Access to a Key Building Block for the Prostaglandin Family via Stereocontrolled Organocatalytic Baeyer–Villiger Oxidation

Article abstract of DOI:10.1002/anie.201902371

A new protocol for the construction of a crucial bicyclic lactone of prostaglandins using a stereocontrolled organocatalytic Baeyer–Villiger (B-V) oxidation was developed. The key B-V oxidation of a racemic cyclobutanone derivative with aqueous hydrogen peroxide has enabled an early-stage construction of a bicyclic lactone skeleton in high enantiomeric excess (up to 95 %). The generated bicyclic lactone is fully primed with two desired stereocenters and enabled the synthesis of the entire family of prostaglandins according to Corey′s route. Furthermore, the reactivity and enantioselectivity of B-V oxidation of racemic bicyclic cyclobutanones were evaluated and 90–99 % ee was obtained, representing one of the most efficient routes to chiral lactones. This study further facilitates the synthesis of prostaglandins and chiral lactone-containing natural products to promote drug discovery.

Full text of DOI:10.1002/anie.201902371

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Accepted Article
Title: Collective Total Synthesis of the Prostaglandins Family via
Stereocontrolled Organocatalytic Baeyer-Villiger Oxidation
Authors: Kejie Zhu, Sha Hu, Minjie Liu, Haihui Peng, and Fener Chen
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10.1002/anie.201902371
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Asymmetric Total Synthesis
Collective Total Synthesis of the Prostaglandins Family via Stereocontrolled
Organocatalytic Baeyer-Villiger Oxidation
Kejie Zhu,# Sha Hu,# Minjie Liu, Haihui Peng* and Fen-Er Chen*
was constructed in one step in 99% ee. With this strategy, the entire
family of prostaglandins could be synthesized. Reactivity and
enantioselectivity of B-V oxidation of racemic bicyclic
cyclobutanones were also evaluated and 90-99% ee was obtained,
representing one of the most efficient ways for chiral lactone
formation.
Abstract: A new protocol for the synthesis of prostaglandins using a
stereocontrolled organocatalytic Baeyer-Villiger (B-V) oxidation
was described for the first time. The key B-V oxidation of racemic
cyclobutanone with aqueous hydrogen peroxide has enabled an early
stage construction of bicyclic lactone skeleton in high enantiomeric
excess (up to 99%). The generated bicyclic lactone is fully primed
with two desired stereocenters and enabled the assembly of the entire
family of prostaglandins. Furthermore, reactivity and
enantioselectivity of B-V oxidation of racemic bicyclic
cyclobutanones were evaluated and 90-99% ee was obtained,
representing one of the most efficient ways for chiral lactones
synthesis. This study further facilitates the synthesis of
prostaglandins and chiral lactone-containing natural products to
promote new drug discoveries.
Prostaglandins are a family of important hormone-like chemical
messengers that regulate a broad range of biological activities and
have wide medicinal applications.[1-2] So far, there have been more
than 20 drugs related to prostaglandins marketed, some of which,
such as latanoprost, have become billion-dollar drugs.[3] Pioneered
by Corey’s landmark synthesis of prostaglandin F2 (PGF21), many
ingenious strategies and new methodologies of general use have been
developed.[4] And a variety of related natural compounds and
structurally modified analogs have been produced both by academia
and pharmaceutical laboratories. More recently, efficient total
synthesis of PGF2 and PGE2 has been accomplished by Aggarwal
Scheme 1. Retrosynthetic analysis of PGF2.
and Hayashi using
a new bond disconnection strategy via
organocatalysis.[5,6] Elegant contributions to the total synthesis of
We recognized that prostaglandins, PGF2 as an example,[10] can
be simplified into a truncated chiral lactone diol 3 through an
intermediate of 2 via a five-step sequence of primary alcohol
oxidation, HWE olefination, CBS reduction, DIBAL-H reduction
and Wittig olefination (Scheme 1). Diol 3 was synthesized from
lactone 4 by Prins reaction and deprotection. 4 was generated from
the precursor 5. At this stage, we envisioned that lactone 5 could be
accessed from bicyclic cyclobutanone 6 via a stereocontrolled B-V
oxidation, which would install the sterically congested lactone
moiety with the two desired stereocenters at an early stage. 6 could
be easily prepared from cyclopentadiene 7. Vital to the success of this
synthesis is the generation of the key intermediate 5 with high
stereocontrol within a few steps. There is no direct method to
construct the chiral bicycliclactone skeleton in one step. In the
Corey’s original synthesis of PGF2, an analogous of 3 (the Corey’s
lactone) was synthesized in nine steps from 7.
We commenced our endeavors with the development of a
stereocontrolled catalytic B-V oxidation of racemic cyclic
ketones.[11] Notably, previously reported B-V oxidation mainly
focused on prochiral cyclobutanones via a desymmetrization
strategy.[12] And B-V oxidation of racemic ketones are still limited in
number and are inferior to prochiral ketones in terms of
enantiospecificity and topos selectivity (Scheme 2a).[13] Specifically,
a mixture of the desired normal lactone (NL) and undesired abnormal
lactone (AL) were formed while rates of AL formation were found to
PGJ compounds have also made by Nicolaou, Carreira and Stoltz.[7-
9]
However, owing to the challenges of forging three or four
contiguous stereogenic centers and instability due to the facile
dehydration of the hydroxy groups, the reported syntheses of
prostaglandins still suffered from lengthy steps, complex protection
and deprotection manipulations and lack of general protocols toward
structure related molecules. Thus, a general and practical approach to
prepare the core structure of prostaglandins in a highly efficient and
stereocontrolled fashion was highly desirable. Herein, we presented
a collective total synthesis of prostaglandins using a highly
enantioselective organocatalytic B-V oxidation strategy. The key
chiral bicycliclactone skeleton containing two desired chiral centers
[] K. Zhu, S. Hu, M. Liu, Prof. Dr. H. Peng, Prof. Dr. F. Chen
Engineering Center of Catalysis and Synthesis for Chiral Molecules,
Department of Chemistry, Fudan University, Shanghai 200433, China
Shanghai Engineering Center of Industrial Asymmetric Catalysis for
Chiral
Molecules,
Shanghai
200433,
China
E-mail: haihui_peng@fudan.edu.cn, rfchen@fudan.edu.cn
[#] co-first author
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/anie.201902371
Angewandte Chemie International Edition
be faster than those of NL (Scheme 2b).[14-15] Moreover, the
separation of these mixtures is difficult. Major breakthroughs in this
area were made by Ding’s group using a Brønsted acid-catalysis
strategy, achieving asymmetric B-V oxidation of prochiral
cyclobutanones in good yield and enantioselectivity. However, for
the racemic cyclobutanones, the normal lactone was dominant albeit
with middle diastereoselectivity (Scheme 2c).[16]
Table 1. Conditions screening for asymmetric B-V oxidation.[a]
Time
(h).
Yield, 5a
Ee, 5a
S-factor
5a
Yield, 5a’
Entry
cat.
[b]
(%)[c,d]
(%)[e]
(%)
1
2
8a
8b
8c
8d
8e
8f
68
68
68
48
48
48
48
60
33
36
41
47
39
35
31
46
37
91
58
81
53
78
47
2.5
35.0
5.5
23
26
31
37
29
25
21
44
3
4
20.0
4.5
5
6
12.0
3.4
7
8[f]
8g
8b
99
118
.
[a] General conditions: 6a (0.2 mmol), H2O2 H2O (0.6 mmol, 3 equiv.) and 8
o
(10 mol%) in CDCl3 (0.4 M), -20 C; [b] isolated yield; [c] determined by
HPLC; [d] absolute configuration; [e] 1H NMR yield with 1,3,5-
trimethoxybenzene as internal standard; [f] 0.4 M at -15 oC.
We therefore tested the B-V oxidation of racemic bicyclic
cyclobutanone 6a using spiro-phosphonic acid as catalyst under a
variety of conditions (Table 1). Remarkably, this novel
organocatalytic system proved to be very efficient and gave the
corresponding lactone product 5a with excellent enantioselectivity.
Especially, with the sterically bulky triisopropyl-substituted 8b, 36%
yield with 91% ee was obtained (entries 1-3). In comparison, 2,2’-
dihydroxy-1,1’-binapthyl (binol)- or H8-binol-derived phosphonic
acid gave decreased enantioselectivity but with faster kinetics
(entries 4-7).[20] Through NMR monitoring, formal kinetic resolution
was demonstrated when using catalyst 8b and desired NL 5a was
given in preference to undesired AL 5a’. Moreover, the remaining
substrate largely converted to AL 5a’, indicating one epimer of
substrate led to the desired 5a while another epimer led to 5a’.[21]
Increasing reaction concentration and temperature improved both
reactivity and enantioselectivity to give 5a in 46% yield and 99% ee
with good selectivity factor (entry 8).[22] But byproduct 5a’ was only
detected at low temperature. Due to the notorious instability,
warming up the reaction to room temperature discomposed 5a’ and
purification is straightforward just passing through a plug of silica
gel. The structure and enantiomeric excess of 5a and 5a’ were further
confirmed via LiAlH4 reduction of lactone to 1,4-diol and subsequent
protection of alcohol group (Scheme 3). This strategy thus provides
a convenient way to chiral 1,4-diols, which are versatile building
blocks in the synthesis of many natural products.[23]
Scheme 2. Asymmetric B-V oxidation of racemic cyclobutanones.
The difficulty in developing a catalytic asymmetric version of B-
V oxidation of racemic cyclobutanones may be ascribed to weak
chiral recognition of substrates and poor stereoelectronic control over
the Criegee intermediate. Inspired by previous fundamental results,
we reasoned that chiral spiro-phosphonic acid may provide sufficient
control over stereospecificity and topos selectivity due to the chiral
environment generated by spiro-backbone and bulky substituents in
3,3’-positions.[17] Moreover, the hydrogen bonding interaction
between the spiro-phosphonic acid with the Criegee intermediate
would dictate the desired orientation to satisfy the stereoelectronic
requirement. Dichloro-moiety was also introduced into
cyclobutanone ring to improve topos selectivity and increase the
desired normal lactone since the migratory rate of electrodeficient
carbon is slower than electron-rich carbon.[18] Notably, dichloro-
moiety could be easily eliminated via zinc reduction. Furthermore,
chloride-containing abnormal lactone could be converted to
cyclopentene dicarboxylic acid via an intermediate of acetyl chloride
in the presence of water and could be easily removed from reaction
mixture (Scheme 2d).[19]
Scheme 3. Derivatization of 5a and 5a’.
2
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10.1002/anie.201902371
Angewandte Chemie International Edition
The asymmetric B-V oxidation of various bicyclic cyclobutanones
was then evaluated under above optimal conditions. As shown in
Table 2, excellent enantioselectivities were obtained in all cases. The
presence of an olefin, or aromatic ring, or different ring sizes, had
little influence on stereoselectivities of this reaction and gave the
desired products in 30-47% yield with 90-99% ee. Using (S)-
enantiomer of catalyst 8b, the corresponding (-)-5a could be easily
obtained with 45% yield in 95% ee, which could be directly utilized
in the asymmetric total synthesis of prostaglandins. However, using
bicyclic cyclopentenone or acyclic ketones, no reaction occurred.
These results clearly indicated efficient chiral recognition and
stereoelectronic control of the bicyclic cyclobutanones using our
organocatalytic system. Notably, chemical versions of asymmetric B-
V oxidation are generally inferior to biocatalyzed B-V oxidation.[24]
This organocatalysis with unusually high enantioselectivity thus
represented one of few examples that could attain enantioselectivity
at a level comparable to enzymes and provided an efficient way to
prepare chiral lactones using H2O2 as the oxidant.
Table 2. Substrate scope for asymmetric B-V oxidation.[a,b]
.
[a] General conditions: 6 (0.3 mmol), H2O2 H2O (0.9 mmol, 3 equiv) and 8b
(10 mol%) in CHCl3 (0.4 M), -15 oC, 60-80 h; [b]isolated yield; [c] compound
(-)-5a was obtained via the enantiomer of catalyst 8b.
Scheme 4. Asymmetric total synthesis of prostaglandins.
a) Zn; b) (HCHO)n; c) K2CO3; d) TEMPO/PHI(OAc)2; e) 9 (or 11); f) (R)-CBS-Me; g) DIBAL-H; h) PPh3Br(CH2)4CO2H; i) DIP-Cl; j) Pd/C, H2; k) iPrI; l) PPh3Br(CH2)4CO2NHEt;
m) TBSCl; n) DMP; o) HF/pyridine; p) HCl; q) KOH then HCl.
Having rapidly synthesized the bicycliclactone in one step with
desired two chiral centers, the total synthesis of PGF2 was
completed (Scheme 4). PGF2is the most complex prostaglandin
containing four continuous stereocenters. From lactone (-)-5a,
reductive dechlorination via Zn/NH4Cl produced lactone 4 in
quantitative yield. The following Prins reaction using
paraformaldehyde and H2SO4/CH3COOH followed by deformylation
gave diol 3 in 79% yield in two steps. At this stage, instead of using
complex protecting group strategies, we found that a modified
TEMPO/PhI(OAc)2 oxidation could result in the selective oxidation
of primary alcohol while keeping the secondary alcohol intact.[25]
Moreover, with this strategy, no protecting group is needed in the
following synthesis of PGF2. The resulting aldehyde was not stable
enough and was directly subjected to HWE-olefination to give the
desired conjugated enone 10 in 60% yield in 2 steps. From enone 10,
the synthesis of PGF2 was simple. Firstly, CBS reduction of keto-
functionality furnished allylic alcohol 2 with the desired lower-side
chain in 85% yield and 9:1 diastereomeric ratio. The following
sequential DIBAL-H reduction of lactone to hemi-acetal and
followed by Wittig olefination gave PGF2 1 in 55% yield within last
3
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10.1002/anie.201902371
Angewandte Chemie International Edition
Conflict of interest
two steps. In this route, the synthesis of PGF2 1 was completed in
overall 8 steps from (-)-5a with 20% yield. Interestingly, in Corey’s
original synthesis of racemic PGF2, B-V oxidation was first
introduced to construct the bicycliclactone skeleton. This synthesis
thus represents the first example of diastereoselective asymmetric B-
V oxidation applied to the total synthesis of prostaglandins in the past
four decades.[26]
The versatility of this synthesis was further demonstrated in the
synthesis of the other prostaglandins and analogues. Firstly, two
analogs of PGF2, latanoprost (14) and bimatoprost (15), were
synthesized with slightly different procedures. Using lactone diol 3,
the phenyl-substituted lower-side chain was firstly introduced to give
enone 12 in 60% yield in two steps. Then DIP-Cl reduction of enone
12 gave allylic alcohol 13 in 76% yield. From 13, the synthesis of
latanoprost 14 was straightforward and completed in another four
steps in 41% yield. Bimatoprost 15 could also be synthesized from
13 in two more steps with 58% yield. In this way, the PGF family of
prostaglandins were synthesized in overall 8-10 steps from the
lactone (-)-5a with 15-21% yields.
The authors declare no conflict of interest.
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and its analogues, the other prostaglandins were also accessible using
only one simple protecting group. From enone 10, CBS reduction
followed by TBS-protection of the corresponding allylic alcohol gave
silyl ether 16 in 68% yield in two steps. The following sequential
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PGA2 (19) and PGC2 (20) under slightly different conditions. Using
HF/pyridine in CH3CN solution, desilylation was processed to give
PGE2 18 in 91% yield. With HCl/THF solution, simultaneous
desilylation and dehydration were processed to furnish PGA2 19 in
89% yield. Moreover, using KOH/MeOH and followed by
acidification
with
an
HCl/THF
solution,
sequential
deprotection/dehydration/isomerization gave PGC2 20 in 80% yield.
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key intermediate (-)-5a.
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In conclusion, we have successfully developed a collective
synthesis of prostaglandins empowered by stereocontrolled
organocatalytic B-V oxidation of racemic bicyclic cylcobutanones
with H2O2. This synthesis is featuring with 1) the key B-V oxidation
provided a generic intermediate of lactone as a versatile building
block for the synthesis of the entire family of prostaglandins, with
high enantiomeric excess in an environmentally benign fashion, 2)
through a highly selective primary alcohol oxidation strategy, the
synthesis of six prostaglandins was accomplished in 10-13 steps
without or with one simple protecting group. Furthermore, reactivity
and enantioselectivity of organocatalytic B-V oxidation of racemic
bicyclobutanones were evaluated and 90-99% ee were achieved in all
cases. The modularity and expediency of this chemistry thus opens a
new avenue for the synthesis of prostaglandins and lactone-
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ACKNOWLEDGMENT
Dr. Haihui Peng thank Shanghai Pujiang Program (18PJ1401400),
NSFC (21801042) and Fudan University for financial support.
4
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10.1002/anie.201902371
Angewandte Chemie International Edition
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5
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10.1002/anie.201902371
Angewandte Chemie International Edition
Entry for the Table of Contents
Asymmetric Total Synthesis
Kejie Zhu, Sha Hu, Minjie Liu, Haihui
Peng* and Fener Chen*__________
Page – Page
Collective Total Synthesis of the
Prostaglandins
Family
Via
Stereocontrolled
Organocatalytic
Baeyer-Villiger Oxidation
A new protocol for the synthesis of prostaglandins using stereocontrolled
organocatalytic Baeyer-Villiger (B-V) oxidation was described for the first time. The
key B-V oxidation of racemic cyclobutanone with aqueous hydrogen peroxide has
enabled an early stage construction of bicyclic lactone skeleton with high
enantiomeric excess (up to 99%). The generated bicyclic lactone contained two
desired stereocenters and enabled the assembly of the entire family of
prostaglandins. Furthermore, reactivity and enantioselectivity of B-V oxidation of
racemic bicyclic cyclobutanones were evaluated and 90-99% ee were obtained. This
study further facilitates the synthesis of prostaglandins and chiral lactone-containing
natural products to promote new drug discoveries.
6
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