Synthesis of Alfaprostol and PGF2α through 1,4-Addition of an Alkyne to an Enal Intermediate as the Key Step

Article abstract of DOI:10.1021/acs.orglett.7b03057

The veterinary drug Alfaprostol and prostaglandin PGF_2α have been synthesized in just nine steps. The strategy involved the conjugate addition of an alkyne to a bicyclic enal, available in three steps by a proline-catalyzed aldol reaction of succinaldehyde. In the case of Alfaprostol, this resulted in the shortest synthesis reported to date. For PGF_2α, this approach improved our previous route by making the 1,4-addition and ozonolysis more operationally simple.

Full text of DOI:10.1021/acs.orglett.7b03057

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Synthesis of Alfaprostol and PGF2α through 1,4-Addition of an
Alkyne to an Enal Intermediate as the Key Step
Hannah Baars,† Moritz J. Classen,† and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
S
* Supporting Information
ABSTRACT: The veterinary drug Alfaprostol and prostaglandin
PGF2α have been synthesized in just nine steps. The strategy
involved the conjugate addition of an alkyne to a bicyclic enal,
available in three steps by a proline-catalyzed aldol reaction of
succinaldehyde. In the case of Alfaprostol, this resulted in the
shortest synthesis reported to date. For PGF2α, this approach
improved our previous route by making the 1,4-addition and
ozonolysis more operationally simple.
rostaglandins are involved in many reproductive processes
in mammals.1 Control of such processes, particularly in
Scheme 1. Previous and Current Strategy toward Alfaprostol
P
veterinary medicine, is critical to food production and animal
welfare.2 For example, prostaglandin PGF2α (1) is known for its
luteolytic effect (degradation of the corpus luteum) in cattle
(Figure 1).3 This activity is exploited in veterinary practice for
Figure 1. Prostaglandin PGF2α and its synthetic analogue Alfaprostol.
the timing of insemination and increasing reproductive
efficiency. Alfaprostol (2) was developed as a more stable
and selective analogue of PGF2α and is widely used as a potent
luteolytic agent in cows4 and mares.5 In addition to its
application in the treatment of glaucoma,6 continued research
on PGF2α and its analogues (including Alfaprostol) have
uncovered a diverse array of new biological activity from
reduction of adipose tissue7 to the treatment of neuro-
psychiatric conditions (e.g., bipolar disorders).8 These new
applications warrant renewed and improved syntheses of this
important class of compounds.9
While numerous diverse strategies have been reported for the
synthesis of PGF2α,1c strategies toward Alfaprostol have been
more limited. In fact, they all utilize the Corey lactone as an
intermediate, only differing in the method for the introduction
of the alkyne moiety (Scheme 1A). Gandolfi et al. applied a
sequence of Horner−Wadsworth−Emmons olefination, bromi-
nation, and double dehydrobromination to install the triple
bond.10 Monteiro et al. used a Seyferth−Gilbert homologation
to give the alkyne directly, which was converted into a stannane
and finally coupled with acyl chloride in a Stille coupling.11
Both approaches required ca. 17 steps from cyclopentadiene.
Received: September 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03057
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Organic Letters
Letter
12
We recently reported a seven-step synthesis of PGF2α and
similarly short syntheses of Latanoprost and Bimatoprost.13 We
employed the (L)-proline catalyzed aldol reaction of
succinaldehyde as the key step to rapidly assemble the bicyclic
enal, which was ideally set up to enable the stereoselective
incorporation of the remaining side chains (Scheme 1B).
Herein, we report the application of this strategy to a nine-step
synthesis of Alfaprostol based on the conjugate addition of an
alkyne to our key enal intermediate.
ozonide with PPh3 before addition of NaBH4,17 leading to the
formation of alcohol 7 in 50% yield over the two steps.
Having established that the conjugate addition to our enal
substrate was feasible, we moved on to the synthesis of
Alfaprostol itself. The lower side chain 11 was prepared in four
steps starting from 3-cyclohexylpropanoic acid (8; Scheme 3).
Scheme 3. Synthesis of the ω Side Chain
1,4-Additions of alkynes to α,β-unsaturated aldehydes are
challenging, as alkynes usually form stable complexes with
copper14 (in fact, they have been used as nontransferable
groups in mixed organocuprates) and alternative organo-
metallics either led to undesired 1,2-addition or no reaction.
There is just one report of the addition of copper acetylides to
an enal, which employed iodotrimethylsilane as an activator.15
We initially tested this methodology on lactone 313 with the
commercially available alkyne 4 (protected as a silyl ether;
Scheme 2a).7 Under the reported conditions (at −40 °C), we
Scheme 2. Model Studies To Investigate (a) the 1,4-Addition
to Enal 3 and (b) a 1,4 Addition/Ozonolysis Sequence
Transformation of acid 8 into the corresponding Weinreb
amide, and subsequent coupling with ethynylmagnesium
bromide gave alkyne 9 in 85% yield over two steps. Chiral
alcohol 10 was obtained by asymmetric CBS-reduction18 in
87% yield and 97:3 er. Alcohol 10 was protected as a silyl ether
in 93% yield in the final step.
To complete the synthesis of Alfaprostol (Scheme 4), copper
acetylide 12 was generated from alkyne 11 and added to enal 6,
to form intermediate silyl enol ether 13. Subsequent ozonolysis
and reduction with NaBH4 furnished alcohol 14 in 56% yield
over the two steps, and with complete stereocontrol over the
two newly created stereogenic centers at C11 and C12. Double
deprotection of the silyl and acetal groups under acidic
conditions gave the hemiacetal intermediate 15, which was
used without purification in the subsequent Wittig reaction.
Accordingly, treatment of hemiacetal 15 with the commercially
available Wittig salt gave Z-alkene 16 with essentially perfect
selectivity. Finally, esterification19 of acid 16 with methyl iodide
completed a nine-step synthesis of Alfaprostol (2) with
complete stereocontrol.
By synthesizing Alfaprostol, we recognized that the conjugate
addition of an alkyne to enals 3/6 could also be beneficial for
the synthesis of PGF2α, and other prostaglandin analogues, for
three reasons. First, our original 1,4-addition to the enal
required the formation of an organocuprate bearing the
required vinyl substituent and a nontransferable thiophene
ligand,12 and its preparation was time-consuming and laborious
and required the use of t-BuLi. Second, we had previously
required a more functionalized vinyl iodide rather than using
the commercially available alkyne directly. Third, the ozonolysis
would become simpler and more reliable due to the absence of
a second competing double bond, and so timing of the addition
of ozone would become less critical. We therefore revisited the
synthesis of PGF2α (Scheme 5). From our initial studies, we
found that the sequence of 1,4-addition of alkyne 4 to enal 6
followed by ozonolysis and reduction with sodium borohydride
gave alcohol 7 in good yield and full stereocontrol, over two
steps (Scheme 2). The alkyne was converted into E-allylic
were pleased to find that the addition product 5 was formed,
1
after acidic workup, in good yield (48% H NMR yield). The
yield could be increased to 83% (by 1H NMR) by lowering the
temperature to −78 °C. Crucial for high yields was the quality
of the TMSI, which had to be stored under the exclusion of
light, air, and moisture.16
Next, we explored whether the conditions were also suitable
for the 1,4-addition and subsequent ozonolysis with the
required hemiacetal 6. Thus, the crude reaction mixture
obtained following 1,4-addition was subjected directly to
ozonolyis (Scheme 2b). Our standard protocol used in our
previous prostaglandin synthesis12 involved reaction with
ozone, followed by flushing the reaction mixture with a stream
of N2 and subsequent addition of NaBH4 to reduce the ozonide
and reduce the ketone intermediate. However, under these
conditions an allenic side product was formed instead of the
desired alcohol 7. This problem was overcome by reducing the
B
DOI: 10.1021/acs.orglett.7b03057
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 4. Synthesis of Alfaprostol
Scheme 5. Synthesis of PGF2α
ORCID
alcohol 18 by deprotection of the TBDMS group with TBAF
and subsequent Chan reduction20 with Red-Al. Finally,
deprotection of the acetal and Wittig olefination gave PGF2α 1.
In conclusion, we have developed short routes toward
Alfaprostol (9 steps longest linear sequence, 12 steps in total)
and prostaglandin PGF2α (9 steps longest linear sequence, 10
steps in total). Alfaprostol and PGF2α were synthesized in 23%
and 18% overall yields from 6, respectively (both were obtained
in ∼3% overall yield from succinaldehyde; further optimization
for the synthesis of 6 is currently ongoing in our laboratories).
In comparison to the previous syntheses of Alfaprostol, our key
enal intermediate is not only accessed in substantially fewer
steps compared to the Corey lactone but also perfectly set up to
introduce the alkyne side chain in an efficient, single-step
fashion. This resulted in the marked step count reduction
reported here. Furthermore, the conjugate addition of an alkyne
to the enal intermediate simplifies both the 1,4-addition and
subsequent ozonolysis significantly. The alkyne functionality
can be retained or converted into either an alkene or alkane,
thereby providing access to an even broader array of important
prostaglandin analogues which are currently used in the clinic.
Varinder K. Aggarwal: 0000-0003-0344-6430
Author Contributions
†H.B. and M.J.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank EPSRC for support of this work (EP/M012530/1).
H.B. thanks the Deutsche Forschungsgemeinschaft (DFG) for
a postdoctoral fellowship. We thank Dr. Jonathan P. Knowles
and James Smith (University of Bristol) for helpful discussions.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03057.
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Experimental procedures, characterization data, and
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: v.aggarwal@bristol.ac.uk.
C
DOI: 10.1021/acs.orglett.7b03057
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DOI: 10.1021/acs.orglett.7b03057
Org. Lett. XXXX, XXX, XXX−XXX