Syntheses of tetrahydropyridin-3-ol and tetrahydroazepin-3-ol from a chiral aziridine-2-carboxylate

Article abstract of DOI:10.1016/j.tet.2007.02.045

A method for the stereoselective preparation of 1,2,3,6-tetrahydropyridin-3-ols and 2,3,4,7-tetrahydro-1H-azepin-3-ols, potentially versatile intermediates in the asymmetric synthesis of various piperidine alkaloids and azasugars, has been developed. The

Full text of DOI:10.1016/j.tet.2007.02.045

Tetrahedron 63 (2007) 3321–3327
Syntheses of tetrahydropyridin-3-ol and tetrahydroazepin-3-ol
from a chiral aziridine-2-carboxylate
a
b
Hyeon Kyu Lee,a, Jung Hee Im and Sang Hun Jung
*
aBio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yusung, Taejon 305-606, South Korea
bCollege of Pharmacy, Chungnam National University, Yusung, Taejon 305-764, South Korea
Received 30 December 2006; revised 9 February 2007; accepted 13 February 2007
Available online 15 February 2007
Abstract—A method for the stereoselective preparation of 1,2,3,6-tetrahydropyridin-3-ols and 2,3,4,7-tetrahydro-1H-azepin-3-ols, poten-
tially versatile intermediates in the asymmetric synthesis of various piperidine alkaloids and azasugars, has been developed. The routes start
with a readily available optically pure aziridine-2-carboxylate. The design strategy relies on four key transformations involving (1) stereo-
selective reduction of an acyl-aziridine intermediate derived from the aziridine-2-carboxylate, (2) regioselective aziridine ring opening,
(3) N-allylation, and (4) ring-closing metathesis. The method developed in this investigation provides ready access to stereochemically
defined and highly functionalized 3-hydroxy-substituted tetrahydropyridines and tetrahydroazepines.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
versatile intermediates for asymmetric syntheses of various
piperidine alkaloids and azasugars. The key steps in the
new approaches we have designed for preparation of these
targets involve (1) transformation of the carboxylate group
in the aziridine-2-carboxylate 1 to form the olefin appended
allyl-aziridines G or butenyl-aziridines H, (2) nucleophilic
aziridine ring opening to form the respective amines E
and F, (3) N-allylation processes to generate the correspond-
ing dienes C and D, and (4) ring-closing metathesis to
construct the six- and seven-membered heterocyclic targets
(Scheme 1).
Numerous alkaloids containing piperidine and indolizidine
ring systems, are found frequently in nature. Many of these
substances display a wide range of interesting biological
activities.1,2 As a result, these alkaloids, which commonly
contain a 2-hydroxymethyl-3-piperidinol moiety as a salient
structural feature, have become important synthetic targets.3
In a recent program aimed at uncovering new strategies for
the preparation of these alkaloids, we developed a new
method for preparing 2-piperidones starting with readily
accessible 2-azetidinones.4c In addition, we showed that
this method can be used in routes for the stereoselective syn-
thesis of indolizidines4a and prosopis and cassia alkaloids.4b
2. Results and discussion
This earlier effort provoked an interest in the chemistry of
enantiomerically pure aziridines, which has been exten-
sively probed in the context of the synthesis of various
nitrogen containing compounds.5 Owing to ring strain,
regioselective and stereoselective ring-opening reactions of
aziridines with various nucleophiles take place readily and
in a stereochemically predictable manner. Adding to these
attractive properties is the fact that ethyl (2R)- and (2S)-
aziridine-2-carboxylate are readily available in optically
pure forms.6 These advantageous features led us to design
novel strategies for the synthesis of tetrahydropyridin-3-ols
(A) and tetrahydroazepin-3-ols (B), which are potentially
The optically pure aziridine-2-carboxylate 1, serving as the
starting point in the approaches, is prepared via reaction of
enantiomerically pure (R)-(+)-a-methylbenzylamine and
ethyl 2,3-dibromopropionate by using the reported proce-
dure.6 Aziridine-2-carboxylate (2R)-1 is transformed to the
unsaturated ketone 3 by a two-step sequence involving addi-
tion of the lithium carbanion of methyl dimethylphospho-
nate followed by Horner–Wadsworth–Emmons olefination
with acetaldehyde and the resulting b-ketophosphonate 27
(Scheme 2). The effort to obtain the unsaturated ketone 3
from the reaction of Weinreb amide 88a,11 and vinyl magne-
sium bromide was failed affording low yield of 3 and com-
plex by-products.
Keywords: Aziridine-2-carboxylate; Tetrahydropyridin-3-ol; Tetrahydro-
1H-azepin-3-ol.
* Corresponding author. Tel.: +82 42 860 7016; fax: +82 42 861 0307;
e-mail: leehk@krict.re.kr
Studies on the stereoselective reduction of the aziridinyl
alkyl or aryl ketones with various reducing agents have
been reported earlier by Lee et al.8 In the current effort in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.045

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H. K. Lee et al. / Tetrahedron 63 (2007) 3321–3327
OH
SPh
OH
SPh
OH
OH
SPh
N
R
N
R
HN
R
Ph
N
R
CO2Et
Pyridin-3-ol (A)
C
E
G
Me
(2R)-1
N
CO2Et
H
N
R
OH
OH
SPh
OH
SPh
OH
R = α-Methylbenzyl
SPh
N
R
N
R
HN
R
N
R
Azepin-3-ol (B)
D
F
H
Scheme 1. Retrosynthetic analysis of the preparation of tetrahydropyridin-3-ol A and tetrahydroazepin-3-ol B from chiral aziridine-2-carboxylate 1.
Ph
OH
Me
Me
N
3
(c)
(d)
Ph
Ph
Ph
2
H
O
H
O
P
O
H
(2R,3S)-4
Me
N
Me
N
Me
(b)
N
CO2Et
H
(a)
OMe
OMe
Ph
OH
3
N
3
(2R)-1
2
2
H
(2R,3R)-4
Scheme 2. (a) CH3PO(OMe)2, n-BuLi, ꢀ78 ꢁC, 98%; (b) CH3CHO, K2CO3, CH3CN, rt, 75%; (c) ZnCl2, NaBH4, MeOH, ꢀ78 ꢁC, 96%; and (d) L-Selectride,
THF, ꢀ78 ꢁC, 40%.
which a number of conditions were probed, we observed that
treatment of aziridinyl vinyl ketone 3 with NaBH4/ZnCl2 in
MeOH provides the erythro alcohol (2R,3S)-4 in excellent
yield (96%). The high level of stereochemical control attend-
ing this process was rationalized by using a chelation con-
trolled hydride delivery model.8a Support for this proposal
comes from the observation that reaction of 3 with the non-
chelating bulky reducing agent, L-Selectride, provides the
threo alcohol (2R,3R)-4 exclusively. The low 40% yield of
this process is due to the formation of over-reduced product
that likely arises by initial 1,4-reduction.
with excess (4 equiv) allyl bromide and catalytic amount
of (n-Bu)4NI under reflux condition smoothly affords the
bis-olefin 6 in 94% yield. Under the reaction condition no
detectable amount of N,O-diallylated product was obtained.
In accord with expectation, ring-closing metathesis10 reac-
tion of 6 (10 mol % of the first-generation Grubbs catalyst
((Cy3P)2Cl2Ru]CHPh) in refluxing toluene) produces the
desired (2S,3S)-1,2,3,6-tetrahydropyridin-3-ol (2S,3S)-7
in modestly high yield (Scheme 3). The (2S,3R)-1,2,3,6-
tetrahydropyridin-3-ol (2S,3R)-7 diastereomer can also be
prepared from the diastereomeric threo alcohol (2R,3R)-4
by employing essentially the same procedure used for the
conversion of (2R,3S)-4 to (2S,3S)-7.
A regioselective aziridine ring-opening reaction takes place
when (2R,3S)-4 is treated with thiophenol at room tempera-
ture in CH2Cl2. This process smoothly generates the b-
amino alcohol 5 through attack of the thiolate at the less
sterically hindered C-1 position of the aziridine ring.9 It is
reported that sterically congested amines similar to 5 with
bulky substituent a-methylbenzyl group on nitrogen were
resistant to intramolecular and intermolecular acylation re-
action.8c But N-allylation of the resulting amino alcohol 5
In a conceptually similar manner, we envisaged that the tet-
rahydroazepin-3-ol B could be prepared by a route starting
with the allyl-ketone 9,8a prepared from (2R)-aziridine-2-
carboxylate ethyl ester (2R)-1 by using the corresponding
Weinreb amide 8.11 In practice, reaction of (2R)-1 with
O-methylhydroxylamine hydrochloride in the presence
AlMe3 provided the Weinreb amide 8 in 92% yield. Reaction
Ph
Ph
Ph
OH
Ph
Me
PhS
NH
Me
PhS
N
Me
PhS
N
OH
3
(a)
(b)
(c)
SPh
N
N
Me
Me
N
2
H
Ph
Me
OH
OH
OH
(2R,3S)-4
(2S,3S)-5
(2S,3S)-6
(2S,3S)-7
Ph
Ph
Ph
OH
SPh
Ph
Me
PhS
NH
Me
PhS
N
Me
PhS
N
OH
(a)
(b)
(c)
N
3
2
H
Ph
Me
OH
(2S,3R)-5
OH
(2S,3R)-6
OH
(2S,3R)-7
(2R,3R)-4
Scheme 3. (a) PhSH, CH2Cl2, rt, (2S,3S)-5 (95%), (2S,3R)-5 (83%); (b) allyl bromide, NaH, THF, cat. (n-Bu)4NI, reflux, (2S,3S)-6 (94%), (2S,3R)-6 (73%); and
(c) (Cy3P)2Cl2Ru]CHPh (10 mol %), toluene, reflux, (2S,3S)-7 (91%), (2S,3R)-7 (74%).

H. K. Lee et al. / Tetrahedron 63 (2007) 3321–3327
3323
Ph
Ph
OH
3
Me
Me
N
(c)
(d)
Ph
Ph
Ph
2
H
O
H
O
H
(2R,3S)-10
Me
N
Me
N
Me
N
CO2Et
H
(a)
(b)
OMe
N
OH
Me
N
3
(2R)-1
9
8
H
2
(2R,3R)-10
Scheme 4. (a) CH3NHOCH3HCl, AlMe3, CH2Cl2, rt, 92%; (b) allyl-MgBr, THF, ꢀ78 ꢁC, 90%; (c) ZnCl2, NaBH4, MeOH, ꢀ78 ꢁC, 90%; and (d) L-Selectride,
THF, ꢀ78 ꢁC, (70%).
Ph
Ph
Ph
Ph
OH
SPh
Me
PhS
NH
Me
PhS
N
OH
3
N
Me
(a)
(a)
(b)
(b)
(c)
(c)
Me
Me
N
PhS
N
N
2
H
OH
OH
Ph
Ph
Me
Me
HO
(2R,3S)-10
(2S,3S)-11
(2S,3S)-12
(2S,3S)-13
Ph
Ph
N
Ph
Ph
OH
SPh
Me
PhS
NH
Me
PhS
OH
3
N
Me
N
PhS
2
H
OH
OH
HO
(2R,3R)-10
(2S,3R)-11
(2S,3R)-12
(2S,3R)-13
Scheme 5. (a) PhSH, CH2Cl2, rt, (2S,3S)-11 (85%), (2S,3R)-11 (83%); (b) allylbromide, NaH, THF, cat. (n-Bu)4NI, reflux, (2S,3S)-12 (90%), (2S,3R)-12 (96%);
and (c) second-generation Grubbs catalyst (10 mol %), toluene, reflux, (2S,3S)-13 (90%), (2S,3R)-13 (90%).
of 8 with allyl magnesium bromide affords ketone 9 (90%),
which upon stereoselective, chelation controlled reduction
with ZnCl2/NaBH4 in MeOH produces the erythro alcohol
(2R,3S)-10 (Scheme 4).13 In contrast, reduction of 9 with
L-Selectride produces the threo alcohol (2R,3R)-10 exclu-
sively and in good yield.8
prior to use. CH2Cl2 was distilled from calcium hydride.
DMF, benzene, CH3CN, MeOH, and toluene were dried, dis-
tilled, and stored under nitrogen. All other reagent grade
chemicals obtained from commercial sources were used as
received. Optically pure ethyl (2R)-1-[(1R)-1-phenylethyl]-
aziridine-2-carboxylate [(2R)-1] was prepared from
(R)-(+)-a-methyl-benzylamine and racemic ethyl-2,3-dibro-
mopropionate as reported.6
Treatment of (2R,3S)-10 with thiophenol leads to aziridine
ring opening and exclusive formation of the b-amino alcohol
11 by way of attack of the thiolate anion at the less sterically
hindered C-1 position.9 N-Allylation of the amino alcohol
11 with excess allyl bromide and subsequent ring-closing
metathesis of the resulting bis-olefin 12 with the second-
generation Grubbs catalyst12 smoothly produces (2S,3S)-
2,3,4,7-tetrahydro-1H-azepin-3-ol (2S,3S)-13 (Scheme 5).
(2S,3R)-2,3,4,7-Tetrahydro-1H-azepin-3-ol (2S,3R)-13 can
also be generated from the diastereomeric alcohol (2R,3R)-
10 by using this same general protocol.
3.1.1. {2-Oxo-2-[(2R)-1-(1R)-(1-phenylethyl)-aziridin-
2-yl]ethyl}-phosphonic acid dimethyl ester (2). To a
stirred solution of dimethyl methylphosphonate (4.8 ml,
44.62 mmol) in anhydrous THF (28 ml) at ꢀ78 ꢁC, under
an inert atmosphere of N2 was added n-BuLi (2.5 M,
17.85 ml). After stirring at ꢀ78 ꢁC for 30 min, a solution
of ethyl (2R)-1-[(1R)-1-phenylethyl]-aziridine-2-carboxyl-
ate6 [(2R)-1] (3.9 g, 17.85 mmol) in THF (12 ml) was added
slowly. The reaction mixture was then stirred for 1 h at
ꢀ78 ꢁC and warmed to room temperature and stirred for
an additional 15 min before being quenched with 10% acetic
acid (25 ml). The reaction mixture was extracted with ethyl
acetate (40 mlꢂ2) and the combined organic layers were
washed with saturated aqueous NaHCO3 and brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification
by flash chromatography afforded 2 as yellow oil (5.18 g,
98%).
The strategies developed in this investigation are highly
efficient and they provide ready access to enantiomerically
pure, stereochemically defined, and highly functionalized
3-hydroxy-substituted tetrahydropyridines and tetrahydro-
azepines. Applications of these strategies to the preparation
of biologically important piperidine alkaloids and azasugars
are currently being pursued.
Yield: 98%. Bright yellow oil. Rf 0.45 (only EtOAc); [a]D28
+75.60 (c 0.79, CHCl3); IR (KBr): 2959, 1711, 1258,
3. Experimental section
3.1. General
1043, 815, 703 cmꢀ1
;
1H NMR (CDCl3, 500 MHz)
d 7.40–7.25 (m, 5H), 3.80 (d, 6H, J¼11.1 Hz), 3.28–3.05
(m, 2H), 2.62 (q, 1H, J¼6.6 Hz), 2.37 (dd, 1H, J¼3.0,
6.9 Hz), 2.23 (d, 1H, J¼2.7 Hz), 1.73 (d, 1H, J¼6.9 Hz),
1.44 (d, 3H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3)
d 200, 143.54, 128.47, 127.42, 126.74, 69.35, 53.19,
Flash column chromatographies were performed on silica
gel (230–400 mesh, Merck). THF and Et2O were refluxed
over sodium in the presence of benzophenone and distilled

3324
H. K. Lee et al. / Tetrahedron 63 (2007) 3321–3327
53.14, 52.96, 52.91, 45.68, 45.66, 35.75, 34.69, 34.30,
23.22; HRMS (EI): Calcd for C14H20NO4P1, 297.1130
found, 297.1134.
the combined organic extracts were dried (MgSO4), filtered,
and concentrated in vacuo. Purification by flash chromato-
graphy afforded 9 as brown oil.
3.1.2. (E)-1-{(2R)-1-[(1R)-1-Phenylethyl]-aziridin-2-yl}-
2-buten-1-one (3). To a solution of 2 (1.18 g, 3.97 mmol)
and powdered K2CO3 (1.65 g, 11.91 mmol) in CH3CN
(20 ml) at room temperature was added acetaldehyde
(0.27 ml, 4.76 mmol) and stirred for an additional 24 h.
The reaction mixture was quenched with 5% aqueous citric
acid solution and extracted with methylene chloride
(20 mlꢂ3). The combined organic layers were washed
with saturated aqueous NaHCO3 and brine, dried (MgSO4),
filtered, and concentrated in vacuo. Purification by flash
chromatography afforded 3 as colorless oil (0.6 g, 75%).
Yield: 90%. Rf 0.4 (Hexane–EtOAc 5:1); [a]2D2 +112.4
(c 0.99, CHCl3); IR (KBr): 2980, 2384, 2284, 1711, 795,
1
701, 406 cmꢀ1; H NMR (CDCl3, 200 MHz) d 7.41–7.26
(m, 5H), 6.05–5.84 (m, 1H), 5.21–5.12 (m, 2H), 3.32 (dd,
1H, J¼7.0, 17.0 Hz), 3.10 (dd, 1H, J¼7.0, 17.0 Hz), 2.56
(q, 1H, J¼6.6 Hz), 2.27 (dd, 1H, J¼3.0, 6.2 Hz), 2.08 (d,
1H, J¼3.0 Hz), 1.67 (d, 1H, J¼7.0 Hz), 1.42 (d, 3H,
J¼6.6 Hz); 13C NMR (125 MHz, CDCl3) d 207.01,
143.93, 130.65, 128.55, 127.45, 126.89, 126.85, 118.85,
69.67, 53.65, 45.12, 42.35, 34.66, 23.45; HRMS (EI): Calcd
for C14H17NO, 215.1310 found, 215.1308.
Yield: 75%. Rf 0.6 (Hexane–EtOAc 3:1); [a]2D1 +130.11 (c
1.0, CHCl3); IR (KBr): 3060, 2968, 1687, 1628, 1443,
3.2. Representative procedure for NaBH4 reduction
of 3 or 9
1
1319, 735 cmꢀ1; H NMR (CDCl3, 500 MHz) d 7.42–7.26
(m, 5H), 7.10–7.03 (m, 1H), 6.39 (dd, 1H, J¼1.5,
15.3 Hz), 2.58 (q, 1H, J¼6.6 Hz), 2.35 (dd, 1H, J¼3.0,
6.9 Hz), 2.05 (d, 1H, J¼2.7 Hz), 1.92 (dd, 3H, J¼1.8,
6.9 Hz), 1.67 (d, 1H, J¼6.9 Hz), 1.43 (d, 3H, J¼6.6 Hz);
13C NMR (125 MHz, CDCl3) d 197.08, 143.91, 128.40,
128.40, 127.28, 126.82, 126.82, 126.82, 126.68, 69.71,
44.45, 34.33, 23.31, 18.42; HRMS (EI): Calcd for
C14H17NO, 215.1310 found, 215.1303.
To the solution of 3 (1.00 g, 4.64 mmol) in MeOH (30 ml) at
ꢀ78 ꢁC was added ZnCl2 (0.95 g, 6.97 mmol). The solution
was stirred for 30 min, and NaBH4 (358 mg, 9.28 mmol)
was added at ꢀ78 ꢁC. The mixture was stirred for an addi-
tional 1 h at ꢀ78 ꢁC before being quenched with water
(30 ml). The reaction mixture was extracted with methylene
chloride (30 mlꢂ3) and the combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. Purifica-
tion by flash chromatography afforded (2R,3S)-4 (0.96 g,
96%) as colorless oil.
3.1.3. 1-{(2R)-1-[(1R)-1-Phenylethyl]-aziridine}-2-carb-
oxylic acid methoxy methyl amide (8). To a suspension
of N,O-dimethylhydroxylamine$HCl (1.36 g, 13.68 mmol)
in 20 ml of methylene chloride was added AlMe3 (2 M,
6.84 ml, 13.68 mmol) under nitrogen at ꢀ10 ꢁC and the
solution was stirred for 30 min at room temperature. A
solution of ethyl (2R)-1-[(1R)-1-phenylethyl]-aziridine-2-
carboxylate [(2R)-1)] (1.00 g, 4.56 mmol) in methylene
chloride (5 ml) was added slowly at ꢀ10 ꢁC. The reaction
mixture was stirred for 2 h at room temperature and
quenched carefully by water. After extraction with methyl-
ene chloride (30 mlꢂ3), the combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. Purifica-
tion by fast washing through a short pad of silica gel yielded
pure 8 as a white solid.
3.2.1. (1S,2E)-1-{(2R)-1-[(1R)-1-Phenylethyl]-aziridin-
2-yl}-2-buten-1-ol [(2R,3S)-4]. Yield: 96% (colorless oil).
Rf 0.2 (Hexane–EtOAc 4:1); [a]2D5 +140.40 (c 1.0, CHCl3);
IR (KBr): 3388, 2970, 1449, 1372, 1078, 973, 701 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 7.38–7.25 (m, 5H), 5.85–
5.78 (m, 1H), 5.45 (dd, 1H, J¼7.2, 15 Hz), 4.25 (dd, 1H,
J¼3.0, 7.2 Hz), 2.77 (br, 1H), 2.64 (q, 1H, J¼6.5 Hz),
1.79–1.72 (m, 5H), 1.41 (d, 3H, J¼6.6 Hz), 1.29 (d, 1H,
J¼6.3 Hz); 13C NMR (125 MHz, CDCl3) d 144.59,
130.87, 128.88, 128.54, 127.28, 126.89, 69.93, 68.75,
42.84, 29.11, 23.74, 18.04; HRMS (EI): Calcd for
C14H19NO, 217.1467 found, 217.1469.
3.2.2. (1S,2E)-1-{(2R)-1-[(1R)-1-Phenylethyl]-aziridin-
2-yl}-3-buten-1-ol [(2R,3S)-10]. Yield: 90% (colorless
oil). Rf 0.3 (Hexane–EtOAc 5:1); [a]1D9 +98.71 (c 0.694,
CHCl3); IR (KBr): 3442, 2974, 2389, 1641, 1451, 1302,
Yield: 92%. Mp: 72–75 ꢁC. Rf 0.25 (Hexane–EtOAc 1:1);
[a]2D1 +107.22 (c 1.02, CHCl3); IR (KBr): 2973, 1679,
1
1450, 1329, 1170, 1088, 1007, 766, 702 cmꢀ1; H NMR
(CDCl3, 500 MHz) d 7.44–7.21 (m, 5H), 3.82 (s, 3H), 3.26
(s, 3H), 2.69–2.67 (m, 1H), 2.62 (q, 1H, J¼6.6 Hz), 2.19–
2.17 (m, 1H), 1.58 (d, 1H, J¼6.4 Hz), 1.49 (d, 3H,
J¼7.0 Hz); 13C NMR (125 MHz, CDCl3) d 170.42,
143.72, 128.32, 128.15, 127.41, 127.20, 126.99, 70.12,
61.82, 35.89, 33.62, 32.67, 23.31; HRMS (EI): Calcd for
C13H18N2O2, 234.1368 found, 234.1360.
1075, 914, 772, 735, 700 cmꢀ1 1H NMR (CDCl3,
;
300 MHz) d 7.37–7.23 (m, 5H), 5.96–5.87 (m, 1H), 5.21–
5.11 (m, 2H), 3.85–3.79 (m, 1H), 2.91 (br, 1H), 2.65 (q,
1H, J¼6.6 Hz), 2.33 (t, 2H, J¼7 Hz), 1.78–1.76 (m, 2H),
1.41 (d, 3H, J¼6.6 Hz), 1.30 (d, 1H, J¼6 Hz); 13C NMR
(125 MHz, CDCl3) d 144.56, 134.63, 128.54, 127.28,
126.87, 117.83, 69.01, 68.74, 42.70, 39.62, 29.58, 23.66;
HRMS (EI): Calcd for C14H19NO, 217.1467 found,
217.1460.
3.1.4. 1-{(2R)-1-[(1R)-1-Phenylethyl]-aziridin-2-yl}-3-
buten-1-one (9). To the solution of 8 (1.98 g, 8.45 mmol)
in 40 ml of THF under nitrogen at ꢀ78 ꢁC was added
Allyl-MgBr (1.0 M, 16.9 ml, 16.9 mmol). The solution
was stirred for 30 min at ꢀ78 ꢁC. After the solution was
warmed to room temperature, 50 ml of aqueous NH4Cl
was added and the organic layer was separated. The aqueous
layer was extracted with methylene chloride (40 mlꢂ3) and
3.3. Representative procedure for L-Selectride
reduction of 3 or 9
To the solution of 3 (0.4 g, 1.86 mmol) in anhydrous THF
(10 ml) at ꢀ78 ꢁC was added dropwise L-SelectrideÒ (1 M
in THF, 5.6 ml, 5.6 mmol), and stirred for 4 h at ꢀ78 ꢁC.

H. K. Lee et al. / Tetrahedron 63 (2007) 3321–3327
3325
After the solution was warmed to room temperature, 10 ml
of aqueous 10% NaOH solution was added. The reaction
mixture was extracted with methylene chloride (10 mlꢂ
3) and the combined organic extracts were dried (MgSO4),
filtered, and concentrated in vacuo. Purification by flash
chromatography afforded (2R,3R)-4 as brown oil (163 mg,
40%).
yellow oil). Rf 0.7 (MC–MeOH 10:1); [a]2D4 +34.80 (c 1.0,
CHCl3); IR (KBr): 3356, 2965, 2388, 1488, 1439, 969,
1
740, 703 cmꢀ1; H NMR (CDCl3, 500 MHz) d 7.27–7.18
(m, 10H), 5.66 (dq, 1H, J¼6.2, 15.0 Hz), 5.42 (dd, 1H,
J¼7.0, 15.0 Hz), 3.88–3.80 (m, 2H), 3.02–2.94 (m, 2H),
2.74 (q, 1H, J¼6.5 Hz), 1.71 (d, 3H, J¼6.5 Hz), 1.64 (dd,
1H, J¼7.2, 15.6 Hz), 1.33 (d, 3H, J¼6.5 Hz); 13C NMR
(125 MHz, CDCl3) d 145.60, 136.51, 131.40, 129.81,
129.59, 129.39, 129.35, 129.13, 128.76, 128.73, 127.41,
126.74, 126.41, 72.82, 59.23, 56.63, 36.26, 23.85, 18.10;
HRMS (ESI, MH+): Calcd for C20H26NOS, 328.1735 found,
328.1740.
3.3.1. (1R,2E)-1-{(2R)-1-[(1R)-1-Phenylethyl]-aziridin-
2-yl}-2-buten-1-ol [(2R,3R)-4]. Yield: 40% (brown oil). Rf
0.2 (Hexane–EtOAc 4:1); [a]2D3 +4.23 (c 0.92, CHCl3); IR
(KBr): 2969, 1451, 1377, 1219, 1088, 964, 772, 700 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 7.40–7.19 (m, 5H), 5.58
(dq, 1H, J¼6.4, 15.0 Hz), 5.19 (dd, 1H, J¼1.6, 15.0 Hz),
3.89 (t, 1H, J¼7.8 Hz), 3.78 (q, 1H, J¼6.4 Hz), 3.29–3.20
(m, 1H), 3.10–2.99 (m, 1H), 2.53–2.43 (m, 1H), 1.61 (dd,
3H, J¼1.6, 6.4 Hz), 1.21 (d, 3H, J¼6.4 Hz); 13C NMR
(125 MHz, CDCl3) 144.62, 131.02, 128.90, 128.53,
127.33, 126.71, 61.47, 69.06, 44.01, 30.95, 23.89, 18.19;
HRMS (EI): Calcd for C14H19NO, 217.1467 found,
217.1461.
3.4.3. (2S,3S)-2-[(1R)-1-Phenylethylamino]-1-phenylsul-
fanyl-5-hexen-3-ol [(2S,3S)-11]. Yield: 85% (slightly yel-
low oil). Rf 0.5 (Hexane–EtOAc 5:1); [a]2D3 +67.08 (c 0.6,
CHCl3); IR (KBr): 3403, 2917, 2360, 1583, 1480, 993,
1
911, 780, 689 cmꢀ1; H NMR (CDCl3, 300 MHz) d 7.26–
7.12 (m, 10H), 5.80–5.63 (m, 1H), 5.10–5.99 (m, 2H),
3.88–3.76 (m, 2H), 3.11 (dd, 1H, J¼3.6, 2.8 Hz), 2.86–
2.74 (m, 1H), 2.58–2.49 (m, 1H), 2.35–2.02 (m, 2H), 1.35
(d, 3H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3) d 144.79,
135.62, 134.96, 129.65, 129.08, 128.67, 127.21, 126.64,
126.41, 117.41, 68.85, 55.61, 54.85, 37.01, 33.70, 24.75.
HRMS (EI): Calcd for C20H25NOS, 327.1657 found,
327.1663.
3.3.2. (1R,2E)-1-{(2R)-1-[(1R)-1-Phenylethyl]-aziridin-
2-yl}-3-buten-1-ol [(2R,3R)-10]. Yield: 70% (slightly yel-
low oil). Rf 0.7 (Hexane–EtOAc 1:1); [a]1D9 +65.82 (c
0.404, CHCl3); IR (KBr): 3415, 3063, 2974, 2928, 2360,
1451, 1375, 1070, 961, 913, 781, 710, 560 cmꢀ1; 1H NMR
(CDCl3, 300 MHz) d 7.38–7.32 (m, 4H), 7.28 (t, 1H,
J¼1 Hz), 5.96–5.87 (m, 1H), 5.20–5.12 (m, 2H), 3.47–
3.43 (m, 1H), 2.55 (q, 1H, J¼6.5 Hz), 2.47–2.36 (m, 3H),
1.76–1.71 (m, 3H), 1.45 (d, 3H, J¼7 Hz), 1.37 (d, 1H,
J¼3.7 Hz); 13C NMR (125 MHz, CDCl3) d 144.59,
134.78, 128.56, 127.29, 126.92, 117.65, 70.54, 69.05, 43.55,
40.79, 31.42, 23.81; HRMS (EI): Calcd for C14H19NO,
217.1467 found, 217.1469.
3.4.4. (2S,3R)-2-[(1R)-1-Phenylethylamino]-1-phenylsul-
fanyl-5-hexen-3-ol [(2S,3R)-11]. Yield: 83% (colorless
oil). Rf 0.7 (Hexane–EtOAc 1:1); [a]3D0 +32.22 (c 0.69,
CHCl3); IR (KBr): 2930, 2373, 1748, 1456, 766,
1
701 cmꢀ1; H NMR (CDCl3, 500 MHz) d 7.29–7.14 (m,
10H), 5.88–5.82 (m, 1H), 5.11 (d, 1H, J¼1.5 Hz), 5.08 (s,
1H), 3.83 (q, 1H, J¼6.5 Hz), 3.64–3.60 (m, 1H), 3.02–
2.94 (m, 2H), 2.72 (q, 1H, J¼5.5 Hz), 2.37–2.34 (m, 1H),
2.27–2.23 (m, 1H), 1.32 (d, 3H, J¼7.0 Hz); 13C NMR
(125 MHz, CDCl3) d 145.69, 136.29, 135.15, 129.59,
129.17, 128.78, 127.46, 126.76, 126.38, 117.54, 70.72,
57.84, 56.99, 38.97, 36.25, 23.99; HRMS (ESI, MH+): Calcd
for C20H26NOS, 328.1735 found, 328.1740.
3.4. Representative procedure for aziridine
ring-opening reaction of 4 or 10
To the solution of (2R,3S)-4 (225 mg, 1.03 mmol) in methyl-
ene chloride (5 ml) was added thiophenol (0.35 ml,
3.11 mmol) and stirred for 24 h at room temperature. After
completion of the reaction, the reaction mixture was concen-
trated in vacuo and the residue was purified by flash chroma-
tography affording (2S,3S)-5 as an oil (322 mg, 95%).
3.5. Representative procedure for allylation of 5 or 11
To the suspension of NaH (55% in mineral oil, 33 mg,
0.75 mmol) in THF (1 ml) at 0 ꢁC was added slowly
(2S,3S)-5 (93 mg, 0.28 mmol) in THF (2 ml). After stirring
for 30 min at 0 ꢁC, a solution of (n-Bu)4NI (21 mg,
0.06 mmol) and allyl bromide (0.097 ml, 1.13 mmol) in
THF (4 ml) was added dropwise and the reaction mixture
was warmed to room temperature. The reaction mixture
was heated to reflux for 5 h and cooled to room temperature.
Saturated aqueous NH4Cl was added to the reaction mixture
and extracted with ethyl acetate (10 mlꢂ3). The combined
organic extracts were dried (MgSO4), filtered, and concen-
trated in vacuo. Purification by flash chromatography
afforded (2S,3S)-6 as an oil (98 mg, 94%).
3.4.1. (2S,3S,4E)-2-[(1R)-1-Phenylethylamino]-1-phenyl-
sulfanyl-4-hexen-3-ol [(2S,3S)-5]. Yield: 95% (slightly yel-
low oil). Rf 0.5 (Hexane–EtOAc 4:1); [a]2D1 +31.99 (c 0.84,
CHCl3); IR (KBr): 3422, 3059, 2904, 1480, 1439, 1125,
1
1087, 970, 738, 703 cmꢀ1; H NMR (CDCl3, 300 MHz)
d 7.26–7.11 (m, 10H), 5.75–5.63 (m, 1H), 5.34 (dd, 1H,
J¼6.0, 15.6 Hz), 4.30 (br, 1H), 3.86 (q, 1H, J¼6.6 Hz),
3.30 (br, 1H), 3.03 (dd, 1H, J¼4.5, 13.8 Hz), 2.79 (dd, 1H,
J¼9.0, 13.8 Hz), 2.64–2.58 (m, 1H), 1.68 (d, 3H,
J¼6.6 Hz), 1.35 (d, 3H, J¼6.6 Hz); 13C NMR (125 MHz,
CDCl3) d 144.77, 135.70, 129.22, 129.14, 128.87, 128.52,
128.16, 127.07, 126.45, 126.08, 70.14, 57.06, 54.94,
34.03, 24.48, 17.90; HRMS (ESI, MH+): Calcd for
C20H26NOS, 328.1735 found, 328.1731.
3.5.1. (2S,3S,4E)-2-Allyl-[(1R)-1-phenylethylamino]-
1-phenylsulfanyl-4-hexen-3-ol [(2S,3S)-6]. Yield: 94%
(slightly yellow oil). Rf 0.7 (Hexane–EtOAc 5:1); [a]D24
+1.94 (c 0.72, CHCl3); IR (KBr): 2977, 2687, 1693, 1572,
3.4.2. (2S,3R,4E)-2-[(1R)-1-Phenylethylamino]-1-phenyl-
sulfanyl-4-hexen-3-ol [(2S,3R)-5]. Yield: 83% (slightly
1440, 1303, 1084, 744, 703 cmꢀ1 1H NMR (CDCl3,
;
300 MHz) d 7.34–7.11 (m, 10H), 5.92–5.81 (m, 1H),

3326
H. K. Lee et al. / Tetrahedron 63 (2007) 3321–3327
5.70–5.59 (m, 1H), 5.38 (dd, 1H, J¼7.8 Hz), 5.27–5.13 (m,
2H), 4.04 (dd, 1H, J¼4.8 Hz), 3.95 (d, 2H, J¼6.6 Hz), 3.77
(dd, 1H, J¼4.8, 12.9 Hz), 2.93 (d, 2H, J¼6.0 Hz), 2.75
(q, 1H, J¼4.2 Hz), 1.72 (d, 3H, J¼6.3 Hz), 1.31(d, 3H,
J¼6.6 Hz); 13C NMR (125 MHz, CDCl3) d 145.99,
137.42, 135.32, 130.56, 129.00, 128.87, 128.75, 128.49,
127.22, 127.02, 125.65, 116.69, 80.18, 69.50, 58.22,
56.31, 35.88, 25.12, 18.11; HRMS (ESI, MH+): Calcd for
C23H30NOS, 368.2048 found, 368.2055.
3.6.1. (2S,3S)-1-[(1R)-1-Phenylethyl]-2-phenylsulfanyl-
methyl-1,2,3,6-tetrahydropyridin-3-ol [(2S,3S)-7]. Yield:
91%. Yellow oil. Rf 0.45 (Hexane–EtOAc 10:1); [a]D25
+40.25 (c 0.77, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.31–7.11 (m, 10H), 6.00–5.98 (m, 1H), 5.74–5.71 (m,
1H), 5.12–5.09 (m, 1H), 4.69–4.64 (m, 2H), 3.99 (q, 1H,
J¼6.6 Hz), 2.95–2.86 (m, 2H), 2.78–2.75 (m, 1H), 1.33 (d,
3H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3) d 145.53,
136.75, 128.94, 128.77, 128.37, 128.14, 127.08, 126.90,
125.69, 86.35, 75.70, 57.13, 55.81, 35.41, 25.02; HRMS
(ESI, MH+): Calcd for C20H23NOS, 326.1573 found,
326.1585.
3.5.2. (2S,3R,4E)-2-Allyl-[(1R)-1-phenylethylamino]-
1-phenylsulfanyl-4-hexen-3-ol [(2S,3R)-6]. Yield: 73%
(slightly yellow oil). Rf 0.7 (Hexane–EtOAc 5:1); [a]D21
ꢀ9.99 (c 0.08, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 7.34–7.06 (m, 10H), 5.86–5.81 (m, 1H), 5.69 (dd, 1H,
J¼6.5, 15.4 Hz), 5.46 (ddd, 1H, J¼1.5, 7.5, 17.0 Hz),
5.22–5.11 (m, 2H), 4.07–3.97 (m, 2H), 3.89 (q, 1H,
J¼6.0 Hz), 3.73 (dd, 1H, J¼6.1 Hz), 3.09 (dd, 1H,
J¼6.1 Hz), 2.79–2.71 (m, 2H), 1.75 (d, 3H, J¼6.5 Hz),
1.29 (d, 3H, J¼6.5 Hz); 13C NMR (125 MHz, CDCl3)
d 146.04, 137.15, 135.31, 130.13, 128.89, 128.74, 128.67,
128.53, 127.19, 127.11, 125.51, 116.53, 79.93, 69.54,
58.06, 56.99, 35.58, 24.88, 18.16; HRMS (ESI, MH+): Calcd
for C23H30NOS, 368.2048 found, 368.2051.
3.6.2. (2S,3R)-1-[(1R)-1-Phenylethyl]-2-phenylsulfanyl-
methyl-1,2,3,6-tetrahydropyridin-3-ol [(2S,3R)-7]. Yield:
1
74%. Brown oil; [a]D22 +94.21 (c 0.66, CHCl3); H NMR
(500 MHz, CDCl3) d 7.31–7.22 (m, 5H), 7.14–7.07 (m,
3H), 7.02 (d, 2H, J¼7.3 Hz), 6.01–5.99 (m, 1H), 5.88–
5.87 (m, 1H), 5.16 (s, 1H, br), 4.72–4.70 (m, 1H), 4.68–
4.64 (m, 1H), 3.87 (q, 1H, J¼6.5 Hz), 2.99 (dd, 1H,
J¼7.0, 13.6 Hz), 2.84 (dd, 1H, J¼6.8, 13.6 Hz), 2.74 (td,
1H, J¼3.1, 6.9 Hz), 1.72 (s, 1H, br), 1.28 (d, 3H,
J¼6.6 Hz); 13C NMR (125 MHz, CDCl3) d 145.83,
136.60, 128.99, 128.60, 128.30, 128.14, 127.69, 127.17,
127.10, 125.54, 87.03, 76.05, 57.29, 56.81, 35.79, 25.06;
HRMS (ESI, MH+): Calcd for C20H23NOS, 326.1573 found,
326.1581.
3.5.3. (2S,3S)-2-Allyl-[(1R)-1-phenylethyl]amino-1-
phenylsulfanyl-5-hexen-3-ol [(2S,3S)-12]. Yield: 90%.
Yellow oil. Rf 0.6 (Hexane–EtOAc 10:1); [a]2D1 +29.96 (c
1
1.19, CHCl3); H NMR (CDCl3, 300 MHz) d 7.28–7.15
3.7. Representative procedure for RCM reaction of 12
(m, 10H), 5.98–5.61 (m, 2H), 5.29–4.95 (m, 4H), 4.11–
3.96 (m, 2H), 3.93–3.83 (m, 1H), 3.61–3.53 (m, 1H),
3.07–3.93 (m, 2H), 2.80–2.72 (m, 1H), 2.61–2.15 (m, 2H),
1.31 (d, 3H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3)
d 145.94, 135.23, 135.14, 130.33, 129.17, 128.24, 126.89,
126.72, 116.55, 116.05, 80.27, 72.10, 69.17, 69.07, 57.66,
55.84, 24.87, 17.85; HRMS (EI): Calcd for C23H29NOS,
367.1970 found, 367.1978.
To the solution of (2S,3S)-12 (48 mg, 0.13 mmol) in toluene
(5 ml) was added second-generation Grubbs catalyst
(10 mol %) and refluxed for 3 h with stirring. After comple-
tion of the reaction by TLC, the reaction mixture was cooled
to room temperature and concentrated in vacuo and the
residue was purified by flash chromatography affording
(2S,3S)-7 (40 mg, 90%) as an oil.
3.5.4. (2S,3R)-2-Allyl-[(1R)-1-phenylethyl]amino-1-
phenylsulfanyl-5-hexen-3-ol [(2S,3R)-12]. Yield: 96%.
Yellow oil. Rf 0.5 (Hexane–EtOAc 10:1); [a]2D1 +37.66 (c
3.7.1. (2S,3S)-1-[(1R)-1-Phenylethyl]-1-phenylsulfanyl-
methyl-2,3,4,7-tetrahydro-1H-azepin-3-ol [(2S,3S)-13].
Yield: 90%. yellow oil. Rf 0.5 (Hexane–EtOAc 10:1); [a]D25
ꢀ8.80 (c 0.2, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.30–7.7.12 (m, 10H), 5.83–5.79 (m, 1H), 5.71–5.69 (m,
1H), 4.18–4.07 (m, 2H), 3.89 (q, 1H, J¼6.5 Hz), 3.68–
3.64 (m, 1H), 3.08 (dd, 1H, J¼6.8, 13.5 Hz), 3.00 (dd, 1H,
J¼4.7, 13.7 Hz), 2.77–2.74 (m, 1H), 2.18–2.15 (m, 1H),
1.96–1.91 (m, 1H), 1.33 (d, 3H, J¼6.6 Hz); 13C NMR
(125 MHz, CDCl3) d 146.01, 136.97, 129.45, 128.97,
128.54, 127.10, 127.04, 126.47, 125.99, 124.54, 73.81,
66.49, 57.78, 56.05, 35.41, 29.90, 27.47, 24.63; HRMS
(ESI, MH+): Calcd for C21H25NOS, 340.1730 found,
340.1726.
1
0.43, CHCl3); H NMR (500 MHz, CDCl3) d 7.29–7.25
(m, 5H), 7.23–7.22 (m, 1H), 7.17–7.08 (m, 4H), 5.82–5.76
(m, 2H), 5.18–5.03 (m, 4H), 3.89 (dd, 1H, J¼7.0,
12.6 Hz), 3.80 (q, 1H, J¼6.7 Hz), 3.77 (dd, 1H, J¼5.6,
12.5 Hz), 3.68–3.66 (m, 1H), 3.06 (dd, 1H, J¼6.7,
13.0 Hz), 2.81 (dd, 1H, J¼6.6, 13.0 Hz), 2.70 (td, 1H,
J¼2.8, 6.7 Hz), 2.48–2.47 (m, 1H), 2.33–2.30 (m, 1H),
1.27 (d, 3H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3)
d 146.01, 136.37, 135.77, 135.25, 129.23, 128.97, 128.60,
127.20, 127.01, 125.91, 117.07, 117.00, 71.45, 56.44,
55.28, 35.06, 34.79, 29.92, 24.66; HRMS (ESI, MH+): Calcd
for C23H30NOS, 368.2048 found, 368.2042.
3.7.2. (2S,3R)-1-[(1R)-1-Phenylethyl]-1-phenylsulfanyl-
methyl-2,3,4,7-tetrahydro-1H-azepin-3-ol [(2S,3R)-13].
Yield: 90%. Brown oil. Rf 0.25 (Hexane–EtOAc 5:1); [a]D23
ꢀ24.21 (c 0.64, CHCl3); 1H NMR (CDCl3, 300 MHz)
d 7.35–7.04 (m, 10H), 5.87–5.82 (m, 1H), 5.71–5.69 (m,
1H), 4.20–4.05 (m, 2H), 3.87–3.82 (m, 2H), 3.05 (dd, 1H,
J¼7.8, 13.5 Hz), 2.87 (dd, 1H, J¼5.1, 13.2 Hz), 2.73–2.67
(m, 1H), 1.31 (d, 3H, J¼6.6 Hz); 13C NMR (125 MHz,
CDCl3) d 128.98, 128.65, 128.58, 127.18, 127.10, 126.42,
73.44, 66.50, 60.58, 58.11, 34.81, 21.81, 21.24, 14.39;
3.6. Representative procedure for RCM reaction of 6
To the solution of (2S,3S)-6 (48 mg, 0.13 mmol) in toluene
(3 ml) was added first-generation Grubbs catalyst
(10 mol %) and refluxed for 3 h with stirring. After comple-
tion of the reaction by TLC, the reaction mixture was cooled
to room temperature and concentrated in vacuo and the
residue was purified by flash chromatography affording
(2S,3S)-7 (39 mg, 91%) as an oil.

H. K. Lee et al. / Tetrahedron 63 (2007) 3321–3327
3327
HRMS (ESI, MH+): Calcd for C21H25NOS, 340.1730 found,
340.1728.
Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1995, 60, 398; (n) Cook, G. R.; Beholz, L. G.; Stille,
J. R. J. Org. Chem. 1994, 59, 3575; (o) Casiraghi, G.; Rassu,
G.;Spanu, P.;Pinna,L.;Ulgheri, F. J. Org. Chem.1993, 58, 3397.
4. (a) Lee, H. K.; Chun, J. S.; Pak, C. S. J. Org. Chem. 2003, 68,
2471; (b) Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron 2003,
59, 6445; (c) Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron
Lett. 2001, 42, 3483.
Acknowledgements
We would like to thank the Ministry of Science and Technol-
ogy of Korea for financial support of these studies.
5. (a) Trost, B. M.; Fandrick, D. R. Org. Lett. 2005, 7, 823; (b)
Lee, W. K.; Ha, H.-J. Aldrichimica Acta 2003, 36, 57; (c)
Concellon, J. M.; Riego, E.; Suarez. J. Org. Chem. 2003, 68,
9242; (d) Sweeney, J. B. Chem. Soc. Rev. 2003, 31, 247; (e)
Chandrasekhar, M.; Sekar, G.; Singh, V. K. Tetrahedron Lett.
2000, 41, 10079; (f) Nayak, S. K.; Thijs, L.; Zwanenburg, B.
Tetrahedron Lett. 1999, 40, 981.
6. Haner, R.; Olano, B.; Seebach, D. Helv. Chim. Acta 1987,
70, 1679.
7. (a) Lee, H. K.; Kim, E.-K.; Pak, C. S. Tetrahedron Lett. 2002,
43, 9641; (b) Williams, L. M.; Davis, J. T. Tetrahedron Lett.
1998, 39, 9135.
8. (a) Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J.
J. Org. Chem. 2003, 68, 7675; (b) Kim, B. C.; Lee, W. K.
Tetrahedron 1996, 52, 12117; (c) Choi, S. K.; Lee, J. S.;
Kim, J. H.; Lee, W. K. J. Org. Chem. 1997, 62, 743.
9. Bae, J. H.; Shin, S.-H.; Park, C. S.; Lee, W. K. Tetrahedron
1999, 55, 10041.
10. (a) Park, S. O.; Kang, H. J.; Ko, S.; Park, S.; Chang, S.
Tetrahedron: Asymmetry 2001, 12, 2621; For recent reviews
on RCM, see: (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18; (c) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413.
11. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815;
(b) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 4171; (c) Lee, E.; Song, H. Y.; Kang, J. W.; Kim,
D. S.; Jung, C. K.; Joo, J. M. J. Am. Chem. Soc. 2002, 124,
384; (d) Jonghe, S. D.; Lamote, I.; Venkataraman, K.;
Boldin, S. A.; Hillaert, U.; Rozenski, J.; Hendrix, C.; Busson,
R.; Keukeleire, D. D.; Calenbergh, S. V.; Futerman, A. H.;
Herdewijn, P. J. Org. Chem. 2002, 67, 988.
12. (a) Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M. Org. Lett.
2004, 6, 1469; (b) Trost, B. M.; Yeh, V. S. C. Org. Lett. 2002, 4,
3513; (c) Sletten, E. M.; Liotta, L. J. J. Org. Chem. 2006, 71,
1335.
References and notes
1. (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701; (b) Weintraub,
P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron
2003, 59, 2953; (c) Asano, N.; Nash, R. J.; Molyneux, R. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645; (d)
Michael, J. P. Nat. Prod. Rep. 2004, 21, 625; (e) Bailey,
P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998,
633; (f) O’Hagen, D. Nat. Prod. Rep. 1997, 14, 637; (g)
Schneider, M. J. Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon: Oxford, 1996;
Vol. 10, pp 155–299.
2. For polyhydroxylated piperidines (azasugars), see: (a)
Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005, 16,
1239; (b) Stutz, A. E. Iminosugars as Glycosidase Inhibitors;
Wiley-VCH: Weinheim, 1998; (c) Sears, P.; Wong, C. H.
Angew. Chem., Int. Ed. 1999, 38, 2300; (d) Jacob, G. S. Curr.
Opin. Struct. Biol. 1995, 5, 605; (e) Hughes, A. B.; Rudge,
A. J. Nat. Prod. Rep. 1994, 11, 135.
3. For some representative examples of previous work in this area,
see: (a) Martin, R.; Murruzzu, C.; Pericas, M. A.; Riera, A.
J. Org. Chem. 2005, 70, 2325; (b) Kato, A.; Kato, N.; Kano,
E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.;
Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005, 48,
2036; (c) Toyooka, N.; Nemoto, H. Drugs Future 2002, 27,
143; (d) Mehta, G.; Mohal, N. Tetrahedron Lett. 2000, 41,
5741; (e) Sun, H.; Millar, K. M.; Yang, J.; Abboud, K.;
Horenstein, B. A. Tetrahedron Lett. 2000, 41, 2801; (f)
Yokoyama, H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.;
Yamaguchi, S.; Hirai, Y. Org. Lett. 2000, 2, 2427; (g) Davis,
F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000, 2,
1041; (h) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T.
J. Org. Chem. 1999, 64, 4914; (i) See Ref. 1e; (j) Yoda, H.;
Kawauchi, M.; Takabe, K. Synlett 1998, 137; (k) Goti, A.;
Cardona, F.; Brandi, A. Synlett 1996, 761; (l) Altenbach, H.-J.;
Himmeldirk, K. Tetrahedron: Asymmetry 1995, 6, 1077; (m)
13. Stereoselective reduction of the diastereomeric (2S)-9 was
reported under the same reaction condition.8a