Total Synthesis of (±)-Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen-Oxygen Bonds

Article abstract of DOI:10.1002/anie.202003829

The development of a concise total synthesis of (±)-phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring

Full text of DOI:10.1002/anie.202003829

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Total Synthesis of (±)-Phyllantidine: Development and
Mechanistic Evaluation of a Novel Ring Expansion for Installation
of Embedded Nitrogen-Oxygen Bonds
Authors: Kyle Lambert, Joshua Cox, Lin Liu, Amy Jackson, Sam
Yruegas, Kenneth Wiberg, and John Wood
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003829
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Angewandte Chemie International Edition
10.1002/anie.202003829
RESEARCH ARTICLE
Total Synthesis of (±)-Phyllantidine: Development and
Mechanistic Evaluation of a Novel Ring Expansion for Installation
of Embedded Nitrogen-Oxygen Bonds
Dr. Kyle M. Lambert,†[a] Dr. Joshua B. Cox,†[a] Lin Liu,[a] Amy C. Jackson,[a] Dr. Sam Yruegas,[a]
Prof. Kenneth B. Wiberg,[b] and Prof. John L. Wood*[a]
O
O
O
O
Abstract: The development of a concise total synthesis of (±)-
phyllantidine (1), a member of the securinega family of alkaloids
containing an unusual oxazabicyclo[3.3.1]nonane core, is described.
The synthesis employs a unique synthetic strategy featuring the ring
expansion of a substituted cyclopentanone to a cyclic hydroxamic acid
as a key step that allows facile installation of the embedded nitrogen-
oxygen (N–O) bond. The optimization of this sequence to effect the
desired regiochemical outcome and its mechanistic underpinnings
were assessed both computationally and experimentally. This
synthetic approach also features an early-stage diastereoselective
aldol reaction to assemble the substituted cyclopentanone, a mild
reduction of an amide intermediate without N–O bond cleavage, and
the rapid assembly of the butenolide found in (1) via use of the
Bestmann ylide.
H
D
HO
HO
H
O
N
C
O
H
A
B
O
N
N
H
N
H
O
H
(–)-Phyllantidine (1)
(–)-Securinine (2)
(–)-Allosecurinine (3)
O
O
O
H
O D
O
O
H
O
N
H
N
H
N
C
H
O
A
B
O
N
O
H
H
H
(
+)-Phyllantidine (1)
(+)-Virosecurinine (4) (+)-Viroallosecurinine (5)
1
total synthesis
> 20 total syntheses completed
Other Securinega Alkaloids Containing a N–O Bond
O
O
HO
H
O
O
O
O
H
N
O
H
N
H
OH
Introduction
MeO
MeO
H
N H
O
H
O
H
H
The securinega alkaloids, isolated from the Euphorbiaceae
family of plants, are a class comprised of over 70 known members
featuring unique bridged tetracyclic or pentacyclic cores (e.g. 1-
(
+)-Securingine A (6)
(–)-Securingine B (7)
(–)-Virosaine A (8)
O
O
O
O
O
O
H
H
O
O
H
H
O
1
1; Figure 1).1,2 The diverse molecular architectures found within
O
O
N
H
H
N
this class of natural products, combined with their wide-ranging
biological activities, have inspired dozens of synthetic efforts
aimed at their preparation, most of which have focused on the
parent alkaloids securinine (2), allosecurinine (3), and their
enantiomers (4 and 5).1-3 As illustrated in Figure 1, a subset of the
securinega alkaloids contain an embedded nitrogen-oxygen (N–
O) bond (e.g. 1 and 6-11), which offers an additional synthetic
challenge not found in 2-5.
H
H
N
O
H
N
H
O
H
O
OMe
HO
N
H
H
H
HO
O
(
+)-Virosaine B (9)
(–)-Flueggine A (10)
(–)-Flueggeacosine B (11)
Figure 1. Members of the Securinega family of alkaloids.
structure was incorrectly assigned upon isolation, but later
corrected in 1972 to that of (–)-phyllantidine (1).
+)-phyllantidine (1), was isolated in 1992 from the leaves of
Breynia coronata.
oxazabicyclo[3.3.1]nonane structure and exhibits leishmanicidal
activity and anti-inflammatory properties.7,8 Interestingly,
Flueggeacosine B (11), a heterodimer of phyllantidine (1) and a
5
Its enantiomer,
Phyllantidine (a.k.a. “Phyllanthidine”) (1, Figure 1), the
parent N–O bond-containing securinega alkaloid, was first
(
6
Phyllantidine possesses
a
unique
isolated in 1965 from the root bark of Phyllanthus discoides. Its
4
novel
securinega
alkaloid
fragment
containing
a
[
[
a]
b]
Dr. K. M. Lambert, Dr. J. B. Cox, L. Liu, A. C. Jackson, Dr. S.
Yruegas, and Prof. J. L. Wood
Department of Chemistry and Biochemistry, Baylor University
One Bear Place 97348, Waco, TX 76798 (USA)
E-mail: john_l_wood@baylor.edu
Prof. K. B. Wiberg
Department of Chemistry, Yale University
New Haven, CT 06520 (USA)
azabicyclo[3.2.1]octane system, was isolated recently in 2018
from the roots of Flueggea suffruticosa and displays potent
neuronal differentiation activity.
Securinega alkaloids containing a N–O bond are among the
most structurally complex members of the family, and have thus
been the subject of far fewer synthetic efforts.10,11 Biosynthetically,
the isoxazolidine cores of the Virosaines (8 and 9) and Flueggine
A (10) are postulated to arise via 1,3-dipolar nitrone-alkene
cycloadditions,12 a transformation that served to inspire the
reported Virosaine A (8)10a-b, Virosaine B (9)10c, and Flueggine A
9
Present Address: 865 Central Avenue, Needham, MA 02492 (USA)
Dr. K. M. Lambert and Dr. J. B. Cox contributed equally to this work.
†
Supporting information for this article is given via a link at the end of the
document.
(10) syntheses.10c-d Since the isolation of phyllantidine (1) over
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Angewandte Chemie International Edition
10.1002/anie.202003829
RESEARCH ARTICLE
oxidation
five decades ago, only one total synthesis has been reported.11
In contrast to 8-10, the tetrahydro-1,2-oxazine residing at the core
of 1 is not accessible via a classical 1,3-dipolar cycloaddition thus,
Carson and Kerr turned to an analogous homo [3+2] cycloaddition
between a nitrone and an electron-deficient, chiral cyclopropane.
Given the limited accessibility of this ring system1a,13 and our
O
O
O
butenolide
formation
HO
amide
reduction
H
H
N
O
N
H
O
H
O
iodocyclization or
epoxide opening
(
±)-phyllantidine (1)
16
ring
OTBS
HO
general interest in securinega alkaloid synthesis,
3
we sought to
expansion
OTBS
HO
H
H
develop an innovative, modular approach that allows for the
installation of N–O bonds embedded in densely functionalized
scaffolds, such as those found in 1.
N
OH
O
aldol
reaction
O
17
18
Efforts toward 1 began by examining ways to furnish the
tetrahydro-1,2-oxazine core. We recognized that cyclic
hydroxamic acids are versatile synthetic intermediates as they
can serve as precursors to cyclic hydroxamic esters,
hydroxylamines, and nitrones.14 However, the ambident
nucleophilicity, acidity, and inherent lability of the hydroxamic acid
N–O bond can complicate installation within highly functionalized
systems.15 In searching for preparative methods that would avoid
these inherent limitations, we were drawn to a report by King and
co-workers describing a mild ring-expansion sequence to afford
cyclic hydroxamic acids from cycloalkanones.16a This unique
O
OTBS
2
-step
oxidation
HO
preparation
commercially
available
19
20
(
known)
Scheme 2. Initial retrosynthetic analysis of 1. TBS = tert-butyldimethylsilyl
for generating unsubstituted cyclic hydroxamic acids.15 In the
context of preparing 1 (Scheme 2), we envisioned employing this
ring expansion in the stereo- and regioselective conversion of
ketone 18 to key intermediate 17. Setting the stage for this event
would require the stereoselective aldol addition of
cyclopentanone to the ketone derived from oxidation of known
TBS-protected diol 19.19 Harnessing the nucleophilicity of the
hydroxamic acid moiety in the derived ring expansion product (17)
would then allow construction of the B-ring via intramolecular
haloetherification to afford 16. Selective amide reduction and
butenolide formation would then complete the synthesis.
oxime
O
O
N
N
OH
formation
Pb(OAc)4
2 M NaOH
OAc
N
OH
0
°C to r.t.
0 °C to r.t.
MeOH
n = 1, 2
n = 1, 2
DCM
n = 1, 2
O
O
O
AcO
N
O
N
2
M NaOH
H2O
+
2
N O
MeOH-H2O
12
13
effective HNO donor
O
O
N
O
AcO
N
O
OH
N
CH3 2 M NaOH
MeOH-H2O
H2O
Results and Discussion
CH3
(77% yield)
CH3
15
single regioisomer
1
4
Efforts toward 1 began as shown in Scheme 3 with
preparation of known mono TBS-protected diol 1919 from 1,4-
cyclohexadiene (20). Upjohn dihydroxylation of 2020 and
subsequent protection with tert-butyldimethylsilyl chloride
Scheme 1. Reported ring expansion to cyclic hydroxamic acids by King and co-
workers.16a
reactivity was discovered serendipitously during their work
developing small molecule HNO surrogates from compounds
bearing an acyloxy nitroso moiety (Scheme 1).16b Interestingly,
King noted that upon treatment with base, acyloxy nitroso
moieties on ring systems with six or greater carbons (i.e. 12) are
effective HNO donors, whereas strain relief in ring systems
containing four or five carbons (i.e. 14) drives an efficient ring
expansion producing five- and six-membered cyclic hydroxamic
(
TBSCl) proved to be the most effective sequence to deliver multi-
gram quantities of 19. Oxidation of alcohol 19 with Dess-Martin
OH
OTBS
TBSCl
imidazole
HO
HO
OsO4, NMO
acetone, 25 °C
DMF, 25 °C
20 h
(93% yield)
72 h
20
21
19
(54% yield)
OLi
OTBS
acids (14
→
15; Scheme 1).16a,17 Importantly, when
OTBS
HO
Dess-Martin
periodinane
H
unsymmetrical systems were employed (e.g. 14), migration of the
more electron-rich alkyl group predominates yielding a single
regiomer (e.g. 15), reactivity akin to that observed in Baeyer-
Villiger oxidations.18
O
DCM, 0 to 25 °C
THF, –78 °C
1 h
4 h
O
(87% yield)
22
(90% yield)
18
Given the ease of accessing cyclic ketone precursors and
the efficiency of this expansion when performed on substituted
systems, we viewed this as a promising approach to the synthesis
of complex N-O-containing molecules. If generalizable, this
chemistry would allow for the installation of N–O bonds into
functionally dense architectures, such as 1, in a manner that is
both orthogonal and complementary to more traditional
nucleophilic substitution-based strategies which are better suited
OTBS
HO
NH2OH•HCl
pyridine
H
EtOH, 25 °C
15 h
N
(88% yield)
HO
23
X-ray structure of 23
Scheme 3. Preparation of ring expansion precursor 23. NMO
methylmorpholine N-oxide, DMF = dimethylformamide, DCM = dichloromethane.
=
N-
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Angewandte Chemie International Edition
10.1002/anie.202003829
RESEARCH ARTICLE
periodinane (DMP) gave the desired -silyloxy ketone 22 in 87%
yield, without any observable isomerization of the olefin.
Subsequent aldol addition of the lithium enolate, derived from
cyclopentanone, proceeded as expected to the least hindered
diastereotopic face of ketone 22 and, to our delight, with complete
selectivity for the illustrated relative stereochemistry between the
two newly formed stereogenic centers, thus producing 18 as the
only isolable product. Although, when considering the two
possible chair-like Zimmerman-Traxler transitions states
substituted alkyl group is uncommon,18,23 but has been observed
in the rearrangement of -alkoxy ketones.24
OTBS
HO
OTBS
H
PhI(OAc)2
AcOH
HO
H
DCM, 0 °C to 25 °C
N
N
45 min
AcO
25
HO 23
O
OTBS
OTBS
HO
HO
H
H
K2CO3
(
Scheme 4)21 it appeared that at least one diastereomer (18;
+
MeOH, 0 °C
N
desired) would be favored over the other (24; undesired), due to
the steric clash of the TBS group and solvated lithium cation, the
extent of the observed selectivity was not fully anticipated.
Furthermore, based on this analysis, we suspected that 18
OH
N
O
5
h
(66% yield)
O
OH
17
26
over two steps
(17:26 = 1:2)
Scheme 5. Evaluation of the stereochemical and regiochemical outcome of the
possessed the desired stereochemistry.
ring expansion sequence.
t-Bu CH3
H3C
t-Bu
H3C Si
Si
CH3
OTBS
HO
Although desired hydroxamic acid 17 was the minor
component of the regiochemical mixture, the reasonable overall
yield and facile separation of 17 from 26 via column
chromatography allowed us to attempt completing the A-B-C ring
system via intramolecular halocyclization of 17. To this end, we
turned to conditions reported by Kim and co-workers (Scheme
6);25 in contrast to the excellent yields observed on their
substrates (e.g. 27 → 28 or 29), halocyclization of 17 produced
complex mixtures of products with no trace of desired iodide 30.
Commonly employed iodolactonization conditions, which utilize
excess elemental iodine and sodium bicarbonate, exclusively
gave oxabicyclic iodoether 31 (63% yield), thus clearly indicating
a change in substrate would be required.
O
O
H
H
O
H
H
Li(solvent)n
O
O
O
Li(solvent)n
O
18
proposed Zimmerman-Traxler TS
single diasteromer
observed
affording 18
t-Bu
H3C
unfavorable
steric interaction CH3
CH3
Si
OTBS
HO
O
Si
t-Bu
O
H
CH3
H
Li(solvent)n
O
O
O
Li(solvent)n
O
24
O
H
H
proposed Zimmerman-Traxler TS
not observed
required for 24
Scheme 4. Proposed pathway leading to formation of 18.
Kim and co-workers:
O
O
CH3
Optimistically, 18 was carried forward to access ring
expansion precursor 23 which, fortuitously, was obtained as a
crystalline solid in 88% yield. Single crystal X-ray analysis of 23
confirmed that we had indeed obtained the relative
stereochemistry necessary to access 1 (Scheme 3). Given ready
access to multi-gram quantities of oxime 23, we turned to the key
ring-expansion step.16a To this end, 23 was found to undergo
oxidation to acyloxy nitroso intermediate 25 upon treatment with
NBS, 0 °C (84% yield)
ICl, –40 °C (90% yield)
CH3
3
H C
N
H3C
N
O
HO
28; X = Br
H
X
27
29; X = I
OTBS
HO
H
OTBS
HO
H
N
I
O
O
30
N
OTBS
OH
H
1
.5 equivalents of phenyliodonium diacetate (PIDA) in
AcOH/DCM solvent while warming from 0 °C to 25 °C (Scheme
).22 Although 25 was not particularly stable at room temperature,
I2, NaHCO3
O
17
MeCN, 0 °C
O
I
N
OH
2
h
O
5
(63% yield)
31
it could be separated from excess oxidant by quickly passing the
reaction mixture through a plug of silica. Subsequent cleavage of
Scheme 6. Competitive iodoether 31 formation during attempted iodocyclization
of hydroxamic acid 17. NBS = N-bromosuccinimide.
the acetate by exposure to anhydrous K
2
CO in MeOH at 0 °C
3
induced ring expansion to the desired hydroxamic acid 17.
Unfortunately, this desired material was produced as the minor
component of a 1:2 regiochemical mixture with undesired
hydroxamic acid 26 (Scheme 5). Based on initial observations
reported by King and co-workers,16a the predominance of
undesired regiomer (26) was rather surprising but not entirely
unexpected given the known regiochemical outcomes in Baeyer-
Villiger oxidations; the latter also proceed by carbon bond
migration to an electronically deficient heteroatom and have been
demonstrated to be influenced by inductively withdrawing
functionality adjacent to the migrating center. Migration of the less
Experimental Investigations into the Origins of the
Regioselectivity Observed in the Ring Expansion
The unfavorable product mixture obtained in the ring
expansion of 25 (Scheme 5), coupled with undesired reactivity of
the tertiary alcohol in 17 (Scheme 6), led us to take a step back
and further explore, both experimentally and computationally, the
impact of the tertiary hydroxyl group on the regiochemical
outcome of the ring-expansion. To confirm that this moiety was
indeed playing a significant role, we prepared substrates 32 and
36 wherein only the former contains a tertiary alcohol.26
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Angewandte Chemie International Edition
10.1002/anie.202003829
RESEARCH ARTICLE
H
N
likely arising led us to wonder if the ring expansions to 33 and 34
were also proceeding via initial attack of hydroxide on the nitroso
moiety followed by acyl transfer, rather than simple collapse of an
initially formed tertiary alkoxide and bond migration (Schemes 8-
9, pathway I vs. II). To evaluate the mechanistic possibilities, we
conducted two isotopic labeling experiments. As illustrated
(Scheme 9), incorporation of doubly 18O-labeled acetate into 36
followed by ring expansion upon exposure to 5 M aqueous NaOH
in methanol confirmed that the acetate derived oxygen resides at
HO
H
HO
HO
O
2
M NaOH
MeOH
N
+
+
N
AcO
0 to 25 °C
4 h
(62% yield)
OH
33
N
O
MeO C
2
O
2
O
OH
32
34
35
ratio = 33 : 34 : 35 = 1.0 : 1.1 : 2.5
(X-ray structure of 35)
2
M NaOH
single regioisomer
observed
MeOH, 0 °C, 1 h
then 25 °C for 36 h
N
OH
37
H
(
93% yield)
O
N
OR
N
the hydroxyamic acid carbonyl, as evidenced by HRMS and 13
C
AcO
3.0 equiv. K2CO3
MeOH, 0 °C, 1 h
then 25 °C for 36 h
O
36
not observed
NMR analyses.29 Additionally, we performed the ring expansion
of unlabeled substrate 36 using Na18OH/H218O solution in
methanol solvent30 and found it led to facile expansion 36 → 37
with no 18O incorporation into the product 37, which eliminates
pathway II as a valid mechanistic pathway (Scheme 9).31 Given
the results of the above studies, the ring expansion appears to
proceed through initial acetate cleavage followed by alkyl
migration onto the nitroso moiety (pathway I; Scheme 8)
O
(
65% yield)
OH
38
Scheme 7. Ring expansion of model acyloxy nitroso substrates 32 and 36.
Exposure of 36 to either NaOH or K
2
CO in MeOH resulted
3
in conversion to a single regiomeric product corresponding to
hydroxamic acid 37, the product arising from migration of the
more heavily-substituted carbon (Scheme 7). Having established
the inductively withdrawing hydroxyl as the likely culprit, we
reintroduced this single group by preparing acyloxy nitroso 32 via
a sequence similar to that described above for 22 → 25, and
subjected it to ring expansion with a small subset of bases.26 As
with 36, hydroxide bases in methanol solvent proved most
effective. The counterion, however, had little effect and all
conditions produced unfavorable mixtures of hydroxamic acids 33
and 34. Interestingly, in contrast to 25, the reaction of 32 was
found to also produce a spirocyclic product (35). As illustrated in
Scheme 8, we suspect 35 arises from 32 via initial attack of the
now less sterically encumbered tertiary alcohol onto the nearby
Pathway II.
OH
HO
HO
N
HO
H
H
H
O
OH
RO
A
O
B
N
OH
N
O
N
RO
N
5
CH3
AcO
AcO OR
O
OH
O
O
3
2
O
33 (Path A) 34 (Path B)
H
M NaOH
MeOH, 0 °C, 1 h
then 25 °C for 2 h
unlabeled
3
18O labeled
7
37
N
N
18O
18O
OH
O
(
50% yield)
18O
3
6
37
[M+H]+ = 200.1538
Found: 200.1578
95%
1
8
O incorporation
5
M Na18OH in H218
O
H
18
95% O incorporation
MeOH, 0 °C, 1 h
N
then 25 °C for 2 h
N
O
OH
O
(40% yield)
3
6
O
37
O
M+H]+ = 198.1489
Found: 198.1488
13C NMR shifts (ppm)
[
Scheme 9. 18O-labeling experiments for the expansion of 36 → 37 and possible
mechanism pathway II.
Computational Investigations into the Origins of the
Regiochemical Discrepancies of the Ring Expansion
To gain further insight into the undesirable regiochemical
outcome of ring expansions containing the requisite -oxygen
substituent, we investigated the two model systems (32 → 33 and
Scheme 8. Ring expansion of acyloxy nitroso 32, proposed mechanism
pathway I, and a proposed mechanism for the formation of spirocycle 35.
3
4; and 36 → 37 and 38) computationally at the RB3LYP/6-
nitroso group which, in turn, induces an acyl shift that sets the
stage for carbon bond migration to bicycle 32C. The latter
undergoes facile methanolysis to furnish 35 due to the twisted
nature of its bridgehead hydroxamic ester.27,28 In an attempt to
avoid the formation of 35 by increasing the rate of acetolysis we
prepared a trifluoroacetate derivative of 32.26 As expected this
variant was found to react much more rapidly and produced only
311+G* level. The calculated free energies are for the gas phase,
but are expected to reasonably represent the trend in free
energies in the solution phase, which are often difficult to compute
due to the need to apply thermal corrections to account for
diffusion, versus translational effects in the gas phase.26,32 As
illustrated in Figure 2, the calculations reveal that, in the
expansion of 32, which contains a -tertiary alcohol, the preferred
reaction pathway should proceed from anion 32A through 33TS
3
3 and 34 (1:1.3). Unfortunately, the latter were isolated in low
yield and regeneration of the starting ketone through loss of HNO
was observed as the predominant event.16
(
+10.1 kcal/mol) to afford product 33A (–27.0 kcal/mol), which
yields 33 upon protonation. The pathway leading to 34A (–22.6
kcal/mol) via 34TS (+10.6 kcal/mol) is only 0.5 kcal/mol higher in
Further consideration of the mechanism by which 35 was
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
–
–
–
–
‡
‡
‡
1
1.5 kcal/mol
38TS
34TS
38TS
‡
1
0.6 kcal/mol
DDG° = 1.9 kcal/mol
3
4TS
DDG° = 0.5 kcal/mol
9
.6 kcal/mol
1
0.1 kcal/mol
=
37TS
=
=
33TS
HO
H
H
=
33TS
37TS
N
N
O
=
O
36A
=
32A
O
O
=
=
O
3
6A
32A
N
O
O
H
–
22.6 kcal/mol
N
O
O
–21.6 kcal/mol
38A
34A
O
34A
38A
22.0 kcal/mol
37A
DDG° = 0.6 kcal/mol
–
DDG° = 4.4 kcal/mol
O
H
N
O
N
–27.0 kcal/mol
O
37A
33A
O
33A
Figure 2. Computed profile (RB3LYP/6-311+G*) for the ring expansion process of (32A → 33A and 34A; and 36A → 37A and 38A) in the gas phase. Depicted free
energy differences (G°) for the transition states and products are reported relative to the starting anion in kcal/mol.
energy. Given the computed energetics, both regiomers 33 and
4 are expected to be observed, a result consistent with the
of -tertiary alcohol substrates, as the TS energies are already
computed to be close in energy in the gas phase (0.5 kcal/mol).
The starting materials, products, and transition states of the
model systems (32A → 33A and 34A; 36A → 37A and 38A) were
also modeled using the default Integral Equation Formalism
Polarizable Continuum Model (IEFPCM) in Gaussian 16 to probe
possible solvent effects. It is important to note the energies
calculated here are free energies for a system confined to a
predetermined, modeled solvent cavity “a continuum” based on
the properties of the chosen model solvent. They are not solvation
energies and do not fully account for diffusion, hydrogen-bonding
and aggregative properties of the substrate etc. However, such
calculations offer a reasonable platform to model the general
trend of potential solvent effects in systems.32 The calculations
revealed that in a THF or methanol continuum, the transition state
energies reverse with 34TS being preferred by 2.4 kcal/mol and
38TS by 1.1 kcal/mol for THF and 2.6 kcal/mol and 1.5 kcal/mol
respectively for methanol. These results suggest that a solvent
effect may be observed experimentally, and solvents with higher
dielectric constants (i.e. methanol) may help to stabilize the
transition state with the higher dipole moment (34TS and 38TS)
to a greater extent. However, such calculations do not take into
account the donor-acceptor or hydrogen-bonding properties of
the solvent, as well as charge transfer from the solute to the
solvent, which can dominate the overall solvent effect.26,32
3
experiment, albeit with the reverse regiochemical outcome, as 34
predominates over 33 experimentally (Scheme 7).
For the expansion of 36, which lacks a -tertiary alcohol, the
preferred reaction pathway proceeding from anion 36A was found
to pass through 37TS (+9.6 kcal/mol) to afford product 37A (–22.0
kcal/mol). The pathway leading to 38A (+11.5 kcal/mol) via 38TS
(11.5 kcal/mol) is 1.9 kcal/mol higher in energy. Given the
computed energetics, only product 37 would be expected, again
consistent with experimental observations.
The ring expansion is computed to be fairly exothermic in
both cases, as the products (37A, 38A, 34A, and 33A) are found
to be >21 kcal/mol more stable than starting anions 36A and 32A;
the result of ring strain reduction. However, a major difference
between the two model systems is the clear participation of the
neighboring H-bond in both 34TS and 33TS. In the former this
interaction engages the neighboring nitroso -system in a nearly
anti-periplanar fashion relative to the C-C bond undergoing
migration to 34A (Figure 2); an effect that serves to stabilize 34TS
relative 33TS thereby minimizing the TS energy difference. The
replacement of the OH in 34TS and 33TS with an OCH
leads to a large transition state difference of (3.2 kcal/mol).26
Given the lack of neighboring hydroxyl in 36A, the
3
group
a
corresponding transition state energies for 37TS and 38TS do not
experience a similar compression.
We also considered the computed dipole moments of the
transition state pairs and found them to be substantially different
for both model substrates ( = 8.0 D, 37TS;  = 10.4 D, 38TS and
An Adjusted Approach to Phyllantidine (1)

= 6.8 D, 33TS;  = 8.8 D, 34TS). This ~ 2 Debye difference
From the brief computational study, it became clear that the
regiochemical course of this ring expansion was not only
impacted by inductive effects but also hydrogen bonding and
solvent. Thus, we continued our efforts toward 1 by exploring the
protection of the -tertiary alcohol. To this end, initial attempts to
protect the remaining alcohol in aldol adduct 18, as a TBS-ether,
between the TS pairs suggests that solvent effects could influence
the regiochemical outcome, as polar solvents may offer greater
stabilization to the higher dipole moment TS’s 34TS and 38TS
thereby bringing the energies of the two transition states closer.
Such an effect would have a greater repercussion on expansions
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
triethylsilyl ether, or an acetate were all unsuccessful.33 Given that
these latter failures were likely due to steric hindrance by the
resident TBS ether, we decided to first deprotect and then
reprotect the resulting 1,2- syn diol as an acetonide. To this end,
we screened conditions to cleave the TBS ether in 18 and, after
considerable experimentation, found that rapid exposure to a
large excess of HF-pyridine gave 39 in an excellent 95% yield
acyloxy nitroso 48 in 64% yield as a single diastereomer. The
illustrated relative stereochemistry of 48, a blue crystalline solid,
was determined via X-ray crystallography.
O
O
OH
Cl
pyridine
Cl
O
HO
NH2OH•HCl
pyridine
HO
H
DCM, 0 to 25 °C
i-PrOH, 40 °C
45 min
24 h
(Scheme 10). In contrast, exposure of 18 to catalytic HCl in
O
(95% yield)
O
39
46
(98% yield)
O
O
MeOH gave exceedingly efficient silyl ether cleavage, but a
completely different product, tricyclic acetal 40 (Scheme 10).
O
O
O
O
H
OH
H
PhI(OAc)2
AcOH, 25 °C
HO
H
HF-pyridine
7
min
N
AcO
OTBS
DCM, 0 °C
N
(
64% yield)
HO
O
(95% yield)
O
HO 47
48
H
39
X-ray structure of 48
H
MeO
O
Scheme 12. Preparation of carbonate-protected acyloxy nitroso adduct 48.
O
18
MeOH, 0 °C
OH
(95% yield)
H
Upon treatment of 48 with K
2
CO in MeOH, we were
3
40
surprised to find that the desired hydroxamic acid (49) was
obtained as the major product, along with methyl carbonate 50,
diol 51, and undesired hydroxamic acid 52 in a 2.4:1.6:1.3:1 ratio;
(
X-ray structure of 40)
Scheme 10. Deprotection of TBS ether in aldol adduct 18.
(
4
49:50:51:52) (Table 1, Entry 2). Since 50 and 51 originate from
9, the regiochemical outcome of the ring expansion is
With 1,2-syn diol 39 in hand, we explored protection as the
corresponding acetonide and found that exposure to an excess of
,2-dimethoxypropane (2,2-DMP) and pyridinium p-toluene
significantly altered, now favoring migration of the more heavily
substituted alkyl group (ca. 5:1 ratio). This regioselectivity
appears to be general among the carbonate and hydroxide bases
screened in MeOH solvent (Table 1, Entries 1–7) and lithium
methoxide (LiOMe), which was found to produce less of 50 and
2
sulfonate (PPTS) smoothly afforded acetonide 41, which was
then carried forward to acyloxy nitroso 43 (Scheme 11). To our
chagrin, we found that exposure of 43 to our standard ring
expansion conditions afforded a 1:1.5 regiochemical mixture of
hydroxamic acids (44:45) (Scheme 11). Therefore, removing the
hydrogen-bond donor ability of the tertiary alcohol appeared to
have only a modest positive affect on regiochemistry compared to
that observed for the expansion of 25 (Scheme 5). Puzzled by
the minimal change of regioselectivity, we chose to install a
carbonate protecting group to explore the effect of altering the
electronics and Lewis basicity of the protecting group34 on the
regioselectivity of the ring expansion.
5
1 (Table 1, Entries 8–9) under short reaction times.
Given the computational observations, we decided to
conduct a screen to identify any possible solvent effects. After
screening various solvents using LiOMe as the base (Table 1,
Entries 9, 12, and 14–18), it became clear that non-Lewis basic
and non-polar solvents were ineffective in altering the
regiochemical preference toward 49. Medium polarity, aprotic,
ethereal solvents such as THF and Et O were found to engender
2
the ring expansion process, affording 49 preferentially over 52
with small amounts of 50 arising from partial carbonate cleavage
(Table 1, Entries 10–14). By lowering the temperature to –80 °C
in THF solvent, albeit with longer reaction times (50 h), (Table 1
Entry 13) 49 could be obtained exclusively!
The last factor evaluated was whether the metal counter-ion
was important in obtaining this high degree of regioselectivity
(Table 1, Entries 19–21). The rate of reaction was found to follow
the expected trend for metal alkoxides (KOMe > NaOMe >
LiOMe),35 and, since the basicity of LiOMe is moderated in
ethereal solvents due to aggregation effects,35–36 it results in less
carbonate cleavage products (50 and 51). Overall, the degree of
regioselectivity was found to be >17:1 across all the metal
alkoxides in THF solvent at low temperature (–15°C).
CH3
CH3
H3C
H3C
OH
O
O
2,2-DMP
HO
O
H
HO
NH2OH•HCl
H
PPTS
benzene, 25 °C
pyridine, 25 °C
4 h
(90% yield)
9
h
O
O
N
(83% yield)
41
3
9
42
CH3
HO
CH3
H3C
CH3
H3C
H3C
O
O
O
PhI(OAc)2
AcOH
O
H
O
H
O
H
K2CO3
+
DCM, 0 to 25 °C
MeOH, 0 °C
36 h
(37% yield)
over two steps
N
4
5 min
OH
N
O
OAc
N
O
OH
O
43
44
45
(
44:45 = 1:1.5)
Scheme 11. Ring expansion of acetonide-protected acyloxy nitroso 43.
To this latter end, treatment of diol 39 with phosgene and
pyridine furnished cyclic carbonate 46, and oxime formation gave
We again turned to computational studies, to gain insight
into the observed switch in regioselectivity of the ring expansion
process when employing a carbonate protecting group versus an
acetonide, and to evaluate the positive role of the ethereal solvent.
The likely intermediates formed when employing acetonide 43
and cyclic carbonate 48 as substrates were explored. In contrast
to our previous calculations, we incorporated the Li counterion
into the model and explored the energetics in both the presence
and absence of THF. To this end, the effect of a single THF
4
4
7, both proceeding in excellent yields (Scheme 12). Oxidation of
7 with phenyliodonium diacetate, using the previously developed
protocol (i.e. 23 → 25; Scheme 5), gave only 12% yield of 48. The
oxidation was found to be promoted by AcOH, but 48 was only
transiently stable to the reaction conditions. Conducting the ring
expansion in AcOH solvent, and immediate separation of 48 from
the reaction mixture via flash column chromatography provided
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Table 1. The effect of various bases/solvents/temperatures on the
regiochemical outcome of the ring expansion of carbonate acyloxy nitroso 48.[a]
expansion proceeds regioselectively via migration of the more
substituted carbon; similar to that observed for the Baeyer-Villiger
oxidation (e.g., 53 → 54).38–39 Placing a -hydroxy group adjacent
to the migrating center negates this regioselective preference, as
observed experimentally for both the Baeyer-Villiger oxidation
O
O
O
O
O
O
O
O
O
OCH3
OH
O
O
HO
HO
H
H
H
H
H
base
(e.g., 55 → 56 and 57) and our initial model substrate (i.e. 32 →
N
N
N
solvent
temperature
time
OH
OH
50
OH
N
O
3
3 and 34, Figure 3); a consequence of the inductively electron-
N
AcO
O
O
O
OH
52
O
48
withdrawing hydroxyl group retarding migration and, in the latter,
the added effect of hydrogen-bonding to the nitroso moiety (vide
supra).40 Our efforts to overcome the hydrogen bonding effects
by hydroxyl protection (Figure 3, bottom) unexpectedly revealed
that a carbonate protecting group (e.g., 48) is more effective than
an acetonide (e.g., 43) in shifting the ring expansion toward
migration of the more heavily substituted (electron-rich) carbon.
Our initial expectation was that the electronegative carbonyl
carbon of the carbonate group would diminish the desired
regiochemical outcome relative to the acetonide by further
enhancing the inductively withdrawing effect of its -oxygen.
Exploring the impact of solvent (cf. 44:45 and 49:52 in
Figure 3) revealed that although both MeOH and THF are Lewis
bases, MeOH, a high polarity hydrogen-bonding solvent, appears
to be less effective whereas the medium polarity/aprotic THF is
optimal. This observation guided our choice to model the effect
of an explicit THF molecule.26 The latter suggests that THF is able
to disrupt metal-substrate coordination in the carbonate system
49
51
Time Temp. Conv.[b]
Ratio[b]
49 : 50 : 51 : 52
Entry
Base (Equiv.)
Solvent
(min) (°C)
(%)
1
[c]
Na
2
CO
3
(1.6)
(1.2)
(1.6)
(1.6)
CH
CH
CH
CH
CH
CH
CH
3
OH 120
OH 120
OH 120
0
0
37
100
100
63
1.3 : 0 : 1 : 1
2.4 : 1.6 : 1.3 : 1
5.3 : 6.0 : 1.8 : 1
3.3 : 2 : 0.8 : 1
2.5 : 1.5 : 0.7 : 1
4 : 0 : 0: 1
2
K
K
2
2
CO
CO
3
3
3
4
5
6
7
8
3
3
3
3
3
3
3
–15
0
Cs
2
CO
3
OH
OH
OH
OH
OH
30
5
KOH (1.6)
NaOH (1.6)
LiOH (1.6)
0
66
5
0
53
5
0
63
3 : 0 : 0 : 1
2.5 M LiOMe (1.1) CH
1.0 M LiOMe (1.6) CH
5
0
100
3 : 0 : 0 : 1
9
3
OH
60
5
–15
0
100
100
100
100
100
44
2.2 : 1 : 0 : 1
4 : 2 : 0 : 1
1
0
1
2
3
1.0 M LiOMe (1.6)
1.0 M LiOMe (1.0)
1.0 M LiOMe (2.0)
1.0 M LiOMe (5.0)
THF
THF
THF
THF
1
1
1
20
45
–10
–15
5.5 : 1.3 : 0 : 1
> 20 : 1 : 0 : 1
1 : 0 : 0 : 0
(eg. 48Li, Figure 3), but not in the acetonide (eg. 43Li, Figure 3).
These computational results are consistent with the known
differences in Lewis basicities of acetonide and carbonate
oxygens and disruptive effects of THF on metal coordination.34,36
In general if one considers the impact of the metal coordination
and tighter binding to the more Lewis basic acetonide versus the
carbonate (cf. 43Li and 48Li, Figure 3), an enhancement of the
deleterious effects of the inductively withdrawing oxygen would
be expected in 43Li, resulting in the observed decrease in
selectivity. This difference is predicted by the computational
studies incorporating THF, which also suggests that the solvent
is capable of completely disrupting coordination of the lithium ion
to the carbonate in 48Li.26 Thus, effectively increasing electron
density and restoring the propensity for migration of the more
substituted, electron-rich carbon to furnish the desired
hydroxamic acid 49.34-36
3000 –80
1
4
5
[c] 1.0 M LiOMe (1.6) Et O
120
CN 120
–15
5 : 1 : 0 : 1
2
1
[c] 1.0 M LiOMe (1.6) CH
3
–15
–15
–15
10
17
90
1.6 : 0 : 0 :1
1: 1 : 0 : 1
1
6
7
8
9
0
1
1.0 M LiOMe (1.6) CH
2
Cl2
15
60
5
1
1
1
2
2
1.0 M LiOMe (1.6) CH -C
3
6H
5
84
1 : 0.8 : 0 : 1
1 : 1 : 0 : 1
1.0 M LiOMe (1.6)
1.0 M KOMe (1.6)
C6H6
100
100
100
100
THF
5
–15
–15
–15
13 : 4 : 0 : 1
6 : 2 : 20 : 1
15 : 3.5 : 0 : 1
1.0 M NaOMe (1.6) THF
25
1.0 M LiOMe (1.6) THF
45
[
a] Reactions were conducted on 10 mg scale in 2 mL of the given solvent at
the given temperature and were monitored by TLC analysis for disappearance
of 48; Entries 2 and 13 were run on larger scale.26 [b] Ratios and % conversions
were determined by integration of the proton signals in the 1H NMR spectra of
Having finally identified a substrate and conditions suited for
a regioselective ring expansion affording 49, we turned toward
the crude mixtures. [c] The reaction was not complete after 120 min and the
ratio was taken at this cut-off.
completing the synthesis of
1 (Scheme 13). Noting that
molecule on the transition state geometries was modeled in the
gas phase at the RB3LYP/6-311+G* level, which was chosen due
to its ability to provide reasonable execution times for large
systems combined with its general applicability for modeling
organic reactions in the gas-phase.37 Although, at the B3LYP level
of theory, without dispersion, one cannot expect to precisely
model experimental outcomes, the trends one observes can be
helpful in developing reasonable hypotheses.26 As described
below these calculations did illustrate differences in the extent of
lithium ion coordination in 43 and 48 and the potential impact of
the solvent.
halocyclization was successful at functionalizing the internal olefin
in substrate 17, during previous attempts to construct the A-B-C
ring system of 1 (Scheme 6), we applied those same conditions
to hydroxamic acid 49. Gratifyingly, we were able to construct
iodide 58 in 90% yield, establishing the A–B–C ring system of 1.
Elimination of the secondary iodide in 58 was accomplished by
treatment with DBU in refluxing benzene to afford 59 (90% yield)
and set the stage for reduction of the hydroxamic ester (Scheme
13). The conversion of 59 to oxazine 60 was envisioned to be
difficult given the potential for facile reductive cleavage of the N–
O bond.14g,41 After screening various known methods for the
reduction of hydroxamic esters to O-alkyl hydroxylamines,14b-e
conditions adapted from Reinhoudt and co- workers,42 employing
monochloroalane as the reductant, proved most effective and
From an experimental perspective (Figure 3 (top)), the ring-
expansion regiochemistry of acyloxy nitroso compounds mirrors
that observed in Bayer-Villiger oxidations. Specifically, in the
absence of any heteroatoms (i.e. 36 → 37, Figure 3) ring-
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Baeyer-Villiger Oxidation:
Acyloxy Nitroso Ring Expansion:
acyloxy nitroso intermediate.
Efforts to apply this ring
expansion protocol revealed
that, akin to the Baeyer-Villiger
No Heteroatom:
H
peracetic acid
single
regiomer
observed
2 M NaOH
single
regiomer
observed
N
O
OH
H2SO4/AcOH
O
MeOH
N
O
0 °C
53
54
97% yield)
0 to 25 °C
O
AcO
37
(
O
36
oxidation,
inductively
oxygen
(
93% yield)
Inductively Electron-Withdrawing Heteroatom:
withdrawing
HO
substituents adjacent to the
migrating center can override
H
HO
HO
CH3
CH3
OH
CH3
2
M NaOH
TFPAA
O
O
+
N
+
O
MeOH
the
migration of the most heavily
substituted (electron-rich)
carbon. Evaluation of these
intrinsically
favored
N
OH
33
(14% yield)
N
O
O
OH
57
(36% yield)
OH
56
24% yield)
O
AcO
0 to 25 °C
O
32
O
OH 34
55
(
(15% yield)
How the Choice of Protecting Group Influences the Regioselectivity of the Acyloxy Nitroso Ring Expansion:
effects through
experimental
computational
revealed that the deleterious
inductive effects could be
mitigated by careful selection
of solvent and electronic
modification of the substrate.
Specifically, the introduction of
a
combined
and
approach
CH3
CH3
H3C
H3C
O
O
O
O
O
H3C CH3
O
O
O
Li
Li
O
O
O
O
H
H
O
N
O
O
O
O
N
O
O
H
H
H
H
LiOMe
15 °C
LiOMe
+
+
–
N
–15 °C
N
OH
N
O
OH
49
N
O
43Li
O
44
OH
48Li
O
45
OH 52
acetonide oxygen → stronger Lewis base →
stronger lithium coordination →
more electron-withdrawing through induction
carbonate oxygen → weaker Lewis base →
weaker lithium coordination →
less electron-withdrawing through induction
4
4
4:45 = 1:1.5 (MeOH)
4:45 = 1.5:1 (THF)
49:52 = 2.2:1 (MeOH)
49:52 = >20:1 (THF)
Figure 3. Summary of the regiochemical outcomes of the various acyloxy nitroso
ring expansion substrates evaluated and comparison to the outcomes of related
substrates in the Baeyer-Villiger oxidation. TFPAA = trifluoroperacetic acid.
functionality capable of diminishing oxygen’s Lewis basicity
coupled with the use of ethereal solvents to disrupt
counterproductive metal-substrate coordination were found to
completely reverse the observed migratory aptitudes. In addition
to the ring expansion chemistry, the synthesis features: an early-
stage diastereoselective aldol reaction to assemble the
substituted cyclopentanone, a mild reduction of an amide
intermediate without N–O bond cleavage, and rapid butenolide
assembly via use of the Bestmann ylide. Overall, the synthesis
requires 12-steps to prepare 1 from readily available, known
materials (19) or 14-steps from commercially available 1,4-
cyclohexadiene and is accomplished in 9% yield from 19.
simultaneously removed the cyclic carbonate thereby producing
the oxazabicyclo[3.3.1]nonane core of
1 in 63% yield.
Subsequent oxidation of 60 with DMP gave relatively unstable
enone 61, which was taken directly to the next step to minimize
decomposition. Exposure of 61 to 5 equivalents of Bestmann
ylide43 in benzene with microwave heating under high dilution
conditions provided (±)-phyllantidine (1) in 62% yield over the two
step sequence.44
O
O
O
O
O
O
O
O
O
H
H
H
I2
LiOMe
NaHCO3
Experimental Section
N
N
I
OAc
THF, –80 °C
50 h
(62%)
MeCN, 80 °C
2.5 h
(90% yield)
OH
O
N
H
O
O
O
48
All Experimental Procedures, Computational Details, and
Compound Characterization Data (X-ray crystallographic data,45 NMR
spectra, FTIR data, HRMS data, and atomic coordinates of computed
structures) can be found in the Supporting Information.
4
9
58
O
O
OH
H
HO
DBU
benzene, 75 °C
0 h
90% yield)
O
H
AlH2Cl
H
ether/THF, 25 °C
30 min
(63% yield)
1
N
N
(
O
O
H
O
59
60
O
Acknowledgements
O
Dess-Martin
periodinane
HO
Ph P=C=C=O
3
O
H
H
mW, 90 °C
We gratefully acknowledge financial support from Baylor
University, the Welch Foundation (Chair, AA-006), the Cancer
Prevention and Research Institute of Texas (CPRIT, R1309), the
National Science Foundation (NSF, CHE-1764240), and the
National Institute of General Medical Sciences of the National
Institutes of Health (NIGMS-NIH, R01GM136759). K.M.L. is
grateful for an NIH NRSA postdoctoral fellowship (NIGMS-NIH,
F32GM129969) to explore this ring expansion chemistry.
benzene
6 h
62% yield)
N
DCM, 26 °C
N
O
O
H
1
1 h
H
(
(
±)-Phyllantidine (1)
61
over two steps
Scheme 13. Completion of the total synthesis of (±)-phyllantidine (1). DBU =
,8-diazabicyclo[5.4.0]undec-7-ene.
1
Conclusion
Phyllantidine (1) has proven to be an inspriational target for
Keywords: total synthesis • ring expansion • phyllantidine •
nitrogen heterocycles • computational chemistry
the development of a ring expansion approach for the installation
of embedded N–O bonds into functionally dense architectures.
The sequence involves the stereoretentive conversion of a
substituted cyclopentanone to a cyclic hydroxamic acid, via an
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Angewandte Chemie International Edition
10.1002/anie.202003829
RESEARCH ARTICLE
[
1]
For comprehensive reviews on the isolation, identification, and
syntheses of the securinega alkaloids see: a) R. Wehlauch, K.
Gademann, Asian J. Org. Chem. 2017, 6, 1146–1159; b) E. Chirkin, W.
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[
[
2]
3]
For examples of dimeric, trimeric, tetrameric, and pentameric securinega
alkaloids see: a) J. Park, S. Jeon, G. Kang, J. Lee, M-H. Baik, S. Han J.
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[22] A screen of oxidants revealed that PIDA was the most effective oxidant;
the originally reported conditions of 1 equivalent of lead tetraacetate at
2
017, 139, 6302–6305 and references therein.
0 °C in DCM solvent (Ref. 16a) only lead to trace product. Full
a) J.-H. Chen, S. R. Levine, J. F. Buergler, T. C. McMahon, M. R.
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[23] S. Moulay, Chem. Educ. Res. Pract. Eur. 2002, 3, 33–64.
[24] Coffen, D. L.; Katonak, D. A. Helv. Chim. Acta 1981, 64, 1645.
[25] H. R. Kim, S. I. Shin, H. J. Park, D. J. Jeon, E. K. Ryu, Synlett 1998, 7,
789–791.
[
[
4]
5]
J. Parello, S. Munavalli, Compt. Rend. 1965, 260, 337–340
Z. Horii, T. Imanishi, M. Yamauchi, M. Hanaoka, J. Parello, S. Munavalli,
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[26] See the Supporting Information for further details.
[
[
6]
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1
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Angewandte Chemie International Edition
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[
44] Phyllantidine (1), as well as compounds 35, 40, 59, 60, and 61, were
selected for screening against the U. S. National Cancer Institutes’ 60
cancer cell line panel. However, all compounds tested were found to be
essentially inactive against these cell lines after the single dose screen.26
45] The supplementary crystallographic data for this paper can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures. The CCDC numbers are as follows:
compound 23 (CCDC 1950718), compound 35 (CCDC 1950719),
compound 40 (CCDC 1950720), compound 47 (CCDC 1950721), and
compound 48 (CCDC 1950722).
[
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Entry for the Table of Contents (Please choose one layout)
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RESEARCH ARTICLE
N–O Problem: The development of a
concise total synthesis of (±)-
phyllantidine (1) a member of the
securinega family of alkaloids, from
Dr. Kyle M. Lambert,†[a] Dr. Joshua B.
Cox,†[a] Lin Liu,[a] Amy C. Jackson,[a] Dr.
Sam Yruegas,[a] Prof. Kenneth B.
Wiberg,[b] and Prof. John L. Wood*[a]
H
O
N
O
H
O
1,4-cyclohexadiene is described. The
(±)-Phyllantidine
synthesis features key ring
a
Page No. – Page No.
O
O
O
O
expansion which allows for the facile
installation of an embedded nitrogen-
oxygen (N–O) bond, allowing for the
O
Total Synthesis of (±)-Phyllantidine:
O
Key Ring
Expansion:
Development
and
Mechanistic
H
H
Evaluation of a Novel Ring Expansion
for Installation of Embedded Nitrogen-
Oxygen Bonds
rapid
construction
of
the
N
oxazabicyclo[3.3.1]nonane core of (1).
OAc
OH
N
O
O
This article is protected by copyright. All rights reserved.