New optically active 4-alkoxyprolinol ethers derived from trans-4-Hydroxy-L-proline

Article abstract of DOI:10.1002/ejoc.201101156

(2S,4R)-trans-4-Hydroxy-L-proline has been used as thechiral-pool source in the efficient syntheses of optically active protected 4-hydroxyprolinols. After N-acyl protection andester formation, the first ether moiety was introduced maintaining the chiral

Full text of DOI:10.1002/ejoc.201101156

FULL PAPER
DOI: 10.1002/ejoc.201101156
New Optically Active 4-Alkoxyprolinol Ethers Derived from
trans-4-Hydroxy- -proline
L
Nora M. Friedemann,[a] Astrid Eustergerling,[a] and Udo Nubbemeyer*[a]
Keywords: Asymmetric synthesis / Nitrogen heterocycles / Chiral auxiliaries / Protecting groups
(2S,4R)-trans-4-Hydroxy-
L
-proline has been used as the
with the N-protecting group. Finally, the N-acyl function was
removed to generate the target methyl and tert-butyl ethers
displaying defined substitution patterns. The so-formed op-
tically active 4-alkoxyprolinol ethers can be used as core
fragments in biologically active compounds or as stable
chiral auxiliary subunits in suitable starting materials.
chiral-pool source in the efficient syntheses of optically active
protected 4-hydroxyprolinols. After N-acyl protection and
ester formation, the first ether moiety was introduced main-
taining the chiral centre adjacent to the ester. Then, re-
duction of the ester delivered the corresponding carbinol,
which had to be alkylated selectively to avoid side reactions
tional groups have to be taken into account. Ester and carb-
onate groups suffer from low stability under basic, re-
ductive, metal organic transformation conditions and enol-
ate chemistry. Silyl ethers and mixed acetals can be removed
upon treatment with mild acid and in the presence of fluo-
ride. In contrast, simple alkyl ethers promised much more
stability under a variety of conditions. Overall, such stable
pyrrolidines should be easily introduced into a variety of
starting materials and defined substitution patterns should
enable high diastereoselectivities to be achieved in various
transformations. Finally, the trans-2,4-di-O-alkyl-4-hy-
droxy-l-prolinols should be removable without being de-
stroyed under various conditions. Furthermore, auxiliary
recycling offers additional advantages for efficient transfor-
mations by using stable defined pyrrolidine derivatives.
Herein we report on the use of (2S,4R)-4-hydroxyproline
as a chiral starting material in the synthesis of several
(2S,4R)-4-hydroxyprolinol ethers 1–4, suitable as building
blocks and auxiliaries for the introduction into more com-
plex compounds (Figure 1). The 2-hydroxymethyl and 4-hy-
droxy groups are protected as small methyl and bulky tert-
butyl ethers.
Introduction
Enantiomerically pure trans-4-hydroxyprolinol ethers are
useful building blocks in organic synthesis. On the one
hand, such defined substituted and configured pyrrolidines
are found as core substructures in pharmaceutically impor-
tant compounds, as reported in the literature and, predomi-
nantly, in several patents.[1] On the other hand, the use of
prolinol derivatives as chiral auxiliaries in stereoselective
syntheses is well known. The Enders RAMP/SAMP meth-
odology should be mentioned as an example:[2] because 2-
hydroxymethyl and amino functions serve as the reactive
centres in various diastereoselective enolate alkylations, the
4-hydroxy group has been used to attach the auxiliary to a
resin enabling solid-phase supported enantioselective trans-
formations to be investigated.
Focusing on pyrrolidine core chiral auxiliaries, C2-sym-
metric pyrrolidines like trans 2,5-disubstituted compounds
as well as proline-derived simple 2-monosubstituted conge-
ners have been introduced into various processes.[3] Pyrrol-
idine auxiliary-directed alkylations,[4] reductions,[5] cycload-
ditions,[6] radical reactions,[7] aldol reactions[8] and re-
arrangements[9] are often used to generate new chiral build-
ing blocks. In contrast, trans-4-hydroxyprolinol ethers are
rarely found as stereodirecting groups. Until now, no ef-
ficient synthetic procedures for generating such potentially
useful auxiliaries have been reported.
In the synthesis of new chiral auxiliaries based on trans-
4-hydroxy-l-prolinol, the stabilities of the pyrrolidine func-
[a] Institut für Organische Chemie, Johannes-Gutenberg-
Universität Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
Fax: +49-6131-3924533
E-mail: nubbemey@uni-mainz.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101156.
Figure 1. Ex-chiral-pool syntheses of di-O-alkyl-trans-4-hy-
droxyprolinols.
Eur. J. Org. Chem. 2012, 837–843
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. M. Friedemann, A. Eustergerling, U. Nubbemeyer
FULL PAPER
duction of the ester moiety with lithium borohydride gave
the corresponding diol 11 in 89% yield (Scheme 2).[22,23]
Subsequent double O-methylation with an excess of methyl
iodide in the presence of silver(I) oxide succeeded in giving
ether 12 in 91% yield.[18,24] Finally, catalytic hydrogenation
with H2 and Pd/C in ethyl acetate enabled removal of the
Cbz group under mild conditions.[25,26] The product
(2S,4R)-4-hydroxyprolinol dimethyl ether 1 was isolated in
almost quantitative yield.[20] In comparison to the first syn-
thesis, this sequence is shorter (three steps from 10) and
higher yielding (81%). Because much more expensive rea-
gents were used (Cbz-protected proline ester, Ag2O-medi-
ated ether formation), this sequence is recommended for
small scale and sensitive prolinol ether syntheses.
Results and Discussion
To start our syntheses we used commercially available
trans-N-acetyl-4-hydroxyproline (5)[10] and N-Cbz-protected
trans-4-hydroxyproline methyl ester 10.[11] Because of the
generally high price of these compounds, an alternative syn-
thetic access following well-known literature procedures en-
abled us to generate these reactants in one and two steps,
respectively, starting from the cheaper trans-4-hydroxy-l-
proline. A literature search showed that some of our inter-
mediates have been mentioned previously. However, several
of the references reported incomplete preparation pro-
cedures and, likewise, spectroscopic data.[12] Selected com-
pounds have been published as patents.[13]
The first series of experiments started from trans-N-
acetyl-4-hydroxyproline (5). Although reduction of the acid
with LiAlH4 gave unsatisfactory results, a two-step alterna-
tive proved to be successful. After ethyl ester 6 formation
using acetyl chloride in ethanol,[14] lithium borohydride re-
duction gave the product diol 8,[15] which was easily isolated
as the corresponding bis-acetate 7 in 78% yield (from 5;
Scheme 1).[16] Zemplén transesterification with catalytic
amounts of sodium methoxide in methanol regenerated the
trans-N-acetyl-4-hydroxyprolinol (8) pure enough for ether
synthesis.[17] Double O-methylation was carried out with an
excess of methyl iodide in the presence of sodium hydride
in 61% yield (from 7).[18,19] The final removal of the amide
protecting group upon treatment with 3 n aqueous HCl
gave the trans-4-hydroxyprolinol dimethyl ether 1 (hydro-
chloride) in 96% yield.[20,21] Thus, this robust six-step se-
quence enabled us to synthesize the target molecule 1 on a
multigram scale in an overall yield of 46% (from 5) by using
inexpensive reagents.
Scheme 2. Synthesis of (2S,4R)-4-hydroxyprolinol dimethyl ether 1
from trans-N-Cbz-4-hydroxy-l-proline methyl ester 10. Reagents:
i) LiBH4, THF; ii) MeI, Ag2O, CH3CN; iii) H2, Pd/C, EtOAc.
Initial attempts to perform the double tert-butylation
starting from N-Cbz-diol 11 did not give satisfactory re-
sults.[27] Consequently, the (2S,4R)-4-hydroxyprolinol di-
tert-butyl ether 2 was synthesized in two consecutive alk-
ylation steps as described below.
Stepwise introduction of the alkyl groups enabled us to
synthesize non-symmetrically substituted 4-hydroxy-l-pro-
linol ethers. Starting from (2S,4R)-N-Cbz-4-hydroxyproline
methyl ester 10, standard Williamson conditions (strong
base, alkyl halide and aprotic solvent) resulted in some epi-
merization of the stereogenic centre adjacent to the ester
moiety.[18,28] In contrast, the use of iodomethane in the
presence of silver(I) oxide gave 4-methyl ether 13 in 94%
yield (Scheme 3).[18,24] The mono-4-tert-butyl ether 14 was
obtained in 86% yield by using isobutylene/BF3.[29] The
stereogenic centres were always found to be preserved.
The ester groups of 13 and 14 were reduced with lithium
borohydride in THF. Again, no epimerization of the centre
adjacent to the ester (and some intermediately formed 2-
carbaldehyde) was observed. Both mono-methyl ether
15[24,30] and the corresponding tert-butyl ether 16[31] were
obtained in yields of 98 and 99%, respectively.
Scheme 1. Synthesis of (2S,4R)-4-hydroxyprolinol dimethyl ether 1
(hydrochloride) from trans-N-acetyl-4-hydroxy-l-proline. Reagents:
i) AcCl, EtOH; ii) 1. LiBH4, THF; 2. Ac2O, AcOH; iii) NaOMe
(cat.), MeOH; iv) NaH, MeI, THF; v) 3 n aq. HCl.
Although a primary OH group has to be addressed and
no labile stereogenic centres are present, the second alk-
The harsh reaction conditions used to achieve the final ylation led to the formation of oxazolidinone 17 under vari-
cleavage of the pyrrolidine amide prevented the synthesis of ous conditions.[32] Again, methyl ether formation gave the
acid-sensitive prolinol ethers. In contrast, the N-Cbz pro- best results, achieved by treating carbinol 16 with iodo-
tecting group is well known because of its easy cleavage methane in the presence of silver(I) oxide. The 4-hydroxy-
by palladium-catalysed hydrogenation. The second series of prolinol 2-methyl 4-tert-butyl ether 18 was formed in 84%
reactions started from the known (2S,4R)-N-Cbz-4-hy- yield after purification. The tert-butyl ether was formed
droxyproline methyl ester 10.[11] An initial test of this start- with isobutylene in the presence of catalytic amounts of
ing material focused on the efficiency of synthesis of the sulfuric acid.[25,33] The 4-hydroxyprolinol 2,4-di-tert-butyl
(2S,4R)-4-hydroxyprolinol dimethyl ether 1. Selective re- ether 19 was obtained in 83% yield starting from mono-
838
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 837–843

4-Alkoxyprolinol Ethers Derived from 4-Hydroxy-l-proline
by the benzyl carbamate. Thus, the syntheses of symmetri-
cally and unsymmetrically alkylated trans-4-hydroxyprolin-
ols 1–4 succeeded in three to four steps in overall yields of
up to 79% and with complete preservation of the chiral
information. Further investigations using 4-alkoxyprolinol
ethers as chiral auxiliaries in stereoselective syntheses are in
progress.
Experimental Section
General: Reaction solvents were dried by standard procedures prior
to use when necessary. All reactions involving moisture- or air-
sensitive reagents were carried out under argon. 1H and 13C NMR
and 2D COSY, HSQC and HMBC spectra were recorded at room
temperature with a Bruker ARX400 or AV400 spectrometer in
CDCl3 using the signal of residual CHCl3 as internal standard.
Additional signals from the amide’s rotational isomers are given in
brackets. IR spectra were recorded with a FT/IR-400+ spectrome-
ter. High-resolution mass spectra (HRMS) were recorded with a
Waters Q Tof Ultima 3 Micromass spectrometer. Optical rotations
were recorded with a Perkin–Elmer P 241 polarimeter using dichlo-
romethane (Uvasol) as solvent. Column chromatography was per-
formed on MN silica gel 60M from Macherey–Nagel (grain size:
0.040–0.063 mm). Reaction progress was monitored by thin-layer
chromatography (TLC) performed on aluminium sheets precoated
with 60F254 silica gel from Merck. EA = ethyl acetate, PE = petro-
leum ether.
Scheme 3. Synthesis of (2S,4R)-4-hydroxyprolinol dialkyl ethers
from trans-N-Cbz-4-hydroxy-l-proline methyl ester. Reactions:
i) MeI, Ag2O, CH3CN; ii) isobutylene, BF3, CH2Cl2; iii) LiBH4,
THF; iv) isobutene, H2SO4 (cat.), CH2Cl2; v) MeI, Ag2O, CH3CN;
vi) H2, Pd/C, EtOAc; vii) cyclohexene, Pd/C.
(2S,4R)-4-Acetoxy-2-(acetoxymethyl)-N-acetylpyrrolidine
(7):
(2S,4R)-N-Acetyl-4-hydroxyproline (5; 1.0 g, 5.78 mmol) in ethanol
(p.a., 20 mL) was heated at reflux overnight in the presence of
(0.4 mL, 4.41 mmol) acetyl chloride. Then the solvent was evapo-
rated and the crude material was pure enough for the proceeding
reduction. The crude ester 6 in THF (23 mL) was cooled to 0 °C.
tert-butyl ether 16 and the 2-tert-butyl 4-methyl ether 20
was isolated in 87% yield from mono-methyl ether 15.[34]
Finally, removal of the Cbz-protecting group delivered
the pyrrolidines 2–4. Subjecting the 4-methyl ether 20 to H2
and Pd/C in ethyl acetate gave the best results, with the Lithium borohydride (654 mg, 30.06 mmol, 5.2 equiv.) was added
and the reaction was stirred at room temperature overnight. To
quench the reaction, methanol (8 mL) and acetyl chloride (2 mL)
were slowly added at 0 °C. After evaporation of the solvents a
sticky, white residue was obtained. To enable a proper work-up the
crude product was acetylated: after dissolving in acetic acid
(13 mL) and acetic anhydride (5 mL, 5.9 g, 57.8 mmol, 10 equiv.)
the mixture was heated at reflux at 70 °C overnight. The solvents
were removed under reduced pressure and the yellow or brown resi-
due was dissolved in dichloromethane (30 mL) and washed with
NaHCO3 solution (satd., 15 mL). The aqueous phase was extracted
three times with dichloromethane and the combined organic layers
were dried (MgSO4) and the solvent evaporated. The product was
purified by column chromatography (EA/PE, 5:1); yield 1.1 g
(4.52 mmol, 78.3%); pale-yellow oil. Rf = 0.24 (EA). [α]D = –24.3
(2S,4R)-2-O-tert-butyl-4-O-methyl-4-hydroxyprolinol
(3)
formed in 99% yield. In contrast, for the deprotection of
the 4-tert-butyl ethers 18 and 19 transfer hydrogenation
conditions were applied. The Cbz group was removed with
cyclohexadiene in the presence of Pd/C in ethanol. The
4-O-tert-butyloxy-2-O-methyl-(2S,4R)-prolinol (4) was
formed in 76% yield and the (2S,4R)-2,4-di-O-tert-butyl-4-
hydroxyprolinol (2) was isolated in 95% yield.
Conclusions
Enantiopure (2S,4R)-2,4-di-O-alkyl-4-hydroxyprolinols
have been generated following ex-chiral-pool syntheses
starting from trans-4-hydroxy-l-proline derivatives. By in-
(c = 1.53, 23 °C). IR: ν = 2949 (m), 1735 (s), 1645 (s), 1415 (s),
˜
1
1365 (m), 1223 (br), 1025 (s), 968 (w) cm–1. H NMR (400 MHz,
corporating a stable N-acetyl protecting group the dimethyl CDCl3, COSY): δ = 2.00 [s, 6 H, O(CO)CH3], 2.01 [s, 3 H, N(CO)-
3
CH3], 2.11 (m, 1.7 H, CH2), 2.21 (m, 0.3 H, CH2), 3.47 (dd, JH,H
ether 1 (hydrochloride) was constructed in six steps in gram
quantities in an overall yield of 46%. Only one column
chromatographic purification step was necessary and the se-
quence was carried out with exclusively inexpensive rea-
gents. The harsh conditions required for the cleavage of the
acetamide limited the synthesis to stable ethers (e.g.,
methyl). In contrast, the use of the N-Cbz protecting group
allowed cleavage under milder conditions, which allowed
the use of more sensitive ether functions (e.g., tert-butyl).
2
2
= 3.3, JH,H = 11.4 Hz, 0.7 H, CH2O), 3.71 (dd, 3JH,H = 5.8, JH,H
3
= 12.1 Hz, 0.7 H, CH2O), 3.87 (m, 0.6 H, CH2O), 3.99 (dd, JH,H
2
= 5.8, 2JH,H = 11.4 Hz, 0.3 H, CH2N), 4.07 (dd, 3JH,H = 4.9, JH,H
3
2
= 11.4 Hz, 0.3 H, CH2N), 4.15 (dd, JH,H = 3.2, JH,H = 11.2 Hz,
3
2
0.7 H, CH2N), 4.21 (m, 0.3 H, CHO), 4.27 (dd, JH,H = 4.9, JH,H
= 11.2 Hz, 0.7 H, CH2N), 4.40 (m, 0.7 H, CHO), 5.24 (m, 0.7 H,
CHN), 5.27 (m, 0.3 H, CHN) ppm. 13C NMR (100 MHz, CDCl3,
HSQC, HMBC): δ = 20.75, 20.85 [20.64, 21.40] [O(CO)CH3], 22.79
[22.11] [N(CO)CH3], 33.47 [35.27] (CH2), 53.26 [50.73] (CH2O),
The O-alkylation conditions applied prevented interference 54.05 [55.20] (CHO), 64.14 [65.25] (CH2N), 72.31 [71.32] (CHN),
Eur. J. Org. Chem. 2012, 837–843
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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839

N. M. Friedemann, A. Eustergerling, U. Nubbemeyer
FULL PAPER
169.50 [N(CO)CH3], 170.46, 170.49 [170.35] [O(CO)CH3] ppm. vents evaporated; yield 1.36 g (5.43 mmol, 89.1%); colourless oil.
HRMS (ESI): calcd. for C11H17NO523Na 266.1004; found Rf = 0.36 (EA). [α]D = –42.4 (c = 1.45, 23 °C). IR: ν = 3400 (br),
˜
266.1001.
2947 (s), 2884 (s), 1672 (s, br), 1414 (s, br), 1338 (s, br), 1192 (s),
1116 (s), 1080 (s), 1050 (s), 980 (s), 910 (m), 769 (m), 733 (s), 696
(s), 662 (m) cm–1. 1H NMR (400 MHz, CDCl3, COSY): δ = 1.73
(2S,4R)-N-Acetyl-4-methoxy-2-(methoxymethyl)pyrrolidine (9): The
diacetate 7 (5.60 g, 23.14 mmol, 1.0 equiv.) in methanol (350 mL)
was stirred at room temperature with sodium methoxide (30% solu-
tion in methanol; 1.3 mL, 7.0 mmol, 0.3 equiv.) for 2 h. To remove
the sodium methoxide the reaction mixture was filtered through
the Amberlite IRC 50 ion exchanger until neutral pH. The solvent
was then evaporated. To remove residual ion exchange material the
mixture was dissolved in methanol, filtered and again the solvent
was evaporated. The product was dried by repeated evaporation
with toluene. For the subsequent alkylation the product was dis-
solved in THF (110 mL) in an ultrasonic bath (1 h). For activation,
sodium hydride (4.63 g, 115.7 mmol, 5 equiv., 60% in mineral oil)
was washed twice with hexane. Then the alcohol solution and iodo-
methane (7.2 mL, 115.7 mmol, 5 equiv.) were added and the reac-
tion mixture was heated slowly to 80 °C for 2 h. To quench the
reaction aqueous NaHCO3 (satd., 20 mL) and water (100 mL) were
subsequently added at 0 °C. The mixture was extracted twice with
diethyl ether and five times with dichloromethane. The combined
organic layers were dried (MgSO4) and the solvents evaporated.
The crude product can be purified by kugelrohr distillation (110 °C,
3
2
(m, 1 H, CH2), 2.07 (m, 1 H, CH2), 3.50 (dd, JH,H = 3.6, JH,H
=
12.1 Hz, 1 H, CH2OH), 3.68 (m, 2 H, CH2N, CH2OH), 3.78 (d,
2JH,H = 11.8 Hz, 1 H, CH2N), 4.21 (m, 1 H, CHO), 4.41 (m, 1 H,
CHN), 5.15 (br. s, 2 H, CH2Ph), 7.31–7.37 (m, 5 H, PhH) ppm.
13C NMR (100 MHz, CDCl3, HSQC): δ = 37.28 (CH2), 55.54
(CH2OH), 59.28 (CHO), 66.20 (CH2N), 67.33 (CH2Ph), 69.11
(CHN), 127.81, 128.05, 128.45 (CPh), 136. 18 (CPh),
157.11(C=O) ppm. HRMS (ESI): calcd. for C13H17NO423Na
274.1055; found 274.1052.
(2S,4R)-N-(Benzyloxycarbonyl)-4-methoxy-2-(methoxymethyl)pyr-
rolidine (12): The diol 11 (1.36 g, 5.43 mmol, 1.0 equiv.) was dis-
solved in acetonitrile (30 mL) and silver(I) oxide (2.52 g,
10.86 mmol, 2 equiv.) and iodomethane (30 mL) were added. The
reaction mixture was heated at reflux overnight. Because the reac-
tion was not completed a second portion of silver(I) oxide (1.67 g,
7.2 mmol) was added and the heating was continued for 3 h. The
solid residues were then removed by filtration. NaHCO3 solution
(satd.) was added and the reaction mixture was extracted with ethyl
5.2ϫ10–2 mbar); yield 2.65 g (14.16 mmol, 61.2%); colourless oil. acetate (5ϫ). The combined organic layers were dried (MgSO4)
Rf = 0.21 (EA/CH2Cl2, 1:3). [α]D = –42.7 (c = 0.98, 23 °C). IR: ν
and the solvents evaporated. The crude product was purified by
column chromatography (EA); yield 1.37 g (4.92 mmol, 90.5%);
pale-yellow oil. Rf = 0.52 (EA). [α]D = –34.1 (c = 1.00, 23 °C). IR:
˜
= 2922 (br), 2853 (s), 1658 (s), 1460 (s), 1377 (s), 1200 (br), 1146
1
(br), 722 (s), 637 (s) cm–1. H NMR (400 MHz, CDCl3, COSY): δ
3
2
= 2.00 (ddd, 3JH,H = 0.8, JH,H = 5.6, JH,H = 13.1 Hz, 1 H, CH2),
ν = 2937 (m), 2892 (m), 2826 (w), 1698 (s), 1446 (m), 1411 (s), 1354
˜
2.04 [2.11] [s, 3 H, N(CO)CH3], 2.17 (ddd, 3JH,H = 4.8, 3JH,H = 5.8,
(m), 1200 (m), 1176 (m), 1104 (s), 1075 (s), 965 (w), 770 (m), 737
2JH,H = 13.1 Hz, 1 H, CH2), 3.31 (s, 3 H, OCH3), 3.32 (s, 3 H, (m), 697 (s) cm–1. H NMR (400 MHz, CDCl3, COSY): δ = 1.99–
1
OCH3), 3.35–3.43 (m, 2 H, CH2N, CH2O), 3.61–3.66 (m, 1.5 H,
2.18 (m, 2 H, CH2), 3.33 [3.26], 3.30 [3.29] (s, 6 H, OCH3, OCH3),
3
2
CH2O, CH2N), 3.88 (dd, JH,H = 3.5, JH,H = 12.7 Hz, 0.5 H, 3.39–3.79 (m, 4 H, CH2O, CH2N), 3.97 (m, 1 H, CHO), 4.10 (m,
CH2O), 4.09 (m, 1 H, CHO), 4.31 [4.01] (m, 1 H, CHN) ppm. 13C 1 H, CHN), 5.10, 5.15, 5.21 (d, JH,H = 12.8 Hz, 2 H, CH2Ph),
2
NMR (100 MHz, CDCl3, HSQC, HMBC): δ = 22.89 [21.54]
[N(CO)CH3], 33.38 [35.50] (CH2), 53.20 [49.92] (CH2N), 55.49
7.29–7.36 (m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3,
HSQC): δ = 33.81 [35.07] (CH2), 51.60 (CH2N), 56.18 [55.53]
[56.71] (CHN), 56.64 [56.62] (OCH3), 58.99 [59.10] (OCH3), 72.69 (CHN), 59.09 (OCH3), 56.58 (OCH3), 66.61 [66.85] (CH2Ph), 72.88
[74.87] (CH2O), 78.72 [77.81] (CHO), 169.37 [169.73] (C=O) ppm.
[73.87] (CH2O), 78.66 [78.22] (CHO), 127.70, 127.82, 128.37 (CPh),
136.79 (CPh), 154.93 (C=O) ppm. HRMS (ESI): calcd. for
C15H21NO423Na 302.1368; found 302.1371.
HRMS (ESI): calcd. for C9H17NO323Na 210.1106; found 210.1114.
(2S,4R)-4-Methoxy-2-(methoxymethyl)pyrrolidine Hydrochloride 1
(HCl): The amide 9 (3.27 g, 17.5 mmol) in hydrochloric acid (3 N,
200 mL) was heated at reflux under argon for 15 h. The amine
could not be extracted from the aqueous phase and so the water
and hydrochloric acid were removed by evaporation; yield 3.13 g
(2S,4R)-4-Methoxy-2-(methoxymethyl)pyrrolidine (1): The Cbz-pro-
tected amine 12 (1.24 g, 4.43 mmol) and 5 % Pd/C (235 mg,
0.11 mmol, 2.5 mol-%) in EA (40 mL) were stirred overnight at
room temperature under hydrogen. Then the catalyst was separated
by filtration and the solvent was evaporated; yield 0.652 g
(16.73 mmol, 95.6%); dark crystalline mass, m.p. 82 °C. [α]D
=
+10.5 (c = 0.95, 23 °C). IR: ν = 3747 (br), 3593 (br), 3082 (br), 2889 (4.46 mmol, 100%); clear colourless oil. Rf = 0.05 (EA/PE, 1:1).
˜
(s), 2851 (s), 2758 (br), 2360 (s), 1100 (s), 1039 (s), 979 (br) cm–1. 1H
NMR (400 MHz, MeOD, COSY): δ = 1.81 (m, 1 H, CH2), 2.18 (m), 2823 (w), 1650 (w), 1453 (m), 1390 (w), 1368 (w), 1193 (m),
[α]D = +17.2 (c = 1.00, 25 °C). IR: ν = 3340 (w, br), 2928 (m), 2878
˜
1
(m, 1 H, CH2), 3.25 (s, 3 H, OCH3), 3.30 (m, 2 H, CH2O), 3.33 (s,
3 H, OCH3), 3.49 (m, 1 H, CH2N), 3.60 (m, 1 H, CH2N), 3.85, (m, 1.47 (ddd, JH,H = 6.1, JH,H = 8.3, JH,H = 13.6 Hz, 1 H, CH2),
1098 (s), 809 (w) cm–1. H NMR (400 MHz, CDCl3, COSY): δ =
3
3
2
3
2
1 H, CHN), 4.09 (m, 1 H, CHO) ppm. 13C NMR (100 MHz, 1.85 (dd, JH,H = 7.2, JH,H = 13.6 Hz, 1 H, CH2), 2.13 (s, 1 H,
4
3
2
MeOD, HSQC, HMBC): δ = 33.43 (CH2), 51.13 (CH2O), 56.88 NH), 2.88 (ddd, JH,H = 1.2, JH,H = 2.7, JH,H = 11.9 Hz, 1 H,
(OCH3), 59.34 (OCH3), 59.41 (CHN), 71.68 (CH2N), 80.13 CH2N), 2.95 (dd, JH,H = 4.7, JH,H = 11.9 Hz, 1 H, CH2N), 3.21
3
2
(CHO) ppm. HRMS (ESI): calcd. for C7H16NO2 146.1181; found
146.1194.
(s, 3 H, OCH3), 3.19–3.27 (m, 2 H, CH2O), 3.28 (s, 3 H, OCH3),
3.39 (m, 1 H, CHN), 3.82 (m, 1 H, CHO) ppm. 13C NMR
(100 MHz, CDCl3, HSQC): δ = 34.49 (CH2), 51.81 (CH2N), 56.20,
56.27 (CHN, OCH3), 58.83 (OCH3), 75.82 (CH2O), 81.78
(CHO) ppm. HRMS (ESI): calcd. for C7H16NO2 146.1181; found
146.1191.
(2S,4R)-N-(Benzyloxycarbonyl)-4-hydroxy-2-(hydroxymethyl)pyr-
rolidine (11): Cbz-protected proline ester 10 (1.70 g, 6.09 mmol,
1 equiv.) in THF (50 mL) was cooled to 0 °C. Then lithium borohy-
dride (530 mg, 24.3 mmol, 4 equiv.) was added. The reaction mix-
ture was stirred overnight at room temperature. Work-up started
by hydrolysis with ice and water at 0 °C (2 h) and the aqueous
phase was then extracted with diethyl ether (3ϫ). The combined
organic layers were washed with brine, dried (MgSO4) and the sol-
(2S,4R)-N-(Benzyloxycarbonyl)-4-methoxy-2-(methoxycarbonyl)pyrr-
olidine (13): The proline ester 10 (1.70 g, 6.09 mmol, 1 equiv.) in
acetonitrile (30 mL) was heated at reflux with silver(I) oxide
(1.41 g, 6.09 mmol, 1 equiv.) and iodomethane (30 mL) for 6 h.
840
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 837–843

4-Alkoxyprolinol Ethers Derived from 4-Hydroxy-l-proline
Then the solid residue was removed by filtration. An aqueous
NaHCO3 solution (satd., 20 mL) was added and the reaction mix-
ture was extracted with diethyl ether (3ϫ). The combined organic
layers were dried (MgSO4), filtered through silica gel and the sol-
vents were evaporated; yield 1.68 g (5.72 mmol, 93.9%); colourless
2JH,H = 11.4 Hz, 1 H, CH2N), 4.14 (m, 1 H, CHO), 4.19 (m, 1 H,
CHN), 4.31 [4.02] (s, 1 H, OH), 5.13 (s, 2 H, CH2Ph), 7.35 (m, 5
H, PhH) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 28.24
[C(CH3)3], 36.87 (CH2), 54.55 (CH2OH), 59.36 (CHO), 66.55
(CH2N), 67.14 (CH2Ph), 68.71 (CHN), 73.83 [C(CH3)3], 127.76,
127.98, 128.43 (CPh), 136.41 (CPh), 156.91 (C=O) ppm. HRMS
oil. Rf = 0.40 (EA/PE, 1:1). [α]D = –45.3 (c = 1.22, 23 °C). IR: ν =
˜
2951 (m), 2897 (m), 1747 (s), 1703 (s), 1414 (s), 1352 (m), 1203 (s), (ESI): calcd. for C17H25NO423Na 330.1681; found 330.1679.
1167 (s), 1117 (s), 1094 (s), 1063 (m), 1014 (w), 989 (w), 914 (w),
(2S,4R)-N-(Benzyloxycarbonyl)-4-tert-butoxy-2-(methoxymethyl)-
769 (m), 737 (m), 698 (s), 607 (m) cm–1 1H NMR (400 MHz,
.
pyrrolidine (18): A solution of alcohol 16 (0.58 g, 1.89 mmol) in
acetonitrile (p.a., 10 mL), iodomethane (10 mL) and silver(I) oxide
(0.88 g, 3.77 mmol, 2 equiv.) was heated at reflux (40–50 °C) for
26 h. In the case of incomplete conversion further iodomethane
(5 mL) and silver(I)oxide (0.44 g, 1.89 mmol, 1 equiv.) were added
and heating was continued (50 °C) for 24 h. Then the solid residue
was removed by filtration and saturated aqueous NaHCO3 (30 mL)
was added and the aqueous phase was extracted with ethyl acetate
(3ϫ). The organic layers were dried (MgSO4) and the solvent re-
moved. The crude product was purified by column chromatography
(EA/PE, 1:4); yield 0.51 g (1.59 mmol, 84.1%); clear colourless oil.
CDCl3, COSY): δ = 2.06 (m, 1 H, CH2), 2.36 (m, 1 H, CH2), 2.29
[2.30] (s, 3 H, OCH3), 3.53 [3.74] (s, 3 H, COOCH3), 3.63 [3.72]
(m, 2 H, CH2N), 3.98 (m, 1 H, CHO), 4.43 (m, 1 H, CHN), 5.00,
2
5.11, 5.16, 5.19 (d, JH,H = 12.4 Hz, 2 H, CH2Ph), 7.28–7.35 (m, 5
H, PhH) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 35.10
[36.33] (CH2), 51.29 [51.43] (CH2N), 52.01 [52.27] (COOCH3),
56.62 [56.64] (OCH3), 57.63 [57.86] (CHN), 67.08 [67.11] (CH2Ph),
77.92 [78.63] (CHO), 127.73 [127.83], 127.88 [127.93], 128.30
[128.38] (CPh), 136.28 [136.41] (CPh), 154.27 [154.27] (C=O),
172.96 [173.10] (COOMe) ppm. HRMS (ESI): calcd. for
C15H19NO523Na 316.1161; found 316.1154.
Rf = 0.28 (EA/PE, 1:4). [α]D = –21.1 (c = 1.23, 22 °C). IR: ν = 2974
˜
(2S,4R)-N-(Benzyloxycarbonyl)-2-(hydroxymethyl)-4-methoxypyrr-
olidine (15): The ester 13 (1.68 g, 5.73 mmol, 1 equiv.) in THF
(s), 2935 (m), 2875 (m), 1700 (s), 1450 (w), 1410 (s), 1360 (m), 1192
(s), 1101 (s), 1069 (s), 1027 (w), 902 (w), 770 (w), 747 (w), 697
(80 mL) was treated with lithium borohydride (250 mg, 11.5 mmol, (w) cm–1. 1H NMR (400 MHz, CDCl3, COSY): δ = 1.72 [s, 9 H,
3
2 equiv.) at 0 °C. The mixture was stirred at room temperature over-
night and then was quenched at 0 °C with ice/water. The hetero-
genic mixture was extracted with diethyl ether and the organic
phase was washed with brine. The combined aqueous layers were
extracted with diethyl ether (3ϫ), the combined organic layers were
dried (MgSO4) and the solvents were evaporated; yield 1.48 g
(5.59 mmol, 97.6%); colourless oil. Rf = 0.36 (EA). [α]D = –33.3 (c
C(CH3)3], 1.92 (m, 1 H, CH2), 2.09 (ddd, 3J = 2.9, JH,H = 6.5,
2JH,H = 12.6 Hz, 1 H, CH2), 3.21 (dd, 3JH,H = 6.4, 2JH,H = 10.5 Hz,
1 H, CH2N), 3.34 [3.27] (s, 3 H, OCH3), 3.41 (m, 1 H, CH2OMe),
3
2
3.54 (m, 1 H, CH2OMe), 3.60 (dd, JH,H = 6.8, JH,H = 10.8 Hz, 1
H, CH2N), 4.09 (m, 1 H, CHN), 4.33 (m, 1 H, CHO), 5.12 (m, 2
H, CH2Ph), 7.28–7.36 (m, 5 H, PhH) ppm. 13C NMR (100 MHz,
CDCl3, HSQC): δ = 28.29 [C(CH3)3], 36.55 [37.33] (CH2), 53.36
[53.92] (CH2N), 56.19 [55.51] (CHN), 59.11 (OCH3), 66.54 [66.70]
= 1.36, 25 °C). IR: ν = 3432 (br), 2936 (m), 2897 (m), 1696 (s),
˜
1681 (s), 1417 (s), 1355 (s), 1198 (m), 1115 (s), 1099 (s), 1075 (s), (CH2Ph), 69.31 [68.64] (CHO), 73.33 [74.15] (CH2OMe), 73.33
975 (m), 770 (m), 752 (m), 698 (s), 605 (m) cm–1
.
1H NMR
[C(CH3)3], 127.69, 127.80, 128.37 (CPh), 136.87 (CPh), 154.89
(C=O) ppm. HRMS (ESI): calcd. for C18H27NO423Na 344.1838;
found 344.1839.
(400 MHz, CDCl3, COSY): δ = 1.66 (ddd, 3JH,H = 4.7, 3JH,H = 9.1,
2JH,H = 13.6 Hz, 1 H, CH2), 2.15 (dd, 3JH,H = 7.2, 2JH,H = 13.6 Hz,
3
2
1 H, CH2), 3.28 (s, 3 H, OCH3), 3.43 (dd, JH,H = 4.3, JH,H
=
(2S,4R)-N-(Benzyloxycarbonyl)-4-tert-butoxy-2-(tert-butoxymethyl)-
pyrrolidine (19): Sulfuric acid (conc., 0.01 mL) was added dropwise
through a syringe to a solution of carbinol 16 (1.00 g, 3.25 mmol)
in dichloromethane (20 mL) and isobutene (10 mL). After stirring
for 14 d at room temperature the reaction mixture was neutralized
by adding saturated aqueous NaHCO3. The organic phase was
dried (MgSO4) and the solvent was removed. Extraction of the
aqueous phase is not recommended. The crude product was puri-
fied by column chromatography (EA/PE, 1:4); yield 0.98 g
(2.71 mmol, 83.4%); clear colourless oil. Rf = 0.41 (EA/PE, 1:4).
2
12.1 Hz, 1 H, CH2N), 3.59 (dd, 3JH,H = 7.1, JH,H = 11.5 Hz, 1 H,
2
CH2OH), 3.70 (d, JH,H = 12.2 Hz, 1 H, CH2N), 3.75 (m, 1 H,
CH2OH), 3.86 (m, 1 H, CHO), 4.11 (m, 1 H, CHN), 4.58 [4.56] (s,
2
1 H, OH), 5.12, 5.15 (d, JH,H = 15.3 Hz, 2 H, CH2Ph), 7.31–7.36
(m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3, HSQC,
HMBC): δ = 33.88 (CH2), 52.24 (CH2N), 56.29 (OCH3), 59.41
(CHN), 66.34 (CH2OH), 67.29 (CH2Ph), 78.00 (CHO), 127.83,
128.04, 128.45 (CPh), 136.27 (CPh), 156.98 (C=O) ppm. HRMS
(ESI): calcd. for C14H19NO423Na 288.1212; found 288.1207.
(2S,4R)-N-(Benzyloxycarbonyl)-4-tert-butoxy-2-(hydroxymethyl)pyrr- [α]D = –28.6 (c = 2.12, 22.5 °C). IR: ν = 2972 (s), 2935 (m), 2872
˜
olidine (16): A solution of ester 14 (1.25 g, 3.72 mmol) in THF
(20 mL) was cooled to 0 °C. Lithium borohydride (325 mg,
14.9 mmol, 4 equiv.) was added. After stirring overnight at room
temperature the reaction was quenched by adding water and hydro-
chloric acid (1 n) until neutral pH. The aqueous phase was ex-
(w), 1702 (s), 1412 (s), 1362 (s), 1193 (s), 1107 (s), 1069 (s), 1022
1
(m), 904 (w), 873 (w), 769 (w), 697 (m) cm–1. H NMR (400 MHz,
CDCl3, COSY): δ = 1.08 [1.13] [s, 9 H, C(CH3)3], 1.17 [s, 9 H,
3
3
C(CH3)3], 1.90 (m, 1 H, CH2), 2.07 (ddd, JH,H = 2.4, JH,H = 7.2,
2JH,H = 13.4 Hz, 1 H, CH2), 3.14 (dd, 3JH,H = 7.0, 2JH,H = 10.5 Hz,
3
2
tracted with ethyl acetate (3 ϫ), the organic layers were dried 0.5 H, CH2N), 3.22 (dd, JH,H = 6.5, JH,H = 10.7 Hz, 0.5 H,
3
2
(MgSO4) and the solvent was removed. The crude product can be
purified by column chromatography (EA/PE, 1:1); yield 1.13 g
(3.68 mmol, 98.8%); clear colourless oil. Rf = 0.31 (EA/PE, 1:1).
CH2N), 3.33 (m, 1.5 H, CH2O), 3.55 (dd, JH,H = 4.3, JH,H =
9.4 Hz, 0.5 H, CH2O), 3.62 (dd, 3JH,H = 7.5, 2JH,H = 10.5 Hz, 1 H,
CH2N), 4.04 [3.99] (m, 2 H, CHN), 4.46 (m, 1 H, CHO), 5.08,
5.10, 5.14, 5.19 (d, JH,H = 12.6 Hz, 2 H, CH2Ph), 7.29–7.35 (m, 5
2
[α]D = –23.3 (c = 1.13, 22 °C). IR: ν = 3431 (br), 2973 (s), 2875
˜
(br), 1701 (s), 1681 (s), 1415 (s), 1360 (m), 1260 (w), 1189 (s), 1103 H, PhH) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 27.45
1
(s), 1070 (s), 1025 (s), 901 (w), 769 (w), 750 (m), 697 (w) cm–1. H [27.39] [C(CH3)3], 28.28 [C(CH3)3], 36.67 [37.43] (CH2), 53.14
NMR (400 MHz, CDCl3, COSY): δ = 1.17 [s, 9 H, C(CH3)3], 1.76
[53.75] (CH2N), 57.05 [56.33] (CHN), 62.53 [63.29] (CH2O), 66.40
(m, 1 H, CH2), 1.96 (ddd, 3JH,H = 5.3, 3JH,H = 7.8, 2JH,H = 13.0 Hz, [66.63] (CH2Ph), 69.55 [68.75] (CHO), 72.65, 73.41 [C(CH3)3,
3
2
1 H, CH2), 3.36 (dd, JH,H = 4.1, JH,H = 11.2 Hz, 1 H, CH2OH),
C(CH3)3], 127.65, 127.74, 127.84, 127.92, 128.35 (CPh), 137.03
3
2
3.56 (dd, JH,H = 5.6, JH,H = 11.2 Hz, 1 H, CH2OH), 3.58 (dd, [136.84] (CPh), 154.68 [154.54] (C=O) ppm. HRMS (ESI): calcd.
2
3
3JH,H = 7.2, JH,H = 11.4 Hz, 1 H, CH2N), 3.70 (dd, JH,H = 2.4,
for C21H33NO423Na 386.2307; found 386.2295.
Eur. J. Org. Chem. 2012, 837–843
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
841

N. M. Friedemann, A. Eustergerling, U. Nubbemeyer
(2S,4R)-N-(Benzyloxycarbonyl)-2-(tert-butoxymethyl)-4-methoxy- 2.34 g (12.5 mmol, 76%); clear colourless oil that crystallizes on
FULL PAPER
pyrrolidine (20): The alcohol 15 (1.11 g, 4.17 mmol) was dissolved
in dichloromethane (30 mL) and isobutene (10 mL). H2SO4 (conc.,
0.01 mL) was added and the reaction mixture was stirred for 8 d at
room temperature. Then the reaction mixture was neutralized with
saturated aqueous NaHCO3 and the mixture was extracted with
dichloromethane. The organic phase was washed with brine and
the combined aqueous layers were extracted with dichloromethane
(3ϫ). The combined organic layers were dried (MgSO4) and the
solvent evaporated. The crude product was purified by column
standing. Rf = 0.0 (EA). [α]D = –2.1 (c = 1.00, 22 °C); m.p. 113 °C.
IR: ν = 2975 (br), 2928 (m), 2875 (m), 1651 (w), 1460 (br), 1389
˜
(w), 1362 (s), 1192 (s), 1093 (br), 1010 (br), 903 (m), 811 (m), 742
1
(w), 608 (w) cm–1. H NMR (400 MHz, CDCl3, COSY): δ = 1.15
[s, 9 H, C(CH3)3], 1.62–1.75 (m, 2 H, CH2), 2.61 (s, 1 H, NH), 2.73
3
2
3
(dd, JH,H = 4.8, JH,H = 11.1 Hz, 1 H, CH2N), 3.13 (dd, JH,H
=
=
2
3
2
5.8, JH,H = 11.1 Hz, 1 H, CH2N), 3.27 (dd, JH,H = 6.6, JH,H
3
9.3 Hz, 1 H, CH2O), 3.33 (s, 3 H, OCH3), 3.34 (dd, JH,H = 4.3,
2JH,H = 9.3 Hz, 1 H, CH2O), 3.46 (m, 1 H, CHN), 4.13 (m, 1 H,
chromatography (EA/PE, 1:2); yield 1.17 g (3.62 mmol, 86.9%). Rf CHO) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 28.39
= 0.38 (EA/PE, 1:4). [α]D = –44.4 (c = 1.02, 25 °C). IR: ν = 2974
(m), 2937 (m), 1702 (s), 1446 (w), 1414 (s), 1362 (s), 1235 (w), 1195
[C(CH3)3], 37.32 (CH2), 54.74 (CH2N), 56.68 (CHN), 58.97
(OCH3), 71.81 (CHO), 73.30 [C(CH3)3], 75.84 (CH2OMe) ppm.
˜
(s), 1107 (s), 1078 (s), 994 (w), 918 (w), 770 (m), 752 (m), 735 (s), HRMS (ESI): calcd. for C10H22NO2 188.1646; found 188.1651.
698 (s) cm–1. H NMR (400 MHz, CDCl3, COSY): δ = 1.06 [1.12]
1
(2S,4R)-2-(tert-Butoxymethyl)-4-methoxypyrrolidin (3): Cbz-pro-
3
2
[s, 9 H, C(CH3)3], 2.03 (m, 1 H, CH2), 2.14 (dt, JH,H = 5.2, JH,H
= 13.2 Hz, 1 H, CH2), 3.29 [3.30] (s, 3 H, OCH3), 3.35–3.65 (m, 4
H, CH2N, CH2O), 4.04 (m, 2 H, CHN, CHO), 5.06, 5.21 (d, 2JH,H
= 12.4 Hz, 1 H, CH2Ph), 5.12 (s, 1 H, CH2Ph), 7.27–7.37 (m, 5 H,
PhH) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 27.43 [27.36]
[C(CH3)3], 33.97 [35.20] (CH2), 51.74 (CH2N), 56.65 (OCH3), 56.95
[56.27, CHN), 62.15 [63.07] (CH2O), 66.46 [66.78] (CH2Ph), 72.74
[C(CH3)3], 78.92 [78.35] (CHO), 127.66 [127.75], 127.96 [127.87],
128.35 (CPh), 136.95 [136.70] (CPh), 154.69 [154.83] (C=O) ppm.
HRMS (ESI): calcd. for C18H27NO423Na 344.1838; found
344.1831.
tected amine 20 (1.44 g, 4.47 mmol) in ethyl acetate (40 mL) and
5% Pd/C (238 mg, 0.112 mmol, 2.5 mol-%) were stirred overnight
at room temperature under hydrogen. Then the catalyst was sepa-
rated by filtration and the solvent was evaporated; yield 0.836 g
(4.46 mmol, 99%); clear colourless oil. Rf = 0.07 (EA/PE, 1:1).
[α]D = +6.9 (c = 1.06, 25 °C). IR: ν = 3342 (br, w), 2937 (m), 2929
˜
(m), 2872 (w), 1651 (w), 1464 (w), 1390 (m), 1363 (s), 1232 (m),
1197 (s), 1079 (s), 878 (w), 810 (m), 732 (s) cm–1. 1H NMR
(400 MHz, CDCl3, COSY): δ = 1.11 [s, 9 H, C(CH3)3], 1.53 (ddd,
3
2
3JH,H = 6.5, JH,H = 8.0, JH,H = 13.7 Hz, 1 H, CH2), 1.83 (dddd,
3
3
2
4JH,H = 1.0, JH,H = 2.0, JH,H = 6.8, JH,H = 13.7 Hz, 1 H, CH2),
4
3
2
(2R,4S)-4-tert-Butoxy-2-(tert-butoxymethyl)pyrrolidine (2): Cbz-
protected amine 19 (3.63 g, 10.0 mmol) in ethanol (p.a., 15 mL) was
heated with cyclohexene (15 mL) and 10% Pd/C (0.724 g, 6.8 mol-
%) at 80–100 °C for 2 h. After cooling the catalyst was removed by
filtration and the solids were washed with diethyl ether. Then 1 m
hydrochloric acid and 0.5 m citric acid were added to acidify the
filtrate to a pH of 2–3. After phase separation and extraction with
dichloromethane (2ϫ), the organic layers were discarded and the
pH of the aqueous layers was brought to 9–10 with saturated
Na2CO3 solution. The aqueous layers were then extracted with
dichloromethane (5ϫ) and the combined organic layers were dried
(MgSO4). After this work-up, the product did not need further pu-
rification; yield 2.18 g (9.49 mmol, 95%); clear colourless oil. Rf =
2.30 (s, 1 H, NH), 2.84 (ddd, JH,H = 1.0, JH,H = 3.2, JH,H =
11.7 Hz, 1 H, CH2N), 3.06 (dd, 3JH,H = 5.2, JH,H = 11.7 Hz, 1 H,
CH2N), 3.22 (s, 3 H, OCH3), 3.22–3.29 (m, 2 H, CH2O), 3.31 (m, 1
H, CHN), 3.84 (m, 1 H, CHO) ppm. 13C NMR (100 MHz, CDCl3,
HSQC): δ = 27.40 [C(CH3)3], 34.71 (CH2), 52.09 (CH2N), 56.34
(OCH3), 57.11 (CHN), 64.44 (CH2O), 72.48 [C(CH3)3], 81.77
(CHO) ppm. HRMS (ESI): calcd. for C10H22NO2 188.1651; found
188.1653.
2
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR, COSY and HSQC spectra of compounds
1, 1·HCl, 2–4, 7, 9, 11–13, 15, 16 and 18–20.
0.07 (EA/PE, 1:4). [α]D = +1.1 (c = 1.27, 23 °C). IR: ν = 2972 (s),
˜
Acknowledgments
2935 (m), 2870 (w), 1472 (w), 1389 (m), 1362 (s), 1255 (w), 1233
(w), 1194 (s), 1079 (br), 1020 (br), 879 (m), 810 (m), 750 (w) cm–1.
1H NMR (400 MHz, CDCl3, COSY): δ = 1.17 [s, 18 H, C(CH3)3,
We are grateful to Dr. Harald Waldeck, Solvay AG, for N-acetyl-
trans-4-hydroxy-l-proline used as the starting material.
3
C(CH3)3], 1.70 (t, JH,H = 6.5 Hz, 2 H, CH2), 2.16 (s, 1 H, NH),
2.71 (dd, 3JH,H = 5.5, 2JH,H = 10.9 Hz, 1 H, CH2N), 3.18 (dd, 3JH,H
[1] J. U. Peters, T. Hoffmann, P. Schnider, H. Stadler, A. Koblet,
A. Alker, S. M. Poli, T. M. Ballard, W. Spooren, L. Steward,
A. J. Sleight, Bioorg. Med. Chem. Lett. 2010, 20, 3405–3408.
[2] a) D. Enders, J. H. Kirchhoff, J. Köbberling, T. H. Pfeiffer, Org.
Lett. 2001, 3, 1241–1244; b) E. Alza, S. Sayalero, P. Kasaplar,
D. Almasi, M. A. Pericàs, Chem. Eur. J. 2011, 17, 11585–11595;
c) E. Alza, M. A. Pericàs, Adv. Synth. Catal. 2009, 351, 3051–
3056.
2
3
2
= 6.1, JH,H = 10.9 Hz, 1 H, CH2N), 3.25 (dd, JH,H = 5.3, JH,H
= 7.8 Hz, 1 H, CH2O), 3.36 (m, 2 H, CHN, CH2O), 4.14 (m, 1 H,
CHO) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 27.44, 28.34
[C(CH3)3, C(CH3)3], 37.33 (CH2), 54.67 (CH2N), 57.40 (CHN),
64.48 (CH2O), 71.71 (CHO), 72.49, 73.13 [C(CH3)3, C(CH3)3] ppm.
HRMS (ESI): calcd. for C13H28NO2 230.2120; found 230.2109.
(2R,4S)-4-tert-Butoxy-2-(methoxymethyl)pyrrolidine (4): Cbz-pro-
tected amine 18 (5.33 g, 16.58 mmol) in ethanol (p.a., 15 mL) was
heated with cyclohexene (15 mL) and 10% Pd/C (1.2 g, 6.8 mol-%)
at 80–100 °C for 2 h. After cooling the catalyst was removed by
filtration and the solids were washed with diethyl ether. Then 1 m
hydrochloric acid and 0.5 m citric acid were added to acidify the
filtrate to a pH of 2–3. After phase separation and extraction with
dichloromethane (2ϫ) the organic layers were discarded and the
pH of the aqueous layers was brought to 9–10 with saturated
Na2CO3 solution. The aqueous layers were then extracted with
dichloromethane (10ϫ) and the combined organic layers were
dried (MgSO4). The product did not need further purification; yield
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4-Alkoxyprolinol Ethers Derived from 4-Hydroxy-l-proline
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N-Acetyl-trans-4-hydroxy-l-proline (commercially available)
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Selected data for 1, 11, 13 and 14 have been published in the
literature.
Selected data for 13, 15 and 16 have been published in the
patent literature.
[8]
[9]
[10]
[11]
[23] In contrast to the corresponding N-acetamide 8, this material
was easily separated from the inorganic salts because of its less
distinct polarity.
[24] W. H. Romines, R. S. Kania, J. Lou, S. Cripps, R. Zhou, M.
He, US Patent US2004/19065A1 (Chem. Abstr. 2003, 139,
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[25] E. Vedejs, M. Gingras, J. Am. Chem. Soc. 1994, 116, 579–588.
[26] Complete purification could be achieved by simple filtration of
the catalyst and vacuum distillation of the solvents.
[27] The long reaction time required in this special case resulted in
some concurring cleavage and transformation of the carbamate
protecting group.
[28] In the presence of reactive alkyl halides, enolate C-alkylation
delivers some 4-O,2-C-dialkylproline derivatives as side prod-
ucts, including some C-2 epimerization products.
[29] J. Häusler, Liebigs Ann. Chem. 1992, 1231–1237.
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[32] Standard Williamson conditions (strong base, etc., e.g., NaH/
MeI) suffered from the option of intramolecular transesterifi-
cation including of the N-protecting group. The formation of
an oxazolidinone 17 via a five-membered ring intermediate (5-
exo-trig) with release of benzyl alcohol had to be avoided.[35]
Furthermore, the conversion of the hydroxy moiety in a leaving
group (e.g., halide, sulfonate, etc.) enabled the carbonyl group
of the N-carbamate to act as a nucleophile inducing 5-exo-tet
cyclization and releasing a stable benzyl cation to yield the cy-
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[12]
[13]
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salts immediately after the reduction was found to be difficult.
Therefore the crude diol 8 was dried upon removing the sol-
vents in vacuo. Subsequent treatment with an excess of Ac2O
and AcOH enabled the generation of the bis-acetate 7, which
was easily extracted with organic solvents to achieve complete
separation from the salts.
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methyl ether was found as a side product (intermediate forma-
tion of an amide enolate and subsequent C-methylation). How-
ever, subjecting this material to acid-cleavage conditions also
resulted in the formation of the desired hydrochloride of 1.
Thus, separation of this side product was not necessary.
[20] T. Fujisawa, M. Watanabe, T. Sato, Chem. Lett. 1984, 2055–
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[21] Alternative amide cleavage conditions (NaOH, heat and micro-
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[34] The tert-butylation, in analogy to the alkylation of the 4-hy-
droxy group using BF3 as a Lewis acid, caused incomplete con-
version of the starting material.
[35] For a similar example, see ref.[9a]
[36] K. Tanaka, H. Iwabuchi, H. Sawanishi, Tetrahedron: Asym-
metry 1995, 6, 2271–2279.
Received: August 6, 2011
Published Online: December 7, 2011
Eur. J. Org. Chem. 2012, 837–843
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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