A Boron Alkylidene–Alkene Cycloaddition Reaction: Application to the Synthesis of Aphanamal

Article abstract of DOI:10.1002/anie.201705720

We describe an unusual net [2+2] cycloaddition reaction between boron alkylidenes and unactivated alkenes. This reaction provides a new method for the construction of carbocyclic ring systems bearing versatile organoboronic esters. Aside from surveying the scope of this reaction, we provide details about the mechanistic underpinnings of this process, and examine its application to the synthesis of the natural product aphanamal.

Full text of DOI:10.1002/anie.201705720

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Accepted Article
Title: A Boron Alkylidene-Alkene Cycloaddition Reaction: Application to
the Synthesis of Aphanamal
Authors: James Patrick Morken, Xun Liu, Timothy Maxwell Deaton,
and Fredrik Haeffner
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705720
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10.1002/anie.201705720
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COMMUNICATION
A Boron Alkylidene-Alkene Cycloaddition Reaction: Application
to the Synthesis of Aphanamal
Xun Liu, T. Maxwell Deaton, Fredrik Haeffner and James P. Morken*[a]
Abstract: We describe an unusual net 2+2 cycloaddition reaction
between boron alkylidenes and unactivated alkenes. This reaction
provides a new method for construction of carbocyclic ring systems
bearing versatile organoboronic esters. In addition to surveying the
scope of this reaction, we provide details about the mechanistic
underpinnings of this process, and examine application to the
synthesis of the natural product aphanamal.
of this process and examine the utility of this reaction in the
construction of the terpene-derived natural product aphanamal.
Scheme 1.
via:
B(pin)
B(pin)
NaOtBu
O
O
O
O
(1)
B
B
R1 B(pin)
R2
R1
C
Na
Geminal bis(boronates) are readily available reagents[ 1 ] that
engage in an array of functional group transformations under
catalytic[1b,g,i,j, 2 ] and non-catalytic[1e, 3 ] conditions. In recent
studies, it was found that metal-alkoxide-induced deborylative
alkylation (eq. 1, Scheme 1) of these compounds can be brought
about under mild conditions, even for relatively hindered
substrate pairings.[3b] Mechanistic investigations suggested that
these reactions proceed through the intermediacy of a boron-
stabilized carbanion (i.e. 3), a compound that is generated upon
Na
C
X
R2
R1 R2
R1 R2
1
2
3
4
carbanion
alkylidene
B(pin)
Ph
NaOtBu
X
R
(2)
R
B(pin)
B(pin)
6
Ph
This work:
(pin)B
E
5
(pin)B
E+
reaction of the bis(boronate)
1 with the metal alkoxide.
H
(3)
base
Ph
Ph
Spectroscopic study of the boron-stabilized carbanion revealed
significant p-bonding between the carbanionic carbon and the
three-coordinate boron center indicating that the anion can
alternately be represented as boron alkylidene structure 4, a
compound related to other[4] boron alkylidenes. To probe the
reactivity of the boron alkylidene, we examined deborylative
alkyation of bis(boronate) 5, a compound bearing a tethered
alkene. In the presence of an alkyl halide electrophile, alkoxide-
induced deborylation of 5 furnished alkylation product 6 without
involvement of the tethered olefin. In this manuscript, we report
that an alternate reactivity mode operates when the electrophile
is omitted from deborylation of alkene-containing substrates
such as 5: in this circumstance, a deborylative cyclization
7
8
Studies of the 2+2 reaction in eq. 3 began with the
observation that treatment of geminal bis(boronate) 5 with
sodium tert-butoxide furnished a small amount (13% yield) of
cyclopentane-containing product 9 (Figure 1). Notably, while the
cyclization product was formed in low yield, it was furnished as a
13:1 ratio of diastereomers. After optimization (see Supporting
Information, Table S1), it was determined that KOt-Bu gave
improved yield of the reaction product. It was also found that
while the reaction efficiency was higher in toluene solvent at
room temperature, when THF was employed as the reaction
reaction is observed that is consistent with
a net 2+2
cycloaddition between the tethered, unactivated alkene and the
boron alkylidene giving 7 (eq. 3).[5] After 14 hours, addition of an
electrophile furnishes 8. Overall, this unusual mode of reactivity
solvent, an efficient reaction and
a
higher level of
diastereoselectivity was generally observed. Subsequently, we
surveyed other substrates and electrophiles. As depicted in
Figure 1, when deborylative cyclization of 5 was followed by
]
results in net non-catalyzed carboboration[6 of an unactivated
alkene, a process that has some resemblance to hexenyllithium
and related cyclization reactions[7], but as far as we are aware,
does not find precedent in reactions of stabilized carbanion
equivalents. Importantly, this reaction provides a compound
with a new carbocyclic ring system and has the capacity to
establish three new stereocenters from simple precursor building
blocks. Herein, we describe mechanistic and synthetic features
addition of either D2O, NBS, or I2, electrophilic trap[ 8 of the
]
reaction intermediate occurred and delivered 10, 11, and 12,
respectively. It merits mention that relative to the example with
protic work-up, the diastereoselectivity in formation of
compounds 10-13 is considerably enhanced (>20:1 dr vs. 4:1 dr).
The enhanced diastereoselection in production of 10-13 relative
to 9 appears to result from protonolysis of the minor trans
diastereomer prior to addition of electrophile such that
electrophilic trap of the remaining cis isomer furnishes
isomerically-enriched product.[9] As noted in Figure 1, reactions
of other substrates show that a tethered styrene can also
engage in the reaction (product 15) and that with substitution on
the alkene, a third stereocenter can be generated with useful
levels of stereocontrol (product 16). Also of note, prospective
internally-coordinating Lewis bases such as benzyl ethers
[a]
X. Liu, T. M. Deaton, Prof. Dr. F. Haeffner, Prof. Dr. J. P. Morken
Department of Chemistry
Boston College
2609 Beacon Street, Chestnut Hill, MA USA
morken@bc.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201705720
Angewandte Chemie International Edition
COMMUNICATION
(product 14) and silyl ethers (18) are tolerated. Similarly,
substrates bearing substituents at the alkylidene center ranging
from large aliphatic groups (products 17, 19) to a simple proton
(20) provide cyclic products in reasonable yields and selectivity.
Lastly, a tethered diene engages in the reaction and furnishes
an internal alkene upon protic work-up (22→23).
to KOtBu in THF-d8 and the reaction followed by proton-
decoupled 13C NMR spectroscopy.[10] Over the course of the
reaction, the 13C resonance for the starting material (20.1 ppm;
broad due to the boron quadrupole) was replaced by a broad
resonance at 44.0 ppm (assigned to 25).[11] Upon quench of the
reaction mixture with H2O, the signal at 44.0 ppm was replaced
with a broad resonance at 38.5 ppm. In a second experiment,
reaction of 13C-labeled 26 (d = 114.0 ppm; sharp singlet)
furnished a new structure that exhibits a broad resonance at
26.9 ppm (assigned to 27). Addition of H2O to putative bicycle
27 furnishes a compound with a labeled methyl group resonating
at d = 18.0 ppm. The similar chemical shift and linewidth of
the labeled carbons in 25 and 27 is suggestive of a related
environment for both carbon atoms, a feature most readily
accommodated by the intermediacy of the boracyclic compound.
B(pin)
R
6
E
R
R
R
H
KOtBu (2 equiv)
E+
(pin)B
R
(pin)B
R
R
B(pin)
R
1-2 h
THF, 22
12 h
(0.2 M)
°C
R
R
R
R
(pin)B
(pin)B
(pin)B
H
D
Br
B(pin)
Ph
Ph
Ph
Ph
R
B(pin)
9: 52% yield
4:1 dr
10: 49% yield
>20:1 dr
11: 51% yield
>20:1 dr
To learn about the properties of the boron alkylidene/a-boryl
carbanion, the experiments in Figure 2B were conducted. First,
it was determined that deborylative alkylation of a non-racemic
secondary alkyl bromide (29) occurs stereospecifically,
furnishing 30 with inversion of configuration at the electrophilic
carbon atom. Thus, in the context of an alkyl halide substitution
reaction, the nature of the a-boryl carbanion is more consistent
with a two-electron nucleophile as opposed to a single electron
donor that undergoes alkylation by single-electron transfer to the
alkyl halide, followed by fragmentation and radical
combination.[12] In a second experiment, it was shown that a
cyclopropyl group attached to the boron-stabilized carbanion
center does not undergo fragmentation during the course of
deborylative cyclization (31→32).[13] While these experiments
suggest that the boron-stabilized carbanion does not have a
proclivity to react by single-electron-transfer pathways, the
concerted carbometallation pathway by which hexenyllithium[7a]
undergoes cyclization does not appear to operate:
cyclization/iodination of 33 (Figure 2C) leads to a 1:1 mixture of
deuterium-labeled diastereomers 34 (epimeric at the iodination
site). Assuming iodination of the ate complex is stereospecific[8a]
this observation suggests that the cycloaddition is a non-
concerted step-wise process, proceeding through an
intermediate capable of bond rotation prior to closure to the
boretane. We considered that a thermally-accessible open shell
structure[14] such as 35 – formed by a process analogous to that
proposed for dimerization of strained olefins[15] and for allene-
yne intramolecular 2+2 reactions[16] – and closed-shell system
36 (see inset, Figure 2C) were most plausible intermediates;
however, both raise questions. The radical-based pathway is
not supported by experiments in Figure 2B, while addition of a
stabilized carbanion to an unactivated alkene appears to have
little precedent.[17] Nonetheless, the capacity for stereochemical
scrambling at the reactive olefin site extends to other systems:
cyclization/alkylation of cis and trans substrates 37 and 21
(Figure 2D) occurs with stereoconvergence – the intermediate
"ate" complex is presumed to undergo stereoinvertive SE2
(pin)B
(pin)B
Ph
(pin)B
I
H
I
R'
substrate
1
2
Ph
OBn
3
12: 49% yield
>20:1 dr
13: 65% yield
>20:1 dr
14: 55% yield
2.9:1 dr (C2:C3)
Ph
H
H
(pin)B
(pin)B
Ph
Ph
(pin)B
H
Ph
Ph
Ph
B(pin)
B(pin)
R
15: 68% yield
4:1 dr
16: 66% yield
>5:1 dr
17: 80% yield
>20:1 dr
H
H
H
(pin)B
Me
(pin)B
(pin)B
Ph
Ph
Ph
R' Ph
cis-substrate
H
Me
19: 52% yield
>20:1 dr
TBSO
18: 65% yield
>20:1 dr
20: 45% yield
>20:1 dr
H
KOtBu
THF, 22
B(pin)
(pin)B
Ph
Ph
°
C
B(pin)
Ph
12 h
(0.2 M)
Ph
15: 68% yield
4:1 dr
then H2O
,
trans-21
H
KOtBu
B(pin)
Ph
(pin)B
THF, 22
12 h
(0.2 M)
°C
B(pin)
Ph
23: 55% yield
>20:1 dr
22
then H2O
Figure 1. Boron alkylidene-alkene 2+2 cycloaddition followed by reaction with
an electrophile. After deborylative cyclization, the following electrophiles were
employed: H2O (H), D2O (D), N-bromosuccinimide (Br), I2 (I), benzyl bromide
(CH2Ph).
We propose that the deborylative cyclization proceeds
through the intermediacy of a 5-borata-[3.2.0]-bicycloheptane
"ate" complex 7 (Scheme 1). Structure 7 explains the following
observations: (1) a carbanion equivalent (boron "ate" complex)
is formed and is stable enough that it persists for the duration of
the first step (up to 14 h) such that it may be trapped with an
electrophile; (2) only one stereoisomer of cyclization
intermediate (syn) appears to be stable and subject to trap with
the electrophile, while the other is protonated prior to addition of
trapping reagent. To gain evidence for the intermediacy of
complexes such 7, the experiments in Figure 2A were
conducted. In the first, 13C-labeled compound 24 was subjected
alkylation[8] via 39
– furnishing 38 in excellent yield and
stereoselection.
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10.1002/anie.201705720
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COMMUNICATION
B(pin)
Ph
H
INTcis is that the carbanion center does not yet exhibit bonding
with the three-coordinate boron atom and therefore may be
subject to bond rotation and stereoinversion, features required
for stereoconvergence with styrene derivatives 18 and 39, as
well as the stereochemical scrambling observed with deuterium-
labeled terminal alkene substrate 35. As a final step in the
reaction sequence, internal electrophilic trap of the carbanion in
INTcis by the adjacent boron atom occurs with stereoinversion at
a:
(pin)B
13
n-C13H26
13
C
KOtBu (2 equiv)
C
B(pin)
n-C13H26
THF, 22 °C
12 h
24
13C δ = 20.1 ppm
(broad)
25
13C δ = 44.0 ppm
(broad)
Ph
B(pin)
Ph
13
(pin)B
C
KOtBu (2 equiv)
H
B(pin)
Ph
13
THF, 22 °C
12 h
C
26
13C δ = 114.5 ppm
(sharp)
carbon and furnishes
a stable four-membered boracyclic
27
13C δ = 26.9 ppm
(broad)
intermediate. Importantly, for the simplified model system used
in these calculations, a similar reaction pathway is accessible for
production of the trans product and the barrier is comparable to
that observed for the syn compound (DGrel TS1TRANS = +19.8
kcal/mol, INTTRANS = +9.4 kcal/mol, TS2TRANS = +15.1 kcal/mol);
B(pin)
NaOtBu (2.6 equiv)
THF, 22 °C, 3 h
B(pin)
b:
hexyl
Ph
Ph
B(pin)
Br
hexyl
Me
Me
30: 49% yield
1.1:1 dr, >98:2 er
28
B(pin)
B(pin)
29
however, the trans boracycle is much less stable (PDTTRANS
=
+1.2 kcal/mol) and this feature may explain its inability to persist
until the end of the reaction period. Overall, the mechanism that
appears most consistent with experimental and computational
(pin)B
Ph
KOtBu (2 equiv)
THF, 22 °C
6 h
then H2O
32: 46% yield
>20:1 dr
observations is
a step-wise 2+2 cycloaddition proceeding
Ph
31
through the intermediacy of a carbanionic intermediate.
I
6
B(pin)
c:
(pin)B
D
KOtBu (2 equiv)
Ph
2
H
B(pin)
THF, 22 °C
1.5 h
Ph
H
H
δ
34: 68% yield
1:1 dr (C2:C6)
H
(pin)B
H
then I2
H
33
D
(pin)B
H
H
H
K
K
D
H
H
K
D
pinB
D
•
20.7
TS1CIS
•
pinB
R
H
pinB
R
15.6
TS2CIS
H
R
H
– or –
10.9
INTCIS
35
36
H
H
0.0
GSSM
(pin)B
H
d:
H
KOtBu (2 equiv)
toluene, rt, 12 h
B(pin)
(pin)B
Ph
-11.1
(pin)B
H
Ph
38
PDTCIS
B(pin)
69% yield
>10:1 dr
then
(pin)B
H
Ph
Br
H
37
21
Ph
B(pin)
KOtBu (2 equiv)
toluene, rt, 12 h
Ph
(pin)B
H
Ph
76% yield
>10:1 dr
B(pin)
Ph
then
38
Ph
Br
Ph
H
E+
(pin)B
Figure 3. DFT Analysis of the boron alkylidene/alkene cycloadddition reaction.
Reaction to give the syn stereoisomer of product proceeds through an
intermediate carbanion. Values are relative DG in kcal/mol at 298 K;
calculations performed by density functional theory (DFT; M06-2x/6-31+G*
with PCM solvent model (THF).
H
Ph
39
xray of 38
Figure 2. Mechanistic investigation of the boron alkylidene/alkene
cycloaddition reaction. (a) Isotope labeling studies support the intermediacy of
a four-membered boretane. (b) Stereochemical and radical clock experiments
suggest that radical intermediates may not be involved. (c) Use of a labeled
alkene suggests the 2+2 reaction is not a stereospecific process. (d) The lack
of stereospecificity in 2+2 reactions can enables stereoconvergent reactions.
Considering the prevalence of cyclopentane-containing
natural products (>49,000 according to the Reaxys database), it
was of interest to study the cycloaddition in construction of
natural product targets.[18] In this context, we addressed the
natural product aphanamal, a bicyclic terpene isolated from the
folk-medicine plant chromolaena laevigata.[19,20] As depicted in
Figure 4, when geminal bis(boronate) 40 was subjected to
deborylative 2+2 cycloaddition followed by trap with
Eschenmoser salt[21], alkyl amine derivative 41 was isolated in
good yield and with good levels of stereoinduction. Importantly,
the tertiary boronate could be readily converted to methyl ketone
42 by a modified[ 22 ] Evans-Zweifel olefination. Subsequent,
Key steps of the reaction mechanism were probed using
density functional theory (DFT). As depicted in Figure 3,
minimization of the a-boryl carbanion gives the structure GSSM
bearing a planar boron atom and a shortened B-C bond (1.46 Å)
indicative of p-bonding. Cyclization of the boron alkylidene gives
a non-stablized carbanion (INTcis) by way of transition state
TS1CIS (calculated barrier = 20.7 kcal/mol) wherein the terminal
carbon of the alkene undergoes pyramidalization as it
accommodates a pair of electrons. An important feature of
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10.1002/anie.201705720
Angewandte Chemie International Edition
COMMUNICATION
oxidation of the amine and Hoffmann elimination[23] furnished
terminal alkene 43 in good yield. Finally, alkylation of the methyl
ketone with methallyl iodide, followed by ring-closing olefin
metathesis[ 24 ], and allylic oxidation[ 25 ] furnished the natural
product.
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O
Me
B(pin)
B(pin)
a.
Li
Me
Me
KOtBu
THF, rt, 3 h
Me
Me
NMe2
NMe2
B(pin)
1
2
OEt
3
then
b. I2
c. NaOMe
d. HCl
I
Me
Me
Me
N
Me
Me
41: 65% yield
>20:1 dr (C1:C2)
6:1 dr (C2:C3)
Me
Me
40
THF, rt, 17 h
42: 70% yield
O
Me
O
Me
O
LDA, THF
0 °C, 1 h
Me
Me
Me3NO
H2O2
NMe2
Me
MeOH
rt, 18 h
DMF
130 °C, 1 h
then
I
Me
Me
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Me
43: 63% yield
Me
Me
O
Me
O
Me
O
H
O
Me
Me
HG2
SeO2
dioxane
80 °C, 3 h
toluene
80 °C, 8 h
H
H
Me
Me
Me
Me
Me
Me
aphanamal
44: 91% yield
49% yield
Figure 1. Stereoselective synthesis of aphanamal.
In conclusion, the addition of a carbanion to an unactivated
alkene is an uncommon event in organic chemistry. While the
overall transformation of the boron alkylidene bears some
similarity to transition metal alkylidene-based processes (i.e. in
olefin metathesis)[26], the stepwise mechanism that operates with
boron appears to be distinct from the concerted nature of
transition metal-based 2+2 reactions and the energetic profile is
much different, offering an opportunity to intercept the
metallacyclobutane in alternate processes. This feature is likely
to find use in construction of complex target structures from
simple starting materials.
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Acknowledgements
We thank Professors William F. Bailey (University of
Connecticut) and Lawrence T. Scott (Boston College and
University of Nevada, Reno) for helpful discussion, and we thank
Dr. Bo Li (Boston College) for x-ray crystallography. This
research was supported in part by the U.S. National Institutes of
Health, Institute of General Medical Sciences (GM 59417).
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Keywords: Cyclization • Boron • Total Synthesis • Alkenes •
Reaction mechanisms
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Xun Liu, Timothy M. Deaton, Prof. Dr.
Fredrik Haeffner and Prof. Dr. James P.
Morken*
Page No. – Page No.
A Boron Alkylidene-Alkene
Cycloaddition Reaction: Application
to the Synthesis of Aphanamal
Two plus two, or not two plus two, that is the question: Boron alkylidenes are
generated by alkoxide induced deborylation of geminal bis(boronates). These
alkene analogs are shown to undergo a net 2+2 cycloaddition reaction with tethered
alkenes and the resulting boronate complex can be trapped with electrophiles to
generate substituted carbocyclic products. Mechanistic studies and application to
synthesis are described.
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