Access to enantiopure 4-substituted 1,5-aminoalcohols from phenylglycinol-derived δ-lactams: Synthesis of Haliclona alkaloids

Article abstract of DOI:10.1021/jo5002627

LiNH₂BH₃-promoted reductive opening of 8-substituted phenylglycinol-derived oxazolopiperidone lactams leads to enantiopure 4-substituted-5-aminopentanols, which are used as starting building blocks in the synthesis of the Haliclona alkaloids haliclorensin C, haliclorensin, and halitulin (formal). The starting lactams are easily accessible by a cyclocondensation reaction of (R)-phenylglycinol with racemic γ-subtituted δ-oxoesters, in a process that involves a dynamic kinetic resolution.

Full text of DOI:10.1021/jo5002627

Note
pubs.acs.org/joc
Access to Enantiopure 4‑Substituted 1,5-Aminoalcohols from
Phenylglycinol-Derived δ‑Lactams: Synthesis of Haliclona Alkaloids
Mercedes Amat,* Guillaume Guignard, Nuria Llor, and Joan Bosch*
́
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona, 08028
Barcelona, Spain
S
* Supporting Information
ABSTRACT: LiNH2BH3-promoted reductive opening of 8-substituted phenylglycinol-derived oxazolopiperidone lactams leads
to enantiopure 4-substituted-5-aminopentanols, which are used as starting building blocks in the synthesis of the Haliclona
alkaloids haliclorensin C, haliclorensin, and halitulin (formal). The starting lactams are easily accessible by a cyclocondensation
reaction of (R)-phenylglycinol with racemic γ-subtituted δ-oxoesters, in a process that involves a dynamic kinetic resolution.
Scheme 1. Synthesis of Enantiopure 4-Substituted 5-
Aminopentanoic Acid Derivatives
henylglycinol-derived oxazolopiperidone lactams have
Pproven to be multipurpose enantiomeric scaffolds for the
synthesis of diversely substituted piperidine, indolizidine,
quinolizidine, decahydroquinoline, tetrahydroisoquinoline, and
tetrahydro-β-carboline derivatives, as well as complex polycyclic
piperidine-containing alkaloids.1 These lactams are easily
accessible by a cyclocondensation reaction between the
amino alcohol and a δ-oxoacid derivative and, because of
their versatile functionality and conformational rigidity, allow
the regio- and stereocontrolled introduction of substituents at
the different positions of the piperidine ring to ultimately
provide enantiopure piperidine derivatives bearing virtually any
type of substitution pattern.
Taking into account that the stereocontrolled generation of
chiral centers is generally more efficient and easier to
accomplish in conformationally rigid cyclic systems than in
acyclic compounds, we envisaged the above δ-lactams as
potential building blocks for the synthesis of enantiopure
substituted 1,5-aminoalcohols or δ-amino acid derivatives. Our
approach would involve the stereoselective formation of the
appropriate substituted lactam and then the opening of the
lactam ring, with prior or subsequent removal of the
phenylethanol moiety of the chiral inductor.
Initially, the conversion of lactams 2 into functionalized
linear-chain amino derivatives was performed by the four-step
sequence outlined in Scheme 1, involving the hydrolytic
opening of a 2-piperidone as the key step. Thus, removal of the
chiral auxiliary from lactams 2a and 2b was accomplished by
successive treatment with triethylsilane in the presence of
TiCl4, which brought about the reductive cleavage of the
oxazolidine C−O bond, and sodium in liquid NH3, which
caused the cleavage of the benzylic C−N bond. After the
resulting N-unsubstituted 2-piperidones 4a and 4b were
We report herein our studies aimed at developing this
concept from lactams 2, which incorporate a substituent at the
5 position of the 2-piperidone ring, and illustrate the usefulness
of the resulting substituted linear-chain amino intermediates in
the total synthesis of natural products.
Lactams 2 were stereoselectively prepared2 by cyclo-
condensation of racemic δ-oxoesters 1,3 which bear a
substituent (alkyl, phenyl, benzyl) at the epimerizable carbon
α to the aldehyde carbonyl group, with (R)-phenylglycinol, in a
process that involves a dynamic kinetic resolution of the
racemic substrate4,5 (Scheme 1).
Received: February 3, 2014
Published: February 20, 2014
© 2014 American Chemical Society
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Note
converted to the corresponding N-Boc derivatives 5a and 5b, a
final alkaline hydrolysis with lithium hydroxide in aqueous THF
at room temperature,6 followed by esterification of the resulting
crude δ-amino acids with trimethylsilyldiazomethane, led to
esters 6a and 6b. The overall process 1 → 6 can be envisaged as
a reductive amination of racemic aldehyde-esters 1 using a
chiral latent form of ammonia, with concomitant dynamic
kinetic resolution.
would allow the target azacyclic structures to be assembled
using a ring-closing metathesis reaction as the key step.
Thus, the methyl substituted aminopentanol 9a was
envisaged as the N1−C6 fragment of haliclorensin C (Scheme
4). Alkylation of 9a with 10-undecenyl bromide, followed by
Scheme 4. Enantioselective Synthesis of Haliclorensin C
A more straightforward preparation of substituted linear-
chain functionalized amino derivatives was accomplished by
treatment of lactams 2 with lithium amidotrihydroborate
(LiNH2BH3), which was generated in situ by deprotonation
of the borane-ammonia complex with n-BuLi7 (Scheme 2).
Scheme 2. Synthesis of Enantiopure 4-Substituted 5-
Aminoalcohols
Dess−Martin oxidation of the resulting alcohol 11 and
subsequent Wittig methylenation from the resulting aldehyde,
gave the required N-hexenyl N-undecenyl amino derivative 12.
As expected, a ring-closing metathesis reaction provided the 16-
membered azacycle 1316 in excellent yield. Removal of the
nosyl group followed by catalytic hydrogenation completed the
first total synthesis of haliclorensin C. Unfortunately,
haliclorensin C had been isolated13 only in minute amounts
(2 mg), and the 1H and 13C NMR spectra included in the paper
show considerable contamination. These spectra probably
correspond to a protonated sample since they essentially
coincide with the spectra of the hydrochloride of our synthetic
material (see Experimental Section and Supporting Informa-
tion).
Although this reagent has been used to reduce acyclic tertiary
amides to primary alcohols,8 N-alkyl δ-lactams are usually
reduced to the corresponding cyclic amines,9 and there are only
a few examples in the literature of the LiNH2BH3 reductive
opening of crowded δ-lactams.10
Under LiNH2BH3 reduction conditions, bicyclic lactams 2a−
e were directly converted into N-substituted 1,5-aminoalcohols
7a−e in an unprecedented process featuring the reductive
opening of both the oxazolidine and lactam rings,11 most
probably through a stepwise sequence involving a 3-aza-Grob
fragmentation,12 as outlined in Scheme 3.
A conceptually similar strategy from the same aminoalcohol
9a, but using 4-pentenyl bromide as the alkylating agent, can be
used for the synthesis of halitulin and isohaliclorensin,17 the
latter being the structure initially proposed15a for haliclorensin
(Scheme 5). Oxidation of alcohol 15 under Dess−Martin
conditions, followed by Wittig methylenation of the resulting
aldehyde, led to the N-hexenyl N-pentenyl amino derivative 16,
from which the synthesis of halitulin and isohaliclorensin has
already been reported14c,17a using a ring-closing metathesis
reaction to construct the azacyclodecane ring.
Similarly, the protected aminopentanol 10a was envisaged as
the N5−C10 fragment of haliclorensin. The synthesis of this
alkaloid from 10a was also planned via a ring-closing metathesis
reaction from an appropriate long-chain amino derivative, 21,
bearing two terminal carbon−carbon double bonds. The
synthesis is outlined in Scheme 6.
Scheme 3. Proposed Mechanism for the LiNH2BH3
Reduction of Lactams 2
A subsequent removal of the phenylethanol moiety by
hydrogenolysis, followed by protection of the resulting primary
amines, led to the enantiopure N-protected 4-substituted-5-
aminopentanols 8−10. These aminoalcohols possess a stereo-
genic center with a well-defined configuration at the position β
to the nitrogen atom, a structural motif (when R = methyl)
found in several macrocyclic alkaloids, such as haliclorensin
C,13 halitulin,14 and haliclorensin,15 isolated from the marine
sponge Haliclona tulearensis. The synthesis of these alkaloids
from the above aminoalcohols would require the latter to be
converted into appropriate long-chain secondary amino
derivatives bearing two terminal alkene functionalities, which
Alkylation of the tosylamide moiety of the silyl derivative 17
with 3-(phthalimido)propyl iodide,18 followed by removal of
the silyl protecting group and, as in the above syntheses, a
Dess−Martin oxidation/Wittig methylenation sequence, led to
the orthogonally protected diamino derivative 20. Hydrazinol-
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Note
(LiNH2BH3) induces the reductive opening of both the
oxazolidine and lactam rings in a single synthetic step. A
subsequent removal of the phenylethanol moiety by hydro-
genolysis leads to 4-substituted-5-aminopentanols, whose value
as chiral building blocks is illustrated by the synthesis of the
marine alkaloids haliclorensin C, haliclorensin, and halitulin
(formal).
Scheme 5. Formal Syntheses of Halitulin and
Isohaliclorensin
EXPERIMENTAL SECTION
■
Methyl 4-Isopropyl-5-oxopentanoate (1c). Isovaleraldehyde
(7.54 mL, 69.7 mmol) was added dropwise to a cooled (0 °C) mixture
of piperidine (10.3 mL, 104.5 mmol) and K2CO3 (3.47 g, 25.1 mmol)
and the mixture was stirred for 18 h at room temperature. Insoluble
material was filtered through Celite, and the filtrate was washed with
Et2O, dried, filtered, and concentrated in a vacuum to remove the
excess of piperidine. Methyl acrylate (7.64 mL, 84.8 mmol) was slowly
added to a stirred solution of the resulting residue in anhydrous
acetonitrile (21 mL) at 0 °C. The mixture was stirred at reflux
overnight. Glacial acetic acid (4.8 mL) and water (21 mL) were added,
and the resulting solution was heated at reflux for 2 h. The mixture was
allowed to cool to room temperature, the aqueous phase was saturated
with NaCl, and the solution was extracted with Et2O. The combined
organic extracts were dried, filtered, and concentrated to give an oil.
Flash chromatography (8:2 hexane−Et2O) afforded compound 1c (8.7
Scheme 6. Enantioselective Synthesis of Haliclorensin
g, 73%) as a colorless oil: IR (film) 1738 cm−1; H NMR (400 MHz,
1
CDCl3, COSY, g-HSQC) δ 0.97 (d, J = 6.8 Hz, 3H, CHCH3), 1.00 (d,
J = 6.8 Hz, 3H, CHCH3), 1.74−1.83 (m, 1H, H-3), 1.90−1.99 (m, 1H,
H-3), 2.02−2.10 (m, 1H, CHMe2), 2.12−2.18 (m, 1H, H-4), 2.25
(ddd, J = 16.1, 8.5, 7.4 Hz, 1H, H-2), 2.38 (ddd, J = 16.1, 8.9, 6.0 Hz,
1H, H-2), 3.67 (s, 3H, CH3O), 9.65 (s, 1H, CHO); 13C NMR (100.6
MHz, CDCl3) δ 19.3 (CH3), 19.9 (CH3), 20.8 (C-3), 28.3 (CHMe2),
31.8 (C-2), 51.3 (CH3O), 57.3 (C-4), 173.3 (CO2), 204.4 (CHO);
HRMS (ESI-TOF) m/z [M + H]+ Calcd for C9H17O3 173.1172,
found 173.1168.
Methyl 4-Benzyl-5-oxopentanoate (1e). Operating as above,
from 3-phenylpropanal (5.89 mL, 44.7 mmol), piperidine (6.61 mL,
67.1 mmol), K2CO3 (2.23 g, 15.6 mmol), and methyl acrylate (7.0 mL,
77.5 mmol) in anhydrous acetonitrile (20 mL), with subsequent
treatment with a mixture of glacial acetic acid (5 mL) and water (20
mL), compound 1e (5.58 g, 57%) was obtained as a yellow oil after
flash chromatography (from 95:5 hexane−Et2O to 9:1 hexane−Et2O):
IR (film) 1732 cm−1. 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ
1.76−1.85 (m, 1H, H-3), 1.93−2.01 (m, 1H, H-3), 2.34 (m, 2H, H-2),
2.66−2.71 (m, 1H, H-4), 2.71−2.77 (m, 1H, CH2Ar), 3.02 (dd, J =
13.4, 6.6 Hz, 1H, CH2Ar), 3.65 (s, 3H, CH3), 7.15−7.32 (m, 5H,
ArH), 9.68 (d, J = 2.0 Hz, 1H, CHO); 13C NMR (100.6 MHz, CDCl3)
δ 23.5 (C-3), 31.3 (C-2), 35.1 (CH2Ar), 51.6 (CH3), 52.4 (C-4),
126.5 (C-p), 128.6, 128.8 (C-o, C-m), 138.1 (C-i), 173.2 (CO2), 203.5
(CHO); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C13H17O3
221.1099, found 221.1089.
ysis of the phthalimido group, followed by acylation of the
resulting primary amine with 4-pentenoyl chloride, installed the
required terminal alkene functionality in 21. The synthesis of
haliclorensin was completed by a ring-closing metathesis
reaction, followed by catalytic hydrogenation of the carbon−
carbon double bond of the resulting diazacyclotetradecane
derivative 2219 and LiAlH4 reduction, which brought about
both the reductive removal of the tosyl group and the reduction
of the lactam carbonyl. The NMR spectroscopic data of our
synthetic haliclorensin were coincident with those reported for
(3R,8S,8aR)-8-Methyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahy-
dro-5H-oxazolo[3,2-a]pyridine (2a). Method A. A mixture of
racemic oxoester 1a21 (565 mg, 3.92 mmol), (R)-phenylglycinol (537
mg, 3.92 mmol) and anhydrous Na2SO4 (2.17 g, 15.3 mmol) in Et2O
(10 mL) was stirred at 0 °C for 5 h. The resulting suspension was
filtered, and the filtrate was concentrated under reduced pressure. The
residue was heated at 90 °C for 5 h under a vacuum (10−15 mmHg).
Column chromatography (SiO2 previously washed with 7:3 hexane−
Et3N; gradient from 7:3 hexane−EtOAc to EtOAc) of the residue
afforded lactam 2a (670 mg, 74%) and its (3R,8R,8aS) diaster-
eoisomer (85 mg, 9%). 2a: [α]22 −43.7 (c 1.0, MeOH); IR (film)
previously synthesized haliclorensins,15b,c whereas the [α]22
D
D
1658 cm−1; 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 1.20 (d, J
= 6.3 Hz, 3H, CH3), 1.46−1.58 (m, 1H, H-7), 1.88−1.94 (m, 1H, H-
7), 1.95−2.00 (m, 1H, H-8), 2.28−2.44 (m, 2H, H-6), 4.00 (dd, J =
8.8, 1.2 Hz, 1H, H-2), 4.13 (dd, J = 8.8, 6.4 Hz, 1H, H-2), 4.43 (d, J =
8.8 Hz, 1H, H-8a), 4.92 (d, J = 7.2 Hz, 1H, H-3), 7.21−7.40 (m, 5H,
ArH); 13C NMR (100.6 MHz, CDCl3) δ 16.6 (CH3), 26.9 (C-7), 31.4
(C-6), 34.5 (C-8), 59.1 (C-3), 73.7 (C-2), 93.5 (C-8a), 126.3 (C-o),
127.4 (C-p), 128.4 (C-m), 141.5 (C-i), 167.3 (CO); HRMS (ESI-
value of our sample [−17.2 (c 0.5, MeOH)] was consistent
with that of both the natural product13 [−19 (c 0.57, MeOH)]
and synthetic haliclorensins.15b,c,20
In summary, we have developed a straightforward procedure
for the preparation of enantiopure 1,5-aminoalcohols from
phenylglycinol-derived oxazolopiperidone lactams. Starting
from 8-substituted lactams 2, lithium amidotrihydroborate
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Note
TOF) m/z [M + H]+ Calcd for C14H18NO2 232.1332, found
232.1325. Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06.
Method B. Operating as described in the above Method B, from
racemic oxoester 1c (1.09 g, 6.32 mmol) and (R)-phenylglycinol (867
mg, 6.32 mmol) in toluene (20 mL), lactam 2c (white solid, 1.06 g,
64%) and its (3R,8S,8aS) diastereoisomer (230 mg, 14%) were
obtained after flash chromatography (SiO2 previously washed with 7:3
hexane−Et3N; gradient from 7:3 hexane−EtOAc to EtOAc).
Found: C, 72.66; H, 7.20; N, 5.98. (3R,8R,8aS) diastereoisomer:
1
[α]22 −115.3 (c 1.0, MeOH); IR (film) 1658 cm−1; H NMR (400
D
MHz, CDCl3, COSY, g-HSQC) δ 1.18 (d, J = 6.0 Hz, 3H, CH3),
1.42−1.63 (m, 1H, H-7), 1.65−1.71 (m, 1H, H-8), 1.80−1.85 (m, 1H,
H-7), 2.34−2.44 (m, 1H, H-6), 2.53 (dd, J = 18.0, 6.0 Hz, 1H, H-6),
3.75 (dd, J = 9.0, 7.8 Hz, 1H, H-2), 4.47 (dd, J = 9.0, 7.8 Hz, 1H, H-2),
4.60 (d, J = 8.0 Hz, 1H, H-8a), 5.25 (t, J = 7.8 Hz, 1H, H-3), 7.20−
7.45 (m, 5H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 17.1 (CH3),
25.9 (C-7), 31.5 (C-6), 34.9 (C-8), 58.4 (C-3), 72.4 (C-2), 93.7 (C-
8a), 126.1 (C-o), 127.5 (C-p), 128.7 (C-m), 139.5 (C-i), 168.7(CO).
Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C,
72.56; H, 7.35; N, 5.81.
(3R,8R,8aR)-8-Benzyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahy-
dro-5H-oxazolo[3,2-a]pyridine (2e). Operating as described in the
above Method A, from racemic oxoester 1e (626 mg, 2.84 mmol), (R)-
phenylglycinol (390 mg, 2.84 mmol), and anhydrous Na2SO4 (1.57 g,
11.1 mmol) in Et2O (9 mL), lactam 2e (478 mg, 55%) and its
(3R,8S,8aS) diastereoisomer (white solid, 80 mg, 9%) were obtained
after flash chromatography (SiO2 previously washed with 7:3 hexane−
Et3N; gradient from 7:3 hexane−EtOAc to EtOAc). 2e: [α]22D −144.8
1
(c 0.1, MeOH); IR (film) 1658 cm−1; H NMR (400 MHz, CDCl3,
Method B. (R)-Phenylglycinol (1.97 g, 14.4 mmol) was added to a
solution of racemic oxoester 1a21 (1.9 g, 14.4 mmol) in anhydrous
toluene (45 mL), and the mixture was heated at reflux for 25 h with
azeotropic elimination of water produced by a Dean−Stark apparatus.
The resulting mixture was cooled and concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 and washed with
saturated aqueous NaHCO3 solution. The combined organic extracts
were dried, filtered, and concentrated to give an oil. Flash
chromatography (SiO2 previously washed with 7:3 hexane−Et3N;
gradient from 7:3 hexane−EtOAc to EtOAc) afforded lactam 2a (1.7
g, 56%) as a brown solid and its (3R,8R,8aS) diastereoisomer (0.55 g,
18%).
Method C. (R)-Phenylglycinol (190 mg, 1.39 mmol) and oxoester
1a21 (200 mg, 1.39 mmol) in toluene (4.5 mL) were mixed in a
capped 10 mL microwave vessel. The mixture was heated at 110 °C
(average effective ramp time = 5 min). The power was set at 100 W
and the pressure at 218 psi for 10 min. The reaction mixture was then
concentrated under reduced pressure, and the crude product was
dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3
solution. The organic phase was dried, filtered, and concentrated. Flash
chromatography (SiO2 previously washed with 7:3 hexane−Et3N;
gradient from 7:3 hexane−EtOAc to EtOAc) afforded lactam 2a (185
mg, 58%) and its (3R,8R,8aS) diastereoisomer (70 mg, 22%).
(3R,8R,8aR)-8-Isopropyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexa-
hydro-5H-oxazolo[3,2-a]pyridine (2c). Operating as described in
the above Method A, from racemic oxoester 1c (1.07 g, 6.18 mmol),
(R)-phenylglycinol (848 mg, 6.18 mmol), and anhydrous Na2SO4
(3.43 g, 24.1 mmol) in Et2O (20 mL), lactam 2c (1.16 g, 73%) and its
(3R,8S,8aS) diastereoisomer (white solid, 180 mg, 11%) were
obtained after flash chromatography (SiO2 previously washed with 7:3
COSY, g-HSQC) δ 1.39−1.51 (m, 1H, H-7), 1.83−1.88 (m, 1H, H-7),
2.08−2.13 (m, 1H, H-8), 2.21 (ddd, J = 18.2, 11.6, 6.9 Hz, 1H, H-6),
2.36 (ddd, J = 18.2, 6.9, 1.8 Hz, 1H, H-6), 2.54 (dd, J = 13.5, 9.7 Hz,
1H, CH2Ar), 3.27 (dd, J = 13.5, 3.5 Hz, 1H, CH2Ar), 4.06 (dd, J = 9.0,
1.2 Hz, 1H, H-2), 4.18 (dd, J = 9.0, 6.4 Hz, 1H, H-2), 4.58 (d, J = 9.0
Hz, 1H, H-8a), 4.94 (d, J = 6.4 Hz, 1H, H-3), 7.23−7.35 (m, 10H,
ArH); 13C NMR (100.6 MHz, CDCl3) δ 23.4 (C-7), 31.3 (C-6), 37.2
(CH2Ar), 41.0 (C-8), 59.1 (C-3), 73.9 (C-2), 91.9 (C-8a), 126.3 (C-
o), 126.5 (C-p), 127.5 (C-p), 128.5 and 129.2 (2C-m, C-o), 138.2 and
141.4 (2C-i), 167.2 (CO); HRMS (ESI-TOF) m/z [M + H]+ Calcd
for C20H22NO2 308.1645, found 308.1645. (3R,8S,8aS) diaster-
1
eoisomer: [α]22 −45.0 (c 0.15, MeOH); IR (film) 1659 cm-1; H
D
NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 1.43−1.55 (m, 1H, H-
7), 1.79−1.90 (m, 2H, H-7, H-8), 2.26 (dd, J = 12.1, 6.6 Hz, 1H, H-6),
2.47−2.54 (m, 2H, H-6, CH2Ar), 3.23 (dd, J = 13.5, 3.4 Hz, 1H,
CH2Ar), 3.81 (dd, J = 8.9, 7.8 Hz, 1H, H-2), 4.53 (dd, J = 8.9, 7.8 Hz,
1H, H-2), 4.76 (d, J = 8.4 Hz, 1H, H-8a), 5.28 (t, J = 7.8 Hz, 1H, H-3),
7.19−7.36 (m, 10H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 22.4 (C-
7), 31.4 (C-6), 37.7 (CH2Ar), 41.6 (C-8), 58−5 (C-3), 72.5 (C-2),
92.1 (C-8a), 126.1 (C-o), 126.5 (C-p), 127.6 (C-p), 128.5 (C-o),
128.8, 129.4 (C-m), 138.4 and 139.5 (2C-i), 168.7 (CO); HRMS
(ESI-TOF) m/z [M + H]+ Calcd for C20H22NO2 308.1645, found
308.1644.
Method B. Operating as in the preparation of 2a in the above
Method B, from racemic aldehyde ester 1e (627 mg, 2.85 mmol) and
(R)-phenylglycinol (391 mg, 2.85 mmol) in toluene (9 mL), lactam 2e
(white solid, 483 mg, 55%) and its (3R,8S,8aS) diastereoisomer
(white solid, 122 mg, 14%) were obtained after flash chromatography
(SiO2 previously washed with 7:3 hexane−Et3N; gradient from 7:3
hexane−EtOAc to EtOAc).
hexane−Et3N; gradient from 7:3 hexane−EtOAc to EtOAc). 2c:
1
[α]22 −18.6 (c 1.2, MeOH); IR (film) 1658 cm−1; H NMR (400
(S)-[(1R)-2-Hydroxy-1-phenylethyl]-5-methyl-2-piperidone
(3a). Triethylsilane (0.52 mL, 3.24 mmol) and TiCl4 (0.52 mL, 4.76
mmol) were added to a solution of lactam 2a (500 mg, 2.16 mmol) in
anhydrous CH2Cl2 (35 mL), and the mixture was stirred at 50 °C for
24 h. Then, additional TiCl4 (0.52 mL, 4.76 mmol) and triethylsilane
(0.52 mL, 3.24 mmol) were added, and the stirring was continued at
50 °C for 24 h. The mixture was poured into saturated aqueous
NaHCO3 (100 mL). The aqueous phase was filtered over Celite and
extracted with CH2Cl2. The combined organic extracts were dried,
filtered, and concentrated to give a residue, which was chromato-
graphed (from 8:2 hexane−EtOAc to EtOAc) to afford 3a22 (315 mg,
63%) as a colorless oil: [α]22D −150.4 (c 0.1, MeOH); [α]22D −88.3 (c
1.1, CH2Cl2), lit22 [α]D −86.8 (c 1.1, CH2Cl2); IR (film) 3372, 1616
D
MHz, CDCl3, COSY, g-HSQC) δ 0.98 (d, J = 6.9 Hz, 3H, CH3), 1.07
(d, J = 6.9 Hz, 3H, CH3), 1.50−1.61 (m, 1H, H-7), 1.76−1.83 (m, 1H,
H-8), 1.86−1.93 (m, 1H, H-7), 2.08−2.16 [m, 1H, CH(CH3)2], 2.30
(ddd, J = 17.9, 11.2, 6.8 Hz, 1H, H-6), 2.43 (ddd, J = 17.9, 6.8, 2.4 Hz,
1H, H-6), 4.01 (d, J = 9.0 Hz, 1H, H-2), 4.14 (dd, J = 9.0, 6.6 Hz, 1H,
H-2), 4.67 (d, J = 9.2 Hz, 1H, H-8a), 4.92 (d, J = 6.6 Hz, 1H, H-3),
7.22−7.32 (m, 5H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 17.7
(CH3), 19.6 (C-7), 20.5 (CH3), 27.7 [CH(CH3)2], 31.6 (C-6), 44.6
(C-8), 58.9 (C-3), 73.8 (C-2), 90.6 (C-8a), 126.3 (C-o), 127.4 (C-p),
128.5 (C-m), 141.6 (C-i), 167.3 (CO); HRMS (ESI-TOF) m/z [M +
H]+ Calcd for C16H22NO2 260.1645, found 260.1640. (3R,8S,8aS)
diastereoisomer: [α]22 −87.7 (c 1.2, MeOH); IR (film) 1666 cm−1;
D
1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.96 (dd, J = 6.9, 2.1
Hz, 3H, CH3), 1.05 (dd, J = 6.9, 2.1 Hz, 3H, CH3), 1.47−1.63 (m, 2H,
H-7, H-8), 1.83−1.88 (m, 1H, H-7), 2.01−2.05 [m, 1H, CH(CH3)2],
2.30−2.39 (m, 1H, H-6), 2.59 (dm, J = 18.5 Hz, 1H, H-6), 3.74 (dt, J
= 8.2, 2.1 Hz, 1H, H-2), 4.48 (dt, J = 8.2, 2.1 Hz, 1H, H-2), 4.80 (dd, J
= 8.2, 2.1 Hz, 1H, H-8a), 5.26 (t, J = 7.8 Hz, 1H, H-3), 7.26−7.37 (m,
5H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 18.0 (CH3), 19.2 (C-7),
20.6 (CH3), 28.1 [CH(CH3)2], 31.7 (C-6), 45.3 (C-8), 58.1 (C-3),
72.4 (C-2), 90.7 (C-8a), 126.1 (C-o), 127.5 (C-p), 128.8 (C-m), 139.7
(C-i), 169.1 (CO); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C16H22NO2 260.1645, found 260.1639.
1
cm−1; H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.93 (d, J =
6.4 Hz, 3H, CH3), 1.44−1.54 (m, 1H, H-4), 1.77−1.86 (m, 2H, H-4,
H-5), 2.48 (ddd, J = 17.9, 11.4, 6.5 Hz, 1H, H-3), 2.59 (ddd, J = 17.9,
6.3, 2.9 Hz, 1H, H-3), 2.85 (dd, J = 11.8, 10.2 Hz, 1H, H-6), 2.98
(ddd, J = 11.8, 4.8, 2.1 Hz, 1H, H-6), 4.09 (dd, J = 11.4, 9.6 Hz, 1H,
CH2O), 4.17 (dd, J = 11.4, 5.1 Hz, 1H, CH2O), 5.81 (dd, J = 9.6, 5.1
Hz, 1H, CHN), 7.17−7.38 (m, 5H, ArH); 13C NMR (100.6 MHz,
CDCl3) δ 18.6 (CH3), 28.9 (C-5), 29.1 (C-4), 32.0 (C-3), 50.3 (C-6),
58.5 (CHN), 61.6 (CH2O), 127.6 (C-o), 127.7 (C-p), 128.7 (C-m),
137.0 (C-i), 171.5 (CO); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C14H20NO2 234.1489, found 234.1484.
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Note
(S)-5-Ethyl-[(1R)-2-hydroxy-1-phenylethyl]-2-piperidone
(3b). Operating as above, from lactam 2b (500 mg, 2.12 mmol) in
CH2Cl2 (32 mL), TiCl4 (1.20 mL, 11.03 mmol), and Et3SiH (1.02 mL,
9.54 mmol), lactam 3b22 was obtained (316 mg, 60%) after flash
chromatography (from hexane−EtOAc 8:2 to EtOAc−EtOH 8:2) as a
yellow oil: [α]22D −127.2 (c 0.9, EtOH), [α]22D −73.5 (c 1.1, CH2Cl2),
lit22 [α]D −74.2 (c 1.1, CH2Cl2); IR (film) 3360, 1617 cm−1; 1H NMR
(400 MHz, CDCl3, g-HSQC) δ 0.84 (t, J = 7.6 Hz, 3H, CH3CH2),
1.17−1.35 (m, 2H, CH3CH2), 1.37−1.49 (m, 1H, H-4), 1.50−1.60
(m, 1H, H-5), 1.88−1.93 (m, 1H, H-4), 2.44 (ddd, J = 18.0, 10.4, 7.2
Hz, 1H, H-3), 2.57 (ddd, J = 18.0, 6.0, 3.6 Hz, 1H, H-3), 2.90 (dd, J =
12.0, 9.6 Hz, 1H, H-6), 3.03 (ddd, J = 12.0, 5.0, 2.0 Hz, 1H, H-6), 4.05
(t, J = 10.4 Hz, 1H, CH2O), 4.16 (dd, J = 11.6, 5.0 Hz, 1H, CH2O),
5.86 (dd, J = 9.6, 5.0 Hz, 1H, CHN), 7.20−7.35 (m, 5H, ArH); 13C
NMR (100.6 MHz, CDCl3) δ 11.4 (CH3CH2), 26.0 (CH3CH2), 26.5
(C-4), 31.8 (C-3), 35.6 (C-5), 48.3 (C-6), 58.2 (CHN), 61.2 (CH2O),
127.5 (C-o), 127.6 (C-p), 128.6 (C-m), 137.1 (C-i), 171.8 (CO). Anal.
Calcd for C15H21NO2.1/2 H2O: C, 70.28; H, 8.65; N, 5.46. Found: C,
70.36; H, 8.37; N, 5.27.
[C(CH3)3], 152.7 (NCO), 172.6 (CO); HRMS (ESI-TOF) m/z [M +
Na]+ Calcd for C11H19NO3Na 236.1257, found 236.1258.
(S)-1-(tert-Butoxycarbonyl)-5-ethyl-2-piperidone (5b). Oper-
ating as above, from lactam 4b (180 mg, 1.4 mmol), n-BuLi (1.6 M in
hexanes, 0.57 mL, 1.4 mmol), and di-tert-butyl dicarbonate (309 mg,
1.4 mmol) in THF (5 mL), lactam 5b was obtained (221 mg, 70%) as
a colorless oil after flash chromatography (from 9:1 hexane−EtOAc to
1:1 hexane−EtOAc): 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ
0.96 (t, J = 7.5 Hz, 3H, CH3CH2), 1.30−1.46 (m, 3H, CH3CH2, H-4),
1.53 [s, 9H, (CH3)3], 1.68−1.77 (m, 1H, H-5), 1.89−1.98 (m, 1H, H-
4), 2.45 (ddd, J = 17.3, 10.6, 6.4 Hz, 1H, H-3), 2.55 (ddd, J = 17.3, 6.4,
4.3 Hz, 1H, H-3), 3.17 (dd, J = 12.7, 10.1 Hz, 1H, H-6), 3.82 (ddd, J =
12.7, 4.8, 1.7 Hz, 1H, H-6); 13C NMR (100.6 MHz, CDCl3) δ 11.3
(CH3CH2), 26.2 (C-4), 26.3 (CH3CH2), 28.0 [(CH3)3], 34.1 (C-3),
35.2 (C-5), 50.9 (C-6), 82.8 [C(CH3)3], 152.8 (NCO), 171.5 (CO);
HRMS (ESI-TOF) m/z [M − tBu]+ Calcd for C8H12NO3 170.0812,
found 170.0808.
Methyl (S)-5-[(tert-Butoxycarbonyl)amino]-4-methylpenta-
noate (6a). A solution of LiOH (50.2 mg, 1.20 mmol) in water
(1.25 mL) was added to a solution of lactam 5a (85 mg, 0.40 mmol) in
THF (19 mL), and the mixture was stirred at room temperature for 4
h. THF was removed under reduced pressure, and the residue was
dissolved in Et2O. The organic extract was washed with aqueous 1 N
HCl, dried, filtered, and concentrated to afford a carboxylic acid (85
mg) as a colorless oil, which was used without purification in the next
(S)-5-Methyl-2-piperidone (4a). Into a three-necked, 100 mL,
round-bottomed flask equipped with a coldfinger condenser charged
with dry ice acetone were condensed 30 mL of NH3 at −78 °C. A
solution of 3a (290 mg, 1.24 mmol) in dry THF (5 mL) was added,
and the temperature was raised to −33 °C. Sodium metal was added in
small portions until the blue color persisted, and the mixture was
stirred at −33 °C for 3 min. The reaction was quenched by addition of
solid NH4Cl until the blue color disappeared, and then the mixture
was stirred at room temperature for 5 h. CH2Cl2 was added, the solid
was filtered, and the solvent was removed under reduced pressure. The
resulting oil was chromatographed (from 8:2 hexane−EtOAc to 8:2
1
step: H NMR (400 MHz, CDCl3) δ 0.91 (d, J = 6.8 Hz, 3H, CH3),
1.44 [s, 10H, (CH3)3, CH2) 1.58−1.76 (m, 2H), 2.32−2.45 (m, 2H),
2.95−3.05 (m, 2H), 4.65 (br.s, 1H, NH); HRMS (ESI-TOF) m/z [M
- H]+ Calcd for C11H20NO4 230.1392, found 230.1397. TMSCHN2
(0.28 mL, 0.55 mmol) was added at 0 °C to a solution of the above
carboxylic acid (85 mg) in toluene−methanol (2.5:1, 12.3 mL), and
the mixture was stirred at this temperature for 1 h, quenched with
some drops of AcOH, and concentrated under reduced pressure to
EtOAc−EtOH) to afford 4a23 (93 mg, 66%): [α]22 −29.0 (c 0.55,
D
MeOH), [α]22 −80.0 (c 1.0, CHCl3), lit23 [α]23 −82.5 (c 1.0,
D
D
1
CHCl3); IR (film) 3232, 1659 cm−1; H NMR (300 MHz, CDCl3,
COSY, g-HSQC) δ 1.01 (d, J = 6.6 Hz, 3H, CH3), 1.45−1.51 (m, 1H,
H-4), 1.83−1.99 (m, 2H, H-4, H-5), 2.34 (ddd, J = 17.8, 10.8, 6.4 Hz,
1H, H-3), 2.43 (ddd, J = 17.8, 6.4, 3.5 Hz, 1H, H-3), 2.92 (t, J = 10.8
Hz, 1H, H-6), 3.26−3.33 (m, 1H, H-6), 6.10 (br.s, 1H, NH); 13C
NMR (75.4 MHz, CDCl3) δ 18.2 (CH3), 28.0 (C-5), 28.8 (C-4), 30.6
(C-3), 48.8 (C-6), 172.6 (CO); HRMS (ESI-TOF) m/z [M + H]+
Calcd for C6H12NO 114.0914, found 114.0913.
afford pure ester 6a (88 mg, 90%): [α]22 −5.45 (c 0.8, MeOH); IR
D
(film) 3375, 1735, 1715 cm-1; 1H NMR (400 MHz, CDCl3, COSY, g-
HSQC) δ 0.85 (d, J = 6.6 Hz, 3H, CH3), 1.38 [s, 10H, (CH3)3, H-3],
1.52−1.61 (m, 1H, H-4), 1.62−1.71 (m, 1H, H-3), 2.20−2.37 (m, 2H,
H-5), 2.92−3.02 (m, 2H, H-2), 3.61 (s, 3H, CH3O), 4.71 (br.s, 1H,
NH); 13C NMR (100.6 MHz, CDCl3) δ 17.1 (CH3), 28.3 [(CH3)3],
28.9 (C-3), 31.4 (C-5), 33.2 (C-4), 45.9 (C-2), 51.4 (CH3O), 78.9
[C(CH3)3], 156.0 (NCO), 174.1 (CO2); HRMS (ESI-TOF) m/z [M
+ Na]+ Calcd for C12H23NO4Na 268.1519, found 268.1527.
(S)-5-Ethyl-2-piperidone (4b). Operating as above, from lactam
3b (300 mg, 1.21 mmol) in THF (5 mL), sodium, and liquid NH3 (35
mL) at −33 °C for 5 min, lactam 4b24 was obtained (119 mg, 77%)
after column chromatography (from 8:2 hexane−EtOAc to 8:2
Methyl (S)-5-[(tert-Butoxycarbonyl)amino]-4-ethylpenta-
noate (6b). Operating as above, from lactam 5b (80 mg, 0.35
mmol) in THF (1.7 mL) and a solution of LiOH (44.3 mg, 1.06
mmol) in water (1.1 mL), a carboxylic acid (80 mg) was obtained as a
colorless oil: 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.90 (t,
J = 7.5 Hz, 3H, CH3CH2), 1.25−1.36 (m, 2H, CH3CH2), 1.44 [s, 9H,
(CH3)3], 1.43−1.48 (m, 1H, H-4), 1.55−1.67 (m, 2H, H-3), 2.30−
2.42 (t, J = 7.6 Hz, 2H, H-2), 2.90−3.17 (m, 2H, H-5), 6.07 (br.s, 1H,
NH); 13C NMR (100.6 MHz, CDCl3) δ 10.8 (CH3CH2), 24.0
(CH3CH2), 25.9 (C-3), 28.4 [(CH3)3], 31.3 (C-2), 39.3 (C-4), 42.9
(C-5), 79.3 [C(CH3)3], 156.2 (NCO), 179.0 (CO2); HRMS (ESI-
TOF) m/z [M + Na]+ Calcd for C12H23NO4Na 268.1519, found
268.1519. Operating as in the preparation of 6a, from the above crude
carboxylic acid (80 mg) and TMSCHN2 (0.24 mL, 0.47 mmol) in a
mixture of toluene−methanol (2.5:1, 11 mL), ester 6b (73 mg, 80%)
EtOAc−EtOH): [α]22 −58.3 (c 0.75, MeOH); IR (film) 1665
D
cm−1; 1H NMR (300 MHz, CDCl3, COSY, g-HSQC) δ 0.95 (t, J = 7.5
Hz, 3H, CH3CH2), 1.34−1.50 (m, 3H, CH3CH2, H-4), 1.62−1.78 (m,
1H, H-5), 1.87−1.98 (m, 1H, H-4), 2.25−2.50 (m, 2H, H-3), 2.94 (t, J
= 12.0 Hz, 1H, H-6), 3.35 (m, 1H, H-6), 5.93 (br.s, 1H, NH); 13C
NMR (75.4 MHz, CDCl3) δ 11.4 (CH3CH2), 25.9 (CH3CH2), 26.6
(C-4), 30.7 (C-3), 34.7 (C-5), 47.3 (C-6), 172.7 (CO); HRMS (ESI-
TOF) m/z [M + H]+ Calcd for C7H14NO 128.1070, found 128.1067.
(S)-1-(tert-Butoxycarbonyl)-5-methyl-2-piperidone (5a). n-
BuLi (1.6 M in hexanes, 0.55 mL, 0.88 mmol) was added at −78
°C to a solution of lactam 4a (100 mg, 0.88 mmol) in THF (2.5 mL),
and the mixture was stirred at this temperature for 30 min. Then, a
cooled (−78 °C) solution of di-tert-butyl dicarbonate (289 mg, 1.32
mmol) in dry THF (1.2 mL) was added, and the resulting mixture was
stirred for 90 min at this temperature. Saturated aqueous NH4Cl was
added, and the resulting mixture was extracted with EtOAc. The
combined organic extracts were dried and concentrated. The residue
was chromatographed (95:5 hexane−EtOAc) affording lactam 5a (150
was obtained: [α]22 −8.4 (c 0.58, MeOH); IR (film) 3371, 1740,
D
1715 cm-1; 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.90 (t, J
= 7.2 Hz, 3H, CH3), 1.32 (m, 2H, CH3CH2), 1.44 [s, 9H, (CH3)3],
1.46 (m, 1H, H-4), 1.62 (m, 2H, H-3), 2.34 (t, J = 7.7 Hz, 2H, H-2),
3.02 (m, 1H, H-5), 3.09 (m, 1H, H-5), 3.70 (s, 3 H, CH3O), 4.67
(br.s, 1H, NH); 13C NMR (100.6 MHz, CDCl3) δ 10.8 (CH3), 23.9
(CH3CH2), 26.0 (C-3), 28.3 [(CH3)3], 31.2 (C-2), 39.3 (C-4), 42.9
(C-5), 51.5 (CH3O), 79.0 [(CH3)3], 156.0 (NCO), 174.2 (CO2);
HRMS (ESI-TOF) m/z [M + H]+ Calcd for C13H26NO4 260.1856,
found 260.1852.
mg, 80%) as a colorless oil: [α]22 −19.5 (c 0.3, CHCl3); IR (film)
D
1
1770, 1715 cm−1; H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ
1.04 (d, J = 6.6 Hz, 3H, CH3), 1.41−1.50 (m, 1H, H-4), 1.52 [s, 9H,
(CH3)3], 1.84−1.92 (m, 1H, H-4), 1.93−2.03 (m, 1H, H-5), 2.47
(ddd, J = 17.4, 10.8, 6.5 Hz, 1H, H-3), 2.57 (ddd, J = 17.4, 6.5, 4.0 Hz,
1H, H-3), 3.11 (dd, J = 12.6, 10.4 Hz, 1H, H-6), 3.79 (ddd, J = 12.6,
4.8, 2.0 Hz, 1H, H-6); 13C NMR (100.6 MHz, CDCl3) δ 18.7 (CH3),
28.0 [(CH3)3], 28.7 (C-4), 28.7 (C-5), 34.2 (C-3), 52.8 (C-6), 82.8
(S)-5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-4-methyl-1-
pentanol (7a). n-BuLi (4.13 mL of a 2.5 M solution in hexanes, 10.3
mmol) was added to a solution of NH3·BH3 (319 mg, 10.3 mmol) in
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The Journal of Organic Chemistry
Note
anhydrous THF (9.0 mL) at 0 °C, and the resulting mixture was
stirred at this temperature for 10 min and at room temperature for 15
min. Then, a solution of lactam 2a (555 mg, 2.40 mmol) in THF (4.5
mL) was added, and the stirring was continued at 40 °C for 1 h. The
reaction mixture was quenched with H2O, and the resulting solution
was extracted with Et2O. The combined organic extracts were dried,
filtered, concentrated. Flash chromatography (from 8:2 hexane−
EtOAc to 8:2 EtOAc−EtOH) of the residue gave (S)-[(R)-2-hydroxy-
1-phenylethyl]-3-methylpiperidine22 (40 mg, 7%) as a colorless oil,
(R)-5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-4-phenyl-1-
pentanol (7d). Operating as described for preparation of 7a, from
lactam 2d (200 mg, 0.68 mmol), n-BuLi (1.17 mL of a 2.5 M solution
in hexanes, 2.93 mmol), and NH3·BH3 (91 mg, 2.93 mmol) in
anhydrous THF (5 mL), aminoalcohol 7d (116 mg, 57%) was
obtained as a colorless oil after flash chromatography (from hexane−
EtOAc 1:1 to EtOAc−EtOH 8:2): [α]22 −48.1 (c 0.4, MeOH); IR
D
1
(film) 3323 cm−1; H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ
1.39−1.46 (m, 2H, H-3), 1.54−1.61 (m, 1H, H-2), 1.66 (br.s, 3H, OH,
NH), 1.76−1.80 (m, 1H, H-2), 2.65−2.72 (m, 2H, H-4, H-5), 2.78−
2.82 (m, 1H, H-5), 3.44 (dd, J = 10.2, 8.5 Hz, 1H, CH2O), 3.56 (t, J =
6.4 Hz, 2H, H-1), 3.60−3.68 (m, 2H, CH2O, CHN), 7.13−7.34 (m,
10H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 30.1 (C-2), 30.5 (C-3),
46.0 (C-4), 53.3 (C-5), 62.7 (C-1), 64.8 (CHN), 66.4 (CH2O), 126.5,
126.9 (C-p), 127.2, 127.7, 128.6, 128.6 (C-o, C-m), 140.4, 143.4 (C-i);
HRMS (ESI-TOF) m/z [M + H]+ Calcd for C19H26NO2 300.1958,
found 300.1952.
and aminoalcohol 7a (425 mg, 75%): [α]22 −50.9 (c 0.68, MeOH);
D
IR (film) 3314 cm−1; 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ
0.90 (d, J = 6.4 Hz, 3H, CH3), 1.13−1.21 (m, 1H, H-2), 1.44−1.56
(m, 2H, H-2, H-3), 1.57−1.67 (m, 2H, H-3, H-4), 2.31 (br.s, 3H, OH,
NH), 2.33 (dd, J = 11.7, 6.0 Hz, 1H, H-5), 2.43 (dd, J = 11.7, 7.0 Hz,
1H, H-5), 3.55 (dd, J = 10.6, 8.8 Hz, 1H, CH2O), 3.61 (t, J = 6.0 Hz,
2H, H-1), 3.70 (dd, J = 10.6, 4.4 Hz, 1H, CH2O), 3.75 (dd, J = 8.8, 4.4
Hz, 1H, CHN), 7.25−7.37 (m, 5H, ArH); 13C NMR (100.6 MHz,
CDCl3) δ 18.6 (CH3), 29.7 (C-3), 30.3 (C-2), 32.8 (C-4), 53.4 (C-5),
62.6 (C-1), 64.7 (CHN), 66.5 (CH2O), 127.2 (C-o), 127.6 (C-p),
128.6 (C-m), 140.4 (C-i); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C14H24NO2 238.1802, found 238.1799.
(R)-4-Benzyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-
pentanol (7e). Operating as described for the preparation of 7a, from
lactam 2e (324 mg, 1.05 mmol), n-BuLi (2.83 mL of a 2.5 M solution
in hexanes, 4.53 mmol), and NH3·BH3 (140 mg, 4.53 mmol) in
anhydrous THF (4 mL), aminoalcohol 7e (233 mg, 70%) was
obtained as a colorless oil after flash chromatography: [α]22D −35.8 (c
(S)-4-Ethyl-5-{[(1R)-2-hydroxy-1-phenylethyl]amino}-1-pen-
tanol (7b). Operating as above, from lactam 2b (200 mg, 0.82 mmol),
n-BuLi (1.40 mL of a 2.5 M solution in hexanes, 3.51 mmol), and
NH3·BH3 (108 mg, 3.51 mmol) in anhydrous THF (3 mL),
aminoalcohol 7b (165 mg, 80%) was obtained after flash
1
1.15, MeOH); IR (film) 3331 cm−1; H NMR (400 MHz, CDCl3,
COSY, g-HSQC) δ 1.23−1.40 (m, 1H, H-3), 1.44−1.59 (m, 3H, H-3,
H-2), 1.84 (br.s, 1H, H-4), 2.35−2.47 (m, 2H, H-5), 2.48−2.63 (m,
2H, CH2Ar), 2.92 (br.s, 3H, OH, NH), 3.50−3.63 (m, 3H, H-1,
CH2O), 3.64−3.73 (m, 2H, CH2O, CHN), 7.05−7.33 (m, 10H, ArH);
13C NMR (100.6 MHz, CDCl3) δ 27.8 (C-3), 29.3 (C-2), 39.2
(CH2Ar), 39.6 (C-4), 50.1 (C-5), 62.4 (C-1), 64.8 (CHN), 66.5
(CH2O), 125.8 (C-p), 127.3 (C-m), 127.6 (C-p), 128.2 (C-m), 128.5,
128.9 (C-o), 140.1, 140.5 (C-i); HRMS (ESI-TOF) m/z [M + H]+
Calcd for C20H28NO2 314.2115, found 314.2111.
(S)-5-[(tert-Butoxycarbonyl)amino]-4-methyl-1-pentanol
(8a). A solution of aminodiol 7a (1.4 g, 5.9 mmol) in anhydrous
MeOH (35 mL) containing 45% Pd(OH)2 (630 mg) was hydro-
genated at 75 °C for 22 h under 5 bar of pressure. Then, di-tert-butyl
dicarbonate (1.55 g, 7.08 mmol) was added, and the mixture was
stirred at room temperature for 24 h. The catalyst was removed by
filtration and washed with hot MeOH. The combined organic
solutions were concentrated to give an oil. Flash chromatography
(8:2 hexane−EtOAc) afforded pure alcohol 8a (893 mg, 70%) as a
colorless oil: [α]22D −2.89 (c 1.0, MeOH); IR (film) 3355, 1692 cm−1;
1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δδ 0.90 (d, J = 6.8 Hz,
3H, CH3), 1.05−1.18 (m, 1H, H-3), 1.30−1.40 (m, 1H, H-3), 1.38 [s,
9H, (CH3)3], 1.45−1.57 (m, 3H, H-2, H-4), 2.60 (br.s, 1H, OH), 2.88
(ddd, J = 13.2, 6.4, 6.4 Hz, 1H, H-5), 2.99 (ddd, J = 13.2, 6.4, 6.4 Hz,
1H, H-5), 3.55 (t, J = 6.4 Hz, 2H, H-1), 4.77 (br.s, 1H, NH); 13C
NMR (100.6 MHz, CDCl3) δ 17.4 (CH3), 28.3 [C(CH3)3], 29.8 (C-
3), 30.1 (C-2), 33.4 (C-4), 46.3 (C-5), 62.6 (C-1), 79.1 [C(CH3)3],
156.3 (CO); HRMS (ESI-TOF) m/z [M − Boc + 2H]+ Calcd for
C6H16NO 118.1226, found 118.1227.
chromatography (from EtOAc to EtOAc−EtOH 8:2): [α]22 −44.9
D
1
(c 0.16, MeOH); IR (film) 3330 cm−1; H NMR (400 MHz, CDCl3,
COSY, g-HSQC) δ 0.82 (t, J = 7.6 Hz, 3H, CH3), 1.23−1.40 (m, 3H,
H-3, CH3CH2), 1.42−1.50 (m, 4H, H-2, H-3, H-4), 2.40 (dd, J = 11.6,
6.4 Hz, 1H, H-5), 2.46 (dd, J = 11.6, 5.0 Hz, 1H, H-5), 3.41 (br.s, 3H,
OH, NH), 3.57−3.64 (m, 3H, H-1, CH2O), 3.71 (dd, J = 10.8, 4.0 Hz,
1H, CH2O), 3.77 (dd, J = 8.8, 4.0 Hz, 1H, CHN), 7.24−7.38 (m, 5H,
ArH); 13C NMR (100.6 MHz, CDCl3) δ 11.3 (CH3), 24.9 (CH3CH2),
27.4 (C-3), 29.2 (C-2), 38.8 (C-4), 50.2 (C-5), 60.3 (C-1), 64.8
(CHN), 66.5 (CH2O), 127.3 (C-o), 127.6 (C-p), 128.6 (C-m), 139.9
(C-i); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C15H26NO2
252.1958, found 252.1947.
(R)-5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-4-isopropyl-1-
pentanol (7c). Operating as described for preparation of 7a, from
lactam 2c (400 mg, 1.54 mmol), n-BuLi (4.14 mL of a 2.5 M solution
in hexanes, 6.6 mmol), and NH3·BH3 (205 mg, 6.6 mmol) in
anhydrous THF (9 mL), (S)-[(R)-2-hydroxy-1-phenylethyl]-3-
isopropylpiperidine (30 mg, 7%) and aminoalcohol 7c (292 mg,
71%) were obtained as colorless oils after flash chromatography (from
hexane−EtOAc 1:1 to EtOAc−EtOH 8:2). (S)-[(R)-2-hydroxy-1-
phenylethyl]-3-isopropylpiperidine: [α]22 −47.5 (c 0.25, MeOH);
D
IR (film) 3406 cm−1; 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ
0.78−0.84 (m, 1H, H-4), 0.84 (d, J = 6.4 Hz, 3H, CH3), 0.88 (d, J =
6.4 Hz, 3H, CH3), 1.35−1.47 [m, 3H, H-3, H-5, CH(CH3)2], 1.60−
1.70 (m, 3H, H-4, H-5, H-6), 2.03 (t, J = 10.5 Hz, 1H, H-2), 2.82
(br.m, 2H, H-2, H-6), 3.61 (dd, J = 10.3, 5.2 Hz, 1H, CH2O), 3.70
(dd, J = 10.2, 5.2 Hz, 1H, CHN), 3.98 (t, J = 10.2 Hz, 1H, CH2O),
7.17−7.19 (m, 2H, ArH), 7.30−7.37 (m, 3H, ArH); 13C NMR (100.6
MHz, CDCl3) δ 19.9 (CH3), 20.3 (CH3), 25.8 (C-5), 27.9 (C-4), 30.9
[CH(CH3)2], 43.3 (C-3), 46.6 (C-6), 57.1 (C-2), 59.9 (CH2O), 70.3
(CHN), 127.7 (C-p), 128.0, 128.9 (C-o, C-m), 135.5 (C-i); HRMS
(ESI-TOF) m/z [M + H]+ Calcd for C16H26NO 248.2009, found
248.2005. 7c: [α]22D −44.9 (c 0.65, MeOH); IR (film) 3320 cm−1; 1H
NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.78 (d, J = 6.8 Hz, 3H,
CH3), 0.82 (d, J = 6.8 Hz, 3H, CH3), 1.31−1.41 (m, 3H, H-3, H-4),
1.45−1.52 (m, 1H, H-2), 1.54−1.61 (m, 1H, H-2),1.64−1.72 (m, 1H,
CHCH3), 2.31 (dd, J = 11.8, 4.2 Hz, 1H, H-5), 2.48 (dd, J = 11.8, 7.7
Hz, 1H, H-5), 3.54−3.65 (m, 3H, H-1, CH2O), 3.68 (dd, J = 10.8, 4.0
Hz, 1H, CH2O), 3.76 (dd, J = 9.1, 4.0 Hz, 1H, CHN), 7.24−7.35 (m,
5H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 19.3 (CH3), 19.4 (CH3),
25.3 (C-3), 29.3 (CHCH3), 30.2 (C-2), 43.2 (C-4), 48.8 (C-5), 61.8
(C-1), 64.9 (CHN), 66.5 (CH2O), 127.3 (C-o), 127.5 (C-p), 128.5
(C-m), 140.1 (C-i); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C16H28NO2 266.2115, found 266.2109.
(S)-5-[(tert-Butoxycarbonyl)amino]-4-ethyl-1-pentanol (8b).
Operating as above, from a solution of aminodiol 7b (325 mg, 1.29
mmol) in anhydrous MeOH (10 mL), 45% Pd(OH)2 (146 mg), and
Boc2O (339 mg, 1.55 mmol), alcohol 8b (195 mg, 65%) was obtained
as a colorless oil after column chromatography (from hexane−EtOAc
7:3 to hexane−EtOAc 1:1): [α]22 −3.3 (c 0.84, MeOH); IR (film)
D
1
3348, 1692 cm−1; H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ
0.89 (t, J = 7.4 Hz, 3H, CH3), 1.24−1.37 (m, 5H, CH3CH2, H-2, H-4),
1.44 [s, 9H, (CH3)3], 1.56−1.63 (m, 2H, H-3), 2.21 (br.s, 1H, OH),
3.03−3.15 (m, 2H, H-5), 3.64 (t, J = 6.3 Hz, 2H, H-1), 4.54 (br.s, 1H,
NH); 13C NMR (100.6 MHz, CDCl3) δ 10.9 (CH3), 24.1 (CH3CH2),
26.9 (C-2), 28.4 [(CH3)3], 29.5 (C-3), 39.6 (C-4), 43.0 (C-5), 62.9
(C-1), 79.0 [C(CH3)3], 156.3 (NCO); HRMS (ESI-TOF) m/z [M −
tBu + 2H]+ Calcd for C8H18NO3 176.1281, found 176.1279.
(R)-5-[(tert-Butoxycarbonyl)amino]-4-isopropyl-1-pentanol
(8c). Operating as described for the preparation of 8a, from a solution
of 7c (500 mg, 1.88 mmol) in anhydrous MeOH (12 mL), 45%
Pd(OH)2 (225 mg), and Boc2O (493 mg, 1.2 mmol), alcohol 8c (208
2797
dx.doi.org/10.1021/jo5002627 | J. Org. Chem. 2014, 79, 2792−2802

The Journal of Organic Chemistry
Note
mg, 45%) was obtained after column chromatography (from hexane−
a colorless oil after column chromatography (from 7:3 hexane−EtOAc
1
EtOAc 8:2 to EtOAc): [α]22 + 2.5 (c 1.25, MeOH); IR (film) 3347,
to EtOAc): [α]22 + 0.95 (c 0.84, MeOH); IR (film) 3348 cm−1; H
D
D
1693 cm−1; 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.89 (d, J
= 6.9 Hz, 6H, 2CH3), 1.24−1.33 (m, 3H, H-2, H-4), 1.44 [s, 9H,
(CH3)3], 1.59−1.63 (m, 2H, H-3), 1.67−1.74 [m, 1H, CH(CH3)2],
3.06−3.17 (m, 2H, H-5), 3.64 (t, J = 6.4 Hz, 2H, H-1), 4.52 (br.s, 1H,
NH); 13C NMR (100.6 MHz, CDCl3) δ 19.2 (CH3), 19.5 (CH3), 24.6
(C-3), 28.4 [CH(CH3)2, (CH3)3], 30.5 (C-2), 41.4 (C-5), 44.3 (C-4),
62.9 (C-1), 79.1 [C(CH3)3], 156.2 (NCO); HRMS (ESI-TOF) m/z
[M − tBu + 2H]+ Calcd for C9H20NO3 190.1438, found 190.1438.
(R)-5-[(tert-Butoxycarbonyl)amino]-4-phenyl-1-pentanol
(8d). Operating as described for the preparation of 8a, from a solution
of 7d (193 mg, 0.65 mmol) in anhydrous MeOH (16 mL), 45%
Pd(OH)2 (86 mg), and Boc2O (169 mg, 0.77 mmol), alcohol 8d (97
mg, 53%) was obtained after column chromatography (from hexane−
EtOAc 8:2 to hexane−EtOAc 1:1): [α]22D + 10.9 (c 0.65, MeOH); IR
(film) 3363, 1693 cm−1; 1H NMR (400 MHz, CDCl3, COSY, g-
HSQC) δ 1.40 [s, 9H, (CH3)3], 1.43−1.49 (m, 2H, H-2), 1.57−1.67
(m, 1H, H-3), 1.73−1.80 (m, 1H, H-3), 2.76 (br.s, 1H, H-4), 3.18
(ddd, J = 13.6, 8.7, 4.9 Hz, 1H, H-5), 3.47−3.42 (m, 1H, H-5), 3.57 (t,
J = 6.4 Hz, 2H, H-1), 4.43 (br.s, 1H, NH), 7.15−7.17 (m, 2H, ArH),
7.21−7.27 (m, 1H, H-p), 7.30−7.34 (m, 2H, ArH); 13C NMR (100.6
MHz, CDCl3) δ 28.3 [(CH3)3], 29.6 (C-3), 30.4 (C-2), 45.9 (C-4),
46.2 (C-5), 62.6 (C-1), 79.2 [C(CH3)3], 126.7 (C-p), 127.8, 128.6 (C-
o, C-m), 142.6 (C-i), 156.0 (NCO); HRMS (ESI-TOF) m/z [M +
H]+ Calcd for C16H26 NO3 280.1907, found 280.1905.
NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.84 (t, J = 7.6 Hz, 3H,
CH3), 1.30−1.40 (m, 4H, H-3, CH3CH2), 1.47−1.54 (m, 3H, H-2, H-
4), 1.65 (br.s, 1H, OH), 3.02 (dt, J = 6.1, 3.7 Hz, 2H, H-5), 3.60 (t, J =
6.4 Hz, 2H, H-1), 5.41 (t, J = 6.0 Hz, 1H, NH), 7.76 (m, 2H, H-5Ns,
H-6Ns), 7.85 (m, 1H, H-4Ns), 8.13 (m, 1H, H-3Ns); 13C NMR
(100.6 MHz, CDCl3) δ 10.7 (CH3), 23.9 (CH3CH2), 26.9 (C-3), 29.3
(C-2), 33.1 (C-4), 46.2 (C-5), 62.8 (C-1), 125.3, 131.1 (C-3 Ns, C-
6Ns), 132.7 (C-4Ns), 133.5 (C-1Ns), 133.6 (C-5Ns), 148.0 (C-2Ns);
HRMS (ESI-TOF) m/z [M + H] Calcd for C13H21N2O5S 317.1166,
found 317.1161.
(S)-4-Methyl-5-[(p-methylbenzenesulfonyl)amino]-1-penta-
nol (10a). A solution of aminodiol 7a (1.5 g, 6.32 mmol) in
anhydrous MeOH (110 mL) containing 20% Pd(OH)2 (300 mg) was
hydrogenated at 68 °C for 19 h under 11 bar of pressure. The catalyst
was removed by filtration and washed with hot MeOH, and the
combined organic solutions were concentrated. The resulting residue
was dissolved in CHCl3 (30 mL), and p-toluenesulfonyl chloride (1.33
g, 6.96 mmol) and Et3N (1.06 mL, 7.56 mmol) were added. The
mixture was allowed to react at room temperature for 15 h. The
solvent was evaporated under reduced pressure, and the residue was
chromatographed (from 9:1 hexane−EtOAc to EtOAc) to give alcohol
10a (1.01 g, 59%) as a yellow oil: [α]22 + 0.61 (c 0.8, MeOH); IR
D
(film) 3507, 3286 cm−1; 1H NMR (400 MHz, CDCl3, COSY, g-
HSQC) δ 0.86 (d, J = 6.8 Hz, 3H, CH3), 1.09−1.16 (m, 1H, H-3),
1.38−1.48 (m, 1H, H-3), 1.50−1.64 (m, 3H, H-2, H-4), 2.42 (s, 3H,
CH3Ts), 2.74 (dd, J = 12.5, 6.4 Hz, 1H, H-5), 2.79 (dd, J = 12.5, 6.8
Hz, 1H, H-5), 3.57 (t, J = 6.1 Hz, 2H, H-1), 5.32 (br.s, 1H, NH), 7.24
(d, J = 8.3 Hz, 2H, H-3 Ts, H-5 Ts), 7.74 (d, J = 8.3 Hz, 2H, H-2 Ts,
H-6 Ts); 13C NMR (100.6 MHz, CDCl3) δ 17.4 (CH3), 21.4
(CH3Ts), 29.4 (C-3), 29.7 (C-2), 32.8 (C-4), 48.7 (C-5), 62.6 (C-1),
126.9 and 129.6 (CHTs), 136.9 (C-4Ts), 143.2 (C-1Ts); HRMS
(ESI-TOF) m/z [M + H]+ Calcd for C13H22NO3S 272.1315, found
272.1317.
(R)-4-Benzyl-5-[(tert-butoxycarbonyl)amino]-1-pentanol
(8e). Operating as described for the preparation of 8a, from a solution
of 7e (260 mg, 0.83 mmol) in anhydrous MeOH (10 mL), 45%
Pd(OH)2 (117 mg), and Boc2O (217 mg, 1.0 mmol), alcohol 8e (123
mg, 51%) was obtained as a colorless oil after column chromatography
(from hexane−EtOAc 8:2 to EtOAc): [α]22 −1.87 (c 0.8, MeOH);
D
1
IR (film) 3348, 1689 cm−1; H NMR (400 MHz, CDCl3, COSY, g-
HSQC) δ 1.33−1.39 (m, 2H, H-3), 1.43 [s, 9H, (CH3)3], 1.54−1.68
(m, 2H, H-2), 1.82−1.86 (m, 1H, H-4), 2.04 (br.s., 1H, OH), 2.57 (d,
J = 7.2 Hz, 2H, CH2Ar), 3.09 (t, J = 5.6 Hz, 2H, H-5), 3.58 (t, J = 6.3
Hz, 2H, H-1), 4.62 (br.s, 1H, NH), 7.14−7.20 (m, 3H, ArH), 7.25−
7.29 (m, 2H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 27.2 (C-3),
28.3 [(CH3)3], 29.5 (C-2), 38.6 (CH2Ar), 40.4 (C-4), 43.2 (C-5), 62.7
(C-1), 79.2 [C(CH3)3], 126.0 (C-p), 128.3, 129.0 (C-o, C-m), 140.3
(C-i), 156.3 (NCO); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C17H28NO3 294.2064, found 294.2063.
(S)-4-Methyl-5-[N-(2-nitrobenzenesulfonyl)-10-undecenyla-
mino]-1-pentanol (11). 11-Bromo-1-undecene (0.10 mL, 0.44
mmol) was added to a suspension of alcohol 9a (110 mg, 0.36
mmol) and Cs2CO3 (154 mg, 0.47 mmol) in anhydrous DMF (2.5
mL), and the resulting mixture was stirred at 55 °C for 3 h. The
mixture was cooled to room temperature, poured into brine, and
extracted with Et2O. The combined organic extracts were dried,
filtered, and concentrated to give an oil. Flash chromatography (7:3
(S)-4-Methyl-5-[(2-nitrobenzenesulfonyl)amino]-1-pentanol
(9a). A solution of aminodiol 7a (1.36 g, 5.73 mmol) in anhydrous
MeOH (35 mL) containing 20% Pd(OH)2 (272 mg) was hydro-
genated at 68 °C for 18 h under 10 bar of pressure. The catalyst was
removed by filtration and washed with hot MeOH. The combined
organic solutions were concentrated, and the resulting residue was
dissolved in CH2Cl2 (19 mL). 2-Nitrobenzenesulfonyl chloride (1.4 g,
6.3 mmol) and Et3N (0.88 mL, 6.3 mmol) were added, and the
mixture was allowed to react at room temperature for 18 h. The
solvent was removed under reduced pressure, and the residue was
chromatographed (from 7:3 hexane−EtOAc to EtOAc) to give alcohol
9a (1.25 g, 72%) as a colorless oil: [α]22D + 2.66 (c 1.05, MeOH); IR
hexane−EtOAc) afforded alkene 11 (130 mg, 79%) as a colorless oil:
1
[α]22 −10.2 (c 1.25, MeOH); IR (film) 3334 cm−1; H NMR (400
D
MHz, CDCl3, COSY, g-HSQC) δ 0.87 (d, J = 6.6 Hz, 3H, CH3),
1.05−1.13 (m, 1H, H-3), 1.15−1.29 (m, 9H, H-3, 4CH2), 1.32−1.38
(m, 2H, CH2), 1.40−1.52 (m, 5H, CH2), 1.58−1.67 (m, 1H, CH2),
1.71−1.80 (m, 1H, H-4), 1.99−2.05 (m, 2H, CH2CHCH2), 3.12
(dd, J = 14.2, 8.1 Hz, 1H, H-5), 3.20 (dd, J = 14.2, 7.1 Hz 1H, H-5),
3.18−3.32 (m, 2H, CH2N), 3.61 (t, J = 6.4 Hz, 2H, H-1), 4.91−5.02
(m, 2H, CH2CH), 5.81 (qt, J = 17.0, 10.2, 6.7, 6.7 Hz, 1H, CH2
CH), 7.60−7.70 (m, 3H, H-3Ns, H-5Ns, H-6Ns), 7.99−8.02 (m, 1H,
H-4Ns); 13C NMR (100.6 MHz, CDCl3) δ 17.0 (CH3), 26.6 (CH2),
27.6 (CH2), 28.9 (CH2), 29.0 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4
(CH2), 29.9 (CH2), 29.9 (CH2), 31.0 (C-4), 33.7 (CH2CHCH2),
47.2 (CH2N), 53.2 (C-5), 62.9 (C-1), 114.1 (CH2CH), 124.1 and
130.9 (C-3Ns, C-6Ns), 131.4 (C-4Ns), 133.2 (C-1Ns), 133.8 (C-
5Ns), 139.1 (CH2CH), 148.0 (C-2Ns); HRMS (ESI-TOF) m/z [M
+ H]+ Calcd for C23H39N2O5S 455.2574, found 455.2570.
1
(film) 3349 cm−1; H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ
0.93 (d, J = 6.4 Hz, 3H, CH3), 1.22−1.28 (m, 1H, H-3), 1.42−1.54
(m, 3H, H-3, H-2, OH), 1.55−1.62 (m, 1H, H-2), 1.64−1.74 (m, 1H,
H-4), 2.92 (ddd, J = 13.2, 6.8, 6.8 Hz, 1H, H-5), 3.01 (ddd, J = 13.2,
6.8, 6.8 Hz, 1H, H-5), 3.61 (t, J = 6.4 Hz, 2H, H-1), 5.35 (t, J = 6.2 Hz,
1H, NH), 7.73−7.75 (m, 2H, H-5Ns, H-6Ns), 7.85 (m, 1H, H-4Ns),
8.12 (m, 1H, H-3Ns); 13C NMR (100.6 MHz, CDCl3) δ 17.4 (CH3),
29.6 (C-2), 29.9 (C-3), 33.1 (C-4), 49.5 (C-5), 62.8 (C-1), 125.3,
131.1 (C-3Ns, C-6Ns), 132.7 (C-4Ns), 133.5 (C-1Ns), 133.7 (C-
5Ns), 148.1 (C-2Ns); HRMS (ESI-TOF) m/z [M + H] Calcd for
C12H19N2O5S 303.1009, found 303.1008.
(S)-4-Ethyl-5-[(2-nitrobenzenesulfonyl)amino]-1-pentanol
(9b). Operating as above, from a solution of 7b (1.15 g, 4.56 mmol) in
anhydrous MeOH (25 mL), 20% Pd(OH)2 (230 mg), 2-nitro-
benzenesulfonyl chloride (1.12 g, 5.0 mmol), and Et3N (0.7 mL, 5.0
mmol) in CH2Cl2 (16 mL), alcohol 9b (1.09 g, 76%) was obtained as
N-[2-Methyl-5-hexenyl)-N-(2-nitrobenzenesulfonyl)-10-un-
decenamine (12). Dess−Martin reagent (168 mg, 0.40 mmol) was
added to a solution of alcohol 11 (90 mg, 0.20 mmol) in anhydrous
CH2Cl2 (1.5 mL), and the mixture was stirred at room temperature for
1.5 h. Then, saturated aqueous Na2S2O4 (0.75 mL) and saturated
aqueous NaHCO3 (0.75 mL) were added, and the resulting mixture
was stirred for 1 h. The aqueous layer was extracted with CH2Cl2, and
the combined organic extracts were washed with brine, dried, filtered,
and concentrated to give an aldehyde, which was used without
purification in the next step: 1H NMR (300 MHz, CDCl3) δ 0.88 (d, J
2798
dx.doi.org/10.1021/jo5002627 | J. Org. Chem. 2014, 79, 2792−2802

The Journal of Organic Chemistry
Note
= 8.8 Hz, 3H, CH3), 1.12−1.29 (m, 9H), 1.31−1.51 (m, 6H), 1.73−
1.84 (m, 2H), 1.99−2.07 (m, 2H, CH2CHCH2), 2.37−2.58 (m, 2H,
CH2COH), 3.10−3.28 (m, 4H, 2CH2N), 4.91−5.02 (m, 2H, CH2
CH), 5.80 (qt, J = 16.9, 10.1, 6.7, 6.7 Hz, 1H, CH2CH), 7.60−7.70
(m, 3H, H-Ns), 7.99−8.02 (m, 1H, H-Ns), 9.76 (s, 1H, COH). t-
BuOK (0.99 mL of a 1 M solution in THF, 0.99 mmol) was added to a
solution of methyltriphenylphosphonium bromide (497 mg, 1.38
mmol) in THF (10 mL) at room temperature, and the mixture was
stirred for 1 h. Then, a solution of the above aldehyde in THF (10
mL) was added via cannula, and the resulting mixture was stirred at
room temperature for 3 h. Saturated aqueous NH4Cl was added, and
the resulting mixture was extracted with EtOAc. The extracts were
dried, filtered, and concentrated. The residue was chromatographed
(9:1 hexane−EtOAc) to give diene 12 (55 mg, 61%) as a colorless oil:
[α]22D −3.58 (c 0.9, MeOH); 1H NMR (400 MHz, CDCl3, COSY, g-
HSQC) δ 0.85 (d, J = 6.6 Hz, 3H, CH3), 1.09−1.30 (m, 11H, CH2),
1.32−1.33 (m, 2H, CH2), 1.41−1.50 (m, 3H, CH2), 1.70−1.75 (m,
1H, CH), 1.95−2.06 (m, 3H, CH2), 2.08−2.17 (m, 1H, CH2), 3.12
(dd, J = 14.2, 8.3 Hz, 1H, CH2N), 3.18 (dd, J = 14.2, 8.8 Hz, 1H,
CH2N), 3.13−3.21 (m, 2H, CH2N), 4.91−5.02 (m, 4H, CH2
CHCH2), 5.74 (qt, J = 17.0, 10.1, 10.1, 6.7 Hz, 1H, CH2CH), 5.80
(qt, J = 17.3, 10.3, 10.3, 7.0 Hz, 1H, CH2CH), 7.59−7.62 (m, 1H,
H-3Ns), 7.63−7.70 (m, 2H, H-5Ns, H-6Ns), 7.99−8.03 (m, 1H, H-
4Ns); 13C NMR (100.6 MHz, CDCl3) δ 17.0 (CH3), 26.6 (CH2), 27.6
(CH2), 28.9 (CH2), 29.0 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2),
30.4 (CH), 31.1 (CH2), 33.0 (CH2CHCH2), 33.8 (CH2
CHCH2), 47.1 (C-1), 53.1 (CH2N), 114.1 (CH2CH), 114.7
(CH2CH), 124.1 (C-3Ns), 130.9 (C-6Ns), 131.4 (C-4Ns), 133.2
(C-5Ns), 133.9 (C-1Ns), 138.4 (CH2CH), 139.1 (CH2CH),
148.0 (C-2Ns); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C24H39N2O4S 451.2625, found 451.2622.
(CH), 130.9 (CH); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C16H32N 238.2529, found 238.2523.
Haliclorensin C. A solution of alkene 14 (46 mg, 0.19 mmol) in
anhydrous MeOH (10 mL) containing 25% Pd/C (12 mg) was
hydrogenated at room temperature for 14 h under 10 bar of pressure.
The catalyst was removed by filtration and washed with hot MeOH,
and the combined organic solutions were concentrated. Flash
chromatography (from 95:5 hexane−EtOAc to 8:2 EtOAc−Et3N) of
the residue gave haliclorensin C (15a, 33 mg, 71%) as a brown oil:
[α]22 −6.04 (c 0.85, MeOH), lit13 [α]20 + 53 (c 0.15, MeOH). H
1
D
D
NMR [500 MHz, 4:1 CDCl3−CD3OD, COSY, g-HSQC; see Table S1
in Supporting Information] δ 0.73 (d, J = 6.8 Hz, 3H, CH3), 1.08−
1.22 (m, 1H, H-4), 1.30−1.41 (m, 20H, 10CH2), 1.42−1.56 (m, 3H,
H-4, CH2), 1.60−1.63 (m, 1H, H-3), 2.30 (dd, J = 11.8, 7.7 Hz, 1H,
H-2), 2.36 (dd, J = 11.8, 5.2 Hz, 1H, H-2), 2.48−2.54 (m, 1H, H-16),
2.64−2.70 (m, 1H, H-16); 13C NMR [125 MHz, 4:1 CDCl3−CD3OD;
see Table S2 in Supporting Information] δ 18.2 (CH3), 24.2 (CH2),
24.9 (CH2), 26.0 (CH2), 26.1 (2CH2), 26.2 (CH2), 26.3 (CH2), 26.4
(CH2), 26.5 (CH2), 27.0 (2CH2), 30.7 (C-3), 32.4 (C-4), 47.0 (C-16),
53.8 (C-2); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C16H34N
1
240.2686, found 240.2681. Haliclorensin C hydrochloride: H NMR
[400 MHz, 4:1 CDCl3−CD3OD, COSY, g-HSQC; see Table S1 in
Supporting Information] δ 1.06 (d, J = 6.8 Hz, 3H, CH3), 1.26−1.40
(m, 22H, 11CH2), 1.75 (m, 2H, H-15), 1.89 (m, 1H, H-3), 2.78−2.84
(m, 2H, H-2), 2.89−2.99 (m, 2H, H-16); 13C NMR [100.6 MHz, 4:1
CDCl3−CD3OD; see Table S2 in Supporting Information] δ 17.9
(CH3), 23.7 (C-15), 24.7 (CH2), 24.9 (CH2), 26.2 (CH2), 26.3
(CH2), 26.4 (CH2), 26.5 (CH2), 26.6 (CH2), 26.7 (CH2), 26.8 (CH2),
27.1 (CH2), 28.7 (C-3), 32.6 (C-4), 45.6 (C-16), 50.9 (C-2).
(S)-4-Methyl-5-[N-(2-nitrobenzenesulfonyl)-4-pentenylami-
no]-1-pentanol (15). Operating as described for the preparation of
alcohol 11, from 9a (1.15 g, 3.80 mmol), Cs2CO3 (1.61 g, 4.95 mmol),
and 5-bromo-1-pentene (0.54 mL, 4.56 mmol) in anhydrous DMF (25
mL), compound 15 (1.06 g, 75%) was obtained as a yellow oil after
flash chromatography (from 7:3 hexane−EtOAc to 1:1 hexane−
EtOAc): [α]22D −13.4 (c 1.85, MeOH); 1H NMR (400 MHz, CDCl3,
COSY, g-HSQC) δ 0.86 (d, J = 6.7 Hz, 3H, CH3), 1.05−1.14 (m, 1H,
H-3), 1.40−1.52 (m, 2H, H-2, H-3), 1.55−1.66 (m, 4H, H-2, CH2,
OH), 1.71−1.80 (m, 1H, H-4), 1.95−2.00 (m, 2H, CH2CHCH2),
3.11 (dd, J = 14.2, 8.1 Hz, 1H, H-5), 3.20 (dd, J = 14.2, 7.1 Hz, 1H, H-
5), 3.19−3.33 (m, 2H, CH2N), 3.59 (t, J = 6.4 Hz, 2H, H-1), 4.93−
4.99 (m, 2H, CH2CH), 5.69 (qt, J = 16.9, 10.2, 10.2, 6.6, Hz, 1H,
CH2CH), 7.59−7.63 (H-3Ns), 7.64−7.71 (m, 2H, H-5Ns, H-6Ns),
7.97−8.02 (m, 1H, H-4Ns); 13C NMR (100.6 MHz, CDCl3) δ 17.0
(CH3), 26.8 (CH2), 29.8 (CH2), 29.9 (CH2), 30.6 (CH2CHCH2),
31.1 (C-4), 46.8 (CH2N), 53.5 (C-5), 62.9 (C-1), 115.4 (CH2CH),
124.1 (C-3Ns), 130.9 (C-6Ns), 131.5 (C-4Ns), 133.3 (C-5Ns), 133.6
(C-1Ns), 137.1 (CH2CH), 147.9 (C-2Ns); HRMS (ESI-TOF) m/z
[M + H]+ Calcd for C17H27N2O5S 371.1635, found 371.1635.
(S)-3-Methyl-1-(2-nitrobenzenesulfonyl)azacyclohexadec-6-
ene (13). A solution of 12 (58 mg, 0.13 mmol) in anhydrous CH2Cl2
(10 mL) was added to a solution of second-generation Grubbs catalyst
(16.4 mg, 0.02 mmol) in CH2Cl2 (650 mL) at reflux. The resulting
mixture was stirred at reflux temperature for 14 h. The solvent was
evaporated, and the resulting residue was chromatographed (95:5
hexane−EtOAc) to yield a 86:14 (calculated by GC−MS) mixture of
1
E/Z diastereoisomers 13 (44 mg, 80%). Major diastereoisomer: H
NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.84 (d, J = 6.6 Hz, 3H,
CH3), 1.06−1.18 (m, 1H, H-4), 1.19−1.59 (m, 15H, H-4, 7CH2),
1.78−1.87 (m, 1H, H-3), 1.97−2.10 (m, 3H, H-5, H-8), 2.12−2.18
(m, 1H, H-8), 3.08 (dd, J = 13.9, 6.7 Hz, 1H, H-2), 3.14−3.24 (m, 3H,
H-2, H-16), 5.26−5.45 (m, 2H, H-6, H-7), 7.59−7.62 (m, 1H, H-
3Ns), 7.64−7.69 (m, 2H, H-5Ns, H-6Ns), 7.97−8.02 (m, 1H, H-4Ns);
13C NMR (100.6 MHz, CDCl3) δ 15.9 (CH3), 24.4 (CH2), 25.7
(CH2), 26.2 (CH2), 26.3 (CH2), 26.8 (CH2), 27.0 (CH2), 27.4 (CH2),
28.1 (C-3), 28.9 (CH2CH), 30.9 (CH2CH), 33.3 (C-4), 46.5 (C-
16), 54.1 (C-2), 124.0 (C-3Ns), 130.0 (CH), 130.8 (C-6Ns), 131.3
(CH), 131.4 (C-4Ns), 133.1 (C-5Ns), 133.6 (C-1Ns), 148.1 (C-
2Ns); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C22H35N2O4S
423.2312, found 423.2301.
(S)-3-Methylazacyclohexadec-6-ene (14). K2CO3 (194 mg,
1.41 mmol) and thiophenol (0.058 mL, 0.56 mmol) were added to
a solution of 13 (198 mg, 0.47 mmol) in anhydrous DMF (9 mL), and
the mixture was stirred at room temperature for 14 h. The reaction was
quenched by the addition of aqueous 2 M NaOH, and the resulting
mixture was extracted with CH2Cl2. The combined organic extracts
were dried, filtered, and evaporated. The resulting residue was
chromatographed (from 95:5 hexane−EtOAc to 8:2 EtOAc−Et3N) to
afford compound 14 (64 mg, 58%) as a 84:16 (calculated by GC−MS)
mixture of E/Z diastereoisomers as a brown oil. Major diaster-
eoisomer: 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.87 (d, J
= 6.6 Hz, 3H, CH3), 1.14−1.22 (m, 1H, H-4), 1.24−1.54 (m, 15H, H-
4, 7CH2), 1.68−1.77 (m, 1H, H-3), 1.95−2.16 (m, 4H, H-5, H-8),
2.46 (m, 2H, H-2), 2.48−2.58 (m, 1H, H-16), 2.62−2.72 (m, 1H, H-
16), 5.35−5.40 (m, 2H, H-6, H-7); 13C NMR (100.6 MHz, CDCl3) δ
17.8 (CH3), 25.0 (CH2), 26.0 (CH2), 26.5 (CH2), 27.3 (CH2), 27.3
(CH2), 27.6 (CH2), 28.3 (CH2), 29.2 (CH2), 30.1 (C-3), 31.9
(CH2CH), 34.0 (CH2CH), 47.0 (C-16), 55.4 (C-2), 130.7
(S)-2-Methyl-N-(2-nitrobenzenesulfonyl)-N-(4-pentenyl)-5-
hexenamine (16). Operating as described for the preparation of 12,
from alcohol 15 (355 mg, 1.0 mmol) and Dess−Martin reagent (1.49
g, 3.52 mmol) in anhydrous CH2Cl2 (9 mL), an aldehyde was
1
obtained: H NMR (300 MHz, CDCl3) δ 0.88 (d, J = 6.6 Hz, 3H,
CH3), 1.33−1.39 (m, 1H), 1.53−1.63 (m, 2H), 1.74−1.83 (m, 2H),
1.95−2.02 (m, 2H), 2.40−2.52 (m, 2H, CH2COH), 3.11−3.30 (m,
4H, 2CH2N), 4.94−5.00 (m, 2H, CH2CH), 5.64−5.75 (m, 1H,
CH2CH), 7.50−7.60 (m, 3H, H-Ns), 7.99−8.00 (m, 1H, H-Ns),
9.75 (s, 1H, COH). Then, from the above aldehyde, t-BuOK (5.9 mL
of a 1 M solution in THF, 5.9 mmol), and methyltriphenylphospho-
nium bromide (2.94 g, 8.22 mmol) in anhydrous THF (60 mL), diene
1614c (175 mg, 50%) was obtained as a colorless oil after flash
chromatography (9:1 hexane−EtOAc): [α]22 −12.0 (c 1.3, CHCl3),
D
lit14c [α]22 −15.0 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3,
D
COSY, g-HSQC) δ 0.85 (d, J = 6.6 Hz, 3H, CH3), 1.09−1.18 (m, 1H),
1.41−1.50 (m, 1H), 1.53−1.65 (m, 2H), 1.70−1.79 (m, 1H), 1.95−
2.02 (m, 3H, CH2CHCH2, CH2), 2.07−2.17 (m, 1H, CH2
CHCH2), 3.13 (dd, J = 14.2, 8.3 Hz, 2H, C-1), 3.19 (dd, J = 14.2, 7.2
Hz, 2H, C-1), 3.26 (m, 2H, CH2N), 4.92−4.97 (m, 3H, CH2
CHCH2), 4.99−5.01 (m, 1H, CH2CHCH2), 5.65−5.72 (m, 1H,
2799
dx.doi.org/10.1021/jo5002627 | J. Org. Chem. 2014, 79, 2792−2802

The Journal of Organic Chemistry
Note
CH2CH), 5.72−5.79 (m, 1H, CH2CH), 7.59−7.62 (m, 1H, H-
3Ns), 7.65−7.68 (m, 2H, H-5Ns, H-4Ns), 7.99−8.02 (m, 1H, H-4Ns);
13C NMR (100.6 MHz, CDCl3) δ 16.9 (CH3), 26.8 (CH2), 30.4
(m, 2H, H-Phth), 7.84 (m, 2H, H-Phth); 13C NMR (100.6 MHz,
CDCl3) δ 17.4 (CH3), 21.5 (CH3Ts), 27.9 (CH2CH2N), 29.8 (CH2),
30.1 (CH2), 31.9 (CH), 35.8 (CH2NPhth), 46.9 (CH2NTs), 55.4 (C-
5), 62.9 (C-1), 123.3 (CH-Phth), 127.2 (CHTs), 129.6 (CHTs),
131.9 (C-Phth), 134.0 (CH-Phth), 136.2 (C-4Ts), 143.2 (C-1Ts),
168.2 (CO); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C24H31N2O5S 459.1948, found 459.1941.
(CH), 30.7 (CH2), 30.9 (CH2), 33.0 (CH2), 46.7 (CH2), 53.4 (CH2),
114.7 (CH2CH), 115.4 (CH2CH), 124.1 (C-3Ns), 130.9 (C-
6Ns), 131.4 (C-4Ns), 133.3 (C-5Ns), 133.7 (C-1Ns), 137.1 (CH2
CH), 138.3 (CH2CH), 147.9 (C-2Ns).
(S)-2-Methyl-N-[3-(phthalimido)propyl]-N-tosyl-5-hexen-
amine (20). Operating as described for the preparation of compound
12, from alcohol 19 (95 mg, 0.21 mmol) and Dess−Martin reagent
(220 mg, 0.52 mmol) in anhydrous CH2Cl2 (2 mL), an aldehyde was
(S)-5-[(tert-Butyldimethylsilyl)oxy]-2-methyl-N-tosylpentan-
amine (17). tert-Butyldimethylsilyl chloride (773 mg, 5.13 mmol) was
added to a solution of alcohol 10a (870 mg, 3.20 mmol) and imidazole
(349 mg, 5.13 mmol) in anhydrous CH2Cl2 (10 mL), and the mixture
was heated at reflux for 15 h. The reaction was quenched by a
saturated aqueous solution of NH4Cl, and the mixture was extracted
with CH2Cl2. The combined organic extracts were dried, filtered, and
concentrated to give an oil (1.2 g). Purification by flash
chromatography (from 9:1 hexane−EtOAc to 1:1 hexane−EtOAc)
1
obtained: H NMR (400 MHz, CDCl3) δ 0.91 (d, J = 6.8 Hz, 3H,
CH3), 1.78−1.93 (m, 4H), 2.39−2.51 (m, 5H), 2.40 (s, 3H, CH3Ts),
2.87 (dd, 1H, J = 13.6, 7.6 Hz, CH2N), 2.98 (dd, J = 13.6, 7.2 Hz, 1H,
CH2N), 3.13−3.19 (m, 2H, CH2N), 3.67 (t, J = 6.8 Hz, 2H, CH2N),
7.27 (d, 2H, J = 8.2 Hz, H-Ts), 7.64 (d, J = 8.2 Hz, 2H, H-Ts), 7.75
(dd, J = 5.6, 3.2 Hz, 2H, H-Phth), 7.80 (dd, J = 5.6, 3.2 Hz, 2H, H-
Phth), 9.75 (s, 1H, COH). Then, from the above aldehyde (95 mg), t-
BuOK (0.62 mL of a 1 M solution in THF, 0.62 mmol), and
methyltriphenylphosphonium bromide (296 mg, 0.83 mmol) in
anhydrous THF (5 mL), alkene 20 (66 mg, 70%) was obtained as a
colorless oil after flash chromatography (from 9:1 hexane−EtOAc to
85:15 hexane−EtOAc): [α]22D + 2.71 (c 0.65, EtOH); IR (film) 1772,
1712 cm−1; 1H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.90 (d, J
= 6.3 Hz, 3H, CH3), 1.15 (m, 1H, H-3), 1.45 (m, 1H, H-3), 1.65 (m,
1H, H-2), 1.90 (m, 2H, CH2CH2N), 1.95 (m, 1H, H-4), 2.15 (m, 1H,
H-4), 2.41 (s, 3H, CH3Ts), 2.91 (m, 2H, H-1), 3.14 (m, 2H,
CH2NTs), 3.64 (m, 2H, CH2NPhth), 4.86−4.99 (m, 2H, H-6), 5.73
(m, 1H, H-5), 7.26 (d, J = 8.2 Hz, 2H, H-3Ts, H-5Ts), 7.65 (d, J = 8.2
Hz, 2H, H-2Ts, H-6Ts), 7.72 (dd, J = 5.8, 3.3 Hz, 2H, H-Phth), 7.84
(dd, J = 5.8, 3.3 Hz, 2H, H-Phth); 13C NMR (100.6 MHz, CDCl3) δ
17.3 (CH3), 21.4 (CH3Ts), 27.9 (CH2CH2N), 31.0 (C-3), 31.5 (C-2),
33.4 (C-4), 35.8 (CH2NPhth), 46.7 (CH2NTs), 55.1 (C-1), 114.5 (C-
6), 123.2 (CH-Phth), 127.2 (CHTs), 129.6 (CHTs), 132.2 (C-Phth),
133.9 (CH-Phth), 137.5 (C-4Ts), 138.5 (C-5), 143.1 (C-1Ts), 168.1
(CO); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C25H31N2O4S
455.1999, found 455.2024.
afforded pure compound 17 (1.09 g, 88%) as a colorless oil: [α]22
=
D
−0.19 (c 1.02, MeOH); IR (film) 3564, 3282 cm−1; H NMR (400
MHz, CDCl3, COSY, g-HSQC) δ −0.01 (s, 6H, CH3Si), 0.84 [s, 9H,
(CH3)3], 0.86 (d, J = 6.0 Hz, 3H, CH3), 1.07−1.09 (m, 1H, H-3),
1.28−1.45 (m, 3H, H-4, H-3), 1.52−1.59 (m, 1H, H-2), 2.39 (s, 3H,
CH3Ts), 2.69 (ddd, J = 12.5, 6.8, 6.8 Hz, 1H, H-1), 2.79 (ddd, J =
12.5, 5.6, 5.6 Hz, 1H, H-1), 3.50 (dt, J = 6.4, 1.5 Hz, 2H, H-5), 5.18
(br.s, 1H, NH), 7.26 (d, J = 8.4 Hz, 2H, H-3Ts, H-5Ts), 7.73 (d, J =
8.4 Hz, 2H, H-2Ts, H-6Ts); 13C NMR (100.6 MHz, CDCl3) δ −5.4
(CH3Si), 17.4 (CH3), 18.2 [C(CH3)3], 21.3 (CH3Ts), 25.8 [C-
(CH3)3], 29.8 (C-3), 30.0 (C-4), 32.8 (C-2), 48.8 (C-1), 63.1 (C-5),
126.9 (C-HTs), 129.5 (C- HTs), 137.0 (C-4Ts), 143.0 (C-1Ts);
HRMS (ESI-TOF) m/z [M + H]+ Calcd for C19H36NO3SSi 386.2180,
found 386.2179.
1
(S)-5-[(tert-Butyldimethylsilyl)oxy]-2-methyl-N-[3-
(phthalimido)propyl]-N-tosylpentanamine (18). NaH (95%, 136
mg, 5.39 mmol) was added to a solution of compound 17 (562 mg,
1.46 mmol) and 3-(phthalimido)propyl iodide18 (964 mg, 3.06 mmol)
in anhydrous DMF (9 mL), and the mixture was stirred at room
temperature for 17 h. The reaction was quenched by addition of a
saturated aqueous NH4Cl solution, and the aqueous layer was
extracted with EtOAc. The combined organic extracts were dried,
filtered, and concentrated. The resulting oil (1.03 g) was chromato-
graphed (from 9:1 hexane−EtOAc to 8:2 hexane−EtOAc) to give
(S)-N-[3-(2-Methyl-N-tosyl-5-hexenylamino)propyl]-4-pente-
namide (21). A solution of hydrazine monohydrate (56 mg, 1.1
mmol) in ethanol (1.3 mL) was added to a solution of alkene 20 (506
mg, 1.1 mmol) in ethanol (4.5 mL), and the mixture was heated at
reflux for 2.5 h. Insoluble material was removed by filtration, and the
filtrate was concentrated to give the primary amine as a yellow oil (420
compound 18 (630 g, 75%) as a colorless oil: [α]22 −4.61 (c 1.65,
D
MeOH); IR (film) 1773 cm−1; 1H NMR (400 MHz, CDCl3, COSY, g-
HSQC) δ 0.04 (s, 6H, CH3Si), 0.88 [s, 9H, (CH3)3], 0.91 (d, J = 6.6
Hz, 3H, CH3), 1.03−1.12 (m, 1H), 1.36−1.50 (m, 2H), 1.55−1.61
(m, 1H), 1.74 (m, 1H, H-4), 1.84−1.95 (m, 2H, CH2CH2N), 2.41 (s,
3H, CH3Ts), 2.91 (d, J = 7.5 Hz, 2H, H-1), 3.12−3.17 (m, 2H,
CH2NTs), 3.56 (t, J = 6.5 Hz, 2H, H-5), 3.66 (t, J = 7.1 Hz, 2H,
CH2NPhth), 7.27 (d, J = 8.3 Hz, 2H, H-3Ts, H-5Ts), 7.64 (d, J = 8.3
Hz, 2H, H-2Ts, H-6Ts), 7.73 (dd, J = 5.4, 3.0 Hz, 2H, H-Phth), 7.84
(dd, J = 5.4, 3.0 Hz, 2H, H-Phth); 13C NMR (100.6 MHz, CDCl3) δ
−5.3 (CH3Si), 17.3 (CH3), 18.2 [C(CH3)3], 21.5 (CH3Ts), 25.9
[C(CH3)3], 27.9 (CH2CH2N), 30.1 (C-3), 30.3 (C-4), 31.9 (C-2),
35.6 (CH2NPhth), 46.7 (CH2NTs), 55.2 (C-1), 63.2 (C-5), 123.2
(CH-Phth), 127.1 (C-HTs), 129.6 (C-HTs), 131.9 (C-Phth), 133.9
(CH-Phth), 136.4 (C-4Ts), 143.1 (C-1Ts), 168.1 (CO); HRMS (ESI-
TOF) m/z [M + H]+ Calcd for C30H45N2O5SSi 573.2813, found
573.2813.
1
mg), which was used without purification in the next step: H NMR
(400 MHz, CDCl3) δ 0.87 (d, J = 6.5 Hz, 3H, CH3), 1.10−1.15 (m,
1H), 1.42−1.46 (m, 1H), 1.70−1.75 (m, 3H), 1.95−2.00 (m, 1H),
2.06−2.13 (m, 1H), 2.42 (s, 3H, CH3Ts), 2.66 (br.s., 2H, NH2), 2.80
(m, 2H, CH2N), 2.87−2.90 (m, 2H, CH2N), 3.12−3.19 (m, 2H,
CH2N), 4.91−5.00 (m, 2H, CH2CH), 5.70−5.75 (m, 1H, CH2
CH), 7.20−7.30 (m, 2H, H-Ts), 7.60−7.70 (m, 2H, H-Ts). 4-
Pentenoyl chloride (0.15 mL, 1.34 mmol) and Et3N (0.2 mL, 1.45
mmol) were slowly added to a solution of the above amine in CH2Cl2
(3 mL), and the mixture was stirred at room temperature for 2.5 h.
The reaction was quenched with water, and the resulting mixture was
extracted with CH2Cl2. The combined organic extracts were dried,
filtered, and concentrated under a vacuum to give an oil. Flash
chromatography (from 9:1 hexane−EtOAc to 1:1 hexane−EtOAc)
afforded diene 21 (224 mg, 50%) as a colorless oil: [α]22D + 1.9 (c 1.6,
(S)-4-Methyl-5-{N-[3-(phthalimido)propyl]-N-tosylamino}-1-
pentanol (19). A solution of compound 18 (450 mg, 0.79 mol) in 1.0
N aqueous HCl (10 mL) was stirred at room temperature for 20 min.
Then, the solution was concentrated to give alcohol 19 (360 mg,
1
MeOH); IR (film) 3305, 1644 cm−1; H NMR (400 MHz, CDCl3,
COSY, g-HSQC) δ 0.86 (d, J = 6.6 Hz, 3H, CH3), 1.08−1.17 (m, 1H,
CHCH2), 1.40−1.49 (m, 1H, CHCH2), 1.70−1.76 (m, 3H,
CH2CH2N, CH), 1.92−2.00 (m, 1H, H-2), 2.07−2.16 (m, 1H, H-
2), 2.28−2.31 (m, 2H, CH2CHCH2), 2.38−2.41 (m, 2H, H-3), 2.43
(s, 3H, CH3Ts), 2.84−2.95 (m, 2H, CHCH2N), 3.10 (t, J = 6.7 Hz,
2H, TsNCH2CH2), 3.35 (m, 2H, CH2NH), 4.93−5.10 (m, 4H,
CH2CH), 5.73 (m, 1H, CH2CH), 5.84 (m, 1H, CH2CH), 6.36
(br.s, 1H, NH), 7.31 (d, J = 8.1 Hz, 2H, H-Ts), 7.66 (d, J = 8.1 Hz,
2H, H-Ts); 13C NMR (100.6 MHz, CDCl3) δ 17.2 (CH3), 21.4
(CH3Ts), 28.6 (CH2CH2CH2), 29.5 (CH2CHCH2), 30.8 (C-3),
31.4 (CH), 33.2 (CH2CH2CH), 35.8 (C-2), 36.0 (CH2NH), 46.8
quantitative), which was used in the next step without purification:
1
[α]22 −1.32 (c 1.12, MeOH); IR (film) 3542, 1770, 1716 cm−1; H
D
NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 0.90 (d, J = 6.6 Hz, 3H,
CH3), 1.10−1.17 (m, 1H), 1.44−1.56 (m, 2H), 1.60−1.66 (m, 1H),
1.66−1.78 (m, 2H, H-4, OH), 1.89 (quint, J = 7.4 Hz, 2H,
CH2CH2N), 2.40 (s, 3H, CH3Ts), 2.85 (dd, J = 13.6, 7.5 Hz, 1H,
H-5), 2.95 (dd, J = 13.6, 7.5 Hz, 1H, H-5), 3.14 (m, 2H, CH2NTs),
3.62 (t, J = 6.2 Hz, 2H, H-1), 3.67 (t, J = 7.2 Hz, 2H, CH2NPhth),
7.27 (d, J = 8.2 Hz, 2H, H-3Ts), 7.64 (d, J = 8.2 Hz, 2H, H-2Ts), 7.72
2800
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The Journal of Organic Chemistry
Note
(TsNCH2CH2), 55.9 (CHCH2N), 114.6 (CH2CH), 115.3 (CH2
CH), 127.0 (CH-Ts), 129.6 (CH-Ts), 135.9 (C-4Ts), 137.0 (CH2
CH), 138.3 (CH2CH), 143.3 (C-1Ts), 172.4 (CO); HRMS (ESI-
TOF) m/z [M + H]+ Calcd for C22H35N2O3S 407.2363, found
407.2361.
Supporting Information) δ 18.8 (CH3), 22.0 (CH2), 23.2 (CH2), 24.7
(CH2), 27.3 (CH2), 27.7 (CH2), 29.3 (CH2), 30.5 (CH), 32.7 (CH2),
47.5 (CH2N), 49.8 (CH2N), 50.5 (CH2N), 55.6 (CH2N).
ASSOCIATED CONTENT
■
(S)-13-Methyl-6-oxo-1-tosyl-1,5-diaza-9-cyclotetradecene
(22). Operating as described in the preparation of macrocycle 13, from
compound 21 (101 mg, 0.25 mmol) in CH2Cl2 (10 mL) and second-
generation Grubbs catalyst (32 mg, 0.037 mmol) in anhydrous
CH2Cl2 (1.24 L), diazacycle 22 (72 mg, 77%) was obtained as a 91:9
mixture (calculated by GC−MS) of E/Z diastereoisomers after flash
chromatography (from 8:2 hexane−EtOAc to 3:7 hexane−EtOAc).
S
* Supporting Information
1
Copies of the H and 13C spectra of all new compounds and
tables with NMR data for haliclorensin C and haliclorensin.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
Major diastereoisomer: IR (film) 3300, 1647 cm−1; H NMR (400
MHz, CDCl3, COSY, g-HSQC) δ 0.86 (d, J = 6.6 Hz, 3H, CH3),
1.10−1.27 (m, 2H, H-4), 1.49−1.65 (m, 2H, H-3, H-13), 1.65−1.73
(m, 1H, H-13), 1.92−2.04 (m, 2H, CH2CH), 2.05−2.13 (m, 1H, H-
9), 2.19−2.30 (m, 2H, CH2CH, H-9), 2.33−2.38 (m, 1H,
CH2CH), 2.40 (s, 3H, CH3Ts), 2.75 (dd, J = 12.6, 5.9 Hz, 1H,
H-2), 2.86−2.90 (m, 1H, H-12), 2.95 (dd, J = 12.6, 9.1 Hz, 1H, H-2),
2.98−3.02 (m, 1H, H-14), 3.16−3.24 (m, 1H, H-12), 3.29−3.37 (m,
1H, H-14), 5.22−5.36 (m, 2H, CHCH), 5.96 (br.s, 1H, NH), 7.26
(d, J = 8.2 Hz, 2H, H-3Ts, H-5Ts), 7.62 (d, J = 8.2 Hz, 2H, H-2Ts, H-
6Ts); 13C NMR (100.6 MHz, CDCl3) δ 17.4 (CH3), 21.4 (CH3Ts),
26.9 (C-3), 28.0 (CH2CH), 28.3 (C-13), 28.9 (CH2CH), 32.0
(C-4), 36.2 (C-9), 36.4 (C-14), 44.8 (C-12), 53.5 (C-2), 127.0 (CH-
Ts), 129.5 (CH), 129.6 (CH-Ts), 131.7 (CH), 136.5 (C-4Ts),
143.1 (C-1Ts), 172.4 (CO); HRMS (ESI-TOF) m/z [M + H]+ Calcd
for C20H31N2O3S 379.2053, found 379.2051.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: amat@ub.edu.
*E-mail: joanbosch@ub.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministry of Economy and
Competitiveness, Spain (Project CTQ2012-35250), and the
Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR),
̀ ́
Generalitat de Catalunya (Grant 2009SGR-1111) is gratefully
acknowledged.
(S)-13-Methyl-6-oxo-1-tosyl-1,5-diazacyclotetradecane (23).
A solution of alkene 22 (79 mg, 0.21 mmol) in anhydrous MeOH (7
mL) containing 10% Pd−C (8 mg) was stirred under hydrogen at
room temperature for 48 h. The catalyst was removed by filtration and
washed with hot MeOH. The combined organic solutions were
REFERENCES
■
(1) For reviews, see: (a) Escolano, C.; Amat, M.; Bosch, J. Chem.
Eur. J. 2006, 12, 8198−8207. (b) Amat, M.; Per
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1
[α]22 −12.7 (c 1.18, CHCl3); IR (film) 3410, 1643 cm−1; H NMR
2011, 143−160. (c) Amat, M.; Per
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2011, 17, 7724−7732. For reviews covering pioneering work in the
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been reported: (a) Amat, M.; Llor, N.; Hidalgo, J.; Bosch, J.
(400 MHz, CDCl3, COSY, g-HSQC) δ 0.89 (d, J = 6.5 Hz, 3H, CH3),
1.10−1.20 (m, 1H, 1H−CH2), 1.22−1.35 (m, 6H, 3CH2), 1.36−1.62
(m, 3H, CH2, 1H−CH2), 1.65−1.92 (m, 3H, H-3, CH2), 2.10−2.27
(m, 2H, H-9), 2.42 (s, 3H, CH3Ts), 2.76 (dd, J = 12.9, 5.5 Hz, 1H, H-
2), 2.99 (dd, J = 12.9, 8.5 Hz, 1H, H-2), 2.95−2.98 (m, 1H, H-14),
3.07−3.14 (m, 2H, H-12), 3.42−3.54 (m, 1H, H-14), 6.10 (br.s, 1H,
NH), 7.29 (d, J = 8.2 Hz, 2H, H-3Ts, H-5Ts), 7.65 (d, J = 8.2 Hz, 2H,
H-2Ts, H-6Ts); 13C NMR (100.6 MHz, CDCl3) δ 17.1 (CH3), 21.4
(CH3Ts), 23.3 (CH2), 24.3 (CH2), 25.1 (CH2), 25.8 (CH2), 27.7 (C-
3), 28.7 (CH2), 30.9 (CH2), 35.1 (C-9), 36.6 (C-14), 45.9 (C-12),
54.8 (C-2), 127.1 (CH-Ts), 129.6 (CH-Ts), 136.1 (C-4Ts), 143.2 (C-
1Ts), 173.1 (CO); HRMS (ESI-TOF) m/z [M + H]+ Calcd for
C20H33N2O3S 381.2206, found 381.2207.
Tetrahedron: Asymmetry 1997, 8, 2237−2240. (b) Amat, M.; Canto,
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(3) δ-Oxoesters 1 were prepared by reaction of methyl acrylate with
the piperidine enamine of the appropriate aldehydes, followed by acid
hydrolysis of the resulting adducts (see the Experimental Section).
(4) For reviews, see: (a) Noyori, R.; Tokunaga, M.; Kitamura, M.
Bull. Chem. Soc. Jpn. 1995, 68, 36−56. (b) Ward, R. S. Tetrahedron:
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2008; Chapter 7.
(S)-Haliclorensin. A solution of diazacycle 23 (74 mg, 0.19 mmol)
in dry THF (3.5 mL) was added to a suspension of LiAlH4 (74 mg,
1.95 mmol) in dry THF (4.5 mL) at 0 °C, and the mixture was heated
at reflux for 21 h. After cooling to room temperature, the reaction was
quenched by water (7 mL), and the pH value was adjusted to 4 by
adding 2 M aqueous HCl solution (2 mL). The mixture was extracted
with Et2O, and the aqueous phase was basified with a saturated
aqueous solution of K2CO3 to reach pH 12. The solution was
extracted with CH2Cl2, and the combined organic extracts were dried,
filtered, and concentrated under a vacuum to give a yellow oil. Flash
chromatography (SiO2 previously washed with 18:1:1 CH2Cl2-MeOH-
NH4OH; gradient from 19:1 CH2Cl2-MeOH to 17:3 CH2Cl2-MeOH)
afforded haliclorensin (26 mg, 65%) as a colorless oil: [α]22D= −17.2
(c 0.5, MeOH), lit15a [α]D −2.2 (c 1.3, MeOH), lit13 [α]20 −19 (c
0.57, MeOH), lit15b [α]D −18.5 (c 0.6, MeOH), lit15b [α]D −D8.5, lit15b
[α]20D + 7.0 (1 M HCl), lit15c [α]20D −18.2 (c 0.4, MeOH); 1H NMR
(400 MHz, CD3OD, g-HSQC; see Table S3 in Supporting
Information) δ 0.89 (d, J = 6.9 Hz, 3H, CH3), 1.24−1.31 (m, 1H),
1.36−1.51 (m, 9H), 1.55−1.61 (m, 2H), 1.70−1.77 (m, 3H), 2.40 (dd,
J = 11.8, 9.7 Hz, 1H), 2.55 (dd, J = 11.8, 3.8 Hz, 1H), 2.58−2.63 (m,
1H), 2.64−2.68 (m, 2H), 2.71−2.73 (m, 2H), 2.82 (ddd, J = 11.2, 6.8,
4.0 Hz, 1H); 13C NMR (100.6 MHz, CD3OD; see Table S4 in
(5) Minor amounts of the 8,8a-diastereoisomer were also isolated.
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2424−2426.
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2801
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The Journal of Organic Chemistry
Note
(11) In some cases, minor amounts of the corresponding 3-
substituted N-(2-hydroxy-1-phenylethyl)piperidines were isolated as
byproducts (see the Experimental Section).
(12) Wang, J.-J.; Hu, W.-P. J. Org. Chem. 1999, 64, 5725−5727.
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strongly pH-dependent.13,15a,b In fact, a specific rotation of [α]22
D
−2.2 (c 1.3, MeOH) was reported15a in the first isolation of the
alkaloid, from a sample whose NMR data indicate that it was at least
partially protonated given that as the chemical shifts of the methylene
groups adjacent to the nitrogen atoms are shifted (protons, downfield;
carbons, upfield) with respect to the spectra of synthetic haliclorensin.
An [α]D value of −8.5 has also been reported for the natural product,
which, according to chiroptical measurements and GC−MS
investigations, consisted of a 3:1 mixture of the (S)- and (R)-
enantiomers.15b
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2802
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