2
Tetrahedron
The chemical synthesis of prostaglandins and analogues has
Upon concentration tetranor-PGE1 tended to undergo
decomposition and was therefore kept as a solution in ethyl
acetate. The utility d11-tetranor-PGE1 of the latter in quantifying
tetranor-PGE1 in clinical urine samples will be reported in due
course.
been extensively studied since the 1960’s [8]. Among the
synthetic strategies developed, the two-component (conjugate
addition) coupling process suited our needs as the starting
materials are easily available and introduction of an isotopically
labeled side-chain would be conveniently introduced late in the
synthesis (Figure 2). Key to our approach was -
functionalization of iodoenone 1 by a cross-coupling reaction, a
strategy popularized by Johnson and co-workers [9].
Acknowledgments
This work was supported by National Institute of General
Medical Sciences Grant GM-115722 (G.A.S.) and National
Institutes of Health Shared Resource Grant P30 CA068485.
References and notes
1.
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Scheme 1. Cross-coupling partners examined and successful Heck coupling
with iodoenone 1.
We started our synthetic investigations by examining the cross-
coupling of iodoenone 1 with metal homoenolates (Scheme 1).
Iodoenone 1 was conveniently prepared in high optical purity
following established procedures starting from cyclopentadiene
[9,10]. As B-Alkyl Suzuki cross-coupling of iodoenone 1 has
been employed en route to prostaglandins and analogues we first
examined potassium trifluoroborate 2a as a coupling partner [11].
Unfortunately under reaction conditions used previously to
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decomposition. Similar results were obtained when employing
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Heck coupling with acrolein diethyl acetal 2c with iodoenone 1
under Jeffries conditions, previously reported using aryl halide
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allowed us to proceed toward the synthesis of tetranor PGE1.
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Scheme 2. Synthesis of tetranor-PGE1 and d11-tetranor-PGE1.
As anticipated, addition of the mixed higher-order cuprate
reagent derived from 3S-vinyl iodide 4 to enone 3 afforded
cyclopentanone 5 with expected trans, trans diastereoselectivity
[9,13]. Vinyl iodide 4 (R = n-C5H11) was prepared following
well-established synthetic methods employing an asymmetric
Noyori reduction of an intermediate alkynone derived from
alkynylation of hexanoyl chloride [14]. Deuterium labeled d11-4
was prepared from d11-hexanoyl chloride derived from
commercial d11-hexanoic acid. Saponification of ester 5 proved
problematic due to facile beta-elimination of the TBS ether
within the cyclopentanone core. The elimination problem was
circumvented using a three-step procedure (5 to 6) reported by
15. D. F. Taber, P. Gu, Tetrahedron 65 (2009) 5904-5907.
Supplementary Material
Supplementary data associated with this article can be found
in the online version, at do:XXXXX.
Taber as he encountered the same problem in his synthesis oHf thigehlights
prostaglandin metabolite PGE2UM [15]. Treatment of carboxylic
acid 6 with aqueous HF in acetonitrile afforded tetranor-PGE1.