Tandem enantioselective conjugate addition-Mannich reactions: efficient multicomponent assembly of dialkylzincs, cyclic enones and chiral N-sulfinimines

Article abstract of DOI:10.1016/j.tetlet.2008.02.076

A convenient access to enantiopure β-amino ketones through a multicomponent reaction of dialkyl zinc reagents, cyclic enones and chiral N-tert-butanesulfinimines is disclosed. Four diastereoisomers can be selectively obtained by the appropriate choice of the chiral ligand (L or ent-L) and the chiral N-sulfinimine (R_S or S_S). The protocol is particularly efficient when enolisable N-sulfinimines are used.

Full text of DOI:10.1016/j.tetlet.2008.02.076

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2343–2347
Tandem enantioselective conjugate addition–Mannich reactions:
efficient multicomponent assembly of dialkylzincs,
cyclic enones and chiral N-sulfinimines
*
*
´
´
´
Jose C. Gonzalez-Gomez, Francisco Foubelo , Miguel Yus
Departamento de Quı´mica Orga´nica, Facultad de Ciencias and Instituto de Sı´ntesis Orga´nica (ISO),
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 8 January 2008; revised 12 February 2008; accepted 15 February 2008
Available online 19 February 2008
Dedicated to Professor Elias J. Corey on occasion of his 80th birthday
Abstract
A convenient access to enantiopure b-amino ketones through a multicomponent reaction of dialkyl zinc reagents, cyclic enones and
chiral N-tert-butanesulfinimines is disclosed. Four diastereoisomers can be selectively obtained by the appropriate choice of the chiral
ligand (L or ent-L) and the chiral N-sulfinimine (RS or SS). The protocol is particularly efficient when enolisable N-sulfinimines are used.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Conjugate addition; Multicomponent reaction; Chiral sulfinimines; b-Amino ketones; Dialkyl zincs
Chiral b-amino ketones are important building blocks
for the asymmetric synthesis of biologically active mole-
cules.1 For example, these compounds have been used in
the stereoselective synthesis of 1,3-aminoalcohols,2 homo-
allylic amines,3 piperidines,4 indolizidines5 and other alkal-
oids.6 However, to the best of our knowledge, the only
asymmetric synthesis of a-substituted b-amino ketones is
the diastereoselective addition of lithium enolates to chiral
N-sulfinyl imines (sulfinimines) that was recently developed
by Davis.7 Chiral sulfinimines have been widely studied—
in particular—by Davis, who proposed the use of N-p-tolyl-
sulfinimines,8 and by Ellman, who developed N-tert-butyl
derivatives.9 Indeed, one of the most direct and reliable
methods for the asymmetric synthesis of amine derivatives
is the addition of an organometallic reagent to the C@N
bond of enantiopure sulfinimines.10 In this context, we
envisaged that trapping enolates, generated in the conju-
gate addition of organometallic reagents to enones, with
chiral sulfinimines would provide a convenient route to
chiral b-amino ketones.11
The use of the phosphoramidite ligand L developed by
Feringa enables the generation of chiral enolates (ee
>98%) through the copper-catalyzed addition of dialkyl
zinc reagents to cyclic enones.12 It is also known that these
chiral enolates react stereoselectively with different electro-
philes to give predominately trans substitution, and when
prostereogenic aldehydes are used, the newly generated
stereogenic centre b to the carbonyl group is usually
formed in a stereorandom manner (Scheme 1).13 Herein,
Me
Ph
Ph
O
O
L
P
N
Me
O
O
OH
H
R2Zn
Cu(L) cat.
R'CHO
R
*
R1
Corresponding authors. Tel.: +34 965 909672; fax: +34 965 903549
(F.F.).
Scheme 1.
E-mail addresses: foubelo@ua.es (F. Foubelo), yus@ua.es (M. Yus).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.076

2344
J. C. Gonza´lez-Go´mez et al. / Tetrahedron Letters 49 (2008) 2343–2347
we outline our initial findings on the reactivity of homo-
chiral zinc/copper14 enolates with chiral sulfinimines.
N-tert-Butanesulfinimines (t-BS imines) are known to be
less reactive with lithium enolates than other chiral sulfin-
imines.15 However, we initially explored their reactivity
due to the ready availability of both antipodes16 and the
high stereoinduction of the tert-butyl group.17 In a preli-
minary experiment, an excess of the enolate, generated by
copper-catalyzed conjugate addition of diethylzinc to
cyclohexenone, using PPh3 as a ligand, was quenched with
chiral sulfinimine 2. Under the experimental conditions
used, we obtained a 40% yield of the expected products
3a,b as a 1:1 mixture of diastereoisomers (Scheme 2).18
Two important questions were answered with this experi-
ment: (a) The resulting enolate (Zn or Cu) is reactive
enough to add to t-BS imines; (b) significant kinetic resolu-
tion of the racemic enolate did not take place with chiral
t-BS imines.19
We assumed that chiral t-BS imines overcome the direct-
ing effect of a chiral enolate at the Mannich stereocentre.20
With this in mind, we anticipated that this tandem enantio-
selective conjugate addition–Mannich reaction could pro-
vide a selective route to four diastereomeric b-amino
ketones. The initial screening is summarized in Table 1.
We were pleased to find that on using the chiral phos-
phoramidite L in the test reaction, the expected compound
3a was obtained in good yield as a single diastereoisomer
(Table 1, entry 1). Importantly, similar results were
obtained when Et2Zn was added either before or after
the sulfinimine,21 indicating that enolate formation is pos-
sible in the presence of the electrophile and a truly multi-
component reaction is taking place.22,23 As illustrated in
entries 2–4 of Table 1, 3.5 mol % of copper, 4 equiv of
Et2Zn and 3 equiv of enone were required for a good con-
version of the t-BS imines. The use of the S-sulfinimine
(ent-2) and the enantiomer of ligand L (ent-L), under these
optimized conditions, afforded compound ent-3a in enanti-
omerically pure form (entry 5). When the pairs ent-L
ligand/R-sulfinimine (2) or L ligand/S-sulfinimine (ent-2)
were used, compounds 3b and ent-3b were, respectively,
the major products (entries 6 and 7). The worst stereoselec-
tivity observed in these cases (about 9:1 dr) would seem to
point to a mismatch effect between the corresponding
homochiral enolate and the chiral sulfinimine. Interest-
ingly, we observed that this possible mismatch effect could
be overcome by using a larger excess of Et2Zn (entry 8).
O
S
O
S
3.3 equiv Et2Zn
Cu(OTf)2 (3 mol %)
PPh3 (6 mol %)
H
H
N
t-Bu
O
O
N
t-Bu
2
Ph
Ph
CH2Cl2
-20 ºC, 20 min
-20 ºC, 12 h
Et
3.0 equiv
3a:3b (40%,1:1 ratio)
Scheme 2. Reaction of a racemic Zn/Cu enolate with a chiral N-tert-
butanesulfinimine.
Table 1
Screening and optimization of the reaction conditionsa
O
O
H
H
S
H
H
S
O
N
t
-Bu
O
N
t-Bu
ent-2
L
2
L
Ph
Ph
O
+
Et
Et
3a
ent-3b
{[α]D = +46º}
{[α]D = -115º}
O
S
O
S
Cu(OTf)2 cat.
+
Et2Zn
H
H
H
H
O
N
t-Bu
O
N
t-Bu
ent-2
ent-L
2
Ph
Ph
ent-L
Et
Et
3b
ent-3a
{[α]D = +122º}
{[α]D = -41º}
Entry
Ligand
Imine
Equiv of Et2Zn/enone
CuL2 (mol %)
Yieldb (product) (%)
drb
1
2
3
4
5
6
7
8
a
L
2
3.3:3
3.3:3
4:3
4:2
4:3
4:3
4:3
5:3
3.5
1.7
3.5
3.5
3.5
3.5
3.5
3.5
75 (3a)
42 (3a)
83 (3a)
66 (3a)
75 (ent-3a)
70 (3b)
70 (ent-3b)
75 (ent-3b)
>98:2
>98:2
>98:2
>98:2
>98:2
89:11
91:9
L
2
L
2
L
2
ent-L
ent-L
L
ent-2
2
ent-2
ent-2
L
>98:2
A mixture of Cu(OTf)2, ligand, enone and sulfinimine was stirred over 30 min at room temperature in CH2Cl2. The reaction mixture was cooled down
to ꢀ40 °C before Et2Zn was added and stirred overnight at ꢀ20 °C.
b
Determined by 1H NMR and chiral HPLC analysis of the crude reaction mixture.

J. C. Gonza´lez-Go´mez et al. / Tetrahedron Letters 49 (2008) 2343–2347
2345
a chloro-substituent in the aromatic ring of the sulfinimine
was well tolerated (entry 3). However, the reaction did not
proceed on using the t-BS imine obtained from p-methoxy-
benzaldehyde (entry 4). For aliphatic imines, the reactivity
was even better (entries 5–9). Compounds 3e–k were
obtained in enantiomerically pure form in excellent yields
on using only 1.5 equiv of the enone. Similar efficiency
and asymmetric induction were observed when Bu2Zn
was used (entry 9) and even with the less reactive Me2Zn
(entry 8). Importantly, the tert-butanesulfinyl group mini-
mizes the competitive a-deprotonation of the imines, allow-
ing the otherwise problematic use of enolisable imines. The
mild conditions were also compatible with an ester func-
tionality, providing access to the highly functionalized
compounds 3j (entry 10) and 3k (entry 11) in high yields
and with excellent stereocontrol.26
t
-Bu
O
S
M
N
O
S
MO
-Bu
O
N
t
M
3a
H
Et
H
Ph
Et
Ph
TS1
TS2
Fig. 1.
In order to assign the absolute configuration at the car-
bon bonded to the nitrogen, we assume that the reaction
could proceed through a six-membered chair-like transition
state, in a similar fashion to that proposed by Ellman (TS1,
Fig. 1).24 However, the fact that the reactivity is dependent
on both the load of copper and the amount of dialkylzinc
suggests that an acyclic transition state (TS2) could be
involved.25
In order to evaluate the scope of this reaction, we used
different t-BS imines, cyclic enones and dialkyl zinc
reagents (Table 2). Under the previously optimized condi-
tions, we observed that cycloheptenone behaved in a simi-
lar way to cyclohexenone (entries 1 and 2). The presence of
Following a recently reported procedure,27 piperidone 4
was obtained in good yield by acidic deprotection of com-
pound 3k and subsequent cyclization mediated by Et3N.
Crystals of 4 were obtained from Et2O, and X-ray crystal-
lography revealed the stereochemistry as shown in Scheme
3. This stereochemical outcome can be explained in terms
of the models proposed above for the addition of enolates
Table 2
Scopes and limitations
O
H
H
S
O
O
N
R
t-Bu
O
S
Cu(OTf)2 (3 mol %)
L (6 mol %)
R'
N
t-Bu
+
+
R2Zn
CH2Cl2
-20 ºC, 12 h
( )n
( )n
R'
Entry
Equiv of R2Zn/enone
R2Zn
R0
n
Yielda (%) (product)
1
2
3
4
5
6
7
8
9
4:3
4:3
4:3
4:3
3:1.5
3:1.5
3:1.5
3:1.5
3:1.5
3:1.5
3:1.5
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Me2Zn
Bu2Zn
Et2Zn
Et2Zn
Ph
Ph
1
2
1
1
1
2
1
1
1
1
2
65 (3a)
66 (3c)
68 (3d)
ndb
84 (3e)
95 (3f)
86 (3g)
86 (3h)
90 (3i)
82 (3j)
85 (3k)
p-ClC6H4
p-MeOC6H4
n-C8H17
n-C8H17
(CH2)2Ph
(CH2)2Ph
n-C8H17
10
11
a
(CH2)3CO2Me
(CH2)3CO2Me
Isolated yield after column chromatography. A single stereoisomer was observed by 1H NMR analysis of crude reaction mixtures.
Not determined.
b
O
S
O
H
H
H
H
N
t-Bu
N
O
O
CO2Me
1. HCl/MeOH, 25 ºC
2. Et3N, CH2Cl2, 25 ºC
Et
3k
Et
4 (65%)
Scheme 3. Synthesis and X-ray structure of 4.

2346
J. C. Gonza´lez-Go´mez et al. / Tetrahedron Letters 49 (2008) 2343–2347
13. (a) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron
Lett. 1996, 37, 5141; (b) Feringa, B. L.; Pineschi, M.; Arnold, L. A.;
Imbos, R.; de Vires, A. H. M. Angew. Chem., Int. Ed. 1997, 36, 2620.
For an example where the three stereogenic centres are controlled by a
chiral ligand see: (c) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2005, 44, 5306.
14. For an example of zinc enolate addition to chiral sulfinimines, see: (a)
Staas, D. D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R. G.
J. Org. Chem. 2002, 67, 8276. For a recent report on copper enolates
reacting with N-phosphinoyl imines, see: (b) Suto, Y.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 500.
to t-BS imines (Fig. 1). This situation is consistent with our
presumption that the stereocontrol at the Mannich stereo-
centre arises purely as a result of the asymmetric t-BS imine
induction. Interestingly, an intramolecular hydrogen bond
between the amidic NH and the carbonyl group is not
observed in compound 4.
In summary, we have extended the reactivity of homo-
chiral zinc/copper enolates to include trapping with chiral
t-BS imines. Three contiguous stereocentres and two
carbon–carbon bonds can be generated in a truly multi-
component reaction with excellent stereocontrol. We
observed that whereas the enantioselection at the cycle
stereocentres is governed by the phosphoramidite auxiliary,
in the case of the aminic a-C stereocentre the asymmetric
induction comes from the tert-butylsulfinyl moiety. More-
over, the present methodology allows access to four diaste-
reomeric b-amino ketones in enantiomerically pure form,
with good functional-group tolerance. The reaction can
be applied to a wide range of substrates and is especially
efficient when enolisable t-BS imines are used. Application
of this stereoselective multicomponent reaction to the
synthesis of diverse heterocyclic scaffolds can be easily
envisioned.
15. Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413.
16. N-tert-Butanesulfinylimines are readily prepared from aldehydes and
N-tert-butanesulfinamides (SS and RS are commercially available in
>99% ee), following the procedure reported in: Liu, G.; Cogan, D. A.;
Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278.
17. In the aziridination of sulfinimines, it was early recognized that the
substitution of the p-toluene motif with a tert-butyl group signifi-
cantly increased the stereoinduction: Garc´ıa Ruano, J. L.; Fernandez,
I.; Hamdouchi, C. Tetrahedron Lett. 1995, 36, 295.
18. A 1:1 mixture of diastereoisomers was observed by 1H NMR.
19. High kinetic resolution of racemic allenylzinc reagents took place with
enantiopure tert-butylsulfinimines. See for instance: (a) Chemla, F.;
Ferreira, F. Synlett 2004, 983; (b) Chemla, F.; Ferreira, F. J. Org.
´
Chem. 2004, 69, 8246; (c) Botuha, C.; Chemla, F.; Ferreira, F.; Perez-
Luna, A.; Roy, B. New J. Chem. 2007, 31, 1552.
20. For an example, where a chiral acetal overcomes the directing
induction of the chiral enolate in a tandem enantioselective conjugate
addition–aldol reaction, see: Alexakis, A.; Trevitt, G. P.; Bernar-
dinelli, G. J. Am. Chem. Soc. 2001, 123, 4358.
Acknowledgements
21. Copper-catalyzed addition of dialkylzinc reagents to activated aldi-
mines is well precedented. For selected examples, see: (a) Fujihara, H.;
Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055; (b)
Dahmen, S.; Brase, S. J. Am. Chem. Soc. 2002, 124, 5940; (c) Boezio,
A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 1692; (d) Boezio,
This work was generously supported by the Spanish
´
Ministerio de Educacion y Ciencia (MEC; Grant Nos.
CSD2007-00006, CTQ2004-01261 and Consolider Ingenio
2010). J.C.G.-G. thanks the Spanish MEC for a Juan de
la Cierva contract. We also thank Medalchemy S.L. for a
gift of enantiopure tert-butylsulfinamides (S and R).
´
A. A.; Pytkowicz, J.; Cote, A.; Charette, A. B. J. Am. Chem. Soc.
2003, 125, 14260.
22. Recent discussions of asymmetric multicomponent reactions: (a)
Marcaccini, S.; Torroba, T. In Multicomponent Reactions; Zhu, J.,
´
Bienayme, H., Eds.; Wiley-VCH: Wienheim, 2005; p 33; (b) Ramon,
D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (c) Guo, H.-C.;
References and notes
Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354; (d) Enders, D.; Huttl,
¨
M. R.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; (e) Do¨mling, A.
Chem. Rev. 2006, 106, 17; (f) Domino Reactions in Organic Synthesis;
Tietze, L. F., Brasche, G., Gericke, K., Eds.; Wiley-VCH: Weinheim,
2006.
1. Kleinman, E. F. In Comprehensive Organic Synthesis; Heathcock, C.
H., Ed.; Pergamon Press: Oxford, UK, 1991; Vol. 2, Chapter 4, p 893.
2. For a review, see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
3. For leading references, see: (a) Ishimaru, K.; Kojima, T. J. Org.
Chem. 2000, 65, 8395; (b) Davis, F. A.; Song, M.; Augustine, A. J.
Org. Chem. 2006, 71, 2779.
23. To the best of our knowledge, only few examples of multicomponent
reactions that include chiral sulfinimines have been recently reported:
(a) Kamimura, A.; Okawa, H.; Morisaki, Y.; Ishikawa, S.; Uno, H. J.
Org. Chem. 2007, 72, 3569; (b) Huang, H.; Guo, X.; Hu, W. Angew.
Chem., Int. Ed. 2007, 46, 1337.
24. Model proposed for the addition of a-substituted ester enolates to
tert-butyl sulfinimines: Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002,
67, 7819.
25. Similar transition-states were proposed for nucleophilic additions to
tert-butyl sulfinimines: (a) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org.
Lett. 2006, 8, 4979; (b) Ferreira, F.; Audouin, M.; Chemla, F. Chem.
Eur. J. 2005, 11, 5269–5278.
4. Davis, F. A.; Santhanaraman, M. J. Org. Chem. 2006, 71, 4222.
5. Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
6. (a) Shultz, A. G.; Dai, M. Tetrahedron Lett. 1999, 40, 645; (b) Chan,
C.; Zheng, S.; Zhou, B.; Guo, J.; Heid, R. M.; Wright, B. J. D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2006, 45, 1749.
7. Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398 and
references cited therein.
8. (a) Davis, F. A. J. Org. Chem. 2006, 71, 8993; (b) Zhou, P.; Chen,
B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
9. Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984.
26. Typical procedure for the enantioselective synthesis of amino ketones
3: Cu(OTf)2 (6 mg, 0.016 mmol), phosphoramidite
L (18 mg,
10. For a recent review, see: Morton, D.; Stockman, R. A. Tetrahedron
2006, 62, 8869.
0.032 mmol), enone (0.75 mmol) and the corresponding tert-butane-
sulfinimine (0.50 mmol) were suspended in CH2Cl2 (4.0 mL) and
stirred at room temperature for 20 min before cooling to ꢀ40 °C. A
solution of R2Zn (1.50 mL, 1.0 M in hexane, 3 equiv) was added
dropwise and the reaction mixture was allowed to reach ꢀ20 °C while
stirring overnight (12–14 h). The reaction was quenched at ꢀ20 °C by
adding a saturated solution of NH4Cl in 1:1 H2O/MeOH (1.50 mL)
and left stirring over 15 min at room temperature. The generated
11. For a review on the formation of C–C bonds from enones, see:
Plaquevent, J.-C.; Cahard, D.; Guillen, F. In Science of Synthesis;
Georg Thieme: Stuttgart, New York, 2005; Vol. 26 p 513.
12. For leading references, see: (a) De Vries, A. H. M.; Meetsma, A.;
Feringa, B. L. Angew. Chem., Int. Ed. 1996, 35, 2374; (b) Feringa, B.
L. Acc. Chem. Res. 2000, 33, 346; (c) Alexakis, A.; Benhaim, C. Eur.
J. Org. Chem. 2002, 3221.

J. C. Gonza´lez-Go´mez et al. / Tetrahedron Letters 49 (2008) 2343–2347
2347
precipitate was filtered through a short pad of Celite and after
evaporation of solvents, 1H NMR analysis of the crude sample was
performed to determine the sulfinimine conversion and diastereomeric
ratio of products. Purification by silica gel column chromatography,
using a gradient from 3:1 to 1:1 n-hexane/EtOAc, gave the analyti-
d 217.4, 61.7 (CH), 58.5 (CH), 56.1, 44.6 (CH2), 37.8 (CH), 32.7
(CH2), 31.9 (CH2), 31.4 (CH2), 29.6 (CH2), 29.3 (CH2), 29.2 (CH2),
27.0 (CH2), 26.9 (CH2), 26.8 (CH2), 25.4 (CH2), 22.9 (CH3), 22.8
(CH2), 14.2 (CH3), 10.4 (CH3); IR m (cmꢀ1) 3258 (br), 2965 (s), 2925
(s), 2851 (m), 1696 (s), 1455 (s), 1075 (s); MS (MALDI): m/z 408
(M+Na+). HRMS (MALDI) calcd for C22H43NNaO2S [M+Na]+
20
cally pure compound 3. Compound 3a: mp 122–125 °C; ½aꢁD ꢀ115 (c
20
1.9, CHCl3); Rf: 0.32 (1:1 n-hexane/EtOAc); HPLC analysis [HPLC
analyses were performed on a JASCO 200-series equipped with a
Chiralpak OD-H column] (0.7 mL/min, k = 210, 99:1 n-hexane/
408.2912, found 408.2923. Compound 3g: ½aꢁD ꢀ31 (c 3.0, CHCl3);
Rf: 0.20 (1:1 n-hexane/EtOAc); 1H NMR d 7.26 (m, 3H), 7.15 (m,
2H), 4.63 (d, J 10.6, 1H), 3.26 (t, J 11.2, 1H), 2.89 (m, 2H), 2.52 (m,
1H), 2.29 (m, 2H), 2.12 (m, 1H), 1.95 (m, 1H), 1.82 (m, 1H), 1.60 (m,
3H), 1.44 (t, J 11.5, 1H), 1.26 (s, 9H), 1.06 (m, 1H), 0.83 (t, J 7.3, 3H);
13C NMR d 214.4, 141.9, 128.7 (CH), 128.5 (CH), 126.0 (CH), 59.2
(CH), 56.2, 55.9 (CH), 42.6 (CH2), 41.9 (CH), 33.0 (CH2), 32.2 (CH2),
29.7 (CH2), 25.3 (CH2), 24.9 (CH2), 22.9 (CH3), 9.8 (CH3); IR m
(cmꢀ1) 3307 (br), 2957 (s), 2866 (m), 1696 (s), 1454 (s), 1067 (s); MS
(MALDI): m/z 386 (M+Na+). HRMS (MALDI) calcd for
C21H33NNaO2S [M+Na]+ 386.2130, found 386.2139. Compound
1
i-PrOH), tR = 31.8 min; H NMR d 7.30 (m, 5H), 5.10 (d, J 8.6, 1H),
4.63 (dd, J 8.6/5.9, 1H), 2.96 (dd, J 9.1/5.9, 1H), 2.30 (m, 1H), 1.90
(m, 2H), 1.70 (m, 2H), 1.40 (m, 1H), 1.16 (s, 9H), 0.93 (t, J 7.5, 3H);
13C NMR d 213.7, 139.9, 128.7 (CH), 128.4 (CH), 127.6 (CH), 60.7
(CH), 60.4 (CH), 56.0, 42.0 (CH2), 40.8 (CH), 28.0 (CH2), 25.8 (CH2),
23.5 (CH2), 22.7 (CH3), 10.5 (CH3); IR m (cmꢀ1) 3500–3200 (br), 2960
(m), 2918 (m), 1700 (s), 1454 (s), 1039 (s), 703 (s); MS (MALDI): m/z
358 (M+Na); HRMS (MALDI) calcd for C19H29NNaO2S [M+Na]+
20
20
358.1817, found 358.1811. Compound ent-3a: ½aꢁD +122.7 (c 1.1,
3h: ½aꢁD ꢀ27.7 (c 0.92, CHCl3); Rf: 0.19 (1:1 n-hexane/EtOAc); 1H
CHCl3); HPLC analysis (0.7 mL/min, k = 210, 99:1 n-hexane/i-
PrOH), tRmaj = 30.4 min; other physical and spectroscopic data were
found to be the same than for 3a. Compound ent-3b: mp 108–111 °C;
NMR d 7.26 (m, 3H), 7.17 (m, 2H), 4.64 (d, J 10.8, 1H), 3.28 (t, J
11.0, 1H), 2.90 (m, 1H), 2.80 (dd, J 11.7/3.9, 1H), 2.53 (m, 1H), 2.30
(m, 2H), 1.95 (m, 1H), 1.77 (m, 1H), 1.60 (m, 3H), 1.44 (m, 1H), 1.26
(s, 9H), 0.83 (d, J 6.4, 3H); 13C NMR d 213.9, 141.9, 128.7 (CH),
128.5 (CH), 126.0 (CH), 61.7 (CH), 56.3 (CH), 56.2, 42.6 (CH2), 36.6
(CH), 34.2 (CH2), 33.0 (CH2), 32.0 (CH2), 25.5 (CH2), 22.9 (CH3),
19.4 (CH3); IR m (cmꢀ1) 3301 (br), 2956 (s), 2867 (m), 1697 (s), 1455
(m), 1066 (s); MS (MALDI): m/z 372 (M+Na+). HRMS (MALDI)
calcd for C20H31NNaO2S [M+Na]+ 372.1973, found 372.1979.
20
½aꢁD +46.5 (c 1.0, CHCl3); Rf: 0.35 (1:1 n-hexane/EtOAc); HPLC
analysis (0.7 mL/min, k = 210, 99:1 n-hexane/i-PrOH), tRmaj = 26.9
min, tRmin = 31.2 min; 1H NMR d 7.30 (m, 5H), 4.68 (dd, J 7.0/5.0,
1H), 4.40 (d, J 5.0, 1H), 2.57 (t, J 7.0, 1H), 2.45 (m, 1H), 2.30 (m, 1H),
1.80–2.00 (m, 4H), 1.52 (m, 2H), 1.35 (m, 1H), 1.17 (s, 9H), 0.84 (t, J
7.4, 3H); 13C NMR d 215.0, 141.5, 128.5 (CH), 127.7 (CH), 127.6
(CH), 61.8 (CH), 58.1 (CH), 56.0, 41.1 (CH2), 40.3 (CH), 26.4 (CH2),
25.7 (CH2), 23.7 (CH2), 22.7 (CH3), 10.7 (CH3); IR m (cmꢀ1) 3301 (br),
2959 (s), 2872 (m), 1698 (s), 1455 (s), 1072 (s), 702 (s); MS (MALDI):
20
Compound 3i: ½aꢁD ꢀ33.0 (c 1.75, CHCl3); Rf: 0.35 (1:1 n-hexane/
EtOAc); 1H NMR d 4.50 (d, J 10.6, 1H), 3.27 (m, 1H), 2.89 (dd, J
11.7/4.0, 1H), 2.29 (m, 2H), 1.95 (m, 2H), 1.70 (m, 2H), 1.60–1.25 (m,
20H), 1.20 (s, 9H), 0.92 (t, J 6.7, 3H), 0.88 (t, J 7.0, 3H); 13C NMR d
59.9 (CH), 57.0 (CH), 56.2, 42.7 (CH2), 40.9 (CH), 32.4 (CH2), 32.0
(CH2), 30.3 (CH2), 29.9 (CH2), 29.7 (CH2), 29.4 (CH2), 29.2 (CH2),
28.0 (CH2), 27.0 (CH2), 25.4 (CH2), 23.0 (CH2), 22.9 (CH3), 22.8
(CH2), 14.2 (CH3), 14.1 (CH3); IR m (cmꢀ1) 3307 (br), 2955 (s), 2926
(s), 2856 (m), 1698 (s), 1456 (m), 1071 (s); MS (MALDI): m/z
422 (M+Na+), 400.4 (M+H). HRMS (MALDI) calcd for
C23H45NNaO2S [M+Na]+ 422.3069, found 422.3079. Compound 3j:
20
m/z 358 (M+Na). Compound 3b: ½aꢁD ꢀ41.0 (c 1.1, CHCl3); HPLC
analysis (0.7 mL/min, k = 210, 99:1 n-hexane/i-PrOH), tRmaj = 26.1
min, tRmin = 21.8 min; other physical and spectroscopic data were
20
found to be the same than for ent-3b. Compound 3c: ½aꢁD ꢀ97 (c 2.6,
CHCl3); Rf: 0.30 (1:1 n-hexane/EtOAc); 1H NMR d 7.30 (m, 3H), 7.20
(m, 2H), 4.82 (t, J 4.6, 1H), 4.61 (d, J 4.2, 1H), 2.68 (dd, J 9.5/4.6,
1H), 2.04 (m, 1H), 1.80–1.30 (m, 8H), 1.23 (s, 9H), 1.16 (m, 2H), 0.96
(t, J 7.3, 3H); 13C NMR d 216.2, 138.8, 128.7 (CH), 128.3 (CH), 128.0
(CH), 64.4 (CH), 57.9 (CH), 55.9, 44.0 (CH2), 37.3 (CH), 32.5 (CH2),
28.3 (CH2), 26.7 (CH2), 26.6 (CH2), 22.8 (CH3), 10.4 (CH3); IR m
(cmꢀ1) 3302 (br), 2958 (s), 2925 (s), 2866 (m), 1695 (s), 1450 (s), 1075
(s); MS (MALDI): m/z 372.4 (M+Na). HRMS (MALDI) calcd for
C20H31NNaO2S [M+Na]+ 372.1973, found 372.1979. Compound 3d:
20
½aꢁD ꢀ56 (c 2.7, CHCl3); Rf: 0.22 (1:1 n-hexane/EtOAc); 1H NMR d
4.54 (d, J 10.7, 1H), 3.67 (s, 3H), 3.27 (m, 1H), 2.94 (dd, J 11.7/4.0,
1H), 2.30 (m, 4H), 2.10–1.30 (m, 11H), 1.20 (s, 9H), 0.97 (t, J 7.3, 3H);
13C NMR d 214.4, 174.0, 59.1 (CH), 56.2, 51.6 (CH), 42.7 (CH2), 41.9
(CH3), 33.6 (CH2), 29.7 (CH2), 29.3 (CH2), 25.3 (CH2), 25.1 (CH2),
22.9 (CH3), 9.8 (CH3); IR m (cmꢀ1) 3299 (br), 2951 (s), 2866 (m), 1732
(s), 1696 (s), 1449 (s), 1362 (m), 1161 (m), 1061 (s), 881 (m); MS
(MALDI): m/z 382.4 (M+Na+), 360.5 (M+H). HRMS (MALDI)
calcd for C18H33NNaO4S [M+Na]+ 382.2028, found 382.2035.
20
mp 119–122 °C; ½aꢁD ꢀ137.2 (c 1.1, CHCl3); Rf: 0.22 (1:1 n-hexane/
EtOAc); 1H NMR d 7.25 (m, 4H), 5.13 (d, J 8.8, 1H), 4.59 (dd, J 5.7/
8.8, 1H), 2.98 (dd, J 3.8/9.5, 1H), 2.30 (m, 2H), 1.90 (m, 2H), 1.70–
1.40 (m, 4H), 1.16 (s, 9H), 0.94 (t, J 7.3, 3H); 13C NMR d 213.6, 138.4,
133.4, 130.1 (CH), 128.6 (CH), 60.4 (CH), 59.8 (CH), 56.0, 42.2
(CH2), 40.9 (CH), 28.3 (CH2), 25.7 (CH2), 23.7 (CH2), 22.7 (CH3),
10.4 (CH3); IR m (cmꢀ1) 3292 (br), 2959 (s), 2851 (m), 1696 (s), 1488
(s), 1450 (m), 1055 (s), 1008 (m); MS (MALDI): m/z 392.3 (M+Na).
HRMS (MALDI) calcd for C19H28ClNNaO2S [M+Na]+ 392.1427,
20
Compound 3k: ½aꢁD ꢀ52.5 (c 3.5, CHCl3); Rf: 0.30 (1:1 n-hexane/
EtOAc); 1H NMR d 4.24 (d, J 9.8, 1H), 3.67 (s, 3H), 3.31 (m, 1H),
2.97 (dd, J 7.7/4.0, 1H), 2.45 (m, 2H), 2.32 (t, J 6.9, 2H), 1.80–1.40 (m,
13H), 1.22 (s, 9H), 0.97 (t, J 7.1, 3H); 13C NMR d 214.4, 174.0, 59.1
(CH), 56.2, 51.6 (CH), 42.7 (CH2), 41.9 (CH3), 33.6 (CH2), 29.7
(CH2), 29.3 (CH2), 25.3 (CH2), 25.1 (CH2), 22.9 (CH3), 9.8 (CH3); IR
m (cmꢀ1) 3299 (br), 2951 (s), 2866 (m), 1732 (s), 1696 (s), 1449 (s), 1362
(m), 1161 (m), 1061 (s), 881 (m); MS (ES): MS (MALDI): m/z
396 (M+Na+), 374.3 (M+H). HRMS (MALDI) calcd for
C19H35NNaO4S [M+Na]+ 396.2184, found 396.2195. Compound 4:
20
found 392.1417. Compound 3e: ½aꢁD ꢀ51 (c 1.0, CHCl3); Rf: 0.25 (1:1
n-hexane/EtOAc); 1H NMR d 4.51 (d, J 10.7, 1H), 3.25 (t, J 10.8, 1H),
2.92 (dd, J 4.0/11.6, 1H), 2.31 (m, 2H), 2.05 (m, 1H), 1.88 (m, 1H),
1.70 (m, 2H), 1.55 (m, 3H), 1.26 (m, 15), 1.20 (s, 9H), 0.97 (t, J 7.3,
3H), 0.88 (t, J 6.8, 3H); 13C NMR d 214.4, 59.3 (CH), 57.0 (CH), 56.2,
42.7 (CH2), 41.9 (CH), 31.9 (CH2), 30.0 (CH2), 29.7 (CH2), 29.6
(CH2), 29.4 (CH2), 29.3 (CH2), 27.0 (CH2), 25.3 (CH2), 22.9 (CH3),
22.8 (CH2), 14.2 (CH3), 9.9 (CH3); IR m (cmꢀ1) 3418 (br), 2925 (s),
2854 (m), 1696 (s), 1463 (s), 1455 (m), 1070 (s); MS (MALDI): m/z
394 (M+Na+). HRMS (MALDI) calcd for C21H41NNaO2S [M+Na]+
20
1
mp (Et2O): 100–101 °C; ½aꢁD ꢀ57 (c 0.9, CHCl3); H NMR d 6.15 (s,
1H), 3.93 (m, 1H), 2.45 (m, 4H), 2.25 (m, 1H), 1.90 (m, 1H), 1.80–1.40
(m, 11H), 1.30 (t, J 13.0, 1H), 0.95 (t, J 7.3, 3H); 13C NMR d 213.9,
172.6, 61.0 (CH), 53.1 (CH), 43.4 (CH2), 33.6 (CH), 31.6 (CH2), 28.8
(CH2), 28.0 (CH2), 26.5 (CH2), 24.7 (CH2), 23.2 (CH2), 20.2 (CH2),
11.9 (CH3); IR m (cmꢀ1) 3389 (br), 2929 (s), 2888 (m), 1698 (s), 1649
(s), 1462 (s), 1348 (m), 1175 (m); MS (EI): m/z 237 (M+); HRMS (EI)
calcd for C14H23NO2 [M]+: 237.1729, found 237.1719.
20
394.2756, found 394.2761. Compound 3f: ½aꢁD ꢀ39 (c 1.2, CHCl3); Rf:
0.40 (1:1 n-hexane/EtOAc); 1H NMR d 4.26 (d, J 9.3, 1H), 3.33 (m,
1H), 2.91 (dd, J 8.4/4.0, 1H), 2.48 (m, 2H), 1.80–1.40 (m, 12H), 1.30
(m, 11H), 1.22 (s, 9H), 0.96 (t, J 7.5, 3H), 0.88 (t, J 6.6, 3H); 13C NMR
27. Voituriez, A.; Ferreira, F.; Chemla, F. J. Org. Chem. 2007, 72, 5358.