Lewis acid-catalyzed asymmetric radical additions of trialkylboranes to (1R,2S,5R)-2-(1-methyl-1-phenylethyl)-5-methylcyclohexyl-2H-azirine-3- carboxylate

Article abstract of DOI:10.1016/j.tet.2005.06.076

The asymmetric addition of alkyl radicals to (1R,2S,5R)-2-(1-methyl-1- phenylethyl)-5-methylcyclohexyl-2H-azirine-3-carboxylate (1) yielding the corresponding 2-alkylaziridine-2-carboxylates has been investigated. High diastereoselectivities and good yiel

Full text of DOI:10.1016/j.tet.2005.06.076

Tetrahedron 61 (2005) 8443–8450
Lewis acid-catalyzed asymmetric radical additions of trialkyl-
boranes to (1R,2S,5R)-2-(1-methyl-1-phenylethyl)-
5-methylcyclohexyl-2H-azirine-3-carboxylate
Erik Risberg,a Andreas Fischerb and Peter Somfaia,
*
aKTH Chemistry, Organic Chemistry, KTH, S-100 44 Stockholm, Sweden
bKTH Chemistry, Inorganic Chemistry, KTH, S-100 44 Stockholm, Sweden
Received 13 January 2005; revised 6 June 2005; accepted 23 June 2005
Abstract—The asymmetric addition of alkyl radicals to (1R,2S,5R)-2-(1-methyl-1-phenylethyl)-5-methylcyclohexyl-2H-azirine-3-
carboxylate (1) yielding the corresponding 2-alkylaziridine-2-carboxylates has been investigated. High diastereoselectivities and good
yields were obtained in the addition of primary alkyl radicals to azirine 1, while secondary radicals gave a lower dr. The influence of Lewis
acids was also investigated; 10 mol% of CuCl were found to increase the dr.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
to investigate the use of chiral auxiliaries in the asymmetric
addition of alkyl radical addition to azirines, and herein
detail our results.11
The asymmetric addition of carbon nucleophiles to imines is
an important route to chiral amines and has been employed
in the synthesis of various amino acids and alkaloids.1 In
the search for new, efficient and general methods to generate
enantiopure amines, radical addition to imine derivatives,
particularly oxime ethers and hydrazones, has become an
interesting alternative.2,3 In this respect, it has recently been
shown that 2H-azirines are promising alternative alkyl
radical acceptors,4 yielding aziridines, a class of compounds
that has received much recent attention.5
2. Results and discussion
Azirine carboxylates 1 and 2, having as auxiliaries
8-phenylmenthyl and Oppolzers sultam, respectively, were
selected as substrates for initial screening in the radical
addition reaction (Scheme 1). Initial studies were conducted
using Et3B/O2 as radical initiator; in this reaction Et3B is
believed to function as an initiator and Lewis acid.12,13
Using these reaction conditions azirine 1 gave 3a:4a in
excellent dr (91:9) and good yield (77%), while 2 afforded
5:6 in only modest dr (79:21) but high yield (95%).
There are two common methods to induce stereoselectivity
in intermolecular alkyl radical additions to imines, either
by use of a chiral Lewis acid or by a chiral auxiliary.2,3,6
A large number of Lewis acids have previously been
investigated in order to increase selectivities and reactivities
in radical reactions.6,7 However, difficulties experienced
when studying the asymmetric addition of organolithiums8
and the hetero Diels–Alder reaction using azirines as
substrates and various chiral Lewis acids to mediate the
reactions indicated the difficulties associated with this
approach.9 In contrast, it was shown that 8-phenyl-
menthyl-2H-azirine-3-carboxylate undergoes highly dia-
stereoselective aza-Diels–Alder reactions under Lewis
acid activation.9,10 Prompted by these results we decided
Keywords: Azirines; Asymmetric radical addition; Chiral auxiliaries.
*
Corresponding author. Tel.: C46 8 7906960; fax: C46 8 7912333;
e-mail: somfai@kth.se
Scheme 1. (a) Et3B (5 equiv), EtI (10 equiv) O2, CH2Cl2, K105 8C.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.076

8444
E. Risberg et al. / Tetrahedron 61 (2005) 8443–8450
Consequently azirine 1 was chosen as substrate for further
investigations.
Lewis acids.16 When the reaction was repeated with freshly
distilled c-C6H11I the dr dropped, supporting the notion of
Cu-salts acting as Lewis acids (entry 4).
Optimization of the reaction conditions showed that the
highest diastereoselectivity was obtained in CH2Cl2 or
Et2O, dr 91:9 in both solvents, and CH2Cl2 was chosen for
further studies. The dependence of the temperature on the dr
was then evaluated (Table 1).
Consequently, it was decided to investigate the influence of
Lewis acids on the radical addition reaction (Table 3).
Strong Lewis acids such as BF3$OEt2 and SnCl4 were found
to cause instant decomposition of azirine 1. Weaker Lewis
acids were therefore, selected; initially five different Lewis
acids were investigated (entries 2–6). Catalytic amounts of
AgOTf and CuCl increased the dr, giving aziridine 2a in
moderate yields (entries 2 and 3), while treatment with
Cu(OTf)2 significantly decreased the dr (entry 4). Neither
In(OTf)3 nor YbCl3 altered the diastereoselectivity, but
caused dramatically lowered yields (entries 5 and 6). The
use of Lewis acids lowered the yield in all reactions and
unreacted 1 was present in all reaction mixtures, as judged
by TLC. As a result the reaction time was increased to
60 min in the subsequent experiments. Three Cu(I) salts
were evaluated to investigate the importance of the counter
ion (entries 7–9). Lower yields were obtained in all cases,
compared to the uncatalyzed reaction. The selectivities for
the (CuOTf)2$ PhMe and CuI catalyzed reactions were
lower compared to the uncatalyzed one, while the dr in the
reaction promoted by CuCl was higher. This suggests that
the Lewis acid not only influences the dr but also decreases
the reactivity of 1 to various extents. We have previously
shown that MgBr2$OEt2 and ZnCl2$OEt2 are excellent
catalysts for the hetero Diels–Alder reaction with 1.9,10 In
the present reaction, however, they gave inferior results.
Table 1. Influence of temperature on diastereoselectivitya
Entry
Temperature
(8C)
Yieldb (%)
drc 3a:4a
1
2
3
4
5
6
K105
K78
K40
K20
0
77
76
72
80
70
65
91:9
88:12
85:15
72:28
66:34
55:45
rt
a Reaction conditions: azirine 1 (1 equiv), EtI (10 equiv), Et3B (5 equiv),
O2 (5 mL), CH2Cl2, 5 min.
b Isolated yield.
c Determined by HPLC.
As expected the highest dr was obtained at K105 8C (entry
1), but the selectivity decreased only slightly for tempera-
tures up to K40 8C (entries 2, 3). With temperatures at and
above K20 8C the dr fell dramatically, giving almost a 1:1
mixture at rt (entries 4–6).
The addition of other alkyl radicals was then attempted.
This could potentially be realized by an iodine atom-transfer
process in which the desired radical (R%) is generated from
an initiator, such as Et3B/O2, and R–I to give EtI and the
corresponding alkyl radical (R%).14 A requirement in this
process is that the generated radical (R%) is more stable then
Et%, shifting the equilibrium towards addition of the desired
radical (R%). To test the feasability of this protocol, three
secondary and tertiary alkyl iodides were selected for an
initial screening (Table 2).
Table 3. Influence of Lewis acids on the radical addition to azirine 1a
Entry
Reaction
time (min)
Lewis acid/
equiv
Yieldb (%)
drc 3a:4a
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
60
60
60
—
AgOTf/0.1
CuCl/0.1
81
52
53
91:9
96:4
96:4
75:25
90:10
90:10
96:4
91:9
92:8
Cu(OTf)2/0.1 54
In(OTf)3/0.1
YbCl3/0.1
CuCl/0.1
CuI/0.1
(CuOTf)2$- 61
PhMe/0.1
16
28
69
58
Table 2. Effect of alkyl iodides on the addition of ethyl radical to 1a
Entry
RI
Yieldb (%)
drc 3a:4a
1
2
3
4
i-PrI
t-BuI
c-C6H11
58
62
71
82
94:6
93:7
94:6
89:11
a Reaction conditions: azirine 1 (1 equiv), Et3B (3 equiv), Lewis acid, O2
(5 mL), CH2Cl2, K105 8C.
I
c-C6H11Id
b Isolated yield.
c Determined by HPLC.
a Reaction conditions: azirine 1 (1 equiv), RI (10 equiv), Et3B (5 equiv), O2
(5 mL), CH2Cl2, K105 8C, 5 min.
b Isolated yield of 3a:4a.
From the results in Table 2 it is evident that the atom-
transfer technique is not applicable to the addition of alkyl
moieties, other than ethyl, to 1. To circumvent this
drawback it was decided to investigate the use of other
boranes in the addition reaction (Scheme 2).17
c Determined by HPLC.
d Freshly distilled c-C6H11I was used.
The reaction of azirine 1 with i-PrI, t-BuI and c-C6H11I in
the presence of Et3B/O2 gave selective addition of only the
ethyl radical, furnishing 3a,4a in moderate to good yields
and high diastereoselectivity (entries 1–3). Considering that
the radical transfer rate can be slow at low temperatures and
that all starting material was consumed after 5 min at
K105 8C, these observations are understandable.4,15 Inter-
estingly, the dr obtained in these reactions were somewhat
higher compared to a reaction without an added alkyl iodide
(compare Table 2, entries 1–3 with Table 1, entry 1).
Commercially available alkyl iodides are stabilized with
metallic copper, the salts of which are well known to act as
A requirement in the alkyl radical addition to 1 is the use of
3 equiv of Et3B. Attempts with 0.5 and 2 equiv of Et3B gave
only trace amounts of aziridines 3a:4a. Trialkylboranes
coordinated to a donor atom such as oxygen or nitrogen, as
is the case in the present reaction, might be less inclined to
react with O2 to generate alkyl radicals, and consequently
the formation of radicals from such species might be
retarded. The necessity for excessive amounts of Et3B is
consistent with a mechanism in which the trialkylborane

E. Risberg et al. / Tetrahedron 61 (2005) 8443–8450
8445
(C6H11CH2CH2)3B and (2-methylallyl)3B were employed
to find out if primary radicals generally give higher
selectivities than secondary ones in this reaction. This
gave aziridines 3f:4f and 3g:4g, respectively, in moderate to
good yield and dr (entries 11, 13). In both cases the addition
of CuCl increased the dr, but resulted in lower yields with
(C6H11CH2CH2)3B (entries 12, 14).
Scheme 2. Addition of trialkylboranes to azirine 1.
plays multiple roles: as Lewis acid, radical initiator, and
terminator.4,18 Consequently, it would be valuable if a
radical initiator carrying less than three R-groups could be
applied. B-Alkyl catecholboranes have been used as radical
sources in reactions with enones, vinyl sulfones and in direct
allylations.19 Disappointingly, attempts with B-propyl
catecholborane as a radical initiator only gave decompo-
sition of azirine 1, which might be due to the increased
Lewis activity of the borane compared to Et3B. By the same
reasoning boranes with N- or S- ligands can be expected to
give similar results. As a result, it was decided to investigate
the use of various trialkylboranes in the radical addition to
azirine 1 and the reults are summarized in Table 4.20
The relative stereochemistry of the newly formed stereo-
center in the addition reactions was analyzed as follows.
Compound 3a and 5, the major diastereomers from the
addition of Et3B to 1 and 2, respectively, were separated.
Compound 5 was then recrystallized and the absolute
configuration of the quaternary aziridine carbon was
determined to be (S) by X-ray measurements (Fig. 1).11
In order to further evaluate the influence of Lewis acid
activation, all reactions were run in the presence and the
absence of catalytic amounts of CuCl. As shown previously,
addition of CuCl to azirine 1 prior to addition of Et3B
increased the dr, but lowered the yield (entries 1, 2).
Addition of n-Bu3B, gave 3b:4b in good dr that remained
unchanged upon addition of CuCl, while the yield increased
significantly (entries 3, 4). With the more stable radicals
formed from triallylborane, i-Pr3B and s-Bu3B the
corresponding aziridines 3c:4c, 3d:4d, and 3e:4e
(4 diastereomers) were obtained in modest to good
yields, but poor selectivities (entries 5–10). Finally,
Figure 1. One of the four molecules of 5 in the asymmetric unit. Thermal
ellipsoids are drawn at a 50% probability level.
The absolute stereochemistry of 3a was then deduced as
follows. Reduction of aziridine 3a with LiAlH4 followed by
benzylation and acetylation gave compound 7 (Scheme 3).
Table 4. Addition of various alkyl radicals to azirine 1a
Entry
Reaction time (min)
R3B
Lewis acid/equiv
Products
Yieldb (%)
Ratioc
1
2
3
4
5
6
7
8
5
60
5
60
5
60
5
60
5
60
5
60
5
60
Et3B
Et3B
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
3a:4a
3a:4a
3b:4b
3b,4b
3c:4c
3c:4c
3d:4d
3d:4d
3e:4ee
3e:4ee
3f:4f
81
69
69
81
72
85
51
63
43
63
56
28
71
71
91:9
96:4
n-Bu3B
n-Bu3B
87:13
88:12
59:41
66:34
49:51
61:39
50:50
55:45
72:28
83:17
78:22
83:17
(allyl)3Bd
(allyl)3Bd
i-Pr3Bd
i-Pr3Bd
s-Bu3B
9
10
11
12
13
14
s-Bu3B
(C6H5CH2CH2)3Bd
(C6H5CH2CH2)3Bd
(2-methylallyl)3Bd
(2-methylallyl)3Bd
3f:4f
3g:4g
3g:4g
a Reaction conditions: azirine 1 (1 equiv), R3B (3 equiv), Lewis acid, O2 (5 mL), CH2Cl2, K105 8C.
b Isolated yield.
c Determined by HPLC.
d R3B not isolated and O3 equiv were used.
e Four stereoisomers formed.

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E. Risberg et al. / Tetrahedron 61 (2005) 8443–8450
Scheme 5.
initiated ethyl radical additions to azirine 1, indicating that
these simple models are not applicable to the present study.
The stereochemical outcome in the addition to azirine 2
can be rationalised in analogy to similar reactions with
glyoxylic oxime ethers.13
Scheme 3. (a) LiAlH4, Et2O, K78 8C/rt, 2 h; (b) BnBr, K2CO3, MeCN,
reflux; (c) Ac2O, DMAP, CH2Cl2, 0 8C/rt, 3 h, yield over three steps: 7:
63%, ent-7: 86%.
Treatment of 5 under identical reaction conditions resulted
in a compound that upon comparison with 7 by chiral HPLC
and optical rotation proved to be ent-7. Thus, the absolute
configuration of the quaternary carbon in aziridine 3a is (R).
3. Conclusion
This assignment was also confirmed by chemical correlation
(Scheme 4). Hydrolysis21 of the aziridine moiety in 3a gave
the corresponding amino alcohol, which was benzoylated
followed by hydrolysis of the ester moiety to give (R)-(C)-
Ca-ethyl serine (8), the analytical data of which was in good
agreement with literature data.22
We have shown that radical addition to azirine 1 afford the
corresponding aziridine in modest to excellent dr. The use of
catalytic amounts of CuCl was found to increase the dr,
although the effect on the yield varied. The scope of the
reaction, in terms of varying the trialkylborane used in the
additions, has been investigated.
4. Experimental.26
4.1. General methods
Scheme 4. (a) HClO4, THF/H2O, 80 8C, 10 h; (b) BzCl, Et3N, DMAP,
CH2Cl2, rt, 3 h; (c) KOH, hydroquinone, EtOH/H2O, 80 8C, 14 h, yield over
three steps: 51%.
4.1.1. General procedure for alkyl radical additions to
azirine 1 in the presence of an alkyliodide. Method A. To
1 (17 mg, 0.058 mmol) in CH2Cl2 (2 mL) at K105 8C was
added EtI (46 mL, 0.58 mmol) and Et3B (288 mL,
0.29 mmol, 1 M solution in hexanes) followed by O2
(5 mL). After 5 min the reaction was quenched by addition
of NaHCO3 (1 mL aqueous satd). The resultant mixture was
filtered through an Extrelutew NT3 tube and eluted with
CH2Cl2 (15 mL), EtOAc (15 mL) and CH2Cl2 (15 mL), The
combined organic phases were concentrated and flash
chromatographed (pentane/EtOAc 1:0/4:1) to give 3a:4a
(15 mg, 77%, 91:9) as an oil.
It is likely that trialkylborane plays an important role for
the stereoselectivity obtained in radical addition to azirine 1.
In contrast to the hetero Diels–Alder reaction with azirine 1,
requiring stoichiometric amounts of a chelating Lewis acid
to obtain high diastereoselectivity,10 good selectivity was
observed in the present study in the absence of with Et3B.
Spectroscopic investigations of conjugate radical additions
to a,b-unsaturated carbonyl compounds suggest a com-
plexation of the organoborane to the C]O oxygen prior to
addition of the radical.23 It has also been shown that Lewis
acids such as BF3$OEt2 can catalyze reactions with 2H-
azirines, indicating the possibility of coordination to the
azirine nitrogen.24 Thus, the mode of complexation of the
trialkylborane to azirine 1 is not obvious.
4.1.2. General procedure for alkyl radical additions to
azirine 1 without an alkyliodide. Method B. To 1 (17 mg,
0.058 mmol) in CH2Cl2 (2 mL) at K105 8C was added Et3B
(172 mL, 0.17 mmol, 1 M solution in hexanes) and O2
(5 mL). After 5 min the reaction was quenched by addition
of NaHCO3 (1 mL aqueous satd). The resultant mixture was
filtered through an Extrelutew NT3 tube eluted with CH2Cl2
(15 mL), EtOAc (15 mL) and CH2Cl2 (15 mL). The com-
bined organic phases were concentrated and flash chromato-
graphed (pentane/EtOAc 1:0/4:1) to give 3a:4a (15.2 mg,
81%, 91:9) as an oil.
8-Phenylmenthyl derivatives similar to azirine 1 adopt s-cis
(A) or s-trans (B) conformations as depicted in Scheme 5.25
Assuming that these structures are relevant for the present
study, then a monodentate Lewis acid is expected, for steric
and electronic reasons, to favor s-trans conformer (B).
Addition to this conformer would preferentially take place
to the Re face of the C]N bond, affording the (S)
stereochemistry at the newly formed stereocenter. Similarly,
a chelating Lewis acid would be expected to preferentially
react through structure A, thus, affording an adduct having
(R) stereochemistry. As has been shown (vide supra), the (R)
aziridine is obtained as the major diastereomer in Et3B/O2
4.1.3. General procedure for alkyl radical additions to
azirine 1 in the presence of Lewis acid. Method C. To 1
(17 mg, 58 mmol) in CH2Cl2 at K105 8C was added CuCl
(0.61 mg, 6 mmol). The resultant mixture was stirred for
10 min before Et3B (172 mL, 172 mM, 1 M in hexanes) was

E. Risberg et al. / Tetrahedron 61 (2005) 8443–8450
8447
added followed by O2 (5 mL). After stirring for 60 min at
K105 8C the reaction was quenched by addition of
NaHCO3 (1 mL aqueous satd). This mixture was filtered
through an Extrelutw NT3 tube eluting with CH2Cl2
(15 mL), EtOAc (15 mL) and CH2Cl2 (15 mL). The
combined organic phases were and concentrated and flash
chromatographed (pentane/EtOAc 1:0/4:1) to give 3a:4a
(12.9 mg, 69%, 96:4) as a pale oil.
Analytical data for 3c: Rf 0.34 (pentane/EtOAc 4:1); [a]2D5C
5.1 (c 0.49, CH2Cl2); dH (CDCl3, 500 MHz) 7.31–7.25 (4H,
m, Ph), 7.19–7.15 (1H, m, Ph), 5.71–5.62 (1H, m, CHCH2),
5.03–4.97 (2H, m, CHCH2), 4.86 (1H, dt, JZ10.6, 4.4 Hz,
CHO), 2.18 (1H, dd, JZ14.7, 6.6 Hz, CHHCH]CH2), 2.11
(1H, m, CHCMe2Ph), 1.87–1.76 (3H, m, CHHCHMe,
CHMeCHH, CHHN), 1.70 (1H, br d, JZ12.8 Hz,
CHHN), 1.64 (1H, dd, JZ14.7, 6.6 Hz, CHHCH]CH2),
1.52–1.43 (2H, m, CHMe, CHHCHCMe2Ph), 1.28 (3H, s,
Me), 1.20–1.11 (1H, m, CHHCHMe), 1.18 (3H, s, Me),
0.97–0.85 (3H, m, CHMeCHH, CHHCHCMe2Ph, NH),
0.88 (3H, d, JZ7.1 Hz, CHMe); dC (CDCl3, 125 MHz)
172.5, 151.9, 133.8, 128.1, 125.2, 125.1, 117.2, 75.9, 50.3,
41.5, 39.4, 37.5, 35.2, 34.5, 33.2, 31.3, 29.5, 26.4, 23.3,
21.7; IR (neat) 2957, 2924, 1714, 1094 cmK1; HRMS
(FABC) calcd for C22H32NO2 (MCH) 342.2433, found
342.2432.
4.2. Data for compounds
4.2.1. (2S)-(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)
cyclohexyl 2-ethylaziridine-2-carboxylate (3a). Prepared
according to method A, B or C to give 3a:4a as a colorless
oil; dr was determined by HPLC: (Zorbax Rx-SIL, hexane/
i-PrOH 99.5:0.5, 1.1 mL/min) Rt 4aZ19.5 min, Rt 3aZ
23.0 min.
Analytical data for 4c: Rf 0.41 (pentane/EtOAc 4:1); [a]2D5C
29.9 (c 0.38, CH2Cl2); dH (CDCl3, 500 MHz) 7.33–7.25
(4H, m, Ph), 7.18–7.14 (1H, m, Ph), 5.73–5.63 (1H, m,
CHCH2), 5.06–4.97 (2H, m, CHCH2), 4.94 (1H, dt, JZ10.6,
4.4 Hz, CHO), 2.24–2.16 (1H, m, CHHCH]CH2), 2.07
(1H, m, CHHN), 1.93 (1H, br dd, JZ14.3, 6.6 Hz, CHHN),
1.79 (1H, m, CHHCH]CH2), 1.74–1.68 (2H, m,
CHHCHCMe2Ph, CHHCHMe), 1.64 (1H, app dt, JZ12.8,
2.9 Hz, CHCMe2Ph), 1.50–1.41 (1H, m, NH), 1.32 (3H, s,
Me), 1.20 (3H, s, Me), 1.10 (1H, m, CHMeCHH), 1.05–0.96
(1H, m, CHMe), 0.99 (1H, m, CHHCHMe), 0.92–0.82 (2H,
m, CHMeCHH, CHHCHCMe2Ph), 0.87 (3H, d, JZ6.6 Hz,
CHMe); dC (CDCl3, 125 MHz) 172.8, 151.4, 134.0, 128.2,
125.4, 125.3, 117.2, 76.1, 50.1, 41.8, 39.7, 37.4, 35.0, 34.4,
31.9, 31.3, 28.2, 26.7, 25.3, 21.7; IR (neat) 2959, 2924,
1716, 1093 cmK1; HRMS (FABC) calcd for C22H32NO2
(MCH) 342.2433, found 342.2444.
Analytical data for 3a: Rf 0.38 (pentane/EtOAc 4:1); [a]2D5C
7.4 (c 1.0, CH2Cl2); dH (CDCl3, 400 MHz) 7.37–7.24
(4H, m, Ph), 7.23–7.14 (1H, m, Ph), 4.80 (1H, dt, JZ12.1,
3.5 Hz, CHO), 2.10 (1H, m, CHCMe2Ph) 1.87–1.77 (3H, m,
CH2N, CHHCHMe), 1.73–1.57 (3H, m, CHHMe,
CHMeCHH, CHHCHCMe2Ph) 1.52–1.41 (2H, m,
CHHMe, CHMe), 1.29 (3H, s, Me), 1.18 (3H, s, Me), 1.13
(1H, dt, JZ12.9, 3.3 Hz, CHHCHMe), 1.01–0.79 (9H, m,
CH2Me, CHMe, CHHCHCMe2Ph, CHMeCHH, NH); dC
(CDCl3, 100 MHz) 172.7, 151.8, 128.1, 125.2, 125.1, 75.6,
50.3, 41.5, 39.4, 39.1, 34.5, 33.9, 31.3, 29.1, 26.4,
24.5, 23.7, 21.7, 9.9; IR (neat) 2964, 2926, 1714, 1193,
1093 cmK1; HRMS (FABC) calcd for C21H32NO2 (MCH)
330.2433, found 330.2432.
4.2.2. (2S)-(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)
cyclohexyl 2-butylaziridine-2-carboxylate (3b). Prepared
according to method B or C to give 3b:4b as a colorless oil;
dr was determined by HPLC: (Zorbax Rx-SIL, hexane/
i-PrOH 99.5:0.5, 1.1 mL/min) Rt 4bZ15.6 min, Rt 3bZ
17.6 min.
4.2.4. (2S)-(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)
cyclohexyl 2-isopropylaziridine-2-carboxylate (3d) and
(2R)-(1R,2S,5R)-5-methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl 2-isopropylaziridine-2-carboxylate (4d). Prepared
according to method B or C to give 3d:4d as a colorless oil;
dr was determined by HPLC: (Zorbax Rx-SIL, hexane/
i-PrOH 99.5:0.5, 1.1 mL/min) Rt 4dZ10.1 min, Rt 3dZ
12.3 min.
Analytical data for 3b: Rf 0.38 (pentane/EtOAc 4:1);
[a]2D5C9.2 (c 0.39, CH2Cl2); dH (CDCl3, 400 MHz) 7.32–
7.24 (4H, m, Ph), 7.20–7.15 (1H, m, Ph), 4.85 (1H, dt, JZ
10.6, 4.3 Hz, CHO), 2.10 (1H, dt, JZ11.9, 3.3 Hz,
CHHCHCMe2Ph), 1.86–1.77 (3H, m, CH2N, CHHCHMe),
1.73–1.66 (1H, m, CCHH), 1.62–1.41 (4H, m, CCHH,
CHMeCHH, CHHCHCMe2Ph, CHMe), 1.28 (3H, s, Me),
1.18 (3H, s, Me), 1.33–1.10 (5H, m, CHHCHMe,
CHMeCHH, CHHCMe2Ph, CCH2CH2), 0.98–0.76 (9H,
m, CHMe, CH2Me, CH2Me, NH); dC (CDCl3, 125 MHz)
172.8, 151.9, 128.1, 125.2, 125.0, 75.7, 50.2, 41.4, 39.4,
38.3, 34.5, 33.9, 31.3, 31.1, 29.2, 27.8, 26.4, 23.6, 22.7,
21.7, 14.0; IR (neat) 2954, 2927, 1715, 1094 cmK1; HRMS
(FABC) calcd for C23H36NO2 (MCH) 358.2746, found
358.2747.
Analytical data for 3d: Rf 0.48 (pentane/EtOAc 4:1);
[a]2D5C26.6 (c 0.55, CH2Cl2); dH (CDCl3, 500 MHz)
7.31–7.24 (4H, m, Ph), 7.20–7.16 (1H, m, Ph), 4.88 (1H,
dt, JZ11.0, 4.4 Hz, CHO), 2.10 (1H, m, CHCMe2Ph), 1.85–
1.77 (2H, m, CHHN, CHMe), 1.72–1.61 (3H, m, CHHN,
CHMeCHH, CHHCHCMe2Ph), 1.54–1.44 (2H, m, CHMe2,
CHHCHMe), 1.28 (3H, s, Me), 1.18 (3H, s, Me), 1.15 (1H,
m, NH), 0.95 (1H, m, CHHCHMe), 0.95–0.85 (1H, m,
CHMeCHH), 0.88 (6H, d, JZ7.0 Hz, CHMe2), 0.76 (1H, m,
CHHCHCMe2Ph), 0.67 (3H, d, JZ7.0 Hz, CHMe); dC
(CDCl3, 125 MHz) 172.8, 151.8, 128.1, 125.2, 125.1, 75.6,
50.2, 42.2, 41.5, 39.4, 34.5, 31.9, 31.3, 29.0, 27.4, 26.5,
23.8, 21.7, 19.4, 16.8; IR (neat) 2962, 2925, 1715, 1185,
1091 cmK1; HRMS (FABC) calcd for C22H34NO2 (MCH)
344.2590, found 344.2588.
4.2.3. (2S)-(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)
cyclohexyl 2-allylaziridine-2-carboxylate (3c) and (2R)-
(1R,2S,5R)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexyl
2-allylaziridine-2-carboxylate (4c). Prepared according to
method B or C to give 3c:4c as a colorless oil; dr was
determined by HPLC: (Zorbax Rx-SIL, hexane/i-PrOH
99.5:0.5, 1.1 mL/min) Rt 4cZ15.3 min, Rt 3cZ18.7 min.
Analytical data for 4d: Rf 0.57 (pentane/EtOAc 4:1);
[a]2D5C24.3 (c 0.35, CH2Cl2); dH (CDCl3, 500 MHz)

8448
E. Risberg et al. / Tetrahedron 61 (2005) 8443–8450
7.32–7.26 (4H, m, Ph), 7.19–7.15 (1H, m, Ph), 4.92 (1H, dt,
JZ10.6, 4.4 Hz, CHO), 2.09 (1H, m, CHCMe2Ph), 1.85–
1.75 (2H, m, CHHN, CHMe), 1.70 (1H, m, CHMeCHH),
1.65 (1H, m, CHHN), 1.52–1.42 (1H, m, CHHCHCMe2Ph),
1.45 (1H, m, CHMe2), 1.38 (1H, m, CHHCHMe), 1.31 (3H,
s, Me), 1.19 (3H, s, Me), 1.11 (1H, m, NH), 0.99 (1H, m,
CHHCHMe), 0.92–0.82 (1H, m, CHHCHCMe2Ph), 0.88
(3H, d, JZ6.6 Hz, Me), 0.84 (3H, d, JZ7.0 Hz, Me), 0.82
(3H, d, JZ7.0 Hz, CHMe), 0.76 (1H, m, CHMeCHH); dC
(CDCl3, 125 MHz) 172.6, 151.5, 128.2, 125.3, 125.2, 75.9,
49.9, 42.4, 41.8, 39.7, 34.5, 31.3, 29.9, 28.3, 27.8, 26.7,
25.1, 21.7, 18.7, 18.2; IR (neat) 2961, 2925, 1718, 1183,
1094 cmK1; HRMS (FABC) calcd for C22H34NO2 (MCH)
344.2590, found 344.2593.
4.2.6. (2S)-(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)
cyclohexyl 2-(2-cyclohexylethyl) aziridine-2-carboxylate
(3f) and (2R)-(1R,2S,5R)-5-methyl-2-(2-phenylpropan-2-
yl)cyclohexyl 2-(2-cyclohexylethyl)aziridine-2-carb-
oxylate (4f). Prepared according to method B or C to give
3f:4f as a colorless oil; dr was determined by HPLC:
(Zorbax Rx-SIL, hexane/i-PrOH 99.5:0.5, 1.1 mL/min) Rt
4fZ12.0 min, Rt 3fZ13.6 min.
Analytical data for 3f: Rf 0.48 (pentane/EtOAc 4:1); [a]2D5C
10.3 (c 0.73, CH2Cl2); dH (CDCl3, 500 MHz) 7.30–7.24
(4H, m), 7.19–7.15 (1H, m), 4.84 (1H, dt, JZ10.7, 4.1 Hz),
2.12 (1H, m), 1.87–1.79 (3H, m), 1.75–1.62 (6H, m), 1.59–
1.41 (3H, m), 1.31 (s, 3H), 1.23–1.06 (7H, m), 1.21 (3H, s),
0.99–0.80 (6H, m), 0.91 (3H, d, JZ6.6 Hz); dC (CDCl3,
125 MHz) 172.8, 151.8, 128.1, 125.2, 125.1, 75.7, 50.3,
41.5, 39.4, 38.4, 37.7, 34.5, 33.9, 33.3, 33.14, 33.07, 31.3,
29.2, 28.8, 26.7, 26.4, 26.34, 26.31, 23.6, 21.7; IR (neat)
2920, 2851, 1715, 1201, 1094 cmK1; HRMS (FABC) calcd
for C27H42NO2 (MCH) 412.3216, found 412.3216.
4.2.5. (2R)-(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)
cyclohexyl 2-sec-butylaziridine-2-carboxylate (3e) and
(2R)-(1R,2S,5R)-5-methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl 2-sec-butylaziridine-2-carboxylate (4e). Prepared
according to method B or C to give 3d:4d as a colorless oil;
dr was determined by HPLC: (Zorbax Rx-SIL, hexane/
i-PrOH 99.5:0.5, 1.1 mL/min) Rt 4eZ9.6 min and 10.0, Rt
3eZ12.6 min.
Analytical data for 4f: Rf 0.53 (pentane/EtOAc 4:1); [a]2D5C
15.3 (c 0.40, CH2Cl2); dH (CDCl3, 500 MHz) 7.31–7.26
(4H, m), 7.19–7.15 (1H, m), 4.92 (1H, dt, JZ10.7, 4.4 Hz),
2.05 (1H, m), 1.80 (1H, m), 1.74–1.59 (9H, m), 1.50–1.38
(3H, m), 1.32 (s, 3H), 1.35–1.05 (6H, m), 1.21 (3H, s), 1.02–
0.79 (6H, m), 0.87 (3H, d, JZ6.6 Hz); dH (CDCl3,
125 MHz) 173.0, 151.3, 128.2, 125.4, 125.3, 75.6, 50.1,
41.8, 39.8, 38.5, 37.8, 34.4, 33.39, 33.36, 33.3, 33.2, 31.3,
27.6, 26.8, 26.7, 26.42, 26.35, 26.3, 25.9, 21.7; IR (neat)
2924, 2852, 1092 cmK1; HRMS (FABC) calcd for
C27H42NO2 (MCH) 412.3216, found 412.3216.
Analytical data for 3e, mixture of the two diastereomers, not
separable by preparative HPLC: Rf 0.53 (pentane/EtOAc
4:1); dH (CDCl3, 500 MHz) 7.31–7.24 (4H, m), 7.21–7.17
(1H, m), 4.88 (1H, m), 2.08 (1H, m), 1.85–1.73 (2H, m),
1.71–1.64 (2H, m), 1.53 (1H, m), 1.51–1.44 (1H, m), 1.44–
1.36 (1H, m), 1.35–1.20 (2H, m), 1.28 (3H, br s), 1.18 (3H,
br s), 1.16–1.10 (1H, m), 0.96–0.82 (9H, m), 0.77–0.71 (3H,
m); dC (CDCl3, 125 MHz) 172.7, 172.6, 151.74, 151.68,
128.1, 125.2, 125.1, 75.63, 75.57, 50.19, 50.16, 42.3, 41.8,
41.5, 41.4, 39.46, 39.50, 36.0, 35.3, 34.51, 34.50, 32.0, 31.9,
31.3, 28.8, 28.6, 26.8, 26.54, 26.51, 24.35, 24.29, 24.1, 21.7,
16.2, 14.2, 12.4, 12.0; IR (neat) 2961, 2926, 1716, 1185,
1094 cmK1; HRMS (FABC) calcd for C23H36NO2 (MCH)
358.2746, found 358.2741.
4.2.7. (2S)-(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)
cyclohexyl 2-(2-methylallyl)aziridine-2-carboxylate (3g)
and (2R)-(1R,2S,5R)-5-methyl-2-(2-phenylpropan-2-
yl)cyclohexyl 2-(2-methylallyl)aziridine-2-carboxylate
(4g). Prepared according to method B or C to give 3g:4g
as a colorless oil; dr was determined by HPLC: (Zorbax
Rx-SIL, hexane/i-PrOH 99.5:0.5, 1.1 mL/min) Rt 4gZ
15.3 min, Rt 3gZ16.9 min.
Analytical data for 4e, two minor diastereomers still
containing small amounts of the other isomer after
preparative HPLC, first peak: Rf 0.64 (pentane/EtOAc
4:1); dH (CDCl3, 500 MHz) 7.32–7.25 (4H, m), 7.19–7.15
(1H, m), 4.91 (1H, m), 2.07 (1H, m), 1.82 (1H, m), 1.65 (1H,
m), 1.52–1.33 (5H, m), 1.30 (3H, br s), 1.19 (3H, br s), 1.17–
1.04 (2H, m), 0.98 (1H, app q, JZ11.8 Hz), 0.92–0.83
(10H, m), 0.77 (1H, m); dC (CDCl3, 125 MHz) 172.3, 151.4,
128.2, 125.4, 125.2, 75.9, 49.8, 42.1, 41.8, 39.7, 36.1, 34.4,
31.3, 31.0, 28.0, 26.8, 25.7, 25.5, 21.7, 15.6, 12.2; IR (neat)
2962, 2926, 1714, 1181, 1094 cmK1; HRMS (FABC) calcd
for C23H36NO2 (MCH) 358.2746, found 358.2758.
Analytical data for 3g: Rf 0.44 (pentane/EtOAc 4:1); [a]2D5C
38.2 (c 0.92, CH2Cl2); dH (CDCl3, 400 MHz) 7.32–7.27
(4H, m, Ar), 7.19–7.14 (1H, m, Ar), 4.81 (1H dt, JZ10.8,
4.3 Hz, CHO), 4.72 (1H, s, ]CHH), 4.62 (1H, s, ]CHH),
2.15–2.04 (2H, m, CHCMe2Ph, CHHC(Me)CH2), 1.85–
1.77 (3H, m, CHHC(Me)CH2, CHHN, CHMe), 1.72–1.67
(1H, m, CHHN), 1.66 (3H, s, C(Me)CH2), 1.55–1.40
(3H, m, CHMeCHH, CHHCHCMe2Ph, CHHCHMe), 1.27
(3H, s, Me), 1.17 (3H, s, Me), 1.16–1.07 (2H, m, NH,
CHHCHMe), 0.96–0.84 (2H, m, CHMeCHH,
CHHCHCMe2Ph), 0.87 (3H, d, JZ6.5 Hz, CHMe); dC
(CDCl3, 125 MHz) 172.7, 152.0, 142.3, 128.1, 125.2, 125.1,
111.5, 76.2, 50.2, 41.1, 39.4, 38.4, 37.0, 34.5, 33.4, 31.2,
29.3, 26.4, 23.5, 23.5, 21.7; IR (neat) 2957, 2923, 1716,
1217, 1093 cmK1; HRMS (FABC) calcd for C23H34NO2
(MCH) 356.2590, found 356.2592.
Analytical data 4e, second peak: Rf 0.64 (pentane/EtOAc
4:1); dH (CDCl3, 500 MHz) 7.32–7.25 (4H, m), 7.20–7.15
(1H, m), 4.91 (1H, m), 2.07 (1H, m), 1.82 (1H, m), 1.74–
1.60 (2H, m), 1.52–1.33 (5H, m), 1.30 (3H, br s), 1.19 (3H,
br s), 1.17–1.05 (2H, m), 0.98 (1H, app q, JZ11.6 Hz),
0.92–0.82 (10H, m,), 0.77 (1H, m); dH (CDCl3, 125 MHz)
172.3, 151.4, 128.2, 125.4, 125.2, 75.9, 49.8, 42.1, 41.8,
39.7, 36.1, 34.4, 31.3, 31.0, 28.0, 26.8, 25.7, 25.5, 21.7,
15.6, 12.2; IR (neat) 2962, 2927, 1178, 1093 cmK1; HRMS
(FABC) calcd for C23H36NO2 (MCH) 358.2746, found
358.2742.
Analytical data for 4g: Rf 0.52 (pentane/EtOAc 4:1); [a]2D5C
23.5 (c 0.31, CH2Cl2); dH (CDCl3, 500 MHz) 7.33–7.27
(4H, m, Ar), 7.20–7.14 (1H, m, Ar), 4.89 (1H, dt, JZ10.8,
4.5 Hz, CHO), 4.76 (1H, s, ]CHH), 4.66 (1H, s, ]CHH),

E. Risberg et al. / Tetrahedron 61 (2005) 8443–8450
8449
2.15–1.97 (3H, m, CHCMe2Ph, CHHC(Me)CH2,
CHHC(Me)CH2), 1.83–1.77 (2H, m, CHHN, CHMe),
1.70–1.60 (2H, m, CHHN, CHHCHCMe2Ph), 1.68 (3H, s,
C(Me)CH2), 1.53–1.40 (2H, m, CHHCHMe, m,
CHMeCHH), 1.31 (3H, s, Me), 1.19 (3H, s, Me), 1.14–
0.80 (4H, m, NH, CHMeCHH, CHHCHCMe2Ph,
CHHCHMe), 0.87 (3H, d, JZ6.5 Hz, CHMe); dC (CDCl3,
125 MHz) 172.7, 151.4, 142.3, 128.2, 125.4, 125.3, 111.5,
76.3, 50.0, 41.5, 39.7, 38.7, 36.9, 34.4, 32.7, 31.3, 27.9,
Comparison of retention times between 7 and ent-7 was
performed by HPLC: (Chiralcel OJ, hexane/i-PrOH 99:1,
0.7 mL/min) Rt 7Z26.5 min, Rt ent-7Z24.6 min.
Analytical data for 7: Rf 0.18 (pentane/EtOAc 4:1); [a]2D5K
5.9 (c 0.58, CH2Cl2); dH (CDCl3, 500 MHz, mixture of
N-invertomers) 7.42–7.21 (10H, m, Ar), 4.42 (1H, d, JZ
12.4 Hz, CHHO), 4.17 (2H, AB q, JZ11.8, 4.8 Hz, CH2O),
3.89 (1H, d, JZ12.4 Hz, CHHO), 3.73 (4H, m, CH2Ph,
CH2Ph), 2.06 (3H, s, MeCO), 1.94 (CHHN1H, s), 1.91 (3H,
s, MeCO), 1.89 (1H, s, CHHN), 1.84 (1H, m, CHHMe), 1.70
(1H, m, CHHMe), 1.62 (1H, m, CHHMe), 1.43 (1H, s,
CHHN), 1.42 (1H, m, CHHMe), 1.34 (1H, s, CHHN), 1.03
(3H, t, JZ7.3 Hz), 0.94 (3H, t, JZ7.3 Hz); dC (CDCl3,
125 MHz) 170.92, 170.88, 139.9, 139.8, 128.3, 127.59,
127.57, 126.7, 68.7, 62.6, 56.8, 56.0, 42.5, 42.4, 37.6, 37.3,
28.3, 20.9, 20.6, 19.6, 11.0, 9.5; IR (neat) 2970, 1740, 1235,
1097, 1034 cmK1; HRMS (FABC) calcd for C14H20NO2
(MCH) 234.1494, found 234.1498.
26.7, 25.5, 23.6, 21.7; IR (neat) 2960, 2924, 1174 cmK1
;
HRMS (FABC) calcd for C23H34NO2 (MCH) 356.2590,
found 356.2591.
4.2.8. Aziridine 5. Prepared according to method A to give
5:6 as crystals; dr was determined by HPLC: (Zorbax
Rx-SIL, hexane/i-PrOH 95:5, 1.1 mL/min) Rt 5Z12.3 min,
Rt 6Z18.2 min.
Analytical data for 5: Rf 0.42 (pentane/EtOAc 1:1); mp 151–
152 8C (from EtOH/H2O); [a]2D5K13.2 (c 1.0, CH2Cl2); dH
(CDCl3, 400 MHz) 3.90 (1H, dd, JZ7.6, 4.5 Hz, CHNSO2),
3.44 (2H, AB q, JZ13.8 Hz, CH2SO2), 2.64–2.54 (1H, m,
CHHCHN), 2.22 (1H, br s, NH), 2.07 (1H, A-part of AB dq,
JZ14.6, 7.3 Hz, CHHMe), 1.98–1.89 (5H, m, CHCMe2,
CHHCHN, CH2N, CHCH2CHH), 1.49–1.35 (3H, m,
CHCH2CHH, CHCH2), 1.35–1.28 (1H, B-part of AB dq,
1H, JZ14.6, 7.3 Hz, CHHMe), 1.19 (3H, s, Me), 0.98
(3H, s, Me), 0.95 (3H, t, JZ7.5 Hz, CH2Me); dC (CDCl3,
100 MHz) 173.5, 77.2, 65.2, 52.9, 48.5, 47.9, 44.5, 43.1,
38.1, 32.7, 27.2, 26.6, 20.4, 19.9, 9.8; IR (neat) 3294, 2955,
1678, 1328, 1200, 1136 cmK1; HRMS (FABC) calcd for
C15H25N2O3S (MCH) 313.1586, found 313.1588.
4.2.10. ((R)-1-Benzyl-2-ethylaziridin-2-yl)methyl acetate
(ent-7). Ent-7 was prepared in analogy with 7 starting from
5 and was spectroscopically identical to 7. Comparison of
retention times between 7 and ent-7 was performed by
HPLC: (Chiralcel OJ, hexane/i-PrOH 99:1, 0.7 mL/min) Rt
ent-7Z24.6 min.
Additional analytical data for ent-7; [a]2D5C8.3 (c 0.56,
CH2Cl2); HRMS (FABC) calcd for C14H20NO2 (MCH)
234.1494, found 234.1489.
4.2.11. (R)-(C)-Ca-Ethyl serine (8). [a]2D5C2.9 (c 0.90,
5 N HCl); dH (1 N DCl/D2O, 400 MHz) 3.89 (1H, d, JZ
12.1 Hz, CHHOH), 3.61 (1H, d, JZ12.1 Hz, CHHOH),
1.79 (1H, m, CHHMe), 1.63 (1H, m, CHHMe), 0.86 (3H, br
t, JZ7.1 Hz, CH2Me).
4.2.9. ((S)-1-Benzyl-2-ethylaziridin-2-yl)methyl acetate
(7). To 3a (25.4 mg, 77 mmol) in MeCN (15 mL) was added
K2CO3 (32 mg, 230 mmol) and BnBr (28 mL, 230 mmol) and
the resultant mixture was heated to reflux. After 5 h the
mixture was cooled to rt and H2O was added. The phases
were separated and the aqueous phase extracted with Et2O.
The combined organic phases were washed with H2O, dried
(MgSO4) and concentrated. Flash chromatography (pen-
tane/EtOAc 1:0/10:1) of the residue gave the correspond-
ing benzylated aziridine (25.6 mg, 80%) as a colorless oil,
which was used directly in the next step.
Acknowledgements
We thank the Swedish Foundation for Strategic Research
(SELCHEM), the Swedish Research Council and Knut and
Alice Wallenberg Foundation for financial support.
To the material from above (25.6 mg, 61 mmol) in Et2O
(5 mL) at K78 8C was added LiAlH4 (183 mL, 183 mmol,
1M in THF) dropwise. After warming to rt for 1.5 h the
reaction was quenched by addition of H2O (7 mL), 15%
aqueous NaOH (7 mL) and H2O (21 mL). After stirring the
resultant mixture for 15 min MgSO4 was added and the
slurry was filtered. Concentration gave a crude product that
was used in the next step without further purification.
References and notes
1. (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99,
1069–1094. (b) Denmark, S. E.; Nicaise, O. J.-C. In Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Comprehensive Organic
Catalysis; Springer: Berlin, 1999; Vol. 2, pp 923–961.
(c) Bloch, R. Chem. Rev. 1998, 98, 1407–1438.
To the crude reaction mixture from above in CH2Cl2 (5 mL)
at 0 8C was added DMAP (18.0 mg, 148 mmol) and Ac2O
(18.6 mL, 197 mmol). After stirring at rt for 3 h the reaction
was quenched by addition of H2O (1 mL). The resultant
mixture was filtered through an Extrelutw NT3 tube eluting
with CH2Cl2 (15 mL), EtOAc (15 mL) and CH2Cl2
(15 mL). Removal of the solvents and flash chromatography
(pentane/EtOAc 1:0/1:1) gave 7 (11.1 mg, 79% over two
steps) as a colorless oil.
2. Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140–1157.
3. Friestad, G. K. Tetrahedron 2001, 57, 5461–5496.
4. Alves, M. J.; Fortes, G.; Guimara˜es, E.; Lemos, A. Synlett
2003, 1403–1406.
5. (a) Lee, W. K.; Ha, H.-J. Aldrichim. Acta 2003, 36, 57–63.
(b) Cardillo, G.; Gentilucci, L.; Tolomelli, A. Aldrichim. Acta
2003, 36, 39–50. (c) Sweeney, J. B. Chem. Soc. Rev. 2002, 31,
247–258. (d) McCoull, W.; Davis, F. A. Synthesis 2000,

8450
E. Risberg et al. / Tetrahedron 61 (2005) 8443–8450
1347–1365. (e) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994,
33, 599–619.
18. (a) Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T. Synlett
1999, 465–467. (b) Miyabe, H.; Ueda, M.; Yoshioka, N.;
Yamakawa, K.; Naito, T. Tetrahedron 2000, 56, 2413–2420.
19. Schaffner, A.-P.; Becattini, B.; Ollivier, C.; Weber, V.;
Renaud, P. Synthesis 2003, 2740–2742.
6. (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003,
103, 3263–3295. (b) Renaud, P.; Gerster, M. Angew. Chem.,
Int. Ed. 1998, 37, 2562–2579.
7. (a) Sibi, M. P.; Jianguo, J. J. Org. Chem. 1996, 61, 6090–6091.
(b) Sibi, M. P.; Jianguo, J. Angew. Chem., Int. Ed. 1997, 36,
274–276. (c) Sibi, M. P.; Jianguo, J. Angew. Chem., Int. Ed.
1996, 35, 190–192. (d) Sibi, M. P.; Jasperse, C. P.; Jianguo, J.
J. Am. Chem. Soc. 1995, 117, 10779–10780. (e) Nishida, M.;
Nishida, A.; Kawahara, N. J. Org. Chem. 1996, 61,
3574–3575.
20. Commercially available or prepared by transmetallation:
(a) Mikhailov, B. M. Organomet. Chem. Rev. A 1972, 8,
1–65. (b) Topchiev, A. V.; Prokhorova, A. A.; Paushkin, Y.
M.; Kurashev, M. V. Izv. Akad. Nauk SSSR, Ser. Khim. 1958,
370–371, or hydroboration: (a) Matteson, D. S. Stereodirected
Synthesis with Organoboranes; Springer: Berlin, 1995.
(b) Onak, T. Organoborane Chemistry; Academic: New York,
1975.
8. Risberg, E.; Somfai, P. Tetrahedron: Asymmetry 2002, 13,
1957–1959.
21. (a) Alezra, V.; Bonin, M.; Micouin, L.; Policar, C.; Husson,
H.-P. Eur. J. Org. Chem. 2001, 2589–2594. (b) Olofsson, B.;
Somfai, P. J. Org. Chem. 2002, 67, 8574–8583.
˚
9. Sjoholm Timen, A; Somfai, P. J. Org. Chem. 2003, 68,
´
¨
9958–9963.
¨
˚
´
10. Sjoholm Timen, A; A., Fischer; Somfai, P. Chem. Commun.
2003, 1150–1151.
22. (a) Witkowska, R.; Kaczmarek, K.; Crisma, M.; Toniolo, C.;
Zabrocki, J. J. Peptide Sci. 2001, 7, 619–625. (b) Ito, Y.;
Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T.
Tetrahedron Lett. 1988, 29, 235–238.
11. Risberg, E.; Fischer, A.; Somfai, P. Chem. Commun. 2004,
2088–2089.
12. (a) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1,
569–572. (b) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro,
C.; Naito, T. Tetrahedron 1998, 54, 11431–11444.
(c) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett
1998, 780–782.
23. Beraud, V.; Gnanou, Y.; Walton, J. C.; Maillard, B.
Tetrahedron Lett. 2000, 41, 1195–1198.
24. (a) Ray, C. A.; Risberg, E.; Somfai, P. Tetrahedron 2002, 58,
5983–5987. (b) Ray, C. A.; Risberg, E.; Somfai, P.
Tetrahedron Lett. 2001, 42, 9289–9291. (c) Hugener, M.;
Heimgartner, H. Helv. Chim. Acta 1995, 78, 1490–1498.
(d) Bader, H.; Hansen, H.-J. Helv. Chim. Acta 1978, 61,
286–304.
13. Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T.
J. Org. Chem. 2000, 65, 176–185.
14. Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415–3434.
15. Halland, N.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1
2001, 1290–1295.
25. (a) Whitesell, J. K.; Lawrence, R. M.; Chen, H. H. J. Org.
Chem. 1986, 51, 4779–4784. (b) Kulesza, A.; Jurczak, J.
Synthesis 2003, 2110–2114. (c) Kulesza, A.; Mieczkowski, A.;
Jurczak, J. Tetrahedron: Asymmetry 2002, 13, 2061–2069.
(d) Kulesza, A.; Jurczak, J. Chirality 2001, 13, 634–635.
(e) Wipf, P.; Stephenson, C. R. J. Org. Lett. 2003, 5,
2449–2452.
16. Sibi, M. P.; Cook, G. R. In Yamamoto, H., Ed.; Lewis Acids
in Organic Synthesis; Wiley: Weinheim, 2000; Vol. 2,
pp 543–574.
17. (a) Brown, H. C.; Rogic, M. M.; Rathke, M. W.; Kabalka,
G. W. J. Am. Chem. Soc. 1967, 89, 5709–5710.
(b) Suzuki, A.; Arase, A.; Matsumoto, H.; Itoh, M.;
Brown, H. C.; Rogic, M. M.; Rathke, M. W. J. Am. Chem.
Soc. 1967, 89, 5708–5709.
˚
26. For general experimental procedures, see: Ahman, J.; Somfai,
P. Tetrahedron 1995, 51, 9747–9756.