The first synthesis of N,O-protected β2,2,3,3-isoserines bearing two adjacent quaternary stereogenic centers and their corresponding β-lactams

Article abstract of DOI:10.1016/j.tetlet.2007.05.087

The reaction of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic and mandelic acids, with (S_R)-tert-butyl sulfinyl ketimines, derived from butan-2-one, pentan-2-one, and decan-2-one, afforded conformationally restrained β^2,2,3,

Full text of DOI:10.1016/j.tetlet.2007.05.087

Tetrahedron Letters 48 (2007) 5081–5085
The first synthesis of N,O-protected b2,2,3,3-isoserines
bearing two adjacent quaternary stereogenic centers
and their corresponding b-lactams
*
`
Andrea Guerrini, Greta Varchi, Cristian Samorı, Rizzo Daniele and Battaglia Arturo
`
Istituto CNR per la Sintesi Organica e Fotoreattivita ‘I.S.O.F.’, Area della Ricerca di Bologna,
Via P. Gobetti 101, 40129 Bologna, Italy
Received 14 March 2007; revised 10 May 2007; accepted 15 May 2007
Available online 18 May 2007
Abstract—The reaction of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic and mandelic acids, with (SR)-tert-butyl sul-
finyl ketimines, derived from butan-2-one, pentan-2-one, and decan-2-one, afforded conformationally restrained b2,2,3,3-isoserines
bearing two adjacent quaternary stereogenic centers in the form of N-sulfinyl protected 10-amino-dioxolan-4-ones. The selective
acid-induced removal of the sulfinyl protecting group provided the corresponding 10-aminodioxolanones, whose base-induced cycli-
zation afforded the corresponding chiral tetra-substituted 3-hydroxy-b-lactams. The synthesis of a dipeptide by reaction coupling
between the 10-aminodioxolanone (2S,5R,10R)-19 and N,N-dimethylglycine was successfully achieved.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the only known methodology for the synthesis of
b2,2,3,3-amino acids is the addition of titanium enolates
to N-sulfinyl ketimines reported by Elmann’s group,4c
although this strategy only provides one stereogenic cen-
ter at the b3,3 position. In this Letter, we describe the
first synthesis of enantiopure b-amino acids, bearing
two adjacent quaternary stereogenic centers in their
backbone (b2,2,3,3-isoserines). The isoserine pattern is
found in a variety of natural products and pharmaceuti-
cal agents like taxoids,5 GABOB,6 and aminopeptidase
inhibitors (bestatin,7 probestatin,7 phebestatin,7 the
bestatin-type MetAP2 inhibitor A-357300,8 and amasta-
tin9). Furthermore, they can be employed as building
blocks for oligopeptides synthesis10 and constrained
analogues of biologically active compounds.11 It is
worth noting that chiral b2,2,3,3-isoserines bear several
structural features, which reveal to be very useful in
terms of folding patterns of the corresponding peptides,
such as the presence of the polar H-bonding donor/
acceptor b2-hydroxy substituent, the presence of dissim-
ilar hydrophobic groups at the two quaternary stereo-
genic centres, as well as the possibility to obtain syn/
anti b2,b3-configurational stereoisomers.
b-Amino acids are important constituents of biologi-
cally active natural products and pharmaceutical
agents,1 as well as valuable precursors to these struc-
tures, such as b-lactams. In addition, oligomers of b-
amino acids, for example, b-peptides,2 have attracted
attention as useful peptidomimetics because of their pro-
teolytic stability relative to natural a-peptides and their
propensity to adopt stable secondary structures. Partic-
ular attention has been lately devoted to the asymmetric
synthesis of b-amino acids containing quaternary b2,2 or
b3,3 stereogenic centers,3,4 due to their resistance to pro-
teolytic degradation, which render them excellent build-
ing blocks for bioactive molecules synthesis.3 However,
structural studies on their peptidomimetics are lacking,
due to the limited availability of these molecules in ste-
reoisomerically pure form. Even more difficult is the
preparation of tetra-substituted enantiopure b2,2,3,3-ami-
no acids, since the control of stereoselectivity in reac-
tions generating two adjacent quaternary stereogenic
centers still represents a synthetic challenge. To date,
Keywords: Tetrasubstituted b2,2,3,3-isoserines; Tetrasubstituted 3-hydr-
oxy-b-lactams; b-Peptides; a-Hydroxy-b-amino acids.
Corresponding author. Tel.: +39 051 6398283; fax: +39 051
6398349; e-mail: g.varchi@isof.cnr.it
A fine tuned combination of these parameters can pro-
vide significant structural diverse b-amino acids, which
will influence the characteristics of their derivatives,
b-peptides. For instance, modifications have been
*
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.087

5082
A. Guerrini et al. / Tetrahedron Letters 48 (2007) 5081–5085
LiO
observed in some hexapeptide structures when assem-
bled with b2,3,3-isoserine frames,12,13 namely, conforma-
tional analyses of a very soluble (2R,3S)-norstatine
based hexapeptide established that its structure was a
right-handed helix,14 while the replacement of the
hydroxyl group with a methyl led to an insoluble
analogue with a pleated-sheet conformation.3b
R
tBu
R
O
O
S
S O
2
S
N E
S
O
Z
+
R
L
N
tBu
L
tBu
R1
S
1a: R=R'=Me
2a: R=Ph; R'=H
THF /HMPA, 85:15
S
L
S
L
S
O
L
S
L
NH
NH
O
NH
S
NH
O
O
O
O
1'
O
O
)
1'
1'
1'
S
S
The following study will present an investigation on the
synthesis of tetra-substituted enantiopure syn/anti
b2,2,3,3-isoserines, by using a protocol already experi-
mented for tri-substituted analogues.15 For this purpose,
the (2S)-enolate of 1,3-dioxolan-4-ones were reacted
with N-sulfinyl ketimines to afford N,O-orthogonally
protected 10-sulfinylamino-dioxolanones. Besides, their
conversion into the corresponding C3,C4-tetra-substi-
tuted b-lactams will be reported. In fact, it has been
demonstrated that lipophilic monobactams show cyto-
toxic16 or inhibitory cholesterol absorption activity.17
Finally, this preliminary study paves the way for further
investigations on the efficiency of coupling reactions
toward the synthesis of b2,2,3,3-isoserine-based peptides.
S
R
5
2
R
R
R
5
5
5
tBu
2
tBu
tBu
tBu
O
O
O
O
2
O
O
O
O
2
R1 tBu
R1 tBu
R1 tBu
R1 tBu
(SR,2S,5R,1'R)
(SR,2 ,5
S
R
,1'S
)
(SR,2S,5S,1'R
(SR,2 ,5S,1'S)
S
S = Small Size Substituent; L = Large Size Substituent
Scheme 1.
(2S)-enolates can provide four diastereoisomers, whose
relative distribution depends on two different factors:
face selectivity, which controls the stereogenic center at
the 5-position, while exo/endo simple selectivity rules the
newly formed C10-carbon stereocenter (Scheme 1).
As reported in Table 1 (entries 1–3), enolate (2S)-1a
approaches the ketimines from the less hindered dia-
stereotopic face, thus only the diastereoisomers derived
from TS I (SR,2S,5R,10R-configuration, major) and TS
II (SR,2S,5R,10S-configuration, minor) were formed.
2. Synthesis of (SS)- and (SR)-10-sulfinylamino-
dioxolan-ones
Based on their different steric demand, dioxolanones
(2S,5S)-118 and (2S,5S)-219 were selected for this study.
Treatment of the dioxolanones with lithiated bases
afforded the corresponding (2S)-chiral enolates 1a and
2a, respectively. (SR)-N-tert-butyl sulfinyl ketimines 3–
5 (Fig. 1)20 were selected as the enolates reaction part-
ners, since preliminary investigations employing (SS)-
N-tert-butyl sulfinyl ketimines 3 and 4 only provided
poor results in terms of either chemical yields (20–
30%) or selectivities. In fact only a complex mixture of
three diastereoisomers, derived from transition states
TS I-TS III, was obtained.21
The stereochemistry at the 10 position strongly depends
on reagents steric requirements. When enolate (2S)-1a
was used as a reaction partner, the selectivity was direc-
ted by the small methyl substituent at the C-5 carbon
atom of the enolate, favoring an exo approach of the
imine to the dioxolanone ring with the formation of
the SR,2S,5R,10R-isomers 6, 8, and 10 as major products
(Table 1). On the other hand, when enolate (2S)-2a,
which bears the more steric demanding phenyl group
at C5 and the smaller hydrogen atom at C2 positions,
was employed the diastereofacial selectivity was
reversed. Thus, (SS,2S,5R,10S)-isomers 12, 14, and 16
were obtained with very high de. Separation of the iso-
meric pairs (10/11), (12/13), (14/15), and (16/17) was
performed by silica gel column chromatography (cyclo-
hexane/acetone, 9:1), while any attempts to separate 6/7
and 8/9 pairs failed. Structural characterization of all
Ketimines 3–5 were prepared by condensation of (R)-
tert-butyl sulfinyl amide with the unbranched aliphatic
ketones: butan-2-one, pentan-2-one, and decan-2-
one.22,23 The use of the sulfinyl protecting group pro-
vides stable electrophilic ketimines, avoiding their well
known rapid isomerization to non-reactive enamines un-
der basic conditions.
1
compounds was carried out by H and 13C NMR spec-
troscopy. In particular, 1H NMR-NOE experiments
allowed the assignment of their (5R)-stereochemistry.
1H NMR spectroscopy data showed that (R)-3 was ob-
tained as a 9:1 (E/Z) mixture, while (R)-4 and (R)-5 were
obtained as a 5:1 (E/Z) mixture. From a stereochemical
point of view, the addition of (SR)-sulfinyl ketimines to
3. Chemistry of the 10-sulfinylamino-dioxolanones
O
Ph
O
In the second part of the present work, we focused our
attention on the selective nitrogen deprotection of deriv-
atives 6–17, and the following transformation of the free
amines 18–25 into the corresponding tetrasubstituted
lypophilic b-lactams 26–31 (Table 2).
5
5
(2S,5S)-2
O O
2
O
O
2
(2S,5S)-1
tBu
tBu
H
O
O
S
S
N
N
R
R
Sulfinyl protecting group removal for pure compounds
10, 11, 13, 15, 17 and 6/7 and 8/9 mixtures was carried
out with 2 N HCl in 1:1 MeOH/Et2O mixed solvent,
affording the corresponding N-unprotected 10-amino-
Z
E
Z
(
R
)-3, (
R
)-4, (
R
)-5
3: R = C2H5
(E
/
= 9:1); 4:C3H7
(E
/
Z
=5:1); 5:C8H17(E/Z = 5:1)
Figure 1. Dioxolanones 1 and 2 and E/Z -(R)-ketimines 3–5.

A. Guerrini et al. / Tetrahedron Letters 48 (2007) 5081–5085
5083
Table 1. Products distribution for the reaction of (2S)-enolates 1a and 2a with (R)-configured ketimines 3–5
Entry
(2S)-Enolate
Ketimine
Products (6–17)24
Yield %, (de)
NH
S
O
NH
S
O
O
1
1a
(R)-3
O
70, (66)
tBu
O
tBu
O
O
O
tBu
tBu
(SR,2S,5R,1'
S
)-7
(SR,2S,5R,1'
R
)-6
H
O
N
O
O
O
NH
S
S
O
tBu
tBu
2
3
4
5
6
1a
1a
2a
2a
2a
(R)-4
(R)-5
(R)-3
(R)-4
(R)-5
74, (74)
76, (82)
55, (90)
53, (84)
52, (84)
O
O
O
tBu
tBu
,5
(SR,2
S
R,1'
S
)-9
(SR,2
S
,5
R
,1'
R
)-8
C8H17
C8H17
O
H
N
O
O
O
NH
S
S
O
tBu
O
O
O
tBu
tBu
,5 ,1'
tBu
(S ,2
R
S,5
R
,1'
S
)-11
(SR,2
S
R
R
)-10
O
S
O
H
H
N
N
S
O
O
tBu
O
tBu
O
O
H
O
tBu
,5
tBu
H
(SR,2
S,5
R,1'
S
)-13
(SR,2
S
R
,1'
R
)-12
O
S
O
H
H
N
N
S
O
O
tBu
O
tBu
O
O
O
tBu
,5
tBu
H
H
(SR,2
S,5
R,1'
S
)-14
(SR,2
S
R
,1'
R
)-13
O
C8H17
O
H
C8H17
O
H
N
N
S
S
O
tBu
tBu
O
O
O
O
H
tBu
,5
H
tBu
,5
(SR,2
S
R,1'
S
)-17
(SR,2
S
R
,1'
R
)-16
dioxolanones 18–25 in high yields. Diastereomeric
excesses of the major (2S,5R,10R)-diastereomers 18
and 20 were identical to those of their precursors 6/7
and 8/9. LHMDS induced cyclization of the 10aminodi-
oxolanones 18, 20, and 22–25 produced 3-hydroxy-b-
lactams (3R,4R)-26–28 and (3R,4S)-29–31. Compounds
(3R,4R)-27 and (3R,4R)-26 were obtained along with
minor amounts of their (3R,4S)-isomers, but chroma-
tography purification (SiO2, CH2Cl2/Et2O, 1:1) allowed
their isolation. The relative stereochemical configuration
of b-lactams 26–31 was assigned by means of 1H NMR-
NOE experiments. This allowed the assessment of ste-
reoconfiguration at the 10 position of their precursors
18–25 and 6–17, hence of their absolute configuration.
ily explored by reacting 10-amino-dioxolanone
(2S,5R,10R)-22 with N,N-dimethylglycine (DMG). We
reasoned that the dioxolanone protecting group would
have favored the coupling reaction, because the 2-OH
and the carboxy groups are ‘tied back’ in the form of
a five-membered ring. Accordingly, the reduced steric
hindrance would have allowed the use of milder cou-
pling conditions. As reported in Scheme 3, the reaction
was performed according to standard procedure.
Namely, the diastereomeric mixture 20/21 was reacted
with DMG in the presence of 1-ethyl-3-(3-dimethyl-
aminopropyl)-carbodiimide hydrochloride in
a 3:1
(DMF/CH2Cl2) mixed solvent, yielding the fully pro-
tected dipeptide mixture 33/34 in 75% yield (74% de).
With the aim of proving protecting group orthogonality
(nitrogen atom and acetal center), we selectively
transformed derivative (SR,2S,5R,10R)-10 into the corre-
sponding methyl ester (SR,2R,3R)-32,26 by base induced
methanolysis (Scheme 2).
In conclusion, we reported the first synthesis of enantio-
pure syn/anti b2,2,3,3-isoserines in the form of N,O-
orthogonally protected 10-amino-dioxolan-4-ones. Our
synthetic protocol allows to achieve good values of over-
all yields and diastereoselectivities, overcoming the diffi-
culties associated with the previously reported
methodologies, such as the not easy differentiation be-
tween the two substituents on the prochiral ketimines
Access to sterically congested oligopeptides bearing two
adjacent quaternary stereogenic centers was preliminar-

5084
A. Guerrini et al. / Tetrahedron Letters 48 (2007) 5081–5085
3. For the rules on the b2,2- and b3,3 nomenclature see: (a)
Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1–15; (b)
Seebach, D.; Abele, S.; Gademann, K.; Juan, B. Angew.
Chem., Int. Ed. 1999, 38, 1595–1597; (c) Chung, Y. J.;
Huck, B. R.; Christianson, L. A.; Stanger, H. E.;
Krauthaˆuser, S.; Powell, D. R.; Gellman, S. H. J. Am.
Chem. Soc. 2000, 122, 3995–4004.
4. (a) Selected references regarding the preparation of
geminally disubstituted b-amino acids: Ref. 3a; (b) Ishi-
tani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 8180–8186; (c) Tang, T. P.; Ellman, J. A. J. Org.
Chem. 2002, 67, 7819–7832; (d) Fuller, A. A.; Chen, B.;
Minter, A. R.; Mapp, A. K. J. Am. Chem. Soc. 2005, 127,
5376–5383; (e) Suto, Y.; Kanai, M.; Shibasaki, M. J. Am.
Table 2. Deprotection of compounds 6/7, 8/9, 10, 13, 15, and 17 and
synthesis of the corresponding b-lactams 26–3125
O
S
NH2
HN
R
OH
R2
R3
O
R
R3
R2
O
R3
R2
R
ii
i
O
O
N
O
O
O
H
tBu
18-25
R1
tBu
R1
26-31
6-17
Entry 6–17 18–25a (de) R, R2, R3
26–31b
Yield (%)
(de); Yield (%)
1
2
3
4
5
6
6/7c
18/19c
(66); 90
Me, Me, C2H5
Me, Me, C3H7
Me, Me, C8H17
C6H5, C2H5, Me
C6H5, C3H7, Me
(3R,4R)-26d
(50); 75
Chem. Soc. 2007, 129, 500–501; (f) Roland Muller, R.;
¨
8/9c 20/21c
(3R,4R)-27d
(55); 72
Helmut Goesmann, H.; Waldmann, H. Angew. Chem., Int.
Ed. 1999, 38, 184–187; Selected references regarding the
synthesis of enantiopure b2,2-amino acids and b2,2-isose-
(74); 90
10c
13d
15d
17d
22c
(3R,4R)-28
(>98); 74
´
rines: (g) Cativela, C.; Diaz de Villegas, M. D.; Galvez, J.
(>98); 88
A. Tetrahedron 1996, 52, 687–694; (h) Pires, R.; Burger, K.
Synthesis 1996, 1277–1279; (i) Huang, Y.; Zhang, Y.-B.;
Chen, Z.-C.; Xu, P.-F. Tetrahedron: Asymmetry 2006, 17,
3152–3157; (l) Avenoza, A.; Busto, J. H.; Corzana, F.;
Jimenez-Oses, G.; Paris, M.; Peregrina, J. M.; Sucunza,
D.; Zurbano, M. M. Tetrahedron: Asymmetry 2004, 15,
131–137; (m) Avenoza, A.; Busto, J. H.; Jimenez-Oses, G.;
Peregrina, J. M. J. Org. Chem. 2005, 70, 5721–5724.
5. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; Mc
Phail, A. T. J. Am. Chem. Soc. 1971, 93, 2321–2327.
6. Nakao, J.; Hasegawa, T.; Hashimoto, H.; Noto, T.;
Nakajima, T. Pharmacol. Biochem. Behav. 1991, 40, 359.
7. Righi, G.; D’Achille, C.; Pescatore, G.; Bonini, C.
Tetrahedron Lett. 2003, 44, 6999–7002.
23d
(3R,4S)-29
(>98); 40
(>98); 88
24d
(3R,4S)-30
(>98); 35
(>98); 94
25d
C6H5, C8H17, Me (3R,4S)-31
(>98); 98
(>98); 46
a 2 N HCl in MeOH/Et2O.
b LHMDS/THF/HMPA.
c R1 = Me.
d R1 = H.
8. Wang, J.; Sheppard, G. S.; Lou, P.; Kawai, M.; BaMaung,
N.; Erickson, S. A.; Tucker-Garcia, L.; Park, C.; Bouska,
J.; Wang, Y. C.; Frost, D.; Tapang, P.; Albert, D. H.;
Morgan, S. J.; Morowitz, M.; Shusterman, S.; Maris, J.
M.; Lesniewski, R.; Henkin, J. Cancer Res. 2003, 63,
7861–7869.
H
O
S
C8H17
O
N
tBu
S
But
NH
HO
O
O
i
O
O
OMe
tBu
,5
9. Rich, D. H.; Moon, B. J.; Harbeson, S. J. Med. Chem.
1984, 27, 417–422.
(SR,2R,3R)-32
(SR,2
S
R
,1'
R)-10
10. For examples see: Vega, S.; Kang, L.-W.; Velazquez-
Campoy, A.; Kiso, Y.; Amzel, L. M.; Freire, E. Proteins:
Struct. Funct. Bioinformatics 2004, 55, 594–602.
11. Battaglia, A.; Ralph, J.; Bernacki, R. J.; Bertucci, C.;
Bombardelli, E.; Cimitan, S.; Ferlini, C.; Fontana, G.;
Guerrini, A.; Riva, A. J. Med. Chem. 2003, 46, 4822–4825,
and references cited therein.
12. Motorina, I. A.; Huel, C.; Quiniou, E.; Mispelter, N.;
Adjadj, E.; Grierson, D. S. J. Am. Chem. Soc. 2001, 123,
8–17.
13. Tromp, R. A.; Van der Hoeven, M.; Amore, A.; Brussee,
J.; Overhand, M.; Van der Marel, G. A.; Van der Gen, A.
Tetrahedron: Asymmetry 2001, 12, 1109–1112.
14. Gademann, K.; Ha¨ne, A.; Rueping, M.; Jaun, B.; Seebach,
S. Angew. Chem., Int. Ed. 2003, 42, 1534–1537.
15. Guerrini, A.; Varchi, G.; Battaglia, A. J. Org. Chem. 2006,
71, 6785–6795.
16. Smith, D. M.; Kazi, A.; Smith, L.; Long, T. E.; Heldreth,
B.; Turos, D.; Dou, Q. P. Mol. Pharm. 2002, 61, 1348–
1358, and references cited therein.
Scheme 2. Reagents and conditions: MeOꢀ/MeOH; 60 ꢁC; 5 h; 86%.
O
N
NH2
C3H7
NH
C3H7
O
i
O
+
N
CO2H
O
O
O
O
tBu
tBu
20/21
33/34
Scheme 3. Reagents and conditions: EDCÆHCl/HOBt/DMF:CH2Cl2,
3:1, 20 ꢁC; 12 h; Y: 75%; de: 74%.
carbon atom and their low reactivity. The results
achieved by us were possible primarily because of the
high enolates stability, along with the high reactivity
of the (SR)-N-tert-butyl sulfinyl ketimines employed.
17. Goel, R. K.; Kulkarni, K. J. Pharmaceut. Sci. 2004, 7, 80–
83.
References and notes
18. Ortholand, Y. J.; Greiner, A. Bull. Soc. Chim. Fr. 1993,
130, 133–142.
1. For b-amino acids applications, see: Enantioselective
Synthesis of b-Amino Acids; Juaristi, E., Soloshonok, V.
A., Eds.; Wiley-Interscience: New York, 2005.
19. Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313–1324.
2. For reviews on b-peptides, see: Fulo¨p, F.; Martinek, T. A.;
20. General procedure for the synthesis of N-sulfinyl 10-
aminodioxolanones: LHMDS (2.8 equiv, 1.0 M in THF)
¨
´
Toth, G. K. Chem. Soc. Rev. 2006, 35, 323–334.

A. Guerrini et al. / Tetrahedron Letters 48 (2007) 5081–5085
5085
was added dropwise to a stirred THF solution of
dioxolanone (2.8 equiv, 0,01 M) at ꢀ78 ꢁC. The solution
was reacted at ꢀ70 ꢁC for further 45 min, then the
temperature was lowered at ꢀ90 ꢁC and HMPA was
added dropwise (final THF/HMPA ratio, 85:15). After
few minutes, the temperature was raised to ꢀ78 ꢁC and a
THF solution of the N-sulfinyl azomethine (1.0 equiv,
0.12 M) was slowly added. The temperature was raised to
ꢀ60 ꢁC during 1 h and then stirred for additional 30 min.
The reaction mixture was quenched with 0.2 N HCl ,
warmed under stirring to room temperature, then
extracted with EtOAc (3·), washed with 0.2 N HCl,
followed by saturated NH4Cl. The organic phase was
dried over Na2SO4, filtered and the solvent removed under
reduced pressure. The crude material was purified by silica
gel column chromatography; eluent: hexanes/ethyl
acetate.
(m, 2H), 1.61 (s, 3H, Me), 1.60 (s, 3H, Me), 1.47 (s, 3H,
C10-Me), 1.48–1.40 (m, 1H), 1.32–1.24 (m, 10H), 1.24 (s,
9H, S-tBu), 1.03 (s, 9H, 3 Me, C2-tBu), 0.88 (t, 3H, Me);
13C NMR (CDCl3) d 175.1 (C), 115.7 (C), 84.8 (C), 62.3
(C), 56.5 (C), 39.5 (C), 37.1 (CH2), 32.0 (CH2), 30.5 (CH2),
29.6 (CH2), 29.4 (CH2), 25.8 (3 Me of StBu), 24.5 (CH2),
23.6 (Me), 23.3 (Me), 23.1 (3 Me of OtBu), 22.8 (CH2),
22.3 (Me), 21.3 (Me),14.3 (Me). Anal. Calcd for
C23H45NO4S: C, 63.99; H, 10.51; N, 3.24. Found: C,
63.82; H, 10.72; N, 3.20.
20
25. (3R,4R)-28: ½aꢁD ꢀ4.6 (c 4.8, CHCl3). IR (neat, cmꢀ1
)
1
3248, 2925, 1773, 1468. MS m/z 227, 210, 114. H NMR
(CD3COCD3) d 7.12 (b, 1H, NH), 4.72 (b, 1H, OH), 1.55–
1.45 (m, 2H), 1.37 (s, 3H, C3-Me), 1.31 (s, 3H, C4-Me),
1.40–1.20 (m, 12H), 0.88 (t, 3H, Me); 13C NMR
(CD3COCD3) d 171.6 (C), 84.6 (C), 63.0 (C), 37.1
(CH2), 31.9 (CH2), 30.3 (CH2), 29.6 (CH2), 29.3 (CH2),
25.1 (CH2), 22.6 (CH2), 20.1 (Me), 18.1 (Me), 13.7 (Me).
Anal. Calcd for C13H25NO2: C, 68.68; H, 11.08; N, 6.16.
Found: C, 68.56; H, 10.95; N, 6.28.
21. These results were confirmed in a test experiment of
addition reaction of (2S)-1a with the (S)-configured
ketimine (SS)-3, which afforded modest amounts (30–
35%) of a mixture of three diastereomers.
22. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman,
J. A. J. Org. Chem. 1999, 64, 1278–1284.
20
26. (SR,2R,3R)-32: ½aꢁD +70.4 (c 0.75, CHCl3). IR (neat,
cmꢀ1) 3319, 2926, 2855, 1717, 1465. MS m/z 349, 332, 301,
1
227, 210, 179. H NMR (CDCl3) d 4.53 (br s, 1 H, NH),
23. Common feature of these reagents was the presence of the
oxo group at the 2-position. Ketimines derived from
isomeric ketones, such as hexan-3-one, or ketones bearing
an aromatic substituent, such as acetophenone, were
unreactive.
3.76 (s, 3H, CH3), 1.86–1.76 (m, 1H), 1.41 (s, 3H, Me),
1.28 (s, 3H, Me), 1.27–1.22 (s+br m, 23 H , Bu+7CH2),
t
1.48–1.40 (m, 1H), 1.32–1.24 (m, 1H), 0.88 (t, 3H, Me);
13C NMR (CDCl3) d 176.1 (C), 79.1, 64.9, 56.3 (C), 52.7
(CH3), 38.7, 32.0 (CH2), 31.1 (CH3), 30.2, 29.8, 29.4, 23.8
23.2 (CH3), 22.9 (CH2), 21.1, 17.5, 14.3 (CH3). Anal.
Calcd for C17H35NO4S: C, 58.42; H, 10.09; N, 4.01.
Found: C, 58.31; H, 9.85; N, 4.27.
20
24. (SR,2S,5R,10R)-10: ½aꢁD ꢀ53 (c 0.5, CHCl3). IR (neat,
1
cmꢀ1) 2958, 1777, 1468. MS m/z 431, 327, 106. H NMR
(CDCl3) d 4.30 (b, 1H, NH), 1.86–1.76 (m, 1H), 1.68–1.62