An improved method of ring closing metathesis in the presence of basic amines: Application to the formal synthesis of (+)-lentiginosine and other piperidines and carbamino sugar analogs

Article abstract of DOI:10.1016/j.tetlet.2010.12.020

A generalized method for performing ring closing metathesis in the presence of basic amines has been established and successfully used in the formal synthesis of (+)-lentiginosine as well as some valuable intermediates for the synthesis of several other a

Full text of DOI:10.1016/j.tetlet.2010.12.020

Tetrahedron Letters 52 (2011) 781–786
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Tetrahedron Letters
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An improved method of ring closing metathesis in the presence of basic amines:
application to the formal synthesis of (+)-lentiginosine and other
piperidines and carbamino sugar analogs
⇑
Rima Lahiri, Hari Prasad Kokatla, Yashwant D. Vankar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A generalized method for performing ring closing metathesis in the presence of basic amines has been
established and successfully used in the formal synthesis of (+)-lentiginosine as well as some valuable
intermediates for the synthesis of several other azasugars and aminocyclitols.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 7 October 2010
Revised 2 December 2010
Accepted 4 December 2010
Available online 9 December 2010
Keywords:
Metathesis
Basic amines
Azasugars
Lentiginosine
The ruthenium based catalyst 1 (bis(tricyclohexylphosphine)
benzylidine ruthenium(IV) chloride,Fig. 1), first developed by Grub-
bs et al. for double bond exchange reactions, has witnessed enor-
mous application in the synthesis of medium to large size
carbacyles as well as heterocycles via a process popularly called as
Ring Closing Metathesis (RCM).1 Further improvement in the
catalyst potency was brought about by changing the ligands around
the metal center resulting in newer generation catalysts (1,3-
bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro (phenyl-
methylene)(tricyclohexylphosphine)ruthenium, 2 and dichloro(o-
isopropoxyphenylmethylene)(tricyclohexylphosphine)-ruthenium
(II), 3.2 The low oxophilicity, ease in handling and their ability to
tolerate a number of functional groups have made these catalysts
extremely useful in complex synthetic endeavours.3 Very recently,
Grubbs and co-workers4 have reported that these ruthenium
catalysts are effective even in concentrations as low as 500 ppm
resulting in carbamate protected cyclic amines in excellent yields.
In the past decade, even though the use of ruthenium catalysts
in the synthesis of azacycles has gained enormous importance5 it
has been well established that the presence of basic amines re-
duces the catalyst efficiency.6 This is attributed to the fact that
the lone pairs on nitrogen coordinate at the metal center making
the latter unreactive toward the olefins.3,7 Thus, amino groups
have been conventionally converted into a carbamate, a sulfon-
amide, or an amide functionality before performing the RCM reac-
tions.5 This often leads to an increase in protection–deprotection
manipulation and in turn reduces the effectiveness of the synthetic
sequence. Although, modifications of the reactant by using the cor-
responding ammonium salts,8 or addition of protic9 or Lewis10
acids have been found useful, the viability of these approaches in
the presence of acid sensitive groups is low. Recently, some spo-
radic reports of cyclization in presence of tertiary amines have
emerged in the literature11 that essentially requires 8–10 mol %
catalyst loading, longer reaction times, and yields are moderate,
especially for the six-membered rings. Considering the high cost
of the commercial catalysts, such reaction conditions become
impracticable in multi-step large scale synthesis.
Recently, synthesis of nitrogen containing sugar mimics has
gained considerable importance12 due to their therapeutic poten-
tial against viral infections, metabolic disorders, lysosomal storage
disorders and cancer.13,14 Among the azasugars, (+)-lentiginosine
24 (Scheme 2) is the least hydroxylated alkaloid, which was
isolated from the leaves of Astragalus lentiginosus in 1990.15 The
PCy3
Ru
PCy3
Ru
Mes
N
N
Mes
Ph
Cl
Cl
Cl
Cl
Ph
Cl
Cl
Ru
O
PCy3
PCy3
Grubbs' 1st
generation catalyst
Grubbs' 2nd
generation catalyst
Hoveyda - Grubbs'
1
1
st generation catalyst
2
3
⇑
Corresponding author.
E-mail address: vankar@iitk.ac.in (Y.D. Vankar).
Figure 1. The most popularly used catalysts for olefin metathesis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.020

782
R. Lahiri et al. / Tetrahedron Letters 52 (2011) 781–786
molecule shows selective amyloglucosidase inhibition activity at
submicromolar concentration (IC50 = 0.43 g/l) and is the most
In order to establish the stereochemistry of the amine, the
cyclohexylidene acetal group of the major isomer 7A (Scheme 1)
was deprotected and the so formed diol 8 was subjected to one
pot N-debenzylation, olefin reduction and protection of the pri-
mary amine as its t-butyloxy carbamate using Pd(OH)2/C in H2
atmosphere. The product was obtained on purification as a white
solid, mp = 89 °C (lit.20 ref. mp = 90–91 °C) and the absolute stereo-
chemistry was confirmed to be as shown in diol 9. Thus, the major
isomer 7A obtained from the Barbier reaction was suitable for the
synthesis of (+)-lentiginosine.
N-Benzylated secondary amine 7A was treated with allyl bro-
mide and NaHCO3 in the presence of tetrabutylammonium bro-
mide and was heated to reflux in CH3CN. The diene 10 (Table 1)
was obtained in 86% yield and its structure was confirmed by the
presence of four terminal olefinic protons in the 1H NMR spectrum
in the region d 5.01–5.16 and two internal olefinic protons in the
region d 5.70–6.02. This diene 10 was first subjected to olefin
metathesis using Grubbs’ 1st generation catalyst 1 (8 mol %) on a
scale of 20 mg (0.059 mmol). The reaction occurred smoothly in
refluxing dichloromethane and after 6 h the reactant was con-
sumed completely and the cyclized product 20 (Scheme 2) was ob-
tained in 69% yield.
l
potent and selective amyloglucosidase inhibitor known till date.
Due to the biological importance, several groups have reported
its synthesis using either a chiral pool starting material or a chiral
catalyst, which has often been achieved through long routes and
intermediates formed in low yields.
In continuation of our ongoing work in multistep syntheses en
route to azasugars utilizing RCM as one of the key steps in C–C
bond formation16 we herein report the formal synthesis of (+)-len-
tiginosine and some advanced azasugar and aminocyclitol inter-
mediates. Further, in contrast to the frequent observation made
by us and others11,17 that the presence of a basic amine in the reac-
tant fails to provide high yield as compared to their conjugated
counterparts, we have developed an improved procedure for olefin
metathesis suitable to practice in the presence of tertiary amines,
which has been used in the syntheses of sugar mimics.
In our present attempt to synthesize (+)-lentiginosine from D-
mannitol 4 we are required to perform olefin metathesis in the
early steps of the synthetic sequence, which demanded a good
yielding reaction condition. The synthesis started from D-mannitol
derived aldehyde 518 (Scheme 1), which was converted to its cor-
responding imine 13 using BnNH2 in the presence of MgSO4 at
0 °C. The Schiff base was formed in 15 min and was used without
further purification. The Barbier reaction19 on the imine derivative
was done by reacting it with allyl bromide and zinc dust in pres-
ence of a catalytic amount of CeCl3Á7H2O in dry THF. The reaction
yielded a mixture of diastereomers 7 in 3:1 ratio, which was sepa-
rated by column chromatography.
An attempt of scaling up the reaction to 100 mg (0.293 mmol)
of the diene resulted in utter disappointment. The reaction failed
to progress more than 20% even on the increment of the catalyst
amount to 15 mol %. Keeping in consideration that second genera-
tion catalysts are more reactive than the first generation we chan-
ged our reaction conditions. The diene 10 (0.293 mmol) was
dissolved in 4 mL of dry toluene and 3 mol % of the catalyst 2
O
O
BnNH2, MgSO4
O
D-mannitol
NBn
Et2O, 0 ºC, 15 min
O
O
4
5
6
O
O
Br
, Zn
(3:1) diastereomers
NHBn
CeCl3.7H2O, THF
7
0
oC - rt, 1 h
HO
HO
HO
HO
O
O
NHBoc
NHBn
Pd(OH)2/C
TFA, H2O
NHBn
º
Boc2O, MeOH
H2, rt, 1 h
0 C - rt, 20 min
8
9
7A
Scheme 1. Structure determination of the major diastereomer 7A.
O
O
O
Br
Bn
N
catalyst 3
NHBn
O
NaHCO3, TBAI
CH3CN, reflux,
4 h
dry Toluene
º
10
90 C, 6 h
7A
O
O
O
O
1. Pd(OH)2/C, H2
MeOH, rt, 12 h
Bn
N
Cbz
N
TFA - H2O
º
0
C - rt, 1 h
2. CbzCl, NaHCO3
EtOAc, rt, 1 h
21
20
HO
HO
EtO2C
1. NaIO4,THF-H2O,
HO
HO
º
Cbz
0
C - rt, 15 min
Cbz
N
N
Ref. 15(g)
N
H
2. Ph3P=CHCO2Et
CH2Cl2, reflux, 4 h
23
24
22
Scheme 2. Formal Synthesis of (+)-lentiginosine from 14A.

R. Lahiri et al. / Tetrahedron Letters 52 (2011) 781–786
783
Table 1
A comparison of RCM under single addition and portionwise addition of catalyst
S. No.
Reactant
Cat (mol %)
Single addition (%)
72
Addition in portions of three (%)
Time (h)
Ph
Ph
O
O
N
N
1
3
94
6
6
10
O
O
2
3
3
3
70
70
90
85
11
O
O
O
6
NBn
O
12
NBn
O
O
4
5
3
3
81
68
98
89
6
6
H
O
BnO
13
NBn
MeO2C
14
O
O
H
BnO
O
O
Bn
N
O
6
7
3
3
54
88
92
4
2
CO2Me
15
Bn2N
HO
Quant.
16
HO
Bn2N
HO
17
8
9
3
2
79
72
95
86
2.5
5
OH
Ph
18
NBn
O
O
Bn
N
O
10
3
86
Quant.
3
19
was added to it. The reaction mixture was heated to 90 °C. After
4 h, almost 50% consumption of the diene was observed by thin
layer chromatographic (TLC) analysis. To our dissatisfaction the
progress of the reaction stopped at this stage even on continuation
of heating. On addition of another 3 mol % of the catalyst the reac-
tion started to progress but came to a standstill after about 80%
conversion. Completion of the reaction was brought about by fur-
ther addition of 3 mol % of the catalyst and on purification, the
product was obtained in 92% yield. To make the above described
reaction cost effective with respect to Grubbs’ catalyst, we wanted
to minimize the amount of the catalyst required. Thus, we used
3 mol % of the catalyst 2, which was divided in three equal portions
and each portion was added to the reaction mixture at equal inter-
vals in 6 h. The same reaction was also repeated using equal
amount of the catalyst but added in a single portion. While the
usual cyclization procedure yielded 72% of the product 20 with
unreacted starting material being recovered, our modified reaction
condition increased the yield to 94% with complete consumption of
the starting material. We have been able to scale up the reaction to
500 mg (1.464 mmol) where the cyclization occurred smoothly. In
order to generalize our newly developed reaction condition, we
tested other dienes derived from sugar and non-sugar starting
materials using 2–3 mol % Grubbs’ 2nd generation catalyst. Our re-
sults are summarized in Table 1. While slow addition protocol has
been employed to achieve RCM in very complicated systems,21 we,
hereby report the use of this tactic in the notoriously unreactive
basic amine substrates for the first time.
In all cases a significant increase in yield was observed ranging
from 12% to 38%. It is worth mentioning that cyclization of amine
with deactivated nitrogen lone pairs 19 also underwent increase in
yield by 14% when subjected to the modified conditions. The most
striking increase was observed in 15 with a hike of 38% in yield. A
plausible explanation for the improved yield of the reaction is the
assumption that the active catalyst reacts with the available dou-
ble bond faster than the nitrogen lone pairs. However, presence
of high concentration of the basic amine in the reaction mixture
in the form of either the diene or the cyclized olefin, eventually
binds to the metal making it inactive. Adding small amounts of

784
R. Lahiri et al. / Tetrahedron Letters 52 (2011) 781–786
the catalyst to the reaction mixture over a period of time ensures
the presence of the active catalyst throughout the reaction time
and reduces the possibility of binding with the basic nitrogen
and thus increasing the yield of the cyclized product. This modified
reaction procedure is expected to be useful in multistep synthesis
as the sufficiently low catalyst loading enhances the utility of the
reaction.
The synthesis of (+)-lentiginosine was continued (Scheme 2) by
subjecting the cyclized product to one pot N-debenzylation and
saturation of olefin using 20% w/w of Pd(OH)2/C in dry MeOH un-
der H2 atmosphere. After 12 h the catalyst was removed by filtra-
tion over CeliteÒ and the crude product was treated with benzyl
chloroformate in 1:1 solution of ethyl acetate and saturated aque-
ous NaHCO3. The corresponding N-carbamate 21 was obtained in
86% yield and its structure was confirmed by the presence of ben-
zylic protons as a singlet at d 5.13 equiv to 2 protons. Also, absence
of olefinic peaks in d 5.50–6.00 region suggested the successful
reduction of the double bond. The cyclohexylidene acetal was
hydrolyzed under acidic conditions to yield 1,2-diol 22 in 78%
yield, which was oxidatively cleaved followed by the Wittig reac-
as its trityl ether 29 and column chromatographic purification of
the product yielded the two diastereomers in 5:1 ratio. The major
isomer 29A was converted to the free diol 30 (Scheme 3) by re-
moval of the ether protection with CF3CO2H. This molecule is an
attractive intermediate for the synthesis of monocyclic azasugars.
Also, cleavage of the diol into aldehyde and the corresponding
reduction by using NaBH4 in MeOH gave a primary hydroxyl group
containing piperidinone 31. The absolute stereochemistry was
determined by COSY and NOESY data of the compound 31 (see
Supplementary data). Both the compounds viz. 30 and 31 could
serve as useful intermediates toward the synthesis of azasugars.
The biological importance22 of aminocyclitols, such as valien-
amine, valiolamine, voglibose, 2-deoxystreptamine, oseltamivir,
and conduramines has attracted the attention of a number of
chemists11c,23 for their synthesis as well as that of their analogs.
In view of this, the dienes 16 and 17, derived from
D-mannitol
and
D
-ribose based aldehydes,24 respectively, were prepared as
shown in Scheme 4. In both the cases the cyclization in the pres-
ence of the acetonide protected 1,2-diol failed but the free hydrox-
ylated compounds underwent RCM reactions successfully giving
the corresponding substituted cyclohexenes in excellent yields.
Although compound 33, the major diastereomer, could be easily
chromatographically purified at this stage, separation of the diaste-
reomeric mixture of 37 was successful only after cyclization giving
the two isomers viz. 39A and 39B in 2:1 ratio.
The absolute stereochemistry of compounds 35, 39A, and 39B
was determined by NOE correlation studies (Fig. 2). Thus, irradia-
tion of H-2 in 39A resulted in enhancement of H-6 proton by 3%.
On the other hand, in 35 and 39B no enhancement of H-6 proton
was observed on irradiation of H-2. Thus, the stereochemistry
was confirmed to be as shown in Figure 2. The N,N-dibenzylated
aminocyclitols are suitable substrates for the synthesis of
tion to give
a,b-unsaturated ester 23. This ester can be converted
to (+)-lentiginosine following a literature procedure.15g
Utilizing the chiral free amine we then proceeded to synthesize
polyhydroxylated piperidinones (Scheme 3). The free amine 7A
was reacted with acryloyl chloride and the corresponding amide
19 was treated with the catalyst 2. The cyclic amide 25 was treated
with a catalytic amount of OsO4 in the presence of NMO for 36 h. A
diastereomeric mixture of diol 26 was obtained in 86% yield, which
was dibenzylated by using benzyl bromide and sodium hydride.
The mixture of diastereomers 27 was subjected to acetal deprotec-
tion in acidic medium. At all these stages we were unable to sepa-
rate the diastereomers. The primary hydroxyl group was protected
O
O
O
O
Cl
, Et3N
Bn
catalyst 3
NHBn
N
O
O
º
Toluene, 90 C,
3 h
º
CH2Cl2, 0 C,
10 min
19
7A
O
O
O
OsO4, NMO, rt, 36 h
H2O-Acetone-tBuOH
BnBr, NaH, DMF
Bn
Bn
N
N
O
O
O
0 oC-rt, 1h
OH
25
27
26
OH
HO
O
O
TrO
Bn
N
Bn
N
Bn
N
O
TrCl, Et3N, DCM
O
HO
THF - H2O
oC - rt, 1 h
O
HO
º
0 C - rt, 6 h
dr : 5:1
0
OBn
OBn
OBn
OBn
28
OBn
O
OBn
29
TrO
HO
HO
HO
Bn
N
1. NaIO4, THF-H2O
0 ºC - rt, 30 min HO
Bn
Bn
N
O
N
TFA,CH2Cl2
0 oC - rt, 1 h
O
2. NaBH4, MeOH
OBn
OBn
OBn
0
ºC, 10 min
OBn
OBn
OBn
31
major isomer 29A
30
Bn
N
O
HO
H
nOe correlations
31
of
OBn
H
X
H
OBn
Scheme 3. Synthesis of polyhydroxylated lactams.

R. Lahiri et al. / Tetrahedron Letters 52 (2011) 781–786
785
NHBn
1. BnNH2, MgSO4
BnBr, K2CO3
CH3CN,
O
O
º
O
O
Et2O, 0 C,15 min
O
D
-mannitol
2. allyl bromide, Zn
CeCl3.7H2O, THF,
º
0 C - rt,1 h
32
major 33
º
0 C - rt, 2 h
NBn2
NBn2
NBn2
O
O
HO
HO
3
catalyst
HO
HO
TFA - H2O
0 oC - rt, 6 h
Toluene, 90 oC,
2.5 h
35
34
16
NHBn
O
1. BnNH2, MgSO4
Et2O, 0 oC,15 min
O
BnBr, K2CO3
CH3CN,
0 ºC - rt, 1 h
O
D-ribose
2. allyl bromide ,Zn
CeCl3.7H2O, THF,
O
O
37
36
º
0 C - rt, 2 h
NBn2
NBn2
NBn2
NBn2
HO
HO
HO
3
catalyst
O
O
HO
HO
TFA - H2O
+
º
0 ºC - rt, 6 h
Toluene, 90 C,
2.5 h
HO
major
17
minor 39B
dr = 2:1
39A
38
Scheme 4. Synthesis of aminocyclitols.
Bn2N
H2
2247–2250; (c) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179; (d) Gessler, S.; Randl, S.; Blechert, S.
Tetrahedron Lett. 2000, 41, 9973–9976.
NBn2
H6
Bn2N
HO
H6
H6
HO
HO
HO
HO
3. Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9858–9859.
4. Kuhn, K. M.; Champagne, T. M.; Hong, S. H.; Wei, W. H.; Nickel, A.; Lee, C. W.;
Virgil, S. C.; Grubbs, R. H.; Pederson, R. L. Org. Lett. 2010, 12, 984–987.
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X
HO
X
H2
39A
H2
35
39B
Figure 2. NOE correlations of aminocyclitols.
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deoxystreptamine, conduramines, and deoxyinosamines via sim-
ple organic transformations.17
In conclusion, we have developed a simple variation of the ring
closing metathesis procedure to achieve excellent yields with low
catalyst loading in the presence of nucleophilic amines. We have
used this approach in the formal synthesis of (+)-lentiginosine,
some piperidinones and carbamino sugar derivatives. Further utili-
zation of this method and conversion of the azacycles into biolog-
ically important molecules are currently under progress in our
laboratory.
Acknowledgments
We thank the Council of Scientific and Industrial Research, New
Delhi for financial support [Grant No. 01(2298)/09/EMR-II]. R.L.
and H.P.K. thank the CSIR, New Delhi for Senior Research
Fellowships.
Supplementary data
Supplementary data (experimental details, spectral data, and
spectra) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.12.020.
References and notes
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