General Synthetic Approach for the Laurencia Family of Natural Products Empowered by a Potentially Biomimetic Ring Expansion

Article abstract of DOI:10.1021/jacs.9b01088

The Laurencia family of C₁₅-acetogenins is Nature's largest collection of halogenated natural products, with many of its members possessing a brominated 8-membered cyclic ether among other distinct structural elements. Herein, we demonstrate that a bromonium-induced ring expansion, starting from a common tetrahydrofuran-containing bicyclic intermediate and using the highly reactive bromenium source BDSB (Et₂SBr·SbCl₅Br), can lead to concise asymmetric total syntheses of microcladallenes A and B, desepilaurallene, laurallene, and prelaureatin. Key advances in this work include (1) the first demonstration that the core bromonium-induced cyclization/ring-expansion can be initiated using an enyne with an internal ether oxygen nucleophile, (2) that reasonable levels of stereocontrol in such processes can be achieved both with and without appended ring systems and stereogenic centers, (3) that several other unique chemoselective transformations essential to building their polyfunctional cores can be achieved, and (4) that a single, common intermediate can lead to five different members of the class encompassing two distinct 8-membered cyclic ether ring collections. Considering this work along with past efforts leading to two other natural products in the collection, we believe the breadth of structures prepared to date affords strong evidence for Nature's potential use of similar processes in fashioning these unique molecules.

Full text of DOI:10.1021/jacs.9b01088

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Article
A General Synthetic Approach for the Laurencia Family of Natural
Products Empowered by a Potentially Biomimetic Ring Expansion
Yu-An Zhang, Natalie Yaw, and Scott A. Snyder
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01088 • Publication Date (Web): 16 Apr 2019
Downloaded from http://pubs.acs.org on April 16, 2019
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Page 1 of 14
Journal of the American Chemical Society
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AꢀGeneralꢀSyntheticꢀApproachꢀforꢀtheꢀLaurenciaꢀFamilyꢀofꢀNatu-
ralꢀProductsꢀEmpoweredꢀbyꢀaꢀPotentiallyꢀBiomimeticꢀRingꢀEx-
pansionꢀ
7
8
9
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9
0
1
2
3
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8
9
0
Yu-An Zhang, Natalie Yaw, and Scott A. Snyder*
DepartmentꢀofꢀChemistry,ꢀUniversityꢀofꢀChicago,ꢀ5735ꢀSouthꢀEllisꢀAvenue,ꢀChicago,ꢀILꢀ60637ꢀꢀ
ꢀ
ABSTRACT:ꢀThe Laurencia family of C -acetogenins is Nature’s largest collection of halogenated natural products, with many of its
1
5
members possessing a brominated 8-membered cyclic ether among other distinct structural elements. Herein, we demonstrate that a bro-
monium-induced ring expansion, starting from a common tetrahydrofuran-containing bicyclic intermediate and using the highly reactive
bromenium source BDSB (Et SBr•SbCl Br), can lead to concise asymmetric total syntheses of microcladallenes A and B, desepilaurallene,
2
5
laurallene, and prelaureatin. Key advances in this work include: 1) the first demonstration that the core bromonium-induced cycliza-
tion/ring-expansion can be initiated using an enyne with an internal ether oxygen nucleophile, 2) that reasonable levels of stereocontrol in
such processes can be achieved both with and without appended ring systems and stereogenic centers, 3) that several other unique
chemoselective transformations essential to building their polyfunctional cores can be achieved, and 4) that a single, common intermediate
can lead to five different members of the class encompassing two distinct 8-membered cyclic ether ring collections. Considering this work
along with past efforts leading to two other natural products in the collection, we believe the breadth of structures prepared to date affords
strong evidence for Nature’s potential use of similar processes in fashioning these unique molecules.
Br
Br
•
PMBO
•
H
H
"Br
"
H
H
O
H
H
H
H
H
H
Br
O
Br
Br
Br
O
O
O
O
TBS
TBS
H
TBS
H
O
H
O
O
common intermediate
microcladallene A
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
4
INTRODUCTION
bromonium-induced cyclization. Using the crude bro-
moperoxidase obtained by the producing species, his team
observed the formation of the desired target (12) in 0.015%
yield (0.085% based on recovered starting material). How
such a process was effected mechanistically, however, was not
described, with no demonstration, to the best of our
knowledge, that simple chemical brominating sources could
achieve a similar transformation from 9 in any yield since this
original disclosure. Key, though, was that it established the
likelihood that such a bromine atom was incorporated biosyn-
Ever since the initial isolation of laurencin (1, Figure 1) in
965, its unique 15-carbon framework featuring an 8-
1
membered brominated cyclic ether ring has captivated the
1
attention of synthetic chemists around the world. Indeed,
nearly 20 total syntheses of this natural product have been
achieved to date, demonstrating the range of creative solutions
that can be brought to bear to fashion such a strained, medium-
2
size ring. Those operations include oxidative ring expan-
2
a
2bc
2d-g
sions, oxonium additions, ring-closing metathesis,
and
4
c
2
hi
2j-q
thetically as an electrophile, not as a nucleophile as has been
typical of the vast majority of the laboratory syntheses of
family members; indeed, nearly every laboratory synthesis has
alkylation-based ring closures, among several others.
As
3
additional members of the collection have been isolated,
many also containing 8-membered bromoether rings albeit
with distinct alkene patterning (as in 3–8), endo- versus exo-
cyclic bromine atoms (as in 3–8), dibromination (as in 6–8), as
well as additional appended ring systems (as in 2 and 5–8),
questions regarding their biogenesis have garnered increasing
significance.
5,6
installed such bromines via alcohol substitution chemistry.
Given this state of affairs, and the global challenges in ef-
fecting what is likely to be both an entropically and enthalpi-
cally unfavorable direct, bromonium-induced 8-endo-trig cy-
clization, several teams have proposed biosynthetic alterna-
tives patterned around this core transformation. Most involve
the initial formation of a smaller, cyclic ether which can serve
as the nucleophilic partner capable of attacking a bromonium-
activated alkene. Those efforts have focused principally on
The first critical insight along these lines came from Murai,
whose group postulated that the linear natural product lauredi-
ol (9, Scheme 1), obtained from the same producing species as
deacyllaurencin (12, sometimes also called deacetyllaurencin),
could serve as a potential precursor through some type of
7
8
either epoxides or oxetanes. In several elegant demonstra-
1
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tions, such intermediates can afford an array of ring systems
Page 2 of 14
Scheme 1. Proposed biosynthesis of several members of the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pertinent to the class broadly upon exposure to several differ-
ent bromenium sources. Of note, these processes tend to pro-
duce mixtures which might be of biosynthetic relevance if
Nature, as well, seeks non-selective reactions to generate this
array of molecules. Such an outcome is not unreasonable, and
could be of evolutionary advantage given that similar diversi-
ty-generation has been observed for several other natural
lauroxocane class based on a series of 5-endo-trig cyclizations and
a successful synthesis of laurefucin (2) based on that analysis as
empowered by BDSB (17) as the bromenium source.
Proposed biosynthesis:
OH
OH
H
HO
"
Br
"
O
9,10
product collections, such as phytoalexin-based polyphenols.
H
9
: laurediol
direct
cyclization]
Br
10
[
"
Br
"
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. Structures of selected lauroxocane natural products.
H
O
OAc
H
H
H
O
OH
H
OH
O
H
[loss of
Br
Br
Br
Br
H
H
Br
]
O
O
H
Br
Nu
11
HO
1: laurencin
2: laurefucin
12: deacyllaurencin
[
intramolecular
cyclization]
[intramolecular
cyclization]
"
Br
"
Br
H
Br
H
H
H
H
O
H
O
O
H
O
H
Br
Br
Br
O
Cl
H
OH
H
O
Br
1
4
13: laureoxanyne
3: Z-pinnatifidenyne
4: prelaureatin
[
oxonium
regeneration]
Br
Br
H
H
H
H
H
H
H
O
Br
O
H
O
O
H
Br
O
O
•
[external
H
O
O
H
O
H O H
nucleophile]
2
Br
HO
5: desepilaurallene
6: laurallene
15
2: laurefucin
Our Previous Work:
•
SbBrCl5
Br
•
H
O
H
H
O
Br
H
H
Br
Br
Br
Br
S
H
H
O
Br
Et
1
Et
H
O
O
O
7: BDSB
O
O
[
5-exo
-trig]
H
TBS
H
Cl
7: microcladallene A
8: microcladallene B
TBS
H
Cl
H
H
Nu
1
6
18
[
Ring-expanding
(61%)
Our strategy, by contrast, has sought biomimetic relevance
but also the capability to generate single natural products ra-
ther than mixtures. In that regard, our efforts have focused on
the use of tetrahydrofuran-containing intermediates as synthet-
ic precursors. As shown in the upper half of Scheme 1, such a
key starting material could arise from laurediol (9) via a bro-
monium-induced 5-endo-trig cyclization. Then, if the oxygen
atom of the tetrahydrofuran ring of 10 were to engage a se-
cond bromenium-activated alkene to generate oxonium inter-
mediate 11, arrow-pushing analysis suggests that subsequent
loss of the endocyclic bromine atom, potentially facilitated by
an external nucleophile, could then afford deacyllaurencin
bromoetherification]
Br
Br
H
H
H
H
O
O
O
Cl
Cl
H
H
3: Z-pinnatifidenyne
19
Armed with these ideas and encouraged by precedent from
Braddock showing that ring expansions through oxonium for-
mation using different systems could lead to 12-membered
1
1,12
rings,
as well as several publications using the opposite
perspective on this idea (i.e. a ring contraction of oxocane via
a similar oxonium intermediate to deliver tetrahydrofuran con-
(
12). Significantly, different mechanistic pathways using that
same intermediate (i.e. 11) could afford viable pathways to
laureoxanyne (13) and laurefucin (2) as well.
1
3-15
taining natural products),
we have explored a variety of
model systems as well as several fully functionalized com-
pounds. Pleasingly, we found that the concept had broad suc-
cess with high levels of stereoselectivity when the right bro-
16
menium source was utilized. The bottom portion of Scheme
1
shows one example leading to a total synthesis of Z-
16
pinnatifidenyne (3), wherein treatment of 16 with our reac-
2
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Journal of the American Chemical Society
1
7
tive bromenium source BDSB (Et SBr•SbCl Br) activated
ence of the appended five-membered lactone ring along with
an additional stereogenic center relative to our past studies
(denoted here with a star). This added motif might restrict the
overall conformational flexibility of the system, reducing the
reaction’s overall diastereoselectivity and/or efficiency by
destabilizing the transition state necessary for stereocontrol.
Such transition state control could be critical since the reacting
alkene is remote from the stereocontrolling elements within
2
5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the exocyclic alkene in the presence of several functional
groups to effect a subsequent cyclization and ring-opening to
afford the alkene-containing product 19 in 61% yield; other
bromenium sources, at least in model studies, have not
demonstrated the ability to effect this functionalizing ring-
expansion chemistry in commensurate yields.
Herein, we report our efforts to extend and further develop
this general approach to a number of additional targets. The
principal goal of our study was to illustrate that tetrahydrofu-
ran-based ring expansions can generate the 8-membered rings
of the lauroxocane collection in a number of diverse settings in
terms of allied ring systems. Two questions were of particular
interest. First, for targets containing an additional ring at-
tached onto the 8-membered core, such as 5–8, does the pres-
ence and/or absence of that ring impact the viability of a tetra-
hydrofuran-induced ring expansion? Second, could a new var-
iant of the ring-expansion process be developed to forge con-
currently an 8-membered ring and a bromoallene motif as
found in 7 and 8, and, if so, could such an event proceed with
reasonable stereocontrol since the enyne is more remote from
the 8-membered ring? As documented below, we have been
able to individually synthesize five additional members of the
the core and bromenium addition to alkenes is reversible at
29
reaction rates similar to diffusion control.
However, if suc-
cess could be achieved in this critical operation leading to
desepilaurallene (5), the goal would then be to utilize the ap-
pended lactone to fashion the requisite patterning of both pre-
laureatin (4) and laurallene (6). Success in these operations
would require chemoselective engagement of that lactone in
the presence of the exocyclic secondary bromide and the ab-
sence of any potentially destructive transannular reactions
involving newly installed functionality with that bromine
group.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Proposed expansions of the developed ring-expansion
approach to substrates containing additional fused ring systems as
well as enynes to fashion desepilaurallene (5) and microcladallene
A (7), starting from a common intermediate.
2
b,18-20
21
collection, prelaureatin (4),
desepilaurallene (5),
and microcladallenes A and B (7 and
starting from a single, common intermediate and using
PMBO
2
0ac,22-24
laurallene (6)
8),
H
O
2
5,26
O
new variants of our previously established ring-expansion
process. These efforts demonstrate, we believe for the first
time, that tetrahydrofuran ether oxygens can successfully add
into bromonium-activated enyne electrophiles to induce such
ring expansions. Those findings, coupled with some critical
model studies, highlight that reasonable levels of stereocontrol
in that ring-expansion process can be achieved independent
from the presence of additional appended ring systems and
chiral centers. Finally, we demonstrate that these syntheses
can be conducted in both racemic and asymmetric formats. In
the majority of cases, the developed routes are of comparable,
if not superior, efficiency to past efforts.
TBS
H
O
H
2
0: common intermediate?
Br
Br
H
H
Br
O
O
O
*O
H
*O
TBS
H
TBS
H
H
21
23
"
Br
"
"Br
"
Br
•
Br
RESULTS AND DISCUSSION
H
H
H
H
H
1. Retrosynthetic Analysis Based on Common Interme-
diate Approach
O
O
Br
O
TBS
TBS
H
O
H
Although lauroxocanes 5–8 possess disparate appended ring
systems, the homology of their 8-membered core in terms of
the site of additional ring fusion and the positioning of their
internal alkene made us question whether all could arise from
a common precursor; such strategies have served our group,
and others, on several occasions for accessing diverse collec-
O
H
22
[Ring
24
[Ring
expansion]
expansion]
Br
H
•
H
O
1
0,27,28
H
H
H
H
O
Br
tions of natural products.
Keeping this idea in our minds
Br
and coupling it with the notion of using a tetrahydrofuran-
based ring expansion as the key step to forge their 8-
membered rings, we posited that bicyclic lactone 20 (Scheme
O
O
O
5: desepilaurallene
7: microcladallene A
2
) might be an ideal starting point for this subset.
In the case of the microcladallenes (7 and 8), our goal was to
convert the lactone ring of 20 and its PMB-protected alcohol
into the 6-membered endocyclic bromoether and enyne do-
mains of 23, respectively. Of particular note for this design,
we anticipated that the 6-membered bromoether ring system
could not likely be constructed through a direct, bromonium-
induced 6-endo-trig cyclization of an alcohol onto a 1,2-
disubstituted alkene given that 5-exo-trig cyclizations domi-
nate as documented both in several total syntheses as well as
As indicated from a forward synthesis perspective, we antic-
ipated that its PMB-protected alcohol could be converted, over
a series of steps, into the trans-disubstituted alkene of 21.
Then, using BDSB, we hoped to effect our ring-expansion
strategy in a format generally similar to that deployed before
as part of our E- and Z-pinnatifidenyne (3, cf. Figure 1) syn-
1
6
theses; the critical difference, however, would be the pres-
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Page 4 of 14
3
0a-i
our own endeavors;
only with an aromatic group present as
30j-l
our bromenium source (BDSB) under similar conditions, some
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
part of the chain does this chemistry succeed smoothly.
product control was observed, albeit in similar yields but with
additional decomposition products also detected (entry 4).
Pleasingly, if the same reaction with BDSB was performed in
Although we would still attempt such a construction here, to
see if the pre-installed THF ring of the precursor could effect
some control in this case, alternate approaches would also be
sought. But, of note, for the key cyclization we would be able
to test the ability of an ether oxygen to engage a bromonium-
activated enyne. To the best of our knowledge, despite exten-
sive efforts exploring racemic and asymmetric variants of the
process using both alcohol and carboxylic acid nucleophiles,
particularly by the Tang group, use of an internal ether oxy-
gen for such purposes has yet to be described. If successful,
then microcladallene A (7) would hopefully result, with the
use of precursors of different oxidation state leading to micro-
cladallene B (8).
EtNO instead, enabling the temperature to be lowered to –78
2
°C given the freezing point of MeNO , the yield improved to
2
~60%, with 26 and 27 being formed in an alkene-specific dr of
3
4
1.9:1 (entries 5 and 6). The stereochemical assignments of
these two product molecules in terms of their oxocane core are
based largely on nOe analysis, as we were unable to obtain
crystals suitable for X-ray diffraction analysis; the bromo-
allene configuration was initially assigned based on transition
state analysis (and later confirmed by our total synthesis of the
microcladallenes, vide infra).
31
32
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Indeed, as shown in Scheme 3, transition state analysis, con-
sidering the alkene geometry of the enyne coupled with the
configuration of the substituents on the THF ring, may provide
the means to understand the observed outcomes for the key
ring-expansion process. In our proposed model, the C–Si
bond and the C–O bond is likely to adopt an anti-periplanar
arrangement typical of the β-silicon effect so the electrons in
the C–Si bond can hyperconjugate with the C–O anti-bonding
2
.
Model Studies for Ring-Openings with Enynes
Given the plans outlined above, its critical element, and one
of equal significance from a biosynthetic perspective, was the
ability and relative ease in effecting the ring expansion process
leading to 8-membered rings with appended ring systems.
And, for the case of the microcladallenes, that process rested
on the ability to do so with the ether oxygen of the tetrahydro-
furan ring by engaging a remote, bromonium-activated enyne.
Thus, to set an initial framework of outcomes from both a
viability and stereoselectivity perspective, particularly for the
latter concern, we elected to pursue model studies using tetra-
hydrofurans of type 25 (with both E- and Z-disposed alkenes
as part of their enyne units) but lacking the extra, appended
ring system of the final molecular targets.
2
b,35
orbital;
such an arrangement would increase the nucleo-
philicity of the oxygen atom and facilitate a trans-arrangement
to deliver the observed cis-alkene from the ring expansion
process. Further, the exocyclic side-chain alkene within E-25
could exist in two different possible orientations, with the ini-
tial drawing likely being preferred on steric grounds based on
the indicated interaction in the second. These features would
account for the formation of the trans-based stereocenters in
the oxocane ring of 26 instead of the cis-substituted ring of 28.
Similar analysis of Z-25, showing here just the productive
transition state, can rationalize the observed formation of 27 as
the major product. In both cases, the bromenium addition
should be favored to occur from the indicated side, away from
the tetrahydrofuran-containing ring; our relative assignments
of the allene units within 26 and 27 are based on such supposi-
tions. If bromenium addition occurred on the other side of the
alkyne within these transition states, then that could account
for the observation of 27 as the minor product with E-25 and
As shown in Table 1, using the E-version of 25 for most of
our initial studies, addition of NBS, either with or without
3
2a
DABCO in MeNO2, afforded no observable formation of
either ring-expanded products 26 or 27 (entries 1 and 2). By
contrast, upon switching the bromenium source to
3
3
Br(coll) PF6 and cooling the reaction temperature to –25 °C,
2
both adducts were formed in modest yield at partial conver
sion, but in a non-selective (1:1) manner (entry 3); such results
suggested the importance of using a more cationic (i.e. reac-
tive) bromenium source. To our delight, when we deployed
2
6 as the minor product with Z-25.
More generally, we surmise that the more rapid reaction at
Table 1. Screening of conditions to achieve bromoallene-
containing 8-membered rings.
lower temperature afforded by BDSB, also considering the
reagent’s relatively large size, might afford better control in
such additions given that the alkyne is relatively remote to the
rest of the structure of the starting material; that difference
might explain how better allene stereoselectivity was observed
as compared to the reaction with Br(coll) PF . Finally, the
nOe
X
nOe
X
Br
•
•
H
H
Br
H
H
O
Br
O
source
O
+
2
6
*
conditions
TBS
H
configuration of the substituents on the core tetrahydrofuran
ring are also critical to the outcome of the process. For in-
stance, an effort using 29 with an E-alkene within the enyne
and a cis-disposition of that sidechain with the neighboring
THF methyl group failed to afford cis-oxocane 30; we postu-
late that no productive transition state could be obtained due to
the indicated steric clash, thereby leading to decomposition
pathways instead. If the developed ring expansion process
was of biological relevance, this result could potentially ex-
plain why the cis-oxocane isomers of microcladallenes A and
B have not yet been observed in Nature.
2
5
26
27
Entry Substrate and Br+ source
o
Solvent Temp. ( C) Yield (%) 26:27
1
2
3
4
5
6
E-25, NBS (1.0 equiv)
E-25, NBS (1.0 equiv), DABCO MeNO2
E-25, Br(Coll) PF (1.2 equiv) MeNO2
MeNO2
23
23
0
0
-
-
32a 1.0 : 1.0
30b 2.7 : 1.0
2
6
-25
-25
-78
-78
E-25, BDSB (0.8 equiv)
E-25, BDSB (0.8 equiv)
Z-25, BDSB (0.8 equiv)
MeNO2
EtNO2
EtNO2
61
60
1.9 : 1.0
1.0 : 1.9
a
Conversion was ~40% with a yield b.r.s.m. being 80%, b large amount of side-
products observed
4
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Page 5 of 14
Journal of the American Chemical Society
a
Scheme 3. Proposed transition state analysis to account for ob-
served ring expansion results with model enyne substrates.
Scheme 4. Racemic synthesis of common intermediate 20.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NtBu
Me
PMBO
O
+
PMBO
32
Me
I
H
31
O
35
O
Br
TBS
TBS
Si
O
Si
a) LDA, TBSCl,
n-BuLi
b) AcOH, H O
h) Karstedt's
catalyst (36),
TBSH
H
•
Pt
H
H
(69%)
(41%)
PMBO
Br
2
6
E-25
2
Me
36
Me
O
O
O
H
X
O
PMBO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TBS
H
TBS
•
H
H
33
37
Br
Br
E-25 Br
28
c) MeMgBr
70%) d) Dess-
Martin [O]
(86%)
(
i) Crabtree's
catalyst, H2
Me
•
Me
O
O
OH
e) LDA,
acrolein
O
Br
Br
O
PMBO
PMBO
TBS
TBS
H
H
TBS
(74%)
TBS
38
f) Et
LiBH
H
H
Z-25
34
2
7
2
BOMe
4
;
Me
H
Me
•
(85%)
2 2
H O , NaOH
O
PMBO
X
g) PdCl
CuCl
2
,
2
,
O
H
O
CO, AcOH
OH OH
H
H
O
PMBO
(
58%)
Br
E-29
30
TBS
H
O
H
TBS
3
9
20: common intermediate
Critically, though, these initial studies highlighted that with
the right bromenium source under appropriate conditions,
enyne systems can be activated and engaged with a tetrahydro-
furan oxygen atom. Such operations can then be terminated
by a TBS-mediated alkene formation to generate the trans-
fused 8-membered oxocane ring systems pertinent to many
members of the class. In addition, despite not having any ap-
pended ring systems and the enyne motif being remote to the
core tetrahydrofuran, the use of BDSB did allow for some
selectivity in bromoallene formation in a manner dependent
upon the initial configuration of the alkene in the enyne unit.
Thus, with these studies completed, the stage was set to ex-
plore the facility and stereoselectivity of similar operations
with appended ring systems to see if there would be any im-
pact on the outcome. Such results, we hoped, could shed light
on the potential biosynthetic order of ring construction within
the class as well as the potential of such a ring-expansion be-
ing part of that process.
a
Reagents and conditions: (a) LDA (1.05 equiv), THF, 0 °C, 30 min; TBSCl
(0.99 equiv), n-Bu I (0.02 equiv), 25 °C, 4 h; n-BuLi (1.05 equiv), 0 °C, 30 min;
2 (1.5 equiv), 25 °C, 12 h; (b) 1 M AcOH, CH Cl , 25 °C, 1 h, 69% over 2
steps; (c) MeMgBr (2.2 equiv), THF, -78 °C, 30 min, 85%; (d) Dess-Martin
periodinane (1.05 equiv), NaHCO (5.0 equiv), CH Cl , 25 °C, 2 h, 82%; (e)
LDA (1.5 equiv), THF, -78 °C, 30 min; acrolein (1.6 equiv), -78 °C, 30 min,
4%, d.r. ~5:1; (f) Et BOMe (1.2 equiv), THF, -78 °C, 30 min; LiBH (15.0
equiv), -78 to 25 °C, 4 h; NaOH (2.5 equiv), H (26 equiv), 0 °C, 1 h, 85%;
(g) PdCl (0.4 equiv), CuCl (3.0 equiv), NaOAc (5.0 equiv), CO (balloon),
AcOH, 25 °C, 12 h, 58%; (h) Karstedt's catalyst 36 (0.05 equiv), TBSH (1.5
equiv), CH Cl , 25 °C, 12 h, 41%; (i) Crabtree's catalyst (0.05 equiv), H
balloon), CH Cl , 25 C, 12 h, 86%.
4
3
2
2
3
2
2
7
2
4
2
O
2
2
2
2
2
2
(
2
2
Thus, pressing forward, treatment of ketone 34 with LDA
set the stage for an aldol reaction with acrolein, an operation
which afforded the β-hydroxy ketone domain of 38 as a 5:1
mixture of inseparable diastereomers favoring the drawn, de-
sired adduct. Next, a Narasaka–Prasad reduction (Et BOMe,
LiBH ) effected its smooth conversion into the desired 1,3-cis-
diol product 39 in 85% yield. That final material was con-
taminated by a few additional and inseparable isomers which
could be removed in the subsequent step. Of note, several
other non-chelating hydride sources were also examined for
2
4
3
9
3
.
Racemic Total Syntheses of Microcladallenes A and B
their ability to effect this reduction [such as LiAl(Ot-Bu) H
3
Our target-based efforts began with the microcladallenes (7
and 8), starting with the preparation of common intermediate
0 (Scheme 4). The first critical operation was the synthesis
of ketone 34. a material we hoped could be elaborated readily
to the final intermediate in a few further steps. In total, we
developed two different racemic routes to this material. The
first deployed a nucleophilic addition/oxidation approach with
aldehyde 33, formed by silylating and alkylating imine 31 with
TBSCl and alkyl iodide 32. The second used Karstedt’s cata-
lyst (36) to effect the addition of a silane across the alkyne of
5, followed by alkene reduction as modulated by Crabtree’s
catalyst. While the latter approach was half as long in terms of
step count, the first route proved far more suitable to scale-up
and, as a result, was used to generate all material supplies in
our initial studies.
and L-Selectride] in hopes of their executing similar control
under a Felkin–Ahn model of stereoselection; none delivered
a higher yield of product. Finally, with all stereocenters and
critical functionality in place, the final goal was to effect a
metal-mediated cyclocarbonylation reaction to sew up the two
ring systems in the form of bicyclic lactone 20. Following
some modest condition screening,
combination of PdCl and CuCl in the presence of a CO at-
mosphere in AcOH could convert diol 39 smoothly into com-
mon intermediate 20 in 58% yield.
2
31d,40
we observed that the
3
6
2
2
3
7
3
8
3
The task now was to construct the 6-membered bromoether
ring system of the microcladallenes from the lactone ring of
20. The first effort was a high-risk attempt, as noted earlier, to
achieve a potentially biomimetic 6-endo-trig bromoetherifica-
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 14
tion from a ring-opened alcohol/alkene-containing substrate.
We felt such a test was worthwhile since its success would
afford a highly concise solution and the test substrate was ex-
pected to be easily accessed. As shown in Scheme 5, that
ring-closure precursor (i.e. 40) could be prepared in just three
steps: DIBAL-H reduction to the lactol, Wittig olefination
with the ring-opened aldehyde, and a cross metathesis with
trans-3-hexene using the Hoveyda–Grubbs second generation
Scheme 6. Synthesis of the core brominated tetrahydropyran from
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
common intermediate 20.
PMBO
PMBO
MeONHMe•HCl
b) TBSCl
a) AlMe
3
,
O
H
O
H
H
O
O
c) DIBAL-H
(45%)
TBS
H
O
TBS
H
H
H
OTBS
H
2
0
45
41
initiator. As originally feared, subsequent efforts to induce
d) Br
2
3
, Et N
P(OPh)3
that 6-endo-trig bromoetherification with a variety of brome-
nium sources, shown here with NBS, failed to deliver 41.
Instead, complex mixtures were observed without any of the
critical signals characteristic of the desired framework as we
had observed in other, successful contexts. As such, an alter-
nate construction was pursued next by forging the tetrahydro-
pyran ring through a Tsuji–Trost-type reaction. Indeed, the
requisite substrate was also readily prepared by a three-step
opening sequence followed by a final acetate cleavage using
PMBO
Br
Br
e) TBAF
f ) ethyl
propiolate
PMBO
TBS
Br Br
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H
O
O
O
(63%
TBS
H
O
OEt from 45)
OTBS
H
H
4
7
O
46
R
H
H
g) AIBN,
n-Bu SnH
H
Br
(57%)
O
O
3
H
4
2
OEt
PMBO
PMBO
TBS
LiAlH4. Upon exposure of the resultant product (i.e. 43) to
4
3
h) LiAlH
i) PhSeCN,
P(n-oct)
4
H
H
H
PdCl (CH CN) , the desired tetrahydropyran ring was indeed
2
3
2
Br
Br
O
O
O
formed in 48% yield, but unfortunately the configuration of the
vinyl side-chain was opposite that desired (based on nOe).
3
;
TBS
H
O
OEt
H
2
O
2
O
H
(79%)
4
8
49
(2.5 equiv), MeONHMe•HCl (5.0 equiv),
THF, 0 to 25 °C, 3 h; (b) TBSCl (2.0 equiv), imidazole (6.0 equiv), DMF, 25 °C, 12
h, 57% over 2 steps; (c) DIBAL-H (1.1 equiv), CH Cl2, -78 °C, 15 min, 79%; (d)
Br (1.7 equiv), P(OPh) (2.0 equiv), Et N (3.0 equiv), CH Cl2, -78 to 25 °C, 12 h;
Thus, as shown in Scheme 6, a more efficacious solution
was ultimately identified where the bromine atom of the final
ring system could be installed directly via a radical-based ring
closure. Here, following an initial 3-step manipulation of
a
Reagents and conditions: (a) AlMe
3
2
2
3
3
2
(e) TBAF (6.2 equiv), THF, 0 to 25 °C, 2 h; (f) NMM (5.0 equiv), ethyl propiolate
44
(5.0 equiv), CH Cl , 25 °C, 4 h, 63% over 3 steps; (g) n-Bu SnH (1.2 equiv), AIBN
2
2
3
functional groups to arrive at protected aldehyde 45, subse-
(0.5 equiv), benzene, 90 °C, 1 h, 57%; (h) LiAlH
4
(1.1 equiv), THF, -78 °C, 30 min,
quent treatment with Br in the presence of Et N and P(OPh) ,
2 2
82%; (i) P(n-Oct)3 (10 equiv), PhSeCN (5.0 equiv), H O (21 equiv), THF, 0 to 25
°C, 12 h, 96%.
2
3
3
4
5
a procedure developed by Prati, afforded the gem-dibromide
of 46. Subsequent silyl ether cleavage and oxygen addition
onto ethyl propiolate then afforded the vinylogous ester of 47,
4
8 occurred in 57% yield, affording only a single stereoiso-
mer. We presume that the preference in adopting a chair-like
transition state for this event, as shown by the inset boxed
structure within Scheme 6, accounts for the observed stereose-
lectivity; Lee and co-workers had previously observed similar
4
6
poised for a radical-based ring closure as inspired by Lee.
Pleasingly, upon its exposure to AIBN in the presence of n-
Bu SnH in benzene at 80 °C, the desired closure to
3
4
6
stereoselection in their related systems. From here, a two-
step process involving reduction and dehydration converted
the exocyclic ester into the vinyl group of microcladallane B
in 79% overall yield.
Scheme 5. Initial failures to generate the brominated tetrahydro-
a
pyran ring of the microcladallenes.
PMBO
PMBO
a) DIBAL-H
e)
H
H
OH
O
MgBr
70%)
O
O
With both rings in place, the stage was now set to com-
mence the final set of operations leading to the key bromeni-
um-induced ring expansion. As indicated in Scheme 7, those
operations began by converting the PMB-protected alcohol
into the Z-enyne of 53 through a three-step procedure. Those
transformations, a DDQ-mediated deprotection, Dess–Martin
periodinane-mediated oxidation, and Julia–Kocienski olefina-
(
TBS
H
O
TBS
H
OH
H
H
2
0
42
a) DIBAL-H
b) Ph P=CH
c) trans-3-hexene,
f) allyl acetate,
H-G II initiator
3
2
(60%)
(51%)
g) LiAlH
4
H-G II initiator
PMBO
TBS
PMBO
TBS
47
H
H
H
tion using the anion derived from 51, proceeded smoothly in
OH
O
O
3
6% overall yield. With the requisite atoms in place, enyne 53
H
OH
H
OH
was then treated with 1.0 equivalent of BDSB in EtNO at –78
2
H
°C. After 30 min of reaction time, we observed the formation
of both microcladallene B (8) as well as its epimer, compound
54, in a 1.9:1 ratio and a combined 73% yield. Significantly,
the enyne could be chemoselectively activated in this event in
preference to the vinyl group to forge the expected trans-
oxocane ring, with the ultimate stereoselectivity of the allene
observed matching that observed from our initial model sys-
tems. Similar operations converting 49 into enyne 23 set the
stage for a similar ring expansion with a compound now lack-
ing a vinyl group, leading here to a 2.2:1 mixture of micro-
cladellene A (7) as well as its epimer which contained some
inseparable grease-based impurity. Again, that outcome near-
ly matched that observed in our earlier model studies. As
such, these two key ring expansions suggest that the additional
4
0
43
OH
(CH
d) NBS
(48%) h) PdCl
2
3 2
CN)
PMBO
TBS
PMBO
TBS
H
H
H
Br
OH
O
O
H
O
H
O
H
4
1
44
a
Reagents and conditions: (a) DIBAL-H (1.1 equiv), CH
min, 79%; (b) t-BuOK (3.1 equiv), Ph PCH Br (3.0 equiv), THF, 0 °C, 6 h,
5%; (c) H-G II initiator (0.05 equiv), trans-3-hexene (8.0 equiv), CH Cl2,
°C, h, 90%; (d) NBS (1.2 equiv), CH Cl2, °C, h; (e)
2 2
Cl , -78 °C, 15
3
3
8
2
2
5
3
2
0
2
vinylmagnesium bromide (10 equiv), toluene, 25 °C, 2 h, 88%; (f) H-G II
initiator (0.1 equiv), allyl acetate, 25 °C, 4 h, 54%; (g) LiAlH (1.0 equiv),
THF, 25 °C, 94%; (h) PdCl (CH CN) (0.05 equiv), THF, 0 °C, 3 h, 48%.
4
2
3
2
6
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Page 7 of 14
Journal of the American Chemical Society
6
-endo-bromoether ring system and its additional stereogenic
As shown in Scheme 8, it proved quite easy to advance
compound 20 into the key BDSB-based precursor (i.e. 21)
designed to fashion desepilaurallene (5). Those operations
included a similar PMB-based deprotection and oxidation
sequence as above, followed now with a Julia–Kocienski ole-
fination using the anion derived from sulfone 56. These steps
proceeded in 27% overall yield from 20. Then, following
exposure of this material to 0.8 equivalents of BDSB in tolu-
ene at –20 °C for 30 min, we observed a 3:4 mixture of desepi-
laurallene (5) and what we have assigned as its exocyclic bro-
mine diastereomer 57. They were obtained collectively in
86% yield, noting that this numerical outcome includes
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
center as expressed in 53 and 23 played little or no role in
determining the stereochemical outcome of the core cycliza-
tion step. Thus, if Nature were to use a similar ring-expansion
as part of her synthesis sequence (noting of course that she
would not use a TBS-group to terminate the sequence), these
findings would suggest that the 6-membered bromoether ring
need not be fashioned initially if high stereocontrol is the aim
of her synthetic approach; of course, enzymatic control in such
a process might be higher than that achieved simply through
inherent substrate preference.
completed 20-step total syntheses of these two targets, respec-
tively. Such lengths are comparable to those developed by the
Kim group in the only other synthesis of these targets, alt-
hough executed here through an entirely distinct strategy.
4
9
6a,48
Overall, these operations
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
6
Scheme 8. Total syntheses of desepilaurallene (5), prelaureatin
a
(4), and laurallene (6).
PMBO
O
a) DDQ
b) Dess-
Martin [O]
H
H
H
H
4
.
Racemic Total Synthesis of Desepilaurallene, Laurallene
and Prelaureatin
O
O
O
O
(48%)
TBS
H
O
TBS
H
O
With racemic routes to the microcladallenes completed, we
20
5
5
next turned our attention to efforts to convert key intermediate
0 into despilaurallene (5), laurallene (6), and prelaureatin (4).
(56%) c) 56, KHMDS
2
Here, it would be the initial lactone, not a 6-membered bromo-
ether, which would be attached to the core tetrahydrofuran
system used in the ring expansion leading to the 8-membered
rings of the targets. In addition, an alkene, not an enyne,
would have to be activated by the bromenium source.
Br
H
H
O
d) BDSB
H
O
O
(86%)
(5:57
O
O
TBS
H
O
H
=
3 : 4)
H
5: desepilaurallene
21
Scheme 7. Total syntheses of microcladallenes A and B (7 and
(96%) e) DIBAL-H
a
8
).
O
Br
H
PMBO
Br
H
H
H
H
O
H
a) Pd/C, H
2
O
Br
Br
g) 61
n-BuLi
H
O
O
b) Dess-
OH
TBS
H
O
TBS
H
O
Martin [O]
73%)
O
H
h) TBAF
(72%)
H
50
(
OH
H
4
9
6
0
20a,23
6
2: Murai/Crimminsintermediate
e) DDQ
f) 51, KHMDS
f) Dess-Martin [O]
g) 51, KHMDS
then TBAF
c) 51, KHMDS
then TBAF
(37%)
(33%) i) TBCO
(36%)
(49%)
then TBAF
Br
Br
H
H
H
H
H
O
O
H
H
Br
Br
O
O
•
H
O
OH
TBS
H
O
TBS
H
O
H
H
Br
H
3
4: prelaureatin
6: laurallene
5
O O
S
TMS
23
(71%)
(7:52 =
S
(
73%)
8:54 =
.9 : 1.0)
Br
H
h) BDSB
N
d) BDSB
(
Ph
O
O
S
2
.2 : 1.0)
H
O
1
51
N
N
3
PPh Br
O
N
•
•
N
TMS
H
O
H
O
O
H
H
Br
Br
H
Br
Br
Br
56
5
7
61
Proposed transition state analysis:
O
H
O
H
O
O
8
: microcladallene B
7: microcladallene A
O
H
Me
H
O
O
H
+
+
Br
Br
O
•
•
TBS
H
H
O
H
O
<
H
O
H
H
Br
TBS
H
H
TBS
H
•
Br
H
H
H
O
H
O
Br
TS*(not favored)
/H O (10:1 v/v), 25 °C,
(5.0 equiv), CH Cl , 25
C, 1 h, 48% over 2 steps; (c) 56 (3.0 equiv), KHMDS (2.7 equiv), DME, -78
C, 30 min, 56%; (d) BDSB (0.8 equiv), toluene, -20 °C, 1 h, 86% 5:57 = 3:4;
Cl , -78 °C, 15 min, 96%; (f) 51 (5.0 equiv),
Br
H
5
8
59 (slightly favored)
5
4: epi-microcladallene B
52: epi-microcladallene A
(balloon), EtOAc, 25 °C, 6 h;
(5.0 equiv), CH Cl2, 25 °C, 1
h, 73% over 2 steps; (c) 51 (3.0 equiv), KHMDS (2.5 equiv), THF, -20 to 0 °C, 1
h; TBAF (3.0 equiv), 0 °C, 10 min, 49%; (d) BDSB (1.0 equiv), EtNO , -78 °C, 30
min, 49% 7, 22% 52; (e) DDQ (1.5 equiv), CH Cl /H O (10/1 v/v), 25 °C, 1 h; (f)
Dess-Martin periodinane (1.1 equiv), NaHCO (5.0 equiv), CH Cl , 25 °C, 1 h,
3% over 2 steps; (g) 51 (3.0 equiv), KHMDS (2.5 equiv), THF, -20 to 0 °C, 1 h;
a
Reagents and conditions: (a) DDQ (1.5 equiv), CH
2
Cl
2
2
a
Reagents and conditions: (a) Pd/C (3.0 equiv), H
2
1 h; (b) Dess-Martin periodinane (1.1 equiv), NaHCO
3
2
2
(b) Dess-Martin periodinane (1.1 equiv), NaHCO
3
2
°
°
(
2
e) DIBAL-H (1.05 equiv), CH
2
2
2
2
2
KHMDS (4.5 equiv), THF, -20 to 0 °C, 6 h; TBAF (5.0 equiv), THF, 0 °C, 10
min, 37%; (g) 58 (3.0 equiv), n-BuLi (2.7 equiv), THF, 0 °C, 2 h, 84%; (h)
TBAF (1.1 equiv), THF, 0 °C, 10 min, 86%; (i) TBCO (1.3 equiv), CH
C, 12 h, 33%.
3
2
2
8
2 2
Cl , 25
2
TBAF (3.0 equiv), 0 °C, 10 min, 43%; (h) BDSB (1.0 equiv), EtNO , -78 °C, 30
min, 48% 8, 25% 54.
°
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Journal of the American Chemical Society
Page 8 of 14
some additional trace impurities that could not be removed;
their isolation and characterization required reduc-
ors sought to identify the means to prepare the lone silicon-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
based stereogenic center of 34 with enantiocontrol. Unfortu-
nately, all attempts to do so were unsuccessful. For example,
use of the Enders’ hydrazone derivative 63 failed to add alkyl
iodide 32 successfully, despite other published examples with
tion/reoxidation sequence (see SI for details) as they could not
be separated directly. Of note for this cyclization, increasing
the amount of BDSB led to inferior results. More interesting-
ly, solvent effects played a key role in the outcome. Although
the reaction proceeded in hexane, MeNO , EtNO , and CH Cl ,
5
1
different electrophiles affording enantioselective alkylations.
Similar efforts using the Myers’ pseudoephedrine amide auxil-
iary or Evans’ oxazolidone auxiliary (not shown) with an at-
2
2
2
2
toluene gave the best yield and selectivity for the desired
product while CH Cl gave the undesired isomer exclusively.
52
tached TBS group (as in 65) failed as well. These results
2
2
To date, this particular tetrahydrofuran-induced ring expansion
process reflects one of the least selective cyclizations ob-
served, though it is in line with some of our previously pub-
lished studies using silanes to terminate the process; it would
thus seem that the presence of the lactone ring system had no
might be due to low nucleophilicity of the substrates and/or
the observed instability of the α-TBS group to basic condi-
tions. Similarly, efforts at either asymmetric hydrogenation
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
3
under a variety of homogenous conditions as well as efforts
5
4
to effect a Rh-catalyzed Si–H insertion from diazo ketone
precursor 67 also were unsatisfactory. Indeed, in the former
case only decomposition or no reaction was observed, while in
the latter the desired adduct was formed as an inseparable mix-
ture of two diastereomers with 2.5:1 dr. Of note, the PMB-
protected variant of the 67 could not undergo the desired si-
lylation due to the much faster intramolecular carbene-
mediated C–H insertion occurred at the benzylic position. For
these reasons, this approach was ultimately abandoned since
enantiomerically pure 68 could not be obtained.
1
6
effect on the cyclization. As shown by the two proposed
transition states, 58 and 59, structures meant to capture bro-
3
monium opening (i.e. greater sp character as opposed to the
initial alkene of the starting material), there is potentially a
minor destabilizing steric interaction as noted within 58 rela-
tive to 59 to forge 5 in enhanced amounts; the overall impact,
though, is modest since a near equal (3:4) mixture of products
3
was formed. We believe that greater sp character of their
brominated carbons might explain the erosion of stereoselec-
tivity versus our earlier explored enyne-containing molecules,
*
reflected here with a drawing of transition state TS (also see
Scheme 9. Failed efforts to effect a direct, asymmetric synthesis
a
E-25 in Scheme 3) which would contain a strong 1,4-
of 34.
interaction that would impede effective formation of the oxo-
2
nium intermediate due to the sp -hybridization of the bromo-
LDA
N
N
N
allene carbon.
N
X
PMBO
PMBO
PMBO
OMe
OMe
I
3
2
In any event, we viewed the overall throughput as accepta-
ble, and effectively non-alterable, with three bonds cleaved
and three bonds forged in the process. From 5, prelaureatin
TBS
64
TBS
6
6
3
O
LDA
O
(
4) could be obtained in two further steps involving partial
X
reduction of the lactone to the lactol as mediated by DIBAL-
N
N
PMBO
TBS
OH
I
TBS
OH
H, followed by a Julia-Kocienski olefination with 51 and silyl
3
2
4
7
5
66
cleavage to unveil the enyne of the target. These two steps
proceeded in 37% overall yield. Similarly, 60 could be con-
verted into 62, using Wittig reagent 61 instead of 51 to effect
PMBO
PMBO
O
O
Chiral [Ir], H
2
5
0
E-selectivity in its enyne formation. A final TBCO-induced
Me
X
Me
2
3
cyclization, as developed originally by Murai and Crim-
TBS
37
TBS
34
2
0a
mins, completed the target molecule (6) in 66% yield. This
natural product was formed as a 1:1 mixture with another,
unassigned diastereomer (undrawn). Of note, we tested BDSB
in this terminal cyclization, but it was not successful. Overall,
these efforts in the context of Scheme 8 completed 3 addition-
al targets from our common intermediate (lactone 20) in 11,
13, and 15 steps in their longest linear sequences, respectively.
Given that these materials have a core distinct from that of the
microcladallenes, these endeavors show the value of common
TBSO
TBSH,
Rh (OAc)
2
TBSO
O
O
4
O
(90%)
O
(d.r. = 2.5:1)
TBS
N
2
6
7
68
As a result, we pursued a fully distinct synthetic approach
for 20 as shown retrosynthetically in Scheme 10 in which the
stereogenic centers would be established in a different order.
This new design was predicated, in part, on our previous ef-
forts to generate stereogenic C–Si groups during our efforts to
accomplish racemic total syntheses of E- and Z-
1
0,27,28
building block analysis
in reaching complex, structural
diversity. They also further highlight the power of the tetra-
hydrofuran-based ring expansion process, one that succeeds in
the presence of an array of functional groups and appended
ring systems.
1
6
pinnatifidenyne (3, cf. Scheme 1). Here, the overall sequence
would hinge on the ability to initially forge key diol configura-
tion from 71, potentially via a Sharpless asymmetric dihy-
droxylation, followed by a regioselective hydrosilylation.
That process would then be followed by a bromenium-induced
ring closure to generate the tetrahydrofuran ring followed by a
radical-based process to excise the quaternary bromide atom;
the latter event would need to proceed with retention of con-
5. Asymmetric Synthesis of Key Common Lactone
Finally, with racemic syntheses achieved, we next sought to
develop an enantioselective synthesis of our key intermediate
20 to afford a formal, asymmetric solution to all 5 of the tar-
gets prepared. However, as indicated in Scheme 9, such a
process proved far from trivial to execute. Our initial endeav-
8
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Journal of the American Chemical Society
this operation completed an effective, 10-step asymmetric
figuration upon H• recapture to deliver the requisite piece as a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
single enantiomer.
synthesis of key lactone 20, thereby establishing formal
asymmetric syntheses of all 5 targets presented in this work.
Pleasingly, that overall plan could be reduced to practice.
Starting from THP-protected propargyl alcohol (72, Scheme
a
1
1), this material was readily converted into 74 via an initial
Scheme 11. Asymmetric synthesis of common intermediate 20.
5
5
56
alkylation followed by a Pd-catalyzed carboxymethylation.
OMe
These events collectively proceeded in 25% overall yield with
the initial alkylation being the throughput limiting step of the
sequence at 33% yield. Next, building on well-established
precedent in achieving asymmetric Sharpless dihydroxylations
a) n-BuLi,
CuBr; 73
O
b) Pd(PPh ) ,
CO, KHCO3,
MeOH
3 4
THPO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
57
(25%)
THPO
of alkenes within α,β-unsaturated esters, 74 was converted
7
2
74
c) AD-mix α,
MeSO NH
2
d) TBDPSCl
2
e) p-TsOH•H O
5
8
into 75 in 47% overall yield and in 90% ee. These opera-
tions involved initial dihydroxylation and concomitant lactoni-
zation, followed by protection of the lone secondary alcohol as
a TBDPS ether and acidic-cleavage of the THP group. At this
stage, the newly unveiled alcohol could be deployed, through
its combination with dimethylvinylsilyl chloride (DMVS-Cl)
(
47%)
2
Br
Br
(90% ee)
73
H
TBDPSO
f) DMVS-Cl
g) Karstedt's
catalyst (36),
TBSH;
H
H
O
HO
O
H
O
and Et N, to facilitate a subsequent directed hydrosilylation as
TBS
HO
3
O
5
9
TBAF, AcOH
developed by Tomooka. This step afforded the desired regio-
control upon exposure to Karstedt’s catalyst (36), with an in
situ TBAF-mediated deprotection of the TBDPS-silyl ether
unveiling the free alcohol of 76. Critical to this final operation
was TBAF buffering with AcOH, as otherwise the β-hydroxyl
group on the lactone ring had a tendency to eliminate to form
an α,β-unsaturated variant.
(84%)
HO
7
6
75
h) Br(coll)
i) 77, MgO, MeOTf
2
PF
6
(62%)
PMBO
PMBO
TBS
j) n-Bu
Et B, air
3
3
SnH,
H
H
H
O
O
Br
TBS
O
(70%)
(20:78= 2 : 1)
O
H
O
H
O
H
6
9
20: common intermediate
Scheme 10. Proposed retrosynthetic analysis to achieve an
asymmetric synthesis of common intermediate 20.
and
PMBO
H
O
PMBO
PMBO
H
[Debromi-
nation]
H
O
O
O
PMB
O
N
TBS
H
O
O
Br
O
77
H
TBS
H
O
TBS
H
O
78
Reagents and conditions: (a) n-BuLi (1.05 equiv), THF, -78 °C, 10 min;
CuBr (1.1 equiv), 0 °C, 1 h; 73 (2.5 equiv), 25 °C, 4 h, 33%; (b) Pd(PPh
(0.05 equiv), KHCO (1.1 equiv), CO (75 atm), MeOH, 25 °C, 24 h, 76%; (c)
AD-mix-α, MeSO NH (1.1 equiv), t-BuOH/H O (1:1 v/v), 0 °C, 36 h; (d)
TBDPSCl (2.0 equiv), imidazole (4.0 equiv), CH Cl 25 °C, 6 h; (e)
TsOH•H O (0.1 equiv), MeOH, 25 °C, 3 h, 47% over 3 steps; (f) DMVSCl
1.2 equiv), Et N (1.5 equiv), CH Cl , 0 °C, 30 min, 88%; (g) Karstedt's
catalyst (0.02 equiv), TBSH (1.5 equiv), THF, 40 °C, 2 h; AcOH (2.2 equiv),
TBAF (2.2 equiv), 25 °C, 3 h, 95%; (h) Br(coll) PF (1.2 equiv), MeNO , 0
C, 30 min; (i) 77 (2.5 equiv), MgO (3.0 equiv), MeOTf (1.1 equiv), PhCF , 0
°C, 4 h, 62%; (j) n-Bu SnH (1.5 equiv), Et B (0.1 equiv), air, toluene, -78 °C,
0 min, 47% 20, 23% 78.
H
H
a
2
0: common intermediate
69
3 4
)
3
[
THF
2
2
2
formation]
2
2
,
OMe
2
H
H
(
3
2
2
HO
O
[
[
Hydrosilylation]
O
TBS
2
6
2
O
°
3
Sharpless AD] RO
3
3
3
RO
7
1
70
CONCLUSIONꢀ
With these operations complete, the remaining tasks were to
forge the tetrahydrofuran ring system of 20 along with its at-
tendant silicon group as a single stereoisomer. The first opera-
tion along these lines, a bromonium-induced cyclization to
generate 69, proceeded smoothly in 62% overall yield using
Br(coll) PF as the halenium source followed by a subsequent
Over the past several decades, the unique structures of the
Laurencia family of natural products has provided a tremen-
dous source of inspiration for the development of novel syn-
thetic strategies and approaches. This article details the cul-
mination of a significant body of studies using tetrahydrofu-
rans to effect ring-expansions leading to 8-membered oxocane
rings. Of critical importance here, we show that such tetrahy-
drofurans can add effectively onto bromonium-activated
enynes, that good levels of inherent stereocontrol in such addi-
tions can be achieved in the absence of additional rings and
stereocenters for a number of targets, and that, at present, 7
natural products (which includes our previously published
2
6
6
0
PMB protection of the remaining primary alcohol with 77.
Of note, the use of other halogen sources afforded less optimal
results both in terms of yield as well as overall stereoselection,
with the use of reagent 77 and acidic conditions being critical
in the second step as the intermediate bromide was not stable
to base. Finally, exposure to n-Bu SnH under radical condi-
tions as initiated by Et B in air afforded a 2:1 separable mix-
ture of 20 and its epimer 78 in 70% overall yield, presumably
due to some equilibration of the radical intermediate to its
thermodynamically most stable form. Several other attempts
with both radical and non-radical conditions failed (n-
3
3
16
work) and an array of model systems can result with good to
excellent selectivity through the general process. In total as
shown here, 5 of those natural products can arise from a single
intermediate, with those materials encompassing two distinct
8
-membered ring collections. As such, we believe that the
Bu SnH/AIBN, TTMS/AIBN, and Raney Nickel). Overall,
3
9
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Journal of the American Chemical Society
core ring-expansion process delineated here for 8-membered
Page 10 of 14
Lett. 2005, 7, 75. (j) Tadashi, M.; Hajime, M. Synthetic Studies of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ring synthesis has biosynthetic relevance, with Nature using
tetrahydrofuran rings as a prelude to her preparation of 8-
membered, polycyclic materials. Outside of this core reaction,
we have also demonstrated a number of chemoselective pro-
cesses on advanced frameworks, and hope, in further work, to
utilize the synthesized materials for more thorough biochemi-
cal evaluations of the class.
Laurencin and Related Compounds. II The Synthesis of cis-Ethyl-
8-formyl-7,8-dihydro-2H-oxocin-3(4H)-one 3-Ethylene Acetal.
Chem. Lett. 1975, 4, 895. (k) Murai, A.; Murase, H.; Matsue, H.;
Masamune, T. The Synthesis of (±)-Laurencin. Tetrahedron Lett.
1
977, 29, 2507. (l) Clark, J. S.; Holmes, A. B. A Strategy for the
Asymmetric Synthesis of Medium Ring Oxygen Heterocycles:
Enantioselective Total Synthesis of (+)-
Octahydrodeacetyldebromolaurencin. Tetrahedron Lett. 1988, 29,
4333. (m) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto,
T. Total Synthesis of (+)-Laurencin. Use of Acetal-Vinyl Sulfide
Cyclizations for Forming Highly Functionalized Eight-Membered
Cyclic Ethers. J. Am. Chem. Soc. 1995, 117, 5958. (n) Krüger, J.;
Hoffmann, R. W. Substituted Oxocanes by Intramolecular Al-
lylboration Reactions. Entry to an Efficient Synthesis of (+)-
Laurencin. J. Am. Chem. Soc. 1997, 119, 7499. (o) Burton, J. W.;
Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.; Holmes, A. B.
Synthesis of Medium Ring Ethers. 5. The Synthesis of (+)-
Laurencin. J. Am. Chem. Soc. 1997, 119, 7483. (p) Fujiwara, K.;
Yoshimoto, S.; Takizawa, A.; Souma, S.-i.; Mishima, H.; Murai,
A.; Kawai, H.; Suzuki, T. Synthesis of (+)-laurencin via ring ex-
pansion of a C-glycoside derivative. Tetrahedron Lett. 2005, 46,
ASSOCIATEDꢀCONTENTꢀ
SupportingꢀInformationꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Detailedꢀ experimentalꢀ procedures,ꢀ copiesꢀ ofꢀ allꢀ spectralꢀ
dataꢀ andꢀ fullꢀ characterization.ꢀ ꢀ Thisꢀ materialꢀ isꢀ availableꢀ
freeꢀofꢀchargeꢀviaꢀtheꢀInternetꢀatꢀhttp://pubs.acs.org.ꢀ
AUTHORꢀINFORMATIONꢀꢀꢀ
Correspondingꢀauthor:ꢀsasnyder@uchicago.edu.ꢀꢀꢀ
Notes:ꢀtheꢀauthorsꢀdeclareꢀnoꢀcompetingꢀfinancialꢀinterest.ꢀ
ACKNOWLEDGMENTꢀꢀ
6
819. (q) Lanier, M. L.; Park, H.; Mukherjee, P.; Timmerman, J.
C.; Ribeiro, A. A.; Widenhoefer, R. A.; Hong, J. Formal Synthe-
sis of (+)-Laurencin by Gold(I)-Catalyzed Intramolecular Dehy-
drative Alkoxylation. Chem. Eur. J. 2017, 23, 7180.
(3) (a) Wang, B.-G.; Gloer, J. B.; Ji, N.-Y.; Zhao, J.-C. Halo-
genated Organic Molecules of Rhodomelaceae Origin: Chemistry
and Biology. Chem. Rev. 2013, 113, 3632. (b) Wanke, T.; Philip-
pus, A. C.; Zatelli, G. A.; Vieira, L. F. O.; Lhullier, C.; Falken-
berg, M. C15 Acetogenins from the Laurencia Complex: 50 Years
of Research – an Overview. Revista Brasileira de Farmacogno-
sia, 2015, 25, 569.
We thank Dr. Antoni Jurkiewicz and Dr. C. Jin Qin for assis-
tance with NMR and mass spectrometry, respectively. Finan-
cial support for this work came from the University of Chica-
go (start-up funds to S.A.S. and a Metcalf Fellowship to N.Y.).
Y.-A. Z. was a 2017 Abbvie Scholar. Some very preliminary
studies related to Table 1 were conducted (by Y.-A. Z.) at The
Scripps Research Institute on their Jupiter, FL campus just
prior to our move to the University of Chicago in September
of 2015.
(
4) (a) Fukuzawa, A.; Aye, M.; Murai, A. A Direct Enzymatic
Synthesis of Laurencin from Laurediol. Chem. Lett. 1990, 19,
579. (b) Fukuzawa, A.; Aye, M.; Takasugi, Y.; Nakamura, M.;
1
Tamura, M.; Murai, A. Enzymatic Bromo-ether Cyclization of
Laurediols with Bromoperoxidase. Chem. Lett. 1994, 23, 2307.
(c) Kaneko, K.; Washio, K.; Umezawa, K.; Matsuda, F.; Mori-
kawa, M.; Okino, T. cDNA Cloning and Characterization of Va-
nadium-Dependent Bromoperoxidases from the Red Alga Lau-
rencia nipponica. Bioscience, Biotechnology, and Biochemistry
REFERENCESꢀ
(
1) (a) Irie, T.; Suzuki, M.; Masamune, T. Laurencin, a Con-
stituent from Laurencia Species. Tetrahedron Lett. 1965, 6, 1091.
b) Irie, T.; Suzuki, M.; Masamune, T. Laurencin, a Constituent of
(
Laurencia Glandulifera Kützing. Tetrahedron 1968, 24, 4193.
(2) (a) Tsushima, K.; Murai, A. Total Synthesis of (+)-
Laurencin. Tetrahedron Lett. 1992, 33, 4345. (b) Li, J.; Suh, J.
M.; Chin, E. Expedient Enantioselective Synthesis of the Δ4-
Oxocene Cores of (+)-Laurencin and (+)-Prelaureatin. Org.
Lett. 2010, 12, 4712. (c) Lin, R.; Cao, L.; West, F. G. Medium-
Sized Cyclic Ethers via Stevens [1,2]-Shift of Mixed Monothio-
acetal-Derived Sulfonium Ylides: Application to Formal Synthe-
sis of (+)-Laurencin. Org. Lett. 2017, 19, 552. (d) Crimmins, M.
T.; Choy, A. L. An Asymmetric Aldol-Ring-Closing Metathesis
Strategy for the Enantioselective Construction of Oxygen Hetero-
cycles:ꢀ An Efficient Approach to the Enantioselective Synthesis
of (+)-Laurencin. J. Am. Chem. Soc. 1999, 121, 5653. (e) Crim-
mins, M. T.; Emmitte, K. A. Total Synthesis of (+)-Laurencin:ꢀAn
Asymmetric Alkylation-Ring-Closing Metathesis Approach to
Medium Ring Ethers. Org. Lett. 1999, 1, 2029. (f) Adsool, V. A.;
Pansare, S. V. An enantioselective approach to (+)-laurencin.
Org. Biomol. Chem. 2008, 6, 2011. (g) Ortega, N.; Martín, V. S.;
Martín, T. An Approach to Lauroxanes by Iterative Use of
Co (CO) -Acetylenic Complexes. A Formal Synthesis of (+)-
2
014, 78, 1310.
5) Fujiwara, K. Total Synthesis of Medium-Ring Ethers from
(
Laurencia Red Algae. Top. Heterocycl. Chem. 2006, 5, 97.
(6) (a) Tan, C. K.; Zhao, Y.; Zhou, J.; Yeung, Y.-Y. Stereose-
lective Halogenations. In Stereoselective Synthesis of Drugs and
Natural Products, 2 Volume Set, First Edition; Andrushko, V.,
Andrushko, N., Eds.; John Wiley & Sons: New Jersey, 2013;
Chapter 42, pp 1281. (b) Chung, W.-j.; Vanderwal, C. D. Stere-
oselective Halogenation in Natural Product Synthesis Angew.
Chem. Int. Ed. 2016, 55, 4396.
(
7) (a) Bonney, K. J.; Braddock, D. C.; White, A. J. P.; Ya-
qoob, M. Intramolecular Bromonium Ion Assisted Epoxide Ring-
Opening: Capture of the Oxonium Ion with an Added External
Nucleophile. J. Org. Chem. 2011, 76, 97. (b) Bonney, K. J.; Brad-
dock, D. C. A Unifying Stereochemical Analysis for the For-
mation of Halogenated C -Acetogenin Medium-Ring Ethers
1
5
From Laurencia Species via Intramolecular Bromonium Ion As-
sisted Epoxide Ring Opening and Experimental Corroboration
with a Model Epoxide. J. Org. Chem. 2012, 77, 9574. (c) Brad-
dock, D. C.; Sbircea, D.-T. Proof-of-Principle Direct Double Cy-
2
6
Laurencin. J. Org. Chem. 2010, 75, 6660. (h) Mujica, M. T.;
Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Enantioselective
Synthesis of Cyclic Ethers via Hetero Diels-Alder Reaction. For-
mal Synthesis of (+)- and (−)-Laurecin. Synlett. 1996, 983. (i)
Baek, S.; Jo, H.; Kim, H.; Kim, H.; Kim, S.; Kim, D. Highly Ste-
reoselective and Efficient Total Synthesis of (+)-Laurencin. Org.
clisation of a Linear C -Precursor to a Dibrominated Bicyclic
15
Medium-Ring Ether Relevant to Laurencia Species. Chem. Com-
mun. 2014, 50, 12691.
1
0
ACS Paragon Plus Environment

Page 11 of 14
Journal of the American Chemical Society
(
8) Keshipeddy, S.; Martínez, I.; Castillo II, B. F.; Morton, M.
(22) Fukuzawa, A.; Kurosawa, E. Laurallene, New Bromo-
allene from the Marine Red Alga Laurencia Nipponica Yamada
Tetrahedron Lett. 1979, 20, 2797.
(23) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.; Fuku-
zawa, A.; Murai, A. Conversion of Prelaureatin into Laurallene, a
Bromo-Allene Compound, by Enzymatic and Chemical Bromo-
Etherification Reaction. Tetrahedron 1997, 53, 8371.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
D.; Howell, A. R. Toward a Formal Synthesis of Laureatin: Un-
expected Rearrangements Involving Cyclic Ether Nucleophiles. J.
Org. Chem. 2012, 77, 7883.
(
9) Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouységu,
L. Plant Polyphenols: Chemical Properties, Biological Activities,
and Synthesis. Angew. Chem. Int. Ed. 2011, 50, 586.
(
10) Snyder, S. A.; Gollner, A.; Chiriac, M. I. Regioselective
(24) (a) Saitoh, T.; Suzuki, T.; Sugimoto, M.; Hagiwara, H.;
Hoshi, T. Total Synthesis of (+)-Laurallene. Tetrahedron.
Lett. 2003, 44, 3175. (b) Sasaki, M.; Hashimoto, A.; Tanaka, K.;
Kawahata, M.; Yamaguchi, K.; Takeda, K. Diastereoselective
Brook Rearrangement-Mediated [3 + 4] Annulation: Application
to a Formal Synthesis of (+)-Laurallene. Org. Lett. 2008, 10,
1803. (c) Yoshimura, F.; Okada, T.; Tanino, K. Asymmetric Total
Synthesis of Laurallene. Org. Lett. 2019, 21, 559.
(25) (a) Kennedy, D. J.; Selby, I. A.; Cowe, H. J.; Cox, P. J.;
Thomson, R. H. Bromoallenes from the Alga Laurencia Micro-
cladia. J. Chem. Soc., Chem. Commun. 1984, 153. (b) Suzuki, M.;
Nakano, S.; Takahashi, Y.; Abe, T.; Masuda, M.; Takahashi, H.;
Kobayashi, K. Brominated Labdane-Type Diterpenoids from an
Okinawan Laurencia sp. J. Nat. Prod. 2002, 65, 801.
(26) (a) Park, J.; Kim, B.; Kim, H.; Kim, S.; Kim, D. Substrate-
Controlled Asymmetric Total Synthesis of (+)-Microcladallene B
with a Bromination Strategy Based on a Nucleophile-Assisting
Leaving Group. Angew. Chem. Int. Ed. 2007, 46, 4726. (b) Sohn,
T.-i.; Kim, D.; Paton, R. S. Substrate-Controlled Asymmetric
Total Syntheses of Microcladallenes A, B, C Based on the Pro-
posed Structures. Chem. Eur. J. 2015, 21, 15988.
(27) Li, L.; Chen, Z.; Zhang, X.; Jia, Y. Divergent Strategy in
Natural Product Total Synthesis. Chem. Rev. 2018, 118, 3752.
(28) Sherwood, T. C.; Trotta, A. H.; Snyder, S. A. A Strategy
for Complex Dimer Formation When Biomimicry Fails: Total
Synthesis of Ten Coccinellid Alkaloids. J. Am. Chem. Soc. 2014,
136, 9743.
Reactions for Programmable Resveratrol Oligomer Synthesis.
Nature, 2011, 474, 461.
(
R. H.; Sheppard, R. N.; Solanki, S.; White, A. J. P. Bromonium
Ion Induced Transannular Oxonium Ion Formation-Fragmentation
in Model Obtusallene Systems and Structural Reassignment of
Obtusallenes V-VII. J. Org. Chem. 2009, 74, 1835.
(12) Braddock, D. C. A Hypothesis Concerning the Biosynthe-
sis of the Obtusallene Family of Marine Natural Products via
Electrophilic Bromination. Org. Lett. 2006, 8, 6055.
11) Braddock, D. C.; Millan, D. S.; Pérez-Fuertes, Y.; Pouwer,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
13) (a) Kim, B.; Lee, M.; Kim, M. J.; Lee, H.; Kim, S.; Kim,
D.; Koh, M.; Park, S. B.; Shin, K. J. Biomimetic Asymmetric
Total Synthesis of (–)-Laurefucin via an Organoselenium-
Mediated Intramolecular Hydroxyetherification. J. Am. Chem.
Soc. 2008, 130, 16807. (b) Dyson, B. S.; Burton, J. W.; Sohn, T.-
i.; Kim, B.; Bae, H.; Kim, D. Total Synthesis and Structure Con-
firmation of Elatenyne: Success of Computational Methods for
NMR Prediction with Highly Flexible Diastereomers. J. Am.
Chem. Soc. 2012, 134, 11781.
(
14) Taylor, M. T.; Fox, J. M. Biosynthesis of the C -
15
Acetogenin Laurepoxide may Involve Bromine-Induced Skeletal
Rearrangement of a Δ4-Oxocene Precursor. Tetrahedron Lett.
015, 56, 3560.
2
(15) Sugimoto, M.; Suzuki, T.; Hagiwara, H.; Hoshi, T. The
First Total Synthesis of (+)-(Z)-Laureatin. Tetrahedron Lett. 2007,
8, 1109.
16) (a) Snyder, S. A.; Treitler, D. S.; Brucks, A. P.; Sattler, W.
4
(
(29) Denmark, S. E.; Burk, M. T.; Hoover, A. J. On the Abso-
lute Configurational Stability of Bromonium and Chloronium
Ions. J. Am. Chem. Soc. 2010, 132, 1232.
I. A General Strategy for the Stereocontrolled Preparation of Di-
verse 8- and 9-Membered Laurencia-Type Bromoethers. J. Am.
Chem. Soc. 2011, 133, 15898. (b) Snyder, S. A.; Brucks, A. P.;
Treitler, D. S.; Moga, I. Concise Synthetic Approaches for the
Laurencia Family: Formal Total Syntheses of (±)-Laurefucin and
(30) (a) Hashimoto, M.; Kan, T.; Yanagiya, M.; Shirahama, H.;
Matsumoto, T. Synthesis of A-B-C-Ring Segment of Thyrsiferol
Construction of a Strained Tetrahydropyran Ring Existent as a
Boat Form. Tetrahedron. Lett. 1987, 28, 5665. (b) Hashimoto, M.;
Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.; Matsumoto, T.
Total Syntheses of (+)-Thyrsiferol and (+)-Venustatriol. Tetrahe-
dron. Lett. 1988, 29, 1143. (c) Corey, E. J.; Ha, D.-C. Total Syn-
thesis of Venustatriol. Tetrahedron. Lett. 1988, 29, 3171. (d)
Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama,
H.; Matsumoto, T. Total Syntheses of (+)-Thyrsiferol, (+)-
Thyrsiferyl 23-Acetate, and (+)-Venustatriol. J. Org. Chem. 1990,
55, 5088. (d) Conzález, I. C.; Forsyth, C. J. Total Synthesis of
Thyrsiferyl 23-Acetate, a Specific Inhibitor of Protein Phospha-
tase 2A and an Anti-Leukemic Inducer of Apoptosis. J. Am.
Chem. Soc. 2000, 122, 9099. (d) Gottwald, T.; Greb, M.; Hartung,
J. Synlett 2004, 65. (e) Crimmins, M. T.; Hughes, C. O. Total
Synthesis of the Proposed Structure of Aldingenin B. Org. Lett.
2012, 14, 2168. (f) Huang, D.; Wang, H.; Xue, F.; Guan, H.; Li,
L.; Peng, X.; Shi, Y. Enantioselective Bromocyclization of Ole-
fins Catalyzed by Chiral Phosphoric Acid. Org. Lett. 2011, 13,
6350. (g) Takahashi, S.; Yasuda, M.; Nakamura, T.; Hatano, K.;
Matsuoka, K.; Koshino, H. Synthesis and Structural Revision of a
Brominated Sesquiterpenoid, Aldingenin C. J. Org. Chem. 2014,
79, 9373. (h) Levinson, A. M.; Milner, P. J.; Snyder, S. A. Studies
in Selective 6-Membered Bromoether Formation via Bromonium
(
1
±)-E- and (±)-Z-Pinnatifidenyne. J. Am. Chem. Soc. 2012, 134,
7714.
17) (a) Snyder, S. A.; Treitler, D. S. Et SBr•SbCl Br: An Ef-
(
2
5
fective Reagent for Direct Bromonium-Induced Polyene Cycliza-
tions. Angew. Chem. Int. Ed. 2009, 48, 7899. (b) Snyder, S. A.;
Treitler, D. S. Synthesis of Et SBr•SbCl Br and Its Use in Bio-
mimetic Brominative Polyene Cyclizations. Org. Synth. 2011, 88,
54.
2
5
(
18) Fukuzawa, A.; Takasugi, Y.; Murai, A. Prelaureatin, a
New Biogenetic Key Intermediate Isolated from Laurencia Nip-
ponica. Tetrahedron. Lett. 1991, 32, 5597.
(
Tamura, M. Enzymatic Single-step Formation of Laureatin and
Its Key Intermediate, Prelaureatin, from (3Z, 6S, 7S)-Laurediol.
Tetrahedron Lett. 1992, 33, 2017.
19) Fukuzawa, A.; Takasugi, Y.; Murai, A.; Nakamura, M.;
(
20) (a) Crimmins, M. T.; Tabet, E. A. Total Synthesis of (+)-
Prelaureatin and (+)-Laurallene. J. Am. Chem. Soc. 2000, 122,
473. (b) Fujiwaraa, K.; Souma, S.-i.; Mishima, H.; Murai, A.
5
Total Synthesis of Prelaureatin. Synlett. 2002, 1493. (c) Sasaki,
M.; Oyamada, K.; Takeda, K. Formal Total Syntheses of (+)-
Prelaureatin and (+)-Laurallene by Diastereoselective Brook Re-
arrangement-Mediated [3 + 4] Annulation. J. Org. Chem. 2010,
75, 3941.
and
Thiiranium-Induced
Cyclizations.
Tetrahedron.
(
21) Li, X.-D.; Miao, F.-P.; Li, K.; Ji, N.-Y. Sesquiterpenes and
Lett. 2015, 56, 3553. (i) Hoshino, A.; Nakai, H.; Morino, M.;
Nishikawa, K.; Kodama, T.; Nishikibe, K.; Morimoto, Y. Total
Synthesis of the Cytotoxic Marine Triterpenoid Isodehydro-
Acetogenins from the Marine Red Alga Laurencia Okamurai.
Fitoterapia, 2012, 83, 518.
1
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 14
thyrsiferol Reveals Enantiodivergency in the Thyrsiferol Family
Oxygen Bond Lengths at the .beta. Position: Some Structural
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of Natural Products. Angew. Chem. Int. Ed. 2017, 56, 3064. (j)
Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Aminothiocarbamate-
Catalyzed Asymmetric Bromolactonization of 1,2-Disubstituted
Olefinic Acids. Org. Lett. 2011, 13, 2738. (k) Denmark, S. E.;
Burk, M. T. Enantioselective Bromocycloetherification by Lewis
Base/Chiral Brønsted Acid Cooperative Catalysis. Org. Lett.
Studies. J. Org. Chem. 1992, 57, 4638.
(36) Tietze, L. F.; Neumann, T.; Kajino, M.; Pretor, M. Effi-
cient Synthesis of Branched Propargyl- and Allylsilanes. Synthe-
sis 1995, 1003.
(37) Stein, J.; Lewis, L. N.; Gao, Y.; Scott, R. A. In Situ De-
termination of the Active Catalyst in Hydrosilylation Reactions
Using Highly Reactive Pt(0) Catalyst Precursors. J. Am. Chem.
Soc. 1999, 121, 3693.
(38) (a) Rooke, D. A.; Ferreira, E. M. Platinum-Catalyzed Hy-
drosilylations of Internal Alkynes: Harnessing Substituent Effects
to Achieve High Regioselectivity. Angew. Chem. Int. Ed. 2012,
51, 3225. (b) Rooke, D. A.; Menard, Z. A.; Ferreira, E. M An
Analysis of the Influences Dictating Regioselectivity in Platinum
catalyzed Hydrosilylations of Internal Alkynes. Tetrahedron
2014, 70, 4232.
(39) Dias, L. C.; Polo, E. C.; Ferreira, M. A. B.; Tormena, C. F.
1,5-Stereoinduction in Boron-Mediated Aldol Reactions of β,δ-
Bisalkoxy Methylketones Containing Cyclic Protecting Groups. J.
Org. Chem. 2012, 77, 3766.
(40) (a) Tang, Y.; Zhang, Y.; Dai, M.; Luo, T.; Deng, L.; Chen,
J.; Yang, Z. A Highly Efficient Synthesis of the FGH Ring of
Micrandilactone A. Application of Thioureas as Ligands in the
Co-Catalyzed Pauson-Khand Reaction and Pd-Catalyzed Car-
bonylative Annulation. Org. Lett. 2005, 7, 885. (b) Xu, X.-S.; Li,
Z.-W.; Zhang, Y.-J.; Peng, X.-S.; Wong, H. N. C. Total Synthesis
of (±)-Pallambins C and D. Chem. Commun. 2012, 48, 8517. (c)
Markovič, M.; Ďuranová, M.; Koóš, P.; Szolcsányi, P.; Gracza, T.
Synthesis of bis-Tetrahydrofuran Subunit of (−)-Neopallavicinin.
Tetrahedron 2013, 69, 4185.
(41) Lacharity, J. J.; Fournier, J.; Lu, P.; Mailyan, A. K.;
Herrmann, A. T.; Zakarian, A. Total Synthesis of Unsymmetrical-
ly Oxidized Nuphar Thioalkaloids via Copper-Catalyzed Thiolane
Assembly. J. Am. Chem. Soc. 2017, 139, 13272.
(42) Mak, S. Y. F.; Curtis, N. R.; Payne, A. N.; Congreve, M.
S.; Wildsmith, A. J.; Francis, C. L.; Davies, J. E.; Pascu, S. I.;
Burton, J. W.; Holmes, A. B. Synthesis of (+)-Obtusenyne. Chem.
Eur. J. 2008, 14, 2867.
2
012, 14, 256. (l) Einaru, S.; Shitamichi, K.; Nagano, T.; Matsu-
moto, A.; Asano, K.; Matsubara, S. trans-Cyclooctenes as Halo-
lactonization Catalysts. Angew. Chem. Int. Ed. 2018, 57, 13863.
(
31) (a) Evans, P. A.; Murthy, V. S.; Roseman, J. D.;
Rheingold, A. L. Enantioselective Total Synthesis of the Noniso-
prenoid Sesquiterpene (−)-Kumausallene. Angew. Chem. Int. Ed.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
999, 38, 3175. (b) Braddock, D. C.; Bhuva, R.; Pérez-Fuertes,
Y.; Pouwer, R.; Roberts, C. A.; Ruggiero, A.; Stokes, E. S. E.;
White, A. J. P. The Stereochemical Course of Bromoetherification
of Enynes. Chem. Commun. 2008, 1419. (c) Sabot, C.; Bérard, D.;
Canesi, S. Expeditious Total Syntheses of Natural Allenic Prod-
ucts via Aromatic Ring Umpolung. Org. Lett. 2008, 10, 4629. (d)
Guérard, K. C.; Sabot, C.; Beaulieu, M.-A.; Giroux, M.-A.; Ca-
nesi, S. ‘Aromatic Ring Umpolung’, a Rapid Access to the Main
Core of Several Natural Products. Tetrahedron 2010, 66, 5893. (e)
Werness, J. B.; Tang, W. Stereoselective Total Synthesis of (–)-
Kumausallene. Org. Lett. 2011, 13, 3664. (f) Yamakawa, M.;
Kurachi, T.; Yoshikawa, Y.; Arisawa, M.; Okino, Y.; Suzuki, K.;
Fujioka, H. Stereoselective Construction of 2,7-Disubstituted
fused-Bis Tetrahydrofuran Skeletons: Biomimetic-Type Synthesis
and Biological Evaluation of (±)- and (−)-Aplysiallene and Their
Derivatives. J. Org. Chem. 2015, 80, 10261. (g) Alnafta, N.;
Schmidt, J. P.; Nesbitt, C. L.; McErlean, C. S. P. Total Synthesis
of (+)-Panacene. Org. Lett. 2016, 18, 6520.
(32) (a) Zhang, W.; Xu, H.; Xu, H.; Tang, W. DABCO-
Catalyzed 1,4-Bromolactonization of Conjugated Enynes: Highly
Stereoselective Formation of a Stereogenic Center and an Axially
Chiral Allene. J. Am. Chem. Soc. 2009, 131, 3832. (b) Zhang, W.;
Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, W. Enanti-
oselective Bromolactonization of Conjugated (Z)-Enynes. J. Am.
Chem. Soc. 2010, 132, 3664. (c) Werness, J. B.; Tang, W. Synthe-
sis of Bromoallenyl Pyrrolidines via 1,4-Addition to 1,3-Enynes.
Sci. China. Chem. 2011, 54, 56. (d) Liu, N.; Werness, J. B.;
Guzei, I. A.; Tang, W. Intramolecular 1,4-Addition of Nitrogen
Nucleophile and Bromine Electrophile to Conjugated 1,3-Enyne.
Tetrahedron 2011, 67, 4385. (e) Zhang, W.; Liu, N.; Schienebeck,
C. M.; Decloux, K.; Zheng, S.; Werness, J. B.; Tang, W. Catalytic
Enantioselective Halolactonization of Enynes and Alkenes. Chem.
Eur. J. 2012, 18, 7296. (f) Wang, H.-Y.; Zhang, W.; Schienebeck,
C. M.; Bennett, S. R.; Tang, W. Intermolecular Bromoesterifica-
tion of Conjugated Enynes: an Efficient Synthesis of Bromo-
allenes. Org. Chem. Front. 2014, 1, 386.
(43) (a) Uenishi, J.; Vikhe, Y. S.; Kawai, N. Stereochemistry
and Mechanistic Study of Intramolecular Pd -Catalyzed Oxypal-
II
ladation and 1,3-Chirality-Transfer Reactions. Chem. Asian J.
2008, 3, 473. (b) Aponick, A.; Li, C.-Y.; Biannic, B. Au-
Catalyzed Cyclization of Monoallylic Diols. Org. Lett. 2008, 10,
669. (c) Yokoyama, H.; Nakayama, S.; Murase, M.; Miyazawa,
M.; Yamaguchi, S.; Hirai, Y. Pd(II)-Catalyzed Cyclization to
Ether and Its Application to the Synthesis of the trans-Fused Pol-
yether Core. Heterocycles 2009, 77, 211. (d) Shin, I.; Hong, S.;
Krische, M. J. Total Synthesis of Swinholide A: An Exposition in
Hydrogen-Mediated C-C bond Formation. J. Am. Chem. Soc.
2016, 138, 14246. (e) Yokoyama, H.; Matsuo, M.; Miyazawa, M.;
Hirai, Y. Stereoselective Construction of Polyether trans-Pyran
Ring System by Gold(I)-Catalyzed Cyclization. Synlett 2016, 27,
2731. (f) Rohrs, T. M.; Qin, Q.; Floreancig, P. E. Re O -Mediated
Dehydrative Cyclization Reactions: Total Synthesis of Herbox-
idiene and Its 12-Desmethyl Analogue. Angew. Chem. Int. Ed.
2017, 56, 10900.
(44) Ball, M.; Gregson, T.; Omori, H.; Thomas, E. J. Syntheses
of C17-C27 Fragments of 20-Deoxybryostatins for Assembly
Using Julia and Metathesis Reactions. Org. Biomol. Chem. 2017,
15, 2740.
(
33) Homsi, F.; Robin, S.; Rousseau, G. Preparation of
Bis(2,4,6-trimethylpyridine) Iodine(I) Hexafluorophosphate and
Bis(2,4,6-trimethylpyridine) Bromine(I) Hexafluorophosphate
Org. Synth. 2000, 77, 206.
(34) Although only 0.8 equiv of BDSB was used in these con-
versions to achieve optimal yields, complete consumption of start-
ing material was observed. We assume that HBr, generated as the
reaction proceeded, likely led to decomposition of some of the
starting material and/or product to push the reaction to comple-
tion.
2
7
(
35) (a) Hudrlik, P. F.; Peterson, D. Stereospecific Olefin-
Forming Elimination Reaction of beta-Hydroxyalkysilanes. J. Am.
Chem. Soc. 1975, 97, 1464. (b) Lambert, J. B.; Finzel, R. B. The
Modes of .beta.-Silyl Involvement in Solvolysis. J. Am. Chem.
Soc. 1982, 104, 2020. (c) White, J. M.; Robertson, G. B. Stereoe-
lectronic Effect of the Trimethylsiyl Substituent upon Carbon-
(45) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F.
A Mild Synthesis of Vinyl Halides and gem-Dihalides Using Tri-
phenyl Phosphite-Halogen-Based Reagents. J. Org. Chem. 2007,
72, 2216.
(46) (a) Lee, E.; Park, C. M.; Yun, J. S. Total Synthesis of Dac-
tomelynes. J. Am. Chem. Soc. 1995, 117, 8017. (b) Lee, E.; Jeong,
1
2
ACS Paragon Plus Environment

Page 13 of 14
Journal of the American Chemical Society
J.-w.; Yu, Y. Diastereoselective Radical Cyclization of Chiral β-
(59) Kawasaki, Y.; Ishikawa, Y.; Igawa, K.; Tomooka, K. Di-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Alkoxyacrylates. Tetrahedron Lett. 1997, 38, 7765.
recting Group-Controlled Hydrosilylation: Regioselective Func-
tionalization of Alkyne. J. Am. Chem. Soc. 2011, 133, 20712.
(60) Nwoye, E. O.; Dudley, G. B. Synthesis of para-
Methoxybenzyl (PMB) Ethers Under Neutral Conditions. Chem.
Commun. 2007, 1436.
(47) (a) Bonini, C.; Chiummiento, L.; Videtta, V. Direct Prepa-
ration of Z-1,3-Enyne Systems with a TMS-Propargylic Sulfone:
Application of a One-Pot Julia Olefination. Synlett. 2006, 2079.
(
b) Kumar, R.; Zajc, B. Stereoselective Synthesis of Conjugated
Fluoro Enynes. J. Org. Chem. 2012, 77, 8417.
48) Weichold, V.; Milbredt, D.; van Pée, K.-H. Specific En-
(
zymatic Halogenation—From the Discovery of Halogenated En-
zymes to Their Applications In Vitro and In Vivo. Angew. Chem.
Int. Ed. 2016, 55, 6374.
(
49) (a) Blakemore, P. R.; Cole, W. J.; Kocieński, P. J.; Morley,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A. A Stereoselective Synthesis of trans-1,2-Disubstituted Alkenes
Based on the Condensation of Aldehydes with Metallated 1-
Phenyl-1H-tetrazol-5-yl Sulfones. Synlett. 1998, 26. (b) Ghosh, A.
K.; Zajc, B. Fluorinated 1-Phenyl-1H-tetrazol-5-yl Sulfone Deriv-
atives as General Reagents for Fluoroalkylidene Synthesis. J. Org.
Chem. 2009, 74, 8531.
(
50) Zürcher, M.; Hof, F.; Barandun, L.; Schütz, A.; Schweizer,
W. B.; Meyer, S.; Bur, D.; Diederich, F. Synthesis of exo-3-
Amino-7-azabicyclo[2.2.1]heptanes as a Class of Malarial Aspar-
tic Protease Inhibitors: Exploration of Two Binding Pockets. Eur.
J. Org. Chem. 2009, 1707.
(51) (a) Enders, D.; Lohary, B. B. Enantioselektive Synthese
von α-Trialkylsilyketonen und aldehyden. Angew. Chem. 1987,
99, 359. (b) Enders, D.; Zamponi, A.; Raabe, G. Enantioselective
Synthesis of 3-Oxoesters and Carboxylic Acid as Polyfunctional
Small Building Blocks with a Quaternary Stereogenic Center.
Synlett. 1992, 897.
(
52) Huang, Z.; Gao, L. Song, Z. Asymmetric Alkylation or Si-
lylation of (S)-(−)-Diphenylprolinol-Derived α-Silyl Amide to
Synthesize Optically Pure α-Monosilyl or Bis(silyl) Amides. Tet-
rahedron Lett. 2016, 57, 2861.
(53(a) Smidt, S. P.; Menges, F.; Pfaltz, A. SimplePHOX, a
Readily Available Chiral Ligand System for Iridium-Catalyzed
Asymmetric Hydrogenation. Org. Lett. 2004, 6, 2023. (b) Hoen,
R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard, A. J.; Meetsma,
A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de Vries, J.
G.; Feringa, B. L. Achiral Ligands Dramatically Enhance Rate
and Enantioselectivity in the Rh/Phosphoramidite-Catalyzed Hy-
drogenation of α,β-Disubstituted Unsaturated Acids. Angew.
Chem. 2005, 117, 4281. (c) Schrems, M.; Neumann, E.; Pfaltz, A.
Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctional-
ized Tetrasubstituted Olefins. Angew. Chem. Int. Ed. 2007, 46,
8
274.
54) (a) Landais, Y.; Planchenault, D. Asymmetric Metal Car-
bene Insertion into the Si-H Bond. Tetrahedron Lett. 1994, 35,
565. (b) Landais, Y.; Planchenault, D. Preparation of Optically
(
4
Active α-Silylcarbonyl Compounds using Asymmetric Alkylation
of α-Silylacetic Esters and Asymmetric Metal-Carbene Insertion
into the Si-H Bond. Tetrahedron 1997, 53, 2855.
(
55) Nicolaou, K. C.; Ladduwahetty, T.; Elisseou, E. M. Stere-
ocontrolled Total Synthesis of (5Z, 8Z, 11Z, 13E)-(15S)-
Hydroxyeicosa-5,8,11,13-tetraenoic Acid (15S-HETE) and Ana-
logues. J. Chem. Soc. Chem. Commun. 1985, 1580.
(
56) Han, X.; Corey, E. J. A Short Catalytic Enantioselective
Synthesis of the Proinflammatory Eicosanoid 12(R)-
Hydroxy5(Z),8(Z),10(E),14(Z)-eicosatetraenoic Acid (12(R)-
HETE). Org. Lett. 2000, 2, 2543.
(
57) Han, X.; Crane, S. N.; Corey, E. J. A Short Catalytic En-
antioselective Synthesis of the Vascular Antiinflammatory Eico-
sanoid (11R,12S)-Oxidoarachidonic Acid. Org. Lett. 2000, 2,
3
437.
58) The enantioselectivity of this process was measured by
HPLC analysis using intermediate 75.
(
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TableꢀofꢀContentsꢀgraphic:ꢀ
Br
Br
•
PMBO
•
H
O
"Br
"
H
H
O
H
H
H
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Br
Br
Br
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TBS
TBS
H
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H
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common intermediate
microcladallene A
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1
2
3
4
5
6
7
8
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0
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2
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4
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