Total Synthesis of Thromboxane B2via a Key Bicyclic Enal Intermediate

Article abstract of DOI:10.1021/acs.orglett.0c02299

A 12-step asymmetric synthesis of thromboxane B2 (TxB2) from 2,5-dimethoxytetrahydrofuran is described. The synthesis employs our organocatalytic aldol reaction of succinaldehyde to give a key bicyclic enal intermediate. From here, the synthetic strategy involves a conjugate addition of an alkenyl side chain to the bicyclic enal, Baeyer-Villiger oxidation, and a highly Z-selective Wittig olefination of a hemiacetal. Key to success was minimizing redox operations and the manipulation of functional groups in the correct order.

Full text of DOI:10.1021/acs.orglett.0c02299

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Total Synthesis of Thromboxane B2 via a Key Bicyclic Enal
Intermediate
Changcheng Jing and Varinder K. Aggarwal*
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ABSTRACT: A 12-step asymmetric synthesis of thromboxane B2
(TxB2) from 2,5-dimethoxytetrahydrofuran is described. The
synthesis employs our organocatalytic aldol reaction of succinalde-
hyde to give a key bicyclic enal intermediate. From here, the
synthetic strategy involves a conjugate addition of an alkenyl side
chain to the bicyclic enal, Baeyer−Villiger oxidation, and a highly
Z-selective Wittig olefination of a hemiacetal. Key to success was
minimizing redox operations and the manipulation of functional
groups in the correct order.
hromboxane B2 (TxB2) is a metabolite of thromboxane A2
wide range of prostanoids, we see our enal intermediate, 8, as
being perfectly set up for further transformations to access the
whole family of prostanoids in an efficient manner. As part of this
effort, we now report the application of this strategy to a 12-step
synthesis of the natural prostanoid TxB2.11
T
(TxA2, t l/2 (37 °C) = 32 s at pH 7.40), a prostanoid which
causes contraction of coronary vessels and platelet aggregation
(thrombosis) (Figure 1).1 Although TxB2 is generally regarded
Our retrosynthetic analysis for the stereoselective synthesis of
TxB2 1 is shown in Scheme 1. We envisaged that the α-side chain
Scheme 1. Retrosynthetic Analysis of Thromboxane B2 from
the Key Bicyclic Enal Intermediate
Figure 1. Structures of thromboxane A2 and thromboxane B2.
as biologically inert, there are reports that it inhibits the
pulmonary inactivation of PGE22 and that it may play a role in
the immune3 and vascular systems too.4 It’s main use is as a
marker for TxA2, and it is recognized as a valuable molecule for
the studies of prostanoid-related biochemical processes.5 For
example, Still employed TxB2 as a synthetic precursor to the
biologically active TxA2.5a,6 The interesting molecular archi-
tecture of the natural product TxB2 has made it an appealing
target for chemists over the years.7 In this context, several
asymmetric syntheses of TxB2 have been reported.8 However,
the previous synthetic strategies are rather lengthy and lack atom
economy, costing time and energy, and so improved syntheses
are still in demand.
We recently developed a short synthetic strategy to
prostaglandins, completing the total synthesis of PGF2α in just
7 steps9a and applied this methodology to several prostaglandin-
based drugs9b,c and to Δ12-PGJ3.9d The key step in the synthesis
employed a (L)-proline catalyzed double aldol dimerization of
succinaldehyde to prepare the key bicyclic enal intermediate
(8).9a,d We were keen to broaden the reach of this chemistry and
in particular to demonstrate its application to other prostanoids.
Just as the Corey lactone10 has been used for the preparation of a
Received: July 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02299
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 2. Initial Attempts to Thromboxane B2 via the Formation of Dilactone 12
a
Reagents and conditions: (a) [Cu(MeCN)4]OTf (5 mol %), 2′-bpyridine (5 mol %), TEMPO (5 mol %), NMI (10 mol %), CH3CN, air, r.t.,
overnight, 91% yield. (b) Cuprate 10 (1.2 equiv), THF/Et2O, −78 °C; then TMSCl (5 equiv), Et3N (6 equiv), −78 °C to −20 °C. (c) O3−O2,
CH2Cl2/MeOH (v/v, 3:1), −78 °C; then PPh3 (1.5 equiv). (d) m-CPBA (2.5 equiv), NaHCO3 (2.7 equiv), CH2Cl2, 0 °C to r.t., 36 h, 20% yield, 3
steps. TEMPO, 2,2,6,6-tetramethyl-1-piperidinyloxy; NMI, N-methylimidazole; TBS, tert-butyldimethylsilyl; TMS, trimethylsilyl; m-CPBA, m-
chloroperoxybenzoic acid; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
could be introduced by a Wittig reaction on the corresponding
hemiacetal 3. This could be obtained by selective reduction of
lactone 4, which itself could be synthesized by Baeyer−Villiger
oxidation of ketone 5. Ketone 5 could be generated from a
stereoselective conjugate addition of the chiral ω-side chain 6 to
the key enal intermediate 7 followed by ozonolysis. Although
selective redox steps are required (4 → 3), this analysis was
deemed preferable over using the acetal since (i) the lactone is a
crystalline compound, (ii) it is a single diastereoisomer whereas
the acetal is a mixture, and (iii) it minimizes the use of protecting
groups.
We began our synthesis with the preparation of enal-lactone 7,
available in just 3 steps on multigram scale with high ee using our
L-proline-catalyzed double aldol reaction of succinaldehyde (9),
generated by hydrolysis of commercially obtainable 2,5-
dimethoxytetrahydrofuran (Scheme 2).9 Subsequent conjugate
addition of the mixed vinyl cuprate 10 to 7 followed by trapping
with TMSCl and selective ozonolysis9a,b gave ketone 11, which
was then converted to the dilactone intermediate 12 via Baeyer−
Villiger oxidation12 [20% yield (unoptimized), over 3 steps].
Unfortunately, all attempts to selectively reduce dilactone 12 to
the corresponding Wittig reaction precursor 14 via the
formation of 13 using Proctor’s SmI2−H2O method13 led to
complex reaction mixtures (see the Supporting Information for
detailed information). Although this method had been reported
to reduce 6-membered lactones to the diol in the presence of 5-
membered ring lactones, we observed the formation of multiple
reaction products when applied to dilactone 12.
Due to the difficulty in selectively reducing one of the two
lactones, we decided to begin with the acetal in place, since the
hemiacetal is formed directly from the proline catalyzed aldol
reaction. Furthermore, this would avoid additional oxidation
and reduction steps. We selected the para-methoxybenzyl acetal
15 to aid deprotection under neutral conditions (Scheme 3).
Although this route has the acetal at the required oxidation state,
it is complicated by having to manipulate and carry through two
diastereoisomers. In fact, we found it better to separate the acetal
diastereomers and manipulate them separately, as this allowed
us to monitor reactions more easily and purify and characterize
compounds more fully. Initially, the major β-isomer of the
acetals was selected, and we carried through the established 1,4-
addition/ozonolysis/Baeyer−Villiger oxidation, delivering the
key lactone intermediate β-17 (64% yield, over 3 steps).
Following PMB deprotection with DDQ, we explored the Wittig
reaction with (4-carboxybutyl)triphenyl-phosphonium bromide
or [4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]-
triphenylphosphonium iodide,14 but these invariably led to
intractable mixtures (Scheme 3b). We suspected that under
basic conditions, the lactone moiety in intermediate 18 was
interfering in this step causing side reactions, and so we decided
to remove it. Initially, we considered reduction to the diol since,
as shown in Scheme 3b, this could lead to a short synthesis of
TxB2, simply requiring reduction, Wittig reaction, selective
oxidation, and deprotection. Unfortunately, while LiAlH4
reduction to diol 20 was successful, we were unable to deprotect
the PMB group cleanly.
We therefore considered an alternative strategy in which we
conducted a controlled reduction of the lactone to the required
oxidation state and employed a protecting group instead, i.e.,
conversion of lactone β-17 into the methoxy acetal. Starting with
β-17, reduction (DIBAL-H, THF, −78 °C) and oxy-
methylation of the “naked” anion generated by deprotonation
with KHMDS in the presence of 18-crown-6 afforded acetal β-
22 as a single diastereoisomer.15 The established 1,4-addition/
ozonolysis/Baeyer−Villiger oxidation protocol was also applied
to the minor α-isomer of PMB-acetals 15, affording lactone α-17
in 63% yield over 3 steps. Reduction with DIBAL-H, followed by
oxy-methylation again furnished a single diastereomer α-22.
Interestingly, the α- and β-isomers of hemiacetal 21 (isomers at
the PMBO acetal) showed quite different reactivity: the α-
isomer was far more labile under oxy-methylation conditions
than the β-isomer giving several unidentified side products (36%
yield for α vs 73% yield for β). Following PMB deprotection of
acetals 22 with DDQ, Wittig olefination using phosphonium salt
24 with t-BuOK now successfully gave the corresponding alkene
25 in 97% yield with Z/E > 95:5. Desilylation of the TBS group
with TBAF gave the required thromboxane B2 methyl glycoside
26 in 89% yield. Finally, subjecting methyl glycoside 26 to
hydrolysis with excess Dowex-50 resin in water furnished
thromboxane B2 (TxB2, 1) in 90% yield.16
B
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a
Scheme 3. Completion of the Synthesis of Thromboxane B2
a
Reagents and conditions: (a) PMBOH (2 equiv), Amberlyst 15 (cat.), MgSO4 (2.5 equiv), CH2Cl2, 0 °C to r.t., 24 h; then MnO2 (6 equiv), r.t.,
12 h, 81% yield, 1.7:1 β/α. (b) Cuprate 10 (1.2 equiv), THF/Et2O, −78 °C; then TMSCl (5 equiv), Et3N (6 equiv), −78 °C to −20 °C. (c) O3−
O2, CH2Cl2/MeOH (v/v, 3:1), −78 °C; then PPh3 (1.5 equiv). (d) m-CPBA (2.5 equiv), NaHCO3 (2.7 equiv), CH2Cl2, 0 °C to r.t., 36 h, 64%
yield for β, 63% yield for α, 3 steps. (e) DIBAL-H (3.0 equiv), THF, −78 °C, 3 h, 96% yield for β, 91% yield for α. (f) MeI (3 equiv), KHMDS (1.1
equiv), 18-crown-6 (1.1 equiv), THF, −78 °C, 18 h, single diastereomer, 73% yield for β, 36% yield for α. (g) DDQ (1.5 equiv), CH2Cl2/H2O (v/
v, 9:1), 0 °C to r.t., 6 h, 80% yield for β, 74% yield for α. (h) (4-Carboxybutyl)triphenyl-phosphonium bromide (4 equiv), t-BuOK (8 equiv), THF,
0 °C to r.t., 2 h, 97% yield with Z/E > 95:5. (i) TBAF (2 equiv), THF, 0 °C to r.t., 12 h, 89% yield. (j) Dowex-50 Resin, H2O, r.t., 16 h, 90% yield.
(k) DDQ (1.5 equiv), CH2Cl2/H2O (v/v, 9:1), 0 °C to r.t., 6 h, 81% yield. (l) LiAlH4 (1.2 equiv), THF, 0 °C to r.t., 6 h, 90% yield. (m) DDQ (1.5
equiv), CH2Cl2/H2O (v/v, 9:1), 0 °C to r.t., 6 h, multiple products. PMBOH, p-methoxybenzyl; TBS, tert-butyldimethylsilyl. TMS, trimethylsilyl;
m-CPBA, m-chloroperoxybenzoic acid; DIBAL-H, diisobutylaluminum hydride; HMDS, bis(trimethylsilyl)amide; DDQ, 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone; TBAF, tetrabutylammonium fluoride.
In conclusion, we have developed a highly stereoselective
synthesis of thromboxane B2 in 12 steps with an overall yield of
5%, utilizing our key enal intermediate, which is readily available
in two steps by a L-proline-catalyzed aldol dimerization of
succinaldehyde in high ee. The key features include an efficient
1,4-addition/ozonolysis/Baeyer−Villiger oxidation protocol
and a Wittig olefination of hemiacetals with excellent levels of
Z selectivity. Although carrying through the diastereomeric
acetals complicates analysis, it avoids additional redox steps
enabling the synthesis to be completed in short order. The
synthesis adds to the growing list of prostanoids that can now be
C
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02299.
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General procedures, characterization data, and copies of
NMR spectra for all novel compounds (PDF)
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1984, 1984, 449−478. (c) Pelyvas, I. F.; Thiem, J.; Toth, Z. G. Access to
Thromboxane Compounds: Syntheses from Carbohydrates, as Natural
Chiral Pools. J. Carbohydr. Chem. 1998, 17, 1−26.
AUTHOR INFORMATION
Corresponding Author
■
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B2 Starting from (R,R)-Tartaric Acid as a Chiral Pool. Tetrahedron Lett.
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Varinder K. Aggarwal − School of Chemistry, University of
Bristol, Bristol BS8 1TS, U.K.; orcid.org/0000-0003-0344-
6430; Email: v.aggarwal@bristol.ac.uk
Author
Changcheng Jing − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02299
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank EPSRC (Grant EP/M012530/1) for financial
support. We thank Riccardo Mega (University of Bristol) and
Steven Bennett (University of Bristol) for useful discussions.
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Trans. 1 2000, 2385−2394.
(16) We obtained full spectroscopic data (1H NMR, 13C NMR,
HRMS, and [α]2D4) of the methyl glycoside, but obtaining high-quality
data for TxB2 itself was more challenging. We were able to obtain
HRMS (see the Supporting Information); mp, 91−94 °C; and [α]D24
=
+57.10 (c 1.0, EtOH) which matched the literature [lit.8b mp, 92.0−
92.5 °C; [α]D = +56.50 (c 1.0, EtOH)]. However, 1H NMR spectrum of
E
https://dx.doi.org/10.1021/acs.orglett.0c02299
Org. Lett. XXXX, XXX, XXX−XXX