A synthetic protocol for (?)-ketorolac; development of asymmetric gold(I)-catalyzed cyclization of allyl alcohol with pyrrole ring core

Article abstract of DOI:10.1016/j.tetlet.2019.151564

An asymmetric synthesis of (?)- and (+)-ketorolac was achieved with 89% ee using a novel Friedel–Crafts (FC) type C–C bond forming cyclization of an allyl alcohol containing a pyrrole ring core in the presence of a bimetallic gold(I) salt complex prepared from a 2:2:1 combination of AuCl·SMe₂, AgOTf and chiral Quinaphos.

Full text of DOI:10.1016/j.tetlet.2019.151564

Journal Pre-proofs
A Synthetic Protocol for (–)-Ketorolac; Development of Asymmetric Gold(I)-
Catalyzed Cyclization of Allyl Alcohol with Pyrrole Ring Core
Ikuo Sasaki, Naoto Yamasaki, Yusuke Kasai, Hiroshi Imagawa, Hirofumi
Yamamoto
PII:
S0040-4039(19)31363-2
DOI:
https://doi.org/10.1016/j.tetlet.2019.151564
TETL 151564
Reference:
Tetrahedron Letters
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20 December 2019
23 December 2019
Please cite this article as: Sasaki, I., Yamasaki, N., Kasai, Y., Imagawa, H., Yamamoto, H., A Synthetic Protocol
for (–)-Ketorolac; Development of Asymmetric Gold(I)-Catalyzed Cyclization of Allyl Alcohol with Pyrrole Ring
Core, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151564
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A Synthetic Protocol for (–)-Ketorolac;
Development of Asymmetric Gold(I)-
Catalyzed Cyclization of Allyl Alcohol with
Pyrrole Ring Core
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Ikuo Sasaki, Naoto Yamasaki, Yusuke Kasai, Hiroshi Imagawa, and Hirofumi Yamamoto

1
Tetrahedron Letters
A Synthetic Protocol for (–)-Ketorolac; Development of Asymmetric Gold(I)-
Catalyzed Cyclization of Allyl Alcohol with Pyrrole Ring Core
Ikuo Sasakia,b, Naoto Yamasakia, Yusuke Kasaia, Hiroshi Imagawaa, and Hirofumi Yamamoto a,
a Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
b Faculty of Science and Technology, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5258, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An asymmetric synthesis of (–)- and (+)-ketorolac was achieved with 89% ee using a novel
Friedel–Crafts (FC) type C-C bond forming cyclization of an allyl alcohol containing a pyrrole
ring core in the presence of a bimetallic gold(I) salt complex prepared from a 2:2:1 combination
of AuCl·SMe2, AgOTf and chiral Quinaphos.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 Ketorolac
Keyword_2 Enantioselective synthesis
Keyword_3 Allyl alcohol cyclization
Keyword_4 Gold(I) catalyst
1. Introduction
(±)-1 and the related racemic intermediates.[3,4] In 2005, the
Baran group reported an enantioselective synthesis of (–)-1
having 90% ee on the basis of an attractive synthetic strategy that
featured an asymmetric direct coupling of unfunctionalized
C(sp2) and C(sp3) atoms.[5]
Ketorolac (±)-1, which acts as a cyclooxygenase (COX)
inhibitor, is well-known racemic non-steroidal anti-
a
inflammatory drug (NSAID) used all over the world. However, it
has been demonstrated experimentally that only (–)-1 shows a
significantly high level of anti-inflammatory activity, while (+)-1
is ineffective.[1] There is sometimes a marked difference in the
biological efficacy of enantiomers, and it not unusual to observe
that only one enantiomer of a racemate displays a desired
medicinal property. Accordingly, in the field of drug discovery,
significant efforts have been devoted to develop enantiopure
drugs with the aim of enhancing beneficial efficacies and/or
eliminating side effects.[2]
2. Result and discussion
The heart of our synthetic plan is illustrated in scheme 1A.
The sole chiral center of (–)-1, which is located between a
benzoyl pyrrole and carboxyl group, is labile under many
reaction conditions via keto–enol tautomerism. Thus, the 2-
benzyl pyrrole derivative 2 was designed as a key intermediate
that could be converted to 1 by an oxidation reaction in the last
stage of the total synthesis.
Figure 1. The stereochemistry of ketorolac (1)
Herein, we describe an enantioselective synthesis of (–)-1
using a novel asymmetric Friedel–Crafts (FC) type cyclization of
a pyrrolic allyl alcohol with a bimetallic gold(I) salt complex,
which was prepared from a 2:2:1 combination of AuCl·SMe2,
AgOTf and (Sa,Rc)-Quinaphos. Nearly 30 years have passed
since (±)-1 was approved as a medical drug. However, an
asymmetric synthesis of (–)-1 has scarcely been developed to
Scheme 1. A) Our synthetic plan of (–)-1. B) Asymmetric C-N
bonding cyclization of anilino allyl alcohol 4
date, except for some methods using enzymatic resolutions of
———
 Corresponding author. Tel.: +88-602-8448; fax: +88-655-3051; e-mail: hirofumi@ph.bunri-u.ac.jp

2
Tetrahedron Letters
Optically active 2 was planned to be constructed using an FC-
water at reflux temperature for 30 minutes, which, without
isolation, was reacted with 9 in the presence of a sodium acetate
buffer.[7] At room temperature with exclusion from light, the
desired Clauson-Kaas type reaction gradually proceeded, giving
the N-substituted pyrrole 10 in 94% yield after 24 hours.[8] Next,
regioselective C2-acylation of 10 with benzoyl chloride was
carried out using 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in
toluene under reflux conditions, and then the resulting 11 was
treated with LiAlH4 in the presence of AlCl3 to give 3 as a single
regioisomer.[9]
type cyclization of pyrrolic allyl alcohol 3 in an enantioselective
manner. Recently, our group developed an asymmetric C-N bond
forming cyclization of anilino allyl alcohol 4 with a 1:1
combination of a Hg(OTf)2 catalyst and the chiral ligand
BINAPHANE (6) (Scheme 1B).[6] Therefore, we anticipated
that optically active 2 could be prepared from 3 using the same
reaction conditions or conceptually similar reactions.
Scheme 3. The asymmetric cyclization of 3 and then the oxidation
reaction to form benzoyl pyrrole derivative 12
Scheme 2. Preparation of pyrrolic allyl alcohol derivative 3
Subsequently, an FC-type cyclization of 3 towards 2 was tried
(Scheme 3). The details of the reaction conditions are described
in Table 1.
The cyclization precursor 3 was prepared from commercially
available 2,5-dimethoxytetrahydrofuran (7) and a trifluoroacetate
salt of methyl (E)-5-aminopent-2-enoate (9) (Scheme 2).
Initially, 7 was hydrolyzed to give the 2,5-diol derivative 8 in
Table 1. Optimization of the asymmetric FC-type cyclization of 3 towards 2a
Entry
Catalyst (mol%)
Ligand (mol%)
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
Temp.
Time (h)
24
Yield (%)b
0 (40)d
ee (%)c
1
Hg(OTf)2 (10)
(R,R)-6 (10)
rt
-
2
Hg(OTf)2 (20)
(R,R)-6 (10)
rt
24
0 (9)d
-
3
Hg(OTf)2 (10)
(R,R)-6 (20)
rt
24
0 (48)d
-
4
Hg(OTf)2 (20)
(R,R)-6 (20)
rt
24
0 (31)d
-
5
Hg(OTf)2 (20)
(R,R)-6 (20)
reflux
24
0 (7)d
-
6
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (20)e
AuCl·SMe2/AgOTf (30)e
AuCl·SMe2/AgOTf (40)e
AuCl·SMe2/AgOTf (20)e
(R,R)-6 (10)
rt
24
20 (65)d
0 (95)d
69
7
(R)-13 (10)
rt
24
-
8
(R)-13 (10)
reflux
24
28 (30)d
0 (92)d
3
-
9
(R)-14 (10)
rt
rt
24
10
11
12
13
14
15
16
17
18
19
20
21
(S,S)-15 (10)
(R,R)-16(10)
(R,R)-17 (10)
(Sa,Rc)-18 (10)
(Sa,Rc)-18 (10)
(Sa,Rc)-18 (10)
(Sa,Rc)-18 (10)
(Sa,Rc)-18 (10)
(Sa,Rc)-18 (10)
(Sa,Rc)-18 (15)
(Sa,Rc)-18 (20)
(Sa,Rc)-18 (20)
24
0 (>95)d
0 (>95)d
trace (70)d
15 (80)d
0 (95)d
-
rt
24
-
rt
24
-
rt
24
–86
-
rt
24
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
24
0 (70)d
-
rt
24
25 (70)d
34 (50)d
20 (34)d
52 (32)d
72 (0)f
–88
–86
< –54
–87
–89
–63
rt
72
reflux
rt
72
72
rt
72
rt
72
13 (67)d
a Reactions were run on a 0.1 mmol scale of 3 at a concentration of 0.01 M with exclusion from light under an argon atmosphere.
b Isolated yield of purified 2.
c Enantiomeric excess of purified 12. See supplementary file for further details.
d Recovery (%) of starting material 3.
e AuCl·SMe2 and AgOTf were mixed in a 1:1 ratio.
f 0.4 mmol of 3 was used in order to synthesize (–)-1. The cyclization was carried out with a 2:2:1 combination of AuCl·SMe2, AgOTf and (Sa,Rc)-18.

3
Our initial experiments focused on the use of a 1:1
combination of Hg(OTf)2 and (R,R)-6 that was developed in our
laboratory for an asymmetric C-N bond forming cyclization of
anilino allyl alcohol. At first, the use of 10 mol% of Hg(OTf)2
and (R,R)-6 was tried (Entry 1). However, the desired cyclization
was very difficult and starting material 3 was recovered in 40%
yield along with complex mixtures not containing 2. Reaction
conditions were attempted changing the ratio of Hg(OTf)2 and
(R,R)-6 to 2:1 and 1:2 (Entries 2 and 3), but 2 was not formed
and 3 remained in either case. Even under reflux conditions in the
presence of 20 mol% of Hg(OTf)2 and the chiral auxiliary, 3 was
still recovered and the cyclic product was not detected (Entries 4
and 5). Thus, we decided to explore more suitable conditions for
the FC-type cyclization of 3.
despite using several HPLC techniques with a variety of chiral
columns, we could not separate the enantiomers. Therefore, 2
was treated with N-hydroxyphthalimide (NHPI) and NaClO2 to
give the benzoyl pyrrole derivative 12,[12] and 69% ee was
determined by chiral HPLC.[13] After obtaining this positive
result that optically enriched 2 was formed in an FC-type
cyclization of 3,[14] we explored finding a more suitable chiral
auxiliary for the asymmetric cyclization.
Unexpectedly, 2,5-tBu2-4-MeO-MeObisphosphine 13, which
has been utilized for the asymmetric cyclization of allyl alcohols
containing an indole ring core, gave no product at room
temperature (Entry 7). Under reflux for 24 hours, the desired FC-
type cyclization of 3 proceeded somewhat, but the product was
nearly racemic (Entry 8). BINAP 14[15a], CHIRAPHOS
15[15b], Me-BPE 16[15c], NORPHOS 17[15d] also gave a
similar result as 13, and either none or a trace amount of 2 was
produced (Entries 9-12). In terms of chiral induction, (Sa,Ra)-
Quinaphos 18[16] furnished the best result, 86% ee (Entry 13).
However, the chemical yield from 3 to 2 was only 15%. Thus, in
order to improve the conversion efficiency, optimization was
tried as shown in Entries 14-21. Consequently, it was found that
CH2Cl2 was the best solvent of choice (Entry 16), and eventually
a 72% yield was achieved by using a double dose of AuCl·SMe2
(40 mo%), AgOTf (40 mo%) and 18 (20 mo%) in CH2Cl2 at
room temperature for 72 hours (Entry 20). The resulting product
2 was transformed to 12, and an 89% ee was determined.
In 2009, Bandini and co-workers reported a conceptually
similar C-C bond forming cyclization of allyl alcohols with an
indole ring core in the presence of a 2:2:1 combination of
AuCl·SMe2, AgOTf and 2,5-tBu2-4-MeO-MeObisphosphine
13.[10] These reaction conditions catalytically induced
asymmetric cyclization to give the corresponding six-membered
ring products (1- and 4-vinyl-tetrahydrocarbazole derivatives)
with high enantioselectivity. In the successful FC-type reactions,
a cationic gold(I) salt, which was prepared by mixing AuCl·SMe2
and AgOTf, played a significant role in the activation of the allyl
alcohol moiety in the adduct, facilitating alkylation of the indole
ring core and then the release of H2O. Thus, we tried using the
combination of AuCl·SMe2 and AgOTf instead of Hg(OTf)2.
Initially, 20 mol% of AuCl·SMe2 and AgOTf was examined.
(R,R)-BINAPHANE (10 mol%) was used as the chiral auxiliary
(Entry 6). When the reaction was carried out in toluene at room
temperature, the desired cyclization proceeded slightly, giving a
desired 5-exo-trig type product 2 in 20% yield after 24 hours.[11]
Although 65% of starting material was recovered, it was obvious
that the combination of AuCl·SMe2 and AgOTf was more
effective than Hg(OTf)2 (Entry 2 vs 6). We attempted to measure
the enantiomeric excess of the resulting product 2; however,
As described above, we managed to prepare 2 with 89% ee by
using the FC-type cyclization of 3 with a 2:2:1 combination of
AuCl·SMe2, AgOTf and 18. Although an intensive search is
required to demonstrate the reaction mechanism completely, we
postulate that the bimetallic structure of the gold complex
(Sa,Rc)-Quinaphos·Au2OTf2, which was formed by mixing
AuCl·SMe2, AgOTf and 18 in a 2:2:1 ratio, probably contributes
to the progress of the reaction smoothly as well as asymmetric
induction.
Scheme 4. Proposed mechanism of FC-type cyclization of 3 with a bimetallic gold(I) catalyst.
As shown in Scheme 4, one gold salt in the formed bimetallic
gold complex A initiates the alkylation of the pyrrole ring core
by activating the allylic C-C double bound in adduct 3. At the
point of nucleophilic attack from the pyrrole ring core, two
plausible conformers 3a and 3b are plausible. However, the
reaction dominantly proceeds through conformer 3a that offers
minimal 1,3-diaxial interactions after the gold complex chooses
the reaction surface. In contrast, another gold salt in complex A
chelates to the hydroxyl group in 3, and then induces β-hydroxy
elimination in cooperation with the HOTf that was generated
through the aromatization of the 2H-pyrrolium intermediate C to
D. The experimental finding that the monometallic condition
with a 1:1:1 combination of AuCl·SMe2, AgOTf and 18
drastically decreased the chemical yield of 2 as well as chiral
induction (Entries 21 vs 17) suggests that the bimetallic structure
of A, which has a function capable of activating both of double
bond and the hydroxy group, is pivotal in facilitating the FC-
type cyclization.

4
Tetrahedron
81 (1998) 899-901. (d) K. P. Fu, S. C. Lafredo, B. Foleno, D. M.
Isaacson, J. F. Barrett, A. J. Tobia, M. E. Rosenthale, Antimicrob.
Agents Chemother. 36 (1992) 860-866.
Finally, optically enriched ketorolac (–)-1 was synthesized
from (–)-12 with 89% ee in 82% yield. The ee was not
diminished by treatment with RuCl3·H2O (10 mol%) and NaIO4
(5 equiv) at 0 °C in a 2:1:2 mixed solvent of CCl4, CH3CN and
3. For synthesis of (±)-1, see: (a) P. Müller, P. Polleux, Helv. Chim. Acta
81 (1998) 317-323. (b) G. C. Schloemer, R. Greenhouse, J. M.
Muchoeski, J. Org. Chem. 59 (1994) 5230-5234. (c) J. M. Muchowski,
S. H. Unger, J. Ackrell, P. Cheung, G. F. Cooper, J. Cook, P. Gallegra,
O. Halpern, R. Koehler, A. F. Kluge, A. R. Van Horn, Y. Antonio, H.
Carpio, F. Franco, E. Galeazzi, I. Garcia, R. Greenhouse, A. Guzmán, J.
Iriarte, A. Leon, A. Peña, V. Peréz, D. Valdéz, N. Ackerman, S. A.
Ballaron, D. V. Krishna Murthy, J. R. Rovito, A. J. Tomolonis, J. M.
Young, W. H. Rooks, J. Med. Chem. 28 (1985) 1037-1049. (d) F.
Franco, R. Greenhouse, J. Org. Chem. 47 (1982) 1682-1688.
4. For enzymatic resolutions of (±)-1 see: (a) Y. H. Kim, C. S. Cheong, S.
H. Lee, K. S. Kim, Tetrahedron: Asymmetry 12 (2001) 1865-1869. (b)
G. Fulling, C. J. Sih, J. Am. Chem. Soc. 109 (1987) 2845-2846.
5. (a) J. M. Richter, B. W. Whitefield, T. J. Maimore, D. W. Lin, M. P.
Castroviejo, P. S. Baran, J. Am. Chem. Soc. 129 (2007) 12857-12869.
(b) P. S. Baran, N. B. Ambhaikar, C. A. Guerrero, B. D. Hafensteiner,
D. W. Lin, J. M. Richter, ARKIVOC, (2006) 310-325. (c) P. S. Baran, J.
M. Richter, D. W. Lin, Angew. Chem. Int. Ed. 44 (2005) 609-612.
6. H. Yamamoto, E. Ho, K. Namba, H. Imagawa, M. Nishizawa, Chem.
Eur. J. 16 (2010) 11271-11274.
1
H2O (Scheme 5A).[17] The H and 13C NMR spectral data of
synthetic (–)-1 correspond well to those previously reported in
the literature.[5] With the established successful pathway to (–)-
1, its enantiomer (+)-1 having 89% ee was also synthesized from
(+)-12, which was prepared using (Ra,Sa)-Quinaphos as the
chiral auxiliary in an asymmetric cyclization of 3 (Scheme 5B).
Naturally, the optical rotations of synthetic (–)-1 and (+)-1 were
close in magnitude, but of opposite sign. Because the absolute
stereochemistry of (–)-1 and (+)-1 is equivalent to (S)- and (R)-
ketorolac, respectively, these findings demonstrate that the FC-
type cyclization of 3 with (Sa,Ra)-Quinaphos afforded the R-
isomer of 2, and (Ra,Sa)-Quinaphos gave the opposite
stereochemistry to that shown.
7. B. S. Gourlay, P. P. Molesworth, J. H. Ryan, J. A. Smith Tetrahedron
Lett. 47 (2006) 799-801.
8. (a) S. Kumar, S. Krishnakanth, J. Mathew, Z. Pomerantz, J.-P.
Lellouche, S. Ghosh, J. Phys. Chem. C 118 (2014) 2570-2579. (b) A. D.
Josey, E. L. Jenner, J. Org. Chem. 27 (1962) 2466-2470.
9. For acylation of 10, see: (a) J. E. Taylor, M. D. Jones, J. M. J. Williams,
S. D. Bull, Org. Lett. 12 (2010) 5740-5743. For reduction of 11, see: (b)
P. Tao, J. Liang, Y. Jia, Eur. J. Org. Chem. (2014) 5735-5748. (c) G.
Rotas, A. Kimbaris, G. Varvounis, Tetrahedron 67 (2011) 7805-7810.
10. M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 48 (2009) 9533-9537.
11. The product 2 is an electron-rich pyrrole, and is sensitive to air and
light.
12. (a) S. M. Silvestre, J. A. R. Salvador, Tetrahedron, 63 (2007) 2439-
2445. (b) S. Sakaguchi, A. Shibamoto, Y. Ishii, Chem. Commun. (2002)
180-181.
Scheme 5. A) Oxidation of (–)-12 leading to (–)-1. B) The structure
of synthetic (+)-2, (+)-12 and (+)-1.
In conclusion, we have developed a novel asymmetric C-C
bond forming cyclization of pyrrolic allyl alcohol 3 with a 2:2:1
combination of AuCl·SMe2, AgOTf and chiral Quinaphos,
which was successfully applied to the asymmetric synthesis of
ketorolac. Using (Sa,Ra)-Quinaphos as the chiral auxiliary,
cyclic (R)-2 was obtained as a key intermediate for the synthesis
of (S/–)-ketorolac. The synthetic procedure (25.8% overall yield
and in 6 steps from a commercially available 7) facilitates the
development of enantiopure (–)-ketorolac and investigations into
the latent biological properties of (–)- and (+)-ketorolac.
13. For HPLC analysis of 12, see supplementary file.
14. The cyclization of 2-benzoyl pyrrole derivative towards 12 was also
examined. However, the cyclization didn’t proceed using a 2:2:1
combination of AuCl·SMe2, AgOTf and 18. For further details, see
supplementary file.
15. (a) R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed. 40 (2001) 40-73. (b)
T. Nishikata, Y. Yamamoto, N. Miyaura, Adv. Synth. Catal. 349 (2007)
1759-1764. (c) J. C. D. Le, B. L. Pagenkopf, J. Org. Chem. 69 (2004)
4177-4180. (d) H. Brunner, W. Pieronczyk, Angew. Chem. Int. Ed.
Engl. 18 (1979) 620-621.
16. (a) T. Pullmann, B. Engendahl, Z. Zhang, M. Hölscher, A. Zanotti-
Gerosa, A. Dyke, G. Franciò, W. Leitner, Chem. Eur. J. 16 (2010) 7517-
7526. (b) S. Burk, G. Franciò, W. Leitner, Chem. Commun. (2005)
3460-3462. (c) G. Franciò, F. Faraone, W. Leitner, Angew. Chem. Int.
Ed. 2000, 39, 1428-1430.
Acknowledgments
We are grateful to Dr Yasuko Okamoto (analysis center in
Tokushima Bunri University) for determining the HRMS. This
study was financially supported by a Grant-in-Aid (No.
23790034) from the MEXT (Ministry of Education, Culture,
Sports, Science, and Technology) of the Japanese Government.
17. (a) D. Grassi, A. Alexakis, Angew. Chem. Int. Ed. 52 (2013) 13642-
13646. (b) G. Borsato, M. Crisma, O. D. Lucchi, V. Lucchini A.
Zambon, Angew. Chem. 117 (2005) 7601-7605. (c) P. H. J. Charlsen, T.
Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem. 46 (1981) 3936-
3938.
Supplementary Material
References and notes
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5
Highlights
• An enantioselective synthesis of ketorolac was
achieved with 89% ee.
• An asymmetric allyl alcohol cyclization was
developed as a key reaction.
A gold(I) catalyst facilitated the allyl alcohol
cyclization.