Synthesis of (2S,3R,4S)-isonorstatine using a solvent-induced highly stereoselective 3-butenyl addition to L-threose imines

Article abstract of DOI:10.1055/s-2006-942426

Isonorstatine was obtained in an 11-step sequence starting from L-tartaric acid, based on a highly stereoselective addition of 1-butene-3-yl to a threose imine. The orientation of the methyl group at C-4 of isonorstatine was determined by transformation o

Full text of DOI:10.1055/s-2006-942426

PAPER
2173
Synthesis of (2S,3R,4S)-Isonorstatine Using a Solvent-Induced Highly
Stereoselective 3-Butenyl Addition to L-Threose Imines
S
ynthesis of (2
e
S
,3
R
,4
S
)-I
n
sonorstatineg Li, Oliver Schwardt, Volker Jäger*
University of Stuttgart, Institut für Organische Chemie, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax +49(711)68564321; E-mail: jager.ioc@oc.uni-stuttgart.de
Received 29 May 2006
Dedicated to Professor Dieter Hoppe on the occasion of his 65th birthday
series of chiral aldehydes and nitro compounds.7 In a com-
plementary way, highly stereoselective additions to a-
alkoxyimines8 have provided an efficient and versatile ac-
cess to aminopolyols,9 1,4-iminopolyol derivatives such
Abstract: Isonorstatine was obtained in an 11-step sequence start-
ing from L-tartaric acid, based on a highly stereoselective addition
of 1-butene-3-yl to a threose imine. The orientation of the methyl
group at C-4 of isonorstatine was determined by transformation of
the key d-xylo adduct into a d-lactone. This also shows that both ter- as anisomycin,10 and to the statine family.11
mini of the key adduct, the diol acetonide and vinyl moiety, can be
The addition of Grignard and lithium reagents to the C=N
elaborated selectively into an acid function leading to both amino-
bond of the N,O-dibenzylthreose derivative 17a,10,12–15 had
hydroxymethyl acid and diacid derivatives.
been found to proceed with high 3,4-threo selectivi-
Key words: threose imines, allyl/1-butene-3-yl addition, aminohy-
droxymethyl acid , solvent effect, N-(1-phenylethyl) auxiliary
ty.10,12,13,15 We then began to wonder if an a-branched
alkyl chain, introducing a new vicinal stereocentre, could
be connected likewise. Indeed, the addition of sec-butyl-
lithium proved highly threo-selective with respect to C-3/
The stereoselective synthesis of b-amino acids and their
C-4; however, both C-5 diastereomers 2 were formed
derivatives has been an active area of research, due to the
non-selectively13a (Scheme 1).
importance of b-amino acids in various fields.1 In partic-
ular, non-proteinogenic b-amino-a-hydroxy acids are
OBn
OBn
s-BuLi (3 equiv), Et2O,
–78 °C, 15 min
found in many natural products and drugs, for example, as
a central moiety of oligopeptide-related structures such as
pepstatin.2 Thus, norstatine A [(2S,3R)-3-amino-2-hy-
droxy-5-methylhexanoic acid] is part of amastatin, an in-
hibitor of leucine aminopeptidase.3 On the other hand, the
enantiomer of A has been found in human renin inhibitors
KRI-1230 and KRI-1314.4 Isonorstatine B [(2R,3S,4S)-3-
amino-2-hydroxy-4-methylhexanoic acid] and other ana-
logues of cyclohexylstatine (cf. C) have been used as the
terminal amino acid part of such renin inhibitors.5,6
O
O
50 %
O
O
N
HN
Bn
Bn
[55:45:<5:<5]
1
2
Scheme 1
In order to overcome this lack of selectivity, we then ex-
amined allyl additions8,16 to the imine 1 and to the auxilia-
ry-adorned N-(1-phenylethyl)imines 3 [N-(S)] and 4 [N-
The synthesis of (2R,3S,4S)-isonorstatine isopropyl ester (R)];9b,11,13,15,16 allyl, methallyl, and crotyl/3-butene-1-yl
by Kiso et al. was based on (2S,3S)-isoleucine, using a Grignard reagents were used (Table 1).
poorly selective cyanide addition to leucinal. (2R,3S,4S)-
Isonorstatine was finally obtained by separation of a dia-
The addition of allylmagnesium bromide to the N-ben-
zylimine led to an 85:15 ratio of D-xylo/L-arabino isomers
stereomeric mixture, but there were no details given for
5a/6a, which is somewhat lower than that obtained with
the intermediates.5 In our group, several approaches to
the vinyl derivative.10,13 With N-(1-phenylethyl)imines 3
variously substituted 1,2-amino alcohols have been devel-
oped, such as diastereoselective nitroaldol additions of a
and 4, due to the additional induction from the auxiliary,
the isomer ratio changed to 92:8 and 77:23, respectively
OH
OH
OH
R
HOOC
HOOC
HOOC (H2C)n
n = 0, 1, 2
NH2
NH2
NH2
R = Ph, i-Bu, Bn, CH2C6H11
C, Statine Family
A, (2S,3R)-Norstatine
B, (2R,3S,4S)-Isonorstatine
Figure 1
SYNTHESIS 2006, No. 13, pp 2173–2182
x
x.
x
x
.
2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-942426; Art ID: C03306SS
© Georg Thieme Verlag Stuttgart · New York

2174
F. Li et al.
PAPER
Table 1 Allyl Additions to Imines
OBn
OBn
HN
OBn
HN
1. R1MgBr (2 equiv)
0–25 °C, 2–17 h
R1
R
R1
R
O
O
O
+
2. NH4Cl, H2O
O
O
O
N
R
1: R = CH2Ph
3: R = (S)-CH(Me)Ph
4: R = (R)-CH(Me)Ph
D-xylo
5, 7, 9 + 10
L-arabino
6, 8, 11 + 12
Entry
Imine
R1
Solvent
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
THF
THF
Product
5a/6a
5b/6b
5c/6c
dra [(D-xylo)/(L-arabino)] Yieldb (%)
1
2
1
3
4
1
3
4
1
3
4
1
3
4
Allyl
85:15
64
77
68
83
78
66
79
77
82
71
81
85
Allyl
92:8
3
Allyl
77:23
4
Methallylc
7a/8a
7b/8b
7c/8c
66:34
5
Methallylc
94: 6
6
Methallylc
22:78
7
3-Butenyl/Crotyld
3-Butenyl/Crotyld
3-Butenyl/Crotyld
3-Butenyl/Crotyld
3-Butenyl/Crotyld
3-Butenyl/Crotyld
9a,10a/11a
9b,10b/–
9c,10c/11c,12c
9a,10a/11a
9b,10b/–
9c
(42:51):(7:<5)
(42:58):(<5:<5)
(57:18):(25:5)
(67:28):(5:<5)
(92:8):(<5:<5)
(>95:<5):(<5:<5)
8
9
10
11
12
a Determined from analyses of the 13C NMR spectra of crude addition products; estimated limit of detection 5%.
b Yield based on imine, after chromatography on basic alumina.
c Incomplete after addition of 2 equiv; 4 equiv required.
d Reagent prepared from crotyl bromide.
(Table 1, entries 2 and 3), which is in line with our earlier A dramatic, unexpected improvement was found when the
results concerning the imines of 2-O-benzylglyceralde- solvent was changed from diethyl ether to tetrahydrofu-
hyde.9,11,13 The methallyl case showed a similar tendency ran. With the ‘parent’ imine 1, the D-xylo 9a and 10a iso-
concerning diastereomeric ratio changes, but now the op- mers were favoured and formed in a ratio of 67:28; this
posite mismatching effect of the N-[(R)-1-phenylethyl] rose to 92:8 with the (S)-imine 3 and, fortunately, to >95:5
substituent was more pronounced, leading to the L-arabi- for 9c with the (R)-imine 4, where none of the other three
no isomer 8c predominantly (Table 1, entry 6).
diastereomers could be detected by NMR analyses of the
crude reaction product.
Since we intended to add a 2-butyl group, the results with
the crotyl/3-butenyl Grignard derivative were of particu- Consequently, the initial objective of finding a method to
lar relevance. Our first attempts paralleled those with sec- access methyl-branched aminohydroxy acids of the iso-
butyl (vide supra) though (Table 1, entries 7–9); the best norstatine type B, which had failed by direct sec-butyl ad-
result was obtained with the (S)-imine 3 which furnished dition, could now be reconsidered and extended. The
a mixture of 5-epimers of the xylo compounds 9b/10b amino-heptenetriol 9 constitutes an advanced intermedi-
only. With the (R)-imine 4 a third diastereomer 11c was ate with orthogonally structured termini capable of under-
formed. The latter was assigned the L-arabino configura- going further transformations to carboxyl groups.17 Either
tion, based on the coupling constant J3,4 = 5.2 Hz. Earlier, end would be amenable to regioselective oxidative degra-
the coupling constant J3,4 had proved diagnostic for all dation, eventually leading to b-amino-a-hydroxy-g-meth-
simple addition products from 1, while the D-xylo-amino- yl acids D (norisostatine type B), to b-amino-g-hydroxy-
triol derivatives consistently showed a small coupling of a-methyl acids E, or to b-amino-a-hydroxy-g-methyl di-
J3,4 = 1.4–1.8 Hz. Similar values of ca. 1.2 Hz were found acids F (Figure 2). A remaining problem, however, con-
with all the diastereomers designated as D-xylo (3,4-threo) cerned the configuration at the methyl-bearing
which are described here.10,13
stereocentre, which had to be elucidated later on.
Synthesis 2006, No. 13, 2173–2182 © Thieme Stuttgart · New York

PAPER
Synthesis of (2S,3R,4S)-Isonorstatine
2175
OR
H
access the second type of C-methyl-branched b-amino ac-
ids E – in mind. Dihydroxylation of the key intermediate
9c according to Sharpless’ procedure20 provided the 6,7-
diol 18. The diol 18 was cleaved by sodium periodate to
furnish the aldehyde 19, which was directly oxidised to
the acid 20. On treatment of the latter with excess diazo-
methane the corresponding ester 21 was isolated. Hydrol-
ysis of the acetonide ester 21 was now expected to lead to
a d-lactone, with the methyl group positioned within the
ring, which should allow to determine its orientation. In-
deed, on acid-mediated hydrolysis the ester and the acetal
group were cleaved, but this was accompanied by partial
loss of the O-benzyl group. Anyway, the lactones 22 and
23 were readily separable by flash column chromatogra-
phy leading to the analytically pure g-benzyloxy-d-lac-
tone 22 (40%) and to the g-hydroxy-d-lactone 23 (26%).
The lactone 22 now permitted to assign the configuration
at C-2, since the proton signals appeared well separated in
O
O
NR'
9
O
O
O
COOH
O
O
N
HOOC
HOOC
COOH
N
E
N
D
F
Figure 2
With the key intermediate 9c in hand, the synthesis of iso-
norstatine 17 was accomplished in a straightforward man-
ner. The aminotriol 13 was obtained pure and in high yield
by hydrolysis of the acetal group under acidic conditions.
The olefinic double bond was then reduced by catalytic
hydrogenation (H2, 1 bar, 5% Pd/BaSO4) at room temper-
ature in good yield without loss of the benzyl protecting
group. Next, the free diol 14 was cleaved by means of so-
dium periodate to give the aldehyde 15, which was oxi-
dised to the carboxylic acid 16 with sodium chlorite.18,19
Finally, the N,O-protected amino acid 16, upon catalytic
hydrogenation, was converted into free, analytically pure
isonorstatine 17 in 93% yield (Scheme 2).
1
the H NMR spectrum. From this, coupling constants
J2,3 = 0.7 Hz, J3,4 = 7.3 Hz, and J4,5 = 5.2 Hz were derived.
This information was complemented by NOE measure-
ments, which showed enhancement of 2-CH3/3-H and 2-
H/4-H. In summary, the 2-methyl and the 3-amino group
are situated trans, as are 3-amino/4-benzyloxy; for 4-
BnO/5-CH2OH the cis-arrangement as present in the start-
ing material L-threose was confirmed. From these cou-
OBn
(ii)
(i)
OH
O
We then turned to the elaboration of the olefinic terminus,
with two objectives – assignment of the configuration at
C-5 in 9c (C-4 in 17), combined with finding a method to
9c
OH
Ph
[82:18]
O
HN
18
OBn
OBn
O
H
OBn
OBn
(i)
O
(iii)
O
HN
Ph
HO HN
Ph
CHO
Ph
COOH
Ph
O
O
O
HN
O
HN
9c
13
19
20
OBn
OBn
H
O
OBn
(ii)
(iii)
O
HN
Ph
(v)
(iv)
COOCH3
Ph
O
Ph
HO HN
O
HN
14
15
21
6
OBn
OH
O
O
O
O
HO
S
S
HO
S
S
(iv)
(v)
HO
R
HO
R
5
2
+
4
BnO
HO
3
Ph
NH2
O
HN
O
HN
Ph
HN
Ph
16
17
22
23
Scheme 2 Reagents and conditions: (i) HCl, dioxane–H2O (1:1),
50 °C, 18 h, 90%; (ii) H2, 1 bar, 5% Pd/BaSO4, MeOH, r.t., 3 h, 90%;
(iii) NaIO4, MeOH–H2O–THF (4:2:1), 0 °C, 2 h, 97%. (iv) NaClO2,
NaH2PO4, t-BuOH, r.t., 3 h, 88%; (v) H2, 4 bar, 20% Pd(OH)2/C,
MeOH, r.t., 30 h, 93%. For assignment of configuration at C-5 in 9c
(C-4 in 17) vide infra.
Scheme 3 Reagents and conditions: (i) K3[Fe(CN)6], K2CO3,
K2OsO2(OH)4, (DHQD)2PHAL, t-BuOH–H2O (1:1), r.t., 6 h, 78%, dr
82:18; (ii) NaIO4, MeOH–H2O–THF (4:2:1), 0 °C, 3 h, 99%; (iii)
NaClO2, NaH2PO4, t-BuOH, r.t., 3 h, 90%; (iv) CH2N2, r.t., 10 min,
86%; (v) HCl, dioxane–H2O (1:1), 50 °C, 18 h, 40% + 26%.
Synthesis 2006, No. 13, 2173–2182 © Thieme Stuttgart · New York

2176
F. Li et al.
PAPER
measured on a Bruker IFS 28 spectrophotometer. The optical rota-
tions were measured on a Perkin-Elmer 241 MC polarimeter using
the Drude method to calculate [a]D from the values found at 546 and
579 nm.
plings, the S4 conformation of the d-lactone is most likely,
where the trans-oriented 2-H/3-H enclose an angle of ca.
90° (Scheme 3).
Finally, a method to access an aminohydroxymethyl di-
acid (type F in Figure 2) remained to be demonstrated, by
twofold oxidative conversion of the diol-acetonide and
the olefinic double bond into carboxyl groups, as had been
effected individually with the approaches to D and E, re-
spectively. To this purpose, the ester 21 with the acetal-
protected 5,6-diol was treated with orthoperiodic acid,
which caused both diol deprotection and cleavage. The re-
sulting aldehyde 24 without purification was oxidised
with sodium chlorite as above to afford the glutaric acid
monoester 25, which with diazomethane was transformed
into the dimethyl ester of the N,O-protected b-amino-g-
methyl-a-oxyglutarate 26 (Scheme 4). The synthesis of
such b-amino-a-hydroxy diacids may be useful as an oli-
gopeptide constituent, as present in the pseudomycins, a
class of antifungal cyclic depsinonapeptides.21
(2S,3S,4R,5RS)-4-Amino-3-O-4-N-dibenzyl-1,2-O-isopropyl-
idene-5-methyl-1,2,3-heptanetriol (2)
Threose imine 110 (504 mg, 1.45 mmol) was dissolved in Et2O (10
mL). Under argon at –78 °C s-BuLi (1.4 M, cyclohexane–hexane,
92:8; 2.57 mL, 3.6 mmol) was added by syringe over 15 min. The
solution turned red and was maintained at –78 °C for 1 h and then
allowed to warm to r.t. with stirring over 1 h. The reaction mixture
was hydrolysed with a sat. solution of NH4Cl (20 mL) and extracted
with Et2O (3 × 50 mL). The combined organic phases were washed
with a sat. solution of NaHCO3 (50 mL) and dried (Na2SO4). The
solvents were removed in vacuo (20 °C/15 mbar, then 0.05 mbar) to
afford a reddish oil (422 mg) containing starting material 1 (ca. 8%)
and the sec-butyl adducts 2 (dr 55:45). The crude product was puri-
fied by flash chromatography (basic Al2O3, column 11 cm × 2 cm,
PE–EtOAc, 20:1 with 1% Et3N) to give 239 mg (50%) of aminodi-
20
ols 2 (dr 55:45) as a colourless, analytically pure oil; [a]D –12.0
(c 15.0, CHCl3).
IR (film): 3349 (NH), 2940, 2912, 2855, 1444, 1370, 1360, 1242,
1200, 1146, 1059, 1013, 715, 679 cm–1.
OBn
Anal. Calcd for C25H35NO (397.6): C, 75.53; H, 8.87; N, 3.52.
Found: C, 75.32, H, 8.67, N, 3.28.
(ii)
(i)
COOCH3
Ph
21
O
HN
Major Isomer
1H NMR (250.1 MHz, CDCl3): d = 0.90 (m, CHCH3, 6 H, 7-CH3),
1.14 (m, 1 H, 6-Ha), 1.37, 1.43 [2 s, 6 H, C(CH3)2], 1.49 (m, 1 H, 6-
Hb), 1.67 (s, 1 H, NH), 1.72 (m, 1 H, 5-H), 2.20 (dd, 3J3,4 = 5.7 Hz,
3J4,5 = 1.7 Hz, 1 H, 4-H), 3.50 (m, 1 H, 3-H), 3.52 (app dd,
2J1a,1b = 8.1 Hz, 3J1a,2 = 8.0 Hz, 1 H, 1-Ha), 3.73–3.91 (m, 3 H, 1-Hb,
24
OBn
OBn
HO
(iii)
COOCH3
Ph
H3COOC
COOCH3
Ph
2
O
HN
HN
NCH2Ph), 4.51 (m, 1 H, 2-H), 4.58, 4.96 (A¢B¢ system, J = 11.5
Hz, 2 H, OCH2Ph), 7.20–7.36 (m, 10 H, 2 Ph).
13C NMR (62.9 MHz, CDCl3): d = 12.14 (q, C-7), 15.8 (q, C-1¢),
26.5 (t, C-6), 26.8 [q, C(CH3)2], 26.75 (d, C-5), 51.6 (t, NCH2Ph),
60.7 (d, C-4), 66.5 (t, C-1), 73.5 (t, OCH2Ph), 79.3 (d, C-2), 80.5 (d,
C-3), 109.1 [s, O2C(CH3)2], 126.8, 127.3, 127.8, 128.1, 128.2, 128.3
[6 d, 2 Ph( o-, m-, p-C)], 139.0, 141.0 [2 s, 2 Ph(i-C)].
25
26
Scheme 4 Reagents and conditions: (i) H5IO6, Et2O, r.t., 6 h, quant.;
(ii) NaH2PO4, t-BuOH, r.t., 3 h, 86%; (iii) CH2N2, Et2O, 72%.
In conclusion, a new route to methyl-branched b-amino-
hydroxy acids of types D, E and F has been outlined,
based on the highly stereoselective reaction of 3-butenyl
Grignard with the threose-derived imine 4. In particular,
the (2S,3R,4S)-isomer 17 of isonorstatine was obtained
via the threose imine 4 from diethyl L-tartrate in 11 steps
and 25% overall yield.
Minor Isomer
1H NMR (250.1 MHz, CDCl3): d = 1.37, 1.44 [2 s, 6 H, C(CH3)2,],
3
3
2.24 (dd, J3,4 = 5.4 Hz, J4,5 = 2.2 Hz, 1 H, 4-H), 3.50 (app dd,
2J1a,1b = 8.1 Hz, 3J1a,2 = 8.0 Hz, 1 H, 1-Ha), 4.55, 4.98 (A¢B¢ system,
2J = 11.4 Hz, 2 H, OCH2Ph); the other signals overlapped with
those of the main isomer.
13C NMR (62.9 MHz, CDCl3): d = 12.04 (q, C-7), 15.1 (q, C-1¢),
25.6 [q, C(CH3)2], 26.0 (t, C-6), 35.7 (d, C-5), 52.4 (t, NCH2Ph),
61.4 (d, C-4), 73.3 (t, OCH2Ph), 81.1 (d, C-3); the other signals co-
incided with those of the main isomers.
For general experimental details, see ref. 10b. 2-O-Benzyl-3,4-O-
isopropylidene-L-threose was prepared in four steps from diethyl L-
tartrate according to known procedures;10,12–14 [a]D20 +35.9 (c 1.50,
N-[(S)-1-Phenylethyl]imine 3
CHCl2) {Lit.10,13 [a]D +34.6 (c 1.51, CHCl3)}. N-Benzylimine
20
Prepared according to the method described for 4; from 2-O-benzyl-
3,4-O-isopropylidene-L-threose (1.00 g, 4.00 mmol), Al2O3 (1.02 g,
10.0 mmol), and (S)-(1-phenylethyl)amine (484 mg, 4.00 mmol) to
give 1.39 g (98%) of 3 as a colourless, spectroscopically pure oil;
[a]D20 +2.72 (c 1.30, CHCl3).
(1)10 and N-(S)-1-phenylethylimine (3)13 were prepared according
to known procedures.
Allylmagnesium bromide was purchased from Aldrich and Pd/
BaSO4 from Degussa. Basic Al2O3 (63–200 mm, activity III) and
neutral Al2O3 type 90 (63–200 mm, activity I) were purchased from
1H NMR (250.1 MHz, CDCl3): d = 1.38, 1.42 [2 s, 6 H, C(CH3)2],
20
3
2
Merck. (R)-1-Phenylethylamine was donated by BASF {[a]D
+29.9 (c 1.50, EtOH)}.
1.48 (d, J = 6.6 Hz, 3 H, NCHCH3), 3.91 (dd, J4a,b = 8.6 Hz,
3J3,4a = 6.6 Hz, 1 H, 4-Ha), 3.98 (dd, 3J2,3 = 6.0 Hz, 3J1,2 = 5.6 Hz, 1
H, 2-H), 4.03 (dd, 2J4a,4b = 8.6 Hz, 3J3,4b = 6.7 Hz, 1 H, 4-Hb), 4.34
1H and 13C NMR spectra were measured on Bruker ARX 300 or
Bruker ARX 500 spectrometers with TMS as internal standard.
Peak assignments are based on DEPT and 2D NMR studies. All dr
values were determined from 13C NMR spectra. IR spectra were
3
(m, 3-H), 4.35 (q, J = 6.6 Hz, NCHCH3) together 2 H, 4.54, 4.61
2
(AB system, J = 12.1 Hz, 2 H, OCH2Ph), 7.21–7.41 (m, 10 H, 2
Ph), 7.68 (d, 3J1,2 = 5.6 Hz, 1 H, 1-H).
Synthesis 2006, No. 13, 2173–2182 © Thieme Stuttgart · New York

PAPER
Synthesis of (2S,3R,4S)-Isonorstatine
2177
13C NMR (62.9 MHz, CDCl3,): d = 24.3 (q, NCHCH3), 25.3, 26.3
[2 q, C(CH3)2], 65.6 (t, C-4), 69.6 (d, NCHCH3), 71.7 (t, OCH2Ph),
76.5 (d, C-3), 80.6 (d, C-2), 109.6 [s, C(CH3)2], 126.4, 126.9, 127.6,
127.9, 128.2, 128.4 [6 d, 2 Ph( o-, m-, p-C)], 137.7 [s, OCH2Ph(i-
C)], 144.3 [s, NCH(CH3)Ph(i-C)], 161.0 (d, C-1).
2 H, OCH2Ph), 4.94–5.04 (m, 2 H, 7-H), 5.65 (m, 1 H, 6-H), 7.20–
7.38 (m, 10 H, 2 Ph).
13C NMR (125.8 MHz, CDCl3): d = 25.8, 26.8 [2 q, C(CH3)2], 35.0
(t, C-5), 51.3 (t, NCH2Ph), 57.8 (d, C-4), 66.4 (t, C-1), 73.7 (t,
OCH2Ph), 78.5 (d, C-2), 80.7 (d, C-3), 108.8 [s, C(CH3)2], 117.3 (t,
C-7), 127.0, 127.5, 128.0, 128.2, 128.3 [5 d, 2 Ph(o-, m-, p-C)],
135.9 (d, C-6), 139.0, 140.6 [2 s, 2 Ph(i-C)].
(2S,3S,1¢R)-2-O-Benzyl-3,4-O-isopropylidene-l-threose N-(1¢-
phenylethyl)imine (4)
Anal. Calcd for C24H31NO3 (381.5): C, 75.56; H, 8.19; N, 3.67.
Found: C, 75.36; H, 8.28; N, 3.56.
2-O-Benzyl-3,4-O-isopropyliden-L-threose (1.95 g, 7.80 mmol)
was mixed with neutral Al2O3 (1.99 g, 19.5 mmol, 2.5 equiv), (R)-
1-phenylethylamine (944 mg, 7.80 mmol) and CH2Cl2 (1 mL). After
stirring for 1 h at r.t. CH2Cl2 (10 mL) was added and stirring was
continued for 10 min. The mixture was filtered, the filter cake was
washed with CH2Cl2 (2 × 5 mL), the filtrate was dried (MgSO4) and
concentrated in vacuo (25 °C/1 mbar; then 0.01 mbar) to give 2.76
5b from a mixture of 5a/5b = 55:45
13C NMR (125.8 MHz, CDCl3): d = 25.7, 26.6 [2 q, C(CH3)2], 34.9
(t, C-5), 51.6 (t, NCH2Ph), 58.1 (d, C-4), 66.6 (t, C-1), 73.8 (t,
OCH2Ph), 78.2 (d, C-2), 80.5 (d, C-3), 108.4 [s, C(CH3)2], 117.2 (t,
C-7), 126.8, 127.9, 128.1, 128.39, 128.44 [5 d, 2 Ph(o-, m-, p-C)],
135.9 (d, C-6), 138.8, 140.5 [2 s, 2 Ph(i-C)].
20
g (quantitative) of imine 4 as a colourless pure oil; [a]D +73.5
(c 1.48, CHCl3). Another run resulted in 96% analytically pure 4;
[a]D21 +71.8 (c 1.66, CHCl3).
(2S,3S,4R,1¢S)-4-Amino-3-O-benzyl-1,2-O-isopropylidene-6-
methyl-N-(1¢-phenylethyl)-6-heptene-1,2,3-triol (7b) and
(2S,3S,4S,1¢S)-Isomer 8b
IR (neat): 1667 (C=N), 1494, 1453, 1370, 1257, 1210, 1066, 846,
737, 696 cm–1.
1H NMR (300.1 MHz, CDCl3): d = 1.33, 1.38 [s, 6 H, C(CH3)3],
A 25 mL 3-necked flask under N2 was charged with Mg chips (98
mg, 4.0 mmol) and Et2O (1 mL), then a crystal of I2 and methallyl
chloride (few mL) were added. The mixture was gently warmed un-
til the reaction started and sustained by careful addition of further
methallyl chloride (total 349 mg, 3.85 mmol) in Et2O (3 mL) over
10 min. The mixture was heated to reflux for 20 min, then a solution
of (S)-phenylethylimine 3 (340 mg, 0.962 mmol) in Et2O (2 mL)
was added over 10 min. After stirring the mixture for 3 h at r.t., a
sat. aq solution of NH4Cl (10 mL) was added. Work-up as described
above for 5a/6a gave 526 mg of 7b/8b (dr 94:6) as a yellow oil,
which was purified by column chromatography [basic Al2O3, 16 g,
column 8 cm × 2 cm; PE (300 mL)®PE–EtOAc, 20:1]. The first
fraction contained 281 mg (71%, dr >95:5) of analytically pure ami-
notriol 7b as a colourless oil; [a]D20 –50.9 (c 1.53, CHCl3). The sec-
ond fraction contained 28 mg (7%, dr 78:22) of 7b/8b.
3
2
1.47 (d, J = 6.6 Hz, 3 H, NCHCH3), 3.85 (dd, J4a,4b = 8.5 Hz,
3J3,4a = 6.7 Hz, 1 H, 4-Ha), 3.86 (dd, 2J4a,4b = 8.5 Hz, 3J3,4b = 6.4 Hz,
1 H, 4-Hb), 4.02 (dd, 3J2,3 = 6.2 Hz, 3J1,2 = 5.6 Hz, 1 H, 2-H), 4.27
(m, 1 H, 3-H), 4.32 (q, 3J = 6.6 Hz, 1 H, NCHCH3), 4.65, 4.71 (AB
2
system, J = 12.2 Hz, 2 H, OCH2Ph), 7.20–7.38 (m, 10 H, 2 Ph),
7.65 (d, 3J1,2 = 5.6 Hz, 1 H, 1-H).
13C NMR (75.5 MHz, CDCl3): d = 24.5 (q, NCHCH3), 25.2, 26.2 [2
q, C(CH3)2], 65.4 (t, C-4), 69.7 (d, NCHCH3), 71.9 (t, OCH2Ph),
76.4 (d, C-3), 80,9 (d, C-2), 109.4 [s, C(CH3)2], 126.3, 126.9,
127.66, 127.86, 128.28, 128.37 (6 d, 2 Ph), 137.9 [s, OCH2Ph(i-C)],
144.1 [s, NCH(CH3)Ph(i-C)], 160.9 (d, C-1).
Anal. Calcd for C22H27NO3: C, 74.76; H, 7.70; N, 3.96. Found: C,
74.67; H, 7.94; N, 3.71.
(2S,3S,4R)-4-Amino-3-O,4-N-dibenzyl-1,2-O-isopropylidene-6-
heptene-1,2,3-triol (5a) and (2S,3S,4S)-Isomer 6a
7b
IR (film): 2982, 2934, 1453, 1378, 1369, 1251, 1211, 1159, 1101,
A 25 mL flask under N2 was charged with allylmagnesium bromide
(1.0 M solution, Et2O; 1.77 mL, 1.77 mmol). The threose N-ben-
zylimine 1 (300 mg, 0.884 mmol) in Et2O (2 mL) was added drop-
wise over 10 min, to give a cloudy yellow mixture. After stirring at
r.t. for 6 h a clear solution formed, which became turbid again. A
sat. aq solution of NH4Cl (10 mL) was then added and the mixture
was extracted with Et2O (3 × 50 mL) at 0 °C. The combined organic
phases were washed with a sat. solution of NaHCO3 (50 mL), dried
(Na2SO4) and concentrated on a rotary evaporator (20 °C/15 mbar,
then 0.05 mbar). The crude product (5a/6a > 90:10) contained some
unidentified impurities and was purified by flash chromatography
[basic Al2O3, column 10 cm × 2 cm, 14.5 g; PE (400 mL), then PE–
EtOAc, 10:1] to give 218 mg (64%) of aminotriol 5a (dr > 95:5) as
1073, 702 cm–1.
1H NMR (300.1 MHz, CDCl3): d = 1.30 (d, 3J = 6.5 Hz, 3 H,
NCHCH3), 1.35 [s, 6 H, C(CH3)2], 1.52 (s, 3 H, 6-CH3), 2.12 (ddd,
3J4,5a = 9.3 Hz, J4,5b = 3.9 Hz, J3,4 = 1.5 Hz, 1 H, 4-H), 2.21 (dd,
2J5a,5b = 12.8 Hz, 3J4,5a = 9.3 Hz, 1 H, 5-Ha), 2.35 (dd, 2J5a,5b = 12.8
Hz, 3J4,5b = 3.9 Hz, 1 H, 5-Hb), 3.00 (t, 2J1a,1b = 3J1a,2 = 8.1 Hz, 1 H,
3
3
3
3
1-Ha), 3.19 (dd, J2,3 = 8.2 Hz, J3,4 = 1.5 Hz, 1 H, 3-H), 3.52 (dd,
2J1a,1b = 8.1 Hz, 3J1b,2 = 6.3 Hz, 1 H, 1-Hb), 3.82 (q, 3J = 6.5 Hz, 1 H,
2
NCHCH3), 4.46 (d, J7a,7b = 1.7 Hz, 1 H, 7-Ha), 4.53 (dt,
3J1a,2 = 3J2,3 = 8.1 Hz, J1b,2 = 6.3 Hz, 1 H, 2-H), 4.53 (A of AB,
3
2J = 11.6 Hz, 1 H, OCHAHBPh), 4.71 (d, 2J7a,7b = 1.7 Hz, 1 H, 7-Hb),
4.95 (B of AB, 2J = 11.6 Hz, 1 H, OCHAHBPh), 7.23–7.40 (m, 10 H,
2 Ph).
20
a colourless, analytically pure oil; [a]D –45.9 (c 1.63, CHCl3). A
13C NMR (75.5 MHz, CDCl3): d = 22.1 (q, 6-CH3), 24.7 (q,
NCHCH3), 25.6, 26.7 [2 q, C(CH3)2], 38.5 (t, C-5), 53.7 (d,
NCHCH3), 54.9 (d, C-4), 66.0 (t, C-1), 73.9 (t, OCH2Ph), 78.5 (d,
C-2), 80.5 (d, C-3), 108.8 [s, C(CH3)2], 113.0 (t, C-7), 127.14,
127.28, 127.33, 128.03, 128.11, 128.21 [6 d, 2 Ph(o-, m-, p-C)],
139.1 [s, OCH2Ph(i-C)], 143.0 (d, C-6), 145.5 [s, NCH(CH3)Ph(i-
C)].
second fraction, a yellow slightly impure oil contained both diaste-
reomers (25 mg, 7%, dr 55:45).
5a
FT-IR (film): 3421, 1453, 1212, 1158, 1076, 1028, 734, 698 cm–1.
1H NMR of (250.1 MHz, CDCl3): d = 1.38, 1.41 [2 s, 6 H, C(CH3)2],
2.31–2.37 (m, 2 H, 5-H), 2.45 (app ddd, 3J4,5b = 7.8 Hz, 3J4,5a = 5.3
Hz, 3J3,4 = 2.4 Hz, 1 H, 4-H), 3.42 (dd, 3J2,3 = 7.5 Hz, 3J3,4 = 2.4 Hz,
1 H, 3-H), 3.48 (app dd, 3J1a,2 = 8.2 Hz, 2J1a,1b = 8.1 Hz, 1 H, 1-Ha),
Anal. Calcd for C26H35NO3 (409.5): C, 76.25; H, 8.61; N, 3.42.
Found: C, 76.28; H, 8.89; N, 3.33.
2
3.65 (A of AB, J = 13.1 Hz, 1 H, NCHAHBPh), 3.82 (app dd,
8b from a mixture of 7b/8b = 78:22
2J1a,1b = 8.1 Hz, 3J1b,2 = 6.3 Hz, 1 H, 1-Hb), 3.85 (B of AB, 2J = 13.1
1H NMR (300.1 MHz, CDCl3): d = 1.18 (d, 3J = 6.6 Hz, 3 H,
NCHCH3), 1.37, 1.43 [2 s, 6 H, C(CH3)2], 1.45 (s, 6-CH3), 3.28 (dd,
3J1a,2 = 8.2 Hz, 2J1a,1b = 8.1 Hz, 1 H, 1-Ha), 3.57 (dd, 3J2,3 = 7.3 Hz,
3
3
Hz, 1 H, NCHAHBPh), 4.50 (app ddd, J1a,2 = 8.2 Hz, J2,3 = 7.5
Hz,3J1b,2 = 6.3 Hz, 1 H, 2-H), 4.60, 4.91 (A¢B¢ system, 2J = 11.7 Hz,
3J3,4 = 2.3 Hz, 1 H, 3-H), 3.78 (dd, J1a,1b = 8.1 Hz, J1b,2 = 6.2 Hz,
2
3
Synthesis 2006, No. 13, 2173–2182 © Thieme Stuttgart · New York

2178
F. Li et al.
PAPER
1-Hb), 4.21 (m, 1 H, 2-H), 4.75 (d, 2J7a,7b = 1.4 Hz, 1 H, 7-Hb), 4.80,
4.89 (AB system, 2J = 12.0 Hz, 2 H, OCH2Ph); some signals were
not clearly identified as they overlapped with those of the major iso-
mer 7b.
13C NMR (75.5 MHz, CDCl3): d = 21.9 (q, C-6¢), 24.6 (q,
NCHCH3), 25.8 [q, C(CH3)2], 39.7 (t, C-5), 53.1 (d, NCHCH3), 55.0
(d, C-4), 66.1 (t, C-1), 73.6 (t, OCH2Ph), 78.1 (d, C-2), 79.4 (d, C-
3), 108.9 [s, C(CH3)2], 125.9, 126.9 [2 d, Ph(o-, m-, p-C)], 139.2 [s,
OCH2Ph(i-C)], 143.1 (d, C-6), 145.6 [s, of NCH(CH3)Ph(i-C)];
some signals overlapped with those of the major isomer 7b.
10c from a mixture of 9c/10c = 76:24
1H NMR (500.1 MHz, CDCl3,): d = 0.88 (d, J5,CH3 = 6.9 Hz, 5-
3
CH3), 1.17 (d, 3J = 6.5 Hz, NCHCH3), 3.41 (dd, J2,3 = 7.9 Hz,
3
3J3,4 = 1.8 Hz, 3-H), 3.59 (dd, 2J1a,1b = 8.2 Hz, 3J1a,2 = 8.1 Hz, 1-Ha),
3.76 (q, 3J = 6.5 Hz, NCHCH3), 3.91 (dd, J1a,1b = 8.2 Hz,
2
3J1b,2 = 6.4 Hz, 1-Hb), 4.43 (m, 2-H), 4.45, 4.81 (AB system,
2J = 11.2 Hz, OCH2Ph), 5.57 (m, 6-H); some signals were not as-
signed as they overlapped with those of 9c.
13C NMR (125.8 MHz, CDCl3): d = 16.1 (q, 5-CH3), 24.05 (q,
NCHCH3), 25.73 [q, C(CH3)2], 40.66 (d, C-5), 55.6 (d, NCHCH3),
58.7 (d, C-4), 66.52 (t, C-1), 73.1 (t, OCH2Ph), 78.8 (d, C-2), 80.8
(d, C-3), 108.9 [s, C(CH3)2], 114.65 (t, C-7), 127.62 [d, 2 Ph(o-, m-,
p-C)], 141.97 (d, C-6), 146.02 [s, NCH(CH3)Ph(i-C)]; some signals
overlapped with those of 9c.
(2S,3S,4R,5S,1¢R)-4-Amino-3-O-benzyl-1,2-O-isopropylidene-
5-methyl-N-(1¢-phenylethyl)-6-heptene-1,2,3-triol (9c); Addi-
tion in THF
A two-necked 50 mL flask was charged with Mg (314 mg, 13.1
mmol) and THF (6.0 mL). A small amount of 3-chloro-1-butene
was added to initiate the reaction. Then 3-chloro-1-butene (1.13 g,
12.5 mmol) in THF (10 mL) was added dropwise over 15 min. The
reaction mixture was heated to reflux for 30 min. The mixture was
allowed to warm to r.t. and stirred for 3 h. The reaction was
quenched with a sat. aq solution of NH4Cl (4 mL) and extracted
with Et2O (4 × 40 mL). The combined organic phases were washed
with a sat. aq solution of NaHCO3 (50 mL) and dried over MgSO4.
The solvent was removed under reduced pressure and the crude
product was purified by column chromatography (silica gel; 25 g, 8
cm × 3 cm, PE–EtOAc, 10:1, 1% Et3N) to afford 2.08 g (85%; dr
>95:<5:<5:<5) of aminotriol 9c as an analytically pure, colourless
oil; [a]D20 +15.6 (c 1.15, CHCl3).
Mixture of 9c/10c = 76:24
Anal. Calcd for C26H35NO3 (409.6): C, 76.25; H, 8.61; N, 3.42.
Found: C, 76.36; H, 8.72; N, 3.39.
11c from a mixture of 9c/10c/11c = 40:19:41
1H NMR (500.1 MHz, CDCl3): d = 1.14 (d, J5,CH3 = 7.0 Hz, 5-
3
3
CH3), 1.26 (d, J = 6.5 Hz, NCHCH3), 1.30, 1.38 [2 s, C(CH3)2],
1.66 (s, NH), 2.46 (dd, 3J3,4 = 5.2 Hz, 3J4,5 = 3.8 Hz, 4-H), 2.59 (m,
3
3
5-H), 3.26 (dd, J2,3 = 6.5 Hz, J3,4 = 5.2 Hz, 3-H), 3.45 (t,
2J1a,1b = 3J1a,2 = 8.0 Hz, 1-Ha), 3.84 (q, 3J = 6.5 Hz, NCHCH3), 3.98
(dd, 2J1a,1b = 8.0 Hz, 3J1b,2 = 6.4 Hz, 1-Hb), 4.12 (ddd, 3J1a,2 = 8.0 Hz,
3
3J2,3 = 6.5 Hz, J1b,2 = 6.4 Hz, 2-H), 4.53, 4.74 (AB system,
2J = 11.5 Hz, OCH2Ph), 5.04 (dd, 3J6,7Z = 17.3 Hz, 2J7E,7Z = 1.6 Hz,
3
2
7-HZ), 5.07 (dd, J6,7E = 10.4, J7E,7Z = 1.6 Hz, 7-HE), 5.66 (ddd,
3J6,7Z = 17.3 Hz, 3J6,7E = 10.5 Hz, 3J5,6 = 7.0 Hz, 6-H), 7.18–7.36 (m,
2 Ph); some signals were not assigned as they overlapped with those
of 9c.
IR (neat): 3348 (NH), 1638, 1494, 1453, 1369, 1252, 1211, 1156,
1069, 697 cm–1.
For 1H, 13C NMR data see below.
13C NMR (125.8 MHz, CDCl3): d = 18.2 (q, 5-CH3), 23.99 (q,
NCHCH3), 25.48, 26.52 [2 q, C(CH3)2], 38.79 (d, C-5), 57.0 (d,
NCHCH3), 60.9 (d, C-4), 67.00 (t, C-1), 73.8 (t, OCH2Ph), 78.0 (d,
C-2), 82.3 (d, C-3), 108.6 [s, C(CH3)2], 114.86 (t, C-7), 126.96,
127.31, 127.82 (3 d, 2 Ph(o-, m-, p-C)], 139.03 [s, OCH2Ph(i-C)],
140.9 (d, C-6), 145.94 [s, NCH(CH3)Ph(i-C)]; some signals over-
lapped with those of 9c.
Anal. Calcd for C26H35NO3 (409.6): C, 76.25; H, 8.61; N, 3.42.
Found: C, 76.25; H, 8.65; N, 3.45.
(2S,3S,4R,5S,1¢R)-Isomer 9c, (2S,3S,4R,5R,1¢R)-Isomer 10c,
and (2S,3S,4S,5RS,1¢R)-Isomer 11c; Addition in Et2O
The reaction was carried out as described above for 9c, but using
Et2O as the solvent. Mg (46 mg, 1.9 mmol), Et2O (1 mL), 3-chloro-
1-butene (164 mg, 1.81 mmol) in Et2O (3 mL) and threose imine 4
(320 mg, 0.906 mmol) in Et2O (2 mL) gave 370 mg of the crude
product 9c/10c/11c/12c (dr 57:18:25:<5) as a yellow oil. Column
chromatography [basic Al2O3, 15 g, column 7 cm × 2 cm; PE (300
mL), PE–EtOAc, 20:1] gave fractions of 183 mg (49%) of 9c/10c
(dr 76:24; 11c and 12c <5%) and 121 mg (33%) of 9c/10c/11c/12c
(dr 40:19:41:<5), both analytically pure.
Mixture of 9c/10c/11c = 40:19:41
Anal. Calcd for C26H35NO3 (409.6): C, 76.25; H, 8.61; N, 3.42.
Found: C, 76.25; H, 8.76; N, 3.26.
(2S,3S,4R,5S,1¢R)-4-Amino-3-O-benzyl-5-methyl-N-(1¢-phenyl-
ethyl)-6-heptene-1,2,3-triol (13)
Amino heptenetriol 9c (1.80 g, 4.40 mmol) was dissolved in diox-
ane–H2O (1:1; 16 mL) and concd HCl (0.4 mL) was added. The re-
action mixture was kept at 50 °C for 18 h. The resulting solution
was concentrated (40 °C/60 mbar) and then dissolved in a sat. solu-
tion of NaHCO3 (20 mL). The mixture was extracted with EtOAc
(4 × 40 mL) and dried (MgSO4). The filtrate was concentrated
(40 °C/220 mbar) and the crude product was purified by chromatog-
raphy (silica gel, 50 g, column 10 cm × 4 cm; PE–EtOAc, 1:1, with
1% Et3N) to give 1.46 g (90%) of the free diol 13 as a colourless,
analytically pure oil; [a]D20 –34.9 (c 1.03, CHCl3).
9c from a mixture of 9c/10c = 76:24
1H NMR (500.1 MHz, CDCl3,): d = 0.87 (d, J5,CH3 = 6.9 Hz, 5-
3
3
CH3), 1.19 (d, J = 6.4 Hz, NCHCH3), 1.33, 1.37 [2 s, C(CH3)2],
1.74 (s, NH), 2.14 (dd, 3J4,5 = 6.1 Hz, 3J3,4 = 1.6 Hz, 4-H), 2.30 (m,
3
3
5-H), 3.47 (dd, J2,3 = 8.1 Hz, J3,4 = 1.6 Hz, 3-H), 3.49 (dd,
3
2J1a,1b = 8.1 Hz, J1a,2 = 8.0 Hz, 1-Ha), 3.83 (q, 3J = 6.4 Hz,
NCHCH3), 3.90 (dd, 2J1a,1b = 8.1 Hz, 3J1b,2 = 6.4 Hz, 1-Hb), 4.48 (m,
2-H), 4.49 (AB system, 2J = 11.5 Hz, OCHAHBPh), 4.80 (dd,
3J6,7Z = 17.2 Hz, J7E,7Z = 1.9 Hz, 7-HZ), 4.83 (dd, J6,7E = 10.3 Hz,
2
3
2J7E,7Z = 1.9 Hz, 7-HE), 4.88 (AB system, J = 11.5 Hz, OCHAHB-
2
IR (neat): 3306, 1494, 1452, 1375, 1056, 912, 697 cm–1.
3
3
3
Ph), 5.62 (ddd, J6,7Z = 17.2 Hz, J6,7E = 10.3 Hz, J5,6 = 8.0 Hz, 6-
1H NMR (300.1 MHz, CDCl3): d = 1.13 (d, 3J5,CH3 = 6.9 Hz, 3 H, 5-
CH3), 1.36 (d, 3J = 6.5 Hz, 3 H, NCHCH3), 1.98 (s, 1 H, NH), 2.86
(m, 1 H, 5-H), 3.11 (dd, J3,4 = 0.8 Hz, 3J4,5 = 4.2 Hz, 1 H, 4-H), 3.57
(dd, 2J1a,1b = 12.7 Hz, 3J1a,2 = 5.7 Hz, 1 H, 1-Ha), 3.79 (dd, 3J2,3 = 4.2
Hz, J3,4 = 0.8 Hz, 1 H, 3-H), 3.88 (m, 1 H, 2-H), 3.90 (dd,
2J1a,1b = 12.8 Hz, 3J1b,2 = 2.7 Hz, 1 H, 1-Hb), 4.07 (q, 3J = 6.5 Hz, 1
H, NCHCH3), 4.48, 4.52 (AB system, 2J = 12.2 Hz, 2 H, OCH2Ph),
H), 7.15–7.28 (m, 2 Ph).
13C NMR (125.8 MHz, CDCl3): d = 17.3 (q, 5-CH3), 24.15 (q,
NCHCH3), 25.68, 26.76 [2 q, C(CH3)2], 40.75 (d, C-5), 55.8 (d,
NCHCH3), 59.4 (d, C-4), 66.43 (t, C-1), 73.3 (t, OCH2Ph), 79.3 (d,
C-2), 80.5 (d, C-3), 109.2 [s, C(CH3)2], 114.15 (t, C-7), 126.88,
127.04, 127.25, 127.72, 128.09, 128.21 [6 d, 2 Ph(o-, m-, p-C)],
139.00 [s, OCH2Ph(i-C)], 142.03 (d, C-6), 146.15 [s,
NCH(CH3)Ph(i-C)].
3
5.00–5.13 (m, 2 H, 7-HE, 7-HZ), 5.87 (ddd, J6,7Z = 17.4 Hz,
3J6,7E = 10.3, 3J5,6 = 7.6 Hz, 1 H, 6-H), 7.24–7.31 (m, 10 H, 2 Ph).
Synthesis 2006, No. 13, 2173–2182 © Thieme Stuttgart · New York

PAPER
Synthesis of (2S,3R,4S)-Isonorstatine
2179
13C NMR (75.5 MHz, CDCl3): d = 17.8 (q, 5-CH3), 20.8 (q,
NCHCH3), 37.0 (d, C-5), 53.4 (d, NCHCH3), 57.3 (d, C-4), 61.5 (t,
C-1), 71.4 (d, C-2), 73.2 (t, OCH2Ph), 78.1 (d, C-3), 115.25 (t, C-7),
127.1, 128.0, 128.2, 128.8, 129.2 (5 d, 2 Ph), 138.2 [s, OCH2C6H5(i-
C)], 140.4 (d, C-6), 145.2 [s, NCH(CH3)Ph(i-C)].
(d, 3J2,3 = 4.4 Hz, 1 H, 2-H), 4.59, 4.89 (AB system, 2J = 12.3 Hz, 2
H, OCH2Ph), 7.26–7.38 (m, 10 H, 2 Ph).
13C NMR (75.5 MHz, CDCl3): d = 11.6 (q, C-6), 14.4 (q, 4-CH3),
21.1 (q, NCHCH3), 26.2 (t, C-5), 33.7 (d, C-4), 56.6 (d, NCHCH3),
59.5 (d, C-3), 72.4 (t, OCH2Ph), 73.3 (d, C-2), 127.2, 128.0, 128.2,
128.5, 128.7, 129.2 (6 d, 2 Ph), 137.5 [s, OCH2Ph(i-C)], 139.7 [s,
NCH(CH3)Ph(i-C)], 174.1 (s, C-1).
Anal. Calcd for C23H31NO3 (369.5): C, 74.76; H, 8.46; N, 3.79.
Found: C, 74.59; H, 8.32; N, 3.71.
(2S,3S,4R,5S,1¢R)-4-Amino-3-O-benzyl-5-methyl-N-(1¢-phenyl-
ethyl)-1,2,3-heptanetriol (14)
(2S,3R,4S)-Isonorstatine (17)
The protected isonorstatine 16 (50 mg, 0.14 mmol) dissolved in
MeOH (3 mL) was hydrogenated (4 bar) in the presence of Pearl-
man’s catalyst Pd(OH)2/C (20 mg, 20% Pd). After 18 h, the reaction
mixture was filtered and the filtrate was concentrated (40 °C/300
mbar) to give 21 mg (93%) of the free hexanoic acid 17 as a light-
A 25 mL flask was charged with Pd/BaSO4 (5%, 35 mg); MeOH
(2.0 mL) and the diol 13 (350 mg, 0.95 mmol) were added. The mix-
ture was hydrogenated for 4 h at normal pressure. After centrifuga-
tion of the solids the filtrate was concentrated (40 °C/300 mbar).
The residue was purified by flash chromatography (silica gel, 10 g,
column 5 cm × 2 cm; PE–EtOAc, 10:25 with 1% Et3N) to afford
318 mg (90%) of heptanetriol 14 as a colourless, analytically pure
oil; [a]D20 –19.9 (c 1.30, CHCl3).
20
yellow, analytically pure powder; mp 204–205 °C; [a]D –20.8
(c 0.36, MeOH).
IR (solid): 3500–2500, 1733, 1599, 1511, 1461, 1377, 1281, 1228,
1143, 1073, 1024, 823, 694 cm–1.
IR (neat): 3329, 1495, 1454, 1064, 761, 734, 698 cm–1.
1H NMR (300.1 MHz, D2O): d = 0.78 (t, 3J5,6 = 7.4 Hz, 3 H, 6-H),
1H NMR (300.1 MHz, CDCl3): d = 0.87 (t, 3J6,7 = 7.3 Hz, 3 H, 7-H),
0.99 (d, 3J5,CH = 6.9 Hz, 3 H, 5-CH3), 1.08 (m, 1 H, 6-Ha), 1.35 (d,
3J = 6.5 Hz, 33H, NCHCH3), 1.54 (m, 1 H, 6-Hb), 1.88 (m, 1 H, 5-
0.89 (d, 3J4,CH = 6.9 Hz, 3 H, 4-CH3), 1.38 (m, 1 H, 5-H), 1.71 (m,
3
1 H, 4-H), 3.53 (dd, 3J3,4 = 5.6 Hz, 3J2,3 = 4.6 Hz, 1 H, 3-H), 4.41 (d,
3J2,3 = 4.3 Hz, 1 H, 2-H).
3
H), 3.03 (dd, J3,4 = 1.3 Hz, J4,5 = 4.0 Hz, 1 H, 4-H), 3.57 (dd,
13C NMR (75.5 MHz, D2O): d = 10.7 (q, C-6), 14.1 (q, 4-CH3), 25.7
(t, C-5), 34.4 (d, C-4), 58.0 (d, C-3), 70.1 (d, C-2), 177.2 (s, C-1).
2J1a,1b = 11.5 Hz, 3J1a,2 = 4.4 Hz, 1 H, 1-Ha), 3.76 (dd, 3J2,3 = 4.8 Hz,
J3,4 = 1.3 Hz, 1 H, 3-H), 3.85–3.96 (m, 3 H, 2-H, 1-Hb, NCHCH3),
4.50, 4.54 (AB system, 2J = 11.2 Hz, 2 H, OCH2Ph), 7.23–7.28 (m,
10 H, 2 Ph).
Anal. Calcd for C7H15NO3⋅HCl (161.2): C, 42.53; H, 8.16; N, 7.09.
Found: C, 42.21; H, 7.82; N, 6.75.
13C NMR (75.5 MHz, CDCl3): d = 12.7 (q, C-7), 16.8 (q, 5-CH3),
20.9 (q, NCHCH3), 24.5 (t, C-6), 34.3 (d, C-5), 53.6 (d, NCHCH3),
56.5 (d, C-4), 61.3 (t, C-1), 70.8 (d, C-2), 72.9 (t, OCH2Ph), 78.6 (d,
C-3), 126.7, 127.5, 127.8, 128.4, 128.8 (5 d, 2 Ph), 137.8 [s,
OCH2Ph(i-C)], 145.0 [s, NCH(CH3)Ph(i-C)].
(2R,3S,4R,5R,6RS,1¢R)-4-Amino-2-O-benzyl-1,2-O-isopropyl-
idene-5-methyl-4-N-(1¢-phenylethyl)heptane-1,2,3,6,7-pentol
(18)
A 50-mL round-bottom flask, equipped with a magnetic stirrer, was
charged with t-BuOH–H2O (1:1, 8.0 mL). To the mixture were add-
ed K3[Fe(CN)6] (724 mg, 2.2 mmol), K2CO3 (306 mg, 2.2 mmol),
K2OsO2(OH)4 (5.4 mg, 0.015 mmol) and hydroquinidine 1,4-
phthalazinediyl diether [(DHQD)2PHAL, 28 mg, 0.036 mmol) at
r.t.20 The mixture was stirred for 15 min at the same temperature,
then heptene 9c (300 mg, 0.73 mmol) was added at 0 °C. The tem-
perature was allowed to rise to r.t. After 8 h, the reaction was treated
with Na2S2O5 (1.67 g, 8.80 mmol) at 0 °C and stirred for 1 h. H2O
(5 mL) was added and the mixture was extracted with EtOAc
(4 × 40 mL). The combined organic phases were dried (MgSO4)
and concentrated. The crude product was purified by flash column
chromatography (silica gel, 8 g, columm 4 cm × 2 cm CH2Cl2–
MeOH, 7:1) to yield 253 mg (78%) of diol 18 (dr 82:18) as a colour-
less oil.
Anal. Calcd for C23H33NO3 (371.5): C, 74.36; H, 8.95; N, 3.77.
Found: C, 74.25; H, 8.67; N, 3.85.
(2S,3R,4S,1¢R)-3-Amino-2-benzyloxy-4-methyl-N-(1¢-phenyl-
ethyl)hexanoic Acid (16)
To a solution of the diol 14 (220 mg, 0.59 mmol) in MeOH–H2O–
THF (4:2:1, 7 mL) was added NaIO4 (218 mg, 1.01 mmol) at 0 °C.
The mixture was stirred for 2 h, then quenched with a sat. solution
of NaHCO3 (4.5 mL) and extracted with CH2Cl2 (4 × 20 mL). The
combined organic phases were dried (MgSO4) and concentrated
(40 °C/60 mbar) to give 192 mg (97%) of the aldehyde 15 as a co-
lourless oil which was used directly in the next step.
The aldehyde 15 was dissolved in t-BuOH (6.0 mL) and 2-methyl-
2-butene (2.5 mL), and then treated with a solution of NaClO2 (93
mg, 1.01 mmol) and NaH2PO4 (122 mg, 1.01 mmol) in H2O (1.2
mL). After stirring for 90 min, the same amounts of NaClO2 and
NaH2PO4 were added again. After stirring for 1 h, NaOH (8 M, 0.5
mL) was added. The solvent was removed under reduced pressure
(40 °C/60 mbar), the resulting residue was dissolved in H2O (8.0
mL) and extracted with Et2O (2 × 10 mL). The pH of the aqueous
phase was adjusted to 3–4 by adding 6 M HCl and the resulting so-
lution was extracted with EtOAc (5 × 50 mL). The combined organ-
ic phases were dried (MgSO4) and concentrated (40 °C/220 mbar);
the remaining solid was recrystallised (EtOAc–heptane) to give 178
mg (88%) of protected hexanoic acid 16 as a colourless powder; mp
112–113 °C; [a]D20 –29.1 (c 0.95, CHCl3).
Major isomer
13C NMR (75.5 MHz, CDCl3): d = 12.7 (q, 5-CH3), 24.5 (q,
NCHCH3), 26.0, 27.1 [2 q, C(CH3)2], 37.9 (d, C-5), 57.6 (d,
NCHCH3), 57.7 (d, C-4), 65.2 (t, C-7), 66.5 (t, C-1), 74.3 (d, C-6),
76.0 (t, OCH2Ph), 80.2 (d, C-2), 80.9 (d, C-3), 110.2 [s, C(CH3)2],
127.8, 127.9, 128.0, 128.1, 128.2, 128.8 (6 d, 2 Ph), 138.8 [s,
OCH2Ph(i-C)], 144.3 [s, NCH(CH3)Ph(i-C)].
Minor isomer
13C NMR (75.5 MHz, CDCl3): d = 14.6 (q, 3-CH3), 25.8 (q,
NCHCH3), 26.1, 27.1 [2 q, C(CH3)2], 39.9 (d, C-3), 57.1 (d,
NCHCH3), 59.6 (d, C-4), 64.9 (t, C-1), 66.3 (t, C-7), 74.1 (d, C-2),
75.6 (t, OCH2Ph), 80.7 (d, C-6), 82.8 (d, C-5), 139.1 [s, OCH2Ph(i-
C)], 144.0 [s, NCH(CH3)Ph(i-C)]; some signals not assigned as they
overlapped with those of the major isomer.
IR (solid): 3307, 1455, 1387, 1108, 1021, 701, 628 cm–1.
1H NMR (300.1 MHz, CDCl3): d = 0.62 (t, 3J5,6 = 7.4 Hz, 3 H, 6-H),
0.88 (d, 3J4,CH = 7.0 Hz, 3 H, 4-CH3), 1.05–115 (m, 2 H, 5-H), 1.48
Anal. Calcd for C26H35NO5 (441.6): C, 70.40; H, 8.41; N, 3.16.
Found: C, 70.10; H, 8.54; N, 3.10.
3
(d, 3J = 6.7 Hz, 3 H, NCHCH3), 1.89 (m, 1 H, 4-H), 2.81 (t, 3J2,3
=
3J3,4 = 4.1 Hz, 1 H, 3-H), 3.79 (q, 3J = 6.7 Hz, 1 H, NCHCH3), 3.98
Synthesis 2006, No. 13, 2173–2182 © Thieme Stuttgart · New York

2180
F. Li et al.
PAPER
(2R,3R,4S,1¢R)-3-Amino-4-O-benzyl-4,6-dihydroxy-3-N-(1¢-
(2R,3R,4S,1¢R)-3-Amino-4-O-benzyl-5,6-O-isopropylidene-2-
methyl-3-N-(1¢-phenylethyl)hexanoic Acid (20)
phenylethyl)-5-hexanolide (22) and (2R,3R,4S,1¢R)-3-Amino-
4,6-dihydroxy-3-N-(1¢-phenylethyl)-5-hexanolide (23)
The methyl ester 21 (240 mg, 0.54 mmol) was dissolved in diox-
ane–H2O (1:1, 4.0 mL), then concd HCl (6 drops) was added. The
reaction mixture was stirred at 50 °C for 16 h. The solvent was
evaporated under reduced pressure, the residue was dissolved in a
sat. solution of NaHCO3 (5.0 mL) and extracted with EtOAc (4 × 20
mL). The combined organic phases were dried (MgSO4) and con-
centrated under reduced pressure. The crude product was purified
by flash chromatography (silica gel; 10 g, 5 cm × 2 cm, PE–EtOAc,
2:1) to give 80 mg (40%) of the lactone 22 as an analytically pure,
colourless oil and 40 mg (26%) of the free g-hydroxy-d-lactone 23
as a colourless powder, (elemental analysis shows a slight deviation
for C).
To a solution of the diol 12 (253 mg, 0.57 mmol) in MeOH–THF–
H2O (4:2:1, 10 mL) was added NaIO4 (428 mg, 2.0 mmol) at 0 °C.
The reaction mixture was stirred for 3 h at the same temperature,
then quenched with a sat. solution of NaHCO3 (10 mL) and extract-
ed with CH2Cl2 (4 × 30 mL). The combined organic phases were
dried (MgSO4) and concentrated to give 234 mg (99%) of the alde-
hyde 19 as a colourless oil which was used directly in the next step.
The aldehyde 19 was dissolved in t-BuOH (5.0 mL) and 2-methyl-
2-butene (2.5 mL). To the mixture was added a solution of NaClO2
(78 mg, 0.86 mmol) and NaH2PO4 (104 mg, 0.86 mmol) in H2O (1.0
mL). After stirring for 90 min the same amounts of NaClO2 and
NaH2PO4 were added again. After further stirring for 1 h, NaOH so-
lution (8 M, 0.5 mL) was added. The solvent was removed under re-
duced pressure and the resulting residue was dissolved in H2O (6.0
mL). The pH was adjusted to 3–4 by dropwise addition of 6 M HCl.
The mixture was extracted with EtOAc (5 × 40 mL), the combined
organic phase was dried (MgSO4) and concentrated to give 219 mg
(90%) of the carboxylic acid 20 as a colourless oil.
g-Benzyloxy-d-lactone 22
[a]D20 +90.2 (c 1.10, CHCl3).
IR (neat): 3320, 1729 (C=O), 1453, 1369, 1247, 1193, 1113, 1054,
1027, 942, 762, 734, 698 cm–1.
3
1H NMR (300.1 MHz, CDCl3): d = 0.99 (d, 3J2,CH3 = 7.2 Hz, 3 H, 2-
1H NMR (300.1 MHz, CDCl3): d = 1.20 (d, J = 6.8 Hz, 3 H, 2-
3
CH3), 1.40, 1.42 [2 s, 6 H, C(CH3)2], 1.47 (d, J = 6.6 Hz, 3 H,
CH3), 1.36 (d, 3J = 6.6 Hz, 3 H, NCHCH3), 2.02 (br, 2 H, OH, NH),
2.22 (m, 1 H, 2-H), 2.57 (dd, 3J3,4 = 7.3 Hz, 3J2,3 = 0.7 Hz, 1 H, 3-
H), 3.66 (app s, 1 H, 5-H), 3.70 (dd, 2J6a,6b = 11.8 Hz, 3J5,6a = 4.8 Hz,
1 H, 6-Ha), 3.87 (q, 3J = 6.6 Hz, 1 H, NCHCH3), 4.00 (dd,
2J6a,6b = 11.8 Hz, 3J5,6b = 7.2 Hz, 1 H, 6-Hb), 4.28, 4.44 (AB system,
2J = 12.0 Hz, 2 H, OCH2Ph), 4.54 (dd, 3J3,4 = 6.6 Hz, 3J4,5 = 5.2 Hz,
1 H, 4-H), 7.19–7.35 (m, 10 H, 2 Ph).
3
3
NCHCH3), 1.94 (m, 1 H, 2-H), 2.84 (dd, J2,3 = 5.7 Hz, J3,4 = 1.3
Hz, 1 H, 3-H), 3.59 (dd, 3J4,5 = 4.0 Hz, 3J3,4 = 1.2 Hz, 1 H, 4-H), 3.74
(dd, 2J6a,6b = 8.2 Hz, 3J5,6a = 7.6 Hz, 1 H, 6-Ha), 3.91 (q, 3J = 6.6 Hz,
1 H, NCHCH3), 4.01 (dd, 2J6a,6b = 8.3 Hz, 3J5,6b = 6.5 Hz, 1 H, 6-Hb),
2
4.21 (m, 1 H, 5-H), 4.51, 4.66 (AB system, J = 10.4 Hz, 2 H,
OCH2Ph), 7.29–7.41 (m, 10 H, 2 Ph).
13C NMR (75.5 MHz, CDCl3): d = 12.5 (q, 2-CH3), 23.1 (q,
NCHCH3), 25.7, 26.3 [2 q, C(CH3)2], 39.0 (d, C-2), 59.0 (d,
NCHCH3), 61.6 (d, C-3), 66.0 (t, C-6), 74.7 (t, OCH2Ph), 75.1 (d,
C-5), 79.1 (d, C-4), 110.0 [s, C(CH3)2], 125.9, 127.1, 128.0, 128.32,
128.38, 128.7, 129.0 (7 d, 2 Ph), 137.1 [s, OCH2Ph(i-C)], 141.9 [s,
NCH(CH3)Ph(i-C)], 176.0 (s, C-1).
13C NMR (75.5 MHz, CDCl3): d = 15.0 (q, 2-CH3), 25.4 (q,
NCHCH3), 41.0, (d, C-2), 55.6 (d, NCHCH3), 59.3 (d, C-3), 62.4 (t,
C-6), 71.1 (t, OCH2Ph), 75.0 (d, C-5), 77.9 (d, C-4), 126.9, 128.0,
128.4, 128.9, 129.2 (5 d, 2 Ph), 137.9 [s, OCH2Ph(i-C)], 144.9 [s,
NCH(CH3)Ph(i-C)], 174.0 (s, C-1).
MS: (EI, 70 eV): m/z (%) = 369 (1.2) [M]+, 206 (38), 105 (77), 91
(100), 57 (13).
Methyl (2R,3R,4S,1¢R)-3-Amino-4-O-benzyl-5,6-O-isopropyl-
idene-2-methyl-3-N-(1¢-phenylethyl)hexanoate (21)
Acid 20 (219 mg, 0.51 mmol) was treated with a solution of ethereal
CH2N2 (excess). After 20 min the solvent was evaporated and the
residue was purified by flash column chromatography (silica gel;
PE–EtOAc, 6:1) to afford 195 mg (86%) of the methyl ester 21 as a
colourless, analytically pure oil; [a]D20 –4.08 (c 1.45, CHCl3).
Anal. Calcd for C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C,
70.91; H, 7.47; N, 3.69.
g-Hydroxy-d-lactone 23
Mp 103–105 °C; [a]D20 +103 (c 0.460, CHCl3).
IR (solid): 3464, 1736 (C=O), 1371, 1348, 1188, 1162, 1127, 1091,
1027, 975, 761, 689 cm–1.
IR (neat): 3029, 1730, 1494, 1453, 1369, 1252, 1199, 1071, 698
cm–1.
1H NMR (300.1 MHz, CDCl3): d = 1.12 (d, J2,CH3 = 7.1 Hz, 3 H, 2-
CH3), 1.38 (d, 3J = 6.6 Hz, 3 H, NCHCH3), 2.69 (m, 3 H, 3-H, OH,
NH), 3.17 (dd, J6a,6b = 10.5 Hz, J5,6a = 7.6 Hz, 1 H, 6-Ha), 3.73–
3.86 (m, 3 H, 2-H, 6-Hb, NCHCH3), 4.15 (m, 1 H, 5-H), 4.44 (dd,
3J3,4 = 7.6 Hz, 3J4,5 = 1.4 Hz, 1 H, 4-H), 7.26–7.38 (m, 5 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 13.9 (q, 2-CH3), 24.7 (q,
NCHCH3), 40.4 (d, C-2), 56.9 (d, NCHCH3), 60.5 (d, C-3), 63.4 (t,
C-6), 70.9 (d, C-5), 84.8 (d, C-4), 126.4, 127.6, 128.8 (3 d, Ph),
144.3 [s, NCH(CH3)Ph(i-C)], 178.5 (s, C-1).
1H NMR (300.1 MHz, CDCl3): d = 1.11 (d, 3J2,CH3 = 6.6 Hz, 3 H, 2-
2
3
3
CH3), 1.25 (d, J = 6.4 Hz, 3 H, NCHCH3), 1.41, 1.44 [2 s, 6 H,
C(CH3)2], 2.66 (m, 2 H, 2-H, NCHCH3), 3.34 (s, 3 H, OCH3), 3.49
3
3
(dd, J3,4 = 7.7 Hz, J4,5 = 0.9 Hz, 1 H, 4-H), 3.69 (app t,
3J5,6a = 2J6a,6b = 8.1 Hz, 1 H, 6-Ha), 3.90 (q, 3J = 6.5 Hz, 1 H,
NCHCH3), 4.09 (dd, J6a,6b = 8.1 Hz, J5,6b = 6.3 Hz, 1 H, 6-Hb),
4.47, 4.94 (AB system, 2J = 11.2 Hz, 2 H, OCH2Ph), 4.59 (m, 1 H,
5-H), 7.22–7.27 (m, 10 H, 2 Ph).
2
3
13C NMR (75.5 MHz, CDCl3): d = 14.7 (q, 2-CH3), 23.6 (q,
NCHCH3), 26.2, 27.2 [2 q, C(CH3)2], 40.3 (d, C-2), 51.7 (q, OCH3),
55.7 (d, NCHCH3), 59.0 (d, C-3), 66.8 (t, C-6), 74.0 (t, OCH2Ph),
79.5 (d, C-5), 81.3 (d, C-4), 109.7 [s, C(CH3)2], 127.5, 127.8, 128.5,
MS (EI, 70 eV): m/z (%) = 279 (9), [M]+, 161 (13), 105 (100), 57
(18).
HRMS-EI: m/z calcd for C15H21NO4: 279.1471; found: 279.1470.
Anal. Calcd for C15H21NO4 (279.3): C, 64.50; H, 7.58; N 5.01.
Found: C, 62.58; H, 7.56; N, 4.69.
128.7 (4 d,
2 C6H5), 139.1 [s, OCH2Ph(i-C)], 146.4 [s,
NCH(CH3)Ph(i-C)], 175.9 (s, C-1).
Anal. Calcd for C26H35NO5 (441.6): C, 70.72; H, 7.99; N, 3.17.
Found: C, 70.57; H, 7.99; N, 3.10.
Dimethyl (2S,3R,4R,1¢R)-2-O-Benzyl-4-methyl-3-N-(1¢-phenyl-
ethyl)pentanedioate (26)
H5IO6 (159.6 mg, 0.70 mmol) was added to a solution of the ace-
tonide ester 21 (123 mg, 0.28 mmol) in Et2O (6.0 mL) and the reac-
tion mixture was stirred under N2 for 6 h. A solution of Na2S2O3 (2
M, 1.5 mL) was added; the mixture was extracted with Et2O (3 × 15
Synthesis 2006, No. 13, 2173–2182 © Thieme Stuttgart · New York

PAPER
Synthesis of (2S,3R,4S)-Isonorstatine
Antibiot. 1970, 23, 259.
2181
mL) and dried (MgSO4). The combined organic phases were con-
centrated in vacuo to afford the aldehyde 24 as a colourless oil.
(3) (a) Rich, D. H.; Moon, B. J.; Boparai, A. S. J. Org. Chem.
1980, 45, 2288. (b) Rich, D. H.; Moon, B. J.; Harbeson, S. J.
Med. Chem. 1984, 27, 417. (c) Sugimura, H.; Miura, M.;
Yamada, N. Tetrahedron: Asymmetry 1997, 8, 4089.
(4) (a) Iizuka, K.; Kamijo, T.; Kubota, T.; Akahane, K.;
Umeyama, H.; Kiso, Y. J. Med. Chem. 1988, 31, 704.
(b) Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota,
T.; Umeyama, H.; Kiso, Y. J. Chem. Soc., Chem. Commun.
1989, 1678.
(5) Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.;
Etoh, Y.; Shimaoka, I.; Tsubaki, A.; Murakami, M.;
Yamaguchi, T.; Iyobe, A.; Umeyama, H.; Kiso, Y. Chem.
Pharm. Bull. 1990, 38, 2487.
The aldehyde was dissolved in t-BuOH (4.0 mL) and 2-methyl-2-
butene (1.5 mL), then NaClO2 (38 mg, 0.42 mmol) and NaH2PO4
(50.4 mg, 0.42 mmol) were added. After stirring for 90 min, the
same amounts of NaClO2 and NaH2PO4 were added again. After
1 h, NaOH solution (4 M, 2.0 mL) was added and the solvent was
removed under reduced pressure (40 °C, 60 mbar). The residue, a
colourless powder, was dissolved in H2O (4.0 mL), then the pH was
adjusted to 3–4 by dropwise addition of 6 M HCl. The mixture was
extracted with EtOAc (5 × 30 mL) and dried (MgSO4). The solvent
was removed to give the diacid monoester 25 which was obtained
as a colourless oil.
Without purification, this acid 25 was treated with a solution of
ethereal CH2N2 (excess). After stirring for 10 min, the solvent was
evaporated and the light-yellow oil was purified by flash column
chromatography (silica gel, 8 g, 2 cm × 5 cm; PE–EtOAc, 4:1) to
give 80 mg (72%) of the diester 26 as a spectroscopically pure, co-
lourless oil; [a]D20 –8.7 (c 1.02, CHCl3).
(6) Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.;
Umeyama Ishida, T.; Kiso, Y. J. Med. Chem. 1990, 33,
2707.
(7) (a) Jäger, V.; Wehner, V. Angew. Chem., Int. Ed. Engl. 1989,
28, 469. (b) Kieß, F.-M.; Poggendorf, P.; Picasso, S.; Jäger,
V. Chem. Commun. 1998, 119. (c) Menzel, A.; Öhrlein, R.;
Griesser, H.; Jäger, V. Synthesis 1999, 1691. (d) Review:
Jäger, V.; Öhrlein, R.; Wehner, V.; Poggendorf, P.; Steuer,
B.; Raczko, J.; Griesser, H.; Kieß, F.-M.; Menzel, A.
Enantiomer 1999, 4, 205; and references cited therein.
(8) Reviews: (a) Risch, N.; Arend, M. In Houben-Weyl,
Methoden der Organischen Chemie, 4th ed., Vol. E21b;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995, 1833. (b) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(c) Bloch, R. Chem. Rev. 1998, 98, 1047. For related
additions to ribose imines see: (d) Lay, L.; Nicotra, F.;
Paganini, A.; Pangrazio, L.; Panza, L. Tetrahedron Lett.
1993, 34, 4555. (e) Cippola, L.; Lay, L.; Nicotra, F.;
Pangrazio, L.; Panza, L. Tetrahedron 1995, 51, 4679.
(f) Kleemann, H.-W.; Heitsch, H.; Henning, R.; Kramer, W.;
Kocher, W.; Lerch, U.; Linz, W.; Nickel, W.-U.; Ruppert,
D.; Urbach, H.; Utz, R.; Wagner, A.; Weck, R.; Wiegand, F.
J. Med. Chem. 1992, 35, 59. (g) Clark, R. D.; Jahangir;
Souchet, M.; Kern, J. R. J. Chem. Soc., Chem. Commun.
1989, 930.
IR (neat): 1731 (C=O), 1453, 1434, 1345, 1256, 1198, 1162, 1105,
1027, 749, 698 cm–1.
1H NMR (300.1 MHz, CDCl3): d = 1.09 (d, 3J4,CH3 = 7.1 Hz, 3 H, 4-
CH3), 1.23 [d, 3J = 6.4 Hz, 3 H, NCHCH3], 2.66 (m, 1 H, 4-H), 3.21
3
3
(dd, J3,4 = 6.3 Hz, J2,3 = 2.4 Hz, 1 H, 3-H), 3.39 (s, 3 H, OCH3),
3.79 (m, 4 H, NCHCH3, OCH3), 4.01 (d, 2J2,3 = 2.3 Hz, 1 H, 2-H),
4.34, 4.76 (AB system, 2J = 11.0 Hz, 2 H, OCH2Ph), 7.19–7.28 (m,
10 H, 2 Ph).
13C NMR (75.5 MHz, CDCl3): d = 14.1 (q, 4-CH3), 24.1 (q,
NCHCH3), 41.5 (d, C-4), 51.4, 51.8 (2 q, 2 OCH3), 55.6 (d,
NCHCH3), 59.5 (d, C-3), 72.9 (t, OCH2Ph), 77.4 (d, C-2), 127.0,
127.1, 127.9, 128.2, 128.3, 128.4 (6 d, 2 Ph), 137.2 [s, OCH2C6H5(i-
C)], 145.6 [s, NCH(CH3)Ph(i-C)], 172.6, 175.4 (2 s, C-1, C-5).
MS (CI, +): m/z (%) = 400 (100) [M + H]+, 220 (35).
HRMS (CI): m/z calcd for C23H30NO5 [M + H]+: 400.2124; found:
400.2111.
Anal. Calcd for C23H29NO5: C, 69.15; H, 7.32; N, 3.51. Found: C,
68.31; H, 7.43; N, 3.59.
(9) (a) Franz, T.; Hein, M.; Veith, U.; Jäger, V.; Peters, E.-M.;
Peters, K.; von Schnering, H. G. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1298. (b) Veith, U.; Leurs, S.; Jäger, V. J.
Chem. Soc., Chem. Commun. 1996, 329.
(10) (a) Veith, U.; Schwardt, O.; Jäger, V. Synlett 1996, 1181.
(b) Schwardt, O.; Veith, U.; Gaspard, C.; Jäger, V. Synthesis
1999, 1473.
Acknowledgment
We are grateful to Altana Pharma, Konstanz, and to Fonds der Che-
mischen Industrie for financial support of this work.
(11) Meunier, N.; Veith, U.; Jäger, V. J. Chem. Soc., Chem.
Commun. 1996, 331.
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