Diastereoselective synthesis of (R)-phenanthrenyl-9yl-[(S)-pyrrolidin-2yl)] methanol

Article abstract of DOI:10.1080/00397911.2011.609303

A four-step synthesis of sterically demanding (R)-phenanthren-9-yl-[(S)- pyrrolidin-2-yl] methanol has been easily accomplished starting from L-proline in high diastereoselectivity. These compounds are potentially useful ligands in metal-catalyzed reactio

Full text of DOI:10.1080/00397911.2011.609303

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Diastereoselective Synthesis of (R)-
Phenanthrenyl-9yl-[(S)-pyrrolidin-2yl)]
Methanol
a
a
a
Alessio Russo , Tiziana Fuoco & Alessandra Lattanzi
a
Dipartimento di Chimica e Biologia, Università di Salerno, Fisciano,
Italy
Accepted author version posted online: 21 Feb 2012.Version of
record first published: 21 Dec 2012.
To cite this article: Alessio Russo , Tiziana Fuoco & Alessandra Lattanzi (2013): Diastereoselective
Synthesis of (R)-Phenanthrenyl-9yl-[(S)-pyrrolidin-2yl)] Methanol, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:6, 784-790
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1
Synthetic Communications , 43: 784–790, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.609303
DIASTEREOSELECTIVE SYNTHESIS OF
R)-PHENANTHRENYL-9YL-[(S)-PYRROLIDIN-2YL)]
METHANOL
(
Alessio Russo, Tiziana Fuoco, and Alessandra Lattanzi
Dipartimento di Chimica e Biologia, Universit a` di Salerno, Fisciano, Italy
GRAPHICAL ABSTRACT
Abstract A four-step synthesis of sterically demanding (R)-phenanthren-9-yl-[(S)-pyrrolidin-
2-yl] methanol has been easily accomplishedstarting from L-proline in high diastereoselectivity.
These compounds are potentially useful ligands in metal-catalyzed reactions and
organocatalysts.
Supplemental materials are available for this article. Go to the publisher’s online edition
1
of Synthetic Communications to view the free supplemental file.
Keywords b-Amino alcohols; diastereoselective synthesis; L-proline derivatives
INTRODUCTION
Chiral nonracemic b-amino alcohols are of notable importance as synthetic
targets thanks to their pharmacological activities and employment as building
[
1]
[
2]
blocks and ligands in metal-catalyzed processes and more recently as organocata-
[
3]
lysts. Among the different structural motifs, b-amino alcohols derived from
L-proline received a lot of attention and they proved to be among the most effective
ligands in metal-catalyzed asymmetric reactions. One of the most striking example of
their usefulness as ligands is the diethyl zinc addition to aldehydes to obtain chiral
[
4]
nonracemic alcohols reported by Soai and coauthors. Another fundamental
Received July 20, 2011.
Address correspondence to Alessandra Lattanzi, Dipartmento di Chimica e Biologia, Universit a` di
Salerno, Via Ponte don Melillo, 84084, Fisciano, Italy. E-mail: lattanzi@unisa.it
7
84

DIASTEREOSELECTIVE SYNTHESIS OF PROLINOLS
785
Scheme 1. Synthetic route to a,a-L-diaryl prolinols.
transformation concerns the asymmetric reduction of ketones mediated by
,3,2-oxazaborolidines based on a,a-L-diaryl prolinols developed by Corey and
1
[
5]
coauthors. More recently, a,a-L-diaryl prolinols have been used as effective orga-
nocatalysts in several carbon–carbon and carbon–heteroatom bond forming
[
3]
reactions.
The synthesis of prolinols has been predominantly restricted to the production
of symmetrically a,a-diaryl substituted derivatives exploiting a simple three-step
sequence starting from L-proline (Scheme 1).
[
6]
A variety of a,a-diaryl and dialkyl prolinols are thus accessible using different
[7]
Grignard reagents. A single stereocenter is present in the final products, whose
absolute configuration is established according to the L- or D-proline used as the
staring material. The approach to prolinols bearing two contiguous stereocenters
would be also of synthetic interest. A simple access to this class of compounds would
be the formation of a secondary alcoholic moiety instead of the tertiary one
illustrated in Scheme 1.
0
0
Soai and coauthors reported the first example of (1S, 2 S)- and (1R, 2 S)-
0
phenyl-(2 -pyrrolidinyl) methanol via a modified sequence to obtain the intermediate
ketone, which was then reduced and hydrolyzed under different conditions, afford-
[
8]
ing alcohol 6 in variable diastereoimeric ratios (Scheme 2).
We envisaged that the approach reported in Scheme 1 could have been a viable
route to obtain alcohols of type 6 when reacting the N-protected L-proline methyl
ester with sterically hindered aryl Grignard reagents. In this case, a double Grignard
addition would be disfavored and the key intermediate ketone necessary for the fol-
lowing reduction would be formed.
According to the reaction Scheme 1, compound 1, which is obtained in quan-
titative yield from L-proline, was reacted with in situ–generated 9-phenanthrenyl-
magnesium bromide to afford the corresponding ketone 7 in 34% yield (Scheme 3).
Compound 7 was reduced with different reagents and the crude mixture was
then hydrolyzed to the final product 8 (Table 1).
Scheme 2. Soai’s synthetic route to a,a-L-diaryl prolinols.

786
A. RUSSO, T. FUOCO, AND A. LATTANZI
Scheme 3. Synthesis of the 9-phenanthrenyl ketone 7.
Diastereoisomer 8a was always preferentially formed. K-Selectride enabled the
reduction of compound 7 with high diastereoselectivity and a good overall yield for
the amino alcohol was achieved after hydrolysis (entry 2). In the reduction=hydrolysis
sequence reported by Soai on the corresponding phenyl ketone 5 (Scheme 2), the treo
diastereoisomer was obtained with high diastereoseletivity when using K- or
Li-selectride, a 1=1 mixture of isomers was isolated with NaBH , and finally the
4
highly diastereoselective formation of the erythro diastereoisomer was obtained with
diisobutylaluminumhydride (DIBAL-H). These findings contrast with our results on
the sterically demanding ketone 7. In this case diastereoisomer 8a was always pro-
duced in good to excellent ratio. It appears that only one prochiral face of the ketone
is preferentially accessible, irrespective of the different nature of the reducing agents
employed. To check this assumption and to determine which diastereoisomer was
1
likely obtained, a simulation of H NMR spectra of both diastereoisomers 8a and
9,10]
[
8
b was performed using density functional theory (DFT) calculations.
As shown in Fig. 1, on the calculated spectra all protons H , H , H , and H of
threo-8b proved to be more shielded than corresponding protons of erythro-8a.
1
2
3
4
0
0
Accordingly, the H proton of (1R, 2 S)-phenyl-(2 -pyrrolidinyl) methanol 6 obtained
1
[
8]
by Soai was found downfield with respect to threo diastereoisomer. All these results
confirmed that major diastereoisomer 8 obtained was the erythro-isomer. (For
computational details and all optimized geometries, see the Supplementary Material.)
Table 1. Reduction and hydrolysis of ketone 7
a
b
Entry
Reducing agent
NaBH
Reaction conditions
Yield 8 (%)
8a=8b
ꢀ
1
2
3
4
Et
THF, ꢁ20 C, 5 h
2
O=MeOH, 0 C, 5 h
ꢀ
48
57
14
70=30
92=8
95=5
K-Selectride
DIBAL-H
ꢀ
THF, ꢁ20 C, 6 h
a
Overall yield of compound 8 after two steps.
The diastereoisomeric ratio was determined by H NMR analysis.
b
1

DIASTEREOSELECTIVE SYNTHESIS OF PROLINOLS
787
1
Figure 1. (a) Experimental H NMR spectra of prolinols 8 in highly diastereoselective ratio (up) and as a
1
mixture (down). (b) Simulated H-NMR spectra of 8b. c) Simulated H NMR spectra of 8a.
1
In conclusion, we have synthesized, via a simple sequence starting from
L-proline, (R)-phenanthren-9-yl-[(S)-pyrrolidin-2-yl] methanol, a sterically encum-
bered novel b-amino alcohol, which can be potentially employed as chiral ligand
or organocatalyst. The reduction of the intermediate ketone 7 proceeds with good
to excellent diastereocontrol in favor of the erythro-isomer, irrespective of the nature
of the reducing agent used, and a satisfactory yield for the reduction=hydrolysis
steps has been achieved when using K-selectride. The preferential formation of the
1
erythro-isomer has been established by matching the experimental H NMR spectra
and those determined by DFT calculation of both diastereoisomers 8a and 8b.
EXPERIMENTAL
All reactions requiring dry or inert conditions were conducted in flame-dried
glassware under a positive pressure of nitrogen. Tetrahydrofuran (THF) was freshly
distilled before use from LiAlH . Reactions were monitored by thin-layer chromato-
4
graphy (TLC) on Merck silica-gel plates (0.25 mm) and visualized by ultraviolet (UV)
light or by the phosphomolybdic acid = ethanol spray test. Flash chromatography was
1
performed on Merck silica gel (60, particle size: 0.040–0.063 mm). H NMR and
1
3
C NMR were recorded on a Bruker DRX 400 spectrometer at room temperature
in CDCl as solvent. Chemical shifts for protons are reported using residual CHCl
3
3
as internal reference (d ¼ 7.26 ppm). Carbon spectra were referenced to the shift of
1
3
the C signal of CDCl (d ¼ 77.0 ppm). Optical rotations were performed on a Jasco
3
Dip-1000 digital polarimeter using the Na lamp. Fourier transform–infrared (FT-IR)

788
A. RUSSO, T. FUOCO, AND A. LATTANZI
spectra were recorded as thin films on KBr plates using Bruker Vertex 70 spectrometer
ꢁ
1
and absorption maxima are reported in wave number (cm ). Electrospray
ionization—mass spectrometry (ESI-MS) was performed using a Bio-Q triple
quadrupole mass spectrometer (Micromass, Manchester, UK) equipped with an
electrospray ion source. Melting points were measured on a digital Electrothermal
9
EA 1112 analyzer. (S)-proline-N-ethyl carbamate methyl ester was synthesized
100 apparatus. Elemental analyses were recorded on a Thermo Finnigan Flash
[11]
according to the literature.
Synthesis of Ketone 7
Magnesium turnings (217 mg, 8.9 mmol) were placed in a dried two-necked,
round-bottomed flask attached with a reflux condenser under an argon atmosphere.
After adding dry THF (3 mL) and a few iodine crystals to the reaction vessel, the turn-
ings were left to stir for 2 h. 9-Phenanthrenyl bromide (7.4 mmol) in dry THF (15 mL)
was added dropwise over 15 min. The mixture was then refluxed under stirring for
ꢀ
4
5 min. After cooling the reaction mixture at 0 C, a solution of (S)-proline-N-ethyl
carbamate methyl ester (604 mg, 3 mmol) in THF (15 mL) was cannulated into the
reaction vessel. The resulting mixture was warmed up to room temperature gradually
and then refluxed for 4 hs.
The reaction was quenched with saturated ammonium chloride solution
(
50 mL) extracted with CHCl (3 ꢂ 50 mL). The combined organic layer was washed
3
with brine, dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. Purification by flash chromatography eluting with mixtures of PE=ethyl
acetate 95=5 to 80=20 afforded the corresponding ketone 7 (354 mg, 34%).
(
S)-Ethyl 2-(Phenanthrene-9-carbonyl)pyrrolidine-1-carboxylate (7)
2
D
2
ꢁ1
Pale brown gum; ½aꢃ : þ1.6 (CHCl , c ¼ 0.40). nmax(KBr)=cm 3544, 1683,
3
1
1
645, 1421, 1118, 771; HNMR (400 MHz, CDCl , mixture of atropoisomers 1:1
3
ratio): d 8.75–8.67 (2H, m), 8.40 (1H, t, J 8.1 Hz), 8.28–8.15 (1H, s), 7.97 (1H, t,
J 8.1 Hz), 7.77–7.63 (4H, m), 5.43–5.36 (1H, m), 4.25–4.13 (2H, m), 3.82–3.56 (2H,
1
3
m), 2.16–194 (4H, m), 1.35–1.16 (3H, m); C NMR (100 MHz, CDCl ): d 202.7,
3
2
1
1
1
02.1, 155.2, 154.3, 134.0, 133.6, 131.4, 131.3, 130.4, 130.3, 129.7, 129.5, 129.4,
29.0, 128.8, 128.7, 128.4, 128.2, 127.3, 127.1, 127.0, 126.9, 126.8, 125.9, 125.8,
22.7, 122.6, 122.5, 122.3, 64.4, 63.8,61.1, 47.0, 46.5, 29.9, 28.7, 23.8, 23.0, 14.6,
þ
þ
þ
4.4; (ESI , m=z): 348.64 [(M þ H ), 65%], 370.61 [(M þ Na ), 100%]. Anal. calcd.
for C H NO : C, 76.06; H, 6.09; N, 4.03 Found: C, 75.77; H, 6.01; N, 4.00.
2
2
21
3
Reduction and Hydrolysis of Ketone 7
Ketone 7 (286 mg, 0.823 mmol) was dissolved in THF (4 mL) in a dried round-
bottomed flask under a nitrogen atmosphere, and then the reaction mixture was
ꢀ
cooled at ꢁ20 C. K-Selectride (1.65 mmol, 1 M THF solution) was added dropwise,
and stirring was maintained for 5 hs. The reaction was quenched with saturated
ammonium chloride solution (50 mL) and extracted with CHCl (3 ꢂ 50 mL). The
3
combined organic layer was washed with brine, dried over anhydrous sodium sulfate,

DIASTEREOSELECTIVE SYNTHESIS OF PROLINOLS
789
and concentrated under reduced pressure. After the crude mixture was filtered over
silica gel with CHCl , the mixture was directly subjected to hydrolysis. The crude mix-
3
ture (160 mg, 0.46 mmol) was placed in a round-bottomed flask, EtOH (10 mL) and
ꢀ
H O (2 mL) were added, and then the mixture was cooled at 0 C and KOH
2
(9.2 mmol) was added. The mixture was refluxed for 7 hs. The reaction was quenched
with saturated ammonium chloride solution (50 mL) and extracted with CHCl3
(
3 ꢂ 50 mL). The combined organic layer was washed with brine, dried over anhy-
drous sodium sulfate, and concentrated under reduced pressure. Purification by flash
chromatography eluting with mixtures of CHCl =MeOH afforded compound 8
(
3
1
130 mg, 57%). The diastereisomeric ratio was determined by H NMR analysis.
(
R)-Phenanthren-9-yl-[(S)-pyrrolidin-2-yl]methanol 8a
From the diastereoisomeric mixture of 8a=8b (dr 92=8), compound 8a can be
ꢀ
26
precipitated from diethyl ether. Pale yellow powder; mp 157–160 C. ½aꢃ : ꢁ1.3
D
ꢁ
1
1
(
THF, c ¼ 0.23). n (KBr)=cm 3428, 2925, 1634, 756; H NMR (400 MHz, CDCl )
max
3
d 8.76 (1H, d, J 8.1 Hz), 8.66 (1H, d, J 8.2 Hz), 8.07–8.05 (2H, m), 7.94–7.92 (1H, m),
7
3
.69–7.57 (m, 4H), 5.58 (1H, d, J 3.1 Hz), 3.85–3.81 (1H, m), 3.13–3.08 (1H, m),
1
.04–2.96 (m, 1H), 2.58 (bs, 2H), 1.79–1.56 (2H, m), 1.32–1.18 (2H, m); C NMR
3
(
100 MHz, CDCl ): d 134.9, 131.5, 130.5, 129.9, 129.3, 128.9, 126.7, 126.5, 126.1,
3
þ
þ
1
8
6
24.2, 123.3, 122.3, 68.8, 62.5, 46.7, 25.2, 24.0; (ESI , m=z): 278.57 [(M þ H ),
þ
0%], 260.51 [(M-H O) þ H , 100%]. Anal. calcd. for C H NO: C, 82.28; H,
2
19 19
.90; N, 5.05. Found: C, 81.89; H, 6.86; N, 4.95.
ACKNOWLEDGMENTS
Ministero Italiano dell’Universit a` e Ricerca Scientifica e Tecnologica (MIUR)
is gratefully acknowledged for financial support. R. Zanasi is thanked for helpful
suggestions in DFT calculations. P. Iannece is thanked for mass spectra and elemen-
tal analyses.
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