Rhodium-catalyzed desymmetrization by hydroformylation of cyclopentenes: Synthesis of chiral carbocyclic nucleosides

Article abstract of DOI:10.1002/anie.201601478

Excellent enantioselectivities (up to 97 % ee) and diastereoselectivities (up to >99:1 d.r.) have been achieved in the desymmetrization of cyclopentenes by catalytic hydroformylation. This novel methodology provides an efficient and concise synthetic route to chiral cyclopentane carboxaldehydes. The key intermediate, (1S,3S)-(3-hydroxymethyl)cyclopentanol, for the synthesis of carbocyclic-ddA was obtained in three steps. Efficient access: A Rh/Yanphos complex catalyzed the desymmetrization of cyclopentenes through hydroformylation, thus giving cyclopentane carboxaldehydes with good yields and excellent diastereo- and enantioselectivities. This procedure provides efficient access to chiral carbocyclic nucleosides and exhibits good application prospects in organic synthesis.

Full text of DOI:10.1002/anie.201601478

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201601478
German Edition: DOI: 10.1002/ange.201601478
Hydroformylation
Rhodium-Catalyzed Desymmetrization by Hydroformylation of
Cyclopentenes: Synthesis of Chiral Carbocyclic Nucleosides
Cai You+, Biao Wei+, Xiuxiu Li, Yusheng Yang, Yue Liu, Hui Lv,* and Xumu Zhang*
Abstract: Excellent enantioselectivities (up to 97% ee) and
diastereoselectivities (up to > 99:1 d.r.) have been achieved in
the desymmetrization of cyclopentenes by catalytic hydro-
formylation. This novel methodology provides an efficient and
concise synthetic route to chiral cyclopentane carboxaldehydes.
The key intermediate, (1S,3S)-(3-hydroxymethyl)cyclopenta-
nol, for the synthesis of carbocyclic-ddA was obtained in three
steps.
transformations.[5] Tedious reaction sequences, however, are
required for synthesizing the carbocycle in these cases. Thus,
the development of efficient and concise synthetic routes to
carbocyclic nucleosides is highly desirable.
Asymmetric hydroformylation (AHF) is an atom-eco-
nomic method to convert olefins into enantiomerically pure
aldehydes, which are important intermediates for pharma-
ceuticals and fine chemicals.[6] Since the Rh/BINAPHOS
catalyst system was reported,[7] a number of chiral phosphorus
ligand systems have been developed for AHF reactions,
including bis(diazaphospholane) (BDP),[8] Chiraphite,[9] Ph-
BPE,[10] Yanphos,[11] and some monophosphine ligands.[12]
Although good regio- and enantioselectivities have been
achieved for AHF reactions of many substrates, such as
monosubstituted and 1,2-disubstituted olefins, only very
limited examples have been used in desymmetrization
reactions by rhodium-catalyzed hydroformylation. In 2004,
Breit used o-DPPF as a substrate-bound catalyst-directing
group (CDG) in the desymmetrizing hydroformylation of
prochiral bis(alkenylcarbinol)s and bis(allylcarbinol)s. Excel-
lent enantio- and diastereoselectivities were achieved, but an
equivalent of a chiral auxiliary was needed[13] (Scheme 1a).
In 2008, Sherrill and Rubin reported a rhodium-catalyzed
desymmetrizing hydroformylation of cyclopropenes to afford
cyclopropyl carboxaldehydes with only moderate to good
ee values (57–83%; Scheme 1b), albeit with excellent diaste-
reoselectivities.[14] Obviously, employing a desymmetrizing
hydroformylation strategy in catalytic synthesis of chiral
aldehydes with high diastereo- and enantioselectivities is still
C
arbocyclic nucleosides are nucleoside analogues whose
endocyclic oxygen atom is replaced by a methylene group.
These analogues usually exhibit more metabolic stability
towards phosphorylases and hydrolases than natural nucleo-
sides because of the lack of the labile glycosidic bond. More
importantly, many carbocyclic nucleosides show good anti-
viral or antitumor activities, such as carbocyclic-ddA, carbo-
vir, neplanocine A, and aristeromycin[1] (Figure 1). Conse-
quently, the synthesis of carbocyclic nucleosides has attracted
considerable attention. Typically, synthetic approaches
include enzymatic kinetic resolution,[2] asymmetric aldol
condensation with subsequent ring-closing metathesis,[3] pal-
ladium-catalyzed asymmetric allylic substitution,[4] and other
Figure 1. Structures of biologically active carbocyclic nucleosides.
[*] C. You,[+] B. Wei,[+] X. Li, Y. Yang, Y. Liu, Prof. Dr. H. Lv,
Prof. Dr. X. Zhang
Key Laboratory of Biomedical Polymers of Ministry of Education &
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, Hubei 430072 (China)
E-mail: huilv@whu.edu.cn
xumu@whu.edu.cn
[+] These authors contributed equally to this work.
Scheme 1. Examples of desymmetrizing hydroformylation. acac =
acetylacetonate, DPPF=1,1’-bis(dipheny1phosphino)ferrocene,
THF=tetrahydrofuran, TON=turnover number.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601478.
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Table 1: Ligand screening in the asymmetric hydroformylation of methyl
cyclopent-3-ene-1-carboxylate (1a).[a]
a challenge. Herein, we report an efficient access to chiral
cyclopentane carboxaldehydes with high diastereoselectivi-
ties (up to > 99:1 d.r.) and excellent enantioselectivities (up to
97% ee) by desymmetrizing hydroformylation (Scheme 1c).
We started our investigation using methyl cyclopent-3-
enecarboxylate (1a) as a model substrate. The AHF reactions
were carried out with 20 bar CO/H2 (1:1) gas at 608C in the
presence of 0.2 mol% of the catalyst, which was generated in
situ by mixing [Rh(acac)(CO)2] with the ligand in toluene.
Under these reaction conditions, a series of bidentate
diphosphine ligands were tested (Figure 2). To our delight,
Entry
Ligand
Conv. [%][b]
d.r.[b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
62
2
2
95:5
90:10
89:11
88:12
–
–
–
–
91 (1S,3S)
88 (1S,3S)
88 (1S,3S)
92 (1S,3S)
–
–
–
–
1
trace
trace
trace
trace
[a] Reactions were performed on a 0.5 mmol scale at 608C in 1 mL
toluene with substrate/Rh=500:1, L/Rh=3:1, 20 bar CO/H2 (1:1), and
a reaction time of 24 hours. [b] Determined by 1H NMR analysis of crude
reaction mixtures. d.r.=(A+B)/(C+D). [c] Refers to major diastereo-
mer. Determined by GC analysis using a chiral stationary phase. The
absolute configuration was assigned by comparing the sign of the optical
rotation of the derivative, 3-(hydroxymethyl)cyclopentanol, with that
reported in the literature; see Ref. [5c].
Table 2: Asymmetric hydroformylation of 1a.[a]
Figure 2. Chiral ligands for the asymmetric hydroformylation reaction.
when (S,R)-N-Bn-Yanphos was used as the ligand, the desired
aldehyde was achieved with 91% ee, 95:5 d.r., and 62%
conversion (Table 1, entry 1). Further ligand screening, how-
ever, disclosed that P-chiral diphosphine ligands such as (R)-
Binapine, (Rc, Sp)-Duanphos, Tangphos, (S,S)-Me-Duphos,
and (R,R)-QuinoxP* exhibited almost no reactivity in this
transformation (entries 1–6). (S)-BINAP and (S)-Segphos,
having axial chirality, were also unsatisfactory ligands for this
reaction (entries 7 and 8).
The success of (S,R)-N-Bn-Yanphos (L1) encouraged us
to investigate the effects of reaction temperature, solvent, and
syngas pressure in order to obtain optimal reaction condi-
tions, as summarized in Table 2. We found that increasing
reaction temperature beneficial for increasing the conversion,
but the enantio- and diastereoselectivity were remained the
same (entries 1–3). Solvent screening showed that different
solvents have an influence on conversion and diastereoselec-
tivity, but a very small effect on the enantioselectivity
(entries 2 and 4–7). Among them, toluene gave the best
result (91% ee and 95:5 d.r. with 91% conversion). Although
no significant influence of the CO/H2 pressure on the enantio-
and diastereoselectivity was observed, the total pressure
dramatically affected the reaction rate (entries 2, 8, and 9).
The complete conversion was achieved in 24 hours under
10 bar of CO/H2 at 708C, affording the desired product with
Entry Solvent T [8C] CO/H2 [bar] Conv. [%][b] d.r.[b]
ee [%][c]
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
CH2Cl2
THF
60
70
80
70
70
70
70
70
70
70
10:10
10:10
10:10
10:10
10:10
10:10
10:10
5:5
62
91
99
20
12
16
16
99
13
88
95:5
95:5
95:5
93:7
93:7
77:23
94:6
95:5
95:5
95:5
91
91
90
92
91
90
92
91
92
91
EtOAc
CH3CN
toluene
toluene
20:20
5:5
10[d] toluene
[a] Reactions were performed on a 0.5 mmol scale in 1 mL toluene with
substrate/Rh=500:1, L1/Rh=3:1, and a reaction time of 24 hours.
[b] Determined by 1H NMR analysis of crude reaction mixtures.
d.r.=(A+B)/(C+D). [c] Refers to major diastereomer. Determined by
GC analysis using a chiral stationary phase. The absolute configuration
was assigned by comparing the sign of the optical rotation of the
derivative, 3-(hydroxymethyl)cyclopentanol, with that reported in the
literature; see Ref. [5c]. [d] S/C=2000.
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91% ee and 95:5 d.r. Upon decreasing the catalyst loading to
groups were evaluated. When either phenyl or benzyl was
0.05 mol%, the diastereo- and enantioselectivity were
unchanged, and there was a slight decrease in conversion
(entry 10).
used as the protecting group for the amide, excellent distereo-
and enantioselectivities were achieved (2 f,g). Interestingly,
the chiral center on the substrate had no effect on the
enantioselectivity, but somewhat decreased the diastereose-
lectivity, whether the chiral center was either S or R (2h,i).
Notably, substrates with the heteroatoms directly linked to
the rings were tested, and the reaction went smoothly with
excellent results (2j,k). By prolonging the chain length of the
substituent, no effect on the reactivity was observed and
excellent enantio- and diastereoselectivities remained (2l–n).
The diphenylphosphine-oxide-containing substrate is also
tolerated for this reaction, thus affording the product 2o,
which could be used in the synthesis of some chiral phosphine
ligands, with 96% ee and 98:2 d.r.
To demonstrate the synthetic utility of the current
methodology, (1S,3S)-3-(hydroxymethyl)cyclopentanol (3),
a key intermediate of carbocyclic-ddA, was synthesized by
a concise synthetic route (Scheme 3). The asymmetric hydro-
formylation product 2j was reduced by NaBH4 in MeOH and
afforded the corresponding alcohol. Then, by treating the
alcohol with tetrabutylammonium fluoride (TBAF) in THF, 3
was obtained in good yield. Starting from the key intermedi-
ate 3, carbocyclic-ddA can be readily synthesized following
the literature procedure.[5c]
The substrate scope of this reaction was explored under
the optimized reaction conditions (Scheme 2). As the trans
products were obtained, we thought that enhancement of the
steric hindrance of the ester would improve the diastereose-
lectivity. Our predictions were demonstrated by the exper-
imental results. When the substituents were changed from
methyl to isopropyl, the diastereomeric ratio increased from
95:5 to 98:2, but with the similar enantioselectivities (2a–c).
The p-toluenesulfonyl protected cyclopentenylmethanol was
used, and excellent results were obtained (2d). When the OTs
group was replaced by a phthaloyl group, the enantioselec-
tivity slightly decreased, but excellent diastereoselectivity was
obtained (2e). Next, cyclopentenes with different amide
Scheme 3. Synthesis of (1S,3S)-3-(hydroxymethyl)cyclopentanol (3).
TBAF=tetra-n-butylammonium fluoride, TBS=tert-butyldimethylsilyl.
In conclusion, we developed an efficient approach for
synthesizing chiral cyclopentane carboxaldehydes by a cata-
lytic desymmetrizing hydroformylation of cyclopentenes. This
transformation exhibits excellent enantioselectivities and
high diastereoselectivities under mild reaction conditions
with low catalyst loading. More importantly, this method
provides a concise route to the synthesis of chiral carbocyclic
nucleosides and has potential applications in the synthesis of
bioactive molecules. Further studies on the applications of the
desymmetrizing hydroformylation strategy in organic syn-
thesis are in progress in our lab.
Scheme 2. Rhodium-catalyzed desymmetrizing hydroformylation of
cyclopentene. [a] Reactions were performed on a 0.5 mmol scale at
708C in toluene with substrate/Rh=500:1, L1/Rh=3:1, 10 bar CO/H2
(1:1), and a reaction time of 24 hours. [b] Determined by GC or HPLC
Acknowledgments
1
analysis using a chiral stationary phase. [c] Determined by H NMR
spectroscopy. [d] Yield of the isolated product. [e] S/C=200. [f] The
ee values were not determined. [g] Because of the solubility, CH2Cl2
was used as the solvent for 2 f–i and 2l.
We are grateful for the financial support by a grant from
Wuhan University (203273463), the Youth Chen-Guang
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Keywords: alkenes · diastereoselectivity · enantioselectivity ·
hydroformylation · rhodium
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Received: February 10, 2016
Published online: April 15, 2016
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