A rapid and general method for the asymmetric synthesis of 2-substituted pyrrolidines using tert-butanesulfinamide

Article abstract of DOI:10.1039/b502080h

A new method for the asymmetric synthesis of 2-substituted pyrrolidines in three steps from commercially available starting materials is described. Addition of the Grignard reagent prepared from 2-(2-bromoethyl)-1,3-dioxane to N-tert-butanesulfinyl aldimines proceeds in high yields and with good diastereoselectivities. The sulfinamide products are then cleanly converted into pyrrolidines in one step. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b502080h

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A R T I C L E
A rapid and general method for the asymmetric synthesis of
2-substituted pyrrolidines using tert-butanesulfinamide
Kristin M. Brinner† and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Chemistry Department, University of
California, Berkeley, CA 94720, USA.
E-mail: kristin_brinner@chiron.com, ellman@cchem.berkeley.edu; Fax: +1 510 642 8369;
Tel: +1 510 642 4488
Received (Pittsburgh, PA, USA) 8th March 2005, Accepted 11th April 2005
First published as an Advance Article on the web 4th May 2005
A new method for the asymmetric synthesis of 2-substituted pyrrolidines in three steps from commercially available
starting materials is described. Addition of the Grignard reagent prepared from 2-(2-bromoethyl)-1,3-dioxane to
N-tert-butanesulfinyl aldimines proceeds in high yields and with good diastereoselectivities. The sulfinamide products
are then cleanly converted into pyrrolidines in one step.
a variety of Grignard reagents 2a–d (R2 = -(CH2)2-, Me, Et,
Introduction
-(CH2)3-, respectively) with different acetal protecting groups
Pyrrolidines are an important class of biologically active com-
should readily be accessible from commercially available alkyl
pounds as they are found in a wide variety of natural products1
bromides, allowing for optimization of yield and diastereose-
and pharmaceuticals.2 As a result, the synthesis of pyrrolidines
lectivity as necessary. Simultaneous cleavage of the acetal and
has been an active area of research. Substituted pyrrolidines are
sulfinamide protecting groups under acidic conditions would
accessed through a variety of routes. Cycloadditions have been
affect cyclization to form pyrrolines 4, which would afford the
final pyrrolidine product 5 upon reduction. Ideally, these two
transformations could occur in one step, to rapidly access the
pyrrolidine products.
exploited for the synthesis of highly functionalized pyrrolidines.3
Intramolecular addition of nucleophiles into imines can also be
used to construct pyrrolidines.4 Additionally, nitroalkanes and
azides have been used in a variety of routes.5 2-Alkylpyrrolidines
N-Sulfinyl aldimines 1 were prepared by standard Ti(OEt)4
were synthesized via asymmetric alkylation of a chiral for-
condensation conditions.14 Initial reaction of N-sulfinyl ben-
mamidine derived from from L-valinol,6 or preparation from 3-
zaldimine 1a (R1 = Ph) with Grignard reagent 2a (R2 = -(CH2)2-)
acylpropionic acids and phenylglycinol.7 Finally, intramolecular
at −48 ◦C afforded the desired sulfinamide product in good yield
nucleophilic addition of carbon- and nitrogen-based nucle-
and diastereoselectivity (entry 1, Table 1). However, upon addi-
ophiles are utilized to afford variously substituted pyrrolidines.8
tion of this Grignard reagent to N-sulfinyl phenylacetaldimine
tert-Butanesulfinamide chemistry has been extensively ex-
1b (R1 = Bn), a complex mixture of compounds was observed
ploited for the asymmetric synthesis of amines, including a-
(entry 2). Because phenylacetaldimines are sensitive to competi-
branched and a,a-dibranched amines,9 b-amino acids,10 b-
tive a-deprotonation, this result was not surprising. Reactions of
amino alcohols11 and 1,2-amino alcohols.12 Here we report
this sort are typically carried out in non-coordinating solvents to
an efficient asymmetric synthesis of 2-substituted pyrrolidines
5 from simple, commercially available starting materials. This
particular class of pyrrolidines is pharmaceutically relevant,
increase the reactivity of the Grignard reagent towards addition
rather than deprotonation. Unfortunately, no initiation of
Grignard reagent 2a (R2 = -(CH2)2-) was observed in Et2O, even
as over 200 compounds containing this pharmacophore are
when using highly activated Rieke magnesium.15 Initial attempts
currently in advanced biological testing.13
to improve the addition of Grignard reagent 2a (R2 = -(CH2)2-)
to aldimine 1b (R1 = Bn) in THF through the use of additives,
Results and discussion
including AlMe3, BF3·OEt2, ZnCl2 and MgBr2, also did not
prove useful. Given these issues, the capacity of alternative
Grignard precursors to initiate in Et2O was next investigated.
While Grignard reagents 2b (R2 = Me) and 2c (R2 = Et) did
not form in Et2O, 2-(2-bromoethyl)-1,3-dioxane successfully
Synthesis of pyrrolidines
We envisioned the synthesis of pyrrolidines starting with addi-
tion of Grignard reagent 2 to N-sulfinyl aldimines 1 (Scheme 1).
Because the R1 group of aldimine 1 becomes the 2-substituent
in chiral pyrrolidine 5, the commercial availability of over 3000
aldehydes allows for diverse inputs at this position. Additionally,
Table 1 Synthesis of sulfinamide 3a
Entry R1
R2
Solvent Yield (%)a dr
1
2
3
4
5
6
Ph
Bn
Ph
Bn
-(CH2)2- THF
-(CH2)2- THF
-(CH2)3- THF
-(CH2)3- Et2O
85
—
95
82
81
Quant.
90 : 10b
—
90 : 10b
88 : 12b
92 : 8c
CH2CH2Ph -(CH2)3- THF
i-Pr -(CH2)3- THF
>90 : 10d
a Yield of purified material. b Determined by HPLC analysis of crude,
filtered reaction material. c Determined by LCMS analysis of crude,
filtered reaction material. d Determined by LCMS. The lack of any
significant chromophores in this molecule made precise determination
of dr difficult. The minor diastereomer was not observed in the NMR
of the unpurified addition product.
Scheme 1 Synthesis of pyrrolidines.
† Current address: Chiron Corporation, Emeryville, CA 94608, USA.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 0 9 – 2 1 1 3
2 1 0 9
©

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initiated in Et2O. Grignard reagent 2d (R2 = -(CH2)3-) added
cleanly to N-sulfinyl aldimines in both THF and Et2O (entries
3–6). Additionally, Grignard reagent 2d (R2 = -(CH2)3-) formed
much more cleanly than 2a (R2 = -(CH2)2-) in THF, which
was plagued by the production of significant amounts of Wurtz
coupled product, as well as a precedented cyclopropyl ether
byproduct.16
Table 3 Synthesis of pyrrolidines 5
Entry
R
Compound
Yield (%)a
1
2
3
4
Ph
Bn
5a
5b
5c
5d
92
84
63
48
CH2CH2Ph
i-Pr
With the desired sulfinamide intermediates 3 synthesized,
conditions were developed to affect acidic deprotection and
reduction to afford the final pyrrolidine products. Conversion of
sulfinamides 3 to pyrrolidines 5 proceeded in good yield using
1 : 1 EtOH : H2O, 10% TFA and 10 mol% PtO2 under a H2
atmosphere (eqn. 1).17 However, it was difficult to remove all
traces of platinum byproducts that visibly contaminated the
pyrrolidine products. Aqueous workups, column chromatog-
raphy and scavenging using sulfonic acid resin all failed to
completely remove platinum from the pyrrolidines.
a Yield of purified HCl salt of pyrrolidine.20
group.21 Intramolecular chelation of the acetal could explain the
reversal in diastereoselectivity.22
Mechanism of pyrroline formation
Pyrroline 6 was a surprising byproduct of the unoptimized
reaction conditions for the deprotection and reduction of
sulfinamide 3a. We therefore investigated the mechanism of
its formation. Formation of 4a was monitored by NMR upon
treatment of sulfinamide 3a with 95 : 5 d1TFA : D2O. In less than
15 min, pyrroline 4a was formed as the only product (eqn. 3).23
(1)
Because the presence of even trace amounts of platinum
byproducts was undesirable, alternative acidic deprotection and
reduction conditions were investigated. Reaction of sulfinamide
3a (R1 = Ph) in 95 : 5 TFA : H2O with 10 eq. of Et3SiH
gave trace amounts of the desired pyrrolidine 5a (entry 1,
Table 2).18 Surprisingly, pyrroline byproduct 6 was observed to
form as the major product of this reaction (eqn. 2). This requires
isomerization of imine 4a to imine 6. Resubjecting pyrroline 6
to the reaction conditions did not increase conversion to desired
pyrrolidine 5a. Apparently, once the imine double bond is in
conjugation with the phenyl ring, Et3SiH is not a strong enough
reducing agent to affect conversion to 5a. Varying the relative
concentrations of sulfinamide 3a and Et3SiH in 95 : 5 TFA :
H2O, the ratio of TFA to H2O or the use of other cosolvents did
not resolve this issue.
(3)
It has previously been observed that the deprotection of
sulfinamides in 95 : 5 TFA : H2O is not complete after even
24 h.24 Rapid formation of 4a suggests that sulfinamide 3a
is being activated in some manner to dramatically accelerate
deprotection of the N-sulfinyl group. Therefore, the following
mechanism is proposed (Scheme 2). TFA mediates the formation
of transient N-sulfinyl pyrroline 7 through acidic cleavage of the
acetal. There are then two likely pathways for the formation of
pyrrolines 4a and 6 from this intermediate. Firstly, water could
cleave the sulfinyl group to afford pyrroline 4a (pathway A).
This was supported in the NMR experiments as sulfinamide
3a rapidly converts to 4a in 95 : 5 TFA : H2O. Under
the optimized stepwise conditions, pyrroline 4a would then
be reduced upon addition of Et3SiH to afford the desired
pyrrolidine 5a. Alternatively, when Et3SiH is present at the outset
of the reaction, Et3SiH could intercept and reduce the highly
activated N-sulfinyl pyrroline 7 before it reacted with water, to
afford N-sulfinyl pyrrolidine 8 (pathway B). Sulfinamide 8 could
(2)
In order to determine the potential role of the solvent in the
isomerization, experiments were run where the sulfinamide was
dissolved in 95 : 5 TFA : H2O and the Et3SiH was added after a
set period of time. The unexpected results of this experiment
revealed that waiting even 2 min between addition of TFA
and Et3SiH almost entirely eliminated the formation of 6 and
after 10 min the formation of 6 was not observed (entries 3
and 4, Table 2). Using these optimized deprotection/reduction
conditions, 5a–5d were successfully synthesized (Table 3).19
Conversion of sulfinamides 3a and 3b to pyrrolidines 5a and
5b and comparison to literature optical rotation values revealed
that the addition of Grignard 2d proceeded with the opposite
sense of induction typically observed for Grignard additions
to sulfinyl aldimines. This reversal in selectivity has previously
been observed when the sulfinyl aldimine bears a coordinating
Table 2 Optimization of conditions for converting 3a to pyrrolidine 5a
Entry
Time/mina
Ratio 6 : 5ab
1
2
3
4
0
2
10
30
94 : 6
8 : 92
0 : 100
0 : 100
a 3a was dissolved in 95 : 5 TFA : H2O, with time indicating the period
of time between addition of TFA : H2O and Et3SiH. b Ratio determined
by NMR after aqueous workup of crude reaction material.
Scheme 2 Potential mechanism of formation of pyrroline 6.
2 1 1 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 0 9 – 2 1 1 3

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then form pyrroline 6 through an unknown reaction mechanism.
This pyrroline is not reactive to Et3SiH, as resubjecting pyrroline
6 to the reaction conditions does not affect any reduction to
pyrrolidine 5a.
Evidence for pathway B was supported by independent
synthesis of 8 (Scheme 3). After separation, the diastereomers
8-(R,R) and 8-(S,R) were individually subjected to the 95 : 5
TFA : H2O and Et3SiH reaction conditions. While diastereomer
8-(S,R) was converted to pyrrolidine 5a, diastereomer 8-(R,R)
was converted to pyrroline 6, presumably through a concerted
elimination mechanism (eqn. 4).25
in the reaction flask and subsequently suspended in THF (3.0
M). 2-(2-Bromoethyl)-1,3-dioxane (5.0 eq., 3.0 M in THF) was
added dropwise. The reaction mixture was periodically cooled
in a rt water bath to prevent refluxing. After addition of the 2-
(2-bromoethyl)-1,3-dioxane solution was complete, the reaction
mixture was stirred for 1 h. The solution was then transferred
to a different flask to remove the remaining Mg and was cooled
to −48 ◦C. Upon cooling, a small amount of precipitate may
be observed. N-tert-Butanesulfinyl imines (1 M in THF) were
added dropwise to the◦Grignard solution, the solution was
stirred for 12 h at −48 C and then was slowly warmed to rt.
The reaction mixtures were then quenched with sat. NH4Cl(aq)
and extracted with EtOAc (× 3). The combined organic layers
were dried (Na2SO4), concentrated and the products purified to
diastereomeric purity by column chromatography (2 : 1 hexanes :
EtOAc, to 100% EtOAc) to afford the sulfinamide products as
colorless waxy solids. The diastereomeric ratio was determined
by HPLC analysis of crude, filtered material.
From N-sulfinyl aldimine 1 (R1 = Ph, 345 mg, 1.65 mmol),
sulfinamide 3a (R1 = Ph, 507 mg, 1.56 mmol, 95%) was obtained.
◦
Mp 82–84 C. IR 3303, 1136, 1053, 1002 cm−1. 1H NMR
(300 MHz, CDCl3) d 1.21 (s, 9H), 1.26 (m, 1H), 1.31–1.55 (m,
2H), 1.80 (m, 1H), 2.10 (m, 2H), 3.42 (d, J = 3.9, 1H), 3.69 (m,
2H), 4.03 (m, 2H), 4.33 (m, 1H), 4.44 (t, J = 5.1, 1H), 7.25 (m,
5H). 13C NMR (125 MHz, CDCl3) d 22.6, 25.6, 30.8, 31.3, 55.6,
Scheme 3 Evidence for proposed mechanism of pyrroline formation 6.
58.9, 66.7, 101.6, 127.1, 127.7, 128.6, 142.1. HPLC (Microsorb
−1
˚
100 A SiO2, 90 : 10 hexanes : EtOAc, 1 mL min ): major,
16.8 min; minor, 25.5 min, 90 : 10 dr. HRMS (FAB+) calcd
for C17H28N1O3S1 [M + H] 326.178990; found, 326.178991. [a]D25
−46.7 (c 1.04, CHCl3).
From N-sulfinyl aldimine 1 (R1 = CH2CH2Ph, 390 mg, 1.65
mmol), sulfinamide 3c (R1 = CH2CH2Ph, 470 mg, 1.33 mmol,
81%) was obtained. Mp 60–61 ◦C. IR 3300, 1140, 1045,
(4)
1
1009 cm−1. H NMR (300 MHz, CDCl3) d 1.13 (s, 9H), 1.24
In conclusion, a rapid and general method for the asym-
metric synthesis of 2-substituted pyrrolidines using tert-
butanesulfinamide is described. The mechanism of formation
of a surprising byproduct under unoptimized conditions for
the deprotection and reduction step was also investigated. This
byproduct could be completely eliminated by straightforward
modification of the reaction conditions to provide pyrrolidines
in three steps from commercially available aldehydes and 2-(2-
bromoethyl)-1,3-dioxane.
(m, 1H), 1.51–1.88 (m, 7H), 2.63 (t, J = 7.5, 2H), 3.17 (m, 1H),
3.26 (m, 1H), 3.63 (m, 2H), 3.99 (dd, J = 4.5, 11.5, 2H), 4.42 (m,
1H), 7.09–7.21 (m, 5H). 13C NMR (125 MHz, CDCl3) d 22.6,
25.6, 29.8, 31.1, 31.7, 37.9, 55.9, 56.3, 66.8, 101.9, 125.8, 128.3,
128.4, 141.5. LCMS (Eclipse XDB-C8, 5lm, 40 : 60 to 95 : 5
MeCN : H2O, 0.1% TFA, 1 mL min−1): major, 7.3 min; minor,
8.0 min, dr 92 : 8. HRMS (FAB+) calcd for C19H32NO3S [M +
H] 354.209790; found, 354.210291. [a]2D5 −40.8 (c 1.06, CHCl3).
From N-sulfinyl aldimine 1 (R1 = i-Pr, 290 mg, 1.65 mmol),
sulfinamide 3d (R1 = i-Pr, 500 mg, 1.65 mmol, quant.) was
obtained. IR 3259, 1142, 1051, 999 cm−1. 1H NMR (300 MHz,
CDCl3) d 0.77 (d, J = 6.5, 3H), 0.77 (d, J = 7.0, 3H), 1.17 (s, 9H),
1.27 (m, 1H), 1.30 (m, 1H), 1.41 (m, 1H), 1.59 (m, 1H), 1.82–1.92
(m, 2H), 2.88 (m, 1H), 3.15 (m, 2H), 3.58 (m, 2H), 3.92 (dd, J =
4.5, 11, 2H), 4.39 (t, J = 4.5, 1H). 13C NMR (125 MHz,
CDCl3) d 17.3, 18.4, 22.6, 25.6, 25.7, 31.7, 32.4, 56.0, 62.3,
66.7, 101.9. Dr >90 : 10. HRMS (FAB+) calcd for C14H30NO3S
[M + H] 292.194830; found 292.194641. [a]2D5 −14.8 (c 1.00,
CHCl3).
Experimental
General details
Unless otherwise noted, all reagents were obtained from
commercial suppliers and used without further purifica-
tion. Tetrahydrofuran and diethyl ether were distilled from
sodium/benzophenone ketyl, toluene from sodium and
dichloromethane from CaH2 immediately before use. All reac-
tions were carried out in flame or oven dried glassware under
a nitrogen atmosphere unless indicated otherwise. Chromatog-
raphy was carried out using Merck 230–400 mesh silica gel.
IR spectra were recorded on a Nicolet Avatar 370 DTGS
spectrometer using single bounce HATR on a ZnSe crystal,
only partial data is reported. HPLC analysis was performed
on a HP HPLC. Data for 1H NMR are reported as shift
(ppm), multiplicity, coupling constant (Hz) and integration.
Data for 13C NMR are reported as chemical shift (ppm). Mass
spectra were obtained from the University of California at
the Berkeley Micro-Mass facility. tert-Butanesulfinamide and
tert-butanesulfinyl imines (1a-d) were prepared as previously
described.14
Sulfinamide 3b (R1 = Bn). Freshly crushed magnesium
turnings (1.2 g, 50 mmol, 30.0 eq.) were flame dried with
catalytic amounts of I2 in the reaction flask and subsequently
were suspended in Et2O (17 mL). 2-(2-Bromoethyl)-1,3-dioxane
(2.3 mL, 17 mmol, 10.0 eq., in 5.5 mL of Et2O) was added
dropwise. The reaction mixture was periodically cooled in a rt
water bath to prevent refluxing. After the addition of the solution
of 2-(2-bromoethyl)-1,3-dioxane was complete, the reaction
mixture was stirred for 1 h. The solution was transferred to a
different flask to remove the remaining Mg and then was cooled
to −48 ◦C. Upon cooling, a small amount of precipitate may
be observed. N-tert-Butanesulfinyl imine 2 (R1 = Bn, 368 mg,
1.65 mmol, in 1.7 mL of Et2O) was added dropwise to the
Grignard solution, the resulting solution was stirred for 12 h at
−48 ◦C and then was slowly warmed to rt. The reaction mixture
was quenched with sat. NH4Cl(aq) and extracted with Et2O (× 3).
The combined organics were dried (Na2SO4), concentrated
General procedure for addition of Grignard reagent 2 (R =
-(CH2)3-) to N-tert-butanesulfinyl imines 1
(R1 = Ph, CH2CH2Et, i-Pr). Freshly crushed magnesium turn-
ings (15.0 eq.) were flame dried with catalytic amounts of I2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 0 9 – 2 1 1 3
2 1 1 1

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and the product purified to diastereomeric purity by column
chromatography (2 : 1 hexanes : EtOAc to 100% EtOAc) to
afford 3b (460 mg, 1.36 mmol, 82%) as a colorless, waxy solid.
The diastereomeric ratio was dete◦rmined by HPLC analysis of
crude, filtered material. Mp 91–92 C. IR 3139, 1140, 1049 cm−1.
1H NMR (300 MHz, CDCl3) d 1.11 (s, 9H), 1.16 (m, 1H), 1.41–
1.63 (m, 4H), 1.88 (m, 1H), 2.83 (d, J = 6.0, 2H), 3.16 (d, J =
7.8, 1H), 3.39 (m, 1H), 3.59 (m, 2H), 3.92 (m, 2H), 4.36 (t, J =
4.8, 1H), 7.11 (m, 5H). 13C NMR (125 MHz, CDCl3) d 22.6,
25.7, 28.8, 31.5, 42.5, 55.9, 56.9, 66.8, 101.9, 126.5, 128.3, 130.0,
137.1. HPLC (SiO2, 90 : 10 hexanes : EtOAc, 1 mL min−1):
major, 16.0 min; minor, 19.7 min, dr 88 : 12. HRMS (FAB+)
calcd for C18H30N1O3S1 [M + H] 340.194420; found 340.194641.
[a]2D5 −27.6 (c 1.06, CHCl3).
obtained. IR 2925 cm−1. 1H NMR (400 MHz, CDCl3) d 1.42 (m,
1H), 1.75–2.02 (m, 5H), 2.74 (m, 2H), 3.00 (m, 1H), 3.15 (m,
2H), 3.98 (s, br, 1H), 7.20–7.33 (m, 5H). 13C NMR (100 MHz,
CDCl3) d 24.9, 31.5, 33.6, 37.1, 46.0, 59.0, 125.9, 128.4, 128.4,
141.8. HRMS (FAB+) calcd for C12H18N [M + H] 176.144080;
found 176.143925. [a]2D5 −100.9 (c 1.00, MeOH).
From sulfinamide 3d (80 mg, 0.27 mmol), (R)-2-
isopropylpyrrolidine·HCl (5d) (20 mg, 0.13 mmol, 48%), was
obtained. IR 2964 cm−1. NMR of HCl salt of pyrrolidine
1
reported. H NMR (400 MHz, MeOD) d 1.05, (d, J = 6.8,
3H), 1.11 (d, J = 6.8, 3H), 1.72 (m, 1H), 1.95 (m, 3H), 2.05 (m,
1H), 3.19 (m, 1H), 3.34 (m, 2H). 13C NMR (100 MHz, MeOD)
d 19.1, 19.6, 23.7, 28.9, 31.0, 45.4, 67.4. HRMS (FAB+) calcd
for C7H15N [M + H] 114.128290; found 114.128275. [a]2D5 −9.20
(c 1.00, MeOH).
Pyrroline 4a. N-tert-Butanesulfinamide 3a (11 mg,
0.033 mmol) was dissolved in 95 : 5 d1TFA : D2O and the
reaction progress was monitored by 1H and 13C NMR. Complete
conversion to pyrroline 4a was observed at 15 min. Peaks
corresponding to the cleaved diol protecting group and the
tert-butanesulfinic acid are indicated separately. 1H NMR
(300 MHz, 95 : 5 d1TFA : D2O) d 2.45 (m, 1H), 3.02 (m, 1H),
3.46–3.60 (m, 2H), 5.65 (m, 1H), 7.31 (m, 2H), 7.51 (m, 3H),
9.02 (m, 1H). 13C NMR (125 MHz, 95 : 5 d1TFA : D2O) d 37.4,
59.4, 73.9, 127.6, 131.4, 132.0, 136.1, 183.4. HRMS (FAB+)
calcd for C10H12N [M + H] 146.097310; found 146.096974.
General procedure for the deprotection and reduction of 3a–3d to
afford 5a–5d
N-tert-Butanesulfinamides 3a–3d (1.0 eq.) were dissolved in
95 : 5 TFA : H2O to a final concentration of 0.1 M. After
stirring for 30 min, Et3SiH (10.0 eq.) was added to the reaction
solutions and the reaction mixtures were stirred vigorously
for 24 h. The reaction mixtures were concentrated and the
products were purified by column chromatography (20 : 1 : 0.1
to 10 : 1 : 0.5 CH2Cl2 : MeOH : NH4OH) to afford the free
amine products. After concentrating the column fractions, the
products were resuspended in MeOH and concentrated again to
ensure complete removal of all NH3. Resuspension in CH2Cl2
followed by addition of 1 M HCl in Et2O afforded the amine
hydrocholorides as yellow oils. NMRs are reported for the free
amine and purified yields and optical rotation are based on
the HCl salt of the amine products, except where indicated
otherwise.
1
1,3-Propanediol: H NMR (500 MHz, 95 : 5 d1TFA : D2O) d
2.34 (m, 2H), 4.61 (m, 4H). 13C NMR (125 MHz, 95 : 5 d1TFA :
D2O) d 29.9, 66.6. tert-Butanesulfinic acid: 1H NMR (500 MHz,
95 : 5 d1TFA : D2O) d 1.2 (s, 1H). 13C NMR (125 MHz, 95 : 5
d1TFA : D2O) d 21.5, 28.2.
Compounds 8-(R,R) and 8-(R,S). Pyrrolidine 5a (140 mg,
0.11 mmol, 0.2 M) was dissolved in THF (4.0 mL) and i-Pr2EtN
(300 lL, 1.7 mmol, 2.2 eq.) was added. The resulting solution
was added to a solution of THF (4.8 mL) containing DMAP
(23 mg, 0.19 mmol, 0.2 eq.), i-Pr2EtN (240 lL, 1.4 mmol,
1.5 eq.) and tert-butanesulfinyl chloride (0.47 mL, 2.0 M in
toluene, 0.95 mmol, 1.2 eq.). The resulting solution was stirred
at rt for 12 h. The reaction mixture was concentrated and
the products purified by column chromatography (4 : 1 to 2 :
1 hexanes : EtOAc) to afford 8-(R,R) (49 mg, 0.19 mmol,
25%) as a white solid and 8-(R,S) (100 mg, 0.40 mmol, 50%)
From sulfinamide 3a (91 mg, 0.28 mmol), (R)-2-
phenylpyrrolidine·HCl (5a) (45 mg, 0.25 mmol, 88%) was
1
obtained. IR 2957 cm−1. H NMR (500 MHz, CDCl3) d 1.70
(m, 1H), 1.83–1.95 (m, 2H), 2.18 (m, 1H), 2.77 (s, br, 1H), 3.00
(m, 1H), 3.19 (m, 1H), 4.10 (t, J = 7.5, 1H), 7.22–7.35 (m, 5H).
13C NMR (125 MHz, CDCl3) d 25.4, 33.9, 46.6, 62.6, 126.5,
127.0, 128.4, 143.4. HRMS (FAB+) calcd for C10H14N1 [M +
H] 148.112850; found 148.112625. [a]2D5 −9.10 (c 1.00, MeOH),
literature [a]D −22.0 (c 2.0, MeOH).7a
1
as a yellow oil. 8-(R,R): IR 1058 cm−1. H NMR (500 MHz,
To confirm optical purity, pyrrolidine 5a (7 mg, 0.05
mmol) was dissolved in CH2Cl2 (0.5 mL). The solution was
cooled to 0 ◦C and i-Pr2EtN (0.02 mL, 0.1 mmol) was
added to the solution, followed by either (R)-(+)-a-methoxy-
a-(trifluoromethyl)phenylacetyl chloride (MTPA) or (S)-(+)-a-
methoxy-a-(trifluoromethyl)phenylacetyl chloride (25 mg, 0.1
mmol). After stirring for 30 min at 0 ◦C, the solutions were
warmed to rt, diluted with CH2Cl2 and washed with 1.0 M
NaHSO4(aq). The organic layers were dried (Na2SO4) and con-
centrated to afford the MTPA amides. HPLC analysis (2.1 cm ×
5 lM Hypersil Si column, detection at 210 nm, 1 mL min−1,
98 : 2 hexanes : iPrOH) on the unpurified material established
≥99% enantiomeric excess, with the tR = 6.09 min for the amide
derived from the (R)-(+)-MTPA chloride and tR = 8.13 min for
the amide derived from the (S)-(−)-MTPA chloride.
CDCl3) d 1.10 (s, 9H), 1.77–1.90 (m, 3H), 2.13 (m, 1H), 3.57
(m, 1H), 3.67 (m, 1H), 5.06 (dd, J = 2.5, 8, 1H), 7.20–7.32
(m, 5H). 13C NMR (125 MHz, CDCl3) d 23.0, 24.1, 36.6, 54.9,
57.4, 88.7, 123.3, 126.3, 126.5, 144.6. HRMS (FAB+) calcd for
C14H22NOS [M + H] 252.141490; found, 252.142211. [a]2D5 +108.8
1
(1.00 c, CHCl3). 8-(R,S): IR 1060 cm−1. H NMR (300 MHz,
CDCl3) d 1.10 (s, 9H), 1.87 (m, 2H), 1.97 (m, 1H), 2.23 (m,
1H), 2.99 (m, 1H), 3.89 (m, 1H), 4.64 (m, 1H), 7.20–7.35 (m,
5H). 13C NMR (125 MHz, CDCl3) d 23.7, 26.3, 35.9, 42.0,
57.2, 69.2, 127.1, 127.1, 128.2, 143.2. HRMS (FAB+) calcd for
C14H22NOS [M + H] 252.141490; found 252.142211. [a]2D5 +93.6
(c 0.99, CHCl3).
Pyrroline 6. Et3SiH (0.46 mL, 2.8 mmol, 10 eq.) in 95 : 5 TFA :
H2O (2.8 mL) was added to sulfinamide 3a (92 mg, 0.28 mmol).
The reaction mixture was stirred overnight, concentrated and
the product purified by column chromatography (30 : 1 CH2Cl2 :
MeOH, 0.1% NH4OH). To remove traces of Et3SiH, the product
was dissolved in 1 M HCl(aq), washed with Et2O, brought to
basic pH with solid NaHCO3 and extracted with CH2Cl2. The
CH2Cl2 layer was dried (Na2SO4), acidified with 1 M HCl in
Et2O and concentrated to afford◦6 (20 mg, 14 mmol, 50%) as
From sulfinamide 3b (74 mg, 0.22 mmol), (R)-2-
benzylpyrrolidine·HCl (5b) (30 mg, 0.19 mmol, 84%) was
1
obtained. IR 2923 cm−1. H NMR (500 MHz, CDCl3) d 1.70
(m, 1H), 1.94 (m, 1H), 1.97 (m, 2H), 2.88 (m, 1H), 3.12 (m, 2H),
3.26 (m, 1H), 3.63 (m, 1H), 3.97 (s, br, 1H), 7.21 (m, 5H). 13C
NMR (125 MHz, CDCl3) d 22.7, 29.5, 37.4, 44.9, 61.9, 126.9,
128.6, 128.6, 136.6. HRMS (FAB+) calcd for C11H16N1 [M + H]
162.128140; found 162.128275. [a]2D5 −9.20 (c 1.00, MeOH), [a]2D5
−17.0 (c 1.00, 2 N HCl), literature [a]2D5 −15.1 (c 0.6, MeOH),26
for enantiomer [a]2D5 (20.00 (c 0.3, MeOH).7b
1
a glassy, clear solid. Mp 73–74 C. IR 1645 cm−1. H NMR
(500 MHz, MeOD) d 2.46 (m, 2H), 3.69 (m, 2H), 4.27 (m, 2H),
7.69 (m, 2H), 7.85 (m, 1H), 8.09 (m, 2H). 13C NMR (125 MHz,
MeOD) d 19.5, 35.1, 53.6, 125.9, 129.5, 130.2, 136.2, 186.1.
HRMS (FAB+) calcd for C10H12N1 [M + H] 146.097170; found
146.096974.
From sulfinamide 3c (84 mg, 0.24 mmol), (R)-2-
phenethylpyrrolidine·HCl (5c) (33 mg, 0.15 mmol, 63%), was
2 1 1 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 0 9 – 2 1 1 3

View Article Online
10 T. P. Tang and J. A. Ellman, J. Org. Chem., 2002, 67, 7819.
11 T. P. Tang, S. K. Volkman and J. A. Ellman, J. Org. Chem., 2001, 66,
8772.
Acknowledgements
This work was supported by the NSF-CHE-0139468 (J. A. E.).
The Center for New Directions in Organic Synthesis is supported
by Bristol-Myers-Squibb as a sponsoring member and Novartis
as a supporting member.
12 T. Kochi, T. P. Tang and J. A. Ellman, J. Am. Chem. Soc., 2003, 125,
11276.
13 MDL Drug Data Report, MDL Information Systems, Inc., San
Leandro, CA, 2001.
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17 These conditions had previously been used to cyclize and reduce
4-aminobutyraldehyde dimethyl acetal derivatives to afford the
pyrrolidine products. O. Poupardin, C. Greek and J. P. Genet, Synlett,
1998, 1279.
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 0 9 – 2 1 1 3
2 1 1 3