TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 811–814
Synthesis of SB 222618. A potential PDE IV inhibitor†
Jose J. Conde ∗ and Wilford Mendelson
Department of Synthetic Chemistry, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, PO Box 1539,
King of Prussia, PA 19406, USA
Received 1 November 1999; revised 23 November 1999; accepted 24 November 1999
Abstract
PDE IV inhibitor SB 222618 was prepared by regioselective SN20 addition of 9 to bromoallene 6a followed by
a stereoselective borane reduction of 4 to afford 2 which by a palladium mediated coupling with 3, delivered SB
222618 (1) in good yield. © 2000 Elsevier Science Ltd. All rights reserved.
SB 222618 (1) has been a target of synthetic chemists at SmithKline Beecham owing to its potential
PDE IV1 inhibitor activity against inflammatory diseases such as asthma. Apart from its biological
activity, this cyclohexanol provided the opportunity to explore the non-obvious construction of the
quaternary C4 of 1 whose retrosynthesis is shown below (Scheme 1).
As depicted in Scheme 1, SB 222618 (1) could be obtained via the Sonogashira2 coupling protocol
between heterocycle 3 and alkyne 2. The substituted cyclohexanol 2 could then be made from ketone
4 by selectively reducing the keto group delivering the desired stereochemistry at C1. To prepare 4, we
envisioned the possibility of performing a SN20 addition of cuprate 9 to bromoallene 6a which would be
obtained from the corresponding carbinol 7 coming from treating ketone 8 with lithium acetylide.
The most critical steps in the synthesis of SB 222618 are the preparation of intermediate 4 and further
selective reduction of the keto group to deliver 2. The preparation of bromoallenes is well precedented in
5
the literature. Reagents such as HBr,3 PBr3,4 SOBr2 were extensively used to synthesize bromoallenes
from propargylic alcohols. Other conditions such as addition of cuprates6 to propargylic mesylates or
tosylates are also known.
Propargylic alcohol 7 was prepared without incident from commercially available cyclohexanedione
mono-ethyleneketal 8 by reaction with excess of lithium acetylide7 (Scheme 2). For the preparation of
bromoallene 6a, we first decided to investigate the SN20 addition of milder reagents such as LiCuBr28 to
the corresponding mesylate. This reaction afforded a mixture of regioisomers 6a and 6b (2:1).
This poor regioselectivity was later improved by using SOBr2 in the presence of Et3N as acid scavenger
obtaining bromoallene 6a as the sole product in 90% yield.
∗
†
Corresponding author.
This work is dedicated to the memory of Dr. Lendon Pridgen
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02198-X
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