Synthesis of thromboxane B2 via ketalization/ring-closing metathesis

Article abstract of DOI:10.1021/ol7021214

Total synthesis of thromboxane B₂ using intermolecular ketalization followed by ring-closing metathesis is reported. Other key steps include a Sharpless asymmetric epoxidation to form an oxirane on the endo face of the bicyclic acetal, epoxide opening using lithioacetonitrile, an allylic alcohol 1,3-transposition, and Mitsunobu lactonization.

Full text of DOI:10.1021/ol7021214

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5353-5356
Synthesis of Thromboxane B2 via
Ketalization/Ring-Closing Metathesis
Christopher C. Marvin, Alexander J. L. Clemens, and Steven D. Burke*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1322
burke@chem.wisc.edu
Received August 28, 2007
ABSTRACT
Total synthesis of thromboxane B2 using intermolecular ketalization followed by ring-closing metathesis is reported. Other key steps include
a Sharpless asymmetric epoxidation to form an oxirane on the endo face of the bicyclic acetal, epoxide opening using lithioacetonitrile, an
allylic alcohol 1,3-transposition, and Mitsunobu lactonization.
A synthetic strategy that has been of recent interest to our
group is that of ketalization/ring-closing metathesis
(K/RCM).1 An advantage of this strategy is the rapid
assembly of rigid bicyclic acetal scaffolds, which can then
be stereoselectively functionalized. In previous applica-
tions of the K/RCM strategy, use of C2-symmetric
diene diols (1 in Figure 1) was predicated upon
identification of an embedded 1,2- or 1,3-diol segment
within the target, where both secondary carbinol centers
had the same configuration. Conversion to ketal 3 renders
the vinyl groups diastereotopic; one becomes involved in
ring formation via RCM,2 and the other remains available
for alternative reaction as in bicyclic acetal 4. The
availability of reliable means for alkene extension via
cross metathesis and methods for stereoselective 1,3-
transposition of allylic alcohols suggested that application
of the K/RCM strategy to targets where the carbinol
centers have vinylogous 1,2- or 1,3-relationships would
be possible. We became interested in the synthesis of
thromboxane B2 [TXB2 (5), Figure 2] as an illustration of
this concept.
TXB2 is the stable hydrolysis product of thromboxane A2
[TXA2 (6), Figure 2], a prostanoid signaling molecule
generated by blood platelets and involved in blood clotting
(1) (a) Burke, S. D.; Mu¨ller, N.; Beaudry, C. M. Org. Lett. 1999, 1,
1827. (b) Burke, S. D.; Voight, E. A. Org. Lett. 2001, 3, 237. (c) Voight,
E. A.; Rein, C.; Burke, S. D. Tetrahedron Lett. 2001, 42, 8747. (d) Keller,
V. A.; Martinelli, J. R.; Strieter, E. R.; Burke, S. D. Org. Lett. 2002, 4,
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8489. (f) Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D. Org. Lett.
2004, 6, 4045. (g) Marvin, C. C.; Voight, E. A.; Burke, S. D. Org. Lett.
2007, 9, 5357.
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Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (g) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012.
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(c) Nicolaou, K. C.; Gasic, G. P.; Barnette, W. E. Angew. Chem., Int. Ed.
Engl. 1978, 17, 293. Total synthesis: (d) Masaki, Y.; Yoshizawa, K.; Itoh,
A. Tetrahedron Lett. 1996, 37, 9321. (e) Hanessian, S.; Lavallee, P. Can.
J. Chem. 1981, 59, 870. (f) Hanessian, S.; Lavallee, P. Can. J. Chem. 1977,
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10.1021/ol7021214 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

Figure 1. Generalized K/RCM strategy.
(thrombosis).3 At the conclusion of its short half-life within
the body (32 s), the strained oxetane ring is hydrolyzed to
give the essentially biologically inactive TXB2. As TXB2
has seen significant interest from the synthetic community
over the years,4 it is an appealing target for our K/RCM
strategy as there are benchmarks for comparison. Further-
more, it has been demonstrated that TXB2 can be converted
to the biologically active TXA2.5
and provided a means for the installation of the C1-C7
side chain. The embedded C2-symmetric diene diol 9 is dis-
cernible in 7 and 8, encompassing C8 and C12-C14.
Bicyclic acetal 8 would be readily available after a ketal-
ization/ring-closing metathesis sequence involving diethyl
acetal 10 and C2-symmetric diene diol 9, followed by cross
metathesis with 1-heptene to install C15-C20 of the aliphatic
side chain.
Our synthesis commenced with transacetalization of
107 with diene diol 9,8 driven to completion by the azeotropic
removal of ethanol to give pseudo-C2-symmetric acetal 11
as the major product (Scheme 1). RCM was achieved at room
temperature using Grubbs’ second generation metathesis
(6) Review: (a) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1. Also
see: (b) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(c) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(7) Diethyl acetal 10 was made in two steps as shown below from
substituted malonate i. Synthesis of malonate i: Bailey, S.; Harnden, M.
R. J. Chem. Soc., Perkin Trans. 1 1988, 2767. Reduction with LiAlH4:
Marshall, J. A.; Andersen, N. H.; Hochstetler, A. R. J. Org. Chem. 1967,
32, 113. For more details, see the Supporting Information.
Figure 2. The thromboxanes.
Our retrosynthesis is shown in Figure 3. Carbons 1-5
would be installed via a well-precedented Wittig olefination,
(8) Diene diol 9 was synthesized in one step as shown below from known
bisepoxide ii: Robbins, M. A.; Devine, P. N.; Oh, T. Org. Synth. 1999, 76,
101. For more details, see the Supporting Information.
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(10) While we initially pursued a TBS ether protection in 10, conversion
to the RCM product was a disappointing 9%. After some experimentation,
we discovered that an ester was the optimal protecting group for the allylic
alcohol in 10-13. Whereas an acetate provided satisfactory conversion to
the ring-closed product (60%), the benzoate ester was preferred due to its
physical properties. For a similar system, see: Hyldtoft, L.; Madsen, R. J.
Am. Chem. Soc. 2000, 122, 8444.
Figure 3. Thromboxane B2 retrosynthetic analysis.
(11) Fu¨rst, A.; Plattner, P. A. HelV. Chim. Acta 1949, 32, 275.
(12) (a) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc.
2003, 125, 14149. (b) Bartlett, P. A.; Ting, P. C. J. Org. Chem. 1986, 51,
2230.
(13) (a) Criegee, R. Ber. Dtsch. Chem. Ges. 1931, 64, 260. Review: (b)
Mihailovic, M. L.; Cekovic, Z. Synthesis 1970, 209.
(14) Hydroxyl has an A value of only 0.87 kcal/mol in protic solvents:
Hirsch, J. A. Top. Stereochem. 1967, 1, 199.
as in prior syntheses.4 Retrosynthetic 1,3-transposition of the
C15 allylic alcohol provides intermediate 7, which was
envisioned to be accessible from bicyclic acetal 8. The
superfluous allylic carbinol at C9 in 8 enabled Sharpless
asymmetric epoxidation6 for differentiating the olefins
(15) Reviews: (a) Hofle, G.; Steglich, W.; Vorbruggen, H. Angew.
Chem., Int. Ed. Engl. 1978, 17, 569. (b) Scriven, E. F. V. Chem. Soc. ReV.
1983, 12, 129.
(5) (a) Bhagwat, S. S.; Hamann, P. R.; Still, W. C. J. Am. Chem. Soc.
1985, 107, 6372. (b) Bhagwat, S. S.; Hamann, P. R.; Still, W. C.; Bunting,
S.; Fitzpatrick, F. A. Nature 1985, 315, 511.
(16) (a) Overman, L. E.; Knoll, F. M. Tetrahedron Lett. 1979, 20, 321.
(b) Grieco, P. A.; Takigawa, T.; Bongers, S. L.; Tanaka, H. J. Am. Chem.
Soc. 1980, 102, 7587.
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Org. Lett., Vol. 9, No. 26, 2007

K2CO3 in MeOH to give 8 in near quantitative yield.
Reagent-controlled Sharpless asymmetric epoxidation6 pro-
vided endo-epoxide 14 in preference to its exo diastereomer
(77% combined yield, 93% dr). After optimization, it was
found that this epoxide could be opened according to the
Fu¨rst-Plattner rule11 with lithioacetonitrile12 to provide diol
15 in 82% isolated yield as the only observed product.
Scheme 1
Having served its purpose, the exocyclic hydroxymethyl
was removed via oxidative cleavage to the ketone with Pb-
(OAc)4,13 followed by immediate treatment with L-Selectride
at -78 °C to yield axial alcohol 16 as the major product
(9:1 dr). Alternatively, the equatorial C9 alcohol 17 could
be selectively formed from the ketone with NaBH4 (4:1 dr).
Both C9 epimeric alcohols were evaluated in the hydroly-
sis of the bicyclic acetal. Although equatorial alcohol 17
bears the correct stereochemistry at C9 for TXB2, it proved
resistant to hydrolysis after an extensive screening of
conditions. In contrast, the axial epimer 16 opened cleanly
in refluxing methanol with Amberlyst-15 acidic resin (Scheme
2). This difference in reactivity was initially surprising.
Although ease of bicyclic acetal cleavage can be attributed
to the steric relief afforded when axial substituents become
equatorial upon methanolysis, we believe a different rationale
is operative here.14 The axial alcohol likely facilitates bicycle
opening via protonation of the bridging oxygen of the acetal
via intramolecular hydrogen bonding between the acetal and
axial alcohol (see 18). This simultaneously makes the C9
oxygen the most basic site in the molecule, which upon
protonation is poised to deliver a proton to the acetal oxygen,
triggering acetal cleavage.
catalyst9 G2 (73% yield of 12 after one recycle).10 Cross
metathesis of 12 with 1-heptene yielded 13 in 70% yield
(93% BORSM) with >10:1 selectivity for the E olefin.
With two-thirds of the carbons for TXB2 in place, the
benzoate protecting group was removed upon treatment with
After opening the bicyclic acetal in near quantitative yield
to 19, the free alcohols were converted to acetates using
acetyl chloride with pyridine and catalytic DMAP (93%
yield).15 The resulting diacetate 7 was then treated with
palladium(II) to promote allylic transposition4d,16 via cy-
Scheme 2. Completion of Thromboxane B2
Org. Lett., Vol. 9, No. 26, 2007
5355

clization-induced rearrangement to regioisomer 20 in 82%
combined yield favoring 20 by a 4:1 ratio.17
scopic comparison. We also subjected methyl glycoside 23a
to hydrolysis with DOWEX-50 resin in water to provide
thromboxane B2 (5). In our hands, the natural product was
difficult to characterize by NMR because it has a tendency
to aggregate in deuterated chloroform. However, high-
resolution mass spectrometry did confirm methyl glycoside
hydrolysis. As further confirmation of the synthesis of TXB2,
we derivatized the natural product to the triacetate of the
methyl ester (23c).5 This derivative matched published data
Treatment of 20 with NaOH in refluxing methanol/water
hydrolyzed both the acetates and the nitrile to yield car-
boxylic acid 21. The crude acid was subjected to Mitsunobu
lactonization18 to differentiate the alcohols and correct the
stereochemistry at C9. Use of triphenyl phosphine for this
inversion lead to difficulties in purification, as we were
unable to completely separate triphenylphosphine oxide from
lactone 22. Switching to polymer-bound triphenylphosphine19
enabled clean isolation of 22 in 63% yield for this two-step
global hydrolysis/Mitsunobu sequence.
Although 22 is a known intermediate,4i it had not been
fully characterized in the literature. We therefore subjected
lactone 22 to the reported4i three-step sequence to throm-
boxane B2. Reduction of the lactone with i-Bu2AlH followed
by Wittig olefination (53% yield, two steps) provided
thromboxane B2 methyl glycoside (23a). For comparative
characterization, methyl glycoside 23a was derivatized to
its methyl ester 23b. Esterification of the carboxylic acid
with trimethylsilyldiazomethane (23b) intersected the methyl
ester of TXB2 methyl glycoside previously synthesized by
Hanessian4e,f to provide an intermediate for direct spectro-
1
in terms of both HRMS and H NMR.
In summary, the synthesis of thromboxane B2 has been
completed in 16 steps from C2-symmetric diene diol 9.
Central to our strategy was use of K/RCM in establishment
of bicyclic acetal 12 as a scaffold for installation of the C8
stereochemistry and as an expedient solution, intrinsic to 9,
for the C13-C15 trans-allylic alcohol installation via 1,3-
transposition.4d Extension of this K/RCM strategy to other
targets is ongoing in these labs and will be reported in due
course.
Acknowledgment. Financial support for this work from
the NIH grants GM069352 and CA108488, and NIH CBI
training grant T32 GM008505 (C.C.M.) is gratefully ac-
knowledged, as is support of the departmental NMR facilities
by grants from the NIH 1 S10 RR0 8389-01 and NSF CHE-
9208463.
(17) Resubjection of clean 20 to the palladium(II) conditions provided
a 5:1 ratio of 20/7, suggesting this reaction is under thermodynamic control.
(18) Reviews: (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L.
Org. React. 1992, 42, 335. Intramolecular examples: (c) Lucas, B. S.;
Luther, L. M.; Burke, S. D. Org. Lett. 2004, 6, 2965. (d) Boto, A.; Betancor,
C.; Prange´, T.; Sua´rez, E. J. Org. Chem. 1994, 59, 4393. (e) Smith, A. B.,
III; Sulikowski, G. A.; Sulikowski, M. M.; Fujimoto, K. J. Am. Chem. Soc.
1992, 114, 2567.
(19) (a) Relles, H. M.; Schluenz, R. W. J. Am. Chem. Soc. 1974, 96,
6469. Use of polymer-supported phosphine in the Mitsunobu reaction: (b)
Amos, R. A.; Emblidge, R. W.; Havens, N. J. Org. Chem. 1983, 48, 3598.
(c) Tunoori, A. R.; Dutta, D.; Georg, G. I. Tetrahedron Lett. 1998, 39,
8751.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for compounds 5, 7-17, 19, 20,
22, and 23a-c and the comparison of derivatives 23b and
23c with literature data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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