciences for financial support (GM72566 and a fellowship to
A.E.S., GM117710). The authors also thank Liam Kelly
[Massachusetts Institute of Technology (MIT)] and Dr. Bruce
Adams (MIT) for their assistance in obtaining HRMS data and
NMR data, respectively. Lastly, the authors are very grateful to
Dr. Rachel L. Beingessner (MIT) for her help with the
preparation of the manuscript.
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DOI: 10.1021/acs.orglett.9b01019
Org. Lett. XXXX, XXX, XXX−XXX