A general, enantioselective synthesis of N-alkyl terminal aziridines and C2-functionalized azetidines via organocatalysis

Article abstract of DOI:10.1016/j.tetlet.2015.01.140

A short, high-yielding protocol involving the enantioselective α-chlorination of aldehydes has been developed for the enantioselective synthesis of C2-functionalized aziridines and N-alkyl terminal azetidines from a common intermediate. This methodology allows for the rapid preparation of functionalized aziridines in 50-73% overall yields and 88-94% ee, and azetidines in 22-32% overall yields and 84-92% ee. Moreover, we developed a scalable and cost-effective route to the key organocatalyst (54% overall yield, >95% dr).

Full text of DOI:10.1016/j.tetlet.2015.01.140

Tetrahedron Letters 56 (2015) 1276–1279
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A general, enantioselective synthesis of N-alkyl terminal aziridines
and C2-functionalized azetidines via organocatalysis
Timothy J. Senter a, Matthew C. O’Reilly a, Katherine M. Chong a, Gary A. Sulikowski a, Craig W. Lindsley a,b,
⇑
a Department of Chemistry, Vanderbitl Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA
b Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A short, high-yielding protocol involving the enantioselective
a
-chlorination of aldehydes has been
Received 9 January 2015
Revised 19 January 2015
Accepted 20 January 2015
Available online 27 January 2015
developed for the enantioselective synthesis of C2-functionalized aziridines and N-alkyl terminal azeti-
dines from a common intermediate. This methodology allows for the rapid preparation of functionalized
aziridines in 50–73% overall yields and 88–94% ee, and azetidines in 22–32% overall yields and 84–92%
ee. Moreover, we developed a scalable and cost-effective route to the key organocatalyst (54% overall
yield, >95% dr).
Keywords:
Organocatalysis
Azetidine
Ó 2015 Elsevier Ltd. All rights reserved.
Aziridine
Enantioselective
Azetidines comprise an important class of nitrogen-containing
heterocycles due to both their biological significance and increas-
ing use in medicinal chemistry.1 While recent approaches have
made progress in the ability to access various types of azetidines
in an enantioselective fashion, 2-alkyl substituted azetidines are
notably scarce in the literature.2,3
Similarly, aziridines represent an important class of nitrogen-
containing heterocycles that have garnered significant interest
from the synthetic chemistry and chemical biology communities
over the past two decades.4 Aziridine’s intrinsic ring strain posi-
tions them as synthetically valuable intermediates capable of
undergoing highly regio- and stereoselective ring opening transfor-
mations.5 Additionally, the aziridine moiety is found in compounds
that possess interesting biological properties including antitumor
or antibiotic activity. Together, these properties have shown aziri-
dines to be useful synthetic intermediates and attractive targets in
medicinal chemistry and the total synthesis of natural products.6,7
We recently reported a three step, one-pot protocol involving
2-substituted azetidines through a common, configurationally-sta-
ble intermediate.
According to the seminal work of Jorgensen and coworkers for
the organocatalytic
of the -chloro aldehydes with NaBH4 to the corresponding b-
chloro alcohols 5 would occur without loss of enantioselectivity.9
We envisioned that these configurationally stable -chloro alco-
a-chlorination of aldehydes, in situ reduction
a
a
hols 5 could function as bifunctional chiral building blocks.
Essentially, we reasoned that functionalization of this common
intermediate with either an amine (Route A) or nitrile group
(Route B) followed by an intramolecular cyclization strategy could
provide access to both aziridines and azetidines (Fig. 1). As dis-
closed in our previous communication, catalyst 2 was optimal in
terms of enantioselectivity and compatibility for the purposes of
accessing the desired chloro alcohol.8,10,11 This catalyst was diffi-
cult to obtain commercially. In our hands, we found that literature
procedures to prepare 2 resulted in variable yields and an insepa-
rable mixture of our desired catalyst with the meso isomer.12,13
Recrystallization of the final product was achieved, successfully
increasing the purity of the desired isomer to >92%. However, these
conditions limited the scale and required careful temperature reg-
ulation during recrystallization. Therefore, we sought to improve
the synthesis to both increase the yield and reliability of the proto-
col, with the goal of being able to rapidly obtain the pyrrolidine
catalyst on multi-gram scale.
the enantioselective
a-chlorination of aldehydes, subsequent
reductive amination with a primary amine, followed by SN2 dis-
placement to afford chiral N-alkyl terminal aziridnes.8 Under this
protocol, yields and enantioselectivities in many cases were
moderate and variable due to epimerization of the
a-chlorinated
aldehyde 3 during reductive amination. We sought to address
these issues as well as provide a facile route to the synthesis of
We successfully optimized the synthetic route as outlined in
Scheme 1. Notably, we found that flash column chromatography
of the penultimate intermediate 10 with a 7:3 hexanes/toluene
⇑
Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 343 3088.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
http://dx.doi.org/10.1016/j.tetlet.2015.01.140
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

T. J. Senter et al. / Tetrahedron Letters 56 (2015) 1276–1279
1277
Previous work:
i. Tf2O, CH2Cl2, 0 °C
ii. R2-NH2
iii. KOH, THF/H2O
65 °C, 12 h
O
R1
2
1. Reductive
O
2
i. 10 mol%
R1
R1
R1
O
N
(10 mol%)
NCS, CH2Cl2
amination
2. Base-induced
cyclization
OH
R1
NCS, CH2Cl2
ii. NaBH4, MeOH
H
N
R2
H
R2
R1
Cl
H
1
Cl
5
4
4
1
This work:
O
(58-77%)
(81-95%)
3
40-65% yield
56-96% ee
O
O
R1
H
O
N
N
N
1
Ph
Ph
Ph
Route A
Ph
Ph
N
2
i. 10 mol%
11
12
1. Nucleophilic
displacement
2. Base-induced
cyclization
13
R1
R1
H
NCS, CH2Cl2
65%
73%
65%
2
N
ii. NaBH4, MeOH
90% ee
94% ee
92% ee
R2
Ph
N
4
R1
OH
N
1. Nucleophilic
displacement
2. Nitrile reduction,
Base-induced
cyclization
6
Cl
Ph
F
5
15
N
14
H
50%
88% ee
57%
6
92% ee
Route B
Scheme 2. Protocol for enantioselective synthesis of N-alkyl terminal aziridines.14
Figure 1. Top: first-generation organocatalytic approach for the enantioselective
synthesis of N-alkyl aziridines. Bottom: envisioned second generation organocat-
alytic approach for the enantioselective synthesis of C2-functionalized aziridines
and azetidines.
We next focused on the synthesis of the azetidines (Fig. 1, route
B), as there are very few approaches for their preparation. Starting
from the common 2-chloro alcohol intermediate, we planned to
access the b-chloro nitrile intermediates 17–21 through analogous
activation of the primary alcohol as the triflate, followed by dis-
placement with potassium cyanide. Initial conditions using potas-
sium cyanide in CH2Cl2, THF, or acetonitrile led to poor conversion
at room temperature and elimination at elevated temperature.
However, we found that potassium cyanide in acetonitrile, with
18-crown-6 as an additive, was effective in conversion to the
desired nitrile after 24 h at room temperature. Under these opti-
mized conditions, displacement of the in situ prepared triflate with
potassium cyanide facilitated formation to the desired b-chloro
nitrile 17–21 in 66–86% yield. While these products were relatively
stable at room temperature in CH2Cl2 solution, elevated tempera-
tures resulted in the formation of an elimination byproduct. Simi-
larly, the concentrated products were prone to elimination, and
decomposed within hours at room temperature (Scheme 3).
Related to the instability of the b-chloro nitriles, we found that
conventional methods to reduce the nitrile such as lithium alumi-
num hydride and hydrogenation led to either elimination or
dehalogenation of the starting material. After screening various
mild nitrile reduction conditions we found that using an indiu-
m(III) chloride–sodium borohydride system to be generally appli-
cable across substrates in excellent yield and sufficient purity to
carry forward without purification towards cyclization (Scheme 4).
H
N
OH
B(OMe)3
cat.
Ph
Ph
O
8
OH
Ph
BH3-SMe2, THF, rt
Ph
Ph
Ph
MsCl, Et3N then,
Allylamine
Ph
99%
O
7
OH
flash chromatography
7:3 hexanes/toluene
9
77%
Ph
RhCl(PPh3)3
MeCN/H2O (84:16)
N
Ph
Ph
N
H
71%
2
10
>95% dr
no detectable
meso
Scheme 1. Scalable, cost-effective synthesis of organocatalyst 2.
solvent system provided excellent separation of the desired iso-
mer. Additionally, increasing the amount of Wilkinson’s catalyst
in the allyl deprotection to 10 mol % increased the yield of the
deprotection to 71%. These improvements allowed for the gram-
scale production of catalyst 2 in >54% overall yield and <95% dr.
With the
c-chloro amine 22 in hand, we focused on the cycliza-
With sufficient organocatalyst for
a-chlorination in hand, our
tion conditions to afford the desired azetidine 6. We initially
attention was turned towards the synthesis of the aziridines. Prep-
aration of b-chloro alcohols 5 proceeded via facile asymmetric
organocatalytic chlorination and in situ sodium borohydride reduc-
tion of achiral aldehydes 1. To transform primary alcohols into
bifunctional electrophiles, the b-chloro alcohols 5 were treated
with triflic anhydride and lutidine in CH2Cl2 at 0 °C. These condi-
tions smoothly generated the desired triflates, which were then
immediately treated with benzylamine to generate b-chloro
amines in good yields for this one-pot procedure. The resulting
amines were of sufficient purity to subject directly to intramolecu-
lar cyclization. Potassium hydroxide in THF/H2O at 65 °C promoted
clean cyclization to afford the desired chiral N-alkyl terminal aziri-
dines 11–15 in 50–73% overall yield and 88–94% ee from the readily
available aldehyde starting materials. This mild, two-pot protocol
from the common configurationally stable 2-chloro alcohol inter-
mediate represents a robust approach to access aziridines, and this
R1
R1
i. Tf2O, CH2Cl2, 0 °C
ii. KCN, 18-C-6, CH3CN
OH
O
CN
Cl
Cl
16
5
66-86%
O
O
CN
CN
CN
Cl
Cl
Cl
19
70%
17
86%
18
83%
F
CN
CN
5
Cl
Cl
20
66%
21
75%
optimized approach avoids epimerization of the a-chloro aldehyde
and extremely low temperature reaction conditions necessary in
previous methodologies (Scheme 2).8
Scheme 3. Protocol for the synthesis chiral b-chloro nitriles 17–21.

1278
T. J. Senter et al. / Tetrahedron Letters 56 (2015) 1276–1279
R1
R1
R1
NH2
InCl3, NaBH4
THF
R1
1) InCl3, NaBH4
2) KOH, THF/H2O
150 °C, 1 h
CN
CN
N
H
6
Cl
16
Cl
Cl
16
22
(87-98%)
O
O
O
O
O
NH2
NH2
NH2
O
N
H
N
Cl
23
Cl
N
H
Cl
25
96%
32
29
H
31
55%
60%
24
91%
44%
84% ee
92% ee
92% ee
96%
F
NH2
NH2
5
N
H
N
H
5
Cl
Cl
F
33
34
<5%
45%
27
87%
26
98%
90% ee
Scheme 5. Protocol for intramolecular cyclization to C2-functionalized azetidines
31–34.15
Scheme 4. Mild reduction of b-chloro nitriles to c-chloro amines 23–27.
attempted the same conditions that were successful in facilitating
the 3-exo-tet cyclization of the b-chloro amine to aziridines.
However, treatment with KOH in THF/H2O at 65 °C led to minimal
consumption of the starting material. Additionally, a variety of
modifications to the base and solvent system promoted elimina-
tion to an undesired byproduct 30. To find conditions that might
promote 4-exo-tet cyclization, we performed a screen of a broad
selection of organic and inorganic bases, solvents, and tempera-
tures (Table 1).
strained 4-member azetidine ring, which rapidly promoted
elimination to the conjugated olefin. Gratifyingly, the azetidine
and olefin products were readily separated by flash column
chromatography.
In order to determine the scope of this methodology, we pre-
pared several 2-alkyl azetidines from readily available aldehydes.
Nitrile reduction and azetidine cyclization were performed
sequentially without purification of the c-chloroamine in all cases.
This screen revealed that many conditions which promoted
cyclization also facilitated elimination to the olefin 30. We identi-
fied optimal conditions which provided the desired azetidine in a
3:1 ratio with the competing elimination pathway. Specifically,
potassium hydroxide in THF/H2O (1:1), under high thermal condi-
tions (170 °C) was effective in conversion to the desired azetidine
29. Microwave irradiation for 1 h at this temperature resulted in
This provided the desired azetidines in 44–55% yield. Attempts to
induce cyclization to 34 resulted in nearly complete elimination
to the conjugated byproduct, with less than 5% recovered product.
Importantly, this approach provides the azetidines without N-
functionalization, allowing for rapid derivatization using robust
synthetic methods such as reductive amination and N-alkylation
(Scheme 5).
full consumption of the
Of note, the major by-product was identified as the olefin
resulting from chloride elimination. -Chloro amines with
branched alkyl groups or aryl groups b to the secondary chloride
were especially susceptible to elimination, as reflected in the
decreased yields for 34. This can be rationalized by the high ener-
getic requirements necessary to enable ring closure to the highly
c-chloro amine starting material.
In summary, we have developed an optimized three-step proce-
dure for the enantioselective synthesis of N-alkyl terminal aziri-
dines and azetidines with alkyl substituents at the C2 position of
each heterocycle. This methodology allows for the rapid prepara-
tion of the functionalized aziridines in 50–73% overall yields and
88–94% ee, and functionalized azetidines in 22–32% overall yields
and 84–92% ee. This new method addresses deficiencies in our first
c
Table 1
Conditions for the base-induced cyclization of
c
-chloro amines to azetidines 29 and elimination product 30
NH2
Conditions
O
O
NH2
O
N
H
Cl
29
30
28
Entry
Base
Solvent
Temperature (°C)
Additive
Conversion (%) (29:30)
1
2
3
4
K2CO3
K2CO3
K2CO3
—
NMP
NMP
NMP
THF/H2O (1:1)
DMF
25
120
180
150
25
—
—
—
—
0
40 (2:1)
80 (2:1)
75 (1.5:1)
0
5
NaH
—
6
NaH
DMF
65
—
0
7
8
9
NaH
NaH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
25
65
25
25
25
120
25
65
65
15-C-5
15-C-5
—
—
—
—
AgNO3
AgNO3
—
Trace (1:2)
<5 (0:1)
60 (0:1)
100 (0:1)
0
10 (2:1)
0
0
LHMDS
LHMDS
K2CO3
K2CO3
K2CO3
K2CO3
KOH
10
11
12
13
14
15
16
17
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
<5 (3:1)
20 (3:1)
100 (3:1)
KOH
KOH
120
170
—
—
All reactions run at 0.1 mmol, 0.125 M in solvent. Conversion determined by LCMS and 1H NMR.

T. J. Senter et al. / Tetrahedron Letters 56 (2015) 1276–1279
1279
(0.48 g, 4.50 mmol) in CH2Cl2 (1.00 mL) at 0 °C. The flask containing the triflate
solution was washed 2 times with CH2Cl2 (1.00 mL) and added to reaction. The
solution was then slowly warmed to ambient temperature and stirred
overnight. The reaction was quenched with NaHCO3, diluted with CH2Cl2,
and extracted 3 times with CH2Cl2. The organic layers were combined and
washed with brine. The organic layer was dried over Na2SO4 and concentrated
in vacuo to yield the crude product. The crude product was isolated as a pale
yellow oil quantitatively and carried forward directly to the next step. In an
open microwave vial equipped with a stir bar, crude amine (0.14 g, 0.45 mmol)
was dissolved in 1:1 THF/H2O (2.99 mL), followed by the addition of KOH
(0.16 g, 2.92 mmol). The microwave vial was sealed and stirred overnight at
65 °C. The reaction mixture was allowed to cool to ambient temperature, then
extracted 3 times with EtOAc. The organic layers were combined and dried
over Na2SO4, then concentrated in vacuo to give the crude product a pale
yellow oil. Purification by flash column chromatography (1:1 Hexane/EtOAc)
afforded the desired product as pale yellow oil in 0.11 g, (85%). 1H NMR
(400.2 MHz, CDCl3) d (ppm): 7.23 (m, 5H), 4.28 (t, J = 5.0 Hz, 1H), 3.50 (d,
J = 10.8 Hz, 2H), 3.43 (d, J = 13.6 Hz, 1H), 3.27 (m, 3H), 1.61 (m, 2H), 1.55 (d,
J = 3.4 Hz, 1H), 1.47 (m, 3H), 1.32 (d, J = 6.0 Hz, 1H), 1.10 (s, 3H), 0.63 (s, 3H);
13C NMR (100.6 MHz, CDCl3) d (ppm): 139.5, 128.4, 128.3, 127.0, 101.7, 77.3,
generation approach for the synthesis of aziridines while facilitat-
ing the synthesis of azetidines through a common bifunctional
intermediate. Alternative methods to access azetidines that do
not rely on the chiral pool is a demonstrated need in natural prod-
ucts synthesis and medicinal chemistry applications, and the abil-
ity to employ simple aldehydes and organocatalysts towards their
synthesis allows for straightforward access to either enantiomer.
Additional refinements and applications of this methodology to
the synthesis of biologically relevant small molecules are under
development and will be reported in due course.
Acknowledgments
Financial support from the Warren Family and Foundation is
gratefully acknowledged, and both T.J.S. and M.C.O. acknowledge
partial support from the ACS MEDI division and ACS MEDI Predoc-
toral Fellowships.
65.1, 39.5, 34.0, 32.6, 30.2, 27.6, 23.1, 21.9; HRMS (TOF, ES+) C17H25NO2 [M+H]+
23
calcd 276.1886, found 276.1886; specific rotation [
a
]
+4.0° (c 1.0, CH3Cl).
D
15. Representative experimental for the synthesis of C2-functionalized azetidine: (S)-2-
(3-Fluoro-4-methylbenzyl)azetidine (32). To a round bottom flask equipped
References and notes
with
a stir bar, alcohol 39 (0.19 g, 0.89 mmol) and 2,6-lutidine (0.48 g,
4.44 mmol) were dissolved in CH2Cl2 (4.4 mL) and cooled to 0 °C. Tf2O
(0.30 g, 1.07 mmol) was then added dropwise, and solution left to stir at 0 °C
for 30 min. Reaction was diluted with CH2Cl2 and washed with H2O. The
organic fraction was washed with brine, dried over Na2SO4, and concentrated
in vacuo. The crude oil was carried on directly to the next step. The crude
triflate was dissolved in MeCN (4.4 mL), then 18-C-6 (0.05 g, 0.18 mmol) was
added to the mixture and allowed to dissolve. KCN (0.578 g, 8.88 mmol) was
then added, and the reaction was allowed to stir for 12 h at ambient
temperature. The reaction was then quenched with NaHCO3 and extracted
three times with CH2Cl2. The organic fractions were combined and dried over
Na2SO4. The organic layer was concentrated in vacuo, and purification by flash
chromatography (4:1 Hexane/EtOAc) afforded the desired product as a clear/
rose colored oil in 0.11 g (70%). 1H NMR (400.2 MHz, CDCl3) d (ppm): 4.45 (dd,
J = 10.4, 1.6 Hz, 1H, (tt, J = 10.2, 3.5 Hz, 1H), 3.60 (m, 2H), 3.38 (d, J = 8.9 Hz, 1H),
3.20 (m, 3H), 2.54 (m, 1H), 2.07 (m, 2H), 1.71 (dt, J = 15.4, 5.0 Hz, 1H), 0.85 (s,
3H), 0.82 (s, 3H); 13C NMR (100.6 MHz, CDCl3) d (ppm): 117.9, 75.9, 75.7, 72.7,
68.5, 53.86, 36.7, 35.4, 28.2, 23.2, 23.1; HRMS (TOF, ES+) C11H18ClNO2 [M+H]+
1. Bott, T. M.; West, F. G. Heterocycles 2012, 84, 223.
2. Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988.
3. Wells, J. N.; Tarwater, O. R. J. Pharm. Sci. 1971, 60, 156.
4. Yudin, A. K. Aziridines and Epoxides in Organic Synthesis; Wiley-VCH Verlag
GmbH & Co. KGaA, 2006.
5. Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.
6. Degennaro, L.; Trinchera, P.; Luisi, R. Chem. Rev. 2014. ASAP.
7. Majumdar, K. C.; Chattopadhyay, S. K. Heterocycles in Natural Product Synthesis;
Wiley-VCH: Weinheim, Germany, 2011.
8. Fadeyi, O. O.; Schulte, M. L.; Lindsley, C. W. Org. Lett. 2010, 12, 3276.
9. Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 4790.
10. O’Reilly, M. C.; Lindsley, C. W. Org. Lett. 2012, 14, 2910.
11. O’Reilly, M. C.; Lindsley, C. W. Tetrahedron Lett. 2012, 53, 1539.
12. Aldous, D. J.; Dutton, W. M.; Steel, P. G. Tetrahedron: Asymmetry 2000, 11, 2455.
13. Kemppainen, E. K.; Sahoo, G.; Valkonen, A.; Pihko, P. M. Org. Lett. 2012, 14,
1086.
calcd 232.1025, found 232.1025; specific rotation [a]
23 +6.4° (c 1.1, CH3Cl). To a
D
microwave vial with magnetic stir bar was added InCl3 (0.10 g, 0.43 mmol) and
NaBH4 (0.05 g, 1.30 mmol). Anhydrous THF (1.0 mL) was added and the
heterogeneous mixture was stirred under argon for 1 h. 25 (0.10 g, 0.43 mmol)
was then slowly added as a solution in THF (1.0 mL). Reaction mixture was
allowed to stir at ambient temperature for 4 h. The reaction was quenched by
dropwise addition (CAUTION: results in rapid generation of gas) of H2O
(1.0 mL) and the solution was heated to 75 °C for 30 min MeOH (2.0 mL) was
then slowly added, and stirring continued at 75 °C for 30 min. The reaction
mixture was allowed to cool to room temperature, then filtered through a
celite pad to remove solid indium byproducts. The resulting colorless solution
was concentrated in vacuo to provide 32 in 96% yield. The crude residue was
carried forward directly to the next step. To an open microwave vial equipped
with a stir bar, the crude residue from the previous step was dissolved in a
solution of 1:1 THF/H2O (3.40) and KOH (0.16 g, 2.76 mmol) was then added.
The vial was sealed and submitted to microwave irradiation at 170 °C. for 1 h.
The biphasic solution was extracted three times with EtOAc and washed with
brine. The organic fractions combined, dried over Na2SO4, and concentrated in
vacuo. Purification by flash column chromatography (9:0.9:0.1 CH2Cl2/MeOH/
NH4OH) afforded desired product as a light yellow oil in 45 mg (55%). 1H NMR
(400.2 MHz, MeOD) d (ppm): 3.89 (dd, J = 12.5, 3.6 Hz, 1H), 3.63 (m, 1H), 3.62
(d, J = 12.0 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.35 (m, 3H), 1.97 (m, 1H), 1.79 (d,
J = 7.0 Hz, 1H), 1.50 (m, 4H), 1.35 (d, J = 3.4 Hz, 1H), 0.94 (s, 3H), 0.88 (s, 3H);
14. Representative experimental for the synthesis of N-alkyl terminal aziridine: (R)-1-
Benzyl-2-octylaziridine (13). To a round bottom flask equipped with a stir bar,
4-(5,5-dimethyl-1,3-dioxan-2-yl)butanal (0.25 g, 1.34 mmol) was dissolved in
CH2Cl2 (3.84 mL) at 0 °C and to the stirring solution was added (2R,5R)-2,5-
diphenylpyrrolidine (0.03 g, 0.13 mmol) and then N-chlorosuccinimide
(0.233 g, 1.75 mmol). Solution was maintained at 0 °C, and stirring was
continued for 12 h, at which point starting material was consumed by
1HNMR. The reaction was diluted with MeOH (3.84 mL) and cooled to 0 °C,
then NaBH4 (0.254 g, 6.72 mmol) was slowly added while stirring. The reaction
was stirred for additional 30 min at the same temperature, then quenched with
H2O and extracted three times with EtOAc. The organic fractions were
combined, washed with brine, and dried over Na2SO4. The organic layer was
concentrated in vacuo and a crude oil was purified by column chromatography
(4:1 Hexane/EtOAc) to yield desired product as a clear oil in 0.23 g (76%). 1H
NMR (400.2 MHz, CDCl3) d (ppm): 4.49 (t, J = 4.4 Hz, 1H), 4.08 (m, 1H), 3.81 (dd,
J = 12.2, 4.0 Hz, 1H), 3.69 (dd, J = 11.7, 7.0 Hz, 1H), 3.62 (d, J = 10.8 Hz, 2H), 3.44
(d, J = 10.8 Hz, 2H), 2.05 (s, 1H), 2.00–1.74 (m, 4H), 1.20 (s, 3H), 0.74 (s, 3H); 13
C
NMR (100.6 MHz, CDCl3) d (ppm): 101.2, 76.6, 66.8, 64.7, 31.2, 30.1, 28.3, 22.9,
21.7; HRMS (TOF, ES+) C10H19ClO3 [M+H]+ calcd 223.1021, found 223.1020;
23
specific rotation [
with
a
]
D
À3.0° (c 1.0, CH3Cl). To a round bottom flask equipped
a
stir bar, alcohol (0.10 g, 0.45 mmol) and 2,6-lutidine (0.241 g,
2.25 mmol) were dissolved in CH2Cl2 (2.25 mL) and cooled to 0 °C. Tf2O
(0.54 mL, 1 M in CH2Cl2, 0.54 mmol) was then added dropwise, and the
solution was left to stir at 0 °C for 30 min. At this time, the triflate solution was
taken up by syringe and added dropwise to a stirring solution of benzylamine
13C NMR (100.6 MHz, MeOD) d (ppm): 81.8, 81.0, 79.3, 77.2, 38.1, 29.6, 29.3,
20
29.1, 24.1, 23.0, 22.6; specific rotation [
a
]
+1.7 (c 1.0, CHCl3); HRMS (TOF,
D
ES+) C11H22NO3S [M+H]+ calcd 200.1574, found 200.1575.