A tandem isomerization-Mannich reaction for the enantioselective synthesis of β-amino ketones and β-amino alcohols with applications as key intermediates for ent-nikkomycins and ent-funebrine

Article abstract of DOI:10.1002/ejoc.201100352

β-Amino ketones, with a primary amino group, are easily obtained in good yields and excellent enantioselectivities through a short sequence that involves, as a key step, a tandem isomerization-Mannich reaction from allylic alcohols with N-tert-butanesulfi

Full text of DOI:10.1002/ejoc.201100352

FULL PAPER
DOI: 10.1002/ejoc.201100352
A Tandem Isomerization–Mannich Reaction for the Enantioselective Synthesis
of β-Amino Ketones and β-Amino Alcohols with Applications as Key
Intermediates for ent-Nikkomycins and ent-Funebrine
Hai Thuong Cao,[a,b] Thierry Roisnel,[a] Alain Valleix,[c] and René Grée*[a,b]
Dedicated to Dr. Jhillu Singh Yadav on the occasion of his 60th birthday
Keywords: Natural products / Mannich reaction / Amino ketones / Amino alcohols / Allylic compounds
β-Amino ketones, with a primary amino group, are easily ob- with N-tert-butanesulfinimines. This method was used for
tained in good yields and excellent enantioselectivities
through a short sequence that involves, as a key step, a tan-
dem isomerization–Mannich reaction from allylic alcohols
the enantioselective synthesis of corresponding β-amino
alcohols and also for key intermediates in the preparation of
ent-nikkomycins or ent-funebrine.
philes and various catalytic systems.[7] Therefore, the next
logical step was the extension of this tandem process to
asymmetric synthesis and N-tert-butanesulfinyl imines ap-
peared to be the best choice for this goal.[8] These highly
versatile synthetic intermediates are easily accessible in an
optically pure form[9] and, further, the chiral auxiliary can
be recovered and recycled.[10]
Therefore the purpose of this publication is (1) to dem-
onstrate that a nickel-mediated tandem isomerization–
Mannich reaction from allylic alcohols with these N-tert-
butanesulfinyl imines is highly efficient, affording both the
N-protected and the free β-amino ketones with excellent
yields and enantioselectivities; (2) to establish that further
reductions allow the preparation of various β-amino
alcohols, again in very high yields and enantioselectivities;
and (3) to apply this strategy for the enantioselective syn-
thesis of lactones ent-15 and ent-16, which are key interme-
diates for the preparation of ent-nikkomycins and ent-fune-
brine, as well as their analogues.
Introduction
β-Amino ketones and β-amino alcohols are important
key intermediates for the preparation of various types of
nitrogen-containing heterocyclic compounds, as well as for
the total synthesis of many bioactive molecules.[1] However,
for the preparation of β-amino ketones with a primary
amino group, there are only few methods available.[2]
Furthermore, to the best of our knowledge, there is only
one reported procedure to obtain such derivatives in op-
tically active form; however, it involves a multistep sequence
that affords low yields of the desired compounds.[3]
Several years ago we reported a new transition-metal-
catalyzed tandem isomerization–aldolisation reaction start-
ing from allylic alcohols,[4] as well as from lactols for the
intramolecular process.[5] Extensive computational studies,
combined with experimental data, indicated that the mecha-
nism of this reaction was very likely to involve, in the first
step, a transition-metal-catalyzed isomerization of allylic
alcohols to free enols, followed by addition onto aldehydes
in an “hydroxy–carbonyl–ene”-type reaction.[6] This process
was successfully extended to some tandem isomerization–
Mannich reactions by using N-protected imines as electro-
Results and Discussion
The easily available imine 1 was selected, in the racemic
form,[11] for model studies with allylic alcohol 2a. On reac-
[a] Laboratoire Sciences Chimiques de Rennes, CNRS UMR 6226, tion with [Fe(CO)5] (10 mol-%) under UV irradiation, the
Université de Rennes 1,
N-protected β-amino ketones syn-3a and anti-4a were ob-
Avenue du Général Leclerc, 35042 Rennes Cedex, France
tained in 53% overall yield with a 52:48 syn/anti ratio, to-
gether with a large amount of octane-3-one, which was the
classical isomerization product of 2a.
However, a clear improvement was observed by using our
previously described catalytic system [NiHCl(dppe)]/MgBr2
[dppe = 1,2-bis(diphenylphosphanyl)ethane]:[4e] a very clean
reaction was obtained to afford syn-3a and anti-4a in 95%
Fax: +33-2-23236978
E-mail: rene.gree@univ-rennes1.fr
[b] Laboratoire Chimie et Photonique Moléculaires, CNRS UMR
6510, Université de Rennes 1,
Avenue du Général Leclerc, 35042 Rennes Cedex, France
[c] Eurisotope, CEN Saclay,
91191 Gif-sur-Yvette, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100352.
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Enantioselective Synthesis of β-Amino Ketones and Alcohols
overall yield and a ratio of 68:32. These diastereoisomers c also have the same very high ee values. This was con-
were easily separated by silica gel chromatography. There- firmed by chiral HPLC analyses performed on correspond-
fore, these more efficient conditions, which avoid the need ing β-amino ketones 5a, 5b, and 6a–c, giving again excellent
for UV irradiation, were used to extend the use of this reac- ee values (Ն99%).[13]
tion to other allylic alcohols 2b–2e. In all cases, the tandem
To propose a rationale for this high stereocontrol by the
reactions proved to be very efficient and afforded the de- sulfinimine moiety, several factors have to be considered.
sired compounds in high yields and low to moderate selec- The first point to notice is the role of the magnesium cocat-
tivities, except in the case of 2c for which anti-4c was ob- alyst: when the reaction of 1 and 2a was performed with
tained as a single diastereoisomer (Scheme 1 and Table 1).
[NiHCl(dppe)] only, the reaction became slower and the
yield was much lower (42% instead of 95%). Based on our
previous studies,[4] and literature data on additions to N-
tert-butanesulfinyl imine derivatives,[8,14,15,16] we can postu-
late the transition states indicated in Scheme 2. Coordina-
tion of nitrogen and oxygen from sulfinylimine by the mag-
nesium[17,18] induces a rigid system in which the nucleophile
reacts exclusively from the Re face of the (Ss) sulfinylimine
remote from the bulky tBu group.[19] On the other hand,
coordination of the enol oxygen to magnesium allows clas-
sical Zimmermann–Traxler transition states to afford Man-
nich adducts. The syn/anti ratio is controlled by a number
of factors, including the ratio of E and Z enols formed dur-
ing nickel-mediated isomerization and their relative reactiv-
ity in Mannich processes. Further experimental and compu-
tational studies are required to rationalize the correspond-
ing results in detail, however, it is worth noting that, in the
case of the very bulky R substituent (2c), the reaction af-
fords exclusively the anti isomer, which is in agreement with
a reaction occurring only through the Z enol, due to strong
R–RЈ steric interactions in the corresponding E isomer.[20]
Scheme 1. Synthesis of β-amino ketones 3–6 by the tandem isomer-
ization–Mannich reaction. Reagents and conditions: (i) 1 (1 equiv.),
2 (2 equiv.), [NiHCl(dppe)]/MgBr2 (10 mol-%), THF –50 °C to
room temp. (except for 2e, –50 to 40 °C), 12 h, for yields and
syn/anti selectivity see Table 1; (ii) 1 n aq. HCl, dioxane, room
temp., 12 h, for yields see Table 1.
Table 1. Yields and selectivities for the tandem isomerization–Man-
nich reaction, starting from allylic alcohols 2a–2e (step 1), and for
the preparation of β-amino ketones 5a–e and 6a–e (step 2).
Step 1[a]
Step 2[b]
syn (% yield) anti (% yield)
Alcohol % Yield[c]
Ratio 3/4
2a
2b
2c
2d
2e
95
92
82
80
52
68:32
80:20
Յ 3: Ն97
62:38
5a (98)
5b (90)
6a (97)
6b (92)
6c (84)
6d (97)
6e (97)
5d (98)
5e (98)
55:45
[a] Step 1 is the isomerization–Mannich reaction. [b] Step 2 is the
deprotection of the amino group. [c] Overall yield.
Scheme 2. Proposal for the transition states of the Mannich reac-
tions.
The next step was the deprotection of the amino group.
It was performed under mild acidic reaction conditions, af-
The next step was the use of these β-amino ketones
fording efficiently the desired β-amino ketones syn-5 and towards the preparation of optically active β-amino
anti-6 with a free amino group. Therefore, these derivatives alcohols. The reduction of ketones 3 and 4 was performed
were obtained in two steps only and in good to excellent first with NaBH4 to afford, in excellent yields, the corre-
overall yields from readily available starting materials.[12]
sponding β-amino alcohols. Except for 3e and 4e, the
Careful analysis by NMR spectroscopy on the crude re- stereoselectivity was very low and mixtures (close to 1:1) of
action mixtures demonstrated that all of these tandem reac- the two stereoisomers 7 and 8 or 11 and 12 were obtained
tions afforded exclusively the β-amino ketones 3 and/or 4, (Scheme 3 and Table 2). These compounds could be easily
establishing full stereochemical control by the chiral sulfin- separated by chromatography and their stereochemistry was
imine moiety. Therefore, extension to asymmetric synthesis deduced from NMR spectroscopic data. Furthermore, the
appeared to be very attractive and we performed the same spectroscopic data of 9a, 10a, 13a, and 14a were fully con-
reactions starting from imine 1, derived from (S)-sulfon- sistent with literature.[7d] On the other hand, X-ray analyses
amide, and using three representative models 2a–2c.
have been performed on four derivatives: 12a, 11c, 7d, and
Chiral HPLC analyses of β-amino alcohols 9a, 9b, 10a, 11d (see Figure 1 and the Supporting Information).[21]
10b, 13a–c, and 14a–c, obtained by the reduction of 3a–b These structures not only confirmed previous assignments
and 4a–c, as described in next part (Scheme 3), gave enan- but also establish unambiguously that the stereochemistry
tiomeric excess (ee) values Ն99% for all of these com- at the sulfinamine level was consistent with the transition
pounds and established that the precursors 3a, 3b, and 4a– states proposed in Scheme 2 for the tandem process.
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H. T. Cao, T. Roisnel, A. Valleix, R. Grée
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gen was performed under the same mild acidic conditions
as those previously used, affording all β-amino alcohols 9–
10 and 13–14 in excellent yields (Table 2).
Finally, as far as the asymmetric synthesis was con-
cerned, chiral HPLC analyses established ee values Ն99%
for β-amino alcohols 9a, 9b, 10a, 10b, 13a–c, and 14a–c.
Therefore, this strategy appears to be an efficient route also
for the enantioselective synthesis of such β-amino alcohols.
The stage was set for the application of these reactions
to the preparation of some natural product type derivatives
and we selected two α-amino lactones as targets. The first
was the enantiomer of lactone 15, which was a known key
intermediate in the synthesis of nikkomycins; a family of
antibiotics and antifungal compounds.[22] The second was
Scheme 3. Synthesis of β-amino alcohols 7–14. Reagents and con-
ditions: (i) NaBH4 (1.5 equiv.), MeOH, room temp., 3 h or l-se-
lectride (1.5 equiv.) –78 °C, THF, 3 h, yields and selectivities see
Table 2; (ii) aq. HCl 1 n, dioxane, room temp., 12 h, yields see the enantiomer of lactone 16, which was the key component
Table 2.
of funebrine; a compound from traditional medicine in
Central America (Scheme 4).[23]
Table 2. Yields and selectivities for the reduction of β-amino
ketones 3a–e, 4a–e (step 1) and for the deprotection step to β-amino
alcohols 9a–e and 10a–e, 13e, and 14a–d (step 2).
Step 1
Step 2
β-Amino alcohol
(% yield)
Ketone
NaBH4
l-Selectride
(% yield)
syn/anti
(% yield)
syn/anti
3a
4a
3b
4b
4c
3d
4d
3e
4e
(95) 55:45
(94) 52:48
(100) 54:46
(100) 48:52
(95) 45:55
(97) 60:40
(97) 45:55
(98) 95:5
(92) 30:70
(92) 83:17
9a (100)
13a (95)
9b (98)
13b (100)
13c (98)
9d (98)
13d (95)
9e (98)
10a (97)
14a (98)
10b (97)
14b (97)
14c (98)
10d (97)
14d (96)
10e (97)
(87) Յ3:Ն97
(92) Յ3:Ն97
(90) Յ3:Ն97
(93) Յ3:Ն97
(91) Յ3:Ն97
(89) 25:75
Scheme 4. Nikkomycins, funebrine, and their α-amino lactones as
key components.
(97) Յ3:Ն97 (97) Յ3:Ն97
13e (96)
The condensation of easily available (S)-imine 17 with
allylic alcohol 18, under the previously described nickel-cat-
alyzed conditions, afforded, in 96% yield, a mixture of the
β-amino ketones 19 and 20 that were separated by
chromatography. The selectivity was also very good (9:1) in
favor of the desired isomer syn-19. Reduction of the latter
gave the two lactones 21 and 22 in 91% overall yield in a
ratio of 2:1; these lactones were easily separated by
chromatography. Deprotection of 21, under acidic condi-
tions as previously described, afforded the desired
(2R,3S,4R) aminolactone ent-15. The spectroscopic data of
this compound were in agreement with the literature[22] and,
further, the optical purity was excellent (ee Ն99% by chiral
HPLC analyses). Therefore, this compound was obtained
easily in only 3 steps and 54% overall yield from 17
(Scheme 5).
[a] Step 1 is the reduction of β-amino ketones. [b] Step 2 is the
deprotection of amino group.
The optically active 4S diastereoisomer 23 was obtained
in the same way from 22, with a similar excellent ee value
(Ն99%). Furthermore, this lactone could be epimerized to
ent-15 by following literature procedures.[22e] Since ent-15 is
the enantiomer of the intermediate classically employed for
the synthesis of nikkomycins,[22] it could be of use for the
preparation of ent-nikkomycins and/or diastereoisomers of
Figure 1. The molecular structures of β-amino alcohols 12a, 11c,
7d, and 11d.
Other reducing agents can be used and l-selectride was these antibiotics.
found to be more efficient, affording high to complete
The second application was dealing with lactone ent-16.
stereocontrol in this step. Then, the deprotection of nitro- This synthesis started from the same (S)-sulfinyl imine 17,
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Enantioselective Synthesis of β-Amino Ketones and Alcohols
enantioselectivities, including those compounds containing
primary amines. This methodology relied on easily available
starting materials and used a cheap and efficient catalytic
system. There was full control of the facial selectivity by
the sulfinylamine moiety and this could be rationalized by
coordination of the magnesium salt in the postulated transi-
tion state of this reaction, with addition on the face anti
to the bulky tBu group. Finally, it was used for short and
enantiocontrolled preparations of α-aminolactones involved
in the synthesis of nikkomycins and funebrine derivatives.
Scheme 5. Synthesis of lactone ent-15. Reagents and conditions: (i)
17 (1 equiv.), 18 (2 equiv.), [NiHCl(dppe)]/MgBr2 (10 mol-%), THF
–50 °C to room temp., 12 h, 19 (87% yield) and 20 (9% yield); (ii)
NaBH4 (1.5 equiv.), benzyl bromide (BnBr; 4 equiv.), THF, r.t. (2 h)
21 (61% yield), 22 (30% yield); (iii) aq. HCl 1 n dioxane, room
temp., 12 h, ent-15 (98% yield), 23 (87% yield); (iv) BBr3 (1 equiv.),
Experimental Section
Tandem Isomerization–Mannich Using [NiHCl(dppe)/MgBr2] as the
Catalyst. Synthesis of 3a and 4a as Representative Examples: A 1 m
solution of LiBHEt3 in THF (120 μL, 0.12 mmol) was added, un-
der nitrogen at room temperature, to a solution of [NiCl2(dppe)]
(64 mg, 0.12 mmol) in anhydrous THF (6 mL). The reaction mix-
ture was stirred for 5 min at room temperature before being trans-
ferred with a cannula into a flask containing anhydrous MgBr2
(22 mg, 0.12 mmol). The reaction mixture (as a suspension) was
stirred for 5 min at room temperature before being cooled to
–50 °C. Then, a solution of sulfinyl imine 1 (125 mg, 0.6 mmol) in
THF (1 mL) and a solution of allylic alcohol 2a (185 μL, 1.2 mmol,
2 equiv.) in THF (1 mL) were added sequentially. The reaction mix-
ture was allowed to warm to room temperature and kept under
magnetic stirring until the starting material disappeared (TLC
monitoring, usually 24 h). After addition of water (5 mL), the reac-
tion mixture was extracted with EtOAc (3ϫ5 mL). The organic
extracts were combined, dried (Na2SO4), and concentrated under
vacuum. The crude product was purified by chromatography on
SiO2 by using a 1:1 mixture of n-pentane and EtOAc as the eluent.
The two diastereoisomers 3a and 4a were isolated as colorless solids
in 95% overall yield (192 mg).
CH2Cl2, –78 °C (53% yield), see ref.[22e]
.
which was condensed with the allylic alcohol 24 to afford,
in excellent yield, a 3:1 mixture of adducts 25 and 26 that
were separated by silica gel chromatography (Scheme 6).
Isomer syn-3a: 130 mg; m.p. 112–114 °C. Rf = 0.26. 1H NMR
(300 MHz, CDCl3): δ = 7.32–7.21 (m, 5H, HAr), 4.60 (dd, J = 2.6,
J = 5.2 Hz, 1 H, CHC6H5), 4.36 (d, J = 2.1 Hz, 1 H, NH), 2.89
(dq, J = 5.2, J = 7.1 Hz, 1 H, CHCH3), 2.38–2.20 (m, 2H, CH2CO),
1.42 (qt, J = 7.5 Hz, 2H, CH2CH2CO), 1.26–1.07 [m, 16H, (CH3)
3SO, CH3CH, (CH2)2CH3], 0.81 (t, J = 7.1 Hz, 3H, CH2CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 11.7, 13.9, 22.4, 22.6, 22.9, 31.2,
42.9, 51.7, 55.7, 58.7, 127.8, 128.1, 128.4, 139.5, 214.0 ppm.
HRMS: calcd. for C7H7NOS [M – C12H24O]+ 153.02484; found
153.0247. C19H31NO2S: calcd. C 67.61, H 9.26, N 4.15, S 9.50;
found C 67.79, H 9.37, N 4.08, S 9.67. [α]1D8 = +64.6 (c = 0.013,
CHCl3).
Scheme 6. Synthesis of lactones ent-16 and 29. Reagents and condi-
tions: (i) 17 (1 equiv.), 24 (2 equiv.), [NiHCl(dppe)]/MgBr2 (10 mol-
%), THF –50 to 0 °C, 12 h, 25 (74% yield) and 26 (24% yield); (ii)
NaBH4 (1.5 equiv.), BnBr (4 equiv.), THF, room temp., 2 h, 27
(50% yield), 28 (40% yield); (iii) 1 n aq. HCl dioxane, room temp.,
12 h, ent-16 (98% yield), 29 (98% yield).
Reduction of major isomer 25, under the same condi-
tions as those described previously, afforded a 55:45 mix-
ture of lactones 27 and 28, which were separated by HPLC.
Chiral HPLC analysis established that both compounds
had ee values Ն99%. After deprotection of the amino
groups, lactones ent-16 and 29 were obtained in excellent
yields as hydrochlorides. Lactone ent-16 is the enantiomer
of the intermediate commonly used in the synthesis of fune-
brine.[23] On the other hand, it is interesting to note that
minor diastereoisomer 26 has the appropriate skeleton and
the anti stereochemistry required for the synthesis of some
4-hydroxyisoleucine derivatives; another family of bioactive
natural products.[24]
Isomer anti-4a: 62 mg; m.p. 116–118 °C. Rf = 0.32. 1H NMR
(300 MHz, CDCl3): δ = 7.32–7.23 (m, 5H, HAr), 4.63 (d, J =
4.2 Hz, 1 H, NH), 4.47 (dd, J = 4.2, J = 6.8 Hz, 1 H, CHC6H5),
2.97 (qt, J = 7.1 Hz, 1 H, CHCH3), 2.37 (dt, J = 7.3, J = 17.1 Hz,
1 H, CH2CO), 2.16 (dt, J = 7.3, J = 17.1 Hz, CH2CO), 1.44 (qt, J =
7.2 Hz, 2H, CH2CH2CO), 1.27–1.08 [m, 16H, (CH3)3SO, CH3CH,
(CH2)2CH3], 0.83 (t, J = 7.1 Hz, 3H, CH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.9, 15.4, 22.4, 22.7, 23.0, 31.2, 42.7, 52.2,
55.6, 61.5, 127.6, 127.7, 128.5, 140.5, 215.0 ppm. HRMS: calcd. for
C7H7NOS [M
–
C12H24O]+ 153.02484; found 153.0248.
C19H31NO2S: calcd. C 67.61, H 9.26, N 4.15, S 9.50; found C 67.91,
Conclusions
H 9.46, N 4.10, S 9.17. [α]1D8 = +66.0 (c = 0.01, CHCl3).
This tandem isomerization–Mannich reaction using N-
tert-butanesulfinyl imines allowed a short and easy synthe-
Amino Group Deprotection Using HCl in Dioxane. Synthesis of 5a
as a Representative Example: A 1 m solution of HCl (2 mL,
sis of β-amino ketones and β-amino alcohols with very high 0.2 mmol) was added to a solution of 3a (56 mg, 0.16 mmol) in 1,4-
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H. T. Cao, T. Roisnel, A. Valleix, R. Grée
FULL PAPER
dioxane (2 mL) . The reaction mixture was stirred overnight at
room temperature and then extracted with pentane (3ϫ5 mL) to
remove byproducts. After addition of a saturated aqueous solution
of NaHCO3 (up to pH = 8), the reaction mixture was extracted
7.1 Hz, 1 H, CHCH3), 1.69–1.31 [m, 8 H, (CH2)4CH3), 1.28 [s, 9
H, (CH3)3SO], 0.89 [t, J = 6.6 Hz, 3 H, (CH2)4CH3], 0.81 (d, J =
7.1 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.2,
14.1, 22.6, 22.7, 25.7, 31.9, 34.9, 44.8, 55.7, 58.6, 74.3, 126.8, 127.2,
with EtOAc (3ϫ5 mL). The organic extracts were combined, dried 128.1, 142.0 ppm. HRMS: calcd. for C19H33NO2NaS [M + Na]+
(Na2SO4), and concentrated under vacuum to afford pure β-amino
ketone 5a as a colorless oil (36.5 mg, 98%). H NMR (300 MHz,
362.21297; found 362.2132. C19H33NO2S: calcd. C 67.21, H 9.80,
1
N 4.13, S 9.44; found C 67.34, H 9.79, N 4.03, S 9.13. [α]1D8 = +97.5
CDCl3): δ = 7.27–7.17 (m, 5H, HAr), 4.16 (d, J = 6.7 Hz, 1 H, (c = 0.0011, CHCl3).
CHC6H5), 2.78 (qt, J = 6.9 Hz, 1 H, CHCH3), 2.25 (td, J = 7.5, J
Synthesis of ent-Nikkomycin Precursor
= 17.1 Hz, 1 H, CH2CO), 2.06 (td, J = 7.5, J = 17.1 Hz, 1 H,
CH2CO), 1.34 (qt, J = 7.0 Hz, 2 H, CH2CH2CO), 1.24–1.01 [m,
7H, CH3CH, (CH2)2CH3], 0.79 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 12.1, 13.9, 22.4, 23.0, 31.2, 42.6,
53.8, 57.1, 126.7, 127.2, 127.6, 128.4, 128.5, 144.1, 214.0 ppm.
HRMS: calcd. for C14H20NO [M – CH3]+ 218.15449; found
218.1538. [α]1D9 = –66.7 (c = 0.0055, CHCl3). Chiral HPLC: column,
CHIRALPAK AD 250*4.6, eluent hexane/EtOH, 90:10,
1.2 mLminϪ1, retention times for (Ϯ)-5a: 7.2 and 8.5 min. 5a: re-
tention time 7.2 min, ee Ն 99%.
Step 1. Synthesis of 19 and 20: Same procedure as that used for 3a/
4a: [NiCl2(dppe)] (480 mg, 0.91 mmol) in THF (15 mL); 1 m solu-
tion of LiBHEt3 in THF (910 μL, 0.91 mmol); MgBr2 (170 mg,
0.0.91 mmol); sulfinyl imine 17 (930 mg, 4.54 mmol) in THF
(3 mL) and a solution of allylic alcohol 18 (1.49 g, 9.1 mmol) in
THF (5 mL). The two diastereoisomers 19 and 20 were isolated as
colorless solids in 96% yield (1.72 g).
Isomer syn-19: 1.55 g; m.p. 120–122 °C. Rf = 0.30. 1H NMR
(300 MHz, CDCl3): δ = 7.94 (d, J = 8.9 Hz, 2 H, HAr), 6.93 (d, J
= 8.9 Hz, 2 H, HAr), 4.34–3.95 (m, 5 H, NH, CHNH, CHCH3,
CH2CH3), 3.86 (s, 3 H, OCH3), 1.35 (d, J = 7.2 Hz, 3 H, CHCH3),
1.21 [s, 9 H, C(CH3)3], 1.19 (t, J = 6.9 Hz, 3 H, CH2CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 13.9, 14.8, 22.3, 43.2, 55.4, 56.5,
60.3, 61.4 113.9, 128.4, 130.7, 163.7, 171.4, 200.1 ppm. HRMS:
calcd. for C18H27NO5NaS [M + Na]+ 392.15021; found 392.1505.
[α]1D6 = +55.9 (c = 0.0145, CHCl3).
Isomer anti-20: 170 mg; m.p. 128–130 °C. Rf = 0.35. 1H NMR
(300 MHz, CDCl3): δ = 7.92 (d, J = 9.0 Hz, 2 H, HAr), 6.94 (d, J
= 9.0 Hz, 2 H, HAr), 4.96 (d, J = 9.0 Hz, 1 H, NH), 4.16–4.06 (m,
4 H, CHNH, CHCH3, CH2CH3), 3.86 (s, 3 H, OCH3), 1.38 (d, J
= 7.0 Hz, 3 H, CHCH3), 1.26 [s, 9 H, C(CH3)3], 1.17 (t, J = 7.1 Hz,
3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 15.4,
22.5, 42.0, 55.4, 56.7, 61.4, 61.8, 113.9, 128.7, 130.7, 163.8, 171.7,
6a: Same procedure as that used for 5a: Compound 4a (87 mg,
0.26 mmol) in 1,4-dioxane (3 mL) was treated with a 1 m solution
of HCl (3 mL, 0.3 mmol). Isomer anti-6a was isolated as a colorless
1
oil (58 mg; 97%). H NMR (300 MHz, CDCl3): δ = 7.26–7.20 (m,
5H, HAr), 4.00 (d, J = 9.3 Hz, 1 H, CHC6H5), 2.79–2.69 (m, 1 H,
CHCH3), 2.53–2.30 (m, 2 H, CH2CO), 1.62 (br. s, 2 H, NH2) 1.51
(qt, J = 7.1 Hz, 2 H, CH2CH2CO), 1.26–1.17 [m, 4 H, (CH2)2CH3],
0.81 (t, J = 7.1 Hz, 3 H, CH2CH3), 0.76 (d, J = 7.1 Hz, 3 H,
CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 15.2, 22.4,
23.1, 31.4, 42.8, 54.1, 58.8, 127.0, 127.4, 128.5, 128.6, 143.9, 215.2
ppm. HRMS: calcd. for C14H20NO [M – CH3]+ 218.15449; found
218.1538. [α]1D9 = +57.3 (c = 0.0030, CHCl3). Chiral HPLC: col-
umn, CHIRALPAK AD 250*4.6, eluent hexane/EtOH, 95:5,
1.2 mLminϪ1, retention times for (Ϯ)-6a: 7.3 and 9.4 min. 6a: re-
tention time 7.3 min, ee Ն 99%.
201.5 ppm. HRMS: calcd. for C18H27NO5NaS [M
+
Na]+
392.15021; found 392.1504. [α]1D6 = +55.6 (c = 0.0068, CHCl3).
Reduction Using NaBH4. Synthesis of 7a and 8a as Representative
Examples: NaBH4 (35 mg, 0.85 mmol) was added in 3 portions,
under nitrogen at 0 °C, to a solution of β-amino ketone 3a (190 mg,
0.56 mmol) in MeOH (6 mL) . The reaction mixture was kept un-
der magnetic stirring at 0 °C until the starting material disappeared
(TLC monitoring, about 1 h). After addition of water (10 mL) and
extraction with EtOAc (3ϫ10 mL), the organic phases were com-
bined, washed with a saturated solution aqueous of NaCl, dried
(Na2SO4), and concentrated under vacuum. The crude product was
purified by chromatography on SiO2 by using a 1:1 mixture of n-
pentane and EtOAc as the eluent. The two diastereoisomers 7a and
8a were obtained in a ratio of 55:45, as determined by 1H NMR
spectroscopy, and isolated in 95% overall yield (180 mg).
Step 2. Synthesis of Compounds 21 and 22: NaBH4 (70 mg,
1.8 mmol) was added in three portions, under nitrogen at 0 °C, to
a solution of β-amino ketone 19 (328 mg, 0.89 mmol) and BnBr
(0.43 mL, 3.6 mmol) in MeOH (10 mL). The reaction mixture was
kept under magnetic stirring at 0 °C until the starting material dis-
appeared (monitoring by TLC, about 1 h). After addition of water
(15 mL) and extraction with EtOAc (3ϫ15 mL), the organic
phases were combined, washed with a saturated aqueous solution
of NaCl, dried (Na2SO4), and concentrated under vacuum. The
crude product was purified by chromatography on SiO2 by using a
4:6 mixture of n-pentane and EtOAc as the eluent. The two dia-
stereoisomers 21 and 22 were obtained in a ratio of 67:33, as deter-
mined by 1H NMR spectroscopy, and isolated as colorless solids
in 91% overall yield (163 mg).
Isomer anti–anti-21: 109 mg; m.p. 110–112 °C. Rf = 0.46. 1H NMR
(300 MHz, CDCl3): δ = 7.27 (d, J = 8.7 Hz, 2 H, HAr), 6.91 (d, J
= 8.7 Hz, 2 H, HAr), 4.38 (d, J = 10.0 Hz, 1 H, CHCO), 3.93 (dd,
J = 8.0, J = 11.0 Hz, 1 H, CHNH), 3.82 (s, 3 H, OCH3), 3.79 (d,
J = 8.0 Hz, 1 H, NH), 2.34 (ddq, J = 6.4, J = 10.0, J = 11.0 Hz, 1
H, CHCH3), 1.30 [s, 9 H, C(CH3)3], 1.29 (d, J = 6.4 Hz, 3 H,
CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.3, 22.5, 47.7,
55.3, 57.0, 63.4, 84.4, 114.1, 128.1, 160.2, 174.1 ppm. HRMS:
calcd. for C16H23NO4NaS [M + Na]+ 348.1240; found 348.1241.
[α]1D6 = +30.0 (c = 0.005, CHCl3).
Isomer syn–syn-7a: 99 mg; m.p. 116–118 °C. Rf = 0.22. 1H NMR
(300 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H, HAr), 5.12 (d, J =
2.1 Hz, 1 H, NH), 4.70 (t, J = 2.5 Hz, 1 H, CHC6H5), 4.04 (dd, J
= 4.0, J = 7.8 Hz, 1 H, CHOH), 3.65 (br. s, 1 H, OH), 1.84 (ddq,
J = 1.5, J = 3.0, J = 7.1 Hz, 1 H, CHCH3), 1.58–1.22 [m, 17 H,
(CH2)4CH3, (CH3)3SO], 0.89 [t, J = 6.8 Hz, 3 H, (CH2)4CH3], 0.85
(d, J = 7.1 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 4.8, 14.0, 22.6, 22.7, 25.8, 31.8, 36.0, 44.0, 55.6, 63.3, 75.6,
127.0, 127.4, 128.1, 142.1 ppm. HRMS: calcd. for C19H33NO2NaS
[M + Na]+ 362.21297; found 362.2133. [α]1D8 = + 117.6, (c 0.0098,
CHCl3).
1
Isomer syn–anti-8a: 81 mg; m.p. 120–122 °C. Rf = 0.37. H NMR
1
(300 MHz, CDCl3): δ = 7.37–7.23 (m, 5 H, HAr), 4.93 (t, J = Isomer anti–syn-22: 54 mg; m.p. 114–116 °C. Rf = 0.43. H NMR
3.5 Hz, 1 H, CHC6H5), 4.46 (d, J = 4.4 Hz, 1 H, NH), 3.56–3.50 (300 MHz, CDCl3): δ = 7.06 (d, J = 8.7 Hz, 2 H, HAr), 6.92 (d, J
(m, 1 H, CHOH), 3.30 (br. s, 1 H, OH), 1.97 (dqt, J = 3.1, J =
= 8.7 Hz, 2 H, HAr), 5.55 (d, J = 8.0 Hz, 1 H, CHCO), 3.91 (dd, J
3434
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3430–3436

Enantioselective Synthesis of β-Amino Ketones and Alcohols
C. H. Heathcock), Pergamon, Oxford, 1991, pp. 893–952; c)
M. Arend, B. Wastermann, N. Risch, Angew. Chem. 1998, 110,
1096–1122; Angew. Chem. Int. Ed. 1998, 37, 1044–1070; d) M.
Tramontini, L. Angiolini, Tetrahedron 1990, 46, 1791–1837,
and references cited therein .
S. Zawadski, A. Zwierzak, Tetrahedron Lett. 2004, 45, 8505–
8506, and references cited therein.
= 8.2, J = 11.0 Hz, 1 H, CHNH), 3.82 (s, 3 H, OCH3), 3.71 (d, J
= 8.2 Hz, 1 H, NH), 2.77 (ddq, J = 6.9, J = 8.0, J = 11.0 Hz, 1 H,
CHCH3), 1.29 [s, 9 H, C(CH3)3], 0.98 (d, J = 6.9 Hz, 3 H, CHCH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.3, 22.5, 42.6, 55.3, 57.0,
60.2, 81.8, 114.0, 127.0, 159.7, 175.0 ppm. HRMS: calcd. for
[2]
[3]
C16H23NO4NaS [M + Na]+ 348.1240; found 348.1239. [α]1D8
+85.9 (c = 0.0058, CHCl3).
=
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2650.
For clarity and consistency, in Scheme 1 only the derivatives
with the (S) absolute configuration at the sulfur stereocenter
are indicated because these compounds are used later in corre-
sponding asymmetric syntheses.
For another elegant asymmetric synthesis of syn- and anti-1,3-
amino alcohols using metalloenamines derived from N-sulfinyl
imines, see: T. Kochi, T. P. Tang, J. A. Ellman, J. Am. Chem.
Soc. 2003, 125, 11276–11282.
As expected from their structure, these β-amino ketones de-
compose on standing at room temperature, but their stability
appears to be strongly related to the nature of R1. Aryl ketones,
such as 5b and 6b, are more stable, whereas alkyl derivatives
are less stable. For instance, the more sensitive β-amino ketone
5a gives a small amount of epimerization/decomposition
(around 4%) during deprotection.
For representative examples of allyl reagent additions to N-
sulfinyl imines, see: a) D. A. Cogan, G. Liu, J. Ellman, Tetrahe-
dron 1999, 55, 8883–8904; b) J. C. Gonzalez-Gomez, F. Foub-
elo, M. Yus, Synlett 2008, 18, 2777–2780; c) G. Kolodney, G.
Sklute, S. Perrone, P. Knochel, I. Marek, Angew. Chem. 2007,
119, 9451–9454; Angew. Chem. Int. Ed. 2007, 46, 9291–9294,
and references cited therein.
Step 3. Synthesis of ent-15: Same procedure as that used for 5a:
compound 21 (28 mg, 0.086 mmol) in 1,4-dioxane (1.5 mL) was
treated with a 1 m solution of HCl (1.5 mL, 1.5 mmol). Product
ent-15 was isolated as a colorless oil in 98% yield (18.6 mg). 1H
NMR (300 MHz, CDCl3): δ = 7.27 (d, J = 8.7 Hz, 2 H, HAr), 6.94
(d, J = 8.7 Hz, 2 H, HAr), 4.80 (d, J = 10.1 Hz, 1 H, CHCO), 3.83
(s, 3 H, OCH3), 3.41 (d, J = 11.6 Hz, 1 H, CHNH2), 2.14 (ddq, J
= 6.5, J = 10.1, J = 11.6 Hz, 1 H, CHCH3), 1.72 (br. s, 2 H, NH2),
1.19 (d, J = 6.5 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.7, 48.4, 55.3, 58.9, 84.6, 114.1, 128.0, 128.5, 160.1,
[4]
[5]
177.8 ppm. HRMS: calcd. for C12H15NO3Na [M
+
Na]+
244.09496; found 244.09490. [α]1D8 = +28.9 (c = 0.0035, CHCl3).
Lit. values for 15: [α]2D0 = –32.2 (c = 0.57, CHCl3)[22h] and [α]1D9
=
–27.3 (c 0.50, CHCl3).[21f] Chiral HPLC: column: CHIRALPACK
AD 250*4.6, eluent: hexane/EtOH, 85:15, 1.2 mLminϪ1, retention
times for (Ϯ)-15: 8.3 and 11.7 min. ent-15: retention time 11.7 min,
ee Ն 99%.
Step 4. Synthesis of 23: Same procedure as that used for 5a: com-
pound 22 (17 mg, 0.052 mmol) in 1,4-dioxane (1.0 mL) was treated
with a 1 m solution of HCl (1.0 mL, 1.0 mmol). Lactone 23 was
isolated as a colorless oil in 87% yield (10.1 mg). 1H NMR
(300 MHz, CDCl3): δ = 7.07 (d, J = 8.8 Hz, 2 H, HAr), 6.91 (d, J
= 8.8 Hz, 2 H, HAr), 5.55 (d, J = 8.0 Hz, 1 H, CHCO), 3.83 (s, 3
H, OCH3), 3.40 (d, J = 11.1 Hz, 1 H, CHNH2), 2.55 (ddq, J = 6.9,
J = 8.0, J = 11.1 Hz, 1 H, CHCH3), 1.70 (br. s, 2 H, NH2), 0.87
(d, J = 6.5 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 13.9, 43.3, 55.2, 55.3, 82.0, 113.9, 127.1, 127.7, 159.5, 178.8
ppm. HRMS: calcd. for C12H15NO3Na [M + Na]+ 244.09496;
found 244.09490. [α]1D8 = +72.8 (c = 0.0025, CHCl3). Chiral HPLC:
column: CHIRALPACK AD 250*4.6, eluent: hexane/EtOH, 85:15,
1.2 mLminϪ1, retention times for (Ϯ)-23: 6.9 and 12.8 min. 23: re-
tention time 6.9 min, ee Ն 99%.
[6]
[7]
[8]
[9]
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures and characterization data for
the tandem isomerization–Mannich synthesis of adducts 3 and 4;
deprotection to β-amino-ketones 5 and 6; reduction to β-amino
alcohols 7, 8, 11, and 12; deprotection to β-amino alcohols 9, 10,
13, and 14; and synthesis of ent-nikkomycin and ent-funebrine pre-
cursors is given.
[12]
[13]
Acknowledgments
We thank the Vietnamese Government for a Ph. D. fellowship to
H. T. C. and the Centre National de la Recherche Scientifique
(CNRS) and the University of Rennes 1 for financial support. We
thank D. Grée for NMR spectroscopy experiments and CRMPO
(Rennes) for microanalyses and MS analyses. This research has
been performed as part of the Indo-French “Joint Laboratory for
Sustainable Chemistry at Interfaces”. We thank CNRS and the
Council for Scientific and Industrial Research (CSIR) for support.
[14]
[15]
[1] a) D. Mayer, in: Houben-Weyl Methoden der Organischen
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7819–7832; b) D. D. Staas, K. L. Savage, C. F. Homnick, N. N.
Eur. J. Org. Chem. 2011, 3430–3436
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3435

H. T. Cao, T. Roisnel, A. Valleix, R. Grée
FULL PAPER
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chemical shift of the imine proton (δ = –0.46 ppm) and in the
13C NMR chemical shift of the imine carbon atom (δ =
–4.4 ppm); this strongly suggests coordination of magnesium
to the sulfinimine moiety.
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[19] Based on literature data,[8] in an open transition state, addition
should occur on the Si face of our (Ss) sulfinimine to afford
the other stereoisomer, which is not consistent with our experi-
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and -802577 (for 11d) contain the supplementary crystallo-
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Published Online: May 17, 2011
3436
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Eur. J. Org. Chem. 2011, 3430–3436