reactive, chemo- and stereoselective, storable reducing re-
agent.5 To highlight the utility of DTBM-SEGPHOS]CuH
in synthesis, 4-substituted coumarins were selected (eq 1),
the conjugate reduction of which would lead to stereodefined
intermediates of synthetic value. In this Letter we describe
several new applications of [(R)-DTBM-SEGPHOS]CuH
toward the synthesis of important bioactive, coumarin-
derived targets.
by a Wittig-type reaction between 2-hydroxy-5-methyl-
benzophenone and carbethoxymethylenetriphenyl-phospho-
rane in refluxing toluene) as a good candidate for asymmetric
CuH reduction. As such, conjugate reduction of coumarin 2
was complete in less than 30 min at room temperature in
the presence of only 0.1 mol % [(R)-DTBM-SEGPHOS]CuH
and excess DEMS (diethoxymethylsilane) and t-BuOH.
Unexpectedly, however, lactol 3 rather than the correspond-
ing lactone was isolated in near quantitative yield. Although
such reduction of esters by CuH has not previously been
reported, the resulting one-pot procedure fortuitously avoids
a subsequent reduction by alternative means. Determination
of ee by chiral HPLC analysis was made on a sample of
lactol 3 that had been oxidized with PCC to the correspond-
ing lactone, revealing a selectivity of 99% ee in the conjugate
reduction step. Lactol 3 was then transformed into the target
under reductive amination conditions using diisopropylamine
(DIPA), yielding (R)-tolterodine (1) in 93% yield (optical
rotation matched the literature value).6 Overall, this three-
step route compares very favorably with known, lengthier
catalytic asymmetric syntheses that proceed through
lactone 5.6
(R)-Tolterodine (1).6 The tartrate salt of tolterodine
(“Detrol-LA”; Scheme 1) is a competitive muscarine receptor
Scheme 1. Synthesis of (R)-Tolterodine
Double reduction of coumarins by nonracemically ligated
copper hydride yielding optically active lactols is a novel
method8 for the preparation of these versatile intermediates.
This observation can be rationalized by an initial 1,4-
reduction furnishing enolate 4 (Scheme 2), followed by
Scheme 2. Proposed Sequence for Over-reduction
antagonist widely used for the treatment of bladder disorders,
such as urinary incontinence. Patented in 1998, the original
synthetic route relies on chiral resolution to separate (R)-
tolterodine from the racemate.6a Enormous demand for the
drug has since inspired several catalytic asymmetric syntheses
employing transition metals to establish chirality.7 We
envisioned educt 2 (6-methyl-4-phenylcoumarin, prepared
(4) Saito, T.; Yokozawa, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumoba-
yashi, H. AdV. Synth. Catal. 2001, 343, 264.
protonation of the copper-bound enolate with t-BuOH, thus
releasing lactone 5. Unlike typical saturated alkyl esters and
(5) Lipshutz, B. H.; Frieman, B. A. Angew. Chem., Int. Ed. 2005, 44,
6345.
(6) (a) GageJ. R.; CabajJ. E. U.S. Patent 1,996,003,396, 1998. (b)
Mathad, V. T.; Venkataraman, S.; Kumari, R. L.; Arunagiri, M.; Reddy,
C. R.; Ramakrishna, M.; Reddy, K. S.; Srinivasan, N.; Srinivas, K. Org.
Process Res. DeV. 2005, 9, 314. (c) Rhee, H.; Park, S.; Park, D.; Ko, J.;
Castro, K. D. Org. Process Res. DeV. 2007, 11, 918.
(8) This transformation was observed in earlier work: Lipshutz, B. H.;
Frieman, B. A.; Unger, J. B.; Nihan, D. M. Can. J. Chem. 2005, 83, 606.
(9) Kishuku, H.; Shindo, M.; Shishido, K. Chem. Commun. 2003, 3,
350.
(7) (a) Yoo, K.; Kim, H.; Yun, J. J. Org. Chem. 2009, 74, 4232. (b)
Kobayashi, K.; Nishikata, T.; Yamamoto, Y.; Miyaura, N. Bull. Chem. Soc.
Jpn. 2008, 1019. (c) Soergel, S.; Tokunga, N.; Sasaki, K.; Okamoto, K.;
Hayashi, T. Org. Lett. 2008, 10, 589. (d) Ulgheri, F.; Marchetti, M.; Piccolo,
O. J. Org. Chem. 2007, 72, 6056. (e) Hedberg, C.; Andersson, P. G. AdV.
Synth. Catal. 2005, 347, 662. (f) Chen, G.; Tokunga, N.; Hayashi, T. Org.
Lett. 2005, 7, 2285.
(10) Shishido’s intermediate is the lactone derived from 7.
(11) (S)-DTBM-SEGPHOS is now commercially available, CAS no.
210169-40-7.
(12) Wood, J. L.; McGuire, M. A.; Mills, R. J.; Pridgen, L. N.; Yu,
M. S.; Su, Q. International Patent Application WO9717330A1, 1997.
(13) McGuire, M. A.; Shilcrat, S. C.; Sorenson, E. Tetrahedron Lett.
1999, 40, 3293.
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