Bifunctional asymmetric catalysis with hydrogen chloride: Enantioselective ring opening of aziridines catalyzed by a phosphinothiourea

Article abstract of DOI:10.1055/s-0029-1217344

Ring opening of aziridines with hydrogen chloride to form β-chloroamine derivatives is catalyzed by a chiral phosphinothiourea derivative in high yields and with high enantioselectivities. On the basis of ³¹P NMR studies, activation of HCl appears to proceed via quantitative protonation of the catalyst to afford a phosphonium chloride complex. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217344

1680
CLUSTER
Bifunctional Asymmetric Catalysis with Hydrogen Chloride: Enantioselective
Ring Opening of Aziridines Catalyzed by a Phosphinothiourea
E
nantioselective
s
Hydroc
h
u
lorination of
y
m
eso-Aridiz
o
ines
w
ithH
C
s
l
hi Mita, Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
Fax +1(617)4961880; E-mail: jacobsen@chemistry.harvard.edu
Received 28 February 2009
additions to polar organic electrophiles. Although many
Abstract: Ring opening of aziridines with hydrogen chloride to
form b-chloroamine derivatives is catalyzed by a chiral phosphi-
nothiourea derivative in high yields and with high enantioselectivi-
ties. On the basis of 31P NMR studies, activation of HCl appears to
Lewis or Brønsted basic functional groups are expected to
be protonated by HCl, the weak basicity of phosphines
(Ph2CyP+H: pKa = 5.1 in H2O),10 suggested that chiral
proceed via quantitative protonation of the catalyst to afford a phos- phosphinothiourea catalysts such as 1, originally devel-
phonium chloride complex.
oped in our laboratory for the [3+2] cycloaddition of al-
lenes with imines,11 might be particularly effective in the
Key words: asymmetric catalysis, halogenation, ring opening, car-
bocations, aziridines
context of productive HCl activation. Herein, we report
the use of chiral phosphinothioureas to catalyze the cata-
lytic enantioselective addition of HCl to N-acylaziri-
dines.12
Hydrogen chloride (HCl) is a commodity chemical used
in many industrial processes.1 HCl is also a convenient
and inexpensive reagent for use in laboratory-scale chem-
ical synthesis, such as for the hydrochlorination of car-
bon–carbon double2 and triple3 bonds. However, its utility
in catalytic enantioselective transformations has thus far
been limited.4 Indeed, few of the common chiral catalysts
are likely to be compatible with HCl given its extremely
high acidity.5
Enantioselective desymmetrization of meso-epoxides
with various chloride sources is a well-studied method for
the preparation of optically active chlorohydrins, and
many examples using stoichiometric promoters13 as well
as chiral catalysts14 have both been reported. Interesting-
ly, the direct use of HCl for the enantioselective variant of
this transformation has not been reported.15 In pioneering
studies, Denmark reported that Lewis basic, chiral phos-
phoramides catalyze enantioselective opening of meso-
epoxides with SiCl4.14a Under the reaction conditions de-
veloped by Denmark, HCl mediates competitive, unselec-
tive epoxide ring opening, and careful distillation of SiCl4
was necessary to ensure that reproducible enantioselectiv-
ity was obtained. HCl is also very reactive towards aziri-
dines in the absence of any promoters,16 suggesting that a
R2
N
R1
S
R2
N
R1
S
HCl
R3
N
H
N
H
R3
N
H
N
H
O
PPh2
O
P
Ph
Ph
H
activation
1
Cl
Scheme 1 Proposed activation mode of HCl by catalyst 1
Over the past several years, chiral thioureas have emerged
as a useful class of catalysts for a broad range of asymmet-
ric transformations.6 We discovered recently that chiral
thiourea derivatives catalyze enantioselective additions to
N-acyliminium/chloride ion pairs7a–c and a-chloro
ethers.7d These observations have led to the proposal that
thiourea catalysts engage these weakly basic electrophiles
by an anion-abstraction mechanism that involves a thio-
urea chloride hydrogen-bonding interaction.7b We have
found that urea and thiourea catalysts are stable to strong
mineral acids,8 suggesting that these catalysts might be
amenable to productive activation of HCl. In particular,
we considered the possibility that a bifunctional chiral
catalyst9 containing a basic group could undergo protona-
tion by HCl with binding of the chloride counterion to the
thiourea (Scheme 1), thereby activating the molecule to
catalyst (20 mol%)
NHBz
HCl (1 M in Et2O, 1.2 equiv)
>99%
conversion
NBz
Et2O (0.025 M), –78 °C, <1 h
Cl
2a
3a
N
NH2
Me
Ph
1b
S
1a
N
N
N
26% ee
40% ee
(slow addition)
29% ee
40% ee
(slow addition)
H
H
O
N
1c
1d
1e
1f
N(n-Pr)2
3% ee
P(O)Ph2
PPh2
21% ee
HO
4% ee
60% ee (<10 min)
62% ee
(100 mol%)
58% ee
(slow addition)
t-Bu
t-Bu
CF3
t-Bu Me
N
S
1g
1h
HN
O
8% ee
–26% ee
S
Bn
F3C
N
N
SYNLETT 2009, No. 10, pp 1680–1684
x
x
.x
x
.2
0
0
9
H
H
t-Bu
O
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217344; Art ID: Y01509ST
Scheme 2 Screen of thiourea catalysts
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Enantioselective Hydrochlorination of meso-Aridizines with HCl
1681
control over background reaction is necessary for achiev- Strecker methodology,19 and incorporated into the new set
ing efficient asymmetric catalysis.
of phosphinothiourea derivatives 1m–p. A measurable
improvement in ee was observed with these more hin-
dered catalysts. The amino acid used for the preparation of
catalyst 1m is readily accessible in optically pure form,20
so 1m was selected as the preferred catalyst for further
study.
We began our study by investigating different thiourea
catalysts using benzoyl protected aziridine 2a as a model
substrate (Scheme 2).17 In the absence of a chiral catalyst,
hydrochlorination of 2a is complete within 30 minutes,
even under relatively dilute reaction conditions and low
temperatures (0.025 M, –78 °C), indicating that accelera- Absolute concentration has proven to be an important pa-
tion of a catalytic pathway and/or suppression of back- rameter in thiourea-catalyzed reactions, with improve-
ground reactivity would be necessary in order to achieve ments in both enantioselectivity and rate resulting in
high enantioselectivities. 1,2-Diaminocyclohexane-de- certain cases from increased dilution.2b,21 This proved to
rived catalysts 1a–d (20 mol%) promoted formation of be the case in the aziridine hydrochlorination reaction as
product 3a with very modest enantioselectivities (3–29% well, with highest enantioselectivities obtained under
ee). Slow addition of HCl (0.25 M in Et2O) over 110 min- highly dilute conditions (0.0025 M, compare entries 1–3,
utes led only to minor improvements (up to 40% ee for Table 1). However, further dilution led to significant de-
both catalysts 1a and 1b), suggesting that background re- creases in reaction rate, necessitating higher reaction tem-
activity was only partially responsible for the low ee. peratures in order to achieve high conversion at the
While phosphine oxide catalyst 1e as well as thioureas 1g expense of ee (entries 5 and 6). Given that the racemic un-
and 1h also led to product formation with poor enantiose- catalyzed reaction is not competitive with the catalytic
lectivity, phosphinothiourea catalyst 1f promoted hydro- pathway (entry 4),22 it appears that the increased enanti-
chlorination of 2a within 10 minutes in 60% ee.18 In this oselectivity obtained at low concentrations may be as-
case, neither slow addition of HCl nor increased catalyst cribed to the existence competing catalyzed pathways of
loading had any beneficial effect on enantioselectivity, varying kinetic order in catalyst and/or reactants.
suggesting that the catalytic pathway was significantly
Table 1 Concentration Effect
more rapid than the background reaction. This hypothesis
was confirmed by in situ IR spectroscopic experiments
1m (20 mol%)
NHBz
Cl
HCl (1 M in Et2O, 1.2 equiv)
with cycloheptene-derived aziridine 2c: in these studies,
the initial reaction rate of hydrochlorination with catalyst
1f (20 mol% at –40 °C) was measured to be 140 times
greater than in the absence of catalyst.
NBz
Et2O
3a
2a
Entry Concn (M) Temp (°C) Time (h) Conv. (%) ee (%)a
1
0.1
–78
<0.5
<0.5
4
>99
>99
>99
<5
35
65
81
–
catalyst (20 mol%)
NHBz
>99%
conversion
HCl (1 M in Et2O, 1.2 equiv)
NBz
2
0.025
0.0025
0.0025
0.0010
0.0005
–78
Et2O (0.025 M), –78 °C, <1 h
Cl
2a
3a
3
–78
R
Me (1i)
Bn (1j)
i-Bu (1k)
4b
5
–78
2
R
S
ee (%)
12
32
9
(i-Bu)2N
(S)
R
t-Bu (1f)
N
H
N
H
CMe2Ph (1l)
–78 to –50
–78 to –50
3/62
2/45
99
65
59
O
O
PPh2
ee (%)
60
52
6
66
Me
Et
a The ee values were determined by chiral HPLC analysis.
Me
Me
b Background reaction carried out in the absence of catalyst 1m.
R =
Et
Me
1o
R
S
–65% to
–66% ee
1m
1n
(i-Bu)2N
Et
(R)
N
H
N
H
The optimal conditions were successfully applied to a va-
riety of aziridines to provide b-chloroamine products with
high yields and good enantioselectivities with 10–20
mol% catalyst loadings (Table 2). Cyclooctene-derived
substrate 2d (entry 4) was unreactive under highly dilute
conditions (0.0025 M), but efficient hydrochlorination of
this challenging substrate could be achieved at higher con-
centrations (0.025 M). The scope of enantioselective hy-
drochlorinations catalyzed by 1m is noteworthy given that
Lewis base catalyzed variants of this reaction generally
afford only modest ee with cyclic substrates.14
PPh2
1p
Scheme 3 Optimization of the amino acid component of the catalyst
The a-amino acid component of catalyst 1 was varied sys-
tematically in an effort to improve the enantioselectivity
in the model reaction (Scheme 3). It was found that ee
were responsive to increasing steric demand of the a-sub-
stituent (catalysts 1i–f). Accordingly, highly hindered un-
natural amino acids were prepared, taking advantage of
recently developed thiourea-catalyzed asymmetric
Synlett 2009, No. 10, 1680–1684 © Thieme Stuttgart · New York

1682
T. Mita, E. N. Jacobsen
CLUSTER
Table 2 Substrate Scope
Table 3 Hydrochlorination of cis-Stilbene-Derived Aziridine 2g
1m (10 mol%)
catalyst (20 mol%)
R
R
R
R
NHBz
Cl
Ph
NHBz
Ph
Ph
NHBz
HCl (1 M in Et2O, 1.2–2 equiv)
HCl (1 M in Et2O, 1.2 equiv)
NBz
NBz
+
Et2O (0.0025 M)
Et2O (0.025 M)
Ph
Cl
Ph
Ph
syn-3g
Cl
2a–f
3a–f
anti-3g
cis-2g
Entry Product
Temp
(°C)
Time Yield ee
(h)
Entry Catalyst Temp
(°C)
Time Conv.
Ratio
ee of
(%)a (%)b
(h)
(%)
>99
>99
>99
92
(anti/syn)a anti (%)b
1c
2
–
–30
1
18:82
48:52
74:26
94:6
–
–
NHBz
1
–78
4
97
99
96
91
94
96
83
78
90
84
92
70
–
–78 to r.t.
r.t.
19
2
Cl
3a
3
1f
1f
1m
1a
1h
50
NHBz
4
–78 to –30 20
–78 to –30 46
90d
–89d
39
2
–78
6
19
84
13
1
Cl
5e
6
>99 (85f) 93:7
3b
NHBz
–30
–30
67
24
95
62:38
39:61
3c
–78 to –50
–78 to –50
–78 to –50
–78
7
ca. 80
–30
Cl
3c
a Diastereomeric ratios were determined by integration of 1H NMR
resonances.
NHBz
b The ee values were determined by chiral HPLC analysis.
c SiCl4 in CH2Cl2 was used as the chloride source.
d Compound syn-3g is unstable to silica gel column chromatography
and undergoes cyclization to the corresponding trans-oxazoline. The
ee was determined to be 21% with catalyst 1f and –21% with catalyst
1m.
4c,d
Cl
3d
NHBz
Cl
5c
e [cis-2g]0 = 0.01 M. No reaction was observed under more dilute con-
ditions.
3e
f Isolated yield of anti-3g.
Me
NHBz
6
In order to glean insight into the mechanism of the phos-
phinothiourea-catalyzed additions of HCl to aziridines,
we undertook 31P NMR studies of the interaction of cata-
lyst 1f with HCl. An anhydrous, ethereal solution of 1f
was cooled to –78 °C, and excess HCl in Et2O (10 equiv)
was added dropwise via syringe. The solution became
cloudy immediately, and was stirred for 30 minutes at –78
°C. Solvent removal by gradual evaporation under re-
duced pressure at low temperature (–78 °C to ca. –30 °C)
afforded a white solid. Analysis of this material as a
CDCl3 solution by 31P NMR spectroscopy revealed a sin-
gle resonance (d = 4.6 ppm, JP–H = 508 Hz) distinct from
that of 1f (d = –8.0 ppm). The chemical shift and P–H
coupling constant are similar to those of previously char-
acterized protonated phosphines.25,26 Enantioselective
hydrochlorination of 2a (0.0025 M) using the solid, proto-
nated species without added HCl gave the ring-opened
product 3a quantitatively within one hour in 70% ee,27
comparable to the enantioselectivity obtained under cata-
lytic conditions (77% ee). On the basis of these results, it
appears that catalytic hydrochlorinations of benzoyl azi-
Me
Cl
3f
a Isolated yield.
b Determined by chiral HPLC analysis.
c 20 mol% of catalyst was used.
d Reaction was conducted on 0.025 M.
cis-Stilbene-derived aziridine 2g also underwent the ring
opening in the presence of phosphinothiourea catalyst in
reactions carried at 0.025 M (Table 3). Uncatalyzed open-
ings of 2g lead to mixtures of diastereomeric products,
with the ratio dependent on the chloride source used:
SiCl4 leads to selective formation of syn-3g,23 the result of
retentive ring opening (entry 1). In contrast, HCl provides
1:1 mixture of anti and syn products (entry 2). Interesting-
ly, anti-3g23 was obtained in high diastereo- and enantio-
selectivity (up to 90% ee) in reactions promoted by chiral
phosphinothiourea catalysts 1f and 1m (entries 4 and 5).
The observation of predominantly invertive ring opening
suggests an SN2-type pathway in the catalytic reaction.
Other chiral thiourea derivatives 1a and 1h provided low-
er levels of selectivity (entries 6 and 7), indicating that a
bifunctional phosphinothiourea catalyst was important for
this substrate as well.
(S)
NH2
⋅HCl
OH
NHBz
N
O
DBU
4 M HCl
Ph
reflux, 11 h
toluene
reflux, 14 h
Cl
(R)
3a
71% ee
4
5
The absolute configuration of 3a (71% ee) prepared using
1f was determined by conversion into the known cis-ami-
no alcohol 524 in two steps (Scheme 4).
71% yield
72% ee
96% yield
[α]D23 –18.3
(c = 0.44, EtOH)
Scheme 4 Determination of absolute configuration
Synlett 2009, No. 10, 1680–1684 © Thieme Stuttgart · New York

CLUSTER
Enantioselective Hydrochlorination of meso-Aridizines with HCl
1683
Representative Procedure for Catalytic Enantioselective Ring-
Opening Reaction with HCl
trans only
S
PPh2
H
Cl
R
N
To a mixture of catalyst 1m (3.0 mg, 0.005 mmol, 10 mol%) and
aziridine 2a (10.1 mg, 0.050 mmol) in Et2O (20 mL, 0.0025 M),
HCl (1 M stock solution in Et2O, 60 mL, 0.06 mmol, 1.2 equiv) was
added at –78 °C. After 4 h, the solvent was evaporated under re-
duced pressure, and the residue was purified by automated column
chromatography (silica gel, hexane–EtOAc, 19:1 to 3:2) to afford
(1R,2R)-N-(2-chlorocyclohexyl)benzamide (3a, 11.6 mg, 0.0488
mmol) in 98% yield as colorless solid. The ee of the product was de-
termined by HPLC analysis to be 83%.
N
N
H
H
NHBz
R
O
3a
1
rds
enantioselective
chlorination (SN2)
HCl
IR (neat): 3230, 3059, 2950, 2859, 1635, 1575, 1452, 1330, 1125
1
S
cm–1. H NMR (500 MHz, CDCl3): d = 7.78 (d, J = 7.6 Hz, 2 H),
PPh2
H
7.50 (t, J = 7.6 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 6.18 (br d, J = 4.5
Hz, 1 H), 4.06 (ddd, J = 3.8, 9.3, 17.5 Hz, 1 H), 3.88 (dt, J = 3.8,
10.5 Hz, 1 H), 2.34–2.30 (m, 2 H), 1.84–1.74 (m, 3 H), 1.52–1.44
(m, 1 H), 1.40–1.31 (m, 2 H). 13C NMR (125 MHz, CDCl3):
d = 167.2, 134.7, 131.4, 128.5, 127.0, 62.5, 55.6, 36.1, 32.8, 25.4,
24.2. ESI-HRMS: m/z calcd for C13H16ClNNaO [M + Na+]:
260.0813, 262.0783 (chlorine isotope); found: 260.0810, 262.0782
(chlorine isotope) [a]D23 –54.1 (c 0.58, CHCl3; 83% ee). HPLC (Da-
icel Chiralpak AD-H, 2-PrOH–hexane = 1:10, flow rate 1.0 mL/
min, detection at both 210 nm and 254 nm): tR = 13.8 min (major)
and 23.4 min (minor).
S
H
PPh2
R
N
H
N
N
O
H
H
R
N
H
N
R
O
N
Cl
H
Ph
H
N
R
O
Cl
7
6
NBz
2a
Scheme 5 Proposed catalytic cycle for aliphatic aziridine 2a
ridines such as 2a catalyzed by phosphinothioureas may
involve initial heterolysis of HCl to afford a phosphonium
chloride complex as depicted in Scheme 1.
Acknowledgment
This research was supported by the NIH (GM-43214). T.M. thanks
the Japan Society for the Promotion of Science (JSPS) for scholar-
ship support. We thank Mr. Stephan J. Zuend for helpful discussion.
A proposed catalytic cycle for the ring opening of aziri-
dine 2a is provided in Scheme 5. Aliphatic aziridines 2a–
f undergo ring opening exclusively with inversion of ste-
reochemistry to provide trans-addition products 3a–f.
Rates of invertive ring openings of epoxides and aziri-
dines derived from medium-ring cyclic alkenes are typi-
cally highly sensitive to the steric environment defined by
the ring.28 This is observed in the present case as well,
with reactions of five- and six-membered-ring substrates
2a and 2b being considerably more rapid than those of
seven- and eight-membered substrates 2c and 2d. The re-
activity profiles and the observation of exclusive forma-
tion of trans products points to an SN2-type mechanism
(Scheme 5). We propose that HCl–1 complex 6 is gener-
ated in the first step, and that the phosphonium ion serves
to activate substrate 2a by a general acid mechanism.
Chloride addition is suggested to occur from the thiourea-
bound complex, resulting in a highly ordered enantiode-
termining step. Although stilbene-derived aziridines are
generally more prone to SN1-type pathways, the observa-
tion of high enantioselectivity and in the predominant in-
vertive pathway suggests a common SN2 mechanism for
all the aziridines described in this study.
References and Notes
(1) Lacson, J.; Sakuma, Y.; Schlag, S. Chemical Economics
Handbook: Hydrochloric Acid; SRI International: Menlo
Park CA, 2006, 733.4000A–733.4000F.
(2) For the kinetics and mechanism of hydrochlorination of
olefins, see: (a) Porker, Y.; Stevens, K. D.; Champoux, J. J.
J. Am. Chem. Soc. 1969, 91, 4199. (b) Porker, Y.; Stevens,
K. D. J. Am. Chem. Soc. 1969, 91, 4205.
(3) For the synthesis of vinyl chloride from acetylene, see: Patat,
F.; Weidlich, P. Helv. Chim. Acta 1949, 32, 783.
(4) The kinetic resolutions of terminal epoxides with HCl
catalyzed by bimetallic chiral salen complexes were only
reported. See: (a) Thakur, S. S.; Li, W.; Kim, S.-J.; Kim,
G.-J. Tetrahedron Lett. 2005, 46, 2263. (b) Thakur, S. S.;
Li, W.; Shin, C.-K.; Kim, G.-J. Chirality 2006, 18, 37.
(c) Thakur, S. S.; Chen, S.-W.; Li, W.; Shin, C.-K.; Kim,
S.-J.; Koo, Y.-M.; Kim, G.-J. J. Organomet. Chem. 2006,
691, 1862.
(5) HCl: pKa = 1.8 in DMSO and –8.0 in H2O.
(6) For recent reviews, see: (a) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2006, 45, 1520. (b) Doyle, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(7) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004,
126, 10558. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404.
(c) Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. Org. Lett.
2008, 10, 1577. (d) Reisman, S. E.; Doyle, A. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2008, 130, 7198.
(8) For example, catalyst 1g can be used effectively in reactions
catalyzed by triflic acid (pKa = 0.3 in DMSO and –14 in
H2O, respectively). Woll, M. G.; Xu, H.; Tao, Y.; Zuend,
S. J.; Jacobsen, E. N. unpublished results.
(9) Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett
2005, 1491.
In summary, we have a developed a catalytic enantiose-
lective ring-opening reaction of meso-aziridines with HCl
catalyzed by phosphinothioureas. A broad range of cyclic
as well as acyclic substrates undergo clean addition to af-
ford the corresponding b-chlorobenzamide derivatives in
high yields and with high enantioselectivities. Investiga-
tions of other classes of acidic nucleophiles (HX) and po-
tential electrophiles, as well as more detailed mechanistic
studies are under way.
Synlett 2009, No. 10, 1680–1684 © Thieme Stuttgart · New York

1684
T. Mita, E. N. Jacobsen
CLUSTER
(10) Rahman, M. M.; Liu, H.-Y.; Eriks, K.; Prock, A.; Giering,
W. P. Organometallics 1989, 8, 1.
(11) (a) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008,
130, 5660. (b) After our publication, similar type of catalyst
was reported by a different research group: Yuan, K.; Zhang,
L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron Lett. 2008,
49, 6262.
(12) For examples of catalytic enantioselective ring-opening
reactions of meso-aziridines, see: (a) Zhang, Z. D.;
Scheffold, R. Helv. Chim. Acta 1993, 76, 2602.
(15) Ring openings of cyclooctene oxide and cis-stilbene oxide
with HCl in the presence of phosphinothiourea 1f proceeded
to afford the corresponding trans-chlorohydrins in only 22%
ee and 34% ee, respectively.
(16) For example, see: Crotti, P.; Favero, L.; Gardelli, C.;
Macchia, F.; Pineschi, M. J. Org. Chem. 1995, 60, 2514.
(17) Aziridines having different protecting groups such as
benzyl, tosyl, benzylcarbamoyl, and also unprotected
aziridines gave almost racemic compounds.
(18) Diastereomeric phosphinothiourea of 1f previously effective
for [3+2] cyclization11a was not promising for this reaction
(12% ee).
(19) Zuend, S. J; Coughlin, M. P; Lalonde, M. P.; Jacobsen, E. N.
manuscript in preparation.
(20) N-Boc-a-cyclohexcylmethyl glycine was fine solid so that
optically active crystal could be easily obtained after the
recrystallization from the reaction crude (ca. 90% ee) which
was prepared through the enantioselective Strecker reaction
and hydrolysis followed by Boc protection. Other Boc-
protected amino acids are amorphous which need the
crystallization after the salt formation with tert-butylamine.
(21) Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887.
(22) Kinetic studies of the uncatalyzed hydrochlorination of 2b
and 2c using in situ IR spectrometry (Et2O at –40 °C)
revealed a 1.5-order dependence on [HCl].
(b) Hayashi, M.; Ono, K.; Hoshimi, H.; Oguni, N.
Tetrahedron 1996, 52, 7817. (c) Muller, P.; Nury, P. Org.
Lett. 1999, 1, 439. (d) Li, Z.; Fernández, M.; Jacobsen, E. N.
Org. Lett. 1999, 1, 1611. (e) Mita, T.; Fujimori, I.; Wada,
R.; Wen, J.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 11252. (f) Fukuda, Y.; Mita, T.; Fukuda, N.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
6312. (g) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato,
A.; Furusho, S.; Kanai, M.; Shibasaki, M. Tetrahedron 2007,
63, 5820. (h) Arai, K.; Lucarini, S.; Salter, M. M.; Ohta, K.;
Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129,
8103. (i) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.;
Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084. (j) Wu,
B.; Gallucci, J. C.; Parquette, J. R.; RajanBabu, T. V. Angew.
Chem. Int. Ed. 2009, 48, 1126.
(13) (a) Joshi, N. N.; Srebnik, M.; Brown, H. C. J. Am. Chem.
Soc. 1988, 110, 6246. (b) Naruse, Y.; Esaki, T.; Yamamoto,
H. Tetrahedron 1988, 44, 4747.
(14) (a) Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger,
R. A. J. Org. Chem. 1998, 63, 2428. (b) Bruns, S.; Haufe,
G. Tetrahedron: Asymmetry 1999, 10, 1563. (c) Tao, B.;
Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 353.
(d) Nakajima, M.; Saito, M.; Uemura, M.; Hashimoto, S.
Tetrahedron Lett. 2002, 43, 8827. (e) Peak, S. H.; Shim,
S. C.; Cho, C. S.; Kim, T.-J. Synlett 2003, 849.
(23) Authentic samples of anti-3g and syn-3g were prepared
through the benzoylation of anti- and syn-2,3-dipehnyl-2-
chloroethylamine hydrochloride. See: Hassner, A.; Burke,
S. S. Tetrahedron 1974, 30, 2613.
(24) Schaus, S. E.; Larrow, J. F.; Jacobsen, E. N. J. Org. Chem.
1997, 62, 4197; (1R,2S)-2-amino-cyclohexanol: [a]D26 –27.9
(c 1.10, EtOH; >99% ee).
(25) Dillon, K. B.; Waddington, T. C.; Younger, D. J. Chem.
Soc., Dalton Trans. 1975, 790.
(26) Pestovsky, O.; Shuff, A.; Bakac, A. Organometallic 2006,
25, 2894.
(27) PPh3·HBr and PPh3·HCl promoted hydrohalogenation of
epoxides, see: Afonso, C. A. M.; Vieira, N. M. L.;
Motherwell, W. B. Synlett 2000, 382.
(28) For example, see: Jacobsen, E. N. Acc. Chem. Res. 2000, 33,
421.
(f) Tokuoka, E.; Kotani, S.; Matsunaga, H.; Ishizuka, T.;
Hashimoto, S.; Nakajima, M. Tetrahedron: Asymmetry
2005, 16, 2391. (g) Denmark, S. E.; Barsanti, P. A.; Beutner,
G. L.; Wilson, T. W. Adv. Synth. Catal. 2007, 349, 567.
(h) Takenaka, N.; Sarangthem, R. S.; Captain, B. Angew.
Chem. Int. Ed. 2008, 47, 9708. (i) Chelucci, G.; Baldino, S.;
Pinna, G. A.; Benaglia, M.; Buffa, L.; Guizzetti, S.
Tetrahedron 2008, 64, 7574. (j) For chiral bromohydrine
synthesis, see: Nugent, W. A. J. Am. Chem. Soc. 1998, 120,
7139.
Synlett 2009, No. 10, 1680–1684 © Thieme Stuttgart · New York

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