The stereoselective synthesis of α-substituted β-amino secondary alcohols based on the proline-mediated, asymmetric, three-component Mannich reaction and its application to the formal total synthesis of nikkomycins B and Bx

Article abstract of DOI:10.1016/j.tet.2005.09.013

A general method for the asymmetric synthesis of α-substituted β-amino secondary alcohols is described, which comprises the four-reaction sequence (1) the proline-mediated, asymmetric, three-component Mannich reaction of two different aldehydes, (2) nucle

Full text of DOI:10.1016/j.tet.2005.09.013

Tetrahedron 61 (2005) 11393–11404
The stereoselective synthesis of a-substituted b-amino secondary
alcohols based on the proline-mediated, asymmetric,
three-component Mannich reaction and its application to the
formal total synthesis of nikkomycins B and Bx
*
Yujiro Hayashi, Tatsuya Urushima, Makoto Shin and Mitsuru Shoji
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 1 July 2005; revised 12 August 2005; accepted 2 September 2005
Available online 30 September 2005
Abstract—A general method for the asymmetric synthesis of a-substituted b-amino secondary alcohols is described, which comprises the
four-reaction sequence (1) the proline-mediated, asymmetric, three-component Mannich reaction of two different aldehydes, (2) nucleophilic
carbon addition to aldehyde, (3) oxidation of the resulting alcohol to the corresponding ketone, and (4) diastereoselective reduction with
LiAlH(O-t-Bu)3 or catecholborane. The former reductant afforded the 1,2-syn isomer, while the latter gave the 1,2-anti isomer
stereoselectively. The present method was successfully applied to the efficient asymmetric synthesis of the N-terminal amino acid moiety of
nikkomycin B and BX.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
During the application of the high pressure to other proline-
mediated reactions, we have discovered a proline-mediated,
one-pot, three-component, cross-Mannich reaction involv-
ing two different aldehydes and p-anisidine proceeding at
ambient pressure.8 That is, in the presence of proline an
aldehyde and anisidine react to give the corresponding
imine, which reacts with a second, different aldehyde,
affording an a-substituted b-amino aldehyde. As this
b-aminoaldehyde is unstable, it is reduced immediately to
give an a-substituted b-amino primary alcohol in good yield
with excellent syn selectivity and enantioselectivity (Eq. 1).
The similar Mannich reaction has been reported also by
Barbas’6i and Cordova’s6k,u groups, independently. The
a-substituted b-amino aldehyde that was generated is a
versatile synthetic intermediate, which can be further
transformed to give the corresponding a-substituted
b-amino secondary alcohols with a generation of a new
chiral center by formation of a carbon–carbon bond. The
utility of the present method is further demonstrated by an
efficient formal asymmetric total synthesis of nikkomycin,
which is also described in this full paper.
b-Amino alcohols are not only found in many natural
products1 and potent drugs,2 but are also used as a
component of ligands in asymmetric catalysts.3 In spite of
this synthetic utility, there are few methods for their
asymmetric synthesis, which remains a considerable
challenge.4 Recently, Ellman and co-workers reported an
asymmetric synthesis of both syn and anti b-amino alcohols
based on the diastereoselective reactions of metallo-
enamines derived from chiral N-sulfinyl imines, followed
by the diastereoselective reduction, for which an equimolar
amount of the chiral auxiliary is necessary.4d The
development of a general and practical method for the
synthesis of chiral b-amino alcohols based on catalytic
asymmetric reactions is an important goal.
List reported a proline-mediated asymmetric Mannich
reaction in 2000,5 after which organocatalyst-mediated
asymmetric Mannich reactions have been investigated by
several research groups.6 Our group have applied high-
pressure induced by water freezing to the proline-mediated
Mannich reaction, widening the generality of the reaction.7
Keywords: Proline; Mannich reaction; Asymmetric synthesis; Nikkomycin;
Three-component reaction.
*
Corresponding author. Tel.: C81 3 5228 8318; fax: C81 3 5261 4631;
e-mail: hayashi@ci.kagu.tus.ac.jp
(1)
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.013

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Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
2. Results and discussion
We have reported the proline-mediated, three component
coupling Mannich reaction of benzaldehyde, propanal, and
anisidine to afford an unstable, a-substituted b-amino
aldehyde, which was reduced to an a-substituted b-amino
primary alcohol with NaBH4 in 90% yield with high syn
selectivity and excellent enantioselectivity (Eq. 1, R1ZPh,
R2ZMe, syn/antiZO95:5, 98% ee).8 This result indicates
that the b-amino aldehyde is generated as intermediate in
very high optical purity. By employing an organo-metallic
nucleophile instead of NaBH4, a b-amino secondary alcohol
would be prepared, generating a new chiral center. With this
scenario in mind, in a preliminary trial we examined the
introduction of a methyl group, using MeMgI as nucleophile
(Eq. 2). The reaction was performed as follows: the crude
b-amino aldehyde generated as above was treated with
MeMgI in Et2O at K78 8C for 4 h, generating 4-amino-
butan-2-ol derivative 2a in 30% yield, as a 1:1 mixture of
syn and anti isomers (Table 1, entry 1). As both the yield and
diastereoselectivity of this reaction were insufficient, other
organometallic reagents were examined, with the results
summarized in Table 1.
(2)
However, in spite of the successful results using methyl
nucleophiles, aryl nucleophiles such as phenyl metal
reagents gave disappointing results (Eq. 3). Though the
syn isomer predominated with Ph3ZnLi, the use of Ph2CuLi
gave equal amounts of syn and anti isomers. As anti-
selective introduction of the aryl group had not proved
successful, a new general method for the stereoselective
formation of syn and anti b-amino secondary alcohol was
investigated. Thus, the two-step protocol of oxidation
followed by stereoselective reduction was investigated, for
which phenyl-substituted b-amino alcohol 2b was selected
as a model.
Though the moderate yields were obtained in the cases of
MeLi and MeTi(O-i-Pr)3,9 diastereoselectivity was low
(3)
(entries 2 and 3). The anti isomer was obtained predomi-
nantly in good yield in the case of Me2CuLi10 (entry 4),
while the syn isomer was generated predominantly in the
Oxidation of 2b was successfully carried out using
SO3$pyridine14 to afford b-amino ketone 3b in 83% yield
(Eq. 4). Diastereoselective reduction of 3b was investigated
with a variety of reducing reagents (Eq. 5), the results of
which are summarized in Table 2. When NaBH4, LiAlH4,
and DIBAL were employed, the anti isomer was pre-
dominantly obtained (entries 1–3). In the presence of
LiAlH(O-t-Bu)3, the reaction took place with excellent anti
selectivity and quantitative yield (entry 4). On the other
hand, borane reagents afforded the syn isomer stereo-
selectively. In the case of catecholborane the syn isomer was
obtained in good yield and excellent diastereoselectivity
(98:2) (entry 6). As both anti and syn isomers had been
synthesized in high stereoselective manner by the use of
LiAlH(O-t-Bu)3 and catecholborane, respectively, the
generality of these conditions was then examined.
11
reactions of MeCeCl2 and Me4AlLi12 (entries 5 and 6).
When Me3ZnLi13 was used, the syn isomer was generated
selectively (83:17) in good yield (entry 7). Thus either anti
or syn isomers could be selectively synthesized by the
proper choice of metal. Namely, Me2CuLi gave anti isomer,
and Me3ZnLi afforded syn isomer predominantly, though
the selectivities were only moderate.
Table 1. The effect of reagent on diastereoselectivitya
Entry
Reagent
Time (h)
Yield (%)b
Syn:antic
1
MeMgI
MeLi
MeTi(O-i-Pr)3 18
Me2CuLi
MeCeCl2
Me4AlLi
Me3ZnLi
4
4
30
52
60
83
77
71
82
50:50
33:67
33:67
25:75
67:33
67:33
83:17
2
3d
4
4
4
4
4
5e
6
7
a The reaction was performed at K78 8C in Et2O, unless otherwise noted.
(4)
b Isolated yield.
1
c The diastereomeric ratio was determined by H NMR.
d The reaction was performed at K20 8C.
e THF was used as solvent.

Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
11395
(5)
Table 2. The effect of reducing agent on the diastereoselectivity of 2b formation
Entry
Reductant
Solvent
Temperature (8C)
Time (h)
Yield (%)a
syn:antib
1
2
3
4
5
6
NaBH4
LiAlH4
i-Bu2AlH
LiAlH(O-t-Bu)3
BH3$THF
Catecholborane
MeOH
THF
CH2Cl2
THF
THF
K20
K78
K78
K78
0
2
3
2
0.5
0.1
3
96
96
86
Quant.
76
90
17:83
13:87
7:93
5:95
96:4
98:2
THF
0
a Isolated yield.
b The diastereomeric ratio was determined by 1H NMR.
First the synthesis of the starting b-amino ketone 3 was
examined. The b-amino aldehyde was generated according
to our asymmetric three-component Mannich reaction
conditions, and then immediately treated with a lithium
dialkyl- or diarylcuprate to afford b-amino alcohol 2. The
oxidation of 2 with SO3$pyridine gave b-amino ketone 3
(Eq. 6). The yields of 2 and 3 are summarized in Table 3,
which shows that 3 was easily obtained in good yield from
commercially available compounds.
(6)
The stereoselective reduction of b-amino ketones was
examined using LiAlH(O-t-Bu)3 and catecholborane
(Table 4). In the case of LiAlH(O-t-Bu)3, the 1,2-anti
isomer was obtained stereoselectively in quantitative yield.
This anti selectivity can be rationalized by intramolecular
hydride transfer, as shown in Figure 1. A similar model was
proposed by Evans and co-workers for the anti-selective
reduction of b-hydroxy ketones employing tetramethyl-
ammonium triacetoxyborohydride.15 When catecholborane
was employed as reducing reagent, the 1,2-syn isomer was
generated, also with high to exellent diastereoselectivities
and in good yield. The syn-selective reduction of b-hydroxy
ketone with catecholborane16 can be explained using six-
membered chelation model (Fig. 2).
Table 3. Generality of the synthesis of b-amino alcohol 2 and b-amino
ketone 3
Entry
R1
R2
Yield of 2
(%)a
Yield of 3
(%)b
1
2
3
4
5
6
Ph
Ph
Ph
Me
Ph
Bu
Me
Bu
Ph
83 (2a)
98 (2b)
78 (2c)
70 (2d)
62 (2e)
73 (2f)
94 (3a)
83 (3b)
78 (3c)
86 (3d)
93 (3e)
77 (3f)
4-BrC6H4–
4-BrC6H4–
4-BrC6H4–
a Isolated yield over two steps.
b Isolated yield.
(7)
Table 4. Generality of the reduction of 3 with LiAlH(O-t-Bu)3 or catecholborane
Entry
R1
R2
LiAlH(O-t-Bu)3
Syn:antib
Catecholborane
Syn:antib
Yield (%)a
Yield (%)a
1
2
3
4
5
6
Ph
Ph
Ph
Me
Bu
Ph
Me
Bu
Ph
Quant.
Quant.
Quant.
Quant.
84
14:86
11:89
5:95
20:80
16:84
6:94
90
67
90
65
97
86
98:2
75:25
98:2
73:27
73:27
99:1
4-BrC6H4–
4-BrC6H4–
4-BrC6H4–
Quant.
a Isolated yield.
b The diastereomeric ratio was determined by 1H NMR.

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Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
Figure 1. Transition state structure for the reduction with LiAlH(O-t-Bu)3.
Figure 2. Transition state structure for the reduction with catecholborane.
2.1. The determination of the stereochemistry
(8)
As reported in our previous paper (Eq. 1),8 the optical
purity of the Mannich reaction of benzaldehyde,
anisidine, and propanal, and that of p-bromobenzalde-
hyde, anisidine, and propanal were both excellent (98%
ee). As the optical purity does not change during the
oxidation and reduction processes, the a-alkyl b-amino
secondary alcohols are also obtained in excellent
enantiomeric purity, as was confirmed for compound
15 (vide infra).
2.2. Formal total synthesis of nikkomycin
Nikkomycins B and BX are nucleoside peptide antibiotics
isolated from the culture broth of Streptomyces tendae.17
They are potent chitin synthetase inhibitors, exhibiting
fungicidal, insecticidal, and acaricidal activities.18 Because
of these important biological properties, nikkomycins are
attractive synthetic targets. The Konig19 and Barrett20
groups have accomplished the total synthesis of nikko-
mycins B and BX, respectively. The nikkomycins can be
divided into two structural units, the C-terminal nucleoside
amino acid and the N-terminal amino acid 8. The
N-terminal amino acid 8 and its synthetic equivalent 9
contain the three contiguous stereocenters of an a-methyl
b-amino secondary alcohol moiety, the stereoselective
synthesis of which is a synthetic challenge. Several methods
to prepare this moiety in either racemic21 or optically active
form22 have been reported. We have synthesized the
N-terminal amino acid moiety 9 based on the method
developed above, as will be described below (Fig. 4).
The relative stereochemistry of the alkyl and hydroxy
groups of 2a was determined as following: the mixture
of syn and anti isomers 2a was treated with ClCO2Me
and DMAP, affording 4a as a mixture of diastereomers,
which were separated by TLC. When 4a was treated
with NaH in THF, no reaction occurred with the more
polar isomer. On the other hand, the less polar isomer
gave a cyclic urethane 5a, the stereochemistry of
which was determined by NOESY spectra (Fig. 3).
Thus, the configuration of the less polar isomer was
determined to be 1,2-syn. The stereochemistry of
phenyl-substituted 2b was also determined using the
same method.
The synthesis starts with the Mannich reaction of
2-furylaldehyde. We had already found that the enantio-
selectivity of the Mannich reaction of 2-furylaldehyde was
not satisfactory (84% ee).8 In order to improve the
enantioselectivity, we investigated this particular reaction
in detail and found that addition of pyridine increased the
enantioselectivity (Eq. 9). That is, while 84% ee was
obtained under the standard reaction conditions, excellent
enantioselectivity (92% ee) was realized in the presence of
Figure 3. NOE observed in 5a.
Figure 4. The structures of nikkomycin B and BX, and of the N-terminal amino acid 8 and its synthetic equivalent 9.

Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
11397
1.5 equiv of pyridine. It should be noted that this effect of
pyridine was observed only in the reaction of 2-furyl-
aldehyde, and no improvement in ee was seen for other
aldehydes.
generating 1,2-anti alcohol 15 in excellent yield and
diastereoselectivity (98%, 1,2-syn/1,2-antiZ1:32). The
optical purity of the alcohol 15 was determined by chiral
HPLC analysis and shown to be 96% ee.23 As the three
continuous stereocenters had been established in a highly
diastereo- and enantioselective manner, all that remained
was oxidation of the furan to a carboxy group and
transformations of the functional groups. However, the
order of the reactions and the protecting groups used were
found to be crucial for the successful transformation of 15 to
19, because of the presence of three oxidatively-labile
moieties, the furan, p-methoxyphenyl and p-tert-butyl-
dimethylsilyloxyaniline groups.
(9)
First, the hydroxy and amino groups were protected with the
electron-withdrawing benzoyl group by treatment with
benzoyl chloride, Et3N and a catalytic amount of DMAP,
affording 16 in 61% yield. The p-tert-butyldimethylsiloxy-
phenyl substituent on nitrogen was successfully removed by
successive treatment with TBAF and iodobenzene diacetate
in 78% yield over two steps.7 Iodobenzene diacetate is a
mild oxidant, which afford the successful removal of the
p-tert-butyldimethylsiloxyphenyl moiety without affecting
the oxidatively-labile p-methoxyphenyl group and furan. In
spite of several precedents for the conversion of furan into
carboxy group, the oxidative modification of furan of 15 was
found to be difficult. Though ozonolysis24 gave the product
in low yield, the reaction of 17 with sodium periodate and a
catalytic amount of ruthenium dioxide25 afforded the
carboxylic acid, which was treated with diazomethane to
In the total synthesis of nikkomycin, we employed 4-tert-
butyldimethylsiloxyaniline (11) instead of anisidine
because the 4-tert-butyldimethylsiloxyphenyl moiety is
easily cleaved from an amine under nearly neutral
conditions (vide infra).7 The Mannich reaction of 2-furyl-
aldehyde, propanal, and 4-tert-butyldimethylsiloxyaniline
proceeded with high diastereo- and enantioselectivities
(96% ee, vide infra). Crude b-amino aldehyde 12 was
immediately treated with (p-MeOC6H4)2CuMgBr in THF at
K40 8C to give b-amino alcohol 13. The crude mixture of
syn and anti alcohols 13 was oxidized with SO3$pyridine to
afford b-amino ketone 14 in 70% yield over three steps.
These reactions could be easily scaled up because
purification was performed only after the oxidation.
Diastereoselective reduction of b-amino ketone 14 with
LiAlH(O-t-Bu)3 at K78 8C for 1 h proceeded smoothly,
Scheme 1. Total synthesis of the N-terminal of amino acid equivalent 19 of nikkomycin B and BX.

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Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
afford methyl ester 18 in 47% yield over two steps. Even
under these conditions over-oxidation at the p-methoxy-
phenyl moiety proceeded to some extent. Treatment of 18
with K2CO3 in MeOH gave lactone 19 in 84% yield, which
was identical to the literature 21d (Scheme 1).
d, JZ8.8 Hz), 6.66 (2H, d, JZ8.8 Hz), 7.10–7.30 (5H, m);
13C NMR (150 MHz, CDCl3): d 5.5, 21.7, 45.5, 55.6, 63.6,
71.6, 114.6, 116.0, 126.6, 126.8, 128.4, 140.8, 142.2, 152.6;
IR (neat): n 3367, 2927, 2918, 1512, 1450, 1234, 1039, 820,
702 cmK1; HRMS (FAB): calcd for C18H23NO2 285.1729,
found 285.1721.
3. Conclusion
4.1.2. (2R,3S,4S)-4-(p-Anisidino)-3-methyl-4-phenyl-
butan-2-ol (anti-2a). Yellow solid; mp: 115–116 8C; H
1
In summary, we have accomplished a general method for
the synthesis of a-substituted b-amino secondary alcohols
based on the following sequence of four reactions. (1) The
proline-mediated, asymmetric, one-pot, three-component
cross Mannich reaction of two different aldehydes to
generate a-substituted b-amino aldehydes. (2) The nucleo-
philic addition reaction of R2CuLi. (3) Oxidation of alcohol
to ketone. (4) Diastereoselective reduction with LiAlH(O-t-
Bu)3 or catecholborane to generate the 1,2-syn or 1,2-anti
isomer. This synthetic method was successfully applied to
the formal total synthesis of the N-terminal amino acid
moiety of nikkomycins B and BX.
NMR (400 MHz, CDCl3): d 0.85 (3H, d, JZ7.1 Hz), 1.26
(3H, d, JZ6.3 Hz), 1.92 (1H, d of quintet, JZ3.3, 7.1 Hz),
3.67 (3H, s), 3.77 (1H, quintet, JZ6.3 Hz), 4.69 (1H, d, JZ
3.3 Hz), 6.52 (2H, br d, JZ8.9 Hz), 6.67 (2H, br d, JZ
8.9 Hz), 7.15–7.25 (1H, m), 7.26–7.32 (4H, m); 13C NMR
(100 MHz, CDCl3): d 11.8, 21.9, 45.9, 55.7, 59.5, 70.3,
114.8, 115.4, 126.7, 127.1, 128.3, 141.2, 142.0, 152.3; IR
(neat): n 3380, 2968, 2931, 2360, 1512, 1452, 1232, 1037,
820, 702 cmK1; HRMS (FAB): calcd for C18H23NO2
285.1729, found 285.1691; [a]2D0 K34.5 (c 0.10, CHCl3).
4.1.3. (1R,2S,3S)-3-(p-Anisidino)-2-methyl-1,3-diphenyl-
propan-1-ol (syn-2b). Yellow solid; mp: 131–132 8C; H
1
NMR (400 MHz, CDCl3): d 0.82 (3H, d, JZ7.1 Hz), 2.13
(1H, tq, JZ3.6, 7.1 Hz), 3.65 (3H, s), 4.56 (1H, d, JZ
3.6 Hz), 5.01 (1H, d, JZ3.7 Hz), 6.49 (2H, br d, JZ8.9 Hz),
6.66 (2H, br d, JZ8.9 Hz), 7.13–7.37 (10H, m); 13C NMR
(150 MHz, CDCl3): d 6.2, 47.0, 55.6, 62.5, 77.4, 114.6,
115.9, 125.8, 126.6, 126.8, 127.1, 128.2, 128.4, 140.7,
142.2, 143.4, 152.5; IR (neat): n 3379, 2933, 2908, 1512,
1452, 1234, 1036, 820, 740, 702 cmK1; HRMS (FAB):
calcd for C23H25NO2 347.1885, found 347.1862; [a]D22
K5.4 (c 0.81, MeOH).
4. Experimental
4.1. Typical experimental procedures for the
preparation of 2 (Table 3, entry 1)
To a solution of benzaldehyde (53 mL, 0.5 mmol) and
p-anisidine (67.8 mg, 0.55 mmol) in NMP (0.5 mL) was
added L-proline (5.8 mg, 0.05 mmol) and the reaction
mixture was stirred for 2 h at room temperature. To this
reaction mixture was added propanal (60.5 mL, 1.5 mmol) at
K20 8C, which was further stirred for 20 h at this
temperature. After addition of phosphate buffer, the organic
materials were extracted with Et2O three times and the
combined organic phase was washed with brine three times,
dried over MgSO4. After filtration, the volatile materials
were removed under reduced pressure to afford a crude
b-amino aldehyde, which was used immediately in the next
reaction.
4.1.4. (1S,2S,3S)-3-(p-Anisidino)-2-methyl-1,3-diphenyl-
propan-1-ol (anti-2b). Yellow solid; mp: 126–127 8C; H
1
NMR (400 MHz, CDCl3): d 0.82 (3H, d, JZ7.2 Hz), 2.25–
2.35 (1H, m), 3.68 (3H, s), 4.65–4.71 (2H, m), 6.53 (2H, br
d, JZ8.8 Hz), 6.67 (2H, br d, JZ8.8 Hz), 7.14–7.23 (3H,
m), 7.23–7.32 (3H, m), 7.32–7.40 (4H, m); 13C NMR
(150 MHz, CDCl3): d 11.7, 45.8, 55.6, 58.6, 77.6, 114.7,
115.9, 126.2, 126.7, 126.9, 127.5, 128.3, 128.5, 140.6,
141.6, 143.9, 152.5; IR (neat): n 3419, 2912, 1612, 1512,
1448, 1234, 1030, 822, 746, 702 cmK1; HRMS (FAB):
calcd for C23H26NO2 348.1964, found 348.1992; [a]D22
C0.5 (c 0.88, MeOH).
To a suspension of CuI (238 mg, 1.25 mmol) in Et2O
(2.5 mL) was added MeLi (1.14 M in Et2O, 2.19 mL,
2.5 mmol) at K20 8C over 5 min and the reaction mixture
was stirred for 30 min at that temperature. To a Me2CuLi
solution was added a solution of crude b-amino aldehyde in
Et2O (1 mL) at K78 8C over 15 min and the reaction
mixture was stirred for 3 h at this temperature. After
addition of phosphate buffer and filtration of the insoluble
materials via Celite pad, the organic materials were
extracted with AcOEt three times and the combined organic
phase was dried over Na2SO4, and filtered. After removal of
the volatile materials under reduced pressure, the crude
materials were obtained, which was purified by thin-layer
chromatography (TLC) (AcOEt/hexaneZ1:3) to afford
b-amino alcohol 2a in 83% yield.
4.1.5. (1S,2S,3S)-1-(p-Anisidino)-2-methyl-1-phenyl-
heptan-3-ol (syn-2c). Yellow solid; H NMR (600 MHz,
1
CDCl3): d 0.83–0.95 (6H, m), 1.20–1.42 (4H, m), 1.45–1.65
(2H, m), 1.80–1.90 (1H, m), 3.66 (3H, s), 3.88–3.95 (1H,
m), 4.51 (1H, d, JZ3.3 Hz), 6.53 (2H, br d, JZ8.2 Hz), 6.66
(2H, br d, JZ8.2 Hz), 7.15–7.30 (5H, m); 13C NMR
(150 MHz, CDCl3): d 5.6, 14.1, 22.7, 28.3, 35.3, 43.9, 55.6,
64.0, 75.8, 114.6, 116.0, 126.6, 126.7, 128.4, 140.9, 142.3,
152.5; IR (neat): n 3363, 2956, 2931, 1514, 1493, 1452,
1261, 1234, 1037, 976 cmK1; HRMS (FAB): [MCH]C
calcd for C21H30NO2 328.2277, found 328.2263.
4.1.1. (2S,3S,4S)-4-(p-Anisidino)-3-methyl-4-phenyl-
butan-2-ol (syn-2a). Yellow solid; mp: 111–112 8C; 1H
NMR (400 MHz, CDCl3): d 0.90 (3H, d, JZ8.0 Hz), 1.20
(3H, d, JZ6.4 Hz), 1.73–1.86 (1H, m), 3.66 (3H, s), 4.15
(1H, dq, JZ1.8, 6.4 Hz) 4.54 (1H, d, JZ3.6 Hz), 6.53 (2H,
4.1.6. (1S,2S,3R)-1-(p-Anisidino)-2-methyl-1-phenyl-
heptan-3-ol (anti-2c). Yellow solid; H NMR (600 MHz,
CDCl3): d 0.85 (3H, d, JZ7.2 Hz), 0.89 (3H, t, JZ7.0 Hz),
1.25–1.63 (6H, m), 1.91 (1H, d of quintet, JZ3.2, 7.0 Hz),
3.55–3.72 (1H, m), 3.65 (3H, s), 4.69 (1H, d, JZ3.2 Hz),
1

Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
11399
6.49 (2H, br d, JZ8.9 Hz), 6.64 (2H, br d, JZ8.9 Hz), 7.17
(1H, t, JZ7.0 Hz), 7.22–7.29 (4H, m); 13C NMR (150 MHz,
CDCl3): d 11.5, 14.1, 22.8, 28.1, 35.1, 44.0, 55.6, 58.9, 74.7,
114.7, 115.5, 126.6, 126.9, 128.3, 141.0, 142.1, 152.3; IR
(neat): n 3379, 2956, 2931, 1618, 1601, 1514, 1464, 1452,
1234, 1039 cmK1; HRMS (FAB): [MCH]C calcd for
C21H30NO2 328.2277, found 328.2286.
NMR (600 MHz, CDCl3): d 0.82 (3H, d, JZ7.0 Hz), 2.05–
2.12 (1H, m), 3.68 (3H, s), 4.49 (1H, d, JZ3.2 Hz), 5.00
(1H, d, JZ3.7 Hz), 6.45 (2H, d, JZ8.8 Hz), 6.67 (2H, d,
JZ8.8 Hz), 7.13 (2H, d, JZ8.3 Hz), 7.23–7.26 (1H, m),
7.30–7.33 (4H, m), 7.39 (2H, d, JZ8.3 Hz); 13C NMR
(150 MHz, CDCl3): d 6.4, 47.0, 55.6, 61.9, 77.3, 114.7,
115.6, 120.5, 125.8, 127.4, 128.3, 128.4, 131.5, 140.6,
141.6, 143.3, 152.5; IR (neat): n 3374, 2931, 2908, 1512,
1484, 1234, 1178, 1035, 1008, 819 cmK1; HRMS (FAB):
4.1.7. (2S,3S,4S)-4-(p-Anisidino)-4-(p-bromophenyl)-3-
methylbutan-2-ol (syn-2d). Yellow solid; mp: 138–
[MCH]C calcd for C23H BrNO2 426.1069, found
79
25
426.1089; [a]2D0 K7.7 (c 0.75, CHCl3).
1
139 8C; H NMR (400 MHz, CDCl3): d 0.89 (3H, d, JZ
7.2 Hz), 1.21 (3H, d, JZ6.3 Hz), 1.72–1.80 (1H, m), 3.67
(3H, s), 4.10 (1H, dq, JZ2.3, 6.3 Hz), 6.46 (2H, br d, JZ
8.9 Hz), 6.66 (2H, br d, JZ8.9 Hz), 7.14 (2H, br d, JZ
8.4 Hz), 7.40 (2H, br d, JZ8.4 Hz); 13C NMR (150 MHz,
CDCl3): d 5.1, 21.1, 44.8, 55.7, 63.3, 72.4, 114.9, 116.7,
120.7, 128.3, 131.6, 139.8, 140.7, 153.1; IR (neat): n 3369,
4.1.12. (1S,2S,3S)-3-(p-Anisidino)-3-(p-bromophenyl)-2-
methyl-1-phenylpropan-1-ol (anti-2f). Colorless solid; 1H
NMR (400 MHz, CDCl3): d 0.78 (3H, d, JZ7.1 Hz), 2.25
(1H, d of quintet, JZ2.5, 7.1 Hz), 3.68 (3H, s), 4.62–4.66
(2H, m), 6.47 (2H, br d, JZ8.9 Hz), 6.67, (2H, br d, JZ
8.9 Hz), 7.09 (2H, br d, JZ8.5 Hz), 7.25–7.35 (5H, m), 7.38
(2H, br d, JZ8.5 Hz); 13C NMR (150 MHz, CDCl3): d 11.7,
45.8, 55.6, 58.3, 77.5, 114.7, 115.5, 120.4, 126.3, 127.7,
128.5, 128.8, 131.4, 140.5, 140.9, 143.5, 152.4; IR (neat): n
3388, 2931, 1512, 1484, 1234, 1072, 1037, 1009, 819,
2970, 1510, 1485, 1403, 1234, 1178, 1039, 1008, 520 cmK1
;
HRMS (FAB): calcd for C18H BrNO2 363.0834, found
79
22
363.0832.
4.1.8. (2R,3S,4S)-4-(p-Anisidino)-4-(p-bromophenyl)-3-
methylbutan-2-ol (anti-2d). Yellow solid; 1H NMR
(400 MHz, CDCl3): d 0.83 (3H, d, JZ7.1 Hz), 1.26 (3H,
d, JZ6.3 Hz), 1.87 (1H, d of quintet, JZ3.2, 7.1 Hz),
3.67 (3H, s), 3.76 (1H, quintet, JZ6.7 Hz), 4.65 (1H, d,
JZ3.2 Hz), 6.45 (2H, br d, JZ8.9 Hz), 6.66 (2H, br d,
JZ8.9 Hz), 7.17 (2H, br d, JZ8.3 Hz), 7.40 (2H, br d, JZ
8.3 Hz); 13C NMR (100 MHz, CDCl3): d 11.7, 22.0, 45.9,
55.7, 59.0, 70.2, 114.8, 115.2, 120.4, 128.8, 131.4, 141.0,
141.3, 152.3; IR (neat): n 3379, 2968, 2931, 2360, 1512,
702 cmK1
;
HRMS (FAB): [MCH]C calcd for
79
25
C23H BrNO2 426.1069, found 426.1040; [a]2D0 K30.5 (c
0.55, CHCl3).
4.2. Typical experimental procedures for the
preparation of 3 (Table 3, entry 1)
To a solution of b-amino alcohol 2a (205 mg, 0.59 mmol) in
CH2Cl2 (0.6 mL) was added Et3N (0.41 mL, 2.96 mmol),
DMSO (0.6 mL) and SO3$pyridine (278 mg, 1.78 mmol) at
0 8C, and the reaction mixture was stirred for 30 min at that
temperature. After addition of phosphate buffer, the organic
materials were extracted with AcOEt three times and the
combined organic phase was dried over Na2SO4, and
filtered. After removal of the volatile materials under
reduced pressure, the crude material was purified by TLC
(AcOEt/hexaneZ1:3) to afford b-amino ketone 3a in 94%
yield.
1485, 1234, 1178, 1037, 1008 cmK1; HRMS (FAB): [MC
79
H]C calcd for C18H BrNO2 364.0912, found 364.0917.
23
4.1.9. (1S,2S,3S)-1-(p-Anisidino)-1-(p-bromophenyl)-2-
methylheptan-3-ol (syn-2e). Yellow oil; 1H NMR
(400 MHz, CDCl3): d 0.83–0.94 (6H, m), 1.20–1.65 (6H,
m), 1.76–1.85 (1H, m), 3.67 (3H, s), 3.82–3.88 (1H, m),
4.42 (1H, d, JZ4.0 Hz), 6.46 (2H, br d, JZ8.9 Hz), 6.66
(2H, br d, JZ8.9 Hz), 7.14 (2H, br d, JZ8.4 Hz), 7.41 (2H,
br d, JZ8.9 Hz); 13C NMR (150 MHz, CDCl3): d 5.7, 14.0,
22.7, 28.2, 35.4, 43.9, 55.6, 63.5, 75.6, 114.6, 115.7, 120.4,
128.4, 131.5, 140.8, 141.7, 152.5; IR (neat): n 3367, 2931,
4.2.1. (3S,4S)-4-(p-Anisidino)-3-methyl-4-phenylbutan-
2-one (3a). Colorless solid; mp: 110–111 8C; 1H NMR
(400 MHz, CDCl3): d 1.07 (3H, d, JZ7.0 Hz), 2.08 (3H, s),
2.98 (1H, dq, JZ5.4, 7.0 Hz), 3.66 (3H, s), 4.00 (1H, br s),
4.65 (1H, d, JZ5.4 Hz), 6.44 (2H, br d, JZ8.9 Hz), 6.65
(2H, br d, JZ8.9 Hz), 7.18–7.24 (1H, m), 7.27–7.30 (4H,
m); 13C NMR (100 MHz, CDCl3): d 11.0, 29.3, 53.1, 55.7,
59.7, 114.7, 113.8, 114.7, 114.9, 126.9, 127.2, 128.6, 141.1,
141.3, 152.2; IR (neat): n 3403, 2933, 1708, 1514, 1452,
1355, 1243, 1002, 796, 648 cmK1; HRMS (FAB): calcd for
C18H21NO2 283.1572, found 283.1597; [a]2D0 C55 (c 0.85,
CHCl3).
1514, 1484, 1465, 1234, 1039, 1008, 819, 524 cmK1
;
HRMS (FAB): calcd for C21H BrNO2 405.1303, found
79
28
405.1298.
4.1.10. (1S,2S,3R)-1-(p-Anisidino)-1-(p-bromophenyl)-2-
methylheptan-3-ol (anti-2e). Yellow oil; 1H NMR
(400 MHz, CDCl3): d 0.85 (3H, d, JZ6.9 Hz), 0.90 (3H,
t, JZ8.4 Hz), 1.25–1.42 (4H, m), 1.43–1.66 (2H, m), 1.90
(1H, d of quintet, JZ3.0, 6.9 Hz), 3.58 (1H, ddd, JZ4.0,
6.3, 8.2 Hz), 4.65 (1H, d, JZ3.0 Hz), 6.45 (2H, br d, JZ
8.9 Hz), 6.66 (2H, br d, JZ8.9 Hz), 7.15 (2H, br d, JZ
8.3 Hz), 7.40 (2H, br d, JZ8.3 Hz); 13C NMR (150 MHz,
CDCl3): d 11.5, 14.1, 22.7, 28.0, 35.1, 44.0, 55.6, 58.6, 74.6,
114.7, 115.3, 120.3, 128.8, 131.4, 140.8, 141.4, 152.3; IR
(neat): n 3367, 2954, 2931, 1532, 1484, 1234, 1039, 1008,
4.2.2. (2S,3S)-3-(p-Anisidino)-2-methyl-1,3-diphenyl-
propan-1-one (3b). Colorless solid; mp: 120–121 8C; H
1
NMR (400 MHz, CDCl3): d 1.20 (3H, d, JZ7.0 Hz), 3.64
(3H, s), 3.92 (1H, dq, JZ4.8, 7.0 Hz), 4.22 (1H, br s), 4.64
(1H, d, JZ4.8 Hz), 6.39 (2H, br d, JZ8.9 Hz), 6.60 (2H, br
d, JZ8.9 Hz), 7.19 (1H, t, JZ7.4 Hz), 7.29 (2H, t, JZ
7.4 Hz), 7.37 (2H, d, JZ7.4 Hz), 7.43 (2H, t, JZ7.4 Hz),
7.54 (1H, t, JZ7.4 Hz), 7.91 (2H, d, JZ7.4 Hz); 13C NMR
(150 MHz, CDCl3): d 11.3, 46.9, 55.6, 59.9, 114.5, 114.9,
820, 526 cmK1
;
C21H BrNO2 406.1382, found 406.1353.
HRMS (FAB): [MCH]C calcd
79
29
4.1.11. (1R,2S,3S)-3-(p-Anisidino)-3-(p-bromophenyl)-2-
methyl-1-phenylpropan-1-ol (syn-2f). Colorless solid; H
1

11400
Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
126.9, 127.2, 128.3, 128.6, 128.8, 133.3, 136.2, 141.4,
141.8, 152.0, 202.8; IR (neat): n 3394, 2974, 1672, 1514,
1448, 1294, 1257, 1039, 974, 812 cmK1; HRMS (FAB):
calcd for C23H23NO2 345.1729, found 345.1748; [a]D22
K0.1 (c 0.88, MeOH).
4.3. Typical experimental procedures for the prep-
aration of 2-anti by the reduction with LiAlH(O-t-Bu)3
(Table 4, entry 1)
To a solution of 3a (10 mg, 0.035 mmol) in THF (0.5 mL)
was added a solution of LiAlH(O-t-Bu)3 (1 M in THF,
0.175 mL, 0.175 mmol) at K78 8C and the reaction mixture
was stirred for 1 h at that temperature. After addition of a
saturated solution of potassium sodium tartrate, the organic
materials were extracted with AcOEt three times and the
combined organic phase was washed with brine three times
and dried over Na2SO4, and filtered. After removal of the
volatile materials under reduced pressure, the crude
materials were purified by TLC (AcOEt/hexaneZ1:3) to
afford b-amino alcohol 2a quantitatively (2a-anti/2a-synZ
4.2.3. (1S,2S)-1-(p-Anisidino)-2-methyl-1-phenylheptan-
3-one (3c). Colorless solid; 1H NMR (400 MHz, CDCl3): d
0.80 (3H, t, JZ7.3 Hz), 1.08 (3H, d, JZ7.0 Hz), 1.17 (2H,
septet, JZ7.2 Hz), 1.42 (2H, m), 2.27 (1H, dt, JZ7.3,
17.2 Hz), 2.35 (1H, dt, JZ7.3, 17.1 Hz), 2.96 (1H, quintet,
JZ5.9 Hz), 3.66 (3H, s), 4.57 (1H, d, JZ5.7 Hz), 5.43 (2H,
br d, JZ8.8 Hz), 6.64 (2H, br d, JZ8.8 Hz), 7.15–7.24 (1H,
m), 7.26–7.32 (4H, m); 13C NMR (100 MHz, CDCl3): d
11.4, 13.8, 22.1, 25.5, 42.0, 52.5, 55.7, 60.0, 114.7, 114.9,
126.9, 127.2, 128.5, 141.3, 141.5, 152.2, 213.0; IR (neat): n
3396, 2929, 1702, 1518, 1454, 1295, 1267, 1247, 1232,
1036 cmK1; HRMS (FAB): calcd for C21H27NO2 325.2042,
found 325.2039; [a]2D1 C49.9 (c 0.27, CHCl3).
1
86:14). The ratio of anti/syn was determined by H NMR
measurement.
4.4. Typical experimental procedures for the prep-
aration of 2-syn by the reduction with catecholborane
(Table 4, entry 1)
4.2.4. (3S,4S)-4-(p-Anisidino)-4-(p-bromophenyl)-3-
methylbutan-2-one (3d). Colorless solid; 1H NMR
(400 MHz, CDCl3): d 1.06 (3H, d, JZ7.1 Hz), 2.09 (3H,
s), 2.94 (1H, dq, JZ5.4, 7.1 Hz), 3.66 (3H, s), 3.98 (1H, br
s), 4.60 (1H, d, JZ5.4 Hz), 6.40 (2H, br d, JZ8.9 Hz), 6.65
(2H, br d, JZ8.9 Hz), 7.18 (2H, br d, JZ8.4 Hz), 7.41 (2H,
br d, JZ8.4 Hz); 13C NMR (400 MHz, CDCl3): d 10.9,
29.3, 52.8, 55.6, 59.1, 114.7, 114.9, 121.0, 128.7, 131.7,
140.5, 140.7, 152.4, 210.2; IR (neat): n 3392, 2933, 1708,
To a THF solution (1.5 mL) of 3a (50 mg, 0.15 mmol) was
added catecholborane (155 mL, 1.5 mmol) at K10 8C and
the reaction mixture was stirred for 3 h at that temperature.
After addition of MeOH and a saturated solution of
potassium sodium tartrate, the organic materials were
extracted with AcOEt three times and the combined organic
phase was washed with brine five times and dried over
Na2SO4, and filtered. After removal of the volatile materials
under reduced pressure, the crude materials were purified by
TLC (AcOEt/hexaneZ1:3) to afford b-amino alcohol 2a in
90% yield (2a-anti/2a-synZ2:98). The ratio of anti/syn was
1514, 1486, 1357, 1241, 1234, 1039, 1009 cmK1; HRMS
79
20
(FAB): C18H BrNO2 361.0677, found 361.0647; [a]D20
C21.3 (c 0.84, CHCl3).
1
4.2.5. (1S,2S)-1-(p-Anisidino)-1-(p-bromophenyl)-2-
methylheptan-3-one (3e). Colorless solid; 1H MNR
(600 MHz, CDCl3): d 0.81 (3H, t, JZ7.4 Hz), 1.05 (3H,
d, JZ7.0 Hz), 1.16 (1H, dq, JZ2.9, 7.5 Hz), 1.19 (1H, dq,
JZ2.9, 7.5 Hz), 1.40–1.44 (2H, m), 2.30 (1H, td, JZ7.3,
14.9 Hz), 2.37 (1H, td, JZ7.4, 14.9 Hz), 2.92 (1H,
quintet, JZ6.7 Hz), 3.66 (3H, s), 4.07 (1H, br s), 4.52
(1H, d, JZ5.4 Hz), 6.39 (2H, br d, JZ8.9 Hz), 6.64 (2H, br
d, JZ8.9 Hz), 7.18 (2H, br d, JZ8.3 Hz), 7.41 (2H, br d,
JZ8.3 Hz); 13C NMR (150 MHz, CDCL3): d 11.3, 13.8,
22.1, 25.4, 42.1, 52.1, 55.6, 59.3, 114.6, 114.9, 120.9, 128.7,
131.6, 140.7, 140.8, 152.2, 212.8; IR (neat): n 3407, 2960,
determined by H NMR measurement.
4.5. The determination of the relative stereochemistry
4.5.1. (1S,2S,3S)-Carbonic acid 3-(p-anisidino)-1,2-
dimethyl-3-phenylpropyl ester methyl ester (syn-4a).
To a solution of 2a (75.7 mg, 0.29 mmol) in CH2Cl2
(2.9 mL) was added DMAP (715.9 mg, 5.86 mmol), ClCO2-
Me (453 mL, 5.86 mmol) at 0 8C and the reaction mixture
was stirred for 2.5 h at room temperature. After addition of
phosphate buffer, the organic materials were extracted with
AcOEt three times and the combined organic phase was
washed with brine and dried over Na2SO4, and filtered.
After removal of the volatile materials under reduced
pressure, the crude material was purified by TLC (AcOEt/
hexaneZ1:3) to afford syn-4a and anti-4a in 68% yield.
Syn-4a and anti-4a were separated by TLC.
2931, 1701, 1513, 1460, 1408, 1010, 813, 738 cmK1
;
HRMS (FAB): calcd for C21H BrNO2 403.1147, found
79
26
403.1138; [a]2D0 C33.5 (c 0.29, CHCl3).
4.2.6. (2S,3S)-3-(p-Anisidino)-3-(p-bromophenyl)-2-
methyl-1-phenylpropan-1-one (3f). Colorless solid; 1H
NMR (400 MHz, CDCl3): d 1.20 (3H, d, JZ7.0 Hz), 3.64
(3H, s), 3.87 (1H, dq, JZ5.0, 7.0 Hz), 4.22 (1H, br s), 4.59
(1H, d, JZ5.0 Hz), 6.37 (2H, br d, JZ8.9 Hz), 6.62 (2H, br
d, JZ8.9 Hz), 7.26 (2H, br d, JZ8.3 Hz), 7.41 (2H, br d,
JZ8.3 Hz), 7.45 (2H, d, JZ7.8 Hz), 7.55 (1H, t, JZ
7.3 Hz), 7.89 (2H, d, JZ7.3 Hz); 13C NMR (100 MHz,
CDCl3): d 11.7, 46.8, 55.7, 59.6, 114.7, 115.1, 121.0, 128.2,
128.7, 128.8, 131.7, 133.4, 136.2, 141.0, 141.1, 152.4,
202.5; IR (neat): n 3380, 2931, 1676, 1512, 1448, 1241,
1
Yellow solid; H NMR (400 MHz, CDCl3): d 0.99 (3H, d,
JZ6.8 Hz), 1.32 (3H, d, JZ6.4 Hz), 1.93–2.02 (1H, m),
3.66 (3H, s), 3.71 (3H, s), 4.40 (1H, d, JZ4.8 Hz), 4.81
(1H, dq, JZ5.2, 6.4 Hz), 6.41 (2H, br d, JZ8.9 Hz), 6.64
(2H, br d, JZ8.9 Hz), 7.17–7.30 (5H, m); 13C NMR
(150 MHz, CDCl3): d 8.8, 18.4, 29.7, 45.1, 54.7, 55.7, 60.4,
114.5, 114.6, 126.7, 127.0, 128.5, 141.3, 142.4, 151.8,
155.3; IR (neat): n 3415, 2981, 2954, 1743, 1514, 1442,
1271, 1234, 1038, 820 cmK1; HRMS (FAB): calcd for
C20H25NO4 343.1784, found 343.1816; [a]2D1 K8.5 (c 0.17,
MeOH).
1236, 1038, 1010, 971 cmK1; HRMS (FAB): calcd for
79
22
C23H BrNO2 423.0834, found 423.0807; [a]2D0 C51.7 (c
1.83, CHCl3).

Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
11401
4.5.2. (4S,5S,6S)-3-(p-Anisidino)-5,6-dimethyl-4-phenyl-
[1,3]oxazinan-2-one (5a). To a solution of syn-4a
(25.6 mmol) in THF (0.8 mL) was added NaH
(8.95 mmol, 0.373 mmol) at room temperature and the
reaction mixture was stirred for 12 h at that temperature.
After addition of phosphate buffer, the organic materials
were extracted with AcOEt three times and dried over
Na2SO4, and filtered. After removal of the volatile materials
under reduced pressure, the crude material was purified by
TLC (AcOEt/hexaneZ1:1) to afford 5a in 25% yield.
the volatile materials under reduced pressure, the crude
material was purified by column chromatography (AcOEt/
hexaneZ1:25) to afford b-amino ketone 14 in 70% yield
over three steps.
1
Yellow oil; H NMR (400 MHz, CDCl3): d 0.10 (6H, s),
0.92 (9H, s), 1.27 (3H, d, JZ6.9 Hz), 3.84 (3H, s), 4.03 (1H,
quintet, JZ6.9 Hz), 4.75 (1H, d, JZ6.5 Hz), 6.09 (1H, d,
JZ3.2 Hz), 6.17 (1H, dd, JZ2.0, 3.2 Hz), 6.44 (2H, br d,
JZ8.7 Hz), 6.58 (2H, d, JZ8.7 Hz), 6.90 (2H, d, JZ
8.8 Hz), 7.25 (1H, d, JZ2.0 Hz), 7.90 (2H, d, JZ8.8 Hz);
13C NMR (100 MHz, CDCl3): d K4.5, 13.3, 18.1, 25.7,
44.3, 55.46, 55.49, 107.2, 110.2, 113.8, 115.3, 120.4, 129.3,
130.6, 141.4, 141.6, 148.0, 154.6, 163.6, 200.7; IR (neat): n
3381, 2956, 2929, 1672, 1601, 1510, 1254, 1173, 924,
841 cmK1; HRMS (FAB): calcd for C27H35NO4Si
465.2335, found 465.2332; [a]2D2 K37.6 (c 0.39, CHCl3).
Colorless solid; 1H NMR (400 MHz, CDCl3): d 0.88 (3H, d,
JZ7.0 Hz), 1.38 (3H, d, JZ6.5 Hz), 2.17–2.25 (1H, m),
3.66 (3H, s), 4.85 (1H, dq, JZ1.1, 6.5 Hz), 5.26 (1H, d, JZ
5.0 Hz), 6.68 (2H, br d, JZ8.6 Hz), 7.06–7.22 (7H, m); 13C
NMR (100 MHz, CDCl3): d 6.8, 18.1, 37.8, 55.2, 67.3, 75.9,
113.7, 127.5, 127.9, 128.3, 133.8, 137.2, 154.2, 157.5; IR
(neat): n 2937, 1689, 1515, 1454, 1402, 1247, 1170, 1033,
1025, 833 cmK1; HRMS (FAB): [MCH]C calcd for
C19H22NO3 312.1600, found 312.1622; [a]2D0 K53.8 (c
0.47, CHCl3).
4.6.2. (1S,2S,3S)-3-(N-p-tert-Butyldimethylsiloxyphenyl-
amino)-3-(2-furyl)-2-methyl-1-(p-methoxyphenyl)pro-
pan-1-ol (15). To a solution of 14 (673 mg, 1.44 mmol) in
THF (14.4 mL) was of LiAlH(O-t-Bu)3 (1 M in THF,
7.2 mL, 7.2 mmol) at K78 8C and the reaction mixture was
stirred for 1 h at that temperature. After addition of the
saturated solution of potassium sodium tartrate, the organic
materials were extracted with AcOEt three times and the
combined organic phase was washed with brine three
times, dried over Na2SO4, and filtered. After removal of
the volatile materials under reduced pressure, the crude
material was purified by column chromatography (AcOEt/
hexaneZ1:15) to afford b-amino alcohol 15 in 98%
yield.
4.6. Experimental procedures of the formal total
synthesis of nikkomycin
4.6.1. (2S,3S)-3-(N-p-tert-Butyldimethylsiloxyphenyl-
amino)-3-(2-furyl)-2-methyl-1-(p-methoxyphenyl)pro-
pan-1-one (14). To a solution of 2-furylaldehyde (0.25 mL,
3.0 mmol) and p-tert-butyldimethylsiloxyaniline (737 mg,
3.3 mmol) in NMP (3.0 mL) was added L-proline (34.5 mg,
0.03 mmol) and the reaction mixture was stirred for 2 h at
room temperature. To this reaction mixture was added
pyridine (0.363 mL, 4.5 mmol) and propanal (0.972 mL,
4.5 mmol) at K20 8C, which was further stirred for 20 h at
this temperature. After addition of phosphate buffer, the
organic materials were extracted with Et2O three times and
the combined organic phase was washed with brine three
times and dried over MgSO4. After filtration, the volatile
materials were removed under reduced pressure to afford a
crude b-amino aldehyde, which was used without further
purification in the next reaction.
The ee was determined by the chiral HPLC analysis:
Chiralpak AD-H column (hexane/2-propanolZ30:1),
0.5 mL/min, major trZ16.9 min, minor trZ21.5 min.
Pale yellow oil; 1H NMR (400 MHz, CDCl3): d 0.13 (6H, s),
0.84 (3H, d, JZ7.4 Hz), 0.94 (9H, s), 2.41 (1H, d of quintet,
JZ2.5, 7.4 Hz), 3.80 (3H, s), 4.60 (1H, d, JZ7.4 Hz), 4.79
(1H, d, JZ2.5 Hz), 6.05 (1H, d, JZ3.2 Hz), 6.23 (1H, dd,
JZ1.8, 3.2 Hz), 6.57 (2H, br d, JZ8.9 Hz), 6.64 (2H, br d,
JZ8.9 Hz), 6.87 (2H, br d, JZ8.7 Hz), 7.27 (2H, d, JZ
8.7 Hz), 7.29 (1H, d, JZ1.8 Hz); 13C NMR (150 MHz,
CDCl3): d K4.5, 12.5, 18.1, 25.7, 43.4, 54.6, 55.2, 106.7,
110.1, 113.8, 116.0, 120.6, 127.5, 128.3, 136.0, 141.2,
141.4, 148.4, 155.4, 158.9; IR (neat): n 3388, 2956, 2929,
1610, 1508, 1250, 1009, 910, 837, 779 cmK1; HRMS
(FAB): calcd for C27H37NO4Si 467.2492, found 467.2493;
[a]2D2 K22.4 (c 0.81, CHCl3).
To a suspension of CuI (2.85 g, 15 mmol) in Et2O (10 mL)
was added a solution of p-MeOPhMgBr (2.15 M in Et2O,
14 mL, 30 mmol) at K7 8C over 5 min and the reaction
mixture was stirred for 30 min at this temperature. To this
reaction mixture was added a solution of crude b-amino
aldehyde in Et2O (20 mL) at K7 8C and the reaction
mixture was stirred for 3 h at this temperature. After
addition of phosphate buffer and filtration of the insoluble
materials via Celite pad, the organic materials were
extracted with AcOEt three times and the combined organic
phase was dried over Na2SO4, and filtered. After removal of
the volatile materials under reduced pressure, the crude
material was obtained, which was further oxidized.
4.6.3. (1S,2S,3S)-Benzoic acid 3-{benzoyl-[4-(tert-butyl-
dimethylsiloxy)-phenyl]-amino}-3(2-furyl)-1-(4-methoxy-
phenyl)-2-methylpropyl ester (16). To a solution of 15
(253.1 mg, 0.541 mmol) in CH2Cl2 (1 mL) was added Et3N
(0.679 mL, 4.87 mmol), benzoyl chloride (0.377 mL,
3.25 mmol) and catalytic amount of DMAP at 0 8C. After
stirring the reaction mixture for 18 h at room temperature,
the reaction was quenched by the addition of phosphate
buffer. The organic materials were extracted with AcOEt
three times, dried over Na2SO4, and filtered. After removal
of the volatile materials under reduced pressure, the crude
To a solution of crude amino alcohol 13 in CH2Cl2 (2 mL)
was added Et3N (1.3 mL, 10 mmol), DMSO (2 mL) and
SO3$pyridine (937 mg, 6 mmol) at 0 8C, and the reaction
mixture was stirred for 30 min at this temperature. After
addition of phosphate buffer, the organic materials were
extracted with AcOEt three times and the combined organic
phase was dried over Na2SO4, and filtered. After removal of

11402
Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
material was purified by thin-layer chromatography
(AcOEt/hexaneZ1:3) to afford 16 in 61% yield.
filtered. After removal of the volatile materials under
reduced pressure, the crude materials were dissolved in
Et2O. To an Et2O solution of crude carboxylic acid was
added an Et2O solution of diazomethane at 0 8C. After
10 min at this temperature, the volatile materials were
removed under reduced pressure and the crude methyl ester
was purified by thin-layer chromatography (Et2O/HCO2H/
benzeneZ1:1:3) to afford methyl ester 18 in 47% yield over
two steps.
Pale yellow solid; 1H NMR (400 MHz, CDCl3): d 0.06 (6H,
s), 0.88 (9H, s), 1.34 (3H, d, JZ6.7 Hz), 3.05–3.17 (1H, m),
3.77 (3H, s), 5.85 (1H, d, JZ10.7 Hz), 6.10 (1H, d, JZ
4.5 Hz), 6.24–6.28 (1H, m), 6.41 (1H, d, JZ4.1 Hz), 6.45–
6.54 (4H, m), 6.84 (2H, d, JZ8.2 Hz), 7.05–7.20 (7H, m),
7.28 (1H, s), 7.41 (2H, t, JZ7.4 Hz), 7.53 (1H, t, JZ
7.4 Hz), 8.02 (2H, d, JZ7.4 Hz); 13C NMR (150 MHz,
CDCl3): d K4.5, 11.7, 18.2, 25.6, 39.1, 55.16, 55.20, 76.6,
110.4, 110.5, 113.6, 120.2, 127.4, 128.29, 128.31, 128.6,
128.7, 129.0, 129.6, 130.4, 133.0, 136.5, 141.7, 151.6,
154.6, 159.3, 165.3, 170.7; IR (neat): n 1718, 1686, 1655,
1647, 1508, 1269, 1252, 912, 711 cmK1; HRMS (FAB):
[MKOBz]C calcd for C34H40NO4Si 554.2726, found:
554.2714; [a]2D2 K68.9 (c 0.79, CHCl3).
1
Colorless oil; H NMR (400 MHz, CDCl3): d 0.88 (3H, d,
JZ7.1 Hz), 2.86 (1H, dqd, JZ2.8, 7.1, 9.8 Hz), 3.75 (3H,
s), 3.77 (3H, s), 5.31 (1H, dd, JZ2.8, 9.0 Hz), 5.69 (1H, d,
JZ9.8 Hz), 6.66 (1H, d, JZ9.0 Hz), 6.84 (2H, d, JZ
8.7 Hz), 7.30–7.45 (6H, m), 7.47–7.55 (2H, m), 7.72
(2H, d, JZ7.2 Hz), 8.02 (2H, d, JZ7.2 Hz); 13C NMR
(150 MHz, CDCl3): d 12.7, 41.3, 52.7, 53.6, 55.2, 77.4,
113.9, 127.1, 128.4, 128.5, 129.6, 130.4, 131.7, 132.9,
134.0, 159.5, 165.4, 167.3, 172.3; IR (neat): n 3375, 2926,
1739, 1724, 1668, 1514, 1252, 1215, 1109, 1026, 837,
4.6.4. (1S,2S,3S)-Benzoic acid 3-benzoylamino-3-(2-
furyl)-1-(4-methoxyphenyl)-2-methylpropyl ester (17).
To a solution of 16 (251 mg, 0.371 mmol) in THF (7 mL)
was added a solution of tetrabutylammonium fluoride (1 M
in THF, 0.445 mL, 0.445 mmol) at 0 8C. After stirring the
reaction mixture for 10 min at this temperature, the reaction
was quenched by the addition of saturated NH4Cl. The
organic materials were extracted with AcOEt three times,
and the combined organic phase was washed with brine,
dried over Na2SO4, and filtered. After removal of the
volatile materials under reduced pressure, the crude
materials were used directly in the next reaction. To a
CH3CN (1.02 mL) solution of crude phenol derivative was
added water (0.5 mL) and iodobenzene diacetate (119.5 mg,
0.371 mmol) at 0 8C. After stirring the reaction mixture for
1 h at that temperature, the reaction was quenched by the
addition of solution of NaHCO3 and Na2S2O3. The organic
materials were extracted with AcOEt three times, dried over
Na2SO4, and filtered. After removal of the volatile materials
under reduced pressure, the crude material was purified by
thin-layer chromatography (Et2O/benzeneZ1:3) to afford
17 in 78% yield over two steps.
712 cmK1
;
HRMS (FAB): [MKOBz]C calcd for
C20H22NO4 340.1549, found: 340.1526; [a]2D2 C22.0 (c
0.19, CHCl3).
4.6.6. (3S,4S,5R)-N-[5-(4-Methoxyphenyl)-4-methyl-2-
oxo-tetrahydro-furan-3-yl]-benzamide (19). To a solution
of 18 (5.0 mg, 0.011 mmol) in MeOH (0.5 mL) was added
K2CO3 (6.0 mg, 0.044 mmol) at room temperature. After
stirring the reaction mixture for 2.5 h at this temperature, the
reaction was quenched by the addition of phosphate buffer.
The organic materials were extracted with CHCl3 three
times, dried over Na2SO4, and filtered. After removal of the
volatile materials under reduced pressure, the crude material
was purified by thin-layer chromatography (Et2O/HCO2H/
benzeneZ1:1:3) to afford lactone 19 in 84% yield.
1
Colorless oil; H NMR (600 MHz, CDCl3): d 1.24 (3H, d,
JZ6.4 Hz), 2.52 (1H, qdd, JZ6.4, 10.1, 11.8 Hz), 3.80 (3H,
s), 4.80 (1H, dd, JZ7.7, 11.8 Hz), 4.93 (1H, d, JZ10.1 Hz),
6.71 (1H, d, JZ7.2 Hz), 6.90 (2H, d, JZ7.7 Hz), 7.33 (2H,
t, JZ8.8 Hz), 7.42 (2H, t, JZ8.0 Hz), 7.52 (1H, t, JZ
6.5 Hz), 7.81 (2H, d, JZ8.0 Hz); 13C NMR (150 MHz,
CDCl3): d 13.8, 47.2, 55.3, 57.0, 85.3, 114.2, 127.1, 128.0,
128.27, 128.31, 128.7, 132.1, 133.0, 160.3, 167.7, 174.4;
IR (neat): n 2926, 2854, 1780, 1647, 1516, 1250, 1174,
831, 712 cmK1; HRMS (FAB): [MCH]C calcd for
C19H20NO4: 326.1392, found: 326.1400; [a]2D3 C9.5 (c
0.13, CHCl3).
1
Colorless oil; H NMR (400 MHz, CDCl3): d 0.90 (3H, d,
JZ7.1 Hz), 2.85 (1H, d of quintet, JZ3.5, 7.1 Hz), 3.74
(3H, s), 5.63–5.67 (2H, m), 6.23 (1H, d, JZ3.3 Hz), 6.27
(1H, dd, JZ1.8, 3.3 Hz), 6.80–6.88 (3H, m), 7.23–7.42 (7H,
m), 7.45–7.58 (2H, m), 7.68 (2H, d, JZ8.0 Hz), 7.98 (2H, d,
JZ8.0 Hz); 13C NMR (100 MHz, CDCl3): d 13.7, 42.3,
50.1, 55.2, 78.5, 107.3, 110.3, 113.9, 127.1, 128.4, 128.5,
128.7, 129.5, 130.6, 131.1, 132.8, 134.4, 142.2, 152.6,
159.5, 165.3, 166.4; IR (neat): n 3346, 2935, 1720, 1657,
1514, 1269, 1252, 1111, 808, 712 cmK1; HRMS (FAB):
[MKOBz]C calcd for C22H22NO3 348.1600, found
348.1610; [a]2D2 C10.5 (c 0.58, MeOH).
Acknowledgements
4.6.5. (1S,2S,3S)-Benzoic acid 3-benzoylamino-3-
methoxycarbonyl-1-(4-methoxyphenyl)-2-methylpropyl
ester (18). To an aqueous solution (AcOEt 1.0 mL and
water 0.25 mL) of 17 (8.1 mg, 0.017 mmol) was added
RuO2 (1.0 mg, 0.0075 mmol) and NaIO4 (46 mg,
0.22 mmol) at K6 8C. After stirring the reaction mixture
for 2 h at this temperature, the reaction was quenched by the
addition of 1 N HCl solution. The organic materials were
extracted with CHCl3 three times, dried over Na2SO4, and
The authors are indebted to Professors Tohru Fukuyama and
Hidetoshi Tokuyama of The University of Tokyo for their
invaluable suggestions concerning the oxidation of furan
and the usage of the ozone generator. This work was
partially supported by Grand-in-Aid for Scientific Research
on Priority Areas 16073219 from The Ministry of
Education, Culture, Sports, Science and Technology
(MEXT).

Y. Hayashi et al. / Tetrahedron 61 (2005) 11393–11404
11403
Ed.; Modern Synthetic Methods; Otto Salle: Frankfurt am
Main, 1983; Vol. 3, pp 217–353.
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