A General Method for the Synthesis of Enantiopure 1,5-Amino Alcohols

Article abstract of DOI:10.1002/ejoc.201501409

A variety of (R)-phenylglycinol-derived oxazolopiperidone lactams 1–14 were converted to linear-chain enantiopure amino diols 15–26 by reduction with LiNH₂BH₃in an unprecedented process involving the simultaneous reductive opening of the oxazolidine and lactam rings. Subsequent removal of the phenylethanol moiety gave enantiopure 5-amino-1-pentanols bearing substituents at the 2-, 3-, 4-, 2,2-, 2,3- 2,4- and 3,4-positions (28–36), which were isolated as their N-Boc derivatives.

Full text of DOI:10.1002/ejoc.201501409

DOI: 10.1002/ejoc.201501409
Full Paper
Enantiopure 1,5-Amino Alcohols
A General Method for the Synthesis of Enantiopure 1,5-Amino
Alcohols
Guillaume Guignard,[a] Núria Llor,[a] Aina Urbina,[a] Joan Bosch,[a] and Mercedes Amat*[a]
Abstract: A variety of (R)-phenylglycinol-derived oxazolopiper- phenylethanol moiety gave enantiopure 5-amino-1-pentanols
idone lactams 1–14 were converted to linear-chain enantiopure
amino diols 15–26 by reduction with LiNH2BH3 in an unprece-
dented process involving the simultaneous reductive opening
of the oxazolidine and lactam rings. Subsequent removal of the
bearing substituents at the 2-, 3-, 4-, 2,2-, 2,3- 2,4- and 3,4-
positions (28–36), which were isolated as their N-Boc deriva-
tives.
Introduction
Functionalized nitrogen-containing small molecules are useful
starting materials for the synthesis of natural products and
medicinally relevant targets. Thus, the development of general
procedures for the enantioselective preparation of particular
types of these building blocks, enabling access to a variety of
stereochemistries and substitution patterns, represents an im-
portant synthetic goal.
We have previously[1] reported the stereoselective prepara-
tion of chiral nonracemic oxazolopiperidone lactams A by the
cyclocondensation of (R)-phenylglycinol with δ-oxoacid deriva-
tives[2] (Scheme 1). When a keto acid (R1 = alkyl or aryl) is used
as starting material, the reaction directly installs a substituent
at the angular C-8a position, whereas when a racemic γ-substi-
tuted δ-oxoacid derivative (R2 = alkyl or aryl) is used, it stereo-
Scheme 1. Synthetic strategy: access to enantiopure 1,5-amino alcohols
(Prot = protection group).
selectively leads to enantiopure C-8 substituted lactams in a easier to install in conformationally rigid cyclic systems than in
process that involves a dynamic kinetic resolution of the race- acyclic compounds.[3]
mic substrate. Taking advantage of the versatile functionality
and conformational rigidity of these bicyclic lactams, additional
substituents can be stereoselectively introduced at the C-6 ring
position by (di)alkylation reactions, and at C-7 by conjugate ad-
dition to the corresponding α,ꢀ-unsaturated lactams.
With procedures available for the regio- and stereocontrolled
preparation of enantiopure bicyclic lactams B bearing substitu-
ents at the different positions of the piperidine ring, we envi-
sioned that reductive cleavage of the oxazolidine and lactam
rings would open up a general synthetic route to diversely sub-
stituted enantiopure 1,5-amino alcohols. In this way, we would
access a variety of related enantiopure functionalized acyclic
derivatives, taking advantage of the fact that chiral centers are
Several procedures have been used for the ring-opening of
δ-lactams. Although direct acidic or alkaline hydrolysis requires
somewhat drastic reaction conditions, N-Boc (tert-butoxycarb-
onyl) protected lactams undergo alkaline hydrolysis or meth-
anolysis under mild conditions.[4] There are also a few examples
of the reductive cleavage of N-Boc and N-Ts piperidones using
borohydride salts to give 1,5-amino alcohols,[5] as well as of
the ring-opening of N-acyl and N-alkoxycarbonyl δ-lactams with
Grignard reagents to give δ-amino ketones.[6,7] For the specific
case of 8a-substituted oxazolopiperidone lactams, there is also
some precedent for cleavage, either by direct hydrolysis under
acidic conditions to give δ-keto acid derivatives, or by hydride
or organometallic attack on the lactam carbonyl followed by
hydrolysis of the resulting carbinolamine. In the latter cases,
the initially formed 1,5-dicarbonyl derivatives undergo in situ
aldolization to give cyclohexenones.[2a–2c] No nitrogen-contain-
ing open-chain products are formed.
[a] Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of
Biomedicine (IBUB), University of Barcelona,
Av. Joan XXIII 27–31, 08028 Barcelona, Spain
E-mail: amat@ub.edu
http://www.ub.edu/sintefarma/
Results and Discussion
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501409.
For the reductive opening of oxazolopiperidone lactams,[8] we
chose to use lithium amidotrihydroborate (LiNH2BH3),[9] which
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Table 1. Access to enantiopure substituted 1,5-amino alcohols from chiral oxazolopiperidone lactams.
[a] For the preparation of the starting lactams, see the Exp. Section. [b] If isolated, the yields of the corresponding N-[(1R)-2-hydroxy-1-phenylethyl]piperidines
27 are given in parentheses.
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is a highly nucleophilic reducing agent that can easily be gener- molecular mixture of amino diol 18b and the corresponding
ated by in situ deprotonation of the commercially available piperidine (27; R1 = 3S-Et, R2 = H).
BH3·NH3 complex.[10] Although LiNH2BH3 has been extensively
As has been seen in the reduction of tertiary amides with
related LiNR2BH3 reagents,[12] the amount of the tertiary amine
by-product formed in the above LiNH2BH3 reductions may also
be related to the steric requirements of the lactam. Thus, the
formation of piperidines 27 was more favored for the more
sterically demanding lactams, for instance, for lactams 4, 8, and
14, which bear a C-7 axial substituent.
used for the direct reduction of open-chain tertiary amides to
primary alcohols,[9,11,12] there are only two isolated examples of
the LiNH2BH3 reduction of lactams to amino alcohols.[13] On the
other hand, the use of lithium N,N-dialkylaminoborohydrides
(LiNR2BH3) results in the conversion of five- and six-membered
N-alkyl lactams into the corresponding cyclic amines.[14]
Table 1 outlines the results obtained in the LiNH2BH3
(4.3 equiv.) reduction of a variety of oxazolopiperidone lactams
1–14 with 3-H and 8a-H in either a cis or trans relative configu- Conclusions
ration. They include 6-, 7-, 8-, and 8a-substituted as well as 6,6-,
The procedure reported in this paper gives access to structur-
6,7-, 6,8-, and 7,8-disubstituted derivatives that differ not only
in the position but also in the nature of the substituents and
the configuration of stereocenters on the piperidine ring. In all
cases, the reduction gave the corresponding linear-chain amino
diols 15–26 in an unprecedented process involving the reduc-
tive cleavage of both the oxazolidine and lactam rings. Minor
amounts of the corresponding N-(2-hydroxy-1-phenylethyl)-
piperidines 27 were isolated in some cases as by-products.
Subsequent removal of the phenylethanol moiety present in
the above amino diols by hydrogenolysis, followed by treat-
ment of the resulting primary amines with Boc2O, led to a wide
range of enantiopure N-Boc-protected 5-aminopentanols 28–
36 bearing substituents at the 2-, 3-, 4-, 2,2-, 2,3-, 2,4-, and 3,4-
positions.
ally diverse enantiopure 5-amino-1-pentanols with a variety of
substitution patterns, substituents (alkyl, benzyl, aryl, protected
hydroxyl), and stereochemistries. The only limitation encoun-
tered was in the reduction of 8a-substituted lactams such as 8,
which gave the corresponding amino diol (i.e., 20) as a nearly
equimolecular epimeric mixture.
Our approach represents the first general synthetic route to
enantiopure 5-amino-1-pentanols, functionalized nitrogen-con-
taining building blocks that have been only rarely reported in
the literature.[16] As both enantiomers of phenylglycinol are
commercially available, the method allows the preparation of
5-aminopentanols in both enantiomeric series.
The formation of amino diols 15–26 can be rationalized by
considering that intermediate C, formed after the initial hydride
Experimental Section
attack on the lactam carbonyl, undergoes a Grob-type fragmen- General Procedures: All air-sensitive manipulations were carried
tation[15] (Scheme 2, C, see arrows) with cleavage of the B–O,
out under an atmosphere of dry argon or nitrogen. Analytical thin-
layer chromatography was carried out on SiO2 (Merck silica gel 60
F254), and the spots were located with KMnO4 (1 % aq.). Chromatog-
raphy refers to flash chromatography, and was carried out on SiO2
(SDS silica gel 60 ACC, 35–75 mm, 230–240 mesh ASTM). NMR spec-
tra were recorded at 300 or 400 MHz (1H) and 75.4 or 100.6 MHz
C–N, and C–O bonds. This fragmentation is facilitated by the
complexation of borane species to the oxazolidine heteroat-
oms. Subsequent reduction of the resulting imino aldehyde
leads to 15–26. Alternatively, expulsion of lithium dihydrido-
aminoborinate from C promoted by the nitrogen lone pair
would give a tetrahydropyridinium species D, which would un-
dergo further reduction to give piperidines 27. In agreement
with the above concerted mechanism leading to amino diols
(
13C), and chemical shifts are reported as δ values downfield from
tetramethylsilane. Tetramethylsilane or residual chloroform (δ =
7.26 ppm for 1H, δ = 77.0 ppm for 13C) was used as an internal
standard. Data are reported in the following manner: chemical shift,
15–26, a similar LiNH2BH3 reduction of lactam 37, which cannot multiplicity, coupling constant (J) in Hertz (Hz), integrated intensity,
and assignment (when possible). Assignments and stereochemical
determinations are given only when they are derived from defini-
tive two-dimensional NMR experiments (g-HSQC-COSY). IR spectra
were carried out with a Nicolet Avantar 320 FTIR spectrophotome-
ter, and only noteworthy IR absorptions (cm–1) are listed. Optical
rotations were measured with a Perkin–Elmer 241 polarimeter. [α]D
values are given in 10–1 deg cm2 g–1. High-resolution mass spectra
(HRMS; LC/MSD TOF Agilent Technologies) were carried out by Cen-
tres Científics i Tecnològics of the University of Barcelona.
undergo Grob fragmentation, gave (76 % yield) a nearly equi-
(3R,6R,8aS)-6-(3,5-Difluorobenzyl)-5-oxo-3-phenyl-2,3,6,7,8,8a-
hexahydro-5H-oxazolo[3,2-a]pyridine (2c): LiHMDS (4.5 mL,
4.49 mmol) was added to a solution of the lactam (3R,8aS)-5-
oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine[1a]
(650 mg, 3.00 mmol) in anhydrous THF (34 mL) at –78 °C, and the
mixture was stirred at –78 °C for 1 h. Then, 3,5-difluorobenzyl
bromide (0.46 mL, 3.59 mmol) was added. The mixture was stirred
at –78 °C for 8 h, and then at room temperature for 15 h. The
reaction was quenched by the addition of NH4Cl, and the resulting
mixture was extracted with EtOAc. The combined organic extracts
Scheme 2. Proposed mechanism for the LiNH2BH3 reduction.
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were dried, and filtered, and the solvents were evaporated. The re- chromatography (hexane/EtOAc, 1:1) to give pure compound 4b
sulting residue was purified by chromatography (from hexane/
EtOAc, 9:1, to EtOAc) to give 2c (450 mg, 44 %) as a colorless oil,
along with its 6S epimer (120 mg, 12 %), and (3R,8aS)-6,6-bis(3,5-
(630 mg, 80 %). [α]D22 = –121.2 (c = 1.1, CHCl3). IR (film): ν = 1655,
˜
1454 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
2.27 (ddd, J = 12.9, 9.6, 5.9 Hz, 1 H, 8-H), 2.52 (dt, J = 12.9, 5.0 Hz,
difluorobenzyl)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxa- 1 H, 8-H), 2.66 (d, J = 5.4 Hz, 2 H, 6-H), 3.52 (ddd, J = 9.6, 5.4, 5.0 Hz,
zolo[3,2-a]pyridine (40 mg, 3 %). Data for 2c: [α]D22 = +12.4 (c = 0.8, 1 H, 7-H), 4.02 (dd, J = 9.0, 1.4 Hz, 1 H, 2-H), 4.11 (dd, J = 9.0, 6.8 Hz,
1
CHCl3). IR (film): ν = 1649 cm–1. H NMR (300 MHz, CDCl3, COSY, g-
1 H, 2-H), 4.71 (dd, J = 9.3, 4.2 Hz, 1 H, 8a-H), 4.96 (t, J = 5.7 Hz, 1
˜
HSQC, 25 °C): δ = 1.46–1.55 (m, 2 H, 7-H, 8-H), 1.81–1.86 (m, 1 H, 7-
H, CHN), 7.22–7.37 (m, 10 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
H), 2.30–2.36 (m, 1 H, 8-H), 2.60–2.65 (m, 1 H, 6-H), 3.02–3.10 (m, 2 25 °C): δ = 35.2 (C-7, C-8), 36.8 (C-6), 58.7 (C-3), 73.9 (C-2), 86.0 (C-
H, CH2Ar), 3.68 (dd, J = 9.0, 8.1 Hz, 1 H, 2-H), 4.49 (dd, J = 9.0, 8.1 Hz,
1 H, 2-H), 4.88 (m, 1 H, 8a-H), 5.24 (t, J = 8.1 Hz, 1 H, 3-H), 6.65–6.69
(m, 3 H, F-ArH), 7.17–7.20 (m, 2 H, ArH), 7.26–7.37 (m, 3 H, ArH)
ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 22.1 (C-7), 27.9 (C-8),
37.5 (CH2Ar), 43.0 (C-6), 58.5 (C-3), 72.9 (C-2), 88.7 (C-8a), 101.8 (t,
JC,F = 24.7 Hz, F-Ar C-4), 112.2 (dd, JC,F = 16.7, 7.5 Hz, F-Ar C-2 and
8a), 126.4 (C-o), 126.8 (C-o), 126.9 (C-p), 127.6 (C-p), 128.6 (C-m),
128.8 (C-m), 141.3 (C-i), 143.0 (C-i), 167.1 (NCO) ppm. HRMS (ESI-
TOF): calcd. for C19H20NO2 [M + H]+ 294.1489; found 294.1489.
(3R,7R,8aS)-3,7-Diphenyl-5-oxo-2,3,6,7,8,8a-hexahydro-5H-ox-
azolo[3,2-a]pyridine (5): TFA (trifluoroacetic acid; 1.6 mL,
20.4 mmol) was added to a solution of pure lactam 4b (630 mg,
2.15 mol) in anhydrous CH2Cl2 (66 mL), and the mixture was stirred
at room temperature for 47 h. The resulting acidic solution was
C-6), 125.7 (C-o), 127.5 (C-p), 128.8 (C-m), 139.2 (C-i), 142.7 (t, JC,F
=
9.2 Hz, F-Ar C-1), 162.8 (dd, JC,F = 247.9, 13.2 Hz, F-Ar C-3 and C-5),
169.9 (CO) ppm. HRMS (ESI-TOF): calcd. for C20H20F2NO2 [M + H]+
344.1457; found 344.1454.
neutralized with NaHCO3 (2
N aq.; 25 mL). The organic phase was
separated, and the aqueous layer was extracted with CH2Cl2. The
Data for the 6S epimer: [α]D22 = –105.1 (c = 0.55, CHCl3). IR (film): ν = combined organic solutions were dried and concentrated, and the
˜
1724 cm–1 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = residue was purified by chromatography (hexane/EtOAc, 1:1) to give
.
1.59–1.69 (m, 2 H, 7-H, 8-H), 1.70–1.78 (m, 1 H, 7-H), 2.13–2.20 (m,
1 H, 8-H), 2.64 (m, 2 H, 6-H, CH2Ar), 3.01 (m, 1 H, CH2Ar), 3.78 (dd,
J = 9.0, 7.9 Hz, 1 H, 2-H), 4.77 (dd, J = 9.0, 7.9 Hz, 1 H, 2-H), 5.00 (m,
1 H, 8a-H), 5.28 (t, J = 7.9 Hz, 1 H, 3-H), 6.63 (m, 1 H, F-ArH), 6.68–
pure 5 (610 mg, 97 %). [α]D22 = –58.2 (c = 1.0, CHCl3). IR (film): ν =
˜
1647, 1454 cm–1 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C):
.
δ = 1.87 (ddd, J = 13.3, 12.4, 9.3 Hz, 1 H, 8-H), 2.47 (dd, J = 18.0,
12.0 Hz, 1 H, 6-H), 2.56 (dm, 1 H, 8-H), 2.84 (ddd, J = 18.0, 5.6,
6.76 (m, 2 H, F-ArH), 7.25–7.29 (m, 3 H, ArH), 7.32–7.36 (m, 2 H, ArH) 1.72 Hz, 1 H, 6-H), 3.20 (m, 1 H, 7-H), 3.84 (dd, J = 9.0, 7.9 Hz, 1 H,
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 20.4 (C-7), 25.2 (C-8),
36.7 (CH2Ar), 41.4 (C-6), 58.4 (C-3), 72.3 (C-2), 88.2 (C-8a), 101.8 (t,
JC,F = 25.2 Hz, F-Ar C-4), 111.8 (dd, JC,F = 17.9, 6.2 Hz, F-Ar C-2 and
2-H), 4.56 (dd, J = 9.0, 7.9 Hz, 1 H, 2-H), 5.20 (dd, J = 9.3, 4.5 Hz, 1
H, 8a-H), 5.32 (t, J = 7.9 Hz, 1 H, CHN), 7.21–7.37 (m, 10 H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 35.3 (C-7, C-8), 39.7
(C-6), 58.0 (C-3), 72.7 (C-2), 88.4 (C-8a), 126.1 (C-o), 126.4 (C-o), 127.0
(C-p), 127.6 (C-p), 128.7 (C-m), 128.8 (C-m), 139.3 (C-i), 142.4 (C-i),
168.1 (NCO) ppm. HRMS (ESI-TOF): calcd. for C19H20NO2 [M + H]+
294.1489; found 294.1496.
C-6), 126.2 (C-o), 127.6 (C-p), 128.7 (C-m), 139.4 (C-i), 143.7 (t, JC,F
=
9.3 Hz, F-Ar C-1), 163.0 (dd, JC,F = 249.2, 13.3 Hz, F-Ar C-3 and C-5),
170.4 (CO) ppm. HRMS (ESI-TOF): calcd. for C20H20F2NO2 [M + H]+
344.1457; found 344.1454.
Data for (3R,8aS)-6,6-bis(3,5-difluorobenzyl)-5-oxo-3-phenyl-
(3R,6R,7R,8aR)-6,7-(Isopropylidenedioxy)-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine: [α]D22 = –29.6 (c = 2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (10): (3R,8aR)-
1.25, CHCl3). IR (film): ν = 1636 cm–1
.
1H NMR (300 MHz, CDCl3,
5-Oxo-3-phenyl-2,3,8,8a-tetrahydro-5H-oxazolo[3,2-a]pyridine[1d]
(600 mg, 2.79 mmol) was dissolved in CH3CN (28 mL) and H2O
˜
COSY, g-HSQC, 25 °C): δ = 1.06–1.25 (m, 1 H, 7-H), 1.72–1.77 (m, 2
H, 7-H, 8-H), 2.00–2.09 (m, 1 H, 8-H), 2.35 (d, J = 12.9 Hz, 1 H, CH2Ar), (0.1 mL), and N-methylmorpholine N-oxide (323 mg, 2.79 mmol)
2.78 (d, J = 13.3 Hz, 1 H, CH2Ar), 3.28 (d, J = 13.3 Hz, 1 H, CH2Ar),
3.33 (d, J = 12.9 Hz, 1 H, CH2Ar), 3.63 (dd, J = 9.2, 8.1 Hz, 1 H, 2-H),
4.37 (dd, J = 9.2, 8.1 Hz, 1 H, 2-H), 4.65 (dd, J = 9.0, 4.5 Hz, 1 H, 8a-
H), 5.15 (t, J = 8.1 Hz, 1 H, 3-H), 6.47–6.51 (m, 2 H, F-ArH), 6.67–6.77
(m, 1 H, F-ArH), 7.05–7.09 (m, 2 H, ArH), 7.31–7.44 (m, 3 H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 23.8 (C-7), 25.3 (C-8),
44.4 (CH2Ar), 44.8 (CH2Ar), 47.6 (C-6), 59.4 (C-3), 73.1 (C-2), 88.4 (C-
8a), 102.3 (t, JC,F = 24.9 Hz, F-Ar C-4), 102.6 (t, JC,F = 25.6 Hz, F-Ar C-
and OsO4 (2.5 % solution in tBuOH; 1.0 mL) were added. The mix-
ture was stirred at room temperature for 17 h. The resulting solution
was quenched with saturated aqueous Na2S2O5, and the mixture
was stirred for an additional 1 h. The aqueous layer was extracted
with EtOAc, and the combined organic extracts were dried, filtered,
and concentrated. The resulting residue was purified by chromatog-
raphy (EtOAc/EtOH, 8:2), to give (3R,6R,7R,8aR)-6,7-dihydroxy-5-oxo-
3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (390 mg,
4), 113.2 (dd, JC,F = 17.9, 6.9 Hz, F-Ar C-2 and C-6), 113.6 (dd, JC,F
=
62 %). [α]D22 = +9.31 (c = 0.13, EtOH). IR (film): ν = 3416, 1654,
˜
17.9, 7.0 Hz, F-Ar C-2 and C-6), 126.1 (C-o), 127.7 (C-p), 128.9 (C-m), 1469 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
138.8 (C-i), 140.6 (t, JC,F = 8.5 Hz, F-Ar C-1), 141.0 (t, JC,F = 9.3 Hz, F-
Ar C-1), 162.5 (dd, JC,F = 248.5, 12.8 Hz, F-Ar C-3 and C-5), 162.9 (dd,
JC,F = 249.2, 13.3 Hz, F-Ar C-3 and C-5), 171.1 (CO) ppm. HRMS (ESI-
TOF): calcd. for C27H24F4NO2 [M + H]+ 470.1738; found 470.1736.
1.97–2.04 (m, 1 H, 8-H), 2.78 (dt, J = 13.3, 4.0 Hz, 1 H, 8-H), 2.84 (s,
1 H, OH), 2.85 (s, 1 H, OH), 3.93 (d, J = 3.2 Hz, 1 H, 6-H), 4.11 (dd,
J = 9.0, 2.0 Hz, 1 H, 2-H), 4.27 (dd, J = 9.0, 7.5 Hz, 1 H, 2-H), 4.46 (m,
1 H, 7-H), 4.89 (dd, J = 7.5, 2.0 Hz, 1 H, 3-H), 5.21 (dd, J = 9.8, 4.0 Hz,
1 H, 8a-H), 7.26–7.32 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 32.1 (C-8), 58.3 (C-3), 66.1 (C-7), 70.9 (C-6), 74.7 (C-2),
86.5 (C-8a), 126.6 (C-o), 127.9 (C-p), 128.6 (C-m), 140.5 (C-i), 167.8
(NCO) ppm. HRMS (ESI-TOF): calcd. for C13H16NO4 [M + H]+
250.1074; found 250.1075.
(3R,7R,8aR)-3,7-Diphenyl-5-oxo-2,3,6,7,8,8a-hexahydro-5H-ox-
azolo[3,2-a]pyridine (4b): A solution of (3R,7R,8aR)-6-(benzyloxy-
carbonyl)-5-oxo-3,7-diphenyl-2,3,6,7,8,8a-hexahydro-5H-ox-
azolo[3,2-a]pyridine[1d] (1.15 g, 2.69 mmol) in anhydrous MeOH
(100 mL) containing Pd/C (10 %; 115 mg) was stirred under
hydrogen at 25 °C for 17 h. The catalyst was removed by filtration, p-Toluenesulfonic acid (39 mg, 0.22 mmol) and dimethoxypropane
and the filter residue was washed with hot MeOH. The combined
organic solutions were concentrated to give an oil, which was dis-
solved in toluene (80 mL). The solution was heated to reflux for 3 h,
then it was cooled and concentrated. The residue was purified by
(1.07 mL, 8.74 mmol) were added to a solution of the above diol
(390 mg, 1.56 mmol) in CH2Cl2 (7.8 mL), and the mixture was stirred
at room temperature overnight. Solid sodium acetate (2.9 g) was
then added, and the mixture was stirred for 20 min. The mixture
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was then poured into saturated aqueous NaHCO3, and extracted
was added to a solution of lactam (1.0 equiv.) in anhydrous THF,
with CH2Cl2. The combined organic extracts were washed with satu- and the mixture was stirred at 40 °C for 1–2 h. The reaction mixture
rated aqueous NaCl, dried, filtered, concentrated. The residue was
was quenched with H2O, and the resulting solution was extracted
with Et2O. The combined organic extracts were dried, filtered, and
purified by flash chromatography (hexane/EtOAc, 1:1) to give 10
(350 mg, 77 %). [α]D22 = –48.2 (c = 1.05, CHCl3). IR (film): ν = 1664, concentrated, and the residue was purified by flash chromatogra-
˜
1448 cm–1 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = phy. The preparation of 4-substituted amino diols 18a–18e has
.
1.37 (s, 3 H, CH3), 1.48 (s, 3 H, CH3), 1.94 (ddd, J = 13.7, 10.1, 3.7 Hz,
1 H, 8-H), 2.71 (dt, J = 13.7, 2.6 Hz, 1 H, 8-H), 4.11 (dd, J = 9.1, 0.8 Hz,
1 H, 2-H), 4.23 (dd, J = 9.1, 6.5 Hz, 1 H, 2-H), 4.43 (d, J = 6.6 Hz, 1
H, 6-H), 4.67–4.70 (m, 1 H, 7-H), 4.98 (d, J = 6.5 Hz, 1 H, 3-H), 5.11
(dd, J = 10.1, 2.6 Hz, 1 H, 8a-H), 7.23–7.34 (m, 5 H, ArH) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 23.5 (CH3), 26.0 (CH3), 33.6 (C-
8), 58.6 (C-3), 71.4 (C-7), 73.8 (C-2), 74.5 (C-6), 84.4 (C-8a), 109.2
(CMe2), 126.5 (C-o), 127.5 (C-p), 128.3 (C-m), 140.3 (C-i), 163.3 (NCO)
ppm. HRMS (ESI-TOF): calcd. for C16H20NO4 [M + H]+ 290.1387;
found 290.1391.
been reported.[3]
(S)-5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-2-methyl-1-pent-
anol (15a)
From Lactam 1a: Following the general procedure, from lactam
1a[18] (475 mg, 2.05 mmol) in THF (5.5 mL), nBuLi (2.5
M solution in
hexanes; 3.53 mL, 8.84 mmol) and NH3·BH3 (273 mg, 8.84 mmol) in
THF (11 mL), a brown oil was obtained. Flash chromatography (from
hexane/EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (S)-1-[(1R)-2-hydroxy-1-
phenylethyl]-3-methylpiperidine[19] (28 mg, 6 %), and 15a (314 mg,
64 %).
(3R,6S,8S,8aR)-8-Ethyl-6-(isobutyl)-5-oxo-3-phenyl-2,3,6,7,8,8a-
hexahydro-5H-oxazolo[3,2-a]pyridine (13b): A solution of lactam
6b[17] (739 mg, 3.0 mol) in anhydrous THF (5 mL) was added to a
From Lactam 2a: Following the general procedure, from lactam
2a[18] (430 mg, 1.86 mmol) in THF (5 mL), nBuLi (2.5
M solution in
hexanes; 3.2 mL, 8.0 mmol), and NH3·BH3 (247 mg, 8.0 mmol) in
THF (10 mL), an oil was obtained. Flash chromatography (from hex-
ane/EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (S)-1-[(1R)-2-hydroxy-1-
phenylethyl]-3-methylpiperidine[19] (21 mg, 5 %), and 15a (257 mg,
58 %).
cooled (–78 °C) solution of LiHMDS (1
M in THF; 4.52 mL, 4.52 mmol)
in anhydrous THF (33 mL). The resulting solution was stirred at
–78 °C for 1 h, then 1-iodo-2-methylpropane (0.87 mL, 7.53 mmol)
was added, and stirring was continued at –78 °C for 6 h and then
at room temperature for an additional 12 h. The reaction was
quenched by the addition of saturated aqueous NH4Cl, and the
resulting mixture was extracted with EtOAc. The combined organic
extracts were dried, filtered, and concentrated to give an oil. Flash
chromatography (hexane/EtOAc, 8:2 to 1:1) gave 13b (320 mg,
Data for 15a: [α]D22 = –50.7 (c = 0.76, CHCl3). IR (film): ν = 3330,
˜
1454, 1040 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C):
δ = 0.88 (d, J = 6.7 Hz, 3 H, CH3), 1.10–1.19 (m, 1 H, 3-H), 1.39–1.64
(m, 4 H, 2-H, 3-H, 4-H), 2.46–2.58 (m, 2 H, 5-H), 3.27 (br. s, 3 H, NH,
OH), 3.43 (d, J = 6.0 Hz, 2 H, 1-H), 3.61 (dd, J = 10.9, 8.9 Hz, 1 H,
CH2O), 3.72 (dd, J = 10.9, 4.2 Hz, 1 H, CH2O), 3.80 (dd, J = 8.9, 4.2 Hz,
1 H, CHN), 7.25–7.37 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 16.6 (CH3), 26.6 (C-4), 30.4 (C-3), 35.3 (C-2), 47.2 (C-5),
64.7 (CHN), 66.2 (CH2O), 67.5 (C-1), 127.3 (C-o), 127.7 (C-p), 128.6 (C-
m), 139.7 (C-i) ppm. HRMS (ESI-TOF): calcd. for C14H24NO2 [M + H]+
238.1802; found 238.1794.
35 %), and its 6R epimer (95 mg, 11 %). Data for 13b: [α]D22 = –29.4
1
(c = 0.57, CHCl3). IR (film): ν = 2955, 1657 cm–1. H NMR (400 MHz,
˜
CDCl3, COSY, g-HSQC, 25 °C): δ = 0.83 (d, J = 6.5 Hz, 3 H, CH3), 0.89
(d, J = 6.5 Hz, 3 H, CH3), 1.06 (t, J = 7.5 Hz, 3 H, CH3CH2), 1.09–1.16
(m, 1 H, 7-H), 1.21–1.28 (m, 1 H, 8-H), 1.34–1.43 (m, 1 H, CH3CH2),
1.64–1.74 (m, 1 H, CHMe2), 1.76–1.91 [m, 3 H, CH3CH2, CH2(CHMe2)],
2.08–2.14 (ddd, J = 14.0, 7.0, 3.2 Hz, 1 H, 7-H), 2.22–2.30 (m, 1 H, 6-
H), 4.00 (dd, J = 9.0, 1.1 Hz, 1 H, CH2O), 4.12 (dd, J = 9.0, 6.5 Hz, 1
H, CH2O), 4.50 (d, J = 8.8 Hz, 1 H, 8a-H), 4.85 (d, J = 6.5 Hz, 1 H,
CHN), 7.19–7.31 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 10.9 (CH3CH2), 21.0 (CH3), 23.5 (CH3), 24.1 (CH3CH2), 25.0
(CHMe2), 30.4 (C-7), 39.4 (C-6), 40.7 (C-8), 41.0 [CH2(CHMe2)], 59.3
(C-3), 73.7 (C-2), 92.3 (C-8a), 126.4 (C-o), 127.3 (C-p), 128.4 (C-m),
141.8 (C-i), 170.0 (CO) ppm. HRMS (ESI-TOF): calcd. for C19H28NO2
[M + H]+ 302.2115; found 302.2116.
(S)-2-Ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-pent-
anol (15b)
From Lactam 1b: Following the general procedure, from lactam
1b[18] (240 mg, 0.98 mmol) in THF (2.5 mL), nBuLi (2.5
M solution in
hexanes; 1.68 mL, 4.21 mmol), and NH3·BH3 (130 mg, 4.21 mmol)
in THF (5 mL), a brown oil was obtained. Flash chromatography
(from hexane/EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (S)-3-ethyl-1-
[(1R)-2-hydroxy-1-phenylethyl]piperidine[19] (22 mg, 10 %), and 15b
(159 mg, 65 %).
Data for the 6R epimer: [α]D22 = +8.36 (c = 1.1, CHCl3). IR (film): ν =
˜
2956, 1659 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C):
From Lactam 2b: Following the general procedure, from lactam
2b[18] (2.99 g, 12.2 mmol) in THF (25 mL), nBuLi (2.5
M solution in
δ = 0.83 (d, J = 6.5 Hz, 3 H, CH3), 0.89 (d, J = 6.5 Hz, 3 H, CH3), 1.05
(t, J = 7.5 Hz, 3 H, CH3CH2), 1.19–1.26 [m, 1 H, CH2(CHMe2)], 1.32–
1.43 (m, 1 H, CH3CH2), 1.52–1.60 [m, 2 H, 7-H, CH2(CHMe2)], 1.61–
1.68 (m, 1 H, CHMe2), 1.76–1.84 (m, 2 H, CH3CH2, 7-H), 1.87–1.96 (m,
1 H, 8-H), 2.30–2.36 (m, 1 H, 6-H), 4.01 (dd, J = 9.0, 1.1 Hz, 1 H,
CH2O), 4.15 (dd, J = 9.0, 6.9 Hz, 1 H, CH2O), 4.54 (d, J = 8.7 Hz, 1 H,
8a-H), 4.89 (d, J = 5.9 Hz, 1 H, CHN), 7.21–7.32 (m, 5 H, ArH) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.0 (CH3CH2), 21.4 (CH3),
23.1 (CH3), 24.7 (CH3CH2), 25.5 (CHMe2), 29.0 (C-7), 37.6 (C-8), 38.0
(C-6), 40.8 [CH2(CHMe2)], 58.5 (C-3), 73.9 (C-2), 92.3 (C-8a), 126.2 (C-
o), 127.3 (C-p), 128.4 (C-m), 141.7 (C-i), 170.8 (CO) ppm. HRMS (ESI-
TOF): calcd. for C19H27NNaO2 [M + H]+ 324.1934; found 324.1935.
hexanes; 21 mL, 52.4 mmol), and NH3·BH3 (1.62 g, 52.4 mmol) in
THF (50 mL), an oil was obtained. Flash chromatography (from hex-
ane/EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (S)-3-ethyl-1-[(1R)-2-
hydroxy-1-phenylethyl]piperidine[19] (171 mg, 6 %), and 15b (2.45 g,
80 %).
Data for 15b: [α]D22 = –63.9 (c = 0.8, MeOH). IR (film): ν = 3300, 1454,
˜
1037 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
0.83 (t, J = 7.6 Hz, 3 H, CH3), 1.22–1.38 (m, 5 H, CH2CH3, 2-H, 4-H),
1.48 (br. s, 2 H, 3-H), 2.48 (m, 2 H, 5-H), 3.56–3.70 (m, 2 H, 1-H), 3.45
(dd, J = 10.4, 4.8 Hz, 1 H, CH2O), 3.49 (dd, J = 10.4, 3.6 Hz, 1 H,
CH2O), 3.77 (dd, J = 4.8, 3.6 Hz, 1 H, CHN), 7.23–7.30 (m, 5 H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.2 (CH3CH2), 23.5
(CH3CH2), 26.4 (C-3), 27.7 (C-4), 41.5 (C-2), 47.3 (C-5), 64.3 (C-1), 64.7
(CHN), 66.3 (CH2O), 127.3 (C-o), 127.5 (C-p), 128.5 (C-m), 139.9 (C-i)
ppm. HRMS (ESI-TOF): calcd. for C15H26NO2 [M + H]+ 252.1958;
found 252.1955.
General Procedure for the Synthesis of Enantiopure Amino di-
ols 15–26: nBuLi (1.6
M or 2.5 M solution in hexanes; 4.3 equiv.) was
added to a solution of NH3·BH3 (4.3 equiv.) in anhydrous THF at
0 °C, and the resulting mixture was stirred at this temperature for
10 min, and then at room temperature for 15 min. Then, the mixture
Eur. J. Org. Chem. 2016, 693–703
www.eurjoc.org
697
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(R)-2-(3,5-Difluorobenzyl)-5-{[(1R)-2-hydroxy-1-phenyl-
ethyl]amino}-1-pentanol (15c): Following the general procedure,
4-H), 1.77 (m, 1 H, 2-H), 2.52 (m, 2 H, 5-H), 2.55 (m, 1 H, CH2Ar), 2.63
(dd, J = 13.6, 7.5 Hz, 1 H, CH2Ar), 2.83 (br. s, 3 H, NH, OH), 3.47 (dd,
J = 10.8, 5.3 Hz, 1 H, 1-H), 3.56 (dd, J = 10.8, 4.7 Hz, 1 H, 1-H), 3.59–
3.62 (m, 1 H, CH2O), 3.69–3.73 (m, 1 H, CH2O), 3.76–3.78 (m, 1 H,
from lactam 2c (450 mg, 1.31 mmol) in THF (4.5 mL), nBuLi (2.5
M
solution in hexanes; 2.26 mL, 5.64 mmol), and NH3·BH3 (174 mg,
5.64 mmol) in THF (5 mL), an oil was obtained. Flash chromatogra- CHN), 7.13–7.19 (m, 3 H, ArH), 7.24–7.37 (m, 7 H, ArH) ppm. 13C
phy (from hexane/EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (R)-3-(3,5-
difluorobenzyl)-1-[(1R)-2-hydroxy-1-phenylethyl]piperidine (52 mg,
12 %), and 15c (299 mg, 65 %).
NMR (100.6 MHz, CDCl3, 25 °C): δ = 26.7 (C-4), 27.9 (C-3), 37.8
(CH2Ar), 42.2 (C-2), 47.2 (C-5), 64.1 (C-1), 64.6 (CHN), 66.3 (CH2O),
125.8 (C-p), 127.3 (C-p), 127.7 (C-i), 128.3 (C-o), 128.7 (C-o and C-m),
129.1 (C-m), 140.6 (C-i) ppm. HRMS (ESI-TOF): calcd. for C20H28NO2
[M + H]+ 314.2115; found 314.2106.
Data for (R)-3-(3,5-difluorobenzyl)-1-[(1R)-2-hydroxy-1-phenyl-
ethyl]piperidine: 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C):
δ = 1.43–1.72 (m, 4 H, 4-H, 5-H), 1.95–2.00 (m, 1 H, 3-H), 2.37–2.52
(m, 2 H, 2-H), 2.70–2.85 (m, 2 H, 6-H), 2.78–2.85 (m, 2 H, CH2Ar),
3.58–3.75 (m, 2 H, CH2O), 3.93–4.00 (m, 1 H, CHN), 6.60–6.67 (m, 3
H, F-ArH), 7.14–7.17 (dd, J = 7.9, 1.9 Hz, 2 H, ArH), 7.36–7.37 (m, 3
(R)-5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-3-methyl-1-pent-
anol (17a): Following the general procedure, from lactam 4a[1d]
(262 mg, 1.14 mmol) in THF (2 mL), nBuLi (2.5
M solution in hexanes;
1.95 mL, 4.87 mmol), and NH3·BH3 (150 mg, 4.87 mmol) in THF
(4 mL), an oil was obtained. Flash chromatography (from hexane/
EtOAc, 1:1, to EtOAc/EtOH, 8:2) gave 1-[(1R)-2-hydroxy-1-phenyl-
ethyl]-4-methylpiperidine (36 mg, 15 %), and 17a (135 mg, 50 %).
H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 25.3 (d, JC,F
11.7 Hz, C-5), 30.4 (d, JC,F = 29.7 Hz, C-4), 38.0 (d, JC,F = 35.8 Hz, C-
3), 40.5 (CH2Ar), 46.9 (C-6), 52.7 (d, JC,F = 11.7 Hz, C-2), 59.9 (d, JC,F
=
=
3.1 Hz, CHN), 70.1 (d, JC,F = 17.1 Hz, CH2O), 101.4 (dd, JC,F = 24.8,
3.1 Hz, F-Ar C-4), 111.7 (dd, JC,F = 17.9, 6.9 Hz, F-Ar C-2 and C-6),
Data for 1-[(1R)-2-hydroxy-1-phenylethyl]-4-methylpiperidine:
[α]D22 = –18.5 (c = 2.4, CHCl3). IR (film): ν = 3414 cm–1 1H NMR
.
˜
127.9 (C-p), 128.2 (C-o), 128.9 (C-m), 135.1 (C-i), 144.3 (d, JC,F
=
(400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = 0.87 (d, J = 6.0 Hz, 3 H,
CH3), 1.10–1.23 (m, 1 H, 4-H), 1.25–1.34 (m, 2 H, 3-H, 5-H), 1.55–1.72
(m, 3 H, 3-H, 5-H, 2-H or 6-H), 2.29 (ddd, J = 11.3, 11.3, 2.5 Hz, 1 H,
2-H or 6-H), 2.83 (m, 2 H, 2-H, 6-H), 3.20 (br. s, 1 H, OH), 3.62 (dd,
J = 10.1, 5.2 Hz, 1 H, CH2O), 3.70 (dd, J = 10.1, 5.2 Hz, 1 H, CHN),
3.97 (t, J = 10.1 Hz, 1 H, CH2O), 7.17 (m, 2 H, ArH), 7.28–7.36 (m, 3
H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 21.8 (CH3),
30.8 (C-4), 34.6 and 34.9 (C-3 and C-5), 46.2 (C-2 or C-6), 52.8 (C-2
or C-6), 60.0 (CH2O), 69.9 (CHN), 127.7 (C-p), 128.0 (C-o), 128.9 (C-
m), 135.6 (C-i) ppm. HRMS (ESI-TOF): calcd. for C14H22NO [M + H]+
220.1696; found 220.1700.
8.5 Hz, F-Ar C-1), 162.9 (ddd, JC,F = 247.6, 13.3, 3.9 Hz, F-Ar C-3 and
C-5) ppm. HRMS (ESI-TOF): calcd. for C20H23F2NO [M + H]+ 332.1820;
found 332.1820.
Data for 15c: [α]D22 = –33.9 (c = 0.5, CHCl3). IR (film): ν = 3353,
˜
1625 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
1.26–1.31 (m, 1 H, 3-H), 1.35–1.43 (m, 1 H, 3-H), 1.45–1.53 (m, 2 H,
4-H), 1.72 (br. s, 1 H, 2-H), 2.51 (m, 3 H, 5-H, CH2Ar), 2.65–2.70 (m, 1
H, CH2Ar), 3.44 (dd, J = 10.5, 5.2 Hz, 1 H, 1-H), 3.50 (dd, J = 10.5,
6.4 Hz, 1 H, 1-H), 3.55–3.68 (m, 4 H, CH2, OH, NH); 3.72 (dd, J = 10.8,
3.8 Hz, 1 H, CH2O); 3.80 (dd, J = 8.5, 3.8 Hz, 1 H, CHN); 6.59–6.67
(m, 3 H, F-ArH), 7.26–7.31 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ = 26.3 (C-3), 27.7 (C-4), 37.4 (d, JC,F = 9.2 Hz, CH2Ar),
41.7 (d, JC,F = 6.2 Hz, C-2), 47.0 (C-5), 63.2 (C-1), 64.7 (CHN), 66.1
(CH2O), 101.3 (t, JC,F = 24.9 Hz, F-Ar C-4), 111.7 (dd, JC,F = 18.7,
6.2 Hz, F-Ar C-2 and C-6), 127.3 (C-o), 127.8 (C-p), 128.7 (C-m), 139.2
(C-i), 144.7 (t, JC,F = 9.3 Hz, F-Ar C-1), 162.8 (dd, JC,F = 247.7, 13.3 Hz,
F-Ar C-3 and C-5) ppm. HRMS (ESI-TOF): calcd. for C20H26F2NO2 [M
+ H]+ 350.1926; found 350.1926.
Data for 17a: [α]D22 = –51.9 (c = 0.84, CHCl3). IR (film): ν = 3320,
˜
1454 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
0.86 (d, J = 6.6 Hz, 3 H, CH3), 1.28–1.42 (m, 2 H, 2-H, 4-H), 1.46–1.59
(m, 2 H, 2-H, 4-H), 1.64–1.72 (m, 1 H, 3-H), 2.44–2.51 (m, 1 H, 5-H),
2.56–2.63 (m, 1 H, 5-H), 3.48 (br. s, 3 H, NH, OH), 3.57–3.63 (m, 2 H,
1-H, CH2O), 3.65–3.72 (m, 2 H, 1-H, CH2O), 3.78 (dd, J = 8.9, 4.1 Hz,
1 H, CHN), 7.24–7.35 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 19.8 (CH3), 27.2 (C-3), 36.5 (C-4), 39.4 (C-2), 44.8 (C-5),
60.1 (C-1), 64.9 (CHN), 66.3 (CH2O), 127.2 (C-o), 127.6 (C-p), 128.5 (C-
m), 139.9 (C-i) ppm. HRMS (ESI-TOF): calcd. for C14H24NO2 [M + H]+
238.1802; found 238.1802.
(S)-2-Benzyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-pent-
anol (16): Following the general procedure, from lactam 3[18]
(453 mg, 1.47 mmol) in THF (3 mL), nBuLi (2.5
M solution in hexanes;
(R)-5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-3-phenyl-1-pent-
anol (17b)
2.54 mL, 6.34 mmol), and NH3·BH3 (196 mg, 6.34 mmol) in THF
(6 mL), an oil was obtained. Flash chromatography (from hexane/
EtOAc, 1:1, to EtOAc/EtOH, 8:2) gave (S)-3-benzyl-1-[(1R)-2-hydroxy-
1-phenylethyl]piperidine (23 mg, 5 %), and 16 (300 mg, 65 %).
From Lactam 4b: Following the general procedure, from lactam 4b
(240 mg, 0.82 mmol) in THF (2.5 mL), nBuLi (2.5
M solution in hex-
anes; 1.41 mL, 3.52 mmol), and NH3·BH3 (109 mg, 3.52 mmol) in
THF (5 mL), an oil was obtained. Flash chromatography (from hex-
ane/EtOAc, 1:1, to EtOAc/EtOH, 8:2) gave 1-[(1R)-2-hydroxy-1-phen-
ylethyl]-4-phenylpiperidine (35 mg, 15 %), and 17b (105 mg, 43 %).
Data for (S)-3-benzyl-1-[(1R)-2-hydroxy-1-phenylethyl]piperidine:
[α]D22 = +2.1 (c = 0.45, CHCl3). IR (film): ν = 3386, 1453 cm–1. 1H NMR
˜
(400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = 1.19–1.33 (m, 1 H, 4-H),
1.53–1.68 (m, 4 H, 2-H, 4-H, 5-H), 1.74–1.86 (m, 1 H, 3-H), 2.29–2.35
(m, 1 H, 2-H), 2.36 (dd, J = 13.5, 8.1 Hz, 1 H, CH2Ar), 2.56 (dd, J =
13.5, 6.5 Hz, 1 H, CH2Ar), 2.75 (m, 1 H, 6-H), 2.83 (m, 1 H, 6-H), 3.61
(dd, J = 10.3, 5.1 Hz, 1 H, CH2O), 3.74 (dd, J = 10.3, 5.1 Hz, 1 H,
CHN), 3.97 (t, J = 10.3 Hz, 1 H, CH2O), 7.09–7.38 (m, 10 H, ArH) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 25.4 (C-5), 30.3 (C-4), 38.2
(C-3), 40.8 (CH2Ar), 52.8 (C-6), 52.8 (C-2), 59.8 (CH2O), 70.1 (CHN),
125.9 (C-p), 127.9 (C-p), 128.2 (C-o), 128.3 (C-o), 129.0 (C-m), 129.1
(C-m), 135.0 (C-i), 140.2 (C-i) ppm. HRMS (ESI-TOF): calcd. for
C20H26NO [M + H]+ 296.2009; found 296.2010.
From Lactam 5: Following the general procedure, from lactam 5
(510 mg, 1.74 mmol) in THF (9 mL), nBuLi (2.5
M solution in hexanes;
3.0 mL, 7.48 mmol), and NH3·BH3 (231 mg, 7.48 mmol) in THF
(18 mL), an oil was obtained. Flash chromatography (from hexane/
EtOAc, 1:1, to EtOAc/EtOH, 8:2) gave 1-[(1R)-2-hydroxy-1-phenyl-
ethyl]-4-phenylpiperidine (40 mg, 8 %), and 17b (338 mg, 65 %).
Data for 1-[(1R)-2-hydroxy-1-phenylethyl]-4-phenylpiperidine:
[α]D22 = –6.44 (c = 0.26, CHCl3). IR (film): ν = 3417, 1601, 1493,
˜
1451 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
Data for 16: [α]D22 = –45.3 (c = 1.0, CHCl3). IR (film): ν = 3331, 1494, 1.71 (dt, J = 12.4, 3.7 Hz, 1 H, 3-H or 5-H), 1.79–1.82 (m, 1 H, 4-H),
˜
1453 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = 1.82–1.88 (m, 3 H, 3-H, 5-H), 2.32–2.40 (m, 1 H, 2-H or 6-H), 2.42–
1.30–1.37 (m, 1 H, 3-H), 1.37–1.48 (m, 1 H, 3-H), 1.48–1.57 (m, 2 H,
2.48 (m, 1 H, 2-H or 6-H), 2.98–3.05 (m, 2 H, 2-H, 6-H), 3.66 (dd, J =
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Full Paper
10.4, 5.2 Hz, 1 H, CH2O), 3.76 (dd, J = 10.4, 5.2 Hz, 1 H, CHN), 4.02
(t, J = 10.4 Hz, 1 H, CH2O), 7.16–7.39 (m, 10 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 33.7 and 34.1 (C-3 and C-5), 42.6 (C-
4), 46.4 and 53.5 (C-2 and C-6), 60.1 (CH2O), 70.1 (CHN), 126.1 (C-p),
epimers. Data for 20: IR (film): ν = 3350, 1453 cm–1 1H NMR
.
(400 MHz, CDCl3, COSY, g-HSQC, 25 °C, mixture of diastereomers):
δ = 0.98 (d, J = 6.4 Hz, CH3), 1.02 (d, J = 6.2 Hz, CH3), 1.26–1.55 (m,
2-H, 3-H, 4-H), 2.50–2.55 (m, 5-H), 2.59–2.67 (m, 5-H), 3.40 (br. s, OH,
˜
126.7 (C-o), 127.9 (C-p), 128.1 (C-o), 128.4 (C-m), 128.9 (C- m), 135.5 NH), 3.51–3.74 (m, 1-H, CH2O), 3.87 (dd, J = 8.6, 4.3 Hz, 1 H, CHN),
(C-i), 146.1 (C-i) ppm. HRMS (ESI-TOF): calcd. for C19H24NO [M + H]+
282.1852; found 282.1851.
3.92 (dd, J = 8.5, 4.3 Hz, 1 H, CHN), 7.24–7.35 (m, ArH) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 19.3, 21.2 (CH3), 21.3, 21.8 (C-
3), 32.3, 32.5 (C-2), 35.2, 37.1 (C-4), 49.6, 50.4 (C-5), 61.3, 62.1 (CHN),
61.8, 62.1 (CH2O), 66.2, 66.4 (C-1), 126.6, 127.3 (C-o), 127.4, 127.6 (C-
p), 128.6, 128.6 (C-m), 140.1, 140.7 (C-i) ppm. HRMS (ESI-TOF): calcd.
for C14H24NO2 [M + H]+ 238.1802; found 238.1795.
Data for 17b: [α]D22 = –40.9 (c = 3.0, CHCl3). IR (film): ν = 3321,
˜
1452 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
1.70–1.88 (m, 4 H, 2-H, 4-H), 2.32–2.38 (m, 1 H, 5-H), 2.45–2.51 (m,
1 H, 5-H), 2.61 (br. s, 3 H, NH, OH), 2.80–2.87 (m, 1 H, 3-H), 3.39–
3.46 (m, 1 H, 1-H), 3.48–3.54 (m, 2 H, 1-H, CH2O), 3.62–3.66 (m, 2 H, (S)-2-Benzyl-2-ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-
CH2O, CHN), 7.13–7.31 (m, 10 H, ArH) ppm. 13C NMR (100.6 MHz,
pentanol (21a): Following the general procedure, from lactam
CDCl3, 25 °C): δ = 36.1 (C-4), 39.3 (C-2), 39.8 (C-3), 44.9 (C-5), 60.5 9a[22] (356 mg, 1.06 mmol) in THF (2.5 mL), nBuLi (2.5
solution in
hexanes; 1.83 mL, 4.56 mmol), and NH3·BH3 (141 mg, 4.56 mmol)
M
(C-1), 64.6 (CHN), 65.9 (CH2O), 126.4 (C-p), 127.2 (C-o), 127.5 (C-o),
127.8 (C-p), 128.4 (C-m), 128.5 (C-m), 139.4 (C-i), 144.4 (C-i) ppm.
HRMS (ESI-TOF): calcd. for C19H26NO2 [M + H]+ 300.1958; found
300.1957.
in THF (5 mL), and after flash chromatography (from EtOAc to
EtOAc/EtOH, 8:2), amino alcohol 21a (250 mg, 69 %) was obtained.
[α]D22 = –28.4 (c = 0.96, CHCl3). IR (film): ν = 3384, 1601, 1494,
˜
1452 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
(R)-5-{[1(R)-2-Hydroxy-1-phenylethyl]amino}-4-methyl-1-pent-
anol (19a): Following the general procedure, from lactam 7a[3]
0.89 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.15–1.20 (m, 2 H, 3-H), 1.22–1.30
(m, 2 H, 4-H), 1.41–1.53 (m, 2 H, CH3CH2), 2.45–2.49 (m, 2 H, 5-H),
2.52 (d, J = 13.2 Hz, 1 H, CH2Ar), 2.60 (d, J = 13.2 Hz, 1 H, CH2Ar),
3.28 (br. s, 2 H, 1-H), 3.58 (dd, J = 11.0, 8.6, Hz, 1 H, CH2O), 3.72 (dd,
J = 11.0, 4.4 Hz, 1 H, CH2O), 3.78 (dd, J = 8.6, 4.4 Hz, 1 H, CHN),
7.16–7.37 (m, 10 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C):
δ = 7.6 (CH3CH2), 23.2 (CH3CH2), 24.8 (C-3), 30.4 (C-4), 39.9 (CH2Ar),
41.5 (C-2), 47.9 (C-5), 64.7 (CHN), 65.4 (C-1), 66.6 (CH2O), 125.9 (C-
p), 127.3 (C-o), 127.7 (C-p), 127.9 (C-o), 128.7 (C-m), 130.4 (C-m),
138.6 (C-i), 140.4 (C-i) ppm. HRMS (ESI-TOF): calcd. for C22H32NO2 [M
+ H]+ 342.2428; found 342.2425.
(400 mg, 1.73 mmol) in THF (4 mL), nBuLi (2.5
M solution in hexanes;
2.98 mL, 7.44 mmol), and NH3·BH3 (230 mg, 7.44 mmol) in THF
(8 mL), a brown oil was obtained. Flash chromatography (from hex-
ane/EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (R)-1-[(1R)-2-hydroxy-1-
phenylethyl]-3-methylpiperidine[19] (35 mg, 11 %), and 19a
(225 mg, 55 %) as a colorless oil. Data for 19a: [α]D22 = –57.4 (c =
0.9, MeOH). IR (film): ν = 3328, 1492, 1453, 1056 cm–1 1H NMR
.
˜
(400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = 0.88 (d, J = 6.7 Hz, 3 H,
CH3), 1.15–1.20 (m, 1 H, 2-H), 1.40–1.50 (m, 2 H, 2-H, 3-H), 1.55–1.65
(m, 2 H, 3-H, 4-H), 2.36 (m, 2 H, 5-H), 3.27 (br. s, 3 H, OH, NH), 3.55–
3.58 (m, 3 H, 1-H, CH2O), 3.64 (m, 1 H, CHN), 3.70 (m, 1 H, CH2O),
(S)-2-Allyl-2-ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-
7.23–7.35 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): pentanol (21b): Following the general procedure, from lactam
δ = 18.0 (CH3), 29.5 (C-3), 30.5 (C-2), 32.7 (C-4), 53.5 (C-5), 62.3 (C- 9b[22] (400 mg, 1.40 mmol) in THF (2.5 mL), nBuLi (2.5
M solution in
1), 64.8 (CHN), 66.5 (CH2O), 127.3 (C-o), 127.7 (C-p), 128.4 (C-m), hexanes; 2.4 mL, 6.03 mmol), and NH3·BH3 (186 mg, 6.03 mmol) in
140.3 (C-i) ppm. HRMS (ESI-TOF): calcd. for C14H24NO2 [M + H]+
238.1802; found 238.1796.
THF (5.5 mL), an oil was obtained. Flash chromatography (from hex-
ane/EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (S)-3-allyl-3-ethyl-1-[(1R)-
2-hydroxy-1-phenylethyl]piperidine (33 mg, 9 %) and 21b (227 mg,
56 %).
(R)-4-Ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-pentanol
(19b): Following the general procedure, from lactam 7b[17] (395 mg,
1.61 mmol) in THF (3 mL), nBuLi (2.5
M
solution in hexanes; 2.77 mL,
Data for (S)-3-allyl-3-ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]piper-
6.92 mmol), and NH3·BH3 (214 mg, 6.92 mmol) in THF (6 mL), a
brown oil was obtained. Flash chromatography (from hexane/
EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (R)-3-ethyl-1-[(1R)-2-hydroxy-1-
phenylethyl]piperidine[17] (35 mg, 9 %), and 19b (202 mg, 50 %).
idine: [α]D22 = –19.5 (c = 0.5, CHCl3). IR (film): ν = 3440, 1637,
˜
1452 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
0.80 (t, J = 7.6 Hz, 3 H, CH3), 1.15–1.28 (m, 2 H, CH2), 1.31 (m, 2 H,
5-H), 1.60 (m, 2 H, CH2), 2.04–2.18 (m, 2 H, 4-H), 2.20 (m, 2 H, 2-H),
Data for 19b: [α]D22 = –48.8 (c = 0.7, CHCl3). IR (film): ν = 3329, 1453, 2.54 (br. s, 2 H, 6-H), 3.59–3.66 (m, 2 H, CHN, CH2O), 3.99 (t, J =
˜
1058 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = 9.6 Hz, CH2O), 5.03 (m, 2 H, CH2=CH), 5.70–5.80 (m, 1 H, CH2=CH),
0.80 (t, J = 7.5 Hz, 3 H, CH3), 1.28–1.35 (m, 2 H, CH3CH2), 1.36–1.43 7.15–7.35 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C):
(m, 2 H, 3-H), 1.43–1.54 (m, 3 H, 2-H, 4-H), 2.36 (dd, J = 11.5, 6.0 Hz,
1 H, 5-H), 2.48 (dd, J = 11.5, 5.6 Hz, 1 H, 5-H), 3.29 (br. s, 3 H, OH,
NH), 3.59 (obscured signal, 1 H, CH2O), 3.60 (t, J = 6.4 Hz, 2 H, 1-H),
3.72–3.77 (m, 2 H, CH2O, CHN), 7.24–7.36 (m, 5 H, ArH) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 10.8 (CH3), 24.5 (CH3CH2), 27.4
(C-3), 29.2 (C-2), 39.4 (C-4), 50.4 (C-5), 62.5 (C-1), 65.2 (CHN), 66.4
(CH2O), 127.2 (C-o), 127.5 (C-p), 128.5 (C-m), 140.5 (C-i) ppm. HRMS
(ESI-TOF): calcd. for C15H26NO2 [M + H]+ 252.1958; found 252.1954.
δ = 7.15 (CH3), 21.9 (CH2), 28.3 (C-5), 33.4 (CH2), 36.2 (C-3), 39.3 (C-
4), 49.9 (C-6), 58.6 (C-2), 60.1 (CH2O), 70.2 (CHN), 117.1 (CH2=CH),
127.8 (C-p), 128.0 (C-o), 128.9 (C-m), 134.6 (CH2=CH), 135.3 (C-i)
ppm. HRMS (ESI-TOF): calcd. for C18H28NO [M + H]+ 274.2165; found
274.2161.
Data for 21b: [α]D22 = –34.3 (c = 0.8, CHCl3). IR (film): ν = 3331,
˜
1454 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
0.76 (t, J = 7.2 Hz, 3 H, CH3), 1.12–1.14 (m, 4 H, CH3CH2, 3-H), 1.40–
5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-5-methyl-1-pentanol 1.45 (m, 2 H, 4-H), 1.89 (dd, J = 14.0, 7.6 Hz, 1 H, CH2=CHCH2), 1.98
(20): Following the general procedure, from lactam 8[20] (209 mg,
0.90 mmol) in THF (1.5 mL), nBuLi (1.6 solution in hexanes;
2.43 mL, 3.89 mmol), and NH3·BH3 (120 mg, 3.89 mmol) in THF
(3 mL), an oil was obtained. Flash chromatography (from hexane/
EtOAc, 1:1, to EtOAc/EtOH, 8:2) gave 1-[(1R)-2-hydroxy-1-phenyl-
ethyl]-2-methylpiperidine[21] (32 mg, 16 %) as a 1:1 mixture of C-2
epimers, and amino diol 20 (105 mg, 50 %) as a 1:1 mixture of C-5
(dd, J = 14.0, 7.6 Hz, 1 H, CH2=CHCH2), 2.44–2.49 (m, 2 H, 5-H), 3.30
(s, 2 H, 1-H), 3.63–3.70 (m, 2 H, CH2O), 3.82 (dd, J = 8.4, 4.0 Hz, 1 H,
CHN), 4.16 (br. s, 3 H, OH, NH), 4.99 (m, 2 H, CH2=CH), 5.68–5.78 (m,
1 H, CH2=CH), 7.30 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 7.2 (CH3CH2), 22.4 (C-4), 25.3 (CH3CH2), 30.6 (C-3), 37.9
(CH2=CHCH2), 40.0 (C-2), 47.6 (C-5), 64.7 (CHN), 65.5 (CH2O), 65.9 (C-
1), 116.9 (CH2=CH), 127.4 (C-o), 127.7 (C-p), 128.5 (C-m), 134.6 (CH2=
M
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CH), 138.9 (C-i) ppm. HRMS (ESI-TOF): calcd. for C18H30NO2 [M + H]+ lactam 13a[18] (525 mg, 2.03 mmol) in THF (3 mL), nBuLi (2.5
M
292.2271; found 292.2266.
solution in hexanes; 3.48 mL, 8.71 mmol), and NH3·BH3 (269 mg,
8.71 mmol) in THF (6 mL), and after flash chromatography (from
(2S,3R)-5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-2,3-(iso-
propylidenedioxy)-1-pentanol (22): Following the general proce-
dure, from lactam 10 (245 mg, 0.85 mmol) in THF (2.5 mL), nBuLi
hexane/EtOAc, 1:1, to EtOAc/EtOH, 8:2), amino alcohol 25a (349 mg,
65 %) was obtained. [α]D22 = –64.7 (c = 1.0, CHCl3). IR (film): ν = 3319,
˜
1454 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
(2.5
M
solution in hexanes; 1.46 mL, 3.64 mmol), and NH3·BH3
0.81 (t, J = 7.4 Hz, 3 H, CH3CH2), 0.86 (d, J = 6.8 Hz, 3 H, CH3), 1.19–
1.37 (m, 4 H, 3-H, CH3CH2), 1.47–1.55 (m, 1 H, 4-H), 1.70–1.77 (m, 1
H, 2-H), 2.29–2.34 (m, 1 H, 5-H), 2.47 (dd, J = 11.6, 4.5 Hz, 1 H, 5-H),
3.42 (m, 2 H, 1-H), 3.50–3.75 (br. m, 3 H, NH, OH), 3.58 (m, 1 H,
CH2O), 3.68 (m, 1 H, CH2O), 3.75 (m, 1 H, CHN), 7.24–7.35 (m, 5 H
ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.0 (CH3CH2),
17.0 (CH3), 25.6 (CH3CH2), 32.7 (C-2), 35.5 (C-3), 36.0 (C-4), 51.1 (C-
5), 65.0 (CHN), 66.5 (CH2O), 67.6 (C-1), 127.3 (C-o), 127.5 (C-p), 128.5
(C-m), 140.1 (C-i) ppm. HRMS (ESI-TOF): calcd. for C16H28NO2 [M +
H]+ 266.2115; found 266.2113.
(112 mg, 3.64 mmol) in THF (6 mL), and after flash chromatography
(from hexane/EtOAc, 1:1, to EtOAc/EtOH, 8:2), amino alcohol 22
(100 mg, 40 %) was obtained. [α]D22 = –38.3 (c = 1.72, CHCl3). IR
1
(film): ν = 3359, 1454, 1044 cm–1. H NMR (400 MHz, CDCl3, COSY,
˜
g-HSQC, 25 °C): δ = 1.33 (s, 3 H, CH3), 1.43 (s, 3 H, CH3), 1.67–1.76
(m, 1 H, 4-H), 1.78–1.85 (m, 1 H, 4-H), 2.61–2.68 (m, 1 H, 5-H), 2.72–
2.78 (m, 1 H, 5-H), 3.22 (br. s, 3 H, NH, OH), 3.55–3.63 (m, 3 H, 1-H,
CH2O), 3.71 (dd, J = 10.9, 4.1 Hz, 1 H, CH2O), 3.78 (dd, J = 8.5, 4.1 Hz,
1 H, CHN), 4.11–4.15 (m, 1 H, 2-H), 4.17–4.22 (m, 1 H, 3-H), 7.27–
7.37 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ =
25.4 (CH3), 28.1 (CH3), 29.0 (C-4), 44.8 (C-5), 61.3 (C-1), 64.7 (CHN), (2S,4S)-4-Ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-2-iso-
66.3 (CH2O), 76.1 (C-3), 77.9 (C-2), 108.0 (CMe2), 127.2 (C-o), 127.7
(C-p), 128.6 (C-m), 139.8 (C-i) ppm. HRMS (ESI-TOF): calcd. for
C16H26NO4 [M + H]+ 296.1856; found 296.1848.
butyl-1-pentanol (25b): Following the general procedure, from
lactam 13b (440 mg, 1.46 mmol) in THF (4.5 mL), n-BuLi (2.5
M
solution in hexanes; 2.5 mL, 6.28 mmol), and NH3·BH3 (194 mg,
6.28 mmol) in THF (8.5 mL), and after flash chromatography (from
hexane/EtOAc, 8:2, to EtOAc/EtOH, 8:2), amino alcohol 25b (254 mg,
(2R,3S)-5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-2,3-(isoprop-
ylidenedioxy)-1-pentanol (23): Following the general procedure,
57 %) was obtained. [α]D22 = –40.4 (c = 1.1, CHCl3). IR (film): ν = 3330,
from lactam 11[23] (420 mg, 1.45 mmol) in THF (7.5 mL), nBuLi (2.5
M
˜
1454 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
solution in hexanes; 2.5 mL, 6.25 mmol), and NH3·BH3 (193 mg,
6.25 mmol) in THF (15 mL), an oil was obtained. Flash chromatogra-
phy (from hexane/EtOAc, 1:1, to EtOAc/EtOH, 8:2) gave (3R,4S)-1-
[(1R)-2-hydroxy-1-phenylethyl]-3,4-(isopropylidenedioxy)piper-
0.83 (t, J = 7.4 Hz, 3 H, CH3CH2), 0.86 (d, J = 3.1 Hz, 3 H, CH3), 0.88
(d, J = 3.1 Hz, 3 H, CH3), 1.03–1.14 (m, 2 H, 3-H, CH2CHMe2), 1.19–
1.30 (m, 3 H, CH3CH2, CH2CHMe2), 1.39–1.45 (m, 2 H, 3-H, 4-H), 1.54
(br. m, 1 H, 2-H), 1.63 (sept, J = 6.7 Hz, 1 H, CHMe2), 2.23 (dd, J =
11.6, 7.7 Hz, 1 H, 5-H), 2.53 (dd, J = 11.6, 3.3 Hz, 1 H, 5-H), 3.00 (br.
m, 3 H, NH, OH), 3.44 (dd, J = 11.1, 4.8 Hz, 1 H, 1-H), 3.58–3.63 (m,
1 H, CH2O), 3.69–3.73 (m, 2 H, 1-H, CH2O), 3.76 (dd, J = 8.9, 3.8 Hz,
1 H, CHN), 7.26–7.37 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 11.4 (CH3CH2), 22.8 (CH3), 22.9 (CH3), 25.2 (CH), 26.7
(CH3CH2), 34.8 (C-3), 36.6 (C-2), 37.6 (C-4), 42.2 (CH2CHMe2), 51.6 (C-
5), 64.5 (C-1), 65.0 (CHN), 66.7 (CH2O), 127.4 (C-o), 127.5 (C-p), 128.5
(C-m), 140.2 (C-i) ppm. HRMS (ESI-TOF): calcd. for C19H34NO2 [M –
Boc]+ 308.2584; found 308.2583.
idine[23] (50 mg, 12 %) and 23 (172 mg, 40 %). Data for 23: [α]D22
=
–45.9 (c = 2.35, CHCl3). IR (film): ν = 3404, 1493 cm–1 1H NMR
.
˜
(400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = 1.31 (s, 3 H, CH3), 1.41
(s, 3 H, CH3), 1.70–1.76 (m, 1 H, 4-H), 1.80–1.88 (m, 1 H, 4-H), 2.59–
2.66 (m, 1 H, 5-H), 2.68–2.74 (m, 1 H, 5-H), 3.57–3.67 (m, 3 H, 1-H,
CH2O), 3.71 (dd, J = 11.0, 4.1 Hz, 1 H, CH2O), 3.82–3.90 (br. m, 4 H,
CHN, OH, NH), 4.11–4.19 (m, 2 H, 2-H, 3-H), 7.27–7.37 (m, 5 H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 25.3 (CH3), 28.0 (CH3),
28.9 (C-4), 44.5 (C-5), 61.1 (C-1), 64.8 (CHN), 66.1 (CH2O), 75.7 (C-3),
77.7 (C-2), 108.0 (CMe2), 127.4 (C-o), 127.9 (C-p), 128.7 (C-m), 138.8
(C-i) ppm. HRMS (ESI-TOF): calcd. for C16H26NO4 [M + H]+ 296.1856;
found 296.1857.
(3S,4S)-4-Ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-3-
methyl-1-pentanol (26a): Following the general procedure, from
lactam 14a[1d] (252 mg, 0.97 mmol) in THF (3 mL), nBuLi (2.5
M
(2S,4S)-2-Benzyl-4-ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]-
amino}-1-pentanol (24): Following the general procedure, from
solution in hexanes; 1.67 mL, 4.18 mmol), and NH3·BH3 (129 mg,
4.18 mmol) in THF (6 mL), an oil was obtained. Flash chromatogra-
phy (from hexane/EtOAc, 8:2, to EtOAc/EtOH, 8:2) gave (3S,4S)-3-
ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-4-methylpiperidine (32 mg,
13 %) and 26a (142 mg, 55 %).
lactam 12[18] (524 mg, 1.54 mmol) in THF (4.5 mL), nBuLi (2.5
M
solution in hexanes; 2.69 mL, 6.72 mmol), and NH3·BH3 (207 mg,
6.72 mmol) in THF (9 mL), and after flash chromatography (from
hexane/EtOAc, 7:3, to EtOAc/EtOH, 8:2), amino alcohol 24 (295 mg,
55 %) was obtained. [α]D22 = –54.0 (c = 0.38, CHCl3). IR (film): ν = Data for (3S,4S)-3-ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-4-methyl-
˜
3338, 1494, 1453 cm–1 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, piperidine: [α]D22 = –22.3 (c = 0.3, CHCl3). IR (film): ν = 3330,
.
˜
25 °C): δ = 0.74 (t, J = 7.4 Hz, 3 H, CH3CH2), 1.14–1.23 (m, 3 H, 3-H,
CH3CH2), 1.35–1.40 (m, 1 H, 4-H), 1.44–1.51 (m, 1 H, 3-H), 1.73–1.80
(m, 1 H, 2-H), 2.23 (dd, J = 11.6, 8.2 Hz, 1 H, 5-H), 2.50 (dd, J = 11.6,
4.0 Hz, 1 H, 5-H), 2.53 (dd, J = 13.5, 6.8 Hz, 1 H, CH2Ar), 2.67 (dd,
1454 cm–1 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
.
0.73 (d, J = 7.2 Hz, 3 H, CH3), 0.89 (t, J = 7.2 Hz, 3 H, CH3CH2), 1.29
(m. 2 H, CH3CH2), 1.43 (m, 1 H, 4-H), 1.51 (br. m, 1 H, 5-H), 1.58 (br.
m, 1 H, 3-H), 1.70 (br. m, 1 H, 5-H), 2.17–2.48 (br. m, 4 H, 2-H and 6-
J = 13.5, 7.9 Hz, 1 H, CH2Ar), 2.99 (br. s, 3 H, NH, OH), 3.45 (dd, J = H), 3.66 (m, 1 H, CH2O), 3.72 (m, NCH), 3.99 (t, J = 10.0 Hz, 1 H,
11.5, 4.3 Hz, 1 H, 1-H), 3.58 (dd, J = 10.4, 9.2 Hz, 1 H, CH2O), 3.67 CH2O), 7.18–7.37 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
(dd, J = 11.5, 3.8 Hz, 1 H, 1-H), 3.68–3.69 (m, 1 H, CH2O), 3.71–3.76 25 °C): δ = 11.9 (CH3CH2), 14.1 (CH3), 22.7 (CH3CH2), 28.4 (C-4), 31.5
(m, 1 H, CHN), 7.15–7.19 (m, 3 H, ArH), 7.24–7.37 (m, 7 H, ArH) ppm.
(C-5), 41.2 (C-3), and 51.0 (C-2 and C-6), 60.1 (CH2O), 70.2 (CHN),
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.1 (CH3), 26.4 (CH3CH2), 127.9 (C-p), 128.0 (C-o), 129.0 (C-m), 135.4 (C-i) ppm. HRMS (ESI-
34.0 (C-3), 37.3 (C-4), 39.1 (CH2Ar), 41.1 (C-2), 51.6 (C-5), 63.3 (C-1),
65.1 (CHN), 66.7 (CH2O), 125.7 (C-o), 127.5 (C-p), 128.2 (C-m), 128.7
(C-p), 129.1 (C-m), 140.9 (C-i) ppm. HRMS (ESI-TOF): calcd. for
C22H31NO2 [M + H]+ 342.2428; found 342.2424.
TOF): calcd. for C16H26NO [M + H]+ 248.2009; found 248.2007.
Data for 26a: [α]D22 = –74.4 (c = 0.7, CHCl3). IR (film): ν = 3330,
˜
1454 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
0.83–0.87 (m, 6 H, 2 CH3), 1.16–1.22 (m, 1 H, CH3CH2), 1.24–1.30 (m,
1 H, 2-H), 1.32–1.40 (m, 2 H, 4-H, CH3CH2), 1.48–1.57 (m, 1 H, 2-H),
1.82–1.88 (m, 1 H, 3-H), 2.35 (dd, J = 12.0, 5.3 Hz, 1 H, 5-H), 2.48
(2S,4S)-4-Ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-2-
methyl-1-pentanol (25a): Following the general procedure, from
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(dd, J = 12.0, 6.6 Hz, 1 H, 5-H), 2.54 (br. s, 3 H, NH, OH), 3.53–3.61
(m, 2 H, 1-H, CH2O), 3.66–3.72 (m, 2 H, 1-H, CH2O), 3.73–3.75 (m, 1
H, CHN), 7.27–7.37 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 12.5 (CH3CH2), 16.8 (CH3), 22.3 (CH3CH2), 30.1 (C-3), 35.8
(dd, J = 10.0, 4.8 Hz, 1 H, 1-H), 4.20 (br. s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 11.0 (CH3CH2), 23.3 (CH3CH2), 27.1
(C-4), 27.3 (C-3), 28.3 [(CH3)3], 40.7 (C-5), 41.4 (C-2), 64.5 (C-1), 78.9
(CMe3), 155.5 (CO) ppm. HRMS (ESI-TOF): calcd. for C12H25NNaO3 [M
(C-2), 44.9 (C-4), 47.7 (C-5), 61.4 (C-1), 65.0 (CHN), 66.6 (CH2O), 127.2 + Na]+ 254.1727; found 254.1724.
(C-o), 127.6 (C-p), 128.6 (C-m), 140.5 (C-i) ppm. HRMS (ESI-TOF):
(R)-5-[(tert-Butoxycarbonyl)amino]-2-(3,5-difluorobenzyl)-1-
pentanol (28c): Following the general procedure, from a solution
(3S,4S)-4-Ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-3- of amino diol 15c (299 mg, 0.86 mmol) in MeOH (15 mL), Pd(OH)2/
calcd. for C16H28NO2 [M + H]+ 266.2115; found 266.2117.
phenyl-1-pentanol (26b): Following the general procedure, from
lactam 14b[1d] (187 mg, 0.58 mmol) in THF (2 mL), nBuLi (2.5
solution in hexanes; 1.0 mL, 2.5 mmol), and NH3·BH3 (77 mg,
C (20 %; 60 mg), and Boc2O (225 mg, 1.03 mmol), alcohol 28c
(140 mg, 50 %) was obtained as a colorless oil after column chroma-
tography (from CH2Cl2 to CH2Cl2/Et2O, 8:2). [α]D22 = +1.65 (c = 1.0,
M
2.5 mmol) in THF (4 mL), an oil was obtained. Flash chromatography CHCl3). IR (film): ν = 3362, 1685 cm–1 1H NMR (400 MHz, CDCl3,
.
˜
(from hexane/EtOAc, 7:3, to EtOAc/EtOH, 8:2) gave (3S,4S)-3-ethyl-1- COSY, g-HSQC, 25 °C): δ = 1.22–1.36 (m, 2 H, 3-H), 1.39 [s, 9 H,
[(1R)-2-hydroxy-1-phenylethyl]-4-phenylpiperidine[1d] (36 mg, 20 %)
(CH3)3], 1.40–1.55 (m, 2 H, 4-H), 1.73–1.80 (m, 1 H, 2-H), 2.50 (dd,
and 26b (71 mg, 37 %). Data for 26b: [α]D22 = –87.9 (c = 0.75, CHCl3). J = 13.7, 7.2 Hz, 1 H, CH2Ar), 2.66 (dd, J = 13.7, 7.5 Hz, 1 H, CH2Ar),
IR (film): ν = 3332, 3061, 1453 cm–1. 1H NMR (400 MHz, CDCl3, COSY, 3.03 (br. m, 2 H, 5-H), 3.47 (m, 1 H, 1-H), 3.72 (m, 1 H, 1-H), 4.75 (br.
˜
g-HSQC, 25 °C): δ = 0.81 (t, J = 7.3 Hz, 3 H, CH3CH2), 1.29–1.36 (m,
1 H, CH3CH2), 1.51–1.57 (m, 1 H, CH3CH2), 1.58–1.63 (m, 1 H, 4-H),
1.75–1.83 (m, 1 H, 2-H), 1.90–2.02 (br. m, 4 H, 2-H, NH, OH), 2.20
(dd, J = 12.0, 5.0 Hz, 1 H, 5-H), 2.46 (dd, J = 12.0, 5.3 Hz, 1 H, 5-H),
2.85 (br. m, 1 H, 3-H), 3.32–3.39 (m, 1 H, 1-H), 3.41–3.44 (m, 1 H,
CH2O), 3.46–3.53 (m, 2 H, 1-H, CHN), 3.60 (dd, J = 10.3, 3.9 Hz, 1 H,
s, 1 H, NH), 6.59 (m, 1 H, F-ArH), 6.65 (d, J = 6.0 Hz, 2 H, F-ArH) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 27.3 (C-4), 27.4 (C-3), 28.3
[(CH3)3], 37.3 (d, JC,F = 8.5 Hz, CH2Ar), 40.5 (C-5), 41.7 (C-2), 65.2 (C-
1), 79.2 (CMe3), 101.2 (t, JC,F = 25.7 Hz, F-Ar C-4), 111.7 (dd, JC,F
=
17.9, 6.2 Hz, F-Ar C-2 and C-6), 144.7 (t, JC,F = 8.5 Hz, F-Ar C-1), 156.2
(CO), 162.8 (dd, JC,F = 248.4, 13.2 Hz, F-Ar C-3 and C-5) ppm. HRMS
CH2O), 7.13–7.31 (m, 10 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, (ESI-TOF): calcd. for C13H18F2NO3 [M – C(CH3)3 + H]+ 274.1249; found
25 °C): δ = 11.4 (CH3CH2), 22.1 (CH3CH2), 34.9 (C-2), 43.6 (C-3), 45.7 274.1249.
(C-4), 47.6 (C-5), 61.4 (C-1), 64.8 (CHN), 66.4 (CH2O), 126.3 (C-p), 127.2
(S)-2-Benzyl-5-[(tert-butoxycarbonyl)amino]-1-pentanol (29):
(C-o), 127.4 (C-p), 128.3 (C-o), 128.4 (C-m), 128.5 (C-m), 140.7 (C-i),
Following the general procedure, from a solution of amino diol 16
143.6 (C-i) ppm. HRMS (ESI-TOF): calcd. for C21H30NO2 [M + H]+
(290 mg, 0.93 mmol) in MeOH (15 mL), Pd(OH)2/C (20 %; 58 mg),
and Boc2O (242 mg, 1.11 mmol), alcohol 29 (160 mg, 60 %)
328.2271; found 328.2269.
General Procedure for the Synthesis of Enantiopure Amino
was obtained as a colorless oil after column (from CH2Cl2 to
Alcohols 28–36: A solution of amino diol (1.0 equiv.) in anhydrous
CH2Cl2/EtOH, 8:2). [α]22 = –7.3 (c = 0.7, CHCl3). IR (film): ν = 3349,
˜
D
MeOH containing Pd(OH)2 on activated charcoal was hydrogenated 1693 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
at 75 °C for 22 h under 5 bar of pressure. Then, di-tBu dicarbonate
(1.2 equiv.) was added, and the mixture was stirred at room temper-
1.26–1.35 (m, 1 H, 3-H), 1.36–1.42 (m, 1 H, 3-H), 1.43 [s, 9 H, (CH3)3],
1.49–1.59 (m, 2 H, 4-H), 1.76–1.86 (m, 1 H, 2-H), 1.91 (br. s, 1 H, OH),
ature for 24 h. The catalyst was removed by filtration, and the filter 2.59 (dd, J = 13.6, 6.8 Hz, 1 H, CH2Ar), 2.64 (dd, J = 13.6, 7.6 Hz, 1
residue was washed with hot MeOH. The combined organic solu- H, CH2Ar), 3.02–3.14 (m, 2 H, 5-H), 3.49 (dd, J = 10.8, 5.3 Hz, 1 H, 1-
tions were concentrated to give an oil. Flash chromatography gave H), 3.54 (dd, J = 10.8, 5.2 Hz, 1 H, 1-H), 4.59 (br. s, 1 H, NH), 7.16–
the corresponding pure amino alcohol. The preparation of 4-substi-
7.20 (m, 3 H, ArH), 7.25–7.29 (m, 2 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 27.4 (C-4), 27.6 (C-3), 28.4 [(CH3)3],
37.6 (CH2Ar), 40.6 (C-5), 42.1 (C-2), 64.4 (C-1), 79.1 (CMe3), 125.9 (C-
p), 128.3 (C-o), 129.1 (C-m), 140.5 (C-i), 156.1 (CO) ppm. HRMS (ESI-
TOF): calcd. for C12H20NO [M – Boc + H]+ 194.1539; found 194.1536.
tuted aminopentanols 31a–31e has been reported.[3]
(S)-5-[(tert-Butoxycarbonyl)amino]-2-methyl-1-pentanol (28a):
Following the general procedure, from a solution of amino diol 15a
(250 mg, 1.05 mmol) in MeOH (15 mL), Pd(OH)2/C (20 %; 50 mg),
and Boc2O (276 mg, 1.26 mmol), alcohol 28a (110 mg, 48 %) was (R)-5-[(tert-Butoxycarbonyl)amino]-3-methyl-1-pentanol (30a):
obtained as a colorless oil after column chromatography (hexane/ Following the general procedure, from a solution of amino diol 17a
EtOAc, 8:2). [α]D22 = –3.92 (c = 1.15, CHCl3). IR (film): ν = 3356, 1689, (140 mg, 0.59 mmol) in MeOH (16 mL), Pd(OH)2/C (20 %; 28 mg),
˜
1454 cm–1 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = and Boc2O (142 mg, 0.65 mmol), alcohol 30a (77 mg, 60 %) was
.
0.92 (d, J = 6.7 Hz, 3 H, CH3), 1.08–1.18 (m, 1 H, 3-H), 1.44 [s and obtained as a colorless oil after column chromatography (hexane/
obscured signal, 10 H, 3-H, (CH3)3], 1.49–1.51 (m, 1 H, 4-H), 1.55– EtOAc, 8:2). [α]D22 = +4.33 (c = 0.44, CHCl3). IR (film): ν = 3349,
˜
1.58 (m, 1 H, 4-H), 1.60–1.65 (m, 1 H, 2-H), 3.11 (m, 2 H, 5-H), 3.46 1686 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ =
(m, 2 H, 1-H), 4.54 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 0.88 (d, J = 6.6 Hz, 3 H, CH3), 1.27–1.36 (m, 2 H, 2-H, 4-H), 1.39 [s, 9
25 °C): δ = 16.5 (CH3), 27.4 (C-4), 28.3 [(CH3)3], 30.0 (C-3), 35.3 (C-2), H, (CH3)3], 1.43–1.50 (m, 1 H, 4-H), 1.54–1.66 (m, 2 H, 2-H, 3-H), 2.41
40.6 (C-5), 67.8 (C-1), 79.0 (CMe3), 156.1 (CO) ppm. HRMS (ESI-TOF):
(br. s, 1 H, OH), 3.01–3.10 (m, 1 H, 5-H), 3.12–3.20 (m, 1 H, 5-H),
3.57–3.68 (m, 2 H, 1-H), 4.70 (br. s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 19.6 (CH3), 26.8 (C-3), 28.3 [(CH3)3],
37.1 (C-4), 38.3 (C-5), 39.3 (C-2), 60.4 (C-1), 79.0 (CMe3), 156.2 (CO)
ppm. HRMS (ESI-TOF): calcd. for C11H23NNaO3 [M + Na]+ 240.1570;
found 240.1575.
calcd. for C11H24NO3 [M + H]+ 218.1751; found 218.1754.
(S)-5-[(tert-Butoxycarbonyl)amino]-2-ethyl-1-pentanol (28b):
Following the general procedure, from a solution of amino diol 15b
(250 mg, 1.0 mmol) in MeOH (17 mL), Pd(OH)2/C (20 %; 50 mg), and
Boc2O (261 mg, 1.19 mmol), alcohol 28b (127 mg, 55 %) was ob-
tained as a colorless oil after column chromatography (hexane/
(R)-5-[(tert-Butoxycarbonyl)amino]-3-phenyl-1-pentanol (30b):
EtOAc, 8:2). [α]D22 = +0.87 (c = 1.75, CHCl3). IR (film): ν = 3449, Following the general procedure, from a solution of amino diol 17b
˜
1670 cm–1 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = (48 mg, 0.16 mmol) in MeOH (15 mL), Pd(OH)2/C (20 %; 9.6 mg),
.
0.84 (t, J = 7.2 Hz, 3 H, CH3CH2), 1.20–1.37 (m, 5 H, CH2CH3, 2-H, 3-
H), 1.39 [s, 9 H, (CH3)3], 1.45–1.51 (m, 2 H, 4-H), 1.95 (br. s, 1 H, OH),
2.95–2.99 (m, 2 H, 5-H), 3.45 (dd, J = 10.0, 5.6 Hz, 1 H, 1-H), 3.49
and Boc2O (38 mg, 0.18 mmol), alcohol 30b (23 mg, 50 %) was
obtained as a colorless oil after column chromatography (hexane/
EtOAc, 8:2). [α]D22 = +14.3 (c = 1.2, CHCl3). IR (film): ν = 3350,
˜
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1689 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25 °C): δ = amino diol 24 (297 mg, 0.87 mmol) in MeOH (20 mL), Pd(OH)2/C
1.42 [s, 9 H, (CH3)3], 1.49–1.57 (br. s, 1 H, OH), 1.71–1.89 (m, 3 H, 2- (20 %; 60 mg), and Boc2O (209 mg, 0.96 mmol), alcohol 34 (157 mg,
H, 4-H), 1.91–1.98 (m, 1 H, 2-H), 2.78 (m, 1 H, 3-H), 2.93–3.06 (m, 2
55 %) was obtained as a colorless oil after column chromatography
H, 5-H), 3.40–3.47 (m, 1 H, 1-H), 3.51–3.57 (m, 1 H, 1-H), 4.47 (br. s,
(hexane/EtOAc, 8:2). [α]D22 = –14.1 (c = 1.4, CHCl3). IR (film): ν = 3360,
˜
1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 28.4 [(CH3)3], 1685 cm–1
.
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 50 °C): δ =
36.9 (C-4), 38.8 (C-5), 39.3 (C-2), 39.7 (C-3), 60.7 (C-1), 79.1 (CMe3),
126.5 (C-p), 127.5 (C-o), 128.6 (C-m), 144.1 (C-i), 156.0 (CO) ppm.
HRMS (ESI-TOF): calcd. for C16H25NNaO3 [M + Na]+ 302.1727; found
302.1721.
0.83 (t, J = 7.5 Hz, 3 H, CH3CH2), 1.14–1.20 (m, 1 H, 3-H), 1.23–1.30
(m, 2 H, CH3CH2), 1.38–1.50 (m, 2 H, 3-H, 4-H), 1.43 [s, 9 H, (CH3)3],
1.88–1.94 (m, 1 H, 2-H), 2.55–2.69 (m, 2 H, CH2Ar), 2.99 (dt, J =
5.6 Hz, 1 H, 5-H), 3.15 (br. m, 1 H, 5-H), 3.44 (dd, J = 10.5, 5.5 Hz, 1
H, 1-H), 3.55 (dd, J = 10.5, 4.8 Hz, 1 H, 1-H), 4.53 (br. s, 1 H, NH),
7.15–7.19 (m, 3 H, ArH), 7.24–7.28 (m, 2 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3, 50 °C): δ = 10.7 (CH3CH2), 24.9 (CH3CH2), 28.4
[(CH3)3], 33.0 (C-3), 37.7 (C-4), 38.4 (CH2Ar), 40.4 (C-2), 43.5 (C-5),
65.0 (C-1), 79.1 (CMe3), 125.8 (C-p), 128.3 (C-o), 129.1 (C-m), 140.6
(C-i), 156.4 (CO) ppm. HRMS (ESI-TOF): calcd. for C19H31NNaO3 [M +
Na]+ 344.2196; found 344.2184.
(R)-5-[(tert-Butoxycarbonyl)amino]-4-methyl-1-pentanol (ent-
31a): Following the general procedure, from a solution of amino
diol 19a (190 mg, 0.80 mmol) in MeOH (13 mL), Pd(OH)2/C (20 %;
38 mg), and Boc2O (210 mg, 0.96 mmol), alcohol ent-31a (100 mg,
57 %) was obtained as a colorless oil after column chromatography
(hexane/EtOAc, from 9:1 to 1:1). [α]D22 = +2.25 (c = 1.0, MeOH).
(R)-5-[(tert-Butoxycarbonyl)amino]-4-ethyl-1-pentanol (ent-
31b): Following the general procedure, from a solution of amino
diol 19b (105 mg, 0.42 mmol) in MeOH (13 mL), Pd(OH)2/C (20 %;
21 mg), and Boc2O (109 mg, 0.5 mmol), alcohol ent-31b (53 mg,
55 %) was obtained as a colorless oil after column chromatography
(hexane/EtOAc, from 9:1 to 7:3). [α]D22 = +2.8 (c = 0.82, MeOH).
(2S,4S)-5-[(tert-Butoxycarbonyl)amino]-4-ethyl-2-methyl-1-
pentanol (35a): Following the general procedure, from a solution
of amino diol 25a (365 mg, 1.38 mmol) in MeOH (13 mL), Pd(OH)2/
C (20 %; 75 mg), and Boc2O (330 mg, 1.51 mmol), alcohol 35a
(213 mg, 63 %) was obtained as a colorless oil after column chroma-
tography (from CH2Cl2 to CH2Cl2/Et2O, 8:2). [α]D22 = –13.7 (c = 1.41,
CHCl3). IR (film): ν = 3346, 1689 cm–1 1H NMR (400 MHz, CDCl3,
.
(S)-2-Benzyl-5-[(tert-butoxycarbonyl)amino]-2-ethyl-1-pentanol
(32): Following the general procedure, from a solution of amino
diol 21a (200 mg, 0.59 mmol) in MeOH (16 mL), Pd(OH)2/C (20 %;
40 mg), and Boc2O (141 mg, 0.64 mmol), alcohol 32 (96 mg, 50 %)
was obtained as a colorless oil after column chromatography (from
CH2Cl2 to CH2Cl2/Et2O, 8:2). [α]D22 = +8.09 (c = 2.25, CHCl3). IR (film):
˜
COSY, g-HSQC, 25 °C): δ = 0.89 (t, J = 7.5 Hz, 3 H, CH3CH2), 0.91 (d,
J = 6.7 Hz, 3 H, CH3), 1.04 (ddd, J = 13.9, 8.3, 5.8 Hz, 1 H, 3-H), 1.24–
1.37 (m, 3 H, 3-H, CH3CH2), 1.44 [s, 9 H, (CH3)3], 1.53–1.58 (m, 1 H,
4-H), 1.69–1.78 (m, 1 H, 2-H), 3.05–3.09 (m, 2 H, 5-H), 3.41–3.52 (m,
2 H, 1-H), 4.57 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 10.6 (CH3CH2), 16.9 (CH3), 24.0 (CH3CH2), 28.4 [(CH3)3],
33.0 (C-2), 35.2 (C-3), 36.9 (C-4), 43.8 (C-5), 68.4 (C-1), 79.0 (CMe3),
156.2 (CO) ppm. HRMS (ESI-TOF): calcd. for C8H20NO [M – Boc]+
146.1539; found 146.1541.
ν = 3365, 2935, 1689 cm–1. 1H NMR (400 MHz, CDCl3, COSY, g-HSQC,
˜
25 °C): δ = 0.81 (t, J = 7.5 Hz, 3 H, CH3CH2), 1.09–1.21 (m, 4 H, 3-H,
CH3CH2), 1.37 [s, 9 H, (CH3)3], 1.41–1.47 (m, 2 H, 4-H), 1.85 (br. s, 1
H, OH), 2.50 (br. s, 2 H, CH2Ar), 2.97–3.05 (m, 2 H, 5-H), 3.21 (s, 2 H,
1-H), 4.63 (br. s, 1 H, NH), 7.10–7.13 (m, 3 H, ArH), 7.17–7.21 (m, 2
H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 7.5 (CH3CH2),
23.7 (C-4), 25.2 (CH3CH2), 28.4 [(CH3)3], 29.7 (C-3), 40.0 (CH2Ar), 41.1
(C-5), 41.2 (C-2), 65.6 (C-1), 79.1 (CMe3), 125.9 (C-p), 127.9 (C-o),
130.3 (C-m), 138.5 (C-i), 156.1 (CO) ppm. HRMS (ESI-TOF): calcd. for
C19H32NO3 [M + H]+ 322.2377; found 322.2374.
(2S,4S)-5-[(tert-Butoxycarbonyl)amino]-4-ethyl-2-isobutyl-1-
pentanol (35b): Following the general procedure, from a solution
of amino diol 25b (156 mg, 0.51 mmol) in MeOH (17 mL), Pd(OH)2/
C (20 %; 31 mg), and Boc2O (122 mg, 0.56 mmol), alcohol 35b
(75 mg, 51 %) was obtained as a colorless oil after column chroma-
tography (from CH2Cl2 to CH2Cl2/Et2O, 8:2). [α]D22 = –2.47 (c = 1.4,
(2S,3R)-5-[(tert-Butoxycarbonyl)amino]-2,3-(isopropylidenedi-
oxy)-1-pentanol (33): Following the general procedure, from a so-
lution of amino diol 22 (82 mg, 0.28 mmol) in MeOH (14 mL),
Pd(OH)2/C (20 %; 16 mg), and Boc2O (67 mg, 0.31 mmol), alcohol
33 (40 mg, 52 %) was obtained as a colorless oil after column chro-
matography (from CH2Cl2 to CH2Cl2/Et2O, 8:2). [α]D22 = –4.18 (c = 1.8,
CHCl3). IR (film): ν = 3354, 1691 cm–1 1H NMR (400 MHz, CDCl3,
.
˜
COSY, g-HSQC, 25 °C): δ = 0.88–0.93 (m, 9 H, 3 CH3), 1.03–1.10 (m,
2 H, 3-H, CH2CHMe2), 1.14–1.21 (m, 1 H, CH2CHMe2), 1.27–1.35 (m,
2 H, CH3CH2), 1.37–1.50 (m, 2 H, 3-H, 4-H), 1.44 [s, 9 H, (CH3)3], 1.60–
1.70 (m, 2 H, 2-H, CHMe2), 2.18 (br. s, 1 H, OH), 2.99 (dt, J = 13.7,
5.5 Hz, 1 H, 5-H), 3.20–3.28 (m, 1 H, 5-H), 3.36–3.40 (m, 1 H, 1-H),
3.60 (dd, J = 10.5, 3.9 Hz, 1 H, 1-H), 4.74 (br. s, 1 H, NH) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.0 (CH3CH2), 22.7 (CH3), 23.2
(CH3), 25.0 (CH3CH2), 25.4 (CH), 28.4 [(CH3)3], 33.6 (C-3), 35.8 (C-2),
37.5 (C-4), 41.7 (CH2CHMe2), 43.0 (C-5), 65.7 (C-1), 79.1 (CMe3), 156.6
(CO) ppm. HRMS (ESI-TOF): calcd. for C16H34NO3 [M + H]+ 288.2533;
found 288.2543.
CHCl3). IR (film): ν = 3368, 1695 cm–1 1H NMR (400 MHz, CDCl3,
.
˜
COSY, g-HSQC, 25 °C): δ = 1.36 (s, 3 H, CH3), 1.44 [s, 9 H, (CH3)3],
1.46 (s, 3 H, CH3), 1.66–1.75 (m, 2 H, 4-H), 2.23 (br. s, 1 H, OH), 3.18–
3.34 (m, 2 H, 5-H), 3.62 (br. m, 2 H, 1-H), 4.15–4.24 (m, 2 H, 2-H, 3-
H), 4.90 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C):
δ = 25.4 (CH3), 28.0 (CH3), 28.4 [(CH3)3], 29.4 (C-4), 38.4 (C-5), 61.5
(C-1), 75.3 (C-3), 77.7 (C-2), 79.3 (CMe3), 108.2 (CMe2), 156.0 (CO)
ppm. HRMS (ESI-TOF): calcd. for C13H25NNaO5 [M + Na]+ 298.1625;
found 298.1626.
(3S,4S)-5-[(tert-Butoxycarbonyl)amino]-4-ethyl-3-methyl-1-
pentanol (36a): Following the general procedure, from a solution
of amino diol 26a (101 mg, 0.38 mmol) in MeOH (13 mL), Pd(OH)2/
C (20 %; 20 mg), and Boc2O (91 mg, 0.42 mmol), alcohol 36a
(47 mg, 51 %) was obtained as a colorless oil after column chroma-
tography (from CH2Cl2 to CH2Cl2/Et2O, 8:2). [α]D22 = –1.5 (c = 2.6,
(2R,3S)-5-[(tert-Butoxycarbonyl)amino]-2,3-(isopropylidenedi-
oxy)-1-pentanol (ent-33): Following the general procedure, from a
solution of amino diol 23 (150 mg, 0.51 mmol) in MeOH (13 mL),
Pd(OH)2/C (20 %; 30 mg), and Boc2O (122 mg, 0.56 mmol), alcohol
ent-33 (84 mg, 60 %) was obtained as a colorless oil after column
chromatography (from CH2Cl2 to CH2Cl2/Et2O, 8:2). [α]D22 = +4.0 (c =
1.8, CHCl3).
CHCl3). IR (film): ν = 3346, 1692 cm–1 1H NMR (400 MHz, CDCl3,
.
˜
COSY, g-HSQC, 25 °C): δ = 0.88–0.94 (m, 6 H, 2 CH3), 1.15–1.22 (m,
1 H, CH3CH2), 1.26–1.40 (m, 3 H, CH3CH2, 2-H, 4-H), 1.44 [s, 9 H,
(CH3)3], 1.66–1.75 (m, 1 H, 2-H), 1.81 (m, 1 H, 3-H), 2.05 (br. s, 1 H,
OH), 2.96–3.02 (m, 1 H, 5-H), 3.14–3.19 (m, 1 H, 5-H), 3.58–3.64 (m,
(2S,4S)-2-Benzyl-5-[(tert-butoxycarbonyl)amino]-4-ethyl-1-
pentanol (34): Following the general procedure, from a solution of 1 H, 1-H), 3.71–3.76 (m, 1 H, 1-H), 4.66 (br. s, 1 H, NH) ppm. 13C NMR
Eur. J. Org. Chem. 2016, 693–703
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Full Paper
[6] A. Giovannini, D. Savoia, A. Umani-Ronchi, J. Org. Chem. 1989, 54, 228–
234.
(100.6 MHz, CDCl3, 25 °C): δ = 12.4 (CH3CH2), 16.4 (CH3), 21.1
(CH3CH2), 28.4 [(CH3)3], 28.8 (C-3), 35.6 (C-2), 41.0 (C-5), 45.9 (C-4),
61.1 (C-1), 79.2 (CMe3), 156.5 (CO) ppm. HRMS (ESI-TOF): calcd. for
C13H28NO3 [M + H]+ 246.2064; found 246.2067.
[7] Other carbon nucleophiles have been used in this reaction; a) for a phos-
phonate anion, see: K. Tchabanenko, R. M. Adlington, A. R. Cowley, J. E.
Baldwin, Org. Lett. 2005, 7, 585–588; b) for lithium tert-butyl propiolate,
see: T. N. Grant, C. L. Benson, F. G. West, Org. Lett. 2008, 10, 3985–3988.
[8] It is well known that boron- and aluminum-derived hydrides (BH3, AlH3,
LiAlH4, Red-Al) bring about the reductive opening of the oxazolidine
ring and the reduction of the lactam carbonyl group to give the corre-
sponding piperidines; see ref.[1,2]
(3S,4S)-5-[(tert-Butoxycarbonyl)amino]-4-ethyl-3-phenyl-1-
pentanol (36b): Following the general procedure, from a solution
of amino diol 26b (110 mg, 0.34 mmol) in MeOH (15 mL), Pd(OH)2/
C (20 %; 22 mg), and Boc2O (81 mg, 0.37 mmol), alcohol 36b
(52 mg, 50 %) was obtained as a colorless oil after column chroma-
tography (from CH2Cl2 to CH2Cl2/Et2O, 8:2). [α]D22 = +5.09 (c = 0.6,
[9] a) A. G. Myers, B. H. Yang, D. J. Kopecky, Tetrahedron Lett. 1996, 37, 3623–
3626; b) A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky, J. L.
Gleason, J. Am. Chem. Soc. 1997, 119, 6496–6511.
CHCl ). IR (film): ν = 3350, 1694 cm–1
.
1H NMR (400 MHz, CDCl3,
˜
3
COSY, g-HSQC, 25 °C): δ = 0.93 (t, J = 7.4 Hz, 3 H, CH3CH2), 1.31–
1.37 (m, 1 H, CH3CH2), 1.41 [s, 9 H, (CH3)3], 1.43–1.52 (m, 1 H,
CH3CH2), 1.62–1.68 (m, 2 H, 4-H, OH), 1.81–1.90 (m, 1 H, 2-H), 2.02–
2.10 (m, 1 H, 2-H), 2.78 (br. m, 1 H, 3-H), 2.82–2.87 (m, 1 H, 5-H),
3.09–3.15 (m, 1 H, 5-H), 3.32–3.38 (m, 1 H, 1-H), 3.49–3.55 (br. m, 1
H, 1-H), 4.40 (br. s, 1 H, NH), 7.14–7.21 (m, 3 H, ArH), 7.27–7.31 (m,
2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.2
(CH3CH2), 21.3 (CH3CH2), 28.4 [(CH3)3], 34.5 (C-2), 41.2 (C-5), 42.7 (C-
3), 45.8 (C-4), 61.0 (C-1), 79.0 (CMe3), 126.4 (C-p), 128.2 (C-o), 128.4
(C-m), 142.9 (C-i), 156.2 (CO) ppm. HRMS (ESI-TOF): calcd. for
C13H22NO [M – Boc]+ 208.1696; found 208.1696.
[10] For a one-pot procedure for the preparation of the ammonia–borane
complex, see: P. V. Ramachandran, B. C. Raju, P. D. Gagare, Org. Lett. 2012,
14, 6119–6121.
[11] a) For a review, see: A. Lund, in: Encyclopedia of Reagents for Organic
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[12] In contrast, lithium (dialkylamino)borohydrides (LiNR2BH3), which are
more sterically demanding than LiNH2BH3, can reduce tertiary amides to
either the corresponding alcohol or to an amine, depending on the
steric environments of the amide and of the amine moiety of the reduc-
tant, see: a) G. B. Fisher, J. C. Fuller, J. Harrison, C. T. Goralski, B. Singaram,
Tetrahedron Lett. 1993, 34, 1091–1094; b) G. B. Fisher, J. C. Fuller, J. Harri-
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Supporting Information (see footnote on the first page of this
1
article): Copies of the H and 13C spectra of lactams 2c, 4b, 5, 10,
and 13b, amino diols 15–17, 19–26, and amino alcohols 27–30,
32–36.
Acknowledgments
Financial support from the Spanish Ministry of Economy and
Competitiveness (MINECO) and the Fondos Europeos para el
Desarrollo Regional (FEDER) (project number CTQ2012-35250)
and the Generalitat de Catalunya (grant number 2014SGR-155)
is gratefully acknowledged. We also acknowledge networking
contribution by the COST Action CM1407.
801; see also ref.[12c,12d]
.
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Deslongchamps, Stereoelectronic Effects in Organic Chemistry, Pergamon
Press, Oxford, UK, 1983, p. 257–274. For related 3-aza-Grob fragmenta-
tions in the hydride reduction of lactams, see: d) J.-J. Wang, W.-P. Hu, J.
Org. Chem. 1999, 64, 5725–5727; e) W.-P. Hu, J.-J. Wang, P.-C. Tsai, J. Org.
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Keywords: Synthetic methods · Asymmetric synthesis ·
Reduction · Ring opening · Lactams · Amino alcohols
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Received: November 6, 2015
Published Online: December 21, 2015
Eur. J. Org. Chem. 2016, 693–703
www.eurjoc.org
703
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim