Catalytic enantioselective desymmetrization of meso cyclic anhydrides via iridium-catalyzed hydrogenation

Article abstract of DOI:10.1021/ol400533g

A novel method to desymmetrize meso-anhydrides into lactones via asymmetric hydrogenation catalyzed by the Ir-C₃*-TunePhos complex has been developed. Various chiral lactones were synthesized with full conversion and excellent enantioselectivit

Full text of DOI:10.1021/ol400533g

ORGANIC
LETTERS
2
013
Vol. 15, No. 7
740–1743
Catalytic Enantioselective
Desymmetrization of Meso Cyclic
Anhydrides via Iridium-Catalyzed
Hydrogenation
1
†
Tang-Lin Liu, Wei Li, Huiling Geng, Chun-Jiang Wang,* and Xumu Zhang*
,‡
‡
†
,†
,†,‡
College of Chemistry and Molecular Sciences, Wuhan University, 430072, China, and
Department of Chemistry and Chemical Biology and Department of Pharmaceutical
Chemistry, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854,
United States
xumu@rci.rutgers.edu; xumu@whu.edu.cn; cjwang@whu.edu.cn
Received February 26, 2013
ABSTRACT
A novel method to desymmetrize meso-anhydrides into lactones via asymmetric hydrogenation catalyzed by the IrꢀC *-TunePhos complex has
3
been developed. Various chiral lactones were synthesized with full conversion and excellent enantioselectivity under high reaction temperature.
The asymmetric desymmetrization (ADS) of prochiral
molecules in symmetrical bifunctional compounds has
proven to be a straightforward and powerful strategy in
asymmetric syntheses. In particular, ADS of meso com-
pounds is a remarkably valuabletransformation in organic
synthesis because it breaks the symmetry of the molecule
2
without incorporating new stereogenic centers. Stereo-
processes and overall physiological metabolism in human
beings. Furthermore, it not only acts as a coenzyme in
carboxylation reaction but also an essential growth factor
1
4
in living cells, Several efficient methods for preparation of
5
(þ)-biotin (1) are shown in Scheme 1(A). Enantiomeri-
0
cally enriched lactones 3 and 3 serve as the key intermedi-
ates for the practical synthesis of (þ)-biotin (1). After
asymmetricalcoholysisofmeso-anhydride 2 with cinnamyl
alcohol via the cinchona alkaloid-mediated nucleophilic
ring-opening, chemoselective reduction of the ester with
NaBH4 followed by acid-catalyzed lactonization gave
selective catalytic desymmetrization of meso-anhydrides
has been developed as an advantageous methodology in
the synthesis of many biologically active compounds, such
3
as lactones and their derivatives.
Among many important chiral lactones, water-soluble
6
enantiomerically enriched lactone 3. Another route in-
0
B-vitamin (þ)-biotin (1) plays a crucial role in biochemical
volved asymmetric hydrogenation of lactones 3 cata-
7
lyzed by Rh(I)-Josiphos catalyst system. In Scheme 1(B),
†
Wuhan University.
‡
Rutgers, the State University of New Jersey.
1) For reviews on desymmetrization of meso-anhydrides, see:
(
(4) Casutt, M.; Koppe, T.; Schwarz, M. In Ullmann’s Enzyclopedia of
Industrial Chemistry; VCH: Weinheim, 1996; Vol. 27, pp 566 and 609.
(5) (a) Bonrat, W.; Karge, R.; Netscher, T.; Roessler, F.; Spindler, F.
Chimia 2009, 63, 265. (b) Gerecke, M.; Zimmermann, J.-P.; Aschwanden,
W. Helv. Chim. Acta l970, 53, 991. (c) Goldberg, M. W.; Sternbach,
L. H. US 2489232, 1949; Chem. Abstr. 1951, 45, 184. (d) Goldberg,
M. W.; Sternbach, L. H. US 2489235, 1949; Chem. Abstr. 1951, 45, 186a.
(e) Goldberg, M. W.; Sternbach, L. H. US 2489238, 1949; Chem. Abstr.
1951, 45, 186g.
(
(
a) Spivey, A. C.; Andrews, B. I. Angew. Chem., Int. Ed. 2001, 40, 3131.
b) Willis, M. C. J. Chem. Soc., Perkins Trans. 1 1999, 1765. (c) Johnson,
J. B.; Rovis, T. Acc. Chem. Res. 2008, 41, 327. (d) Atodiresei, I.; Schiffers,
I.; Bolm, C. Chem. Rev. 2007, 107, 5683.
(2) (a) Ito, M.; Kobayashi, C.; Himizu, A.; Ikariya, T. J. Am. Chem.
Soc. 2010, 132, 11414. (b) Ito, M.; Ootsuka, T.; Watari, R.; Shiibashi,
A.; Himizu, A.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 4240.
(
c) Takebayashi, S.; John, J. M.; Bergens, S. H. J. Am. Chem. Soc.
010, 132, 12832.
3) Matsuki, K.; Inoue, H.; Ishida, A.; Takeda, M.; Nakagawa, M.;
Hino, T. Chem. Pharm. Bull. 1994, 42, 9.
2
(6) (a) Dai, H. F.; Chen, W. X.; Zhao, L.; Xiong, F.; Sheng, H.; Chen,
F. E. Adv. Synth. Catal. 2008, 350, 1635. (b) Wang, S. X.; Chen, F. E.
Adv. Synth. Catal. 2009, 351, 547.
(
1
0.1021/ol400533g r 2013 American Chemical Society
Published on Web 03/13/2013

enantiomerically pure lactones 5 and 7 can be used to
8
synthesize key drug intermediates of telaprevir (6) and
9
boceprevir (8), respectively.
Scheme 1. Synthesis of (þ)-Biotin and Other Synthetic
Intermediates: (A) Synthesis of (þ)-Biotin from Anhydride 2;
(
B) Lactones as the Key Synthetic Intermediates of Drugs
Figure 1. Asymmetric hydrogenation of meso-anhydrides.
In spite of the above-mentioned protocols developed to
synthesize chiral lactones, the practical synthesis of enantio-
merically enriched lactones from anhydrides remains
1
0
a challenge. Nevertheless, due to the lower reactivity
of anhydrides, quite limited progress has been made in
1
1,5a
Figure 2. Model and origin for asymmetric hydrogenation of
meso-anhydride.
the area of asymmetric hydrogenation.
Therefore, the
(
7) (a) McGarrity, J.; Spindler, F.; Fuchs, R.; Eyer, M. EP 624,587,
994. (b) Eyer, M.; Fuchs, R.; McGarrity, J. EP 602653, 1994. (c) Eyer, M.;
Merril, R. E. WO 9424137, 1994. (d) Imwinkelried, R. Chimia 1997, 51, 300.
8) (a) Revill, P.; Serradell, N.; Bolos, J.; Rosa, E. Drugs Future 2007,
2, 788. (b) Lin, C.; Kwong, A. D.; Perni, R. B. Infect. Disord. Drug
Targets 2006, 6, 3.
9) Degertekin, B.; Lok, A. S. Curr. Opin. Gastroenterol. 2008, 24,
06. (b) Njoroge, F. G.; Chen, K. X.; Shih, N. Y.; Piwinski, J. J. Acc.
Chem. Res. 2008, 41, 50.
1
development of catalytic asymmetric method for the
straightforward synthesis of γ-lactones from anhydrides
is in high demand. We envisioned that the rigid biaryl
(
3
(
diphosphine ligand with steric hindered group such as C *-
3
3
TunePhos, should provide satisfied performance in this
ADS reaction under elevated temperature. Herein, we
discovered an elegant procedure, the asymmetric hydro-
genation of meso-cyclic anhydridesusingIr/C *-TunePhos
3
catalyst system (Figure 1), taking advantage of the rigid
(
10) Dub, P. A.; Ikariya, T. ACS Catal. 2012, 2, 1718.
(11) For the asymmetric hydrogenation of anhydrides to γ-lactones,
see: (a) Osakada, K.; Obana, M.; Ikariya, T.; Saburi, M.; Yoshikawa, S.
Tetrahedron Lett. 1981, 22, 4297. (b) Matsuki, K.; Inoue, H.; Takeda, M.
Tetrahedron Lett. 1993, 34, 1167.
Org. Lett., Vol. 15, No. 7, 2013
1741

and tunable nature of biaryl bisphosphine ligand C *-Tune-
3
12
Phos developed in our laboratory. The catalyst can sustain
high temperature to produce the corresponding chiral
γ-lactones in high yields and with high ee values. Investiga-
tion of this transformation will result in highly efficient ADS,
producing valuable enantiomerically enriched lactones.
a
Table 2. Desymmetrization of Various meso-Anhydrides
a
Table 1. Optimization of the Hydrogenation of meso-Anhydride 9
b
c
d
temp
solvent ( °C)
conv
(%)
ee
TON (%)
entry
L
x (S/C)
1
2
3
4
5
6
7
8
9
L
6
7
1
1
1
1
1
1
1
0.1 (1000)
0.1 (1000)
0.1 (1000)
0.1 (1000)
0.1 (1000)
0.1 (1000)
EtOAc
EtOAc
EtOAc
THF
80
80
80
80
80
80
80
80
80
45
60
450
600
72
85
91
90
90
87
91
91
91
L
L
L
L
L
L
L
L
>99
75
1000
750
PhCH
DCE
3
20
200
30
300
0.05 (2000) EtOAc
0.02 (5000) EtOAc
0.01 (10000) EtOAc
>99
>99
93
2500
5000
9300
a
Reaction conditions: 9 (0.1 mmol), [Ir(COD)Cl]2/L = 1:2.2, solvent
1 mL). The temperature of oil bath. Determined by NMR. Enantio-
b
c
d
(
selectivity was determined by chiral GC analysis.
We attempted to prepare chiral lactone 10 via catalytic
enantioselective hydrogenation of meso-anhydride 9 by
using [Ir(COD)Cl] /C *-TunePhos complex (COD =
2
3
1
,5-cyclooctadiene) as the catalyst. Initially, asymmetric
hydrogenation of meso-anhydride 9 was investigated with
.05 mol % of the [Ir(COD)Cl] and 0.11 mol % of C *-
0
2
3
DTBM-TunePhos (L1) in EtOAc at 80 °C under 80 bar
a
2
Reaction conditions: anhydrides (0.1 mmol), [Ir(COD)Cl] /L =
b
1:2.2, EtOAc (1 mL). Determined by NMR. The value in parentheses
was the isolated yield.e Enantioselectivity was determined by chiral
HPLC or GC analysis. 125 °C was required.
c
of H . To our delight, full conversion was achieved with
91% ee. It was quite encouraging that we achieved such a
2
d
high ee value at the enhanced temperature, in most cases,
which was attributed to the rigidity and bulky biaryl bispho-
sphine in chiral ligands. After hydrogenation of (3aR,7aS)-9
catalyzed by the complex of iridium and various chiral
bisphosphine ligands developed by our group, we selected
acetate gave best reactivity and enantioselectivity (Table 1,
entries 3 vs 4ꢀ6). It was noteworthy that the meso-anhy-
drides were alcoholisedtohemiester when MeOHwas used
as the solvent (not shown in table 1). The highly catalytic
[Ir(COD)Cl] /C *-DTBM-TunePhos (L1) as the promising
catalyst (Figure 2).
2 3
capability of the catalyst [Ir(COD)Cl] /L1 was further
2
While optimizing the conditions of this reaction, further
investigation indicated that solvent played an important
role in this ADS. After screening of various solvents, ethyl
explored at lower catalyst loading (0.05 mol %), the
standard lactone (3aR, 7aS)-9 was smoothly hydrogenated
without any erosion of ee value in 20 h (91% ee, entry 7).
Furthermore, when the substrate/catalyst ratio was further
increased to 5000, full conversion could still be achieved
(entry 8). To test its maximum catalytic reactivity, in an
(
12) (a) Sun, X.; Zhou, L.; Li, W.; Zhang, X. J. Org. Chem. 2008, 73,
143. (b) Li, W.; Sun, X.; Zhou, L.; Hou, G.; Yu, S.; Zhang, X. J. Org.
Chem. 2009, 74, 1397.
1
1
742
Org. Lett., Vol. 15, No. 7, 2013

the catalyst loading could be decreased to 0.02% (S/C =
5000) without any loss of conversion or ee values.
According to our experimental results, we propose
Scheme 2. Proposed Mechanism
a possible mechanism for this desymmetrization reaction
Scheme 2). The reaction might be initiated by the forma-
tion of the Ir(H )/L1 complex A under H . After coordina-
(
2
2
tion and hydride insertion steps, one of the two CdO
bonds of the anhydride was reduced to a semiacetal,
completing the catalytic cycle I. The following hydrolysis
1
3
of D provided intermediateE. HydrogenationofE by the
same catalyst species A enabled the formation of transition
state F, which was then transferred to the readily esterifica-
tion product lactone G.
In conclusion, we have developed a novel and practical
method to desymmetrize meso-anhydrides into lactones via
Ir/C *-DTBM-TunePhos (L1), which contains bulky biaryl
3
bisphosphine, catalyzed asymmetric hydrogenation under
high temperature. In the presence of a catalytic amount
of the catalyst, asymmetric hydrogenation of various meso-
anhydrides proceeded smoothly and afforded the corre-
sponding enantiomerically enriched lactones in high yields
and with good to excellent enantioselectivities. Study of the
desymmetrization of other meso-carbonyl compounds as
well as further modification of steric environment in C *-
3
TunePhos ligand family is in progress and will be reported
in due course.
extreme example of low catalyst loading (S/C = 10000),
this reaction reached 93% conversion without any drop in
enantioselectivity (91% ee) (entry 9).
After successfully optimizing the reaction conditions, we
attempted to expand the substrate range to demonstrate
the synthetic utilities of this strategy, as is listed in Table 2.
By using 0.1 mol % of the catalyst under 80 bar of H , a series
2
of bi- and tricyclic meso-anhydrides were readily desymme-
trized to the corresponding lactones in excellent yields and
with good to excellent enantioselectivities (80ꢀ99% ee).
Notably, for the anhydrides bearing a CdC bond, saturated
double reduction products were detected (Table 2, entries 5,
Acknowledgment. We are grateful for financial support
from the National Institutes of Health (GM58832),
the Fundamental Research Funds for the Central Univer-
sities, and an academic award for excellent Ph.D. candi-
dates funded by the Ministry of Education of China
6, 8, and 9). In further attempts, the desymmetrization of
(5052011203011). The first author is supported by the
cyclic anhydrides with the six-membered rings gave better
results than that of the five-membered rings (Table 2, entries
fellowship provided by the China Scholarship Council
for the studies at Wuhan University.
1
vs 7 and 9, 10 vs 8).
The meso-anhydride (4aS,5aR)-2 was also subjected to
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
this ADS reaction under these reaction conditions, and
full conversion and high enantioselectivity were obtained
under 125 °C (Table 2, entry 11). Under these conditions,
(13) Wheeler, D. D.; Young, D. C.; Erley, D. S. J. Org. Chem. 1957,
2, 547.
2
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
1743