Organocatalytic stereoselective approach to the total synthesis of (-)-halosaline

Article abstract of DOI:10.1039/c3ra44700f

A practical and efficient organocatalytic approach to the synthesis of substituted piperidine alkaloids in high enantio- and diastereomeric excess was achieved using proline-catalyzed sequential α-aminoxylation/α- amination reaction and HWE olefination reaction of an aldehyde.

Full text of DOI:10.1039/c3ra44700f

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Organocatalytic stereoselective approach to the
total synthesis of (ꢀ)-halosaline†
Cite this: RSC Adv., 2014, 4, 3238
*
Vishwajeet Jha and Pradeep Kumar
Received 28th August 2013
Accepted 19th November 2013
A practical and efficient organocatalytic approach to the synthesis of substituted piperidine alkaloids in high
enantio- and diastereomeric excess was achieved using proline-catalyzed sequential a-aminoxylation/
a-amination reaction and HWE olefination reaction of an aldehyde.
DOI: 10.1039/c3ra44700f
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describes its synthesis via Prins cyclization followed by reduc-
tive ring opening reaction. While Radha Krishna et al.7b used an
iterative asymmetric allylation/RCM strategy, Posner et al.7d
have utilized a cyclopentanone ring-expansion based function-
alized strategy. In another report, Lesma et al.7e employed
ruthenium catalyzed ring-opening/ring-closing metathesis
strategy, whereas Takahata et al.7g used an iterative asymmetric
dihydroxylation strategy to arrive at target molecule.
In recent years, there has been growing interest in the use of
small organic molecules to catalyze organic reactions. As a
result, the area of organocatalysis has emerged as a promising
strategy and as an alternative to enzyme catalysis and metal
catalysis,8 thus becoming a fundamental tool in the catalysis
toolbox available for asymmetric synthesis.9 Proline in the
recent past has been dened as ‘universal catalyst’ because of
its utility in different reactions providing rapid access to enan-
tiomerically pure products.10 Similarly organocatalytic tandem
reactions are characterized by high efficiencies and are in a way
biomimetic. They oen proceed with excellent stereocontrol
and are environmentally friendly.11
Introduction
Naturally occurring alkaloids containing multifunctionalized
piperidine rings are found abundantly in nature and many of
them exhibit a wide range of biological and pharmacological
activity.1,2 These include piperidine ring containing oxygenated
side chains such as halosaline, epi-halosaline, etc. and fused
piperidines with bicyclic rings such as elaeokanine A, elaeoka-
nine C etc. or tricyclic ring such as tetraponerine T-4 (Fig 1).
(ꢀ)-Halosaline 1, a 2-(2-hydroxy substituted)-piperidine was
isolated from Haloxylon salicornicum.3 (ꢀ)-8-Epi-halosaline 2, a
diastereomer of (ꢀ)-halosaline, was isolated from Andrachne
aspera spreng,4 a small perennial under shrub commonly found
in Karachi. Tetraponerine T-4 3 was isolated from the venom of
a New Guinean ant Tetraponera sp.5 Elaeocarpus alkaloids
elaeokanine A 4 and C 5 were isolated from Ekaeocarous
kaniensis Schltr.,6 a large rain-forest tree found in New Guinea.
There are several literature reports on the synthesis of
(ꢀ)-halosaline.7 The most recent publication by Yadav et al.7a
Recently, we have developed12 an efficient approach to the
asymmetric synthesis of 1,3-amino alcohols using sequential
a-aminoxylation13a,b/a-amination13c,d and HWE olenation
reaction catalyzed by proline. In continuation of our interest in
organocatalysis14 and asymmetric synthesis of substituted
piperidine alkaloids,15 we further became interested to extrap-
olate the above knowledge to develop a general exible
approach to chiral 2-substituted piperidines. Herein we report
our successful endeavours to devise a simple route towards
synthesis of (ꢀ)-halosaline, employing sequential a-amino-
xylation/a-amination reaction and HWE olenation of an alde-
hyde catalyzed by proline.
Fig. 1 Substituted piperidine alkaloids.
Results and discussion
Our synthetic approach for (ꢀ)-halosaline was envisioned via
the retrosynthetic route shown in the Scheme 1. (ꢀ)-Halosaline
1 was thought to be synthesized from cyclic aminoalcohol 6.
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune
411008, India. E-mail: pk.tripathi@ncl.res.in; Fax: +91 02025902050
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra44700f
The piperidine ring in cyclic aminoalcohol
6 could be
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8 was easily cleaved with concomitant reduction of double
bond under hydrogenation conditions using freshly prepared
RANEY®-Ni at 60 psi to give free amine, which was subsequently
converted into its Boc derivative using Boc2O to furnish ester 12
in 79% yield. Compound 12 was reduced using LiBH4 to give
alcohol 13 which was subsequently converted to its iodo deriv-
ative 14 using Appel reaction conditions. Dehydrohalogena-
tion18 of 14 was attempted using n-BuLi but to our
disappointment we could get only the cyclic aminoalcohol 15
instead of the expected compound 7. The formation of 15 was
Scheme 1 Retrosynthetic route to (ꢀ)-halosaline.
constructed by the allylation and ring closing metathesis of
homoallylic amine 7, which could be synthesized from 1,3-
aminoalcohol 8 using standard protocol. Compound 8 could be
obtained from g-hydroxy ester 9 by a-amination which in turn
could be easily obtained by the sequential a-aminoxylation and
HWE olenation of the corresponding aldehyde 10.
1
conrmed using H NMR spectrum and HRMS.
By analyzing the result, we concluded that due to presence of
NH proton, nucleophilic displacement was the predominant
reaction instead of dehydrohalogenation leading to exclusive
formation of 15. Therefore, further attempts were made to
functionalize the amine group of compound 12. For this
purpose, compound 12 was treated with Boc2O in presence of
catalytic DMAP, but to our disappointment once again we
obtained cyclic amide 17 as the only product instead of di-boc
compound 16 (Scheme 3).
Thus as shown in Scheme 2, synthesis started from the
commercially available valeraldehyde 10 which on sequential a-
aminoxylation using nitroso benzene as oxygen source and
L-proline as catalyst and subsequent Horner–Wadsworth–
Emmons (HWE) olenation using ylide generated from triethyl
phosphonoacetate followed by hydrogenation using catalytic
amount of Pd/C furnished the g-hydroxy esters 916 in 78% yield
and 94% ee.17 The free hydroxy group of g-hydroxy ester 9 was
protected as TBS ether using TBSCl in DMF to furnish
compound 11 in 95% yield. The DIBAL-H reduction of ester 11
at ꢀ78 ꢁC furnished the corresponding aldehyde which was
then subjected to a-amination using commercially available
dibenzyl azodicarboxylate (DBAD) as a nitrogen source and D-
proline as a catalyst to furnish the a-amino aldehyde, which on
in situ trapping by triethyl phosphonoacetate (HWE olenation)
in presence of DBU furnished the anti-1,3-amino alcohol 8 in
71% yield and 98 : 2 diastereomeric ratio as determined from
HPLC analysis.17 The absolute and relative conguration of
amino alcohol 8 is based on L- or D-proline used in the reaction
and analogous to those as reported by us in our earlier studies.12
The N–N-bond of diastereomerically pure 1,3-anti-aminoalcohol
We then switched over to a different strategy to construct the
piperidine ring, via one carbon homologation and further
cyclization of alcohol 13. Towards this end, the free hydroxy
group of 13 was converted into its toluenesulfonate derivative
which on subsequent treatment with NaCN in dry DMF at 100 ꢁC
furnished the cyano compound 18 in 85% yield. Compound 18
was subjected to reduction using DIBAL-H at ꢀ78 ꢁC followed by
acid hydrolysis to give the aldehyde which on subsequent treat-
ment with NaBH3CN afforded the cyclized product 19, along with
small amount of open chain product 20 (Scheme 4). The
formation of compound 19 was conrmed by 1H NMR spectrum
and HRMS. We have used both the products 19 and 20 for the
synthesis of the target molecule (ꢀ)-halosaline.
Towards this end, compound 19 was subjected to the double
bond reduction under hydrogenation conditions using 10% Pd–
C in EtOAc to give piperidine 21 which on global deprotection of
both the TBS and Boc groups with TFA afforded the target
compound (ꢀ)-halosaline 1 (Scheme 4). The physical and
spectroscopic data of compound 1 matched with reported data
25
ꢁ
ꢁ
in literature {solid. Mp 80–82 C [ref. 7b 82 C], [a]D : ꢀ18.9 (c
0.9, EtOH) [ref. 3 [a]2D5: ꢀ19.5 (c 0.6, EtOH)]}.
Similarly, the open chain compound 20 obtained as the
minor product, was also converted into (ꢀ)-halosaline 1 by two-
step process. As shown in the Scheme 4, compound 20 was rst
converted into its p-toluene sulfonate derivative. Subsequent
global deprotection of both the TBS and Boc groups with TFA
Scheme 2 Attempted synthesis of homoallylic amine.
Scheme 3 Attempted functionalization of amino ester compound.
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ethyl acetate was added Pd–C (10%) under hydrogenation
conditions at 4 atm and the reaction mixture was allowed to
stir overnight. On completion of reaction (until 1H NMR
analysis of the crude mixture indicated complete conversion),
the mixture was ltered through
a pad of celite and
concentrated in vacuo to give g-hydroxy ester 9. The crude
product was then puried by using silica gel ash column
chromatography using pet ether : EtOAc (85 : 15) as eluent to
give (R)-ethyl 4-hydroxyheptanoate 9 as a colorless liquid (1.05
g, Yield 78%, based on nitrosobenzene). [a]2D5: +11.66 (c 2.4,
CHCl3) IR (CHCl3, cmꢀ1): nmax 3430, 2934, 1719, 1466, 1177.
1H NMR (200 MHz, CDCl3): d 0.91–0.96 (m, 3H), 1.26 (t, J ¼
7.1 Hz, 3H), 1.38–1.49 (m, 3H), 1.61–2.05 (m, 4H), 2.46 (t, J ¼
7.2 Hz, 2H), 3.58–3.78 (m, 1H), 4.14 (q, J ¼ 7.1 Hz, 2H) ppm.
13C NMR (50 MHz, CDCl3): d 13.9, 18.7, 30.7, 32.1, 39.6, 60.4,
70.8, 174.3 ppm. MS (ESI): m/z 197.1862 (M + Na)+. HRMS:
197.1173 (M + Na)+ calcd 197.1148.
Scheme 4 Revised synthetic strategy and completion of synthesis of
(ꢀ)-halosaline.
followed by nucleophilic displacement of tosylate with the
resultant amine in the presence of diisopropylethyl amine
afforded (ꢀ)-halosaline 1 in 79% yield.
Ethyl (R)-4-((tert-butyldimethylsilyl)oxy)heptanoate (11)
To an ice-cold stirred solution of 9 (1.0 g, 5.75 mmol) in DMF
(12 mL) were added imidazole (0.452 g, 6.64 mmol) and TBSCl
(1.00 g, 6.64 mmol) at room temperature. The resulting
mixture was stirred for 6 h at 0 ꢁC before H2O (20 mL) was
added. The aqueous layer was extracted with diethyl ether (3 ꢂ
25 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated under reduced pressure.
Silica gel column chromatography (petroleum ether : ethyl
acetate: 99 : 1) of the crude product gave ethyl (R)-4-((tert-
butyldimethylsilyl)oxy)-heptanoate 11 as a colorless liquid
(1.57 g, yield 95%). [a]D25: ꢀ7.98 (c 1.34, CHCl3). IR (CHCl3,
cmꢀ1): nmax 2958, 1727, 1463, 1256, 908. 1H NMR (400 MHz,
CDCl3): d 0.04 (s, 6H), 0.87–0.93 (m, 3H), 0.89 (s, 9H), 1.26 (t,
J ¼ 7.1 Hz, 3H), 1.29–1.46 (m, 4H), 1.63–1.83 (m, 2H), 2.36 (t,
J ¼ 7.8 Hz, 2H), 3.68–3.73 (m, 1H), 4.12 (q, J ¼ 7.1 Hz, 2H)
ppm. 13C NMR (50 MHz, CDCl3): d ꢀ4.6, ꢀ4.5, 14.2, 18.0, 18.4,
25.8, 25.9, 31.7, 39.3, 60.2, 70.9, 173.9 ppm. MS (ESI): m/z
311.3840 (M + Na)+. Analysis for C15H32O3Si: calcd C, 62.45; H,
11.18; found: C, 62.64; H, 11.12%.
Conclusions
In conclusion, a stereoselective synthesis of (ꢀ)-halosaline was
accomplished using proline-catalyzed sequential a-amino-
xylation/a-amination reaction and HWE olenation reaction of
an aldehyde as the key step. The strategy used is amenable to
both the syn- and anti-1,3-aminoalcohols with a high degree of
enantio- and diastereoselectivities. The syn- and anti-congu-
ration of the 1,3-amino-alcohol moiety can be manipulated
simply by changing the proline in the a-aminoxylation/a-ami-
nation step. The synthetic strategy described here has signi-
cant potential for stereochemical variations and gives further
access to other stereoisomers as well as various other
substituted piperidine alkaloids.
Experimental section
Ethyl (R)-4-hydroxyheptanoate (9)
Dibenzyl 1-((4S,6R,E)-6-((tert-butyldimethylsilyl)oxy)-1-ethoxy-
1-oxonon-2-en-4-yl)hydrazine-1,2-dicarboxylate (8)
To a solution of valeraldehyde 10 (2.0 g, 23.2 mmol) and
nitroso benzene (0.83 g, 7.74 mmol) in anhydrous CH3CN
ꢁ
(50 mL) was added L-proline (0.27 g, 2.32 mmol) at 0 C. The To a solution of ethyl ester 11 (1.0 g, 3.5 mmol) in CH2Cl2
mixture was vigorously stirred for 24 h under argon (the color (10 mL), was added DIBAL-H (1.7 mL 2.25 M solution in toluene,
ꢁ
of the reaction changed from green to orange red during this 3.85 mmol) at ꢀ78 C under argon atmosphere. The reaction
time) at 0 ꢁC. Thereaer, A premixed and cooled (0 ꢁC) was stirred at this temperature for 40 min. Then solution of
solution of triethylphosphonoacetate (9.25 mL, 46.4 mmol), tartaric acid (5 mL) was added. The resulting mixture was stir-
DBU (6.95 mL, 46.4 mmol) and LiCl (1.969 g, 46.4 mmol) in red for 15 min and the organic layer was separated. The aqueous
CH3CN (40 mL) was added quickly (1–2 min) at 0 ꢁC. The phase was extracted with CH2Cl2 (3 ꢂ 15 mL), the combined
resulting mixture was allowed to warm to room temperature organic layers were dried (Na2SO4), ltered and evaporated
over 1 h, and quenched by addition of ice pieces. The under reduced pressure to give aldehyde as a colorless liquid,
acetonitrile was evaporated under vacuum. This reaction which was directly used in the next step without further
mixture was then poured into water (100 mL) and extracted purication.
with Et2O (5 ꢂ 100 mL). The combined organic layers were
To a cooled solution of dibenzylazodicarboxylate (DBAD)
washed with water, brine, dried (Na2SO4) and concentrated (1.02 g, 2.9 mmol) and D-proline (0.038 g, 0.28 mmol) in CH3CN
in vacuo to give crude product which was directly subjected to (40 mL) at 0 ꢁC was added above aldehyde (1.0 g, 3.5 mmol) and
next step without purication. To the crude allylic alcohol in the mixture was stirred for 2 h at 0 ꢁC and further for 1 h at
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10 ꢁC. This was followed by addition of lithium chloride (0.22 g, CDCl3): ꢀ4.7, ꢀ4.3, 14.2, 17.9, 18.2, 25.9, 28.3, 30.9, 39.4,
4.3 mmol), triethyl phosphonoacetate (1.02 mL, 4.3 mmol) and 40.7, 47.8, 60.3, 69.7, 78.7, 155.6, 173.6 MS(ESI): m/z 454.21
DBU (0.5 mL, 2.9 mmol) in that sequence and the whole mixture (M + Na)+. Analysis for C22H45NO5Si: calcd C, 61.21; H, 10.51;
ꢁ
was stirred at 5 C for 45 min. It was then quenched with aq. N, 3.24; found: C, 61.29; H, 10.44; N, 3.29%.
ammonium chloride solution (15 mL) and extracted with ethyl
acetate (3 ꢂ 15 mL). The combined organic layers were washed
tert-Butyl ((4R,6R)-6-((tert-butyldimethylsilyl)oxy)-1-
hydroxynonan-4-yl)carbamate (13)
with brine, dried over anhyd. Na2SO4 and concentrated under
reduced pressure to give crude product (diastereomeric ratio/
98 : 2). Silica gel column chromatography (petroleum ether : To a stirred suspension of LiBH4 (0.60 g, 2.2 mmol) in dry THF
ethyl acetate: 90 : 10) of the crude product gave dibenzyl (1 mL) was added a solution of 12 (0.60 g, 1.4 mmol) in THF
1-((4S,6R,E)-6-((tert-butyldimethylsilyl)oxy)-1-ethoxy-1-oxonon- (5 mL) at 0 ꢁC and the mixture was stirred at room temperature
2-en-4-yl)hydrazine-1,2-dicarboxylate 8 as a colorless syrupy for 3 h. Aer being cooled to ambient temperature, the mixture
liquid (1.52 g, yield 71%, based on DBAD). [a]2D5: ꢀ1.56 (c 0.5, was quenched with ice pieces and extracted with CH2Cl2 (3 ꢂ 5
CHCl3). IR (CHCl3, cmꢀ1): nmax 3428, 2950, 1717, 1652, 1399, mL). The combined organic layers were washed with brine,
1084. 1H NMR (200 MHz, CDCl3): d 0.02 (s, 6H), 0.84 (m, 12H), dried (Na2SO4), and concentrated under reduced pressure.
1.24–1.31 (m, 5H), 1.40–1.53 (m, 2H), 1.72–1.81 (m, 1H), 1.89– Silica gel column chromatography (petroleum ether : ethyl
2.02 (m, 1H), 3.58–3.90 (m, 1H), 4.17 (q, J ¼ 7.0 Hz, 2H), 4.84– acetate: 65 : 35) of the crude product gave tert-butyl ((4R,6R)-6-
5.25 (m, 5H), 5.92 (d, J ¼ 17.5 Hz, 1H), 6.51 (m, 1H), 6.85 (dd, J ¼ ((tert-butyldimethylsilyl)oxy)-1-hydroxynonan-4-yl)carbamate 13
6.4, 15.1 Hz, 1H), 7.31 (m, 10H) ppm. 13C NMR (50 MHz, CDCl3): as a colorless liquid (0.51 g, 96%). [a]D25: ꢀ8.29 (c 0.9, CHCl3). IR
d ꢀ4.9, ꢀ4.4, 14.0, 14.2, 17.9, 25.8, 39.4, 60.4, 67.5, 68.1, 121.9, (CHCl3, cmꢀ1): nmax 3525, 3365, 2929, 1691, 1100. 1H NMR (200
122.7, 127.9, 128.1, 128.3, 135.6, 146.0, 155.5, 156.3, 166.2 ppm. MHz, CDCl3): d 0.06 (s, 3H), 0.08 (s, 3H), 0.90 (m, 12H), 1.20–
MS (ESI): m/z 635.5057 (M + Na)+, 651.5379 (M + K)+. HRMS: 1.38 (m, 4H), 1.43 (s, 9H), 1.54–1.66 (m, 6H), 3.60–3.91 (m, 4H),
635.3116 (M + Na)+ calcd 635.3123.
Diastereomeric ratio was determined by HPLC analysis; 17.9, 18.2, 25.9, 28.3, 28.6, 32.1, 39.9, 40.3, 47.6, 62.3, 69.7, 78.8,
98 : 2 dr.
5.12 (brs, 1H) ppm. 13C NMR (50 MHz, CDCl3): ꢀ4.8, ꢀ4.4, 14.2,
155.9 ppm. MS(ESI): m/z 412.20 (M + Na)+. HRMS: 390.3032 (M +
H)+ calcd 390.3034.
UV detector: Merck-HITACHI L-7400 series
Column: Grace Denali RP-18, Flow rate: 1.0 mL minꢀ1
,
tert-Butyl ((4R,6R)-6-((tert-butyldimethylsilyl)oxy)-1-
MeOH : H2O ¼ 97 : 3; tR for (anti)-isomer ¼ 6.90 min and tR for
cyanononan-4-yl)carbamate (18)
(syn)-isomer ¼ 6.31 min.
To an ice-cold stirred solution of 13 (0.50 g, 1.33 mmol) and
triethylamine (0.27 mL, 1.99 mmol) in anhydrous CH2Cl2 (8 mL)
was added dropwise toluenesulfonyl chloride (0.5 mL, 2.66
mmol) over 15 min. The resulting mixture was allowed to warm
Ethyl (4R,6R)-4-((tert-butoxycarbonyl)amino)-6-((tert-
butyldimethylsilyl)oxy)nonanoate (12)
The solution of dibenzyl 1-((4S,6R,E)-6-((tert-butyldimethyl up to room temperature and stirred for 6 h. Aer diluting with
silyl)oxy)-1-ethoxy-1-oxonon-2-en-4-yl)hydrazine-1,2-dicarboxylate 10 mL CH2Cl2, the solution was washed with (3 ꢂ 15 mL) brine,
8 (2.0 g, 3.3 mmol) in MeOH (12 mL) and acetic acid (8 dried over Na2SO4 and concentrated to give the crude tosylated
drops) was treated with RANEY® nickel (4.0 g, excess) under product which was subjected to next reaction without
H2 (70 psig) atmosphere for 24 h. The reaction mixture was purication.
then ltered over celite and concentrated to give crude free
To a solution of tosyl ester in DMF was added NaCN
amino alcohol which was further treated with triethylamine (0.13 g, 2.66 mmol) and was stirred at 115 ꢁC for 10 h. Aer
(0.93 mL, 6.7 mmol) and Boc anhydride (1.2 mL, 5.1 mmol) the consumption of starting material the reaction mixture
in dry DCM (4 mL) for 2 h. Ice pieces were added to the was poured into H2O and extracted with ether (25 mL), The
reaction mixture and organic layer was separated. The organic phase was washed with H2O and brine (15 mL),
aqueous layer was extracted with diethyl ether (3 ꢂ 5 mL). dried (NaSO4) and concentrated in vacuo. Silica gel column
The combined organic layers were washed with brine, dried chromatography of the crude product using (petroleum
(Na2SO4) and concentrated under reduced pressure to give ether : ethyl acetate 90 : 10) gave tert-butyl ((4R,6R)-6-((tert-
crude N-Boc derivative. Silica gel column chromatography butyldimethylsilyl)oxy)-1-cyanononan-4-yl)carbamate 18 as
(petroleum ether : ethyl acetate: 85 : 15) of the crude product yellow syrupy liquid. (0.44 g, 85%). [a]2D5: ꢀ18.34 (c 1.4,
gave ethyl (R)-4-((tert-butoxycarbonyl)amino)-8-((tert-butyldi- CHCl3), IR (CHCl3, cmꢀ1): nmax 3369, 2957, 2931, 2247, 1704,
methylsilyl)oxy)octanoate 12 as a viscous liquid (1.11 g, 79%). 1505, 1253, 1056. 1H NMR (200 MHz, CDCl3): d 0.07 (s, 3H),
[a]2D5: ꢀ10.37 (c 1.1, CHCl3). IR (CHCl3, cmꢀ1): nmax 3382, 0.08 (s, 3H), 0.90 (m, 12H), 1.19–1.35 (m, 4H), 1.43 (s, 9H),
1
2956, 1722, 1703, 1173. H NMR (200 MHz, CDCl3): d 0.06 (s, 1.56–1.74 (m, 6H), 2.41 (t, J ¼ 6.7 Hz, 2H), 3.59–3.89 (m, 2H),
3H), 0.07 (s, 3H), 0.90 (m, 12H), 1.25 (t, J ¼ 7.0 Hz, 3H), 1.31– 5.04 (brs, 1H) ppm. 13C NMR (50 MHz, CDCl3): ꢀ4.9, ꢀ4.4,
1.35 (m, 2H), 1.43 (s, 9H), 1.47–1.60 (m, 4H), 1.76–1.86 (m, 14.9, 16.8, 17.8, 18.0, 21.8, 25.7, 28.2, 29.5, 34.9, 39.3, 46.9,
2H), 2.35 (t, J ¼ 7.5 Hz, 2H), 3.59–3.87 (m, 2H), 4.12 (q, J ¼ 69.4, 78.6, 119.5, 155.6 ppm. MS(ESI): m/z 421.20 (M + Na)+
7.0 Hz, 2H), 4.92–4.95 (m, 1H) ppm. 13C NMR (50 MHz, HRMS: 421.2856 (M + Na)+, calcd 421.2857.
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conversion), the mixture was ltered through a pad of celite and
concentrated in vacuo to give 21 as a colorless liquid (0.098 g,
98%). [a]2D5: +23.91 (c 1.05, CHCl3) IR (CHCl3, cmꢀ1): nmax 2931,
2858, 1693, 1416, 1253, 1167. 1H NMR (200 MHz, CDCl3): d 0.05
(s, 3H), 0.07 (s, 3H), 0.89 (m, 12H), 1.26–1.41 (m, 4H), 1.46 (s, 9H),
1.57–1.62 (m, 6H), 1.70–1.83 (m, 2H), 2.69–2.82 (m. 1H), 3.59–
3.71 (m, 1H), 3.91–3.97 (m, 1H), 4.11–4.35 (m, 1H) ppm. 13C NMR
(50 MHz, CDCl3): spectra showed amide rotamers ꢀ4.5, ꢀ4.4,
14.0, 14.3, 18.0, 18.3, 19.0, 19.2, 25.6, 25.9, 28.4, 28.5, 29.7, 30.3,
37.8, 39.3, 48.5, 70.8, 79.1, 154.9 ppm. MS(ESI): m/z 408.18 (M +
Na)+ HRMS: 386.3085 (M + H)+ calcd 386.3085.
tert-Butyl (R)-2-((R)-2-((tert-butyldimethylsilyl)oxy)pentyl)-3,4-
dihydropyridine-1(2H)-carboxylate (19)
To a solution of 18 (0.250 g, 0.65 mmol) in CH2Cl2 (10 mL), was
added DIBAL-H (0.715 mL 1 M solution in toluene, 0.71 mmol)
at ꢀ78 ꢁC under argon atmosphere. The reaction was stirred at
this temperature for 2 h. Then saturated solution of ammonium
chloride (0.8 mL) was added. The resulting mixture was warmed
to ambient temperature and was then diluted with 0.2 M
aqueous HCl (0.67 mL) followed by EtOAc and organic layer was
separated. The aqueous phase was extracted with CH2Cl2 (3 ꢂ
10 mL), the combined organic layers were dried (Na2SO4),
ltered and evaporated under reduced pressure to give alde-
hyde, which was directly used in the next step without further
purication.
To the cooled solution of anhydrous THF and a drop of
MeOH was added NaBH3CN (0.098 g, 2.6 mmol) over 20 min
followed by addition of aldehyde derived from 18. The reaction
mixture was allowed to warm to room temperature and was
stirred for 8 h. Aer being cooled to ambient temperature, the
mixture was quenched with ice pieces and extracted with EtOAc
(3 ꢂ 5 mL). The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated under reduced pres-
sure to give crude product. The crude product was then
puried by silica gel ash column chromatography using (pet
ether : EtOAc: 19 : 1) to give 19 (0.216 g, 90%) as a yellow oil.
Continued chromatography with pet ether : EtOAc/4 : 1
provided 20 (0.026 g, 5%) as a colorless liquid. [a]2D5: +42.97
(c 0.6, CHCl3) IR (CHCl3, cmꢀ1): nmax 2929, 2857, 1702, 1649,
1254 1H NMR (500 MHz, CDCl3): spectra showed 1 : 1 mixture of
amide rotamers d 0.06 (s, 6H), 0.88 (m, 12H), 1.26–1.44 (m, 4H),
1.48 (s, 9H), 1.53–1.63 (m, 2H), 1.69–1.73 (m, 1H), 1.80–1.82 (m,
1H), 1.94–1.98 (m, 1H), 2.06–2.12 (m, 1H), 3.70–3.79 (m, 1H),
4.07–4.15 (m, 0.5H), 4.30–4.33 (m, 0.5H), 4.77–4.88 (m, 1H), 6.65
(d, J ¼ 7.3 Hz, 0.5H), 6.79 (d, J ¼ 7.4 Hz, 0.5H) ppm.13C NMR
(125 MHz, CDCl3): ꢀ4.5, ꢀ4.4, 14.3, 18.0, 23.9, 24.5, 25.9, 28.3,
30.3, 38.3, 38.5, 39.0, 39.3, 47.6, 48.8, 69.9, 80.3, 80.5, 104.5,
104.8, 124.0, 124.4, 151.9, 152.3 ppm. MS(ESI): m/z 406.24 (M +
Na)+ HRMS: 384.2929 (M + H)+ calcd 384.2928.
(ꢀ)-Halosaline (1)
To the solution of 21 (0.1 g, 0.27 mmol) in dry CH2Cl2 (1 mL) was
added TFA (0.075 mL, 0.78 mmol) at 0 ꢁC and reaction mixture
was allowed to stir at rt for 2 h. Then solvent was evaporated and
neutralized with sat. NaHCO3 and extracted with CH2Cl2 (3 ꢂ 10
mL). The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated under reduced pressure to give
crude product. Silica gel column chromatography of the crude
product using (MeOH/CH2Cl2/NH4OH: 8/95/2) gave (ꢀ)-halosa-
ꢁ
line 1 (0.042 g, 92%) as a solid compound. Mp 80–82 C, [a]:
ꢀ18.9 (c 0.9, EtOH) [lit.3 [a]D25: ꢀ19.5 (c 0.6, EtOH); IR (CHCl3,
1
cmꢀ1): nmax 3445, 3373, 2928, 1399, 1125. H NMR (200 MHz,
CDCl3): d 0.90 (t, J ¼ 7.1 Hz, 3H), 1.25–1.95 (m, 12H), 2.84 (dt, J ¼
4.5, 12.1 Hz, 1H), 3.19–3.34 (m, 1H), 3.41 (d, J ¼ 12.7 Hz, 1H),
3.87–4.00 (m, 1H) ppm. 13C NMR (50 MHz, CDCl3): 13.8, 18.7,
22.1, 22.6, 28.6, 39.2, 39.4, 45.0, 55.0, 66.8 ppm. MS(ESI): m/z
194.06 (M + Na)+ HRMS: 172.1696 (M + H)+ calcd 172.1696.
tert-Butyl (R)-2-((R)-2-((tert-butyldimethylsilyl)oxy)pentyl)-5-
oxopyrrolidine-1-carboxylate (17)
To an ice-cold stirred solution of 12 (0.060 g, 0.15 mmol) and
triethylamine (0.03 mL, 0.2 mmol) in anhydrous CH3CN (2 mL)
was added dropwise Boc anhydride (0.05 mL, 0.2 mmol) and
ꢁ
DMAP (catalytic) at 0 C. The resulting mixture was allowed to
warm up to room temperature and stirred for 6 h. Ice pieces were
added to the reaction mixture and organic layer was separated.
The aqueous layer was extracted with diethyl ether (3 ꢂ 5 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated under reduced pressure to give
crude N-Boc derivative. Silica gel column chromatography
(petroleum ether : ethyl acetate: 9 : 1) of the crude product gave
17 as a colorless liquid (0.075 g, 92%). [a]2D5: +17.34 (c 1.7, CHCl3).
IR (CHCl3, cmꢀ1): nmax 3019, 1777, 1728, 1215. 1H NMR (400
MHz, CDCl3): d 0.06 (s, 6H), 0.89 (m, 12H), 1.31–1.47 (m, 4H), 1.53
(s, 9H), 1.60–1.67 (m, 1H), 1.85–2.11 (m, 3H), 2.38–2.45 (m, 1H),
tert-Butyl ((5R,7R)-7-((tert-butyldimethylsilyl)oxy)-1-
hydroxydecan-5-yl)carbamate (20)
[a]2D5: ꢀ18.47 (c 1.0, CHCl3) IR (CHCl3, cmꢀ1): nmax 3365, 2930,
1692, 1366, 1100. 1H NMR (200 MHz, CDCl3): d 0.06 (s, 3H), 0.08
(s, 3H), 0.90 (m, 12H), 1.29–1.35 (m, 4H), 1.43 (s, 9H), 1.47–1.57
(m, 4H), 1.58–1.68 (m, 2H), 1.76–1.88 (m, 2H), 3.58–3.73 (m, 3H),
3.78–3.91 (m, 1H), 5.02 (brs, 1H) ppm. 13C NMR (50 MHz, CDCl3):
ꢀ4.7, ꢀ4.3, 14.3, 17.9, 18.3, 21.8, 25.9, 28.4, 29.7, 32.5, 35.5, 39.5,
47.6, 62.7, 69.8, 78.7, 155.8 ppm. MS(ESI): m/z 426.26 (M + Na)+
2.52–2.62 (m, 1H), 3.74–3.80 (m, 1H), 4.04–4.09 (m, 1H) ppm. 13
C
NMR (100 MHz, CDCl3): d ꢀ4.5, 14.2, 18.1, 23.9, 25.8, 28.0, 31.1,
39.9, 40.7, 57.1, 70.9, 82.7, 149.7, 174.4 ppm. MS (ESI): m/z 408.20
(M + Na)+. HRMS: 408.2541 (M + H)+ calcd 408.2541.
tert-Butyl (R)-2-((R)-2-((tert-butyldimethylsilyl)oxy)pentyl)
piperidine-1-carboxylate (21)
tert-Butyl (R)-2-((R)-2-hydroxypentyl)pyrrolidine-1-carboxylate
(15)
To the solution of 19 (0.1 g, 0.27 mmol) in ethyl acetate was added
Pd–C (10%) under hydrogenation conditions. The reaction
mixture was allowed to stir overnight. On completion of reaction, To a cooled (0 ꢁC), stirred solution of Ph3P (0.35 g, 1.46 mmol) in
(until 1H NMR analysis of the crude mixture indicated complete THF–MeCN (1 : 1, 5 mL) were added imidazole (0.10 g, 1.45
3242 | RSC Adv., 2014, 4, 3238–3244
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mmol) and I2 (0.34 g, 1.46 mmol). The mixture was stirred for 2
h and then a solution of alcohol 13 (0.50 g, 1.33 mmol) in THF
(10 mL) was added at 0 ꢁC. The mixture was stirred for 2 h, then
diluted with 10% aq Na2S2O3 (6 mL) and extracted with EtOAc
(2 ꢂ 6 mL). The combined organic layer was dried (Na2SO4) and
concentrated under reduced pressure and then used without
purication for the next step.
5 (a) P. Merlin, J. C. Braekman, D. Daloze and J. M. Pasteels,
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To the crude iodo compound dissolved in THF (5 mL) was
added n-BuLi (0.4 mL, 2.66 mmol) and the mixture was stirred
at r.t. for 1 h. Then, the mixture was poured into aq. NH4Cl and
the organic layer was separated. The aqueous layer was extrac-
ted with Et2O (3 ꢂ 20 mL) and the combined organic layer was
washed with brine (2 ꢂ 10 mL), dried (Na2SO4) and concen-
trated. Purication of the crude product by silica gel column
chromatography (petroleum ether : ethyl acetate: 9 : 1) afforded
15 as a colorless liquid (0.26 g, 76%). [a]2D5: +21.56 (c 1.7, CHCl3).
1
IR (CHCl3, cmꢀ1): nmax 3419, 2928, 1690, 1415, 1163. H NMR
(400 MHz, CDCl3): d 0.88 (t, J ¼ 7.1 Hz, 3H), 1.24–1.37 (m, 5H),
1.44 (s, 9H), 1.51–1.60 (m, 2H), 1.83–2.00 (m, 3H), 3.28–3.35 (m,
2H), 3.39–3.49 (m, 1H), 4.11–4.21 (m, 1H), 4.94 (m, 1H) ppm. 13
C
8 (a) P. I. Dalko, Enantioselective Organocatalysis: Reactions and
Experimental Procedures, Wiley-VCH, Weinheim, 2007; (b)
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4638.
NMR (50 MHz, CDCl3): d 14.0, 19.1, 23.5, 28.3, 31.1, 38.9, 43.9,
46.4, 53.6, 67.0, 79.7, 156.6 ppm. MS (ESI): m/z 280.20 (M + Na)+.
HRMS: 280.1878 (M + Na)+ calcd 280.1883.
9 D. W. C. MacMillan, Nature, 2008, 455, 304.
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B. List, Chem. Commun., 2006, 819; (f) For
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Acknowledgements
V. J. thanks UGC New Delhi for fellowship. We thank Ms. S.
Kunte for HPLC analysis. The authors thank CSIR, New Delhi
for nancial support as part of XII Five Year Plan under title
ORIGIN (CSC0108).
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17 The enantiomeric excess was determined using chiral GC
analysis whereas diastereomeric ratio was determined
using HPLC analysis (see ESI†). In order to determine the
chiral purity of (R)-ethyl 4-hydroxyoctanoate 9, it was
converted into lactone 22 on treatement with p-TSA in
methanol.Chiral GC using Cyclodextrin TA column (70 kPa
pressure, 140 ꢁC isotherm for 35 min, major enantiomer
19.9 min, minor enantiomer 20.6min). The racemic
standard was prepared in the same way with racemic
g-hydroxy ester, ee 94%.
18 M. Nomura, S. Shuto, M. Tanaka, T. Sasaki, S. Mori,
S. Shigeta and A. Matsuda, J. Med. Chem., 1999, 42, 2901.
3244 | RSC Adv., 2014, 4, 3238–3244
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