Lessons in Strain and Stability: Enantioselective Synthesis of (+)-[5]-Ladderanoic Acid

Article abstract of DOI:10.1002/anie.201910901

The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)-[5]-ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic design that ultimately led to the development of a novel stepwise cyclobutane assembly by an allylboration/Zweifel olefination sequence.

Full text of DOI:10.1002/anie.201910901

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Accepted Article
Title: Lessons in Strain and Stability: An Enantioselective Synthesis of
(+)-[5]-Ladderanoic Acid
Authors: Erin Hancock, Erin Kuker, Dean Tantillo, and Michael Kevin
Brown
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910901
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10.1002/anie.201910901
Angewandte Chemie International Edition
Research Article
Lessons in Strain and Stability: An Enantioselective Synthesis of
(+)-[5]-Ladderanoic Acid
Erin N. Hancock,[a] Erin L. Kuker, [a] Dean J. Tantillo[b] and M. Kevin Brown[a]*
Abstract: The synthesis of structurally complex and highly strained
natural products provides unique challenges and unexpected
opportunities for the development of new reactions and strategies.
Herein, the synthesis of (+)-[5]-ladderanoic acid is reported. En
route to the target, unusual and unexpected strain-release driven
transformations were uncovered. This required a drastic revision of
the synthetic design that ultimately led to the development of a novel
stepwise cyclobutane assembly by allylboration/Zweifel olefination.
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2H
5
OH
6
(-)-[5]-ladderanoic acid (2)
((+)-2: Corey 2006, Burns 2016)
(+)-[3]-ladderanol (1)
(Burns 2016, (-)-1: Brown 2017)
H
H
H
H
O
6
H
H
H
H
H
H
H
H
O
5
H
H
Introduction
O
O
O
Me3N
P
Synthesis of structurally complex natural products continues to
be an inspiration for the development of new methods and
strategies. At times, the unusual positioning of substituents or
strained ring systems often reveals unexpected reactivity en route to
the target.
O
phospholipid 3
(Burns 2016)
O
Scheme 1. Prior Syntheses of Ladderanes
Results and Discussion
The ladderane family of natural products is a unique class of
molecules that is characterized by a series of fused cyclobutanes.1,2
Due to their complex structure and unknown biological function,3
several groups have developed routes to these molecules (Scheme
1). In 2006, Corey reported a synthesis of (+)-[5]-ladderanoic acid
Our initial strategy for the synthesis of (+)-[5]-ladderanoic acid
hinged on a late-stage enantioselective [2+2]-cycloaddition between
[4]-ladderene 4 and an allenoate to assemble the final cyclobutane
(Scheme 2A). Conversion of the cycloadduct to the target was
envisioned to occur through
a chain elongation sequence.
(2), which featured
a diastereoselective photochemical [2+2]-
cycloaddition.4 Ten years later, Burns reported elegant syntheses of
Inspiration for the proposed [2+2]-cycloaddition stemmed from early
work in our lab on related cycloadditions.7 In these reactions, a wide
variety of alkenes, such as cyclopentene (5), could be converted to
(-)-[5]-ladderanoic acid (2), (+)-[3]-ladderanol (1), and the fully
5
assembled phospholipid 3.
The approach towards (-)-[5]-
the
products
through
[2+2]-cycloaddition
promoted
by
ladderanoic acid (2) featured a Mn-catalyzed C-H chlorination and a
desymmertization by an enantioselective Cu-catalyzed protoboration.
In the case of (+)-[3]-ladderanol (1), a diastereoselective [2+2]-
cycloaddition established the core structure.
oxazaborolidine catalysts (e.g., 8) with good levels of
enantioselectivity (Scheme 2B).
Due to our group’s long-standing interest in the chemistry
A) Synthetic Strategy
surrounding cyclobutanes, we recently reported a synthesis of (-)-[3]-
6
chiral
oxazaborolidine
H
H
H
H
H
H
H
H
H
H
H
ladderanol (1).
The route featured an intramolecular
CO2R
CO2R
stereoselective [2+2]-cycloaddition between a chiral allenic ketone
and an alkene to gain access to the [4.2.0]-bicyclooctane core. In
this report, we disclose a synthesis of (+)-[5]-ladderanoic acid (2),
the unexpected challenges we encountered as a result of working
with ladderanes, and highlight the novel solutions we utilized to
address them.
+
C
H
H
H
4
CO2H
H
H
H
H
H
H
6
H
H
(+)-[5]-ladderanoic acid (2)
[a]
[b]
Erin N. Hancock, Erin L. Kuker and Prof. M. Kevin Brown*
Department of Chemistry
Indiana University
800 E. Kirkwood Ave. Bloomington, IN 47401
E-mail: brownmkb@indiana.edu
Prof. Dean J. Tantillo
B) Precedent for [2+2]-Cycloaddition: Brown 2015
H
Ph
O
Ph
H
CO2R
CO2R
20 mol % 8
N
+
Department of Chemistry
University of California Davis
1 Shields Ave. Davis, CA 95616
B
C
H
Tf2N
CH2Cl2
22 ºC, 16 h
6
8
7
Ar
H
74% yield, 10:1 E:Z
94:6 er
5
Ar = 2-CF3-4-Cl-C6H3
R = CH2CF3
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Strategy for the Synthesis of (+)-[5]-Ladderanoic Acid.
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10.1002/anie.201910901
Angewandte Chemie International Edition
Research Article
An initial strategy towards [4]-ladderene is illustrated in
Scheme 3A. In this route, a cycloaddition between [3]-ladderene
ester 9 and 1,2-dichloroethylene would give rise to the [4]-ladderane
10.8 This product could be elaborated to [4]-ladderene 4 by a
sequence involving decarboxylation and dechlorination.
An alternative strategy was developed to access [4]-ladderene
through implementation of [2+2]-cycloaddition with cyclopentenone
and subsequent ring contraction by Wolff rearrangement. Design of
this strategy was influenced by the proclivity of photochemical [2+2]-
cycloadditions to use cyclopentenone10 and prior studies from Corey
and our lab in the synthesis of related structures.4,6 As such, the
synthesis commenced with cycloaddition between cyclopentenone
(17) and 1,2-dichloroethylene to generate [3.2.0]-bicycloheptane 18
(Scheme 4). Ketal formation and reduction of the dichloride resulted
in cyclobutene 19. A second photochemical [2+2]-cycloaddition with
cyclopentenone gave rise to 20 as an inconsequential mixture of
regioisomers. Diazo-formation and subsequent Wolff rearrangement
ultimately provided carboxylic acid 21. Decarboxylation followed by
a similar series of transformations provided access to [4]-ladderane
carboxylic acid 23. Conversion of the carboxylic acid to the bromide
followed by elimination allowed for synthesis of [4]-ladderene 4.
The requisite [3]-ladderene ester 9 was prepared by oxidation of
known [3]-ladderane ester 11 (Scheme 3B).4a Irradiation of 9 and
1,2-dichloroethylene with UVA (λmax = 350 nm) or UVB (λmax = 313
nm) failed to promote conversion of the starting materials. However,
use of UVC (λmax = 254 nm) allowed for consumption of [3]-
ladderene ester 9. Unfortunately, the expected cycloadduct 10 was
not detected, but rather a remarkable conversion to ethylene (13)
and methyl benzoate (12) was observed.9 This highly unusual
reaction likely occured by rearrangement of the excited state
intermediate 14 to diene 15 (formal retro-4π-electrocyclization),
followed by
a second rearrangement of the excited state
intermediate 16 (formal retro-[2+2]-cycloaddition). At this stage, the
intermediacy of diene 15 cannot be confirmed as 14 may undergo
direct transformation to 16 without relaxation to the ground state.
1) ethylene glycol
pTsOH,
benzene, reflux
Dean Stark
Cl
O
O
O
H
H
H
Cl
UVB (313 nm)
Cl
Cl
O
10 days
2) Na Naphthalenide
THF
A) Synthetic Strategy for the Synthesis of [4]-Ladderene
19
H
18
17
O
H
O
59% yield
(3 steps)
OMe
Cl
O
H
H
H
H
H
H
H
H
H
H
H
OMe
Cl
hν
1) -CO2
2) -Cl2
17
Cl
Cl
UVA
(350 nm)
acetone
H
H
10
H
O
O
O
H
H
H
H
H
H
H
H
H
H
H
H
1) trisylN3, KOt-Bu
THF, -78 ºC
9
HO2C
O
4
8 days
B) Unexpected Photoinduced Rearrangement
2) UVA (350 nm)
THF:H2O (1:1)
NaHCO3
UVC (254 nm)
quartz
21
20
O
O
1) i) LDA, THF
-78 ºC
ii) Ph2Se2
75% yield
(2 steps)
H
H
H
H
52% yield
1:1 rr
(inconsequential)
Cl
OMe
OMe
Cl
2) NaIO4
H2O:THF
pyrithione
11
9
H
H
H
H
pyridine, T3P, THF
0 ºC, dark;
HSt-Bu, BEt3
O
H
H
H
H
H
H
1) p-ABSA,
DBU, MeCN
prepared in
5 steps
ref (4a)
57% yield
(2 steps)
2) UVA (350 nm)
THF:H2O (1:1)
NaHCO3
O
OMe
H
O
22
H
H
Cl
61% yield
OMe
+
1) (COCl)2, DMF, CH2Cl2;
10 mol % DMAP
Na-pyrithione
13
12
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2H
10
CBrCl3, light
2:5:0.5 (13:12:9)
not observed
2) KOt-Bu, THF, 50 ºC
! Proposed Pathway for the Formation of Methylbenzoate and Ethylene
23
4
H
O
57% yield
(2 steps)
79% yield, 4:1 dr
(2 steps)
O
O
H
H
H
OMe
OMe
OMe
Scheme 4. Synthesis of [4]-Ladderene 4. T3P = 1-Propanephosphonic
anhydride. p-ABSA = 4-Acetamidobenzenesulfonyl azide.
15
9
12
H
H
H
O
*
*
O
H
H
H
H
H
hν
hν
OMe
OMe
16
With synthesis of [4]-ladderene
4
completed, the key
enantioselective cycloaddition with allenoate 24 was explored
(Scheme 5). Initial investigations revealed that a productive reaction
occurred to generate what was originally thought to be the desired
[5]-ladderane 26 with good yield and enantioselectivity when
oxazaborolidene 25 was used. However, upon rigorous structural
determination by X-ray crystallography of a derivative (30), it was
revealed that [2.1.1]-bicycle 27 was formed as the exclusive
product!11,12 This remarkable transformation is proposed to occur by
14
H
Scheme 3. Attempted Synthesis of [4]-Ladderene 4.
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10.1002/anie.201910901
Angewandte Chemie International Edition
Research Article
initial [2+2]-cycloaddition to generate the desired cycloadduct 26 as
outlined in Scheme 5. However, due to the inherent ring strain, a
retro-[2+2]-cycloaddition occurs rapidly to generate chiral allenoate
28. Upon C-C bond rotation and crossed-[2+2]-cycloaddition (via
29), the observed product 27 could be formed. Density functional
theory (DFT) calculations (ωB97X-D/6-311+G(d,p); see SI for
details) revealed that the [2.1.1]-bicycle 27 is 8 kcal/mol lower in
energy that the [2.2.0]-bicycle 26 While the process shown in
Scheme 5 has not been reported to the best of our knowledge, a
related ketene-alkene [2+2]/retro-[2+2] cycloaddition has been
disclosed.13
allenoate [2+2]-cycloaddition have been reported with varrying
degrees of E/Z selectivities.7
To further probe the proposed mechanism, intermediate 36 was
independently prepared. Subjection of 36 to the reaction conditions
generated the [2.1.1]-bicyclic product 34.
This supports the
hypothesis that 36 could be an intermediate in the conversion of
cyclobutene and allenoates 24 and 32 to products 33 and 34,
respectively. This product is formed in 50:50 er because the
prepared allenoate is also racemic.
H
CO2R
Ar
O
H
Ar
50 mol %
CO2R
50 mol % 25
N
+
B
H
C
CH2Cl2
-78 ºC to -18 ºC
RO2C
H
Cl
Cl
Tf2N
25
31
X-ray of 33
33: R = CH2C6F5
89% yield , 97:3 er
34: R= Bn
24: R = CH2C6F5
32: R = Bn
CO2R
Ar = 3,5-(CF3)C6H3
+
+
C
62% yield , 89:11 er
CH2Cl2
-78 ºC to -18 ºC
24
27
[2+2]
crossed-[2+2]
26
RO2C
4
R = CH2C6F5
73% yield, 89:11 er
>20:1 dr
not observed
H
CO2R(25)
[2+2]
crossed-[2+2]
bond
rotation
retro-[2+2]
C
R1
H
37
retro-
[2+2]
bond
rotation
(25)RO2C
(25)RO2C
35
36
C
Lewis Acid (LA) = 25
R1
R1
28
26
H
H
29
H
H
CO2R
CO2R(25)
CO2R
50 mol %
catalyst 25
R1 = CO2CH2C6F5(25)
Ar
C
O
H
CH2Cl2
-78 ºC
HN
RO2C
H
36
37
34
R = Bn
to -18 ºC
50:50 er
1) hydroylsis
78% yield, 50:50 er
X-ray of 30
2) amide formation
(see SI for details)
Scheme 6. Mechanism Studies.
27
R = CH2C6F5
30
Ar = 4-BrC6H4
Due to the unusual nature of the pericyclic cascade, several
other allenoates were evaluated in the transformation (Scheme 7).
Reaction with γ-substituted allenoates 38 and 39 led to the expected
[2.1.1]-bicyclic products 40 and 41 with high levels of
diastereoselectivity. The reaction likely proceeds in an analogous
manner to that of the unsubstituted allenoate. To rationalize the
formation of the observed diasteromer, [2+2]-cycloaddition must
occur to generate diasteromer 42 in which the R-group is located on
the concave face of the [2.2.0]-bicycle. Finally, while EtAlCl2 was
found to the optimal promoter, the catalyst 25 was also competent
yet give rise to several unidentified byproducts.15
Scheme 5. Ring Strain Induced Pericyclic Cascade.
Two additional points regarding this reaction are important to
1
note: (1) When the reaction is monitored by H NMR (500 MHz), no
intermediates that would correspond to 26 or 28 are detected. This
suggests that the initial [2+2] is rate determining followed by rapid
subsequent steps. (2) The process is not limited to [4]-ladderene 4,
as reaction of cyclobutene (31) was also found to generate the
analogous [2.1.1]-bicyclic product 33 and 34 (Scheme 6).14 This
reaction likely proceeds via chiral allenoate 36. It is interesting that
33 (and likely 34 by analogy) were found epimeric when compared
Reaction with γ,γ-dimethylsubstituted allenoate 45 and
cyclobutene did not give rise to the expected [2.1.1]-bicyclic product
but rather cyclopentene 46 (Scheme 7B). To account for the
formation of 46 it is proposed that the initial sequence of
[2+2]/retro[2+2] occurred to generate 47. However, at this stage, the
crossed-[2+2] is disfavored due to steric considerations of a 4-
to 27.
One possible explanation for the observed epimeric
relationship of 27 and 33 could potentially arise from a change in
E/Z-selectivity between the initial [2+2]-cyloaddition of [4]-ladderene
and cyclobutene. While the basis of this remains unclear, alkene-
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10.1002/anie.201910901
Angewandte Chemie International Edition
Research Article
membered ring transition state relative to a six-membered ring
transition state necessary for the ene-reaction (via 48). The product
was generated in 79:21 er (absolute stereochemistry is unknown)
likely a result of a less selective [2+2]-cycloaddition compared to the
unsubstituted allenoate.
O
Me
Me
O
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
49
O
Me
Me
UVA (350 nm)
MeCN
O
A) Reaction with γ-Substituted Allenoate
50
H
CO2CH2C6F5
88% yield, >20:1 dr
4
CO2CH2C6F5
50 mol % EtAlCl2
+
CO2H
C
H
H
H
H
H
H
H
H
CH2Cl2
-78 ºC to rt
6
31
H
R
50:50 er
50:50 er
R
40: R = Et: 83% yield, 50:1 dr
41: R= Ph: 81% yield, 100:1 dr
38: R = Et
39: R = Ph
(+/-)-[5]-ladderanoic acid (2)
[2+2]
crossed-[2+2]
Scheme 8. Cycloaddition with Furenone 49.
H
CO2R(LA)
bond
rotation
Conscious of the aforementioned problems, we elected to
drastically change the approach by dispensing with the notion that a
[2+2]-cycloaddition would be the best strategy to install the final
cyclobutane. Due to our group’s interest in arylboration reactions of
alkenes,18 we devised a 2nd generation strategy that would involve
allylboration (4 to 51) followed by Zweifel olefination (51 to 54)
(Scheme 9). Inspiring studies from Hoveyda19 and Yun20 on Cu-
catalyzed enantioselective allylboration of styrenyl derivatives and
borylcupration of cyclobutenes from Tortosa21 and Burns5 suggested
that 51 could be prepared by the merging these two methods
(Scheme 9). While Zweifel olefenation is well established in
intermolecular variants,22,23 intramolecular reactions are rare. In only
retro-[2+2]
C
R
44
R
(LA)RO2C
(LA)RO2C
42
43
R
Lewis Acid (LA) = EtAlCl2
B) Reaction with γ,γ-Dimethylsubstituted Allenoate
50 mol %
catalyst 25
CO2CH2C6F5
CO2CH2C6F5
+
C
CH2Cl2
-78 ºC to rt
46
31
Me
Me
Me
45 50:50 er
63% yield, 79:21 er
one example, Aggarwal reported the formation of a cyclobutane
24
formed by Zweifel olefination.
Upon completion of the
[2+2]
ene-reaction
allylboration/Zweifel olefination sequence, it was envisioned that the
[5]-methylene ladderane 54 could be elaborated to the target
through various approaches.
H
CO2R(25)
H
retro-[2+2]
H
CO2R(25)
Me
Me
48
Me
H
H
H
H
H
H
H
H
H
H
H
47
Bpin
R-Li
Cu-catalyst
X
Scheme 7. Reactions with Substituted Allenoates.
(Bpin)2, NaOR
X
H
H
4
51
RO
At this stage, several photochemical [2+2]-cycloaddition
strategies were investigated to elaborate [4]-ladderene 4 to the
natural product. One of the major challenges that we experienced
was the fact that photochemical [2+2]-cycloadditions typically require
cyclic electron deficient alkenes to be one of the reactants. This
greatly narrows the type of products that can be generated and as a
result, multiple steps to manipulate functional groups en route to the
target would be incurred.
H
H
H
H
H
pin
B
H
H
H
H
H
H
H
H
Bpin
I
Li
I2
H
52
53
MeOH
CO2H
H
H
H
H
H
H
H
H
H
H
H
A
specific example that highlights the aforementioned
6
challenges is shown in Scheme 8. We found that the [4]-ladderene
could undergo cycloaddition with 49 to install the final cyclobutane
ring (product 50).16 However, elaboration of this compound to the
target proved challenging, mainly due to ring-opening that resulted
from attempts to remove the oxygen atom bound to the
cyclobutane.17
H
H
H
H
H
(+)-[5]-ladderanoic acid (2)
54
Scheme 9. Second Generation Strategy.
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10.1002/anie.201910901
Angewandte Chemie International Edition
Research Article
1)
5 mol %
(R)-SEGPhosCuCl
(Bpin)2, NaOt-Bu
THF, rt
treatment with Br2 followed by TBAF. Addition of t-BuLi to vinyl
bromide 55 resulted in generation of borate 52 which underwent
reaction smoothly with I2 to generate [5]-methylene ladderene 54
after 1,2-elimination (via 53).
t-BuLi
THF
-78 ºC
SiMe3
H
H
H
H
H
H
H
H
H
H
H
H
Bpin
(EtO)2(O)PO
Br
[5]-methylene ladderane 54 could be elaborated to (+)-[5]-
ladderanonic acid (2) through one of two routes (Scheme 10). The
first involved a hydroboration-oxidation with 9-BBN followed by
Swern oxidation to aldehyde 57. Intermediate 57 can be converted
to (+)-[5]-ladderanoic acid (2) though a sequence of epimerization,
Wittig olefination, and diimide reduction as demonstrated by Corey.4a
Alternatively, we elected to explore an approach that would take
advantage of an emerging set of reactions introduced by Baran,
specifically decarboxylative alkyl-alkyl cross coupling. 25 In this
approach, 54 was converted to carboxylic acid 56 through a
hydroboration-oxidation sequence. Synthesis of the redox active
ester, subsequent Ni-catalyzed cross coupling with dialkylzinc
reagent 58, and hydrolysis provided (+)-[5]-ladderanonic acid (2) in
38% yield over 2 steps.26 It is interesting to note that the Ni-
stabilized cyclobutyl radical 59, or related cylobutyl free radicals
2) Br2, CH2Cl2
-78 ºC;
TBAF, THF, 78 ºC
55
4
50% yield (2 steps)
>20:1 dr, 89:11 er
H
H
H
pin
B
H
H
H
H
H
H
H
Bpin
then I2, MeOH
-78 ºC to rt
Li
I
53
H
H
H
H
52
1) 9-BBN, THF;
NaBO4•H2O
THF:H2O
H
H
H H H
H
H
H
H
H
H
H
H
CO2H
2) 10 mol % TPAP
NMO•H2O
CH2Cl2
56
H
H H
54
63% yield (2 steps) X-ray
1:1 dr (inconsequential)
55% yield
generated in the decarboxylative transformation 21 to 22 and 23 to 4
27
1) 10 mol % DMAP, TCNHPI
DCC, CH2Cl2
2) 20 mol % NiCl2•glyme
40 mol % t-BuBIPY, DMF
THF, ZnR2-58
do not undergo strain release promoted ring-opening.
DFT
1) 9-BBN, THF;
NaBO4•H2O
THF:H2O
calculations (ωB97X-D/6-311+G(d,p); see SI for details) reveal that
the free radical of 60 (no Ni) is 27 kcal/mol lower in energy than the
free radical of 59 (no Ni). In addition, the predicted barrier for
conversion of the free radical of 59 to 60 is only 18 kcal/mol. This
suggests that bimolecular capture of the cyclobutyl free radicals is
rapid.
2) Swern [O]
then, TsOH MeOH:CH2Cl2;
LiOH H2O then HCl
H
H
H
H
H
H
H
CHO
Me
O
O
O
57
Zn
H
6
H
ZnR2-58
2
55% yield (2 steps)
1:1 dr (inconsequential)
Conclusion
H
H
H
H
H
H
NiIILn
alkyl
3 steps
(ref 4a)
In summary, an evolution of a strategy to prepare (+)-[5]-
ladderanoic acid is presented. Only through synthesis of this
complex natural product did we uncover unusual strain-release
promoted transformations that forced a significant change of strategy.
The evolution from realizing that a [2+2]-cycloaddition approach was
not viable led to development of a novel stepwise installation of the
final cyclobutane through an allylboration/Zweifel olefination
sequence. In addition, we have uncovered a novel process for the
synthesis of [2.1.1]-bicycles from unlikely precursors.
X
H
59
CO2H
H
H
H
H
H
H
H
H
H
H
H
H
6
X
alkyl
NiIILn
H
H
38% yield, >20:1 dr (2 steps from 56)
(+)-[5]-ladderanoic acid (2)
60
X-ray of 56
Acknowledgements
We thank Indiana University and the NIH (R01GM110131 and
R35GM128779) for financial support. This project was partially
funded by the Vice Provost for Research through the Research
Equipment Fund and the NSF (CHE1726633). DJT gratefully
acknowledges computational support from the NSF XSEDE
program. We also thank Dr. Johannes Wiest for Dr. Michael
Conner for helpful conversations and informative initial studies.
Dr. Maren Pink is acknowledged for support with X-ray
crystallography.
Scheme 10. Completion of the Synthesis of (+)-[5]-Ladderanoic Acid.
TCNHPI = Tetrachloro-N-hydroxyphthalimide.
The strategy outlined in Scheme 9 has been implemented to
generate (+)-[5]-ladderanonic acid (2), as illustrated in Scheme 10.
Initially, Cu-catalyzed allylboration was examined with an allyl
electrophile that incorporated a vinyl bromide. However, these
reactions failed to deliver the desired product in an appreciable yield.
Therefore, a vinylsilane was used as a surrogate that not only
allowed the allylboration to proceed with good yield and
enantioselectivity, but could be elaborated to the vinylbromide 55 by
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Angewandte Chemie International Edition
Research Article
RESEARCH ARTICLE
Erin N. Hancock,[a] Erin L. Kuker, [a]
Dean J. Tantillo[b] and M. Kevin Brown[a]*
Page No. – Page No.
Lessons in Strain and Stability: An
Enantioselective Synthesis of (+)-[5]-
Ladderanoic Acid
The synthesis of structurally complex and highly strained natural products provides
unique challenges and unexpected opportunities for the development of new
reactions and strategies. Herein, the synthesis of (+)-[5]-ladderanoic acid is
reported. En route to the target, unusual and unexpected strain-release driven
transformations were uncovered. This required a drastic revision of the synthetic
design that ultimately led to the development of a novel stepwise cyclobutane
assembly by allylboration/Zweifel olefination..
This article is protected by copyright. All rights reserved.