A stereoselective approach to indolizidine and pyrrolizidine alkaloids: Total synthesis of (-)-lentiginosine, (-)-epi-lentiginosine and (-)-dihydroxypyrrolizidine

Article abstract of DOI:10.1039/c4ob00461b

A simple and highly efficient approach to hydroxylated pyrrolizidine and indolizidine is developed from an aldehyde as a starting material using organocatalytic and asymmetric dihydroxylation reactions as key steps. Its application to the total synthesis of (-)-lentiginosine, (-)-epi-1,2- lentiginosine and (-)-dihydroxypyrrolizidine is also reported. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00461b

Organic &
Biomolecular Chemistry
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A stereoselective approach to indolizidine
and pyrrolizidine alkaloids: total synthesis
of (−)-lentiginosine, (−)-epi-lentiginosine
and (−)-dihydroxypyrrolizidine†
Cite this: Org. Biomol. Chem., 2014,
12, 4454
Shruti Vandana Kauloorkar,a Vishwajeet Jha,a Ganesh Jogdandb and
Pradeep Kumar*a
Received 28th February 2014,
Accepted 29th April 2014
A simple and highly efficient approach to hydroxylated pyrrolizidine and indolizidine is developed from an
aldehyde as a starting material using organocatalytic and asymmetric dihydroxylation reactions as key
steps. Its application to the total synthesis of (−)-lentiginosine, (−)-epi-1,2-lentiginosine and (−)-dihydroxy-
pyrrolizidine is also reported.
DOI: 10.1039/c4ob00461b
www.rsc.org/obc
Introduction
The synthesis of enantiopure therapeutics with a high medic-
inal value has always been a prime concern among synthetic
chemists. Among them, azasugars have gained much attention
in recent years as they mimic carbohydrates. Structurally, they
are known to contain fused bicyclic systems with nitrogen at
the bridge head and variable ring size based on which they
may be classified as indolizidines1 and pyrrolizidines.2 These
“izidines” show different patterns of oxygenation; for instance,
the highly oxygenated castanospermine 1, its less hydroxylated
congeners such as lentiginosine 2, epi-lentiginosine 3, and
dihydroxypyrrolizidine 4 or the non-oxygenated ring systems
such as coniceine 5, pyrrolizidine 6, etc., are widespread in
plants and microorganisms3 (Fig. 1).
Lentiginosine was isolated in 1990 by Elbein and co-
workers from the source Astralagus lentiginosus.4 It is known to
exhibit excellent anti-HIV, anti-tumour and immunomodulat-
ing activities apart from being a significant inhibitor of amylo-
glycosidases with IC50 = 5 μg mL−1. The mechanism of action
is related to inhibition of the biosynthesis of glycoproteins
which are responsible for recognition and adhesion of exogen-
ous agents.5 Effective inhibitors are known to mimic the term-
inal unit of oligosaccharides competing with the natural
substrate for occupying the enzyme active site.
Fig. 1 Some indolizidine and pyrrolizidine alkaloids.
Owing to its potent biological activity, lentiginosine and its
analogues have attracted a great deal of interest among syn-
thetic organic chemists, in spite of the relatively low degree of
hydroxylation as evident from the number of literature reports.
Lentiginosine was first synthesized in 1993 by Yoda et al.
from a tartaric acid derived imide.6a Several syntheses followed
that employed a chiral pool approach using tartaric acid,6
nitrones,7 carbohydrates8 or amino acids9 as starting
materials. Although the majority of these literature reports
have used a chiral pool approach, they proved to be useful pro-
tocols for only a limited number of molecules and also involve
a large number of synthetic steps. Shibasaki and co-workers
were the first to report an enantioselective approach using a
Heck cyclization as a key step.10a Subsequently a number of
groups have reported the synthesis of lentiginosine and its
analogues using an enantioselective approach.10 Therefore, a
general enantioselective synthetic approach to several azasu-
gars and their unnatural analogues that are amenable to
implementation of requisite stereochemical variations and
different forms of substitution has become necessary. We have
aDivision of Organic Chemistry, CSIR-NCL (National Chemical Laboratory),
Pune 411008, India. E-mail: pk.tripathi@ncl.res.in; Tel: +9102025902050
bCentral NMR Facility, CSIR-NCL (National Chemical Laboratory), Pune 411008,
India
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob00461b
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recently reported the synthesis of indolizidine and pyrrolizi-
dine in our preliminary communication11 employing the
sequential α-amination12 and Horner–Wadsworth–Emmons
(HWE) olefination as the key step. In continuation of our inter-
est in developing new methodologies13 using proline catalyzed
sequential amination/aminoxylation followed by HWE olefina-
tion, we report here a general and efficient strategy for the syn-
thesis of lentiginosine, epi-lentiginosine and dihydroxy
pyrrolizidine.
Scheme 2 Synthesis of indolizidine alkaloid coniceine.
Table 1 Optimization of Sharpless asymmetric dihydroxylation reaction
Results and discussion
conditions
Our general synthetic strategy is outlined in Scheme 1. Lentigino-
sine 2, epi-lentiginosine
3 and dihydroxy pyrrolizidine
4 could be obtained by cyclization of A. Compound A could be
synthesized by Sharpless asymmetric dihydroxylation14 of the
α,β-unsaturated ester B for the introduction of the two hydroxy
groups adjacent to the amine functionality which in turn
could be synthesized from aldehyde C via a proline catalyzed
α-amination reaction. Before embarking on the synthesis of
the target molecules, we considered exploring a model syn-
thesis to test the devised strategy, in particular, the concomi-
tant cleavage of the N–N bond and nucleophilic displacement
under hydrogenation conditions. The synthesis commenced
with the aldehyde 7a which, on proline-catalyzed sequential
α-amination followed by a HWE olefination, furnished the
γ-amino-α,β-unsaturated ester 8a in 68% yield (91% ee).15
Compound 8a was then subjected to ester reduction, ensuing
double bond reduction and TBS deprotection in one step
using LiBH4 in THF to provide the diol 9. Compound 9 on
treatment with toluenesulfonyl chloride and triethylamine
resulted in the formation of ditosylate which was subjected to
hydrogenation conditions for the cleavage of N–N bonds using
RANEY®-Ni to give the free amine which on nucleophilic dis-
placement of ditosylate led to the formation of indolizidine
alkaloid (R)-coniceine 5 (Scheme 2). The extrapolation of this
strategy allowed the successful completion of the synthesis of
all the three target molecules in a very short and efficient
manner.
Entry
Ligandsa
Yield (%)
Ratio (10 : 11)
1
2
3
4
5
6
No ligand
94
95
93
89
96
96
83 : 17
2 : 3
99 : 1
2 : 3
1 : 3
(DHQD)2PHAL (5 mol%)
(DHQ)2PHAL (5 mol%)
(DHQD)2PYR (5 mol%)
(DHQD)2AQN (5 mol%)
(DHQ)2AQN (5 mol%)
99.8 : 0.2
a Reactions were carried out in the presence of 1 mol% of OsO4 and
3 equivalents of K2CO3 and K3FeCN6.
8a (Table 1). At this stage we investigated the use of the Sharp-
less asymmetric dihydroxylation reaction used for embedding
two hydroxy groups in the substrate containing a pre-existing
chiral centre with a bulky substituent at the allylic nitrogen.
The use of cinchona alkaloid ligand variants to achieve the
two requisite stereocentres provided
a general synthetic
pathway to the family of hydroxylated azasugars in a highly
diastereoselective manner. Dihydroxylation of 8a under Sharp-
less conditions in the absence of a chiral ligand interestingly
gave “syn facial selectivity” (syn-10/anti-11 83/17) where both
products were easily separable by silica gel column chromato-
graphy. This result showed that the bulk of the allylic NCbz
substituent had little impact on the stereodifferentiation of the
two π faces. The probable explanation for this diastereofacial
bias could be attributed to the presence of H-bonding between
the OsO4 and NCbz-NHCbz group that facilitates the formation
of syn-diastereomer 10 as a major product (Fig. 2).16 We then
examined the efficacy of various cinchona alkaloid containing
ligands and the results are summarized in Table 1. To achieve
the “anti facial selectivity” (based on the Sharpless mnemonic
device) we used (DHQD)2PHAL, surprisingly the diastereo-
meric outcome (anti-11/syn-10) was found to be 3/2. Switching the
ligand to (DHQD)2PYR gave a similar result (anti-11/syn-10 3/2).
The synthesis of the target molecules (−)-lentiginosine and
its 1,2-epimer commenced with γ-amino-α,β-unsaturated ester
Scheme 1 Retrosynthetic route to indolizidine and pyrrolizidine
alkaloids (2–4).
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Fig. 2 Proposed transition state for syn selectivity.
Finally, (DHQD)2AQN was found to be a better ligand as
the dr for the anti compound 11 increased to 3/1. To favour
the “syn antipode” both (DHQ)2PHAL and (DHQ)2AQN were
found to be useful ligands. In these cases, the reaction pro-
gressed with high diastereoselectivity and we obtained syn-10
essentially as a single diastereomer (Table 1, entries 3 and 6).
In all the cases, however, the yield remained almost the same.
The relative stereochemistry of the three stereocenters gen-
erated were unambiguously determined using 2D NMR spec-
troscopy. For this purpose, diols 10 and 11 were subjected to
hydrogenation conditions using RANEY®-Ni to cleave the N–N
bond to obtain free amine which subsequently undergoes
cyclization to give cyclic derivatives 12 and 13, respectively
(Scheme 3). Extensive NMR studies were carried out on com-
pounds 12 and 13 to determine the relative stereochemistry.
The two cyclic isomers 12 and 13 were subjected to 2D
NMR spectroscopy after carefully studying their peak patterns
in 1D NMR. 1H, 13C and DEPT NMR spectra of the cyclized
compounds were determined in CDCl3. Initially, it was found
that compound 13 showed resolved peaks for the methine
protons α, β and γ whereas this was not the case for compound
12. Acetone-d6 proved to be a more suitable solvent for better
quality NMR spectra. Compounds 12 and 13 were then charac-
terized using the 1D NMR experiments (1H, 13C DEPT) as well
as 2D homonuclear (COSY, and NOESY) and heteronuclear
(HSQC and HMBC) NMR spectroscopy.
Fig. 3 NOESY spectrum of compound 12.
β- and γ-position. The NOESY spectra of compound 12 show a
cross peak between the β and γ protons which confirmed their
syn relationship between the β and γ methine protons, the
α and β protons did not show NOESY correlation which indi-
cated their trans relationship as shown in Fig. 3.
For compound 13, the α, β, γ protons resonated at δ 4.06,
3.77 and 3.28 respectively. The α proton showed as a distinct
doublet at 4.06 ppm having a coupling constant of 7.3 Hz
which indicated the trans stereochemistry between α and
β methine protons. The β and γ protons showed multiplet like
patterns which prohibited extraction of their coupling con-
stants. Therefore the 2D NOESY spectrum was used to find out
the relative stereochemistry at the β and γ positions. The
NOESY spectra of compound 13 did not show a correlation
between the β and γ protons which confirmed their anti stereo-
chemistry. The α and β protons did not show NOESY corre-
lation which indicated the trans relationship between them as
shown in Fig. 4.
After determining the relative stereochemistry of com-
pounds 12 and 13, we proceeded to the synthesis of target
molecules. For the synthesis of (−)-1,2-epi-lentiginosine 3, diol
10 was subjected to LiBH4 reduction to give tetrol 14. Com-
pound 14 was subjected to selective primary tosylation using
TsCl and Et3N to give the ditosyl, which was subjected to
hydrogenation conditions using freshly prepared RANEY®-Ni
to deliver the free amine which on nucleophilic displacement
of ditosylate led to the formation of the desired (−)-1,2-epi-
lentiginosine 3 (Scheme 4).
For compound 12, the α, β, γ protons resonated at δ 4.04,
4.22 and 3.55 ppm respectively. The α proton shows the dis-
tinct doublet at 4.04 ppm having a coupling constant of 6.63
Hz which indicated the trans stereochemistry between the
α and β-methine protons. The β and γ-protons showed multi-
plet like pattern which prohibited extraction of the coupling
constants from the 1D spectrum. Therefore the 2D NOESY
spectrum was used to determine the relative stereochemistry at the
In a similar way, as illustrated in Scheme 5, (−)-lentigino-
sine 2 was synthesized from diol 11 by an analogous series of
reactions to those shown in Scheme 4. The strategy can also be
extended to the synthesis of the natural enantiomer and other
stereoisomers by simply using the other enantiomer of proline
for the α-amination and different ligands for dihydroxylation.
After the successful completion of the synthesis of lentigino-
sine and its 1,2-epimer we thought to extrapolate our strategy
Scheme 3 Preparation of cyclic derivatives.
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Scheme 6 Synthesis of dihydroxy pyrrolizidine.
compound 2 with an overall yield of 23% and target com-
pound 4 with an overall yield of 23%. This strategy is the short-
est synthesis reported so far from easily available starting
materials with high yields.
Fig. 4 NOESY spectrum of compound 13.
Conclusions
In conclusion, we have developed a new, highly efficient and
concise protocol to synthesise dihydroxylated indolizidine and
pyrrolizidine alkaloids using a proline catalyzed α-amination
followed by Sharpless asymmetric dihydroxylation reaction as
the key steps. Its utility was illustrated by the total synthesis of
(−)-lentiginosine, (−)-epi-lentiginosine and (−)-dihydroxypyrro-
lizidine. The synthetic strategy allows implementation of the
desirable stereocenters at C-1, C-2 and C-8a and can be
extended to the synthesis of other stereoisomers and ana-
logues with variable ring sizes and different degrees of
hydroxylation.
Scheme 4 Synthesis of 1,2-epi-lentiginosine.
Experimental section
Dibenzyl (R,E)-1-(8-((tert-butyldimethylsilyl)oxy)-1-ethoxy-1-
oxooct-2-en-4-yl)hydrazine-1,2-dicarboxylate (8a)
(For a procedure to prepare 8a, see ref. 11.) [α]2D5: +2.67 (c 1.0,
CHCl3) HPLC: Kromasil 5-Amycoat (250 × 4.6 mm) (2-propa-
nol–petroleum ether = 10 : 90, flow rate 0.5 mL min−1, λ =
230 nm). Retention time (min): 13.30 (major) and 16.23
(minor). The racemic standard was prepared in the same way
using DL-proline as a catalyst. ee 91%.
Scheme 5 Synthesis of (−)-lentiginosine.
to other analogues. Thus, by simply altering the chain length,
the synthesis of dihydroxy pyrrolizidine 4 was achieved.
As illustrated in Scheme 6, the synthesis started with the
aldehyde 7b, which on sequential α-amination followed by HWE
olefination furnished the γ-amino-α,β-unsaturated ester 8b in
68% yield and 94% enantioselectivity.15 The olefinic com-
pound 8b was subjected to Sharpless asymmetric dihydroxyla-
tion using (DHQD)2AQN as the ligand to give the diol 16. Diol
16 was converted to give the target compound 4 using the
same set of reactions as described in Schemes 3 and 4.
(R,E)-Dibenzyl 1-(7-((tert-butyldimethylsilyl)oxy)-1-ethoxy-1-
oxohept-2-en-4-yl)hydrazine-1,2-dicarboxylate (8b)
(For a procedure to prepare 8b see ref. 11.) [α]2D5: +4.73 (c 1.0,
CHCl3) HPLC: Kromasil 5-Amycoat (250 × 4.6 mm) (2-propa-
nol–pet ether = 10 : 90, flow rate 0.5 mL min−1, λ = 254 nm).
Retention time (min): 13.46 (major) and 18.07 (minor). The
racemic standard was prepared in the same way using
DL-proline as a catalyst, ee 94%.11
Our synthetic approach afforded the target compound 3 in
a linear sequence of 4 steps with an overall yield of 31%, target
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Dibenzyl (R)-1-(1,8-dihydroxyoctan-4-yl)hydrazine-1,2-
dicarboxylate (9)
(200 MHz, CDCl3): δ 0.00 (m, 6H), 0.82–0.91 (m, 9H), 1.22–1.54
(m, 8H), 1.78–1.98 (m, 1H), 3.55–3.64 (m, 2H), 3.90–4.09
(m, 1H), 4.14–4.38 (m, 3H), 4.90–5.34 (m, 4H), 6.68–6.84 (m, 1H),
7.26–7.45 (m, 10H). 13C NMR (50 MHz, CDCl3): −5.3,
14.1, 18.3, 25.9, 25.8, 31.4, 32.3, 61.8, 62.4, 67.8, 68.5,
70.3, 70.4, 72.9, 127.8, 128.0, 128.2, 128.3, 128.5, 135.5, 156.6,
156.9, 172.8. MS (ESI): m/z 655.29 (M + Na)+ HRMS (ESI) m/z:
To a solution of ethyl ester 8a (0.5 g, 0.80 mmol) in THF
(7 mL) was added LiBH4 (0.035 g, 1.6 mmol) at 0 °C. The reac-
tion mixture was stirred at rt for 2 h. It was then quenched
with ice-cold aq. HCl (1 N) and extracted with ethyl acetate (3 ×
5 mL). The combined organic layers were washed with brine,
dried over anhyd. Na2SO4 and concentrated under reduced
pressure to give the crude product. Silica gel column chrom-
atography of the crude product using ethyl acetate as the
eluent gave 9 as a waxy solid (0.312 g, yield 84%). [α]2D5: +0.32
(c 1.0, CHCl3), IR (CHCl3, cm−1): νmax 3289, 2292, 1709, 1662,
1218. 1H NMR (200 MHz, CDCl3): δ 1.26–1.60 (m, 10H), 1.96
(brs, 2H), 3.47–3.67 (m, 4H), 4.02–4.29 (m, 1H), 4.96–5.26
(m, 4H), 7.04 (brs, 1H), 7.31–7.35 (m, 10H). 13C NMR (100 MHz,
CDCl3): as a rotameric mixture δ 22.1, 25.5, 28.7, 29.3, 29.7,
31.9, 32.6, 61.8, 62.2, 62.3, 62.8, 67.7, 67.8, 67.9, 68.3, 127.6,
128.0, 128.2, 128.3, 128.4, 128.5, 135.5, 135.8, 136.0, 156.4,
156.8, 156.9, 157.3. MS (ESI): m/z 467.15 (M + Na)+ HRMS (ESI)
m/z: [M + H]+ Calcd for C24H33O6N2 445.2333; Found 445.2328.
[M
655.3018.
+
Na]+ Calcd for C32H48O9N2SiNa 655.3021; Found
HPLC: Kromasil RP-18 (150 × 4.6 mm) (methanol–H2O =
85 : 15, flow rate 1 mL min−1, λ = 254 nm). Retention time
(min): 7.33 and 8.23.
Dibenzyl 1-((2S,3R,4R)-7-((tert-butyldimethylsilyl)oxy)-1-ethoxy-
2,3-dihydroxy-1-oxoheptan-4-yl)hydrazine-1,2-dicarboxylate (16)
Waxy solid (0.378 g, 95%, dr 3 : 1); [α]2D5: +10.96 (c 1.0, CHCl3)
1
IR (CHCl3, cm−1): νmax 3456, 2956, 2857, 1731, 1416. H NMR
(200 MHz, CDCl3): δ −0.02 (m, 6H), 0.80 (m, 9H), 1.17–1.31
(m, 3H), 1.38–1.68 (m, 3H), 1.87–2.03 (m, 1H), 3.28–3.68 (m, 3H),
3.85–3.99 (m, 1H), 4.16–4.30 (m, 3H), 4.86–5.27 (m, 4H),
7.26 (m, 10H), 7.48–7.70 (m, 1H). 13C NMR (50 MHz, CDCl3):
δ −5.6, 13.9, 18.2, 25.8, 28.7, 60.2, 61.6, 62.2, 68.0, 68.3, 70.9,
71.8, 126.8, 127.5, 127.7, 128.0, 128.3, 128.4, 135.0, 135.7,
156.1, 156.9, 172.7. MS (ESI): m/z 641.31 (M + Na)+ HRMS (ESI)
m/z: [M + Na]+ Calcd for C31H46O9N2SiNa 641.2868; Found
641.2869.
Dibenzyl 1-((2R,3S,4R)-8-((tert-butyldimethylsilyl)oxy)-1-ethoxy-
2,3-dihydroxy-1-oxooctan-4-yl)hydrazine-1,2-dicarboxylate (10)
General procedure for Sharpless asymmetric dihydroxylation:
To a mixture of K3Fe(CN)6 (0.825 g, 2.50 mmol), K2CO3
(0.345 g, 2.50 mmol), and (DHQ)2AQN (6.5 mg, 1 mol%) in
t-BuOH–H2O (1 : 1, 10 mL) at 0 °C was added osmium tetroxide
(0.32 mL, 0.1 M solution in toluene, 0.4 mol%), followed by
methane sulfonamide (0.079 g, 0.83 mmol). After stirring for
5 min at 0 °C, the olefin 8a (0.500 g, 0.83 mmol) was added in
one portion. The reaction mixture was stirred at 0 °C for 24 h
and then quenched with solid sodium sulfite (0.5 g). Stirring
was continued for an additional 15 min and then the solution
was extracted with EtOAc (3 × 20 mL). The combined extracts
were washed with brine, dried over Na2SO4 and concentrated.
Silica gel column chromatography purification (Rf = 0.40,
EtOAc–petroleum ether, 3 : 7) of the crude product gave 10 as a
white waxy solid (0.507 g, 96%). [α]2D5: +0.22 (c 1.0, CHCl3), IR
(CHCl3, cm−1): νmax 3474, 3250, 3036, 2925, 2855, 1718, 1682,
1462. 1H NMR (200 MHz, CDCl3): δ −0.01 (m, 6H), 0.85 (m,
9H), 1.21–1.32 (m, 6H), 1.39–1.53 (m, 3H), 3–3.29 (m, 1H),
3.45–3.82 (m, 3H), 4.02–4.17 (m, 1H), 4.27 (q, J = 7 Hz, 2H),
5.04–5.34 (m, 4H), 6.68–7.02 (m, 1H), 7.14–7.37 (m, 10H).
13C NMR (50 MHz, CDCl3): δ −5.3, −5.4, 14.1, 18.3, 21.7, 25.9,
31.8, 61.8, 62.2, 68.5, 71.1, 71.3, 71.9, 72.1, 127.7, 127.9, 128.1,
128.2, 128.3, 128.5, 128.6, 134.9, 135.7, 156.0, 157.1, 172.7. MS
(ESI): m/z 655.29 (M + Na)+ HRMS (ESI) m/z: [M + Na]+ Calcd
for C32H48O9N2SiNa 655.3021; Found 655.3018.
HPLC: Kromasil RP-18 (150 × 4.6 mm) (methanol–H2O =
85 : 15, flow rate 1 mL min−1, λ = 254 nm). Retention time
(min): 6.18 and 7.28.
(3R,4S,5R)-5-(4-((tert-Butyldimethylsilyl)oxy)butyl)-
3,4-dihydroxypyrrolidin-2-one (12)
General procedure for cyclization: Determination of relative
configuration: a solution of compound 10 in MeOH (10 mL)
and acetic acid (5 drops) was treated with RANEY® nickel
(1 g, excess) under a H2 (60 psi) atmosphere for 24 h. The
reaction mixture was then filtered over celite and concen-
trated to the give the crude free amine which was further
subjected to cyclisation by stirring in EtOH at 55 °C for 5 h.
The reaction mixture was concentrated in vacuo to give the
crude product. Silica gel column chromatography (ethyl
acetate–petroleum ether/6 : 4) of the crude product gave
12 as a syrupy liquid (0.359 g, 75%). [α]2D5: +31.25 (c 0.5, CHCl3)
IR (CHCl3, cm−1): νmax 3285, 2930, 2858, 1712, 1255.
1H NMR (200 MHz, CDCl3): δ 0.05 (s, 6H), 0.89 (s, 9H),
1.29–1.56 (m, 5H), 1.71–1.89 (m, 1H), 3.60–3.66 (m, 3H),
4.24–4.45 (m, 2H), 6.29 (brs, 1H). 1H NMR (500 MHz,
acetone-d6): δ 0.07 (s, 6H), 0.91 (s, 9H), 1.40 (m, 2H), 1.56
(m, 3H), 1.81 (m, 1H), 2.92 (brs, 2H), 3.58 (m, 1H), 3.67 (t,
J = 5.72 Hz, 2H), 4.06 (d, J = 5.35 Hz, 1H), 4.25 (m, 1H).
13C NMR (50 MHz, CDCl3): δ −5.3, 18.4, 22.5, 25.9, 29.7, 32.5,
55.1, 62.9, 74.1, 74.9, 175.4. MS (ESI): m/z 326.18 (M + Na)+
HPLC: Kromasil RP-18 (150 × 4.6 mm) (methanol–H2O =
85 : 15, flow rate 1 mL min−1, λ = 254 nm). Retention time
(min): 6.42 and 7.43.
Dibenzyl 1-((2S,3R,4R)-8-((tert-butyldimethylsilyl)oxy)-1-ethoxy-
2,3-dihydroxy-1-oxooctan-4-yl)hydrazine-1,2-dicarboxylate (11)
Waxy solid (0.380 g, 96%, dr 3 : 1); [α]2D5: +8.04 (c 1.0, CHCl3), HRMS (ESI) m/z: [M + H]+ Calcd for C14H29O4NSiNa 326.1758;
IR (CHCl3, cm−1): νmax 3748, 3421, 3019, 1734, 1541. H NMR Found 326.1764.
1
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(3S,4R,5R)-5-(4-((tert-Butyldimethylsilyl)oxy)butyl)-3,4-
dihydroxypyrrolidin-2-one (13)
(m, 2H), 1.70–1.90 (m, 2H), 3.54–3.66 (m, 5H), 3.83–4.05
(m, 1H), 4.15–4.40 (m, 1H), 5.05–5.15 (m, 4H), 7.10–7.36
(m, 10H). 13C NMR (125 MHz, CDCl3): as a rotameric mixture
δ 23.3, 33.5, 34.1, 63, 64.6, 68.5, 69.3, 72.7, 75.6, 77.5, 80.2,
128.0, 128.7, 129.1, 129.2, 129.4, 129.5, 129.6, 129.7, 137.5,
137.7, 143.5, 157.7, 158.8. MS (ESI): m/z 485.22 (M + Na)+
HRMS (ESI) m/z: [M + Na]+ Calcd for C23H30O8N2Na 485.1894;
Found 485.1891.
Syrupy liquid (0.180 g, 75%); [α]2D5: +3.77 (c 0.5, CHCl3) IR
(CHCl3, cm−1): νmax 3354, 2922, 1711, 1463, 1377. 1H NMR
(200 MHz, CDCl3): δ 0.05 (s, 6H), 0.89 (s, 9H), 1.50–1.53
(m, 4H), 1.73–2.12 (m, 2H), 3.31–3.42 (m, 1H), 3.63 (t, J =
5.9 Hz, 2H), 3.87–3.94 (m, 1H), 4.29–4.32 (m, 1H), 6.67 (brs,
1H) 1H NMR (500 MHz, acetone-d6): δ 0.07 (s, 6H), 0.91 (s, 9H),
1.51–1.58 (m, 5H), 1.75 (m, 1H), 2.94 (brs, 2H), 3.26–3.30
(m, 1H), 3.67 (t, J = 6.10 Hz, 2H), 3.77 (m, 1H), 4.06 (d, J =
7.3 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ −5.3, 18.3, 22.1,
25.9, 32.5, 33.3, 56.8, 62.9, 76.3, 79.8, 175.3. MS (ESI): m/z
326.15 (M + Na)+ HRMS (ESI) m/z: [M + Na]+ Calcd for
C14H29O4NSiNa 326.1758; Found 326.1764.
(1S,2S,8aR)-Octahydroindolizine-1,2-diol (3)
General procedure for cyclization: To an ice-cold stirred solu-
tion of 14 (0.25 g, 0.5 mmol) and triethylamine (0.22 mL,
1.5 mmol) in anhydrous CH2Cl2 (6 mL) was added toluenesul-
fonyl chloride (0.20 g, 1.0 mmol) over 15 min. The resulting
mixture was allowed to warm up to room temperature and
stirred for 48 h. After diluting with 6 mL CH2Cl2, the solution
was washed with water (3 × 15 mL), brine, dried over anhyd.
Na2SO4 and concentrated to give the crude ditosylated product
which was subjected to the next step without further
purification.
A solution of crude tosylated compound in MeOH (10 mL)
and acetic acid (5 drops) was treated with RANEY® nickel (1 g,
excess) under a H2 (60 psi) atmosphere for 24 h. The reaction
mixture was then filtered over celite and concentrated to give
crude free amine which was further subjected to cyclization by
stirring in EtOH at 55 °C for 20 h. The reaction mixture was
concentrated in vacuo to give the crude product. Silica gel (neu-
tralized) column chromatography (methanol–CH2Cl2: 1 : 15) of
the crude product gave 3 as a white solid (0.046 g, 56%). mp:
134–136 °C [lit.:6e 137–138]; [α]D25: −6.48 (c 1, CH3OH). [lit.:6e
[α]2D5: −5.3 (c 0.3, CH3OH)]; 1H NMR (200 MHz, D2O):
δ 1.34–1.55 (m, 3H), 1.67–1.88 (m, 3H), 2.16–2.34 (m, 2H),
2.42–2.49 (m, 1H), 3.15 (d, J = 11.2 Hz, 1H), 3.52 (dd, J = 7 Hz,
11.2 Hz, 1H), 3.98 (d, J = 4.1 Hz, 1H), 4.08–4.15 (m, 1H).
13C NMR (50 MHz, D2O): 25.0, 25.9, 26.0, 55.1, 62.1, 69.6, 77.9,
80.6. (1H and 13C NMR data were in good agreement with those
reported in lit.6e). MS (ESI): m/z 158.11 (M + H)+ HRMS (ESI)
m/z: [M + H]+ Calcd for C8H16O2N 158.1176; Found 158.1175.
Dibenzyl 1-((2S,3S,4R)-1,2,3,8-tetrahydroxyoctan-4-yl)
hydrazine-1,2-dicarboxylate (14)
General procedure for LiBH4 reduction: To a solution of ethyl
ester 10 (0.5 g, 0.79 mmol) in THF (7 mL) was added LiBH4
(0.05 g, 0.24 mmol) at 0 °C. The reaction mixture was stirred at
rt for 2 h. It was then quenched with aq. HCl (1 N) and
extracted with ethyl acetate (3 × 5 mL). The combined organic
layers were washed with brine, dried over anhyd. Na2SO4 and
concentrated under reduced pressure to give the crude
product. Silica gel column chromatography (methanol–
CH2Cl2: 1 : 20) of the crude product gave 14 as a white solid
(0.32 g, yield 85%). mp: 123–125 °C; [α]2D5: +0.13 (c 0.3,
CH3OH), IR (CHCl3, cm−1): νmax 3384, 3282, 3019, 2926, 1749,
1720, 1646, 1215. 1H NMR (200 MHz, CDCl3): δ 1.32–1.58
(m, 6H), 3.45–3.68 (m, 6H), 4.5–4.59 (m, 1H), 5.02–5.24 (m, 4H),
7.24–7.44 (m, 10H). 13C NMR (50 MHz, CDCl3): as a rotameric
mixture 23.4, 30.5, 30.8, 33.1, 33.3, 62.8, 65.0, 69.1, 69.2, 69.4,
71.7, 71.8, 72.2, 72.5, 128.7, 129.1, 129.3, 129.4, 129.7, 137.4,
137.7, 158.6, 158.7, 158.9. MS (ESI): m/z 499.17 (M + Na)+
HRMS (ESI) m/z: [M + Na]+ Calcd for C24H32O8N2Na 499.2051;
Found 499.2047.
Dibenzyl 1-((2R,3R,4R)-1,2,3,8-tetrahydroxyoctan-4-yl)
hydrazine-1,2-dicarboxylate (15)
(1R,2R,8aR)-Octahydroindolizine-1,2-diol (2)
White solid (0.32 g, yield 85%); mp: 116–118 °C; [α]2D5: +0.34
(c 0.85, CH3OH), IR (CHCl3, cm−1): νmax 3384, 3282, 3019,
White solid (0.047 g, 57%). mp: 106–108 °C [lit.:5a 106–107];
[α]D25: −2.92 (c 0.5, CH3OH), [lit.:5a [α]D23 −1.6 (c 0.24, CH3OH),
lit.7c [α]D −3.05 (c 1.0, CH3OH)]. 1H NMR (200 MHz, D2O):
δ 1.28–1.34 (m, 2H), 1.47–1.53 (m, 1H), 1.68–1.70 (m, 1H),
1.82–1.86 (m, 1H), 1.94–1.98 (m, 1H), 2.13–2.27 (m, 2H), 2.81
(dd, J = 7.59, 11.3 Hz, 1H), 2.94 (d, J = 11.3 Hz, 1H), 3.06 (d, J =
11.7 Hz, 1H), 3.70 (dd, J = 3.4, 9.1 Hz, 1H) 4.10–4.13 (m, 1H).
13C NMR (50 MHz, D2O): 25.5, 26.4, 29.9, 55.4, 62.7, 71.4, 78.1,
85.1. (1H and 13C NMR data were in good agreement with those
reported in lit.10g). MS (ESI): m/z 158.11 (M + H)+ HRMS (ESI)
m/z: [M + H]+ Calcd for C8H16O2N 158.1176; Found 158.1174.
1
2926, 1749, 1720, 1646, 1215, 760. H NMR (200 MHz, CDCl3):
δ 1.36–1.41 (m, 1H), 1.49–1.66 (m, 5H), 3.48–3.69 (m, 6H),
4.16–4.36 (m, 1H), 5.02–5.24 (m, 4H), 7.29–7.47 (m, 10H).
13C NMR (100 MHz, CDCl3): as a rotameric mixture δ 27.1,
30.5, 31.1, 33.8, 33.9, 63.0, 63.2, 63.3, 68.7, 69.4, 69.7, 71.8,
72.2, 72.4, 128.9, 129.3, 129.4, 129.5, 129.6, 129.7, 129.9, 137.9,
138.0, 158.5, 158.9, 159.1. MS (ESI): m/z 499.22 (M + Na)+
HRMS (ESI) m/z: [M + Na]+ Calcd for C24H32O8N2Na 499.2051;
Found 499.2047.
Dibenzyl 1-((2R,3R,4R)-1,2,3,7-tetrahydroxyheptan-4-yl)
hydrazine-1,2-dicarboxylate (17)
(1R,2R,7aR)-Hexahydro-1H-pyrrolizine-1,2-diol (4)
White solid (0.32 g, yield 85%); mp: 125–127 °C; [α]2D5: −0.19 Colorless solid (0.047 g, 56%). mp: 138–140 °C [lit.:8f 141–143];
(c 0.55, CH3OH). IR (CHCl3, cm−1): νmax 3376, 3280, 3022, 2929, [α]D25: −6.67 (c 1.3, CH3OH), [lit.:8f [α]D24 −6.4 (c 1, CH3OH),
1
1716, 1638, 1190. 1H NMR (200 MHz, CDCl3): δ 1.27–1.44 lit.10e [α]D +7.6 (c 1.3, CH3OH)]. H NMR (200 MHz, CD3OD):
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δ 1.63–1.80 (m, 2H), 1.84–1.99 (m, 2H), 2.50 (dd, J = 7 Hz, 10.7
Hz, 1H), 2.63–2.74 (m, 1H), 2.84–2.92 (m, 1H), 3.14–3.19
(m, 1H), 3.23–3.26 (m, 1H), 3.60 (t, J = 5.6 Hz, 1H), 3.94–4.05
(m, 1H). 13C NMR (50 MHz, CD3OD): 26.4, 31.5, 56.8, 59.7, 71.0,
78.8, 82.9 (1H and 13C NMR data were in good agreement with
those reported in lit.8f). MS (ESI): m/z 144.12 (M + H)+ HRMS
(ESI) m/z: [M + H]+ Calcd for C7H14O2N 144.1019; Found
144.1020.
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Acknowledgements
SVK and VJ thank UGC, New Delhi for research fellowships.
We thank Ms S. Kunte for HPLC analysis. The authors thank
CSIR, New Delhi for financial support as part of XII Five Year
Plan under the title ORIGIN (CSC0108).
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