Highly stereoselective syntheses of proline-derived vicinal amino alcohols through grignard addition onto N-tosylprolinal

Article abstract of DOI:10.1055/s-0035-1560802

A highly diastereoselective Grignard addition to N-tosyl-l-prolinal has been developed to deliver a variety of proline-derived vicinal amino alcohols in good to excellent yields with high diastereoselectivities. A similar selectivity was also obtained by using N-tosyl-d-prolinal. The methodology has been applied to the synthesis of medicinally important 3-hydroxy-2-phenylpiperidines.

Full text of DOI:10.1055/s-0035-1560802

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, 215–220
letter
215
S. Chaudhuri et al.
Letter
Synlett
Highly Stereoselective Syntheses of Proline-Derived Vicinal Amino
Alcohols through Grignard Addition onto N-Tosylprolinal
Saikat Chaudhuri
OH
RMgBr, THF
–78 °C, 4 h
H
Amarchand Parida
Santanu Ghosh
Alakesh Bisai*
H
H
R
O
R
Ph
OH
+
N
N
N
N
N
R
Ph
up to 92%
dr up to >24:1
H
OH
OH
p-Ts
p-Ts
p-Ts
p-Ts
Department of Chemistry, Indian Institute of Science Education
and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal 462
066, Madhya Pradesh, India
R = Me, 72%
R = Bn, 85%
(major)
(minor)
alakesh@iiserb.ac.in
Received: 08.07.2015
Accepted after revision: 23.09.2015
Published online: 09.11.2015
auristatins6 derived from L-prolinol that are synthetic ana-
logues of the antineoplastic natural product dolastatin 10,3
are also important in the field of antibody drug conju-
gates.7,8 The pseudotetrapeptide protioenol lactone 1a (Fig-
ure 1) is reported to be a potential alternate substrate for
the inhibition of human leukocyte elastase.9 Quinoline-
based L-prolinol derivative 1b is reported to be a new class
of disruptors of biofilm formation in V. cholerae.10 They are
also common structural motifs of pyrrolizidine alkaloids11
and phenanthroindolizidine alkaloids such as tylophoridi-
cine E (1c) (Figure 1).12
DOI: 10.1055/s-0035-1560802; Art ID: st-2015-b0521-l
Abstract A highly diastereoselective Grignard addition to N-tosyl-L-
prolinal has been developed to deliver a variety of proline-derived vici-
nal amino alcohols in good to excellent yields with high diastereoselec-
tivities. A similar selectivity was also obtained by using N-tosyl-D-pro-
linal. The methodology has been applied to the synthesis of medicinally
important 3-hydroxy-2-phenylpiperidines.
Key words prolinol, Grignard addition, diastereoselectivity, aziridini-
um ion, natural products
Functionalized chiral piperidines are found in wide
range of alkaloids and synthetic compounds showing a di-
verse range of biological activities (Scheme 1). Among
these, 2-phenylpiperidin-3-ol derivatives 3a and 3b are vi-
tal for high-affinity binding to the human NK-1 receptor
because they act as precursors of non-peptidic NK-1 recep-
tor antagonists such as (+)-L-733,060 (5a),13 (+)-GR-
205,171 (5b),14 and (+)-CP-99,994 (5c)15 possessing a cis-re-
lationship between the phenyl and the ether or amine
group on the piperidine ring (Scheme 1). Furthermore, 3-
hydroxy pipecolic acids 4a and 4b16 are also significant chi-
ral building blocks for the synthesis of biologically active
natural products such as tetrazomine (8), which exhibits
L-Proline-derived vicinal amino alcohols constitute a
large class of enantioenriched scaffolds that are widely used
in organic synthesis and catalysis.1 These 1,2-amino alco-
hols have received considerable interest because of their ef-
ficiency as ligands in organometallic chemistry.2 They are
also structural targets in several natural products with im-
portant biological properties such as dolastatine 10,3 which
is a highly cytotoxic antineoplastic agent for cancer chemo-
therapy, symplostatins 1 and 3,4 which have tumor-selec-
tive cytotoxic properties, and malevamide D5 and isodo-
lastatin H,5 which have highly cytotoxic properties. Various
R
HO
OH
CH2
H
H
N
H
O
O
O
Me
N
H
N
N
O
N
H
O
N
OH
O
H
O
Me
OMe
MeO
Me
Me
1b R = 4-F3CC6H4
OMe
(+)-tylophoridicine E (1c)
1a
biofilm inhibitor
(EC50 = 17.8)
Figure 1 L-Prolinol derived enol lactone (1a), biofilm inhibitor (1b), and naturally occurring 1c
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 215–220

216
S. Chaudhuri et al.
Letter
Synlett
OH
OH
O
H
Ph
N
OH
N
R
Ph
N
OH
R
H
2a R = Me,
2b R = allyl
3a R = Me,
3b R = allyl
(2R,3R)-trans-
3-hydroxypipecolic acid (4a)
N
N
N
F3C
N
CF3
H
H
N
N
O
CF3
OMe
OMe
N
Ph
N
Ph
N
Ph
H
H
H
(+)-L-733,060 5a
(+)-GR-205,171 5b
(+)-CP-99,994 (5c)
OH
O
OH
Ph
H
Ph
OH
N
N
N
OH
Bn
H
H
7
6
(2S,3R)-cis-
3-hydroxypipecolic acid (4b)
OH
H
H
OH
O
NMe
H
H
H
H
N
N
H
H
O
NH
OMe
tetrazomine (8)
Scheme 1 L-Prolinol 2a and 2b, and 2,3-disubstituted piperidines
antitumor and antibiotic properties.17 Numerous synthetic
strategies have been reported for the synthesis of com-
pounds of type 3 and 4.16,18 One of the ways to synthesize 2-
phenylpiperidin-3-ols 3a, 3b, and 7 is ring expansion of L-
prolinol derivatives 2a, 2b, and 6, respectively, via aziridini-
um ion intermediates,19 which has been developed exten-
sively by Lee,19a Cossy,19b–f and O’Brien19g (Scheme 1). Nev-
ertheless, a highly stereoselective synthesis of L-prolinol de-
rivatives 2a, 2b, and 6 remains a challenge to the synthetic
community.
A survey of previous reports reveals that these prolinol
derivatives are generally prepared by nucleophilic addition
to N-protected prolinals such as 9a and 9d, bearing a benzyl
or a carbalkoxy protecting group on the nitrogen atom (Fig-
ure 2). However, the addition of organometallic nucleop-
hiles to aldehyde 9a20 usually results in lower diastereose-
lectivities. The same behavior is observed with aldehydes
9b,21 9c,22 and 9d.23 However, good stereoselectivities can
be achieved by means of double diastereoselection.24 L-Pro-
linal 9e, having an acid-sensitive N-trityl group, is reported
to be good substrate for 1,2-addition of organometallic re-
agents.25,10 Herein, we report the use of L-prolinal (10) and
D-prolinal (ent-10), having an N-tosyl group26 as a stable
protecting group, in a highly diastereoselective Grignard
addition, and we demonstrate the use of such an approach
in organic synthesis.
H
H
H
H
O
O
O
R
N
N
R
N
N
H
OH
H
H
H
Ts
Ph
Ph
(9a–d)
2
10
Ph
(9a) R = Bn
9e
(9b) R = COOMe
(9c) R = Cbz
(9d) R = Boc
Figure 2 L-Prolinol (2) and N-protected L-prolinals 9a–e and 10
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 215–220

217
S. Chaudhuri et al.
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The proposed transition state of Grignard addition is
shown in Scheme 2. We envisioned that the p-tolyl group of
sulfonamide 10 adopts a position trans to the carbonyl moi-
ety, thereby allowing metal coordination of the carbonyl
oxygen and sulfonyl oxygen atoms (Scheme 2). In this situa-
tion, Grignard addition onto N-tosyl-L-prolinal (10) would
follow a favored Re-face approach of nucleophile to afford L-
prolinol 11 as the major product via 13a as an organized
transition state (TS) (Scheme 2).
SOCl2, MeOH
25 °C, 12 h
H
H
O
O
N
H
N
quant.
H
OH
OMe
•HCl
14b
L-proline methyl ester
14a
L-proline
p-TsCl, Et3N, CH2Cl2
95%
0–25 °C, 2 h
RM, solvent
–78 °C, 2–4 h
H
H
H
R
O
R
DIBAL-H, Et2O
O
–78 °C, 4 h
H
H
O
+
N
p-Ts
11
N
N
high yield
high dr
N
N
H
OH
OH
p-Ts
p-Ts
69%
OMe
H
p-Ts
p-Ts
10
12
(minor)
10
(major)
14c
LiAlH4, THF
70 °C, 8 h
quant.
O
M
M
(COCl)2, DMSO
Et3N, CH2Cl2, –78 °C
H
RM
O
O
O
H
10
S
N
92%
N
11
(major)
O
S
H
OH
O
H
Ar
Ar
N
H
R
p-Ts
favored TS 13a
(Re face attack of nucleophile is favored)
14d
Scheme 3 Synthesis of N-tosylprolinal 10
Scheme 2 Proposed rationale for the observed diastereoselectivity
Table 1 Optimization of PhMgBr Addition to 10a
As proposed, at the outset, we carried out a large-scale
synthesis of N-tosyl-L-prolinal (10) from L-proline in 87%
overall yield starting from L-proline, as shown in Scheme 3.
We found that direct reduction of 14c afforded only 69%
yield of N-tosyl-L-prolinal (10). Thus, we adopted a two-
step synthesis of 10 from ester 14c involving reduction of
the ester using LiAlH4 followed by Swern oxidation (Scheme
3).
PhMgBr, solvent
temp, time
H
H
H
Ph
O
Ph
+
N
N
N
up to 92%
dr up to >24:1
H
OH
OH
p-Ts
p-Ts
p-Ts
15a
16a
10
(major)
(minor)
Entry
Solvent Temp (°C)
Time (h)
Yield (%)b
dr
With N-tosyl-L-prolinal 10 in hand, we then carried out
PhMgBr addition to 10 in different solvents and at different
temperatures (Table 1). After optimization (entries 1–8), we
found that the reaction afforded 15a as the major diastereo-
mer in up to 92% yield with ca. 24:1 dr, when it was carried
out in THF at –78 °C (entry 8). The X-ray crystal structure of
15a unambiguously proved the formation of the major dia-
stereoisomer (Figure 3).
1
2
3
4
5
6
7
8
THF
Et2O
THF
Et2O
THF
THF
THF
THF
0
1
1
2
2
3
3
3
4
89
75
81
70
82
84
86
92
ca. 10:1
ca. 9:1
0
–10
–10
–30
–50
–70
–78
ca. 12:1
ca. 10:1
ca. 15:1
ca. 16:1
ca. 20:1
ca. 24:1
a Reaction conditions: 10 (1.0 mmol), PhMgBr (1.3 equiv), THF (4 mL).
b Isolated yield after column chromatography.
Interestingly, PhMgBr addition to N-tosyl-L-prolinal 10
could be carried out on a 5 g scale, which afforded major di-
astereomer 15a with similar efficiency (90% yield with ca.
24:1 dr). We then tested Grignard reagent addition to N-to-
syl-L-prolinal 10 (Scheme 4). To our delight, methyl and al-
lylmagnesium bromide addition afforded products 15b and
15c in 82–87% yields with up to ca. 8.3:1 dr.27,28 Vinylmag-
Figure 3 X-ray crystal structure of 15a (CCDC 1405916)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 215–220

218
S. Chaudhuri et al.
Letter
Synlett
nesium bromide addition also furnished product 15d in
84% isolated yield with ca. 16:1 dr. Importantly, products
15c and 15d could be used as starting material for the syn-
thesis of a variety of pyrrolizidine alkaloids that are of im-
mense biological importance.29,30 Under the optimized con-
ditions, ethynylmagnesium bromide also added to N-tosyl-
L-prolinal 10 to afford product 15e in 78% yield with ca.
9.8:1 dr. The latter can be utilized in organic synthesis by
exploiting the reactivity of the acetylinic functionality.
PhMgBr, THF, –78 °C to r.t., 6 h
90%, dr >24:1
H
H
Ph
O
N
N
H
OH
p-Ts
p-Ts
5 g scale
15a
10
Mg, MeOH
sonication
25 °C, 0.5 h
CbzCl, NaHCO3
toluene, H2O, 10 min
H
H
Ph
Ph
H
H
RMgBr, THF
–78 °C, 4 h
H
R
O
R
87% over
2 steps
N
N
H
+
N
N
N
OH
OH
Cbz
up to 92%
dr up to ∼24:1
H
OH
OH
18
p-Ts
p-Ts
p-Ts
17
15a–e
(major)
16a–e
(minor)
10
K2CO3
K2CO3, BnBr
MeCN, 70 °C, 1 h
LiAlH4, THF
70 °C, 10 h
allylbromide
MeCN, 70 °C, 1 h
H
H
H
Ph
Me
N
N
p-Ts
15b
87%
dr = ∼8.3:1
N
H
H
H
Ph
Ph
Ph
OH
OH
OH
p-Ts
p-Ts
15c
82%
dr = ∼4.6:1
N
N
N
15a
92%
dr = ∼24:1
OH
OH
OH
Bn
Me
2c
79%
2b
76%
2a
81%
H
H
Scheme 5 Stereoselective syntheses of proline-based vicinal aminoal-
cohols 2a–c
N
N
OH
OH
p-Ts
15d
84%
dr = ∼16:1
p-Ts
15e
78%
dr = ∼9.8:1
Furthermore, to access enantiomeric pairs of proline-
based vicinal aminoalcohols 2a–c, we synthesized N-tosyl-
D-prolinal ent-10 from D-proline by following the route pre-
sented in Scheme 3 (see the Supporting Information for de-
tails). As expected, phenylmagnesium addition to N-tosyl-
D-prolinal ent-10 afforded ent-15a with similar efficiency
(Scheme 6). Vicinal aminoalcohol ent-15a was further elab-
orated to access ent-18 and ent-2a–c with similar efficien-
cies (see the Supporting Information for details).
Scheme 4 Substrate scope of 1,2-addition. Reagents and conditions: 10
(1.0 mmol), Grignard reagent (1.3 equiv), THF (5 mL), –78 °C. Isolated
yield after column chromatography.
To make the strategy more synthetically useful, we be-
came interested in cleaving the N-tosyl protecting group of
15a. To this end, 15a was treated with Mg in MeOH to af-
ford secondary aminoalcohol 17, which was further reacted
with CbzCl to afford 18 in 87% yield in two steps. Carbamate
18 was reduced in the presence of lithium aluminum hy-
dride to afford aminoalcohol 2a in 81% yield (Scheme 5). In
another sequence, crude amino alcohol 17 was reacted di-
rectly with alkylhalides in the presence of K2CO3 in acetoni-
trile to afford aminoalcohols 2b and 2c in 76 and 79% yield,
respectively. Interestingly, (2S,3R)-2-phenyl-3-hydroxyp-
iperidine is known to be an intermediate for the synthesis
of (2R,3R)-trans-3-hydroxypipecolic acid 4a (Scheme 1) as
reported by Cossy et al.19c
(a) Mg, MeOH
PhMgBr, THF
H
H
H
(b) CbzCl
Ph
O
Ph
–78 °C, 4 h
NaHCO3
N
N
N
H
91%
dr = 24:1
OH
85% over
2 steps
OH
p-Ts
p-Ts
Cbz
ent-15a
ent-10
ent-18
H
ent-2a R = Me, 76%
ent-2c R = Bn, 78%
ent-2b R = allyl, 79%
Ph
N
R
OH
ent-2a–c
Scheme 6 Stereoselective synthesis of ent-2a–c from D-proline
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 215–220

219
S. Chaudhuri et al.
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Synlett
In conclusion, N-tosyl-L-prolinal 1031 has been identi-
fied as a good substrate for 1,2-addition of Grignard re-
agents to afford a variety of vicinal amino alcohols 15a–c.
The N-tosyl group of 15a can be removed efficiently by us-
ing Mg in MeOH at room temperature to afford N-alkyl ami-
noalcohols 2a–c. We have also synthesized ent-2a–c with
similar efficiency from N-tosyl-D-prolinal ent-10. These
substrates are important precursors for the synthesis of
2,3-disubstituted piperidines. Further studies to extend the
application of this methodology to the synthesis of natural-
ly occurring alkaloids are currently under active investiga-
tions in our laboratory.
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Acknowledgment
A.B. thanks the SERB, Department of Science and Technology (DST),
India, for generous funding. We also thank the BRNS, Department of
Atomic Energy (DAE) for a research grant through a Young Scientist
Research Award (YSRA). S.C. thanks the UGC for a senior Research Fel-
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560802.
S
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(4) For the isolation of symplostatin 1, see: Harrigan, G. G.; Luesch,
H.; Yoshida, W. Y.; Moore, R. E.; Nagle, D. G.; Paul, V. J.;
Mooberry, S. L.; Corbett, T. H.; Valeriote, F. A. J. Nat. Prod. 1998,
61, 1075.
(5) For the isolation of malevamide D, see: Horgen, F. D.;
Kazmierski, E. B.; Westenburg, H. E.; Yoshida, W. Y.; Scheuer, P.
J. J. Nat. Prod. 2002, 65, 487.
(6) For auristatins, see: Pettit, G. R.; Hogan, F.; Toms, S. J. Nat. Prod.
2011, 74, 962.
(7) Maderna, A.; Doroski, M.; Subramanyam, C.; Porte, A.; Leverett,
C. A.; Vetelino, B. C.; Chen, Z.; Risley, H.; Parris, K.; Pandit, J.;
Varghese, A. H.; Shanker, S.; Song, C.; Sukura, S. C. K.; Farley, K.
A.; Wagenaar, M. M.; Shapiro, M. J.; Musto, S.; Lam, M.-H.;
Loganzo, F.; O’Donnell, C. J. J. Med. Chem. 2014, 57, 10527.
(22) (a) Barrett, A. G. M.; Damiani, F. J. Org. Chem. 1999, 64, 1410.
(b) Konradi, A. W.; Kemp, S. J.; Pedersen, S. F. J. Am. Chem. Soc.
1994, 116, 1316.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 215–220

220
S. Chaudhuri et al.
Letter
Synlett
(23) (a) Soai, K.; Ookawa, A. J. Chem. Soc., Chem. Commun. 1986, 412.
(b) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc.
1987, 109, 7111. (c) Klein, G.; Pandiaraju, S.; Reiser, O. Tetrahe-
dron Lett. 2002, 43, 7503.
(film): 3503, 1654, 1561, 1402, 1331, 1159, 1059, 983, 662 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for [C13H20NO3S]+: 270.1158;
found: 270.1181. [α]D22.2 –64.6 (c = 0.47, CH2Cl2).
(R)-1-[(S)-1-Tosylpyrrolidin-2-yl]but-3-en-1-ol
[(–)-15c)]:
(24) (a) Funabiki, K.; Shibata, A.; Iwata, H.; Hatano, K.; Kubota, Y.;
Komura, K.; Ebihara, M.; Matsui, M. J. Org. Chem. 2008, 73, 4694.
(b) Marquez, F.; Montoro, R.; Llebaria, A.; Lago, E.; Molins, E.;
Delgado, A. J. Org. Chem. 2002, 67, 308. (c) Pettit, G. R.; Grealish,
M. P. J. Org. Chem. 2001, 66, 8640. (d) Pettit, G. R.; Singh, S. B.;
Herald, D. L.; Lloyd-Williams, P.; Kantoci, D.; Burkett, D. D.;
Barkóczy, J.; Hogan, F.; Wardlaw, T. R. J. Org. Chem. 1994, 59,
6287. (e) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem.
Soc. 1987, 109, 7111. (f) Soai, K.; Ookawa, A. Chem. Commun.
1986, 412.
Colorless oil; Rf 0.43 (EtOAc–hexane, 20%). 1H NMR (400 MHz,
CDCl3): δ = 7.67 (d, J = 8.23 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H),
5.80–5.90 (m, 1 H), 5.07–5.13 (m, 2 H), 4.05–4.09 (m, 1 H),
3.49–3.53 (m, 1 H), 3.26–3.38 (m, 2 H), 2.39 (s, 3 H), 2.14–2.26
(m, 2 H), 1.83–1.92 (m, 1 H), 1.70–1.77 (m, 1 H), 1.50–1.58 (m,
1 H), 1.22–1.31 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 143.7,
134.8, 134.1, 129.8, 127.7, 127.6, 117.4, 72.2, 64.4, 50.3,
37.8, 25.8, 24.6, 21.5. HRMS (ESI): m/z [M + H]+ calcd for
22.8
[C15H22 NO3S]+: 296.1315; found: 296.1336. [α]D
–90.3 (c =
0.43, CH2Cl2).
(25) (a) Bejjani, J.; Chemla, F.; Audouin, M. J. Org. Chem. 2003, 68,
9747. (b) For use of 9e in total synthesis, see: Liu, P.; Hong, S.;
Weinreb, S. M. J. Am. Chem. Soc. 2008, 130, 7562.
(26) MeMgBr addition to 4-(S)-TBS-protected-N-tosyl-D-prolinal
afforded the products in 1.32:1 dr, see: Remuzon, P.; Bouzard,
D.; Guiol, C.; Jacquet, J.-P. J. Med. Chem. 1992, 35, 2898.
(27) The diastereoselectivities in case of allylmagnesium halide
addition to N-trityl-L-prolinal (9e) afforded the products with
<2:1 dr [see ref. 25a].
(28) Addition of Grignard Reagents to the Aldehyde; General Pro-
cedure: To a stirred solution of crude 10 (253 mg, 1.0 mmol, 1.0
equiv) in anhydrous THF at –78 °C was added RMgBr (1.3 mmol,
1.3 equiv) slowly over a period of 5 min, and stirring was con-
tinued for 4 h. The reaction was quenched with sat. aq NH4Cl (2
mL) and extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The crude mixture was
purified by column chromatography to afford the desired
product 15.
(R)-1-[(S)-1-Tosylpyrrolidin-2-yl]prop-2-en-1-ol [(–)-15d)]:
Colorless gel; Rf 0.49 (EtOAc–hexane, 20%). 1H NMR (400 MHz,
CDCl3): δ = 7.69–7.71 (m, 2 H), 7.30 (d, J = 7.95 Hz, 2 H), 5.79–
5.86 (m, 1 H), 5.30–5.36 (dt, J = 17.27, 1.58 Hz, 1 H), 5.17–5.21
(dt, J = 10.56, 1.55 Hz, 1 H), 4.46 (br, 1 H), 3.59–3.63 (m, 1 H),
3.26–3.39 (m, 2 H), 2.96 (d, J = 4.61 Hz, 1 H), 2.4 (s, 3 H), 1.70–
1.83 (m, 2 H), 1.53–1.62 (m, 1 H), 1.22–1.30 (m, 1 H). 13C NMR
(100 MHz, CDCl3): δ = 143.9, 136.4, 134.0, 129.8, 127.6, 116.8,
74.5, 64.6, 50.6, 26.7, 24.5, 21.5; IR (film): 3584, 3099, 2981,
2059, 1870, 1655, 1544, 1474, 1154, 933 cm–1. HRMS (ESI): m/z
[M + H]+ calcd for [C14H19NO3S]+: 282.1158; found: 282.1178.
[α]D27.0 –102.24 (c = 0.0352, MeOH).
(R)-1-[(S)-1-Tosylpyrrolidin-2-yl]prop-2-yn-1-ol [(–)-15e)]:
White crystalline solid; Rf 0.47 (EtOAc–hexane, 20%). 1H NMR
(500 MHz, CDCl3): δ = 7.71 (d, J = 8.07 Hz, 2 H), 7.31 (d, J =
7.97 Hz, 2 H), 4.67 (br, 1 H), 3.67–3.70 (m, 1 H), 3.45–3.50 (m,
1 H), 3.42 (br s, 1 H), 3.29–3.34 (m, 1 H), 2.43 (d, J = 1.96 Hz,
1 H), 2.42 (s, 3 H), 1.96–2.0 (m, 1 H), 1.85–1.93 (m, 1 H), 1.73–
1.80 (m, 1 H), 1.70 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ =
144.0, 133.9, 129.9, 127.6, 81.8, 74.4, 65.3, 64.3, 50.9, 27.9, 24.5,
21.6; IR (film): 3500, 3110, 2270, 1460, 1420, 1339, 1158,
(R)-Phenyl [(S)-1-Tosylpyrrolidin-2-yl] methanol [(–)-15a)]:
White crystalline solid; Rf 0.51 (EtOAc–hexane, 20%). 1H NMR
(400 MHz, CDCl3): δ = 7.74 (d, J = 8.25 Hz, 2 H), 7.38 (m, 2 H),
7.29–7.32 (m, 4 H), 7.20–7.24 (m, 1 H), 5.22 (m, 1 H), 3.76–3.80
(m, 1 H), 3.29–3.35 (m, 2 H), 3.21–3.27 (m, 1 H), 2.39 (s, 3 H),
1.77–1.86 (m, 1 H), 1.51–1.60 (m, 1 H), 1.14–1.32 (m, 2 H). 13C
NMR (100 MHz, CDCl3): δ = 143.9, 140.6, 134.0, 129.9, 128.2,
127.7, 127.4, 126.2, 75.0, 66.1, 50.6, 25.7, 24.4, 21.6. IR (film):
3499, 3120, 2980, 1795, 1654, 1560, 1510, 1499, 1475, 1460,
1094 cm–1. HRMS (ESI): m/z [M + Na]+ calcd for [C14H17NO3S +
Na]+: 302.0821; found: 302.0845. [α]D
–105 (c = 0.042,
20.7
MeOH).
(29) (a) Tasso, B.; Novelli, F.; Sparatore, F.; Fasoli, F.; Gotti, C. J. Nat.
Prod. 2013, 76, 727. (b) El-Naggar, M.; Piggott, A. M.; Capon, R. J.
Org. Lett. 2008, 10, 4247. (c) Vargas-Sanchez, M.; Couty, F.;
Evano, G.; Prim, D.; Marrot, J. Org. Lett. 2005, 7, 5861. (d) Snider,
B. B.; Gao, X. Org. Lett. 2005, 7, 4419. (e) Roche, C.; Delair, P.;
Greene, A. E. Org. Lett. 2003, 5, 1741.
930, 750 cm–1
.
HRMS (ESI): m/z [M
+
H]+ calcd for
20.7
[C18H22NO3S]+: 332.1315; found: 332.1333. [α]D
–156.4 (c =
0.042, MeOH).
(30) (a) Pyrrolizidine alkaloids, see: Robertson, J.; Stevens, K. Nat.
Prod. Rep. 2014, 31, 1721; and references cited. (b) For a review
on indolizidine alkaloids, see: Michael, J. P. Nat. Prod. Rep. 2008,
25, 139; and references cited therein.
(31) For the use of N-tosyl-l-prolinal (10) in organic synthesis, see:
Zhang, Z.; Wang, F.; Mu, X.; Chen, P.; Liu, G. Angew. Chem. Int.
Ed. 2013, 52, 7549.
(R)-1-[(S)-1-Tosylpyrrolidin-2-yl]ethanol [(–)-15b)]: Colorless
oil; Rf 0.40 (EtOAc–hexane, 20%). 1H NMR (400 MHz, CDCl3): δ =
7.68 (d, J = 8.12 Hz, 2 H), 7.29 (d, J = 8.01 Hz, 2 H), 4.15 (m, 1 H),
3.44–3.48 (m, 1 H), 3.27–3.37 (m, 2 H), 2.67 (br, 1 H), 2.39 (s,
3 H), 1.67–1.87 (m, 2 H), 1.50–1.62 (m, 1 H), 1.22–1.31 (m, 1 H),
1.12 (d, J = 6.45 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 143.8,
134.1, 129.8, 127.6, 69.0, 65.8, 50.5, 26.1, 24.5, 21.5, 18.4. IR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 215–220