Enzyme and Gold Catalysis: A New Enantioselective Entry into Functionalized 4-Hydroxy-2-pyrrolines

Article abstract of DOI:10.1055/s-0033-1340251

A new route toward functionalized pyrrolines starting from acetylenic aldehydes was developed. Key steps involved a ?hydroxynitrile lyase catalyzed asymmetric hydrocyanation of acetylenic aldehydes and a gold-catalyzed cyclization of substituted acetylene-containing amino alcohols. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340251

270▌
LETTER
letter
Enzyme and Gold Catalysis: A New Enantioselective Entry into Function-
alized 4-Hydroxy-2-pyrrolines
Functionalized 4-Hydroxy-2-pyrrolines
Bas Ritzen, Gaston J. J. Richelle, Laurens Brocken, Floris L. van Delft, Floris P. J. T. Rutjes*
Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Fax +31(24)3653393; E-mail: F.Rutjes@science.ru.nl
Received: 24.09.2013; Accepted: 14.10.2013
cyanohydrins 3, in turn, could arise from HNL-mediated
Abstract: A new route toward functionalized pyrrolines starting
enantioselective addition of hydrogen cyanide onto the
from acetylenic aldehydes was developed. Key steps involved a
functionalized acetylenic aldehydes 4.
hydroxynitrile lyase catalyzed asymmetric hydrocyanation of acet-
ylenic aldehydes and a gold-catalyzed cyclization of substituted
acetylene-containing amino alcohols.
OH
R1
OTBS
Key words: gold catalysis, cyanohydrins, hydroxynitrile lyases,
pyrrolines, pyrrolidines
R1
R
N
R
NH2
Boc
1
2
Functionalized pyrrolidines and pyrrolines are important
structural motifs in a wide array of natural products1 and
pharmaceutically relevant molecules.2 Besides the rele-
vant biological activity, these heterocyclic moieties have
been extensively used as organocatalysts3 and chiral
auxiliaries4 or chiral ligands5 for asymmetric synthesis.
O
OTBS
CN
H
R
R
Over the past decades, a plethora of synthetic methods to
construct functionalized nitrogen heterocycles have been
developed and the search for new synthetic methodolo-
gies is still ongoing.6 In the past years, increasing atten-
tion has been drawn to the use of gold catalysis to create
nitrogen-containing ring systems,7 taking advantage of
the ability of gold to act as a soft Lewis acid toward unsat-
urated carbon–carbon bonds. An example is provided by
the group of Uriac, who reported a convenient route for
synthesizing substituted pyrrolin-4-ones via catalysis with
gold.8
4
3
Scheme 1
We commenced by making key intermediate 3 from com-
mercially available 3-(trimethylsilyl)-2-propynal (5) via
HNL-mediated asymmetric hydrogen cyanide addition.12
We reasoned that the anticipated cyanohydrin 6 would
hold considerable potential since facile removal of the
TMS group would offer the possibility to introduce a
range of aromatic and aliphatic groups via palladium-cat-
alyzed cross-coupling reactions. Therefore, we were
pleased to find that the TMS-protected acetylenic alde-
hyde 5 was well accepted by (S)-HNL providing the de-
sired product 6, after TBS protection, in good yield (83%,
over two steps) and an excellent enantiomeric excess of
99% (Table 1, entry 1). The immediate O-protection
(TBSCl, DMAP, imidazole) was required in order to pre-
vent racemization due to the intrinsic instability of the free
cyanohydrins 7 toward basic conditions. Unfortunately,
however, standard TMS deprotection attempts to liberate
the terminal alkyne failed, even after more extensive
screening, mostly leading to decomposition of the starting
compound.
Recently, we reported novel strategies for the synthesis of
functionalized aziridines9 and morpholines10 starting from
enantiopure cyanohydrins obtained from the correspond-
ing aldehydes via hydroxynitrile lyase (HNL)-mediated
asymmetric hydrogen cyanide addition. We anticipated
that the latter chemoenzymatic reaction in combination
with gold catalysis should also provide a basis for effi-
cient entries into a variety of functionalized hydroxylated
pyrrolines 1.
Retrosynthetic analysis of the target 4-hydroxy-2-pyrro-
lines 1, which can be considered as key precursors for the
synthesis of various pyrrolidines,8,11 might be synthesized
via gold-catalyzed 5-endo-dig cyclization of the acetyle-
nic amino alcohols 2 (Scheme 1). Installation of the
homopropargylic stereogenic center may occur by per-
forming Grignard additions onto cyanohydrins 3, fol-
lowed by stereocontrolled imine reduction. The
In response to these results, the initial strategy to the target
molecules 1 was redesigned. Instead of starting from
TMS-protected aldehyde 5, which would be diversified
after the enzymatic step, we now chose to start from func-
tionalized acetylenic aldehydes which were all subjected
to the HNL-catalyzed hydrocyanation. It is interesting to
note that among the numerous examples of HNL-cata-
lyzed hydrocyanations of aldehydes, additions onto such
α,β-acetylenic aldehydes have only been reported once.13
SYNLETT 2014, 25, 0270–0274
Advanced online publication: 13.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340251; Art ID: ST-2013-B0907-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Functionalized 4-Hydroxy-2-pyrrolines
271
Table 1 HNL-Mediated Cyanohydrin Formation and Protection
TBSCl
DMAP, Im
O
OH
OTBS
CN
HNL, HCN
H
n-BuLi, DMF
H
CN
R1
CH2Cl2
0 °C to r.t.
H2O–MTBE
pH 5.0
R1
THF
R1
R1
10–13
5, 8, 14–17
7
6, 9, 18–21
Entry
Substrate R1
Aldehyde
Yield (%)a Enzyme
Product
Yield (%)a ee (%)b
Config.
1
2
3
4
5
6
–
TMS
Ph
5c
8c
–
(S)-HNL
(R)-HNL
(S)-HNL
(S)-HNL
(S)-HNL
(S)-HNL
6
9
83
86
81
80
22
92
>99
>95
>99
>99
93
S
R
S
S
S
S
–
–
10
11
12
13d
4-MeOC6H4
3-MeOC6H4
4-FC6H4
14
15
16
17
71
61
73
68
18
19
20
21
3-piperonyl
>99
a Isolated yield after column chromatography.
b Determined by chiral HPLC analysis.
c Commercially available.
d Obtained via Corey–Fuchs reaction on piperonal.15
Since substituted α,β-acetylenic aldehydes are not com- the corresponding amino alcohol 22 in an acceptable yield
mercially available [except for 5 and 3-phenyl-2-propynal of 58% as an inseparable mixture of diastereoisomers with
(8)], we turned to a method described by Journet et al. a good syn/anti ratio of 1:8 (Table 2, entry 1).
starting from terminal alkynes and using DMF as the for-
Fairly similar results were obtained upon subjection of
cyanohydrin 9 to 4-fluorophenylmagnesium bromide (Ta-
mylating reagent.14
We were pleased to find that with this methodology alde- ble 2, entry 2). Encouraged by these results, we set out to
hydes 14–17 were readily obtained in acceptable yields of also apply this one-pot methodology to the substituted cy-
61–73% (Table 1, entries 3–6).
anohydrins 18–21 using various Grignard reagents (Table
2, entries 3–8). This resulted in the predominant formation
of anti-amino alcohols in generally satisfactory yields. To
prevent tedious and lengthy chromatographic purifica-
tion, we decided to separate the syn/anti isomers in a later
stage of the synthesis.
As can be seen from Table 1, subjection of aldehydes 8
and 14–17 to the chemoenzymatic reaction conditions
with both R- and S-selective hydroxynitrile lyases, fol-
lowed by TBS protection, provided the corresponding
products 9 and 18–21 in generally excellent enantiomeric
purities and chemical yields. Only in case of the fluorinat- Having the desired acetylenic amino alcohols in hand,
ed aldehyde 16 substantial background addition of cya- subsequent Boc protection smoothly furnished the corre-
nide, most likely due to the more reactive nature of the sponding carbamate analogues 30–37 in 70–85% yield. In
aldehyde, led to a reduction of the enantiomeric excess of this stage, the diastereomeric ratio of most of the sub-
product 20. To optimize the enantioselectivity, the reac- strates could be readily improved through chromato-
tion was stopped in a preliminary stage before reaching graphic purification (Table 2).
full conversion, resulting in a lower isolated yield of 22%,
but a rather good enantiomeric excess of 93%. Addition of
larger amounts of the enzyme also did not lead to an
improvement of the yield or enantiopurity.
Completion of the synthetic route required gold-catalyzed
5-endo-dig cyclization. We decided to explore the strate-
gy developed by Uriac8 in which Au2O3 was used as the
catalyst (THF, 60 °C) as a basis for the construction of the
With the availability of a suitable procedure for the syn- targeted 4-hydroxy-2-pyrroline systems 1. Initially, we
thesis of the acetylenic cyanohydrins 6, 9, and 18–21, the observed complete formation of the aromatic pyrrole
stage was set for performing the Grignard addition. Much when carbamate 30 was subjected to these conditions.
to our satisfaction, when submitted to phenylmagnesium This might be caused by complexation of the gold(III) cat-
bromide, TLC and mass analysis of the crude reaction alyst to the protected hydroxyl substituent, which is then
mixture revealed that cyanohydrin 9 underwent a success- sufficiently activated to act as a leaving group. In an at-
ful transformation into the corresponding imine. Subse- tempt to circumvent pyrrole formation, we deprotected
quent immediate chelation-controlled diastereoselective the hydroxyl group of 30 prior to cyclization, however,
imine reduction to the acetylenic amino alcohols was best this again only afforded the undesired pyrrole after col-
achieved using Zn(BH4)2 at low temperature providing umn chromatography. Pretreatment of silica gel with Et3N
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 270–274

272
B. Ritzen et al.
LETTER
Table 2 Grignard Addition, Reduction, and Boc Protection
1) R2MgBr
OTBS
CN
OTBS
OTBS
2) MeOH, Zn(BH4)2
(Boc)2O, NaHCO3
dioxane–H2O, r.t.
R2
R2
Et2O, –78 °C to r.t.
R1
R1
NHBoc
30–37
R1
NH2
17–21
22–29
Entry
Substrate
R1
R2
Ph
Amino
alcohol
Yield
(%)a
Ratio
Product Yield
Ratio
Config.
syn/antib
(%)a
syn/antib,c
1
2
3
4
5
6
7
8
9
9
Ph
22
23
24
25
26
27
28
29
58
57
42
53
73
66
56
69
1:8
1:7
1:30
1:6
1:7
1:6
1:5
1:7
30
31
32
33
34
35
36
37
73
72
70
75
80
85
79
74
1:17
1:10
1:60
1:6
R,S
R,S
S,R
S,R
S,R
S,R
S,R
S,R
Ph
4-FC6H4
4-FC6H4
Ph
18
19
19
19
20
21
4-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
4-FC6H4
3-piperonyl
4-FC6H4
4-ClC6H4
4-ClC6H4
Ph
1:12
1:7
1:5
1:8
a Isolated yield after column chromatography.
b Determined by 1H NMR of the crude reaction mixture.
c After separation by column chromatography.
(1% v/v) solved the latter problem providing the desired
pyrroline 38 in a rather low yield. Consequently, we set
out to investigate the cyclization of substrate 30 with a se-
ries of gold catalysts in order to identify the optimal con-
ditions. In our hands, NaAuCl4·2H2O turned out to be a
superior catalyst (10 mol%, THF, 50 °C) affording pyrro-
line 38 in 87% yield.16
Table 3 Deprotection and Gold-Catalyzed Cyclization
R2
1) TBAF
OH
OTBS
THF, 0 °C to r.t.
R1
N
R1
NHBoc
30–37
R2
2) NaAuCl4⋅2H2O
THF, 50 °C
Boc
38–45
Encouraged by the successful 5-endo-dig cyclization of
30, we deprotected the amino alcohols 31–37 as well prior
to the gold-catalysis step (Table 3). Clean conversions
were observed for all compounds rendering further col-
umn chromatographic purification redundant. Instead, a
simple extraction was sufficient so that the resulting de-
protected amino alcohols were directly used for the next
step. To our delight, subjection of all precursors to
NaAuCl4·2H2O in THF at 50 °C furnished the desired
pyrrolines 38–45 in good yields of 76–91% over two
steps. An unexpected bonus was that at this point we were
successful in fully separating both diastereoisomers via
column chromatography.
Entry Substrate R1
R2
Product Yield Config.
(%)a
1
2
3
4
5
6
7
8
30
31
32
33
34
35
36
37
Ph
Ph
H
F
38
39
40
41
42
43
44
45
87
80
91
81
82
79
76
83
R,S
R,S
S,R
S,R
S,R
S,R
S,R
S,R
4-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
4-FC6H4
F
H
F
Cl
Cl
H
In conclusion, we have developed a new and facile
enantio- and diastereoselective route to aryl-substituted
4-hydroxy-2-pyrrolines proceeding via 5-endo-dig gold-
catalyzed cyclization of acetylene-containing amino alco-
hols in excellent yield. It has also been demonstrated that
these amino alcohols are readily accessible using a one-
pot Grignard addition–Zn(BH4)2 reduction sequence start-
ing from the corresponding acetylenic cyanohydrins in
reasonable yield and good diastereomeric ratio. Extension
of this methodology to other heterocyclic ring systems is
currently under investigation in our group.
3-piperonyl
a Isolated yield after column chromatography.
Acknowledgment
The Council for Chemical Sciences of The Netherlands Organizati-
on for Scientific Research (NWO-CW) is kindly acknowledged for
financial support. We thank DSM Innovative Synthesis (Geleen, the
Netherlands) for providing the HNL enzymes.
Synlett 2014, 25, 270–274
© Georg Thieme Verlag Stuttgart · New York

LETTER
Functionalized 4-Hydroxy-2-pyrrolines
273
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(16) Representative Procedures
(R)-2-[(tert-Butyldimethylsilyl)oxy]-4-phenylbut-3-
ynenitrile (9)
A solution of 3-phenyl-2-propynal (8, 2.42 g, 15.4 mmol) in
MTBE (15 mL) was added to a cooled (0 °C) solution of
KCN (10.0 g, 154 mmol, 10.0 equiv) in citrate buffer (15
mL, pH 5.0). After addition of a lysate of (R)-HNL17 (4 mL)
the reaction mixture was stirred at 0 °C for 4 h and quenched
with 5 M HCl (10 mL). The precipitated enzyme was filtered
over a glass funnel filled with cotton. The filtrate was
extracted with CH2Cl2 (3 × 50 mL), and the organic layers
were combined, dried (Na2SO4), and concentrated in vacuo.
The residue was dissolved in dry CH2Cl2 (150 mL) at 0 °C,
and TBSCl (2.79 g, 1.2 equiv) and imidazole (2.10 g, 2.0
equiv) were added. After stirring overnight at r.t., the
mixture was quenched with sat. aq NH4Cl the aqueous layer
was extracted with CH2Cl2 (3 × 40 mL). The organic layers
were combined, dried (Na2SO4), and concentrated in vacuo.
Purification by column chromatography (EtOAc–heptane,
0:1 to 1.5:8.5) afforded 9 (3.60 g, 86% yield) as a yellow oil.
Rf = 0.69 (EtOAc–heptane, 1:3). [α]D20 –7.2 (c 1.33,
CH2Cl2); 95% ee [Chiralpak AD-H column: HPLC eluent
hexane–i-PrOH (85:15), flow 1.0 mL/min]; tR1 = 6.12 min
(S); tR1 = 7.01 min (R). IR (ATR): 2958, 2928, 2855, 2228,
2202, 1489, 1256, 1091, 836, 780, 759, 694 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.49–7.46 (m, 2 H), 7.42–7.33 (m, 3
H), 5.50 (s, 1 H), 0.95 (s, 9 H), 0.28 (s, 3 H), 0.26 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 132.0, 129.7, 128.6, 121.0,
116.5, 87.1, 81.9, 52.7, 25.6, 18.3, –4.6. HRMS (EI): m/z
calcd for C16H21NOSi: 271.1392; found: 271.1394.
(1S,2R)-2-[(tert-Butyldimethylsilyl)oxy]-1,4-diphenyl-
but-3-yn-1-amine (22)
To a solution of 9 (1.00 g, 3.68 mmol) in dry Et2O (37 mL)
was added dropwise PhMgBr (3.68 mL of a 3.0 M solution
in Et2O, 3.0 equiv) at 0 °C. After 5 min the reaction mixture
was stirred at r.t. for 2 h. Then dry MeOH (15 mL) was
added, and the reaction mixture was cooled to –78 °C
followed by dropwise addition of a solution of freshly
prepared Zn(BH4)2 in THF–Et2O (1:1) in 30 min, and the
reaction mixture was stirred overnight. The mixture was
quenched with sat. aq NaHCO3 (20 mL) and the product
extracted with EtOAc (3 × 20 mL). The organic layers were
combined, dried (Na2SO4) and concentrated in vacuo.
Purification by column chromatography (EtOAc–heptane,
0:1 to 3:7) afforded 22 (742 mg, 58% yield) as a yellow oil
[inseparable mixture of diastereoisomers (1:8)]. Major
diastereoisomer: Rf = 0.34 (EtOAc–heptane, 1:3). [α]D20 –12.4
(c 1.71, CH2Cl2). IR (ATR): 3031, 2957, 2922, 2850, 1666,
1593, 1493, 1359, 1251, 1091, 836, 788, 758, 702 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.44–7.27 (m, 10 H), 4.61 (d,
J = 5.9 Hz, 1 H), 4.10 (d, J = 5.9 Hz, 1 H), 1.99 (br s, 2 H),
0.85 (s, 9 H), 0.04 (s, 3 H), –0.01 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ = 141.5 131.7, 128.5, 128.4, 128.2, 127.7,
127.6, 122.9, 88.6, 86.4, 69.9, 61.5, 29.9, 25.9, –4.6, –5.1.
ESI-HRMS: m/z calcd for C22H30NOSi [M + H]+: 352.2097;
found: 352.2086.
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© Georg Thieme Verlag Stuttgart · New York
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B. Ritzen et al.
LETTER
(4R,5S)-N-tert-Butoxycarbonyl-2,5-diphenyl-4-hydroxy-
2-pyrroline (38)
60.2, 28.1. ESI-HRMS: m/z calcd for C21H24NO3 [M + H]+:
338.1756; found: 338.1769.
To a solution of 30 (50.0 mg, 0.11 mmol) in dry THF (2 mL)
was added dropwise TBAF (110 μL, 1.1 equiv) at 0 °C. The
reaction mixture was warmed to r.t. and stirred for 1 h. It was
quenched with sat. aq NH4Cl (10 mL), diluted with CH2Cl2
(10 mL), and extracted with CH2Cl2 (3 × 10 mL). The
organic layers were combined, dried (Na2SO4), and
concentrated in vacuo. The resulting colorless oil was
dissolved in dry THF (2 mL) and NaAuCl4·2H2O (4.4 mg,
0.1 equiv) was added at r.t. The reaction temperature was
increased to 50 °C, and the mixture was stirred for 6 h. After
cooling to r.t., Et3N (10 μL, 5.0 equiv) was added, and the
solvent was removed in vacuo. Purification by column
chromatography [EtOAc–heptane–1% Et3N (v/v), 0:1 to
1:3] afforded 38 (30 mg, 87% yield) as a yellowish oil. Rf =
0.17 [EtOAc–heptane–1% Et3N (v/v), 1:3]. [α]D20 +22.4 (c
0.71, CH2Cl2). IR (ATR): 3408, 2980, 2924, 1698, 1636,
1367, 1166, 1018, 752, 697 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.52–7.48 (m, 2 H), 7.42–7.36 (m, 7 H), 7.32–
7.26 (m, 1 H), 5.34 (dd, J = 0.4, 3.3 Hz, 1 H), 5.10 (d, J = 1.2
(17) The gene encoding for (S)-HNL, originating from the rubber
tree Hevea brasiliensis, was cloned and efficiently expressed
in the yeast strain Pichia pastoris as an intracellular protein;
the enzyme preparation was obtained by homogenization
(French press) of the cells, removal of insolubles by
filtration, and subsequent concentration of the clear filtrate
using ultrafiltration/diafiltration.18 The wild-type gene
encoding for (R)-HNL, originating from bitter almonds
(Prunus amygdalus), was cloned and efficiently expressed in
the yeast strain Pichia pastoris. The enzyme was secreted
from the cells and was obtained from cell-free supernatant
by concentration using ultrafiltration/diafiltration.19 The
crude lysates (cell-free extracts) containing (R)-HNL and
(S)-HNL were kindly provided by DSM Innovative
Synthesis (Geleen, the Netherlands).
(18) Hasslacher, M.; Schall, M.; Hayn, M.; Bona, R.; Rumbold,
K.; Luckl, J.; Griengl, H.; Kohlwin, S. D.; Schwab, H.
Protein Expression Purif. 1997, 11, 61.
(19) Glieder, A.; Weis, R.; Skranc, W.; Poechlauer, P.; Dreveny,
I.; Majer, S.; Wubbolts, M.; Schwab, H.; Gruber, K. Angew.
Chem. Int. Ed. 2003, 42, 4815.
Hz, 1 H), 4.35 (dd, J = 1.2, 3.3 Hz, 1 H), 1.15 (s, 9 H). 13
NMR (75 MHz, CDCl3): δ = 154.4, 149.6, 142.5, 135.3,
C
129.8, 129.5, 128.9, 128.5, 126.3, 112.2, 82.1, 79.5, 74.2,
Synlett 2014, 25, 270–274
© Georg Thieme Verlag Stuttgart · New York