A concise enantioselective synthesis of (-)-ranirestat

Article abstract of DOI:10.1021/ol100167w

Chemical Equation Presented A concise enantioselective synthesis of the potent aldose reductase inhibitor ranirestat (1) is reported. The synthesis was accomplished employing inexpensive, commercially available starting materials. A palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) of malonate 4 was utilized as a key transformation to construct the tetrasubstituted chiral center in the target.

Full text of DOI:10.1021/ol100167w

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1276-1279
A Concise Enantioselective Synthesis of
(-)-Ranirestat
Barry M. Trost,* Maksim Osipov, and Guangbin Dong
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
bmtrost@stanford.edu
Received January 22, 2010
ABSTRACT
A concise, enantioselective synthesis of the potent aldose reductase inhibitor ranirestat (1) is reported. The synthesis was accomplished
employing inexpensive, commercially available starting materials. A palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) of malonate 4
was utilized as a key transformation to construct the tetrasubstituted chiral center in the target.
According to the International Diabetes Federation in 2009,
more than 285 million people are suffering from diabetes
worldwide.1 Over the last two decades, this number has
increased by nearly a factor of 10 and continues to grow
each year. Hyperglycemia causes serious health problems,
including decreased sensory motor function, muscle wasting,
bleeding, ulceration of the feet, as well as others.2 Many of
these complications have been linked to the hyperactivity
of aldose reductase, an enzyme of the polyol pathway. Thus,
the development of potent aldose reductase inhibitors (ARIs)
has become an increasingly important task to help manage
complications caused by hyperglycemia.3
Ranirestat (1) is a promising aldose reductase inhibitor
currently in phase III clinical trials.4 Compared to most other
ARIs, ranirestat (1) exhibits superior efficacy and low toxicity,
allowing for low-end dosing and limited side effects. Ranirestat
(1) is a compact, densely functionalized heterocycle.
ranirestat (1) in enantiopure form.5 Later, Shibasaki et al.
reported an asymmetric total synthesis of ranirestat using a
lanthanide-catalyzed asymmetric conjugate addition of a
succinimide derivative which is not commercially available.6
Previous work in our group showed that stabilized prochiral
nucleophiles can undergo a Pd-catalyzed asymmetric allylic
alkylation (Pd-AAA) with various allylic electrophiles to
construct the corresponding C-C bonds with high levels of
enantioselectivity.7 However, use of prochiral amidomalonates
as nucleophiles in the Pd-AAA has not been studied. Intrigued
by its therapeutic value, we asked if the Pd-AAA reaction of
an amidomalonate could provide an efficient solution to
construct the target’s tetrasubstituted stereocenter.
Our retrosynthetic strategy is outlined in Scheme 1. We
planned to construct the A-ring of ranirestat (1) from
carboxylic acid 2 through amide formation followed by
cyclization. Carboxylic acid 2 would arise from a Ru-
catalyzed oxidative cleavage of olefin 3, which would be
accessed by employing a Pd-AAA reaction of amidomalonate
It contains a spirocyclic tetrasubstituted stereocenter, along
with two imide motifs, making its asymmetric synthesis a
challenge. Initially, a chiral resolution was used to obtain
(5) Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya,
A.; Komiya, M.; Suzuki, K.; Matsumoto, J. J. Med. Chem. 1998, 41, 4118–
4129.
(1) International Diabetes Federation. Diabetes Atlas, 4th ed. 2009,
Brussels. King, H.; Aubert, R. E.; Herman, W. H. Diabetes Care 1998, 21,
1414–1431.
(6) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342–11343.
(7) (a) Trost, B. M.; Radinov, R.; Grenzer, E. J. Am. Chem. Soc. 1997,
119, 7879–7880. (b) Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027–
2030. (c) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005,
44, 308–310. (d) Ito, Y.; Kuwano, R. J. Am. Chem. Soc. 1999, 121, 3236–
3237. (e) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am.
Chem. Soc. 2001, 123, 7471–7472.
(2) World Health Organization. Definition, Diagnosis and Classification
of Diabetes Mellitus and its Complications, Geneva, 1999.
(3) (a) Alexiou, P.; Pegklidou, K.; Chatzopoulou, M.; Nicolaou, I.;
Demopoulos, V. J. Curr. Med. Chem. 2009, 16, 734–752. (b) Varkonyi,
T.; Kempler, P. Diabetes, Obesity, Metabolism 2007, 10, 99–108.
(4) Bril, V.; Buchanan, R. A. Diabetes Care 2006, 29, 68–72.
10.1021/ol100167w  2010 American Chemical Society
Published on Web 02/11/2010

With malonate 4 in hand, the stage was set for the key
Pd-AAA reaction. Reaction of 4 with allyl tert-butyl carbon-
ate in the presence of catalytic amounts of Pd(0) and chiral
ligand Ls provided the C-allylated product 3a in high yield,
albeit with poor enantioselectivity (Table 1, entry 1). This
Scheme 1. Retrosynthetic Analysis
Table 1. Selected Optimization Studies on Electrophile 5a
entry substrate
R1
R2 product % yieldb % eec
1
2
3
5a
5b
5c
5d
5e
5f
H
H
Br
I
Br
SiBnMe2
H
Ph
H
H
Ph
H
3a
3b
3c
3d
3e
3f
95
35
98
49
15
25
68
81
4 with an allylic electrophile 5. In turn, amidomalonate 4
would come from the assembly of commercially available
2-trichloroacetylpyrrole (8), benzyl amine 6, and methyl
bromoacetate (7).
Our synthesis of key intermediate 4 was initiated by the
N-alkylation of 2-trichloroacetylpyrrole (8) with methyl
bromoacetate (7), providing trichloroacetyl ketone 9 in 78%
yield (Scheme 2). Reaction of trichloroacetyl ketone 9 with
4
5d
6
86
90
76
76
7
5g
Si(OEt)3
H
3g
a All reactions were performed with 1 equiv of 4 and 1.1 equiv of 5a-g
at 4 °C in toluene. b Isolated yield. c ee determined by chiral HPLC. d No
reaction was observed under the indicated conditions.
transformation proceeded rapidly even in the absence of base
with Pd loadings as low as 0.1 mol %.9 We speculated that
substitution on the allyl coupling partner would have an effect
on the enantioselectivity of this transformation. Previous work
demonstrated that enantioselectivity improves with substitution
at either the 2- or 3-position of the allyl electrophile.7
Scheme 2. Chromatography-Free Synthesis of Amidomalonate 4
We reasoned that substitution of R2 would be flexible since
the distal carbon would ultimately be removed via oxidative
cleavage. On the other hand, the R1 substituent on the
proximal carbon would not be removed in the oxidative
cleavage, and would require either H or an H equivalent.
The effects of allyl substitution are summarized in Table 1.
As expected, introduction of substituents larger than H at
either R1 or R2 improved the enantioselectivity. Introducing
a phenyl group at R2 (entry 2) led to a modest increase in
ee, while incorporation of a bromide at R1 (entry 3) provided
a dramatic improvement. Increasing the steric bulk from Br
to I did improve the ee; however, the product was obtained
in modest yield (entry 4). No reaction was observed under
the indicated conditions when substituents were introduced
at both R1 and R2 (entry 5). Therefore, we focused our efforts
on allyl electrophiles substituted at R1.
benzyl amine 6 in the presence of triethylamine in DMF
facilitated the tandem condensation-cyclization sequence,
forming the B-ring to provide imide 10 in 68% yield.
Attempts to acylate 10 using methyl chloroformate only
provided the O-acylated product. This problem was overcome
by treatment of 10 with Mander’s reagent 11, which provided
the desired C-acylated product 4 exclusively, in near
quantitative yield.8 It is noteworthy that all compounds in
Scheme 2 were prepared on multigram scale and did not
require column chromatography for purification.
The most satisfactory results were obtained using vinyl
silanes, which in turn are readily obtained through the
ruthenium-catalyzed hydrosilylation of the corresponding
(9) This experiment was conducted using 1 equiv of 4, 1.1 equiv of 5a,
(8) Mander, L. N.; Sethi, P. Tetrahedron Lett. 1983, 24, 5425–5428.
Org. Lett., Vol. 12, No. 6, 2010
in PhMe (0.1M) at rt.
1277

propargyl alcohol.10 Using either benzyldimethylsilyl- or
triethoxysilyl-substituted allyl carbonates provided the allyl-
ated product 3 in high yield along with high levels of
enantioselectivity (entries 6 and 7).
Next, we investigated the effects of solvent on the reaction
(Table 2). Enantioselectivities were improved with the use
desilylated product and typically led to substrate decompo-
sition.11 Likewise, the use of acidic conditions, like TFA,
failed to deliver the desired olefin 3a. Fortunately, using
silver fluoride in a mixture of THF, methanol, DMSO, and
water provided the olefin 3a in 96% yield.12 The high
chemoselectivity of this process led us to develop a one-pot
allylation-protodesilylation protocol, which would enhance
the operational simplicity of the synthesis and afford olefin
3a directly from the amidomalonate 4. To our delight, when
amidomalonate 4 was treated under the optimized allylation
conditions (Table 2, entry 3) followed by addition of silver
fluoride upon completion of the allylation, the desired olefin
3a was obtained in 69% yield and 84% ee.
Table 2. Selected Solvent Optimization Studiesa
Next, chemoselective cleavage of the terminal methylene
fragment of olefin 3a to the corresponding carboxylic acid was
investigated. This transformation turned out to be more difficult
than we anticipated, as the pyrrole functionality was prone to
decomposition in the presence of oxidants. Having surveyed a
variety of different conditions,13 we found that a combination
of RuCl3, NaIO4, and K2CO3 facilitated the oxidative cleavage
to the desired carboxylic acid. Use of other oxidative conditions
including ozonolysis, and OsO4 led either to decomposition of
3a or mixtures of oxidation products.14
,
,
entry
solvent
% yieldb c
% eec d
1
2
3
4
5
6
7
PhMe
PhHe
C6F6
90 (51)
76
90 (56)
64
88
91
76 (>99)
69
84 (>99)
54
PhCF3
THF
60
56
40
Dioxaned
DCE
Without further purification, the crude acid 2 was converted
to the acyl chloride by treatment with thionyl chloride in THF,
followed by treatment with ammonium hydroxide to afford
amide 12 in 59% yield from olefin 3a (Scheme 4). At this stage,
82
a All reactions were performed with 1 equiv of 4 and 1.1 equiv 5g at 4
°C. b Isolated yield. c Parentheses indicate yield or ee after recrystallization.
d ee determined by chiral HPLC. e Performed at rt.
of aromatic solvents while polar solvents like THF and
dioxane resulted in lower selectivities. Hexafluorobenzene
proved to be the optimal solvent for this transformation,
providing the allylated product 3g in 90% yield and 84% ee
(entry 3). Recrystallization of 3g in pentane provided 3g as
a single enantiomer in 51-56% yield from malonate 4.
With enantiopure vinyl silane 3g in hand, protodesilylation
of the triethoxysilyl group was examined (Scheme 3). The
Scheme 4
Scheme 3
amide 12 was conveniently cyclized to form the A-ring by
treatment with LiHMDS in THF providing ranirestat (1) in
(11) (a) Trost, B. M.; Ball, Z. T.; Thomas, J. J. Am. Chem. Soc. 2002,
124, 7922–7923. (b) Giraud, A.; Provot, O.; Hamze, A.; Brion, J.-D.; Alami,
M. Tetrahedron Lett. 2008, 49, 1107–1110. (c) Chakrapani, H.; Liu, C.;
Widenhoefer, R. A. Org. Lett. 2003, 5, 157–159.
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(b) Trost, B. M.; Sieber, J. D.; Qian, W.; Dhawan, R.; Ball, Z. T. Angew.
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choice of fluoride source proved crucial to this transforma-
tion. TBAF, TBAT, and HF·pyr failed to furnish the proto-
(10) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726–
12727. (b) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644–
17655.
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Org. Chem. 1981, 46, 3936.
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Org. Lett., Vol. 12, No. 6, 2010

near quantitative yield. The analytical data of our material was
identical to that reported in the literature.5,6
Acknowledgment. We thank the National Institutes of
Health (GM33049) for their generous support of our
programs. We also thank Prof. Masakatsu Shibasaki for
providing an authentic sample of ranirestat (1). M.O. is a
John Stauffer Memorial Fellow. G.D. is a Stanford Graduate
Fellow. Palladium salts were generously supplied by Johnson-
Matthey.
In conclusion, a concise enantioselective synthesis of
ranirestat was accomplished starting from readily available
materials. The efficiency of the synthesis is demonstrated
by its 8-step length, 14% overall yield and minimal use of
column chromatography. During the synthesis, an efficient
Pd-AAA reaction was developed to construct the target
compound’s spiro-stereocenter in high yield and enantiomeric
purity using amidomalonate 4 and a silyl-substituted allyl
carbonate 5g. Moreover, the strategy described in this paper
should not only provide a ready access to the target molecule
1, but also provide strategies for the syntheses of analogues
and related targets.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100167W
Org. Lett., Vol. 12, No. 6, 2010
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