Synthesis of β-amino alcohols via the reduction of lactamides derived from ethyl (2S)-lactate with borane-methyl sulfide

Article abstract of DOI:10.1055/s-0029-1217538

Reactions of ethyl (2S)-lactate with various amines affords lactamides that are reduced with borane-methyl sulfide in the presence of boron trifluoride etherate to generate enantiomerically pure β-amino alcohols in good yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217538

LETTER
1923
Synthesis of b-Amino Alcohols via the Reduction of Lactamides Derived from
Ethyl (2S)-Lactate with Borane–Methyl Sulfide
Synthesis of
br
a
Centre for Synthesis and Chemical Biology, University Chemical Laboratory, Trinity College, Dublin 2, Ireland
Fax +353(1671)2826; E-mail: dgrayson@tcd.ie
Received 30 March 2009
We reasoned that a more cost-effective route to chiral b-
Abstract: Reactions of ethyl (2S)-lactate with various amines af-
fords lactamides that are reduced with borane–methyl sulfide in the
presence of boron trifluoride etherate to generate enantiomerically
pure b-amino alcohols in good yield.
amino alcohols of the type that could be obtained by the
aminolysis of 2-methyloxirane would involve the reduc-
tion of lactamides 8 which can be obtained by either the
reactions of amines with ethyl (2S)-lactate (7), or by the
dehydrative condensation of amines with (2S)-lactic acid
(Scheme 1).13 There are a few reports14 on the reduction of
various lactamides 8 but, surprisingly, borane–methyl sul-
fide does not appear to have been used for this particular
transformation. The reduction of analogous a-hydroxy-
amides derived from mandelic acid and 2-hydroxy-3-me-
thylbutyric acid using borane–methyl sulfide has been
reported.15
Key words: lactamides, borane–methyl sulfide, amino alcohols,
asymmetric synthesis, reductions
Chiral b-amino alcohols have widespread applications in
asymmetric synthesis, both as ligands for asymmetric
catalysis2 as well as building blocks in a number of syn-
thetically important chiral auxiliaries.3 The chiral b-amino
alcohols 1 and 2 were among the first ligands that were
shown to catalyze the highly enantioselective addition of
dialkylzinc reagents to aromatic aldehydes,4 whilst the
Evans’ oxazalidinone5 3 and the Meyers’ oxazoline6 4 are
examples of widely used chiral auxiliaries that are derived
from chiral b-amino alcohols. More recently, ligands 5
and 6 gave high enantioselectivities in the asymmetric
addition of diphenylzinc to aromatic aldehydes7 and the
ruthenium-catalyzed transfer hydrogenation of ketones,8
respectively (Figure 1).
Amongst the many reported routes to b-amino alcohols,9
the most widely employed are the reduction of a-amino
acids10 and the ring opening of epoxides with amines.11
However, a major drawback of the latter route is the cost
and availability of the epoxides in optically active form.
Enantiopure 2-methyloxirane, for example, presents a sig-
nificant cost issue, particularly for large-scale syntheses.12
Brown and co-workers have shown that the rates of reduc-
tion of amides, esters, and nitriles with borane–methyl
sulfide can be significantly increased by the distillation of
dimethyl sulfide from the reaction mixture and by em-
ploying boron trifluoride etherate as Lewis acid.16 We
were thus attracted to the possibility of employing this re-
agent combination for the synthesis of enantiopure b-ami-
no alcohols 9 from lactamides 8, as borane–methyl sulfide
is more convenient to handle than lithium aluminum hy-
dride. Herein are described our results on the synthesis of
various b-amino alcohols 9 derived from ethyl (2S)-lac-
tate (7).
O
O
reducing
agent
R2NH
EtO
R2N
R2N
OH
OH
OH
7
8
9
O
Scheme 1
Ph
N
Ph
OH
NMe2
OH
O
NH
Bn
Me
Initially, we focused on the reduction of lactamide 8a
which was obtained13 in 82% purified yield by heating
ethyl (2S)-lactate (7) with an excess (1.3 equiv) of pyrro-
lidine for 24 hours. Treatment of 8a with borane–methyl
sulfide (1 equiv) and boron trifluoride etherate (2 equiv)
in THF at reflux for 2.5 hours, followed by aqueous work-
up (6 M HCl) according to the procedure of Brown,16 gave
a crude product consisting of the amino alcohol 9a and un-
1
2
3
Ph
O
N
N
OH
OH
Ph
NH2
OMe
Ph Ph
4
5
6
1
reacted lactamide 8a in ca. 2:1 ratio as judged by its H
Figure 1
NMR spectrum. We considered that the presence of the
hydroxy group in 8a meant that an additional equivalent
of borane–methyl sulfide would be needed in order to ef-
fect complete reduction. To our satisfaction, we found that
the use of 2 equivalents of borane–methyl sulfide and a
longer reaction time (24 h) led to complete conversion,
SYNLETT 2009, No. 12, pp 1923–1928
Advanced online publication: 03.07.2009
DOI: 10.1055/s-0029-1217538; Art ID: D08609ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

1924
F. W. Lewis et al.
LETTER
and the desired amino alcohol 9a was obtained in 65% rived from THF. We then carried out the same reductions
yield following purification (Scheme 2).
in 1,2-dimethoxyethane (DME) as an alternative solvent
and were pleased to find that no impurities could be de-
tected in the crude b-amino alcohols, which were obtained
in pure form following vacuum distillation or recrystalli-
zation.
This protocol was subsequently applied to the reduction of
a number of lactamides obtained by the reaction of ethyl
(2S)-lactate (7) with various amines,17 and the results are
summarized in Table 1. Our studies focused on aliphatic
amines because of the superior performance of aliphatic It is worth noting that in the case of the reductions of lac-
b-amino alcohols as ligands for the asymmetric addition tamides 8k, 8m, and 8n (entries 11, 13, and 14), the crude
of organozinc reagents to carbonyl compounds.4
products were obtained in low overall yields and con-
tained significant quantities of additional impurities (as
well as those derived from polymerization of THF) when
THF was used as the solvent. These impurities could not
be characterized. When DME was used as the solvent, the
overall yields were much higher and the crude amino al-
cohols 9k, 9m, and 9n were obtained free from any impu-
rities. 1,2-Dimethoxyethane is thus the preferred solvent
for the reductions of lactamides 8 with borane–methyl sul-
fide.18
The lactamides derived from primary amines (entries 5–
10) and from cyclic secondary amines (entries 1–4) were
formed in high yields and their b-amino alcohols were ob-
tained in good overall yields for the two steps. However,
acyclic secondary amines such as diethylamine failed to
react with ethyl (2S)-lactate, rendering their derived b-
amino alcohols inaccessible by this route. The lactamide
derived from allylamine (entry 6) is particularly interest-
ing since reduction of its amide group is accompanied by
hydroboration of its double bond. Unfortunately, our at- In order to rule out the possibility that any racemization of
tempts to manipulate the intermediate organoborane ei- the stereogenic centre was occurring during the formation
ther by protonolysis (6 M HCl), or by oxidative cleavage of lactamides by the reaction of amines with ethyl (2S)-
(alkaline H2O2) of the B–C bond yielded intractable mix- lactate (7), we synthesized lactamides 8i and 8j that were
tures whose 1H NMR spectra bore no resemblance to the derived from each of (1R)-a-methylbenzylamine and
1
expected amino alcohol products.
(1S)-a-methylbenzylamine, respectively. The H NMR
spectra of both 8i and 8j showed that a single diastereomer
of the lactamide was present in each case, indicating that
the stereochemical integrity of the asymmetric center ad-
jacent to the carbonyl group had been maintained. To fully
validate this NMR-based assay we prepared the lactamide
11 from racemic ethyl lactate 10 and (1R)-a-methylbenzyl-
amine (Scheme 3). The 1H NMR spectrum of the product
displayed signals due to a pair of diastereomers, of which
only one was present in the spectrum of 8i.
The bislactamides derived from ethylene diamine and 1,6-
diaminohexane (entries 11 and 12) each required 4 molar
equivalents of borane–methyl sulfide and boron trifluo-
ride etherate for complete reduction to occur. In all other
cases (for both secondary and tertiary lactamides) 2 molar
equivalents of borane–methyl sulfide and boron trifluo-
ride etherate were used. Notably, lactamides bearing an
additional nitrogen atom (entries 13 and 14) did not re-
quire an additional equivalent of Lewis acid to effect their
complete reduction.
O
O
NH2
+
O
O
EtO
N
NH
BMS
BF3•OEt2
reflux
24 h
H
OH
OH
EtO
N
N
10
11
reflux
24 h
THF
reflux
24 h
OH
OH
OH
Scheme 3
7
8a
9a
Scheme 2
Thus, we have demonstrated that enantiomerically pure b-
amino alcohols can be obtained in a two-step sequence by
the reduction of lactamides19 derived from ethyl (2S)-lac-
tate using borane–methyl sulfide/boron trifluoride ether-
ate. These reductions proceeded more cleanly and, in
some cases, in higher yield when 1,2-dimethoxyethane
was used as the solvent instead of THF. The procedure
represents a more cost-effective alternative route to ho-
mochiral b-amino alcohols than from syntheses involving
the aminolysis of enantiomerically pure 2-methyloxirane.
The novel b-amino alcohols that we have prepared are
currently under investigation in our laboratory to assess
their potential as ligands for the asymmetric addition of
diethylzinc to aromatic aldehydes.
In a number of the reduction experiments minor amounts
of additional products were obtained. These gave rise to a
characteristic pair of triplets at d = 3.60 and 3.69 ppm in
the 1H NMR spectra of the crude products. In many cases,
these impurities could not be fully separated from the b-
amino alcohol. We suspected that these impurities were
oligomers or polymers derived from remaining traces of
THF solvent that had undergone acid-catalyzed polymer-
ization during the strongly acidic workup conditions
(boiling in 6 M HCl). When a ‘blank’ experiment was run
in the absence of lactamide the crude product obtained
gave a 1H NMR spectrum that displayed the same pair of
triplets observed in the spectra of the crude reduction
products, indicating that these impurities were indeed de-
Synlett 2009, No. 12, 1923–1928 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino Alcohols
1925
Table 1 Synthesis of b-Amino Alcohols 9 from the Reduction of Lactamides 8 Derived from Ethyl (2S)-Lactate (7) and Various Amines with
Borane–Methyl Sulfide
Entry
1
Amine
Lactamide 8
Yield (%)a b-Amino alcohol 9
Yield (%)a
65
pyrrolidine
82
O
N
N
OH
9a
OH
8a
8b
2
3
4
piperidine
79
76
67
85
O
N
OH
N
OH
9b
morpholine
60
O
N
O
OH
N
O
OH
O
9c
8c
N-methylpiperazine
81
N
N
OH
N
Me
N
OH
9d
Me
8d
5
6
7
cyclopropylamine
allylamine
72
78
88
75
0
O
N
N
H
H
OH
OH
9e
8e
8f
intractable mixtureb
O
N
H
OH
2-phenylethylamine
56
O
N
N
H
H
OH
OH
8g
8h
8i
9g
8
9
benzylamine
86
83
81
73
78
63
65
61
O
N
H
OH
N
H
OH
9h
(1R)-a-methylbenzylamine
(1S)-a-methylbenzylamine
ethane-1,2-diamine
O
O
N
N
H
H
OH
OH
OH
9i
10
11
N
N
H
H
OH
9j
8j
OH
O
OH
H
H
N
N
N
N
H
H
O
OH
OH
8k
9k
Synlett 2009, No. 12, 1923–1928 © Thieme Stuttgart · New York

1926
F. W. Lewis et al.
LETTER
Table 1 Synthesis of b-Amino Alcohols 9 from the Reduction of Lactamides 8 Derived from Ethyl (2S)-Lactate (7) and Various Amines with
Borane–Methyl Sulfide (continued)
Entry
12
Amine
Lactamide 8
Yield (%)a b-Amino alcohol 9
Yield (%)a
77
hexane-1,6-diamine
97
O
O
NH HN
NH HN
OH
HO
OH
HO
8l
9l
13
14
N,N-dimethylethane-1,2-diamine
N,N-dimethylpropane-1,3-diamine
97
98
70
73
Me2N
O
N
H
Me2N
OH
N
H
9m
OH
O
8m
Me2N
N
H
OH
Me2N
N
H
9n
OH
8n
a Yield of lactamide or b-amino alcohol following purification.
b Obtained following either acidic or oxidative workup.
Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66,
8772. (g) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick,
H. G.; Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051.
From the reduction of nitrogen-stabilized oxallyl cation
[4+3] cycloadducts: (h) Huang, J.; Ianni, J. C.; Antoline, J.
E.; Hsung, R. P.; Kozlowski, M. C. Org. Lett. 2006, 8, 1565.
(10) (a) Karrer, P.; Portmann, P.; Suter, M. Helv. Chim. Acta
1948, 31, 1617. (b) Seki, H.; Koga, K.; Matsuo, H.; Ohki, S.;
Matsuo, I.; Yamada, S. Chem. Pharm. Bull. 1965, 13, 995.
(c) Prasad, B.; Saund, A. K.; Bora, J. M.; Mathur, N. K. Ind.
J. Chem. 1974, 12, 290. (d) Smith, G. A.; Gawley, R. E.
Org. Synth. 1985, 63, 136. (e) Gage, J. R.; Evans, D. A. Org.
Synth. 1989, 68, 77. (f) Giannis, A.; Sandhoff, K. Angew.
Chem., Int. Ed. Engl. 1989, 28, 218. (g) Dickman, D. A.;
Meyers, A. I.; Smith, G. A.; Gawley, R. E. Organic
Syntheses, Collect Vol. VII; Wiley and Sons: New York,
1990, 530. (h) Dharanipragada, R.; Alarcon, A.; Hruby, V. J.
Org. Prep. Proced. Int. 1991, 23, 396. (i) Abiko, A.;
Masamune, S. Tetrahedron Lett. 1992, 33, 5517.
Acknowledgment
The authors gratefully acknowledge Dr. John E. O’Brien and Dr.
Manuel Reuther for obtaining NMR spectra and Dr. Martin Feeney
for obtaining mass spectra. One of us (F.W.L.) received financial
support from Trinity College Dublin.
References and Notes
(1) New address: F. W. Lewis, Department of Chemistry,
University of Reading, Whiteknights, Reading RG6 6AD,
UK.
(2) (a) Handbook of Reagents for Organic Synthesis: Chiral
Reagents for Asymmetric Synthesis; Paquette, L. A., Ed.;
Wiley: Chichester, 2003. (b) Asymmetric Synthesis – The
Essentials; Christmann, M.; Bräse, S., Eds.; Wiley-VCH:
Weinheim, 2007.
(3) (a) Compendium of Chiral Auxiliary Applications; Roos, G.,
Ed.; Academic Press: New York, 2002. (b) Gnas, Y.;
Glorius, F. Synthesis 2006, 1899.
(4) (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
(b) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(c) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
(5) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (b) Ager,
D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30,
3.
(6) (a) Meyers, A. I.; Lutomski, K. A. Acc. Chem. Res. 1978, 11,
375. (b) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50,
2297. (c) Meyers, A. I. J. Org. Chem. 2005, 70, 6137.
(7) Dimitrov, V.; Kostova, K. Lett. Org. Chem. 2006, 3, 176.
(8) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226.
(9) From the reduction of a-amino ketones: (a) Tramontini, M.
Synthesis 1982, 605. (b) Hoffman, R. V.; Maslouh, N.;
Cervantes-Lee, F. J. Org. Chem. 2002, 67, 1045. (c) Fraser,
D. S.; Park, S. B.; Chong, J. M. Can. J. Chem. 2004, 82, 87.
From the manipulation of cyanohydrins: (d) Jackson, W. R.;
Jacobs, H. A.; Jayatilake, G. S.; Matthews, B. R.; Watson,
K. G. Aust. J. Chem. 1990, 43, 2045. From nucleophilic
additions to a-amino aldehydes: (e) Reetz, M. T. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1531. From nucleophilic
additions to chiral imine derivatives: (f) Tang, T. P.;
(j) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M.
J. Org. Chem. 1993, 58, 3568.
(11) (a) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron
1996, 52, 14361. (b) Comprehensive Organic Synthesis,
Part 1.3.4.1., Vol. 6; Mitsunobu, O.; Winterfeldt, E., Eds.;
Pergamon: New York, 1996. (c) Ager, D. J.; Prakash, I.;
Schaad, D. R. Chem. Rev. 1996, 96, 835. (d) Bergmeier,
S. C. Tetrahedron 2000, 56, 2561.
(12) Cost per gram from Aldrich Chemical Company: ethyl (2S)-
lactate: £0.05; (2S)-2-methyloxirane: £8.66.
(13) (a) Ratchford, W. P.; Fisher, C. H. J. Org. Chem. 1950, 15,
317. (b) Fein, M. L.; Filachione, E. M. J. Am. Chem. Soc.
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(14) With LiAlH4: (a) See ref. 13d. (b) Yoneyama, K.; Ichizen,
N.; Konnai, M.; Takematsu, T.; Ushinohama, K.; Jikihara, T.
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Maehara, K.; Ueda, Y. WO 2002070482, 2002.
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Synlett 2009, No. 12, 1923–1928 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino Alcohols
1927
(16) (a) Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis
1981, 996. (b) Brown, H. C.; Choi, Y. M.; Narasimhan, S.
J. Org. Chem. 1982, 47, 3153.
d = 65.0 (CHOH), 56.4 (CH2NH), 29.8 (CH), 19.9 (CH3),
6.5 (CH2), 5.4 (CH2). Anal. Calcd for C6H13NO: C, 62.61; H,
11.30; N, 12.17. Found: C, 62.39; H, 11.58; N, 11.95.
Characterization Data for 9l
(17) Synthesis of Lactamides 8a–n – General Procedure
Ethyl (2S)-lactate (7, 88.2 mmol, 1 equiv) and the
appropriate amine (114.6 mmol, 1.3 equiv) were placed in a
flask and heated under reflux for 24 h. The solution was
allowed to cool to r.t., the volatiles were removed under
reduced pressure (1.33·10–4 bar), and the lactamide was
purified by vacuum distillation or recrystallization. For the
synthesis of bislactamides 8k and 8l, 0.5 equiv of amine
were used. Compounds 8a–d,f–j,l–n are known.20
Characterization Data for 8e
White solid, mp 83–84 °C (CHCl3). [a]D17 +34.2 (c 3.99,
CHCl3). IR (Nujol): 3273 (OH), 3181 (NH), 2914, 1456,
1366, 1135, 1084, 985, 935, 900, 846 cm–1. 1H NMR (400.1
MHz, CDCl3): d = 3.80 (dqd, J = 9.5, 6.0, 3.0 Hz, 2 H,
2 × CHOH), 2.93 (br s, 4 H, exch. D2O, 2 × NH and
2 × OH), 2.70 (dd, J = 12.0, 3.0 Hz, 2 H, CH2CHOH), 2.53–
2.70 (m, 4 H, 2 × CH2NH), 2.42 (dd, J = 12.0, 9.5 Hz, 2 H,
CH2CHOH), 1.46–1.57 (m, 4 H, 2 × CH2CH2NH), 1.31–
1.39 (m, 4 H, 2 × CH2CH2CH2NH), 1.16 (d, J = 6.0 Hz, 6 H,
2 × CH3). 13C NMR (100.6 MHz, CDCl3): d = 65.3
(2 × CHOH), 56.8 (2 × CH2NH), 49.4 (2 × CH2CHOH),
29.8 (2 × CH2CH2NH), 27.0 (2 × CH2CH2CH2NH), 20.7
(2 × CH3). HRMS (EI, MeOH): m/z calcd for C12H28N2O2
[M + H]+: 233.2229; found: 233.2234.
Yellow oil, bp 101–104 °C (1.33·10–4 bar). [a]D16 –16.6 (c
1.31, CHCl3). IR (neat): 3308 (OH, NH), 2978, 1655 (C=O),
1532, 1457, 1364, 1275, 1124, 1048, 978 cm–1. 1H NMR
(400.1 MHz, CDCl3): d = 6.90 (s, 1 H, exch. D2O, NH), 4.18
(q, J = 6.5 Hz, 1 H, CHOH), 3.84 (br s, 1 H, exch. D2O, OH),
2.67–2.74 (m, 1 H, CH), 1.39 (d, J = 6.5 Hz, 3 H, CH3),
0.72–0.84 (m, 2 H, CH2), 0.46–0.58 (m, 2 H, CH2). 13C NMR
(100.6 MHz, CDCl3): d = 176.1 (C=O), 67.7 (CHOH), 21.6
(CH), 20.6 (CH3), 5.9 (CH2), 5.8 (CH2). HRMS (EI, MeOH):
m/z calcd for C6H11NO2 [M + Na]+: 152.0687; found:
152.0680.
Characterization Data for 9m
Colorless liquid, bp 62 °C (1.33·10–4 bar). [a]D16 +34.2 (c
3.61, CHCl3). IR (neat): 3304 (OH, NH), 2942, 2818, 1460,
1370, 1277, 1129, 1055, 846, 778 cm–1. 1H NMR (400.1
MHz, CDCl3): d = 3.78 (dqd, J = 9.5, 6.0, 3.0 Hz, 1 H,
CHOH), 2.65–2.78 (m, 3 H, CH2CHOH and CH2NH), 2.42
(dd, J = 12.0, 9.5 Hz, 1 H, CH2CHOH), 2.37–2.46 [m, 2 H,
CH2N(CH3)2], 2.23 [s, 6 H, N(CH3)2], 1.15 (d, J = 6.0 Hz, 3
H, CH3). 13C NMR (100.6 MHz, CDCl3): d = 65.1 (CHOH),
58.7 [CH2N(CH3)2], 56.5 (CH2CHOH), 46.3 (CH2NH), 45.0
[N(CH3)2], 20.0 (CH3). HRMS (EI, MeOH): m/z calcd for
C7H18N2O [M + H]+: 146.1181; found: 146.1187.
Characterization Data for 8k
White solid, mp 97–98 °C (10% EtOH in THF). [a]D16 –24.7
(c 1.96, MeOH). IR (Nujol): 3323 (OH), 3086 (NH), 2926,
1662 (C=O), 1561, 1458, 1368, 1310, 1274, 1223, 1129,
1079, 937 cm–1. 1H NMR (400.1 MHz, DMSO-d6): d = 7.81
(s, 1 H, exch. D2O, NH), 5.48 (s, 1 H, exch. D2O, NH), 3.94
(q, J = 6.5 Hz, 2 H, 2 × CHOH), 3.36 (br s, 2 H, exch. D2O,
2 × OH), 3.16 (app t, J = 2.5 Hz, 4 H, 2 × CH2NH), 1.19 (d,
J = 6.5 Hz, 6 H, 2 × CH3). 13C NMR (100.6 MHz, DMSO-
d6): d = 174.8 (2 × C=O), 67.2 (2 × CHOH), 38.2
Characterization Data for 9n
Colorless liquid, bp 72–76 °C (1.33·10–4 bar). [a]D16 +37.2 (c
1.68, CHCl3). IR (neat): 3303 (OH, NH), 2941, 2816, 1461,
1372, 1265, 1127, 1061, 839 cm–1. 1H NMR (400.1 MHz,
CDCl3): d = 3.79 (dqd, J = 9.5, 6.3, 3.0 Hz, 1 H, CHOH),
2.70 (dd, J = 12.1, 3.0 Hz, 1 H, CH2CHOH), 2.61–2.75 (m,
2 H, CH2NH), 2.41 (dd, J = 12.1, 9.5 Hz, 1 H, CH2CHOH),
2.34 [t, J = 7.2 Hz, 2 H, CH2N(CH3)2], 2.23 [s, 6 H,
N(CH3)2], 1.66 (q, J = 7.0 Hz, 2 H, CH2), 1.15 (d, J = 6.3 Hz,
3 H, CH3). 13C NMR (100.6 MHz, CDCl3): d = 65.3
(CHOH), 57.7 [CH2N(CH3)2], 56.7 (CH2CHOH), 47.6
(CH2NH), 45.5 [N(CH3)2], 27.9 (CH2), 20.4 (CH3). HRMS
(EI, MeOH): m/z calcd for C8H20N2O [M + H]+: 161.1654;
found: 161.1646.
(2 × CH2NH), 21.0 (2 × CH3). HRMS (EI, MeOH): m/z
calcd for C8H16N2O4 [M + Na]+: 227.1008; found: 227.1010.
(18) Synthesis of b-Amino Alcohols 9a–n – General Procedure
The lactamide 8 (23.7 mmol, 1 equiv) was dissolved in dry
1,2-dimethoxyethane (15 mL/g) in an oven-dried flask
equipped with a Dean–Stark trap and reflux condenser under
a nitrogen atmosphere. Boron trifluoride etherate (47.5
mmol, 2 equiv) was added, and then borane–methyl sulfide
(47.5 mmol, 2 equiv) was added dropwise via syringe. Once
the evolution of H2 had ceased, the solution was heated
under reflux for 24 h (ca. 2–3 mL of distillate collected) and
the solvents were removed in vacuo. The resulting colorless
oil was carefully diluted with 6 M HCl (15 mL/g) and boiled
for ca. 5 min. The resulting clear solution was neutralized
while still hot with 6 M NaOH (15 mL/g) and then allowed
to cool to r.t. before being saturated with solid K2CO3 and
extracted with CHCl3 (3 × 50 mL). The combined organic
extracts were dried over MgSO4 and evaporated to afford the
crude b-amino alcohol 9 which was purified by vacuum
distillation or recrystallization. In the case of bislactamides
8k and 8l, 4 equiv of both boron trifluoride etherate and
borane–methyl sulfide were used. Compounds 9a–d,f–k are
known.21
(19) Lactamides 8a–d have recently been used as chiral
auxiliaries, see: Ammazzalorso, A.; Amoroso, R.; Bettoni,
G.; De Filippis, B.; Fantacuzzi, M.; Giampietro, L.;
Maccallini, C.; Tricca, M. L. Eur. J. Org. Chem. 2006, 4088.
(20) Compound 8a: (a) See ref. 13a. (b) Ito, Y.; Kobayashi, Y.;
Kawabata, T.; Takase, M.; Terashima, S. Tetrahedron 1989,
45, 5767. (c) Schurig, V.; Betschinger, F. Bull. Soc. Chim.
Fr. 1994, 131, 555. Compound 8b: (d) See ref. 13a.
(e) Schurig, V.; Hintzer, K.; Leyrer, U.; Mark, C.; Pitchen,
P.; Kagan, H. B. J. Organomet. Chem. 1989, 370, 81.
(f) See ref. 20c. Compound 8c: (g) See ref. 13a. (h) Tasaka,
A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.
Chem. Pharm. Bull. 1993, 41, 1035. (i) Upadhayaya, R.-S.;
Sinha, N.; Jain, S.; Kishore, N.; Chandra, R.; Arora, S.-K.
Bioorg. Med. Chem. 2004, 12, 2225. Compound 8d: (j) See
ref. 19. Racemic 8f: (k) See ref 13a,c. Compound 8g:
(l) Adamczyk, M.; Grote, J.; Rege, S. Tetrahedron:
Asymmetry 1997, 8, 2509. Compound 8h: (m) Savinov,
S. N.; Austin, D. J. Org. Lett. 2002, 4, 1415. Compound 8i:
(n) See ref. 14c. Compound 8j: (o) Harada, K.; Munegumi,
T.; Nomoto, S. Tetrahedron Lett. 1981, 22, 111.
Characterization Data for 9e
16
Colorless liquid, bp 76 °C (1.33·10–2 to 2.66·10–2 bar). [a]D
+41.9 (c 4.95, CHCl3). IR (neat): 3307 (OH, NH), 2965,
2931, 1451, 1373, 1141, 1103, 1066, 1015, 917, 816 cm–1.
1H NMR (400.1 MHz, CDCl3): d = 3.79 (dqd, J = 10.0, 6.5,
3.0 Hz, 1 H, CHOH), 2.83 (dd, J = 12.0, 3.0 Hz, 1 H,
CH2NH), 2.50 (dd, J = 12.0, 10.0 Hz, 1 H, CH2NH), 2.28 (br
s, 2 H, exch. D2O, OH and NH), 2.13–2.18 (m, 1 H, CH),
1.16 (d, J = 6.5 Hz, 3 H, CH3), 0.41–0.51 (m, 2 H, CH2),
0.29–0.40 (m, 2 H, CH2). 13C NMR (100.6 MHz, CDCl3):
(p) Harada, K.; Munegumi, T. Bull. Chem. Soc. Jpn. 1984,
57, 3203. (q) See ref. 14c. Compound 8l: (r) Kern, T.
Synlett 2009, No. 12, 1923–1928 © Thieme Stuttgart · New York

1928
F. W. Lewis et al.
LETTER
Makromol. Chem. 1955, 16, 89. Compound 8m: (s) Tounsi,
N.; Dupont, L.; Mohamadou, A.; Cadiou, C.; Aplincourt,
M.; Plantier-Royon, R.; Massicot, F.; Portella, C. New J.
Chem. 2004, 28, 785. Compound 8n: (t) See ref. 20s.
1955, 92, 1411. (h) Bourquin, J.-P.; Schwarb, G.; Gamboni,
G.; Fischer, R.; Ruesch, L.; Guldimann, S.; Theus, V.;
Schenker, E.; Renz, J. Helv. Chim. Acta 1958, 41, 1072.
Racemic 9g: (i) Beckett, M. J. Pharm. Pharmacol. 1968, 20,
218. Compound 9h: (j) Kashima, C.; Harada, K. J. Chem.
Soc., Perkin Trans. 1 1988, 1521. (k) Brun, E. M.; Gil, S.;
Parra, M. Tetrahedron: Asymmetry 2001, 12, 915.
(l) Gawronski, J.; Kolbon, H.; Kwit, M. Enantiomer 2002, 7,
85 . Compound 9i: (m) See ref. 14b. (n) See ref. 14c.
Compound 9j: (o) See ref. 14b. (p) See ref. 14c. Racemic
9k: (q) Steck, E. A.; Buck, J. S.; Fletcher, L. T. J. Am. Chem.
Soc. 1957, 79, 4414. (r) Hall, J. L.; Dean, W. E.; Pacovsky,
E. A. J. Am. Chem. Soc. 1960, 82, 3303. (s) Butula, I.;
Karlovic, G. Justus Liebigs Ann. Chem. 1976, 1455.
(21) Racemic 9a: (a) Reid, W. B.; Wright, J. B. Jr.; Kolloff,
H. G.; Hunter, J. H. J. Am. Chem. Soc. 1948, 70, 3100.
(b) Halverstadt, I. F.; Hardie, W. R.; Williams, A. R. J. Am.
Chem. Soc. 1959, 81, 3618. (c) Azizi, N.; Saidi, M. R. Org.
Lett. 2005, 7, 3649. Compound 9b: (d) Rojkovicova, T.;
Lehotay, J.; Cizmarik, J. Pharmazie 2003, 58, 483.
(e) Martin-Matute, B.; Edin, M.; Bogar, K.; Kaynak, F. B.;
Baeckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 8817.
Compound 9c: (f) Angeloni, A. S. Gazz. Chim. Ital. 1977,
107, 421. Racemic 9d: (g) Redel, B. Bull. Soc. Chim. Fr.
Synlett 2009, No. 12, 1923–1928 © Thieme Stuttgart · New York

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