Synthesis of aminocyclitols and trihydroxylated indolizidinone from a D-mannitol-derived common building block

Article abstract of DOI:10.1002/ejoc.201001171

The synthesis of 4-amino-4-deoxy-muco-quercitol (22), 4-amino-4-deoxy-(-)- vibo-quercitol (27) and also a trihydroxylated indolizidinone 38 from D-mannitol is described using ring-closing metathesis and diastereoselective dihydroxylation as the key steps.

Full text of DOI:10.1002/ejoc.201001171

FULL PAPER
DOI: 10.1002/ejoc.201001171
Synthesis of Aminocyclitols and Trihydroxylated Indolizidinone from a
-Mannitol-Derived Common Building Block
D
Preeti Gupta,[a] A. P. John Pal,[a] Y. Suman Reddy,[a] and Yashwant D. Vankar*[a]
Keywords: Carbohydrates / Azasugars / Cyclitols / Ring-closing metathesis / Dihydroxylation
The synthesis of 4-amino-4-deoxy-muco-quercitol (22), 4-
amino-4-deoxy-(–)-vibo-quercitol (27) and also a trihydroxyl-
ring-closing metathesis and diastereoselective dihydrox-
ylation as the key steps.
ated indolizidinone 38 from
D-mannitol is described using
Of the several known inhibitors, aminocyclitols, amino-
substituted polyhydroxylated carbocycles, have not only at-
tracted considerable attention as inhibitors of glycosid-
ases,[5] but they also form the structural components of a
variety of aminoglycoside antibiotics[6] and other families
of biologically active compounds.[7] Owing to their sugar
mimetic structure they have also been referred to as amino-
carbasugars. Validamine (4) and valienamine (5) are exam-
ples of naturally occurring specific α-d-glucosidase inhibi-
tors.[8] Voglibose (6), an N-substituted valiolamine deriva-
tive, is used for lowering postprandial blood glucose levels
in people with Diabetes mellitus type 2. Similarly, N-octyl-
valienamine (7, NOV), is being investigated in the treatment
of Gaucher’s disease.[9] Although several synthetic routes
have been developed in recent years to access a variety of
natural and synthetic aminocyclitols,[10] very few reports are
known of the synthesis of quercitol-like aminocyclitols (also
called deoxyinosamines).[11] As a continuation of our ongo-
ing research towards the synthesis of natural and unnatural
azasugars, carbasugars, bicyclic and hybrid molecules,[12] in
this paper we describe a new approach towards 4-amino-4-
deoxy-muco-quercitol (22), 4-amino-4-deoxy-(–)-vibo-quer-
citol (27) and also the trihydroxylated indolizidinone 38
from commercially available d-mannitol. Ring-closing me-
tathesis and diastereoselective dihydroxylation are the key
steps in the syntheses.
Introduction
Glycosidase inhibitors are attractive target compounds
because of their emerging therapeutic potential in the treat-
ment of a variety of carbohydrate-mediated diseases[1] and
also because of their applications in biochemical studies of
glycosidases.[2] This has led to the synthesis of several poly-
hydroxylated carbocyclic[3a–3c] and heterocyclic[3] (particu-
larly nitrogen containing mono- and bicyclic azasugars)
molecules and some of them have been found to be potent
and specific inhibitors of glycosidases. For instance, miglitol
[1, N-(2-hydroxyethyl)-1-deoxynojirimycin] and miglustat
(2, N-butyl-1-deoxynojirimycin) are already marketed for
use in patients with type II diabetes and type I Gaucher’s
disease, respectively. Tamiflu 3 (Oseltamivir phosphate) is
an orally administered drug used in the treatment of in-
fluenza infections (Figure 1).[4]
Results and Discussion
Our synthesis started from the hydroxyalkene
8
(Scheme 1), which was prepared stereoselectively from d-
mannitol following a reported procedure.[13] The free hy-
droxy group in 8 was protected as a benzyl ether followed
by cleavage of the acetonide moiety to give the diol 10.[14]
Regioselective protection of the primary alcohol as a trityl
ether gave 11 in 96% yield. Mesylation of the secondary
alcohol followed by its nucleophilic displacement with so-
dium azide in DMF furnished the azido compound 13 in
Figure 1. Natural and synthetic glycosidase inhibitors.
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
Fax: +91-512-259-0007
E-mail: vankar@iitk.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001171.
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Synthesis of Aminocyclitols and Trihydroxylated Indolizidinone
Scheme 1. Synthesis of the aminocyclitol precursor 16.
good yield. Reduction of the azide 13 with LiAlH4 provided
Diene 17 when subjected to ring-closing metathesis using
the corresponding free amine, which, on treatment with di- 5 mol-% of the second-generation Grubbs’ catalyst[17] in
tert-butylpyrocarbonate afforded the Boc-protected amine CH2Cl2 at room temperature afforded the cyclised product
14 in 86% yield over two steps. Selective deprotection of 19 in 93% yield. Dihydroxylation of olefin 19 using a cata-
the trityl ether using HClO4·SiO2, a procedure developed[15] lytic amount of osmium tetroxide furnished diol 20 as a
in our laboratory, gave the β-amino alcohol 15 in good single diastereomer as
a white crystalline solid. Its
yield. The amino alcohol was then subjected to chromium recrystallisation with the dichloromethane and hexane sol-
trioxide based oxidation (CrO3, Ac2O, pyridine),[16] which vent system followed by X-ray crystallographic analysis[18]
gave the desired aldehyde 16. Its IR spectrum showed a (Figure 2) confirmed that cis dihydroxylation of the double
strong absorption signal at 1712 cm–1 and its 1H NMR bond had occurred anti to the benzyl ether group in 19. It
spectrum a singlet at δ = 9.60 ppm, which indicate the pres- also facilitated the stereochemical assignment of the newly
ence of the aldehyde moiety. No epimerisation was detected generated chiral centre in 17. The structure of diol 20 was
at this stage.
further confirmed by the spectroscopic data of its acetate
The aldehyde 16 was immediately treated with 3 equiv. of derivative 21. Similarly, diene 18 on ring-closing metathesis
allylmagnesium chloride at –78 °C to obtain an inseparable followed by dihydroxylation gave the diol 24 as a single dia-
mixture of homoallyl alcohols, which on acetylation of the stereomer, the structure of which was further confirmed
crude product furnished a chromatographically separable through its acetate derivative 25 (Scheme 2); the signal of 2-
1
mixture of acetates 17 and 18 in a diastereomeric ratio of H of 25 appeared as a doublet of doublets in the H NMR
1:1.4. The stereochemistry of the newly generated asymmet- spectrum with coupling constants of J1,2 = 3.2 Hz and J2,3
ric centre was confirmed at a later stage and the major dia- = 9.5 Hz. This indicated a trans diaxial orientation of 2-H
stereomer was found to have syn selectivity. On the other and 3-H and thus confirmed that dihydroxylation occurred
hand, allylation under Barbier reaction conditions using al- anti to the benzyl ether group. Hydrogenolysis of the benzyl
lyl bromide and activated zinc gave the homoallyl alcohol,
which on acetylation gave the two diastereomeric acetates
17 and 18 in a 1.8:1 ratio (Table 1).
Table 1. Results of the allylation of 16 under various conditions.
Conditions
Reagent
Temp. [°C], 17/18[a] Yield[b] [%]
time [h]
Grignard
Barbier
CH2=CHCH2MgCl
CH2=CHCH2Br/Zn
–78, 2
0, 2
1:1.4
1.8:1
65
71
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Overall yield over two steps.
Figure 2. Molecular structure of compound 20.
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FULL PAPER
Scheme 2. Synthesis of the aminocyclitols 22 and 27.
protecting group in 25 using a catalytic amount of Pd(OH)2/
After successfully completing the synthesis of the amino-
H2 followed by acetylation of the alcohol gave compound cyclitols, we also used the NHBoc-protected intermediate
26, the spectroscopic data of which, including COSY and 14 for the synthesis of piperidine-based azasugars. Indolizi-
NOE data, permitted the complete assignment of the ste- dine alkaloids like swainsonine, castanospermine, epicas-
1
reochemistry at the newly generated stereocentres. In its H tanospermine and their derivatives are known to exhibit
NMR spectrum, the signal of 3-H appeared as a “triplet” good glycosidase inhibition properties.[19] Such types of mo-
with coupling constants of J2,3 = J3,4 = 10.3 Hz, which indi- lecules and their analogues have been synthesised using dif-
cates a trans diaxial orientation of 2-H, 3-H and 4-H. In ferent starting materials.[20] (+)-1-Deoxy-6,8a-di-epi-cas-
the NOE experiment (Figure 3), irradiation of the signal of tanospermine has been shown to be an inhibitor of α-l-
4-H led to an enhancement of the signals of 2-H and 6-H, fucosidase.[21] We have taken advantage of the above syn-
whereas no enhancement was seen for the signals of 5-H thon in the synthesis of trihydroxylated indolizidinone 38,
and 3-H, which confirms the trans orientation of 4-H to 3- an amidic analogue of 1-deoxy-6,8a-di-epi-castanosperm-
H and 5-H. Similarly, irradiation of the signal of 1-H led ine. The synthesis began with the allylation of NHBoc de-
to an enhancement of the signal of 2-H, which confirms the rivative 14. However, no allylation was observed using so-
cis dihydroxylation. Finally, diols 20 and 24 were depro- dium hydride as base at room temperature or elevated tem-
tected in three steps, namely by deacetylation under peratures. Hence we changed the protecting group on the
Zemplèn conditions, hydrogenolysis of the benzyl groups amine and instead of Boc protection, Cbz protection of the
using catalytic Pd(OH)2/H2 and NHBoc deprotection under amine followed by allylation using sodium hydride gave the
acidic conditions followed by treatment with basic Dowex desired product 29 in 92% yield. Ring-closing metathesis of
to give the deprotected compounds 22 and 27, respectively. diene 29 using first-generation Grubbs’ catalyst (5 mol-%)
The two new aminocyclitols were characterised by spectro- in CH2Cl2 for 12 h at room temperature afforded the
scopic analysis, including 1H and 13C NMR, DEPT and cyclised compound 30 in good yield (Scheme 3). This syn-
COSY experiments and mass spectrometry.
thon can provide access to a variety of compounds, both
mono- and bicyclic azasugars, through the suitable func-
tionalisation of the double bond and manipulation of the
protecting groups.[22]
Dihydroxylation of olefin 30 using a catalytic amount of
osmium tetroxide afforded the diol 31 as a single dia-
stereomer in almost quantitative yield. However, its 1H
NMR spectrum was highly complex due to the rotameric
mixture resulting from the presence of the carbamate pro-
tecting group on the nitrogen. Acetylation of diol 31 fol-
Figure 3. NOE correlations of compound 26.
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Synthesis of Aminocyclitols and Trihydroxylated Indolizidinone
Scheme 3. Synthesis of compound 38.
lowed by hydrogenolysis of the benzyloxycarbonyl group In the 1H NMR spectrum of 36, the appearance of a doub-
gave the free amine 32. The spectroscopic data of com- let of doublets at δ = 3.41 ppm for 8-H with small coupling
pound 32, including the COSY and NOE data, confirmed constants of J8,8a = 4.1 Hz and J7,8 = 2.4 Hz indicated the
the exclusive formation of diol 31 and permitted the assign- diequatorial disposition of the 7-H and 8-H protons. In
ment of the stereochemistry at the newly generated NOE experiments (Figure 4), irradiation of the signal of 8a-
stereocentres C-4 and C-5 (see the Supporting Infor- H led to enhancements of the signals of the 8-H, 5-H and
mation). The hydroxy groups in diol 31 were protected as 1Ј-H protons. Irradiation of the signal of 8-H led to en-
benzyl ethers and cleavage of the trityl group using tri- hancements of the signals of the 8a-H, 7-H and 1-H pro-
fluoroacetic acid afforded compound 34 in 86% yield. The tons, which supports the conformation of lactam 36. Simi-
1
primary alcohol was oxidised using a procedure based on larly, in the H NMR spectrum of 37, the signal of 8-H
chromium trioxide (CrO3, Ac2O, pyridine system) to afford appeared as a “triplet” with coupling constants of J7,8
=
the desired aldehyde, which on treatment with ethoxycarb- J8,8a = 9.2 Hz. This indicated a trans diaxial orientation of
onylmethylenetriphenylphosphorane furnished the α,β-un- the 7-H, 8-H and 8a-H protons, which confirms the epimer-
saturated ester 35a in good yield. Catalytic hydrogenation isation at the C-8a centre. Furthermore, it also indicated
of 35a led to the removal of the benzyloxycarbonyl group that cis dihydroxylation occurred anti to the benzyl ether
and saturation of the double bond to give an intermediate group at C-8. The 7-H proton appeared as a doublet of
amine which was subjected to further reaction without any doublets with coupling constants of J7,8 = 9.2 Hz and J6,7
purification. Cyclisation of the amine using sodium acetate = 2.5 Hz. The 6-H and 7-H protons have to be cis to each
as base in ethanol at reflux afforded the lactam 36 along other because of the cis dihydroxylation and the larger cou-
with a minor amount of epimerised product 37.
pling constant must be due to the coupling of protons 7-H
The stereochemistry of the two lactams was confirmed and 8-H, which suggests a diaxial disposition of 7-H and
by spectral studies, including COSY and NOE experiments. 8-H and thus confirms the trans relationship between them.
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P. Gupta, A. P. J. Pal, Y. S. Reddy, Y. D. Vankar
FULL PAPER
ture for 6–8 h and after completion of the reaction (TLC monitor-
ing), the solvent was evaporated and the crude product was purified
by column chromatography to give the cyclised product.
In NOE experiments (Figure 4), irradiation of the signal of
8a-H led to the enhancement of the signals of the 7-H and
5-H protons. Irradiation of the signal of 8-H led to the en-
hancement of only the signal of the 1Ј-H proton. These cor-
relations support the conformation of lactam 37. To over-
come the problem of epimerisation we tried to oxidise the
Dihydroxylation Using OsO4/NMO. General Procedure B: NMO
(1.3 mmol) and OsO4 (0.004 equiv.) were added to a stirred solution
of olefin (1 mmol) in acetone/water/tert-butyl alcohol (1:1:0.5,
alcohol 34 with other oxidising agents. Interestingly, with 5 mL) at room temperature. The reaction mixture was stirred for
24–48 h (monitored by TLC) and then treated with Na2S2O5
(1.3 mmol). The reaction mixture was stirred for a further 1 h and
extracted with EtOAc (2ϫ50 mL). The organic layer was washed
with 1 n HCl, water and finally with brine, dried with Na2SO4 and
concentrated in vacuo. The diol was purified by silica gel column
chromatography.
PCC as oxidising agent, no epimerisation was detected at
the aldehyde stage, which on Wittig reaction, selective hy-
drogenolysis and cyclisation furnished the lactam 36 as an
exclusive product. Hydrogenolysis of the benzyl protecting
groups in the presence of Pd(OH)2/H2 furnished the trihyd-
roxylated indolizidinone 38 in 90% yield.
Acetylation of Alcohols. General Procedure C: Et3N (1.5 mmol),
Ac2O (1.2 mmol) and a catalytic amount of 4-(dimethylamino)pyr-
idine were added to a solution of alcohol (1 mmol) in CH2Cl2
(4 mL) at 0 °C. The reaction mixture was stirred for 3–4 h at room
temperature (TLC monitoring) and then extracted with CH2Cl2
(3ϫ20 mL). The combined organic extracts were washed with
water and brine, dried with Na2SO4 and concentrated in vacuo.
The acetylated compound was purified by silica gel column
chromatography.
(2R,3S)-3-(Benzyloxy)-1-(trityloxy)pent-4-en-2-ol
(11):
Et3N
(1.457 g, 2.0 mL, 14.4 mmol), TrCl (1.605 g, 5.76 mmol) and a cata-
lytic amount of 4-(dimethylamino)pyridine were added to a solu-
tion of diol 10 (1.0 g, 4.80 mmol) in CH2Cl2 (10 mL) at 0 °C. The
reaction mixture was stirred for 8 h at room temperature and then
extracted with CH2Cl2. The usual work-up gave a crude product,
which, after purification by column chromatography, furnished 11
(2.077 g, 96% yield) as a colourless liquid. Rf = 0.6 (hexane/ethyl
Figure 4. NOE correlations observed in compounds 36 and 37.
Conclusions
acetate, 4:1). [α]2D5 = +3.4 (c = 2.6, CH Cl ). IR (neat): ν = 3448,
We have synthesised two new aminocyclitols 4-amino-4-
deoxy-muco-quercitol (22) and 4-amino-4-deoxy-(–)-vibo-
quercitol (27). These compounds can serve as glycosidase
inhibitors as well as intermediates for the synthesis of anti-
biotics. The scope of the synthesis has further been ampli-
fied by the synthesis of the trihydroxylated indolizidinone
38.
˜
2
2
3059, 3029, 1070 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.42–7.19
(m, 20 H, ArH), 5.76 (ddd, J = 17.1, 10.5, 7.5 Hz, 1 H, olefinic),
5.31–5.24 (m, 2 H, olefinic), 4.58 (d, J = 11.7 Hz, 1 H, OCH2Ph),
4.33 (d, J = 11.7 Hz, 1 H, OCH2Ph), 3.92–3.87 (m, 2 H), 3.30 (dd,
J = 9.5, 5.6 Hz, 1 H), 3.23 (dd, J = 9.5, 4.6 Hz, 1 H), 2.32 (br. s, 1
H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.8, 138.1,
134.7, 128.6, 128.4, 128.3, 127.9, 127.8, 127.7, 127.5, 127.0, 119.8,
86.7, 81.0, 72.6, 70.3, 64.1 ppm. HRMS (ESI): calcd. for C31H30O3
[M + Na]+ 473.2093; found 473.2091.
Experimental Section
(2R,3S)-3-(Benzyloxy)-1-(trityloxy)pent-4-en-2-yl Methanesulfonate
(12): Et3N (0.449 g, 0.62 mL, 4.44 mmol) followed by methanesul-
fonyl chloride (0.305 g, 0.20 mL, 2.66 mmol) and a catalytic
amount of 4-(dimethylamino)pyridine were added to a solution of
alcohol 11 (1.0 g, 2.22 mmol) in CH2Cl2 (10 mL) cooled to 0 °C.
The reaction mixture was stirred for 1 h at the same temperature
and then quenched by the addition of a saturated NaHCO3 solu-
tion. The reaction mixture was extracted with CH2Cl2 (3ϫ20 mL)
and the combined organics were washed with water and brine and
dried with anhydrous Na2SO4. Solvent removal followed by column
chromatography afforded the mesylated compound 12 (1.149 g,
98.0% yield) as a colourless solid. Rf = 0.5 (hexane/ethyl acetate,
General: Infrared spectra were recorded with a Bruker FT/IR Vec-
1
tor 22 spectrometer. H and 13C NMR spectra were recorded with
a JEOL LA-400 (400 and 100 MHz, respectively) or JEOL ECX-
500 spectrometer (500 and 125 MHz, respectively) in solutions of
CDCl3 using tetramethylsilane as the internal standard. The mass
spectra were recorded with a Waters HAB 213 Q Tof Premier
Micromass spectrometer. Optical rotations were recorded with an
Autopol II automatic polarimeter at the wavelength of the sodium
D-line (589 nm) at 25 °C. Column chromatography was performed
on silica gel (100–200 mesh) using hexane and ethyl acetate as sol-
vents. Thin-layer chromatography (TLC) was performed on silica
gel plates made by using grade G silica gel obtained from s.d.fine-
chem Ltd., Mumbai or on Merck silica gel precoated on plastic
plates. Melting points were determined by using a Fischer-John
melting point apparatus. All solvents and common reagents were
purified by established procedures.
4:1). M.p. 90 °C. [α]2D5 = –0.7 (c = 1.48, CH Cl ). IR (neat): ν =
˜
2
2
3097, 2923, 1316, 1173 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.44–7.20 (m, 20 H, ArH), 5.68 (ddd, J = 17.6, 10.2, 7.8 Hz, 1 H,
olefinic), 5.32–5.21 (m, 2 H, olefinic), 4.87–4.83 (m, 1 H), 4.57 (d,
J = 11.7 Hz, 1 H, OCH2Ph), 4.37 (d, J = 11.7 Hz, 1 H, OCH2Ph),
4.07 (dd, J = 7.8, 4.3 Hz, 1 H), 3.43 (dd, J = 10.4, 6.6 Hz, 1 H),
3.30 (dd, J = 10.4, 4.8 Hz, 1 H), 2.99 (s, 3 H, SO2CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 143.3, 137.5, 132.8, 128.5, 128.3,
127.8, 127.7, 127.1, 121.0, 87.2, 82.8, 79.0, 70.5, 62.3, 38.7 ppm.
Ring-Closing Metathesis of Dienes. General Procedure A: First- or
second-generation Grubbs’ catalyst (5 mol-%) was added to a
stirred solution of a diene (1 mmol) in dry CH2Cl2 (15 mL) at room
temperature. The reaction mixture was stirred at the same tempera-
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Synthesis of Aminocyclitols and Trihydroxylated Indolizidinone
HRMS (ESI): calcd. for C32H32O5S [M + Na]+ 551.1868; found
551.1866.
OH), 1.35 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ
= 156.2, 137.7, 134.9, 128.3, 127.8, 127.7, 118.9, 79.4, 70.5, 63.4,
55.4, 28.2 ppm. HRMS (ESI): calcd. for C17H25 NO4 [M + Na]+
330.1682; found 330.1682.
(2S,3S)-2-Azido-3-(benzyloxy)-1-(trityloxy)pent-4-ene (13): NaN3
(0.738 g, 11.34 mmol) was added to a stirred solution of mesylate
12 (1.0 g, 1.89 mmol) in dry DMF (10 mL). This heterogeneous
mixture was stirred at 120 °C for 6 h, cooled to room temperature,
water (5 mL) was added and the mixture was extracted with diethyl
ether (3ϫ10 mL). The combined organic layer was washed with
brine and dried with Na2SO4. Removal of the solvent under re-
duced pressure gave a residue, which was purified by column
chromatography to give azide 13 (0.725 g, 80.6% yield) as a viscous
liquid. Rf = 0.7 (hexane/ethyl acetate, 9:1). [α]2D5 = –16.5 (c = 1.35,
tert-Butyl
(2R,3S)-[3-(Benzyloxy)-1-oxopent-4-en-2-yl]carbamate
(16): CrO3 (0.259 g, 2.59 mmol) was dissolved in anhydrous
CH2Cl2 (4 mL) and cooled to 0 °C. Pyridine (0.82 mL, 0.806 g,
10.2 mmol) and acetic anhydride (0.49 mL, 0.528 g, 5.18 mmol)
were added followed by the slow addition of a solution of alcohol
15 (0.500 g, 1.62 mmol) in of CH2Cl2 (2 mL). After stirring for
20 min, the resulting black solution was poured into EtOAc and
the mixture was filtered through a sintered funnel. The filtrate was
concentrated in vacuo and passed through a short column packed
with silica gel to afford the aldehyde 16 (0.348 g, 70% yield) as a
colourless liquid which was immediately subjected to the next reac-
tion. Rf = 0.6 (hexane/ethyl acetate, 4:1). [α]2D5 = –19.7 (c = 1.5,
CH Cl ). IR (neat): ν = 2924, 2096, 1449, 1073 cm–1. 1H NMR
˜
2
2
(400 MHz, CDCl3): δ = 7.44–7.21 (m, 20 H, ArH), 5.65–5.56 (m,
1 H, olefinic), 5.24–5.19 (m, 2 H, olefinic), 4.58 (d, J = 11.7 Hz, 1
H, OCH2Ph), 4.35 (d, J = 11.7 Hz, 1 H, OCH2Ph), 3.98 (t, J =
6.3 Hz, 1 H), 3.42 (dd, J = 10.0, 6.3 Hz, 1 H), 3.33 (dd, J = 9.7,
3.6 Hz, 1 H), 3.17 (dd, J = 9.7, 6.3 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 143.6, 137.7, 134.3, 128.6, 128.3, 127.8,
127.0, 119.8, 87.0, 79.9, 70.4, 65.0, 63.1 ppm. HRMS (ESI): calcd.
for C31H29 N3O2 [M + Na]+ 498.2158; found 498.2158.
CH Cl ). IR (neat): ν = 3436, 2978, 1712, 1498, 1167 cm–1. 1H
˜
2
2
NMR (400 MHz, CDCl3): δ = 9.60 (s, 1 H, CHO) 7.35–7.23 (m, 5
H, ArH), 5.75 (ddd, J = 16.8, 9.9, 7.6 Hz, 1 H, olefinic), 5.40–5.31
(m, 3 H), 4.57 (d, J = 11.8 Hz, 1 H, OCH2Ph), 4.43 (dd, J = 7.2,
2.7 Hz, 1 H), 4.36–4.32 (m, 2 H), 1.42 [s, 9 H, C(CH3)3] ppm. 13C
NMR (100 MHz, CDCl3): δ = 199.7, 155.8, 137.3, 133.4, 128.4,
127.9, 127.8, 120.0, 80.1, 77.8, 70.7, 63.1, 28.2 ppm.
tert-Butyl (2S,3S)-[3-(Benzyloxy)-1-(trityloxy)pent-4-en-2-yl]carb-
amate (14): A solution of azide 13 (1.0 g, 2.10 mmol) in THF
(5 mL) was added dropwise to a suspension of LiAlH4 (0.160 g,
4.20 mmol) in THF at 0 °C. The reaction mixture was slowly
brought to room temperature and stirred for 1.5 h. The reaction
mixture was again cooled to 0 °C, treated with EtOAc and water,
neutralised with 1 n NaOH and stirred for 1 h. The resulting white
precipitate was removed by filtration and washed with ethyl acetate.
The organic layer was dried with anhydrous Na2SO4. Removal of
the solvent gave a crude amine, which was taken up in ethyl acetate
(10 mL) and cooled to 0 °C. The mixture was treated with a satu-
rated NaHCO3 solution (3 mL) followed by Boc2O (0.72 mL,
0.687 g, 3.15 mmol) and stirred for 4 h. It was extracted with ethyl
acetate, washed with water and brine, and dried with Na2SO4. Sol-
vent evaporation followed by purification by column chromatog-
raphy gave compound 14 (0.998 g, 86.3% yield over two steps) as
a viscous liquid. Rf = 0.5 (hexane/ethyl acetate, 9:1). [α]2D5 = +10.8
Procedure for the Grignard Reaction: Allyl chloride (0.4 mL,
0.376 g, 4.92 mmol) was added to a stirred mixture of THF (4 mL),
Mg (0.196 g, 8.2 mmol) and a catalytic amount of iodine at 0 °C.
After the disappearance of the colour of iodine, the solution was
stirred for a further 15 min at ambient temperature. This freshly
prepared allylmagnesium chloride was added to a solution of alde-
hyde 16 (0.500 g, 1.64 mmol) in THF at –78 °C and stirred at that
temperature for 2 h. The reaction mixture was quenched with a
saturated aqueous solution of NH4Cl. The aqueous layer was ex-
tracted with ethyl acetate. The combined organic extracts were
washed with water and brine and dried with Na2SO4. After removal
of the solvent, the crude product was subjected to acetylation using
Ac2O, Et3N and a catalytic amount of DMAP. Chromatographic
purification provided a separable mixture of diastereomers 17 and
18 (0.415 g, 65% over two steps) in 1:1.4 ratio.
(c = 1.66, CH Cl ). IR (neat): ν = 3448, 3030, 2928, 1715, 1494,
˜
2
2
1
1080 cm–1. H NMR (400 MHz, CDCl3): δ = 7.42–7.12 (m, 20 H,
ArH), 5.85–5.76 (m, 1 H, olefinic), 5.31–5.26 (m, 2 H, olefinic),
4.78 (br. d, J = 9.5 Hz, 1 H), 4.51 (d, J = 11.7 Hz, 1 H, OCH2Ph),
4.23 (d, J = 11.7 Hz, 1 H, OCH2Ph), 4.14 (br. s, 1 H), 3.98 (br. s,
1 H), 3.23–3.14 (m, 2 H), 1.41 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.6, 143.9, 138.1, 135.4, 128.6, 128.1,
127.7, 127.4, 126.9, 118.4, 86.5, 79.0, 78.8, 70.6, 62.9, 53.8,
28.3 ppm. HRMS (ESI): calcd. for C36H39NO4 [M + Na]+
572.2777; found 572.2776.
Procedure for the Barbier Reaction: A saturated solution of NH4Cl
(0.7 mL) was added to a cold (10 °C) and well-stirred mixture of
16 (0.500 g, 1.64 mmol), Zn dust (0.321 g, 4.92 mmol) and allyl
bromide (0.28 mL, 0.397 g, 3.28 mmol) in THF (5 mL). The mix-
ture was stirred for 2 h at ambient temperature and then quenched
by the addition of NH4Cl. The mixture was filtered and then the
filtrate was extracted with ethyl acetate (3ϫ30 mL). The combined
organic layers were washed with water and finally with brine solu-
tion and dried with anhydrous Na2SO4. After removal of the sol-
vent, the residue was subjected to acetylation which gave a separa-
ble mixture of diastereomers 17 and 18 (0.452 g, 71% over two
steps) as a colourless liquid in a 1.8:1 ratio.
tert-Butyl
(2S,3S)-[3-(Benzyloxy)-1-hydroxypent-4-en-2-yl]carb-
amate (15): HClO4·SiO2 (1 g) was added to a stirred solution of
compound 14 (1.0 g, 1.82 mmol) in anhydrous methanol (10 mL)
and the reaction mixture was stirred at room temperature for 4 h.
It was then filtered, washed with methanol and then the combined
organic extracts were concentrated under vacuum. Purification by
silica gel chromatography afforded the pure alcohol 15 (0.510 g,
91.2% yield) as a colourless liquid. Rf = 0.3 (hexane/ethyl acetate,
(4S,5S,6S)-6-(Benzyloxy)-5-(tert-butoxycarbonylamino)octa-1,7-
dien-4-yl Acetate (17): Rf = 0.5 (hexane/ethyl acetate, 4:1). [α]2D5
=
–5.0 (c = 0.6, CH Cl ). IR (neat): ν = 3448, 3078, 1719, 1499, 1234,
˜
2
2
1168 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.26 (m, 5 H,
ArH), 5.82–5.74 (m, 2 H, olefinic), 5.35–5.31 (m, 2 H, olefinic),
5.06–4.98 (m, 3 H), 4.94 (d, J = 10.0 Hz, 1 H), 4.52 (d, J = 11.2 Hz,
1 H, OCH2Ph), 4.24 (d, J = 11.2 Hz, 1 H, OCH2Ph), 3.92 (d, J =
6.6 Hz, 1 H), 3.80 (t, J = 10.2 Hz, 1 H), 2.51 (m, 1 H), 2.30 (dt, J
= 14.6, 7.3 Hz, 1 H), 2.0 (s, 3 H, CH3), 1.41 [s, 9 H, C(CH3)3] ppm.
13C NMR (100 MHz, CDCl3): δ = 169.9, 155.7, 137.5, 134.8, 133.6,
128.4, 128.3, 127.7, 118.5, 117.6, 79.3, 71.9, 71.8, 70.5, 55.6, 35.6,
4:1). [α]2D5 = –48.7 (c = 1.52, CH Cl ). IR (neat): ν = 3445, 2977,
˜
2
2
1696, 1501, 1170, 1055 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.29–7.20 (m, 5 H, ArH), 5.75 (ddd, J = 17.6, 9.7, 7.5 Hz, 1 H,
olefinic), 5.29–5.25 (m, 2 H, olefinic), 5.01 (br. s, 1 H), 4.54 (d, J
= 11.7 Hz, 1 H, OCH2Ph), 4.26 (d, J = 11.7 Hz, 1 H, OCH2Ph),
3.97 (br. d, J = 5.8 Hz, 1 H), 3.64–3.62 (m, 3 H), 2.68 (br. s, 1 H,
Eur. J. Org. Chem. 2011, 1166–1175
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1171

P. Gupta, A. P. J. Pal, Y. S. Reddy, Y. D. Vankar
FULL PAPER
28.2, 20.9 ppm. HRMS (ESI): calcd. for C22H31NO5, [M + H]+
390.2280; found 390.2283.
pound 20 (0.100 g, 0.25 mmol) in dry methanol (4 mL) at 0 °C. The
mixture was stirred for 1 h at the same temperature. Evaporation
of the solvent in vacuo gave a residue which was passed through a
short pad of silica gel (eluent: ethyl acetate) to afford a triol which
was dissolved in MeOH (5 mL), treated with Pd(OH)2 (20 mol-%)
and stirred under hydrogen for 12 h. The catalyst was filtered off
through Celite and concentrated in vacuo to obtain the debenzyl-
ated product which was dissolved in dioxane (4 mL), treated with
12 n HCl (0.25 mL) and heated at reflux for 4 h. After completion
of the reaction, the solvent was evaporated and the residue was
dissolved in methanol and passed through a Dowex (50X) basic
resin column and concentrated under reduced pressure to give the
aminocyclitol 22 (0.036 g, 87% yield) as a viscous liquid. Rf = 0.2
(methanol/ethyl acetate, 2:3). [α]2D5 = +4.0 (c = 0.25, MeOH). 1H
NMR (500 MHz, CDCl3): δ = 3.96 (m, 2 H, 1-H, 5-H), 3.74 (t, J
= 9.7 Hz, 1 H, 3-H), 3.37 (br. d, J = 8.6 Hz, 1 H, 2-H), 2.87 (d, J
= 9.7 Hz, 1 H, 4-H), 1.99 (br. d, J = 16.0 Hz, 1 H, 6-H), 1.62 (br.
d, J = 16.0 Hz, 1 H, 6Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 73.9, 70.1, 68.4, 67.9, 56.5, 32.7 ppm. HRMS (ESI): calcd. for
C6H13NO4, [M + H]+ 164.0923; found 164.0926.
(4R,5S,6S)-6-(Benzyloxy)-5-(tert-butoxycarbonylamino)octa-1,7-
dien-4-yl Acetate (18): Rf = 0.5 (hexane/ethyl acetate, 4:1). [α]2D5
=
+8.3 (c = 0.6, CH Cl ). IR (neat): ν = 3453, 2977, 1739, 1719, 1499,
˜
2
2
1369, 1236, 1167 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.26
(m, 5 H, ArH), 5.77–5.67 (m, 2 H), 5.33–5.26 (m, 2 H), 5.16–5.13
(m, 1 H), 5.05–5.01 (m, 2 H), 4.91 (d, J = 10.0 Hz, 1 H), 4.58 (d,
J = 11.7 Hz, 1 H, OCH2Ph), 4.26 (d, J = 11.7 Hz, 1 H, OCH2Ph),
3.84–3.81 (m, 2 H), 2.26–2.19 (m, 2 H), 1.91 (s, 3 H, CH3), 1.44 [s,
9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 170.3,
155.9, 137.9, 134.8, 132.9, 128.3, 127.9, 127.6, 119.2, 118.2, 79.7,
79.3, 72.5, 70.1, 55.4, 36.2, 28.3, 21.0 ppm. HRMS (ESI): calcd. for
C22H31NO5 [M + H]+ 390.2280; found 390.2284.
(3S,4S,5S)-5-(Acetoxy)-3-(benzyloxy)-4-(tert-butoxycarbonylamino)-
cyclohex-1-ene (19): Diene 17 (0.200 g, 0.513 mmol) was subjected
to ring-closing metathesis following the general procedure A using
second-generation Grubbs’ catalyst and the product was purified
by silica gel column chromatography to give diol 19 (0.172 g, 93%
yield) as a colourless oil. Rf = 0.3 (hexane/ethyl acetate, 4:1). [α]2D5
(3S,4S,5R)-5-(Acetoxy)-3-(benzyloxy)-4-(tert-butoxycarbonylamino)-
cyclohex-1-ene (23): Diene 18 (0.200 g, 0.513 mmol) was subjected
to ring-closing metathesis following the general procedure A using
second-generation Grubbs’ catalyst and the product was purified
by silica gel column chromatography to give 23 (0.140 g, 75.4%
yield) as a white solid. Rf = 0.3 (hexane/ethyl acetate, 4:1). M.p.
= +112 (c = 0.6, CH Cl ). IR (neat): ν = 3370, 2926, 1711,
˜
2
2
1241 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (m, 5 H,
ArH), 5.75–5.73 (m, 2 H, olefinic), 5.23 (br. s, 1 H), 4.64 (d, J =
11.7 Hz, 1 H, OCH2Ph), 4.58 (d, J = 11.7 Hz, 1 H, OCH2Ph), 4.55–
4.53 (m, 1 H), 4.25 (br. s, 1 H), 3.95 (br. s, 1 H), 2.45 (br. d, J =
18.0 Hz, 1 H), 2.20 (dd, J = 18.0, 4.4 Hz, 1 H), 2.0 (s, 3 H, CH3),
1.42 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ =
170.4, 155.4, 138.1, 128.3, 127.8, 127.6, 127.4, 125.8, 79.6, 75.0,
70.4, 69.6, 50.0, 28.4, 28.3, 21.1 ppm. HRMS (ESI): calcd. for
105 °C. [α]2D5 = +94.5 (c = 0.7, CH Cl ). IR (neat): ν = 3356, 2932,
˜
2
2
1728, 1688, 1528, 1249, 1045 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.32–7.25 (m, 5 H, ArH), 5.72 (m, 2 H, olefinic), 4.97–4.90 (m,
1 H), 4.63 (d, J = 11.4 Hz, 1 H, OCH2Ph), 4.52 (d, J = 11.4 Hz, 1
H, OCH2Ph), 4.22 (br. s, 1 H), 4.0 (br. s, 2 H), 2.47–2.43 (m, 1 H),
2.32–2.26 (m, 1 H), 2.0 (s, 3 H, CH3), 1.44 [s, 9 H, C(CH3)3] ppm.
13C NMR (100 MHz, CDCl3): δ = 171.1, 155.8, 138.2, 128.4, 128.0,
127.7, 127.6, 125.9, 79.4, 77.7, 70.1, 69.9, 54.8, 31.1, 28.4,
21.1 ppm. HRMS (ESI): calcd. for C20H27NO5 [M + Na]+
384.1787, [M + H]+ 362.1967; found 384.1789, 362.1964.
C
20H27NO5 [M + H]+ 362.1967, [M + Na]+ 384.1787; found
362.1966, 384.1792.
(1R,2R,3R,4S,5S)-5-(Acetoxy)-3-(benzyloxy)-4-(tert-butoxycarb-
onylamino)cyclohexane-1,2-diol (20): Diol 20 (0.107 g, 97.8% yield,
colourless solid) was obtained by dihydroxylation of olefin 19
(0.100 g, 0.28 mmol) using the general procedure B. Rf = 0.5 (hex-
ane/ethyl acetate, 1:4). M.p. 130 °C. [α]2D5 = –1.38 (c = 1.4, CH2Cl2).
1
IR (neat): ν = 3410, 2925, 1715, 1510, 1243, 1077 cm–1. H NMR
˜
(1R,2R,3R,4S,5R)-5-(Acetoxy)-3-(benzyloxy)-4-(tert-butoxycarb-
onylamino)cyclohexane-1,2-diol (24): Diol 24 (0.105 g, 96.3% yield,
colourless solid) was obtained by dihydroxylation of olefin 23
(0.100 g, 0.28 mmol) using the general procedure B. Rf = 0.5 (hex-
(400 MHz, CDCl3): δ = 7.33–7.26 (m, 5 H, ArH), 5.78 (br. s, 1 H),
5.06 (m, 1 H), 4.73 (d, J = 12.0 Hz, 1 H, OCH2Ph), 4.50 (d, J =
12.0 Hz, 1 H, OCH2Ph), 4.37 (br. s, 1 H), 4.03 (br. s, 1 H), 3.91
(br. s, 1 H), 3.78 (br. s, 1 H), 3.26 (br. s, 1 H), 2.82 (br. s, 1 H),
2.02 (s, 4 H, CH3, 6-H), 1.80 (m, 1 H, 6Ј-H), 1.43 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9, 155.7,
137.5, 128.4, 127.8, 79.3, 77.3, 72.2, 71.7, 69.2, 67.2, 48.1, 29.0,
28.3, 21.1 ppm. HRMS (ESI): calcd. for C20H29NO7 [M + H]+
396.2021; found 396.2021.
ane/ethyl acetate, 1:4). M.p. 152 °C. [α]2D5 = +106.9 (c = 0.9,
1
CH Cl ). IR (neat): ν = 3412, 2927, 1712, 1500, 1071 cm–1. H
˜
2
2
NMR (400 MHz, CDCl3): δ = 7.33–7.26 (m, 5 H, ArH), 5.12 (m,
1 H), 4.95 (br. d, J = 9.48 Hz, 1 H), 4.74 (d, J = 11.1 Hz, 1 H,
OCH2Ph), 4.65 (d, J = 11.7 Hz, 1 H, OCH2Ph), 4.06 (m, 1 H),
3.80–3.78 (m, 1 H), 3.62–3.60 (m, 2 H), 3.31 (m, 2 H), 2.16–2.13
(m, 1 H), 2.02 (s, 3 H, CH3), 1.55 (m, 1 H), 1.42 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 171.1, 155.9,
138.2, 128.5, 128.2, 127.9, 79.5, 74.1, 74.0, 69.8, 67.9, 56.3, 33.3,
28.4, 21.5 ppm. HRMS (ESI): calcd. for C20H29 NO7 [M + Na]+
418.1842, [M + H]+ 396.2022; found 418.1844, 396.2021.
(1R,2R,3R,4S,5S)-3-(Benzyloxy)-4-(tert-butoxycarbonylamino)cyclo-
hexane-1,2,5-triyl Triacetate (21): Acetylation of diol 20 (0.050 g,
0.126 mmol) following the general procedure C gave the triacetate
21 as a colourless liquid (0.054 g, 89% yield). Rf = 0.6 (hexane/
ethyl acetate, 7:3). [α]2D5 = +13.1 (c = 0.9, CH Cl ). IR (neat): ν =
˜
2
2
3374, 2931, 1743, 1236 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.34–7.26 (m, 5 H, ArH), 5.29 (m, 1 H), 5.24 (m, 1 H), 5.15 (m, 1
H), 5.00 (br. s, 1 H), 4.70–4.66 (m, 2 H, OCH2Ph), 4.28 (br. s, 1
H), 3.81 (m, 1 H), 2.08 (s, 3 H, CH3), 2.04 (s, 3 H, CH3), 2.02 (s,
3 H, CH3), 2.08–2.02 (m, 1 H), 1.93–1.89 (m, 1 H), 1.43 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8, 169.6,
169.1, 155.2, 137.2, 128.4, 127.8, 127.7, 79.7, 75.3, 72.8, 71.0, 68.9,
67.6, 50.2, 28.2, 27.5, 21.0, 20.9, 20.8 ppm. HRMS (ESI): calcd. for
C24H33NO9 [M + H]+ 480.2233; found 480.2237.
(1R,2R,3R,4S,5R)-3-(Benzyloxy)-4-(tert-butoxycarbonylamino)cyclo-
hexane-1,2,5-triyl Triacetate (25): Acetylation of diol 24 (0.050 g,
0.126 mmol) following the general procedure C gave the triacetate
25 as a colourless liquid (0.053 g, 88.3% yield). Rf = 0.6 (hexane/
ethyl acetate, 7:3). [α]2D5 = +8.88 (c = 1.1, CH Cl ). IR (neat): ν =
˜
2
2
3368, 2930, 1745, 1244, 1043 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.35–7.26 (m, 5 H, ArH), 5.45 (m, 1 H, 1-H), 5.10 (br. s, 1 H,
5-H), 4.94 (dd, J = 9.5, 3.2 Hz, 1 H, 2-H), 4.69 (d, J = 11.2 Hz, 1
H, OCH2Ph), 4.64 (d, J = 11.2 Hz, 1 H, OCH2Ph), 4.49 (d, J =
8.8 Hz, 1 H, NHBoc), 3.76 (m, 2 H, 4-H, 3-H), 2.11 (s, 4 H, CH3,
6-H), 2.04 (s, 3 H, CH3), 1.99 (s, 3 H, CH3), 1.77 (m, 1 H, 6Ј-H),
(1R,2R,3R,4S,5S)-4-Aminocyclohexane-1,2,3,5-tetraol (22): A cata-
lytic amount of sodium methoxide was added to a solution of com-
1172
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1166–1175

Synthesis of Aminocyclitols and Trihydroxylated Indolizidinone
1.43 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = [α]2D5 = +2.5 (c = 2.1, CH Cl ). IR (neat): ν = 2923, 1697, 1062 cm–1.
˜
2
2
173.4, 172.7, 172.5, 158.1, 140.6, 131.1, 130.6, 130.5, 82.3, 79.4,
77.0, 76.9, 71.4, 70.2, 59.5, 34.4, 31.0, 23.8, 23.7, 23.5 ppm. HRMS
(ESI): calcd. for C24H33NO9 [M + Na]+ 502.2053, [M + H]+
480.2232; found 502.2050, 480.2232.
1H NMR (400 MHz, CDCl3, mixture of rotamers): δ = 7.40–7.15
(m, 25 H, ArH), 5.83–5.75 (m, 1 H, olefinic), 5.66–5.53 (m, 1 H,
olefinic), 5.21–4.87 (m, 7 H), 4.48 (t, J = 10.5 Hz, 1 H), 4.19 (d, J
= 11.9 Hz, 1 H), 4.14 (d, J = 7.5 Hz, 1 H), 3.91–3.83 (m, 2 H),
3.34–3.26 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3, mixture of
rotamers): δ = 156.3, 143.8, 143.7, 138.3, 138.1, 136.9, 136.6, 135.7,
135.5, 128.6, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 126.9, 119.0,
118.7, 116.0, 115.7, 86.8, 79.6, 79.5, 70.4, 70.1, 67.0, 66.8, 62.1,
61.8, 60.7, 49.1 ppm. HRMS (ESI): calcd. for C42H41NO4 [M +
Na]+ 646.2934; found 646.2932.
(1R,2R,3R,4S,5R)-4-(tert-Butoxycarbonylamino)cyclohexane-
1,2,3,5-tetrayl Tetraacetate (26): Compound 25 (0.050 g,
0.104 mmol) was dissolved in MeOH (2 mL). Pd(OH)2 (20 mol-%)
was added and the mixture was stirred under hydrogen for 12 h.
The catalyst was filtered off through Celite and concentrated in
vacuo to obtain the debenzylated product which was acetylated
using Ac2O, Et3N and a catalytic amount of DMAP to afford com-
pound 26 (0.036 g, 80% yield) as a colourless liquid. Rf = 0.4 (hex-
Benzyl
hydropyridine-1-carboxylate (30): Compound 30 (0.787 g, 91.5%
yield) was obtained as viscous liquid from 29 (0.900 g,
(2S,3S)-3-(Benzyloxy)-2-(trityloxymethyl)-1,2,3,6-tetra-
ane/ethyl acetate, 3:2). [α]2D5 = –12.6 (c = 0.5, CH Cl ). IR (neat): ν
a
˜
2
2
= 3374, 1746, 1230 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.47
(m, 1 H, 1-H), 5.19 (t, J = 10.3 Hz, 1 H, 3-H), 5.06 (td, J = 11.1,
4.6 Hz, 1 H, 5-H), 4.94 (dd, J = 10.3, 3.0 Hz, 1 H, 2-H), 4.54 (d, J
= 10.3 Hz, 1 H, NHBoc), 3.86 (m, 1 H, 4-H), 2.17 (m, 1 H, 6Ј-H),
2.11 (s, 3 H, CH3), 2.03 (s, 6 H, CH3), 1.97 (s, 3 H, CH3), 1.79 (m,
1 H, 6-H), 1.38 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.6, 170.5, 169.9, 169.7, 155.4, 79.7, 71.8, 69.8, 68.4,
67.0, 56.1, 31.9, 28.1, 20.9, 20.8, 20.6, 20.5 ppm. HRMS (ESI):
calcd. for C19H29NO10 [M + H]+ 432.1869; found 432.1868.
1.44 mmol) by following the general procedure A and using 5 mol-%
of first-generation Grubbs’ catalyst in CH2Cl2 in 12 h. Rf = 0.5
(hexane/ethyl acetate, 9:1). [α]2D5 = –20.9 (c = 2.68, CH2Cl2). IR
(neat): ν = 3059, 2924, 1702, 1080 cm–1. 1H NMR (400 MHz,
˜
CDCl3, 1:1 mixture of rotamers): δ = 7.45–7.07 (m, 25 H, ArH),
5.54 (br. s, 1.5 H), 5.42 (br. d, J = 10.4 Hz, 0.5 H), 5.28–5.11 (m,
2.5 H), 4.87 (m, 0.5 H), 4.50 (d, J = 11.4 Hz, 0.5 H, OCH2Ph),
4.41 (d, J = 11.4 Hz, 0.5 H, OCH2Ph), 4.33 (s, 1 H), 4.24–4.13 (m,
1.5 H), 4.02 (br. d, J = 18.5 Hz, 0.5 H), 3.50–3.41 (m, 1 H), 3.21–
3.09 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.1, 156.0,
143.9, 137.5, 137.4, 136.6, 136.4, 128.6, 128.5, 128.4, 128.3, 128.1,
128.0, 127.9, 127.8, 127.7, 126.8, 126.7, 126.3, 125.8, 124.6, 124.1,
86.6, 86.5, 72.0, 70.9, 67.4, 67.2, 58.0, 51.7, 50.8, 40.4 ppm. HRMS
(ESI): calcd. for C40H37NO4 [M + H]+ 618.2621; found 618.2626.
(1R,2R,3R,4S,5R)-4-Aminocyclohexane-1,2,3,5-tetraol (27): Com-
pound 27 (0.035 g, 85.4% yield) was obtained from 24 (0.100 g,
0.25 mmol) by following the same procedure as that used to obtain
22 from 20. Rf = 0.2 (methanol/ethyl acetate, 2:3). [α]2D5 = –10.0 (c
1
= 0.1, MeOH). H NMR (500 MHz, CDCl3): δ = 3.96 (s, 1 H, 1-
Benzyl
(2S,3R,4R,5R)-3-(Benzyloxy)-4,5-dihydroxy-2-(trityloxy-
H), 3.74 (td, J = 10.3, 4.6 Hz, 1 H, 5-H), 3.53 (t, J = 10.3 Hz, 1 H,
3-H), 3.40 (dd, J = 9.9, 3.0 Hz, 1 H, 2-H), 2.72 (t, J = 10.3 Hz, 1
H, 4-H), 2.03 (m, 1 H, 6-H), 1.50 (t, J = 10.3 Hz, 1 H, 6Ј-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 73.6, 69.9, 67.9, 65.6, 59.3,
36.2 ppm. HRMS (ESI): calcd. for C6H13NO4 [M + H]+ 164.0923;
found 164.0924.
methyl)piperidine-1-carboxylate (31): Compound 31 (0.733 g, 99%
yield) was obtained from 30 (0.700 g, 1.175 mmol) by following ge-
neral procedure B for dihydroxylation. Rf = 0.5 (hexane/ethyl acet-
ate, 1:1). [α]2D5 = –34.0 (c = 0.9, CH Cl ). IR (neat): ν = 3448, 2925,
˜
2
2
1746, 1230 cm–1. 1H NMR (400 MHz, CDCl3, 1:1 mixture of rota-
mers): δ = 7.42–7.07 (m, 25 H, ArH), 5.32 (d, J = 12.4 Hz, 0.5 H),
5.20–5.11 (m, 2 H), 4.82 (br. s, 0.5 H), 4.58 (br. d, J = 10.7 Hz, 0.5
H), 4.42–4.32 (m, 2 H), 4.21 (d, J = 14.1 Hz, 0.5 H), 3.92 (d, J =
21.0 Hz, 1 H), 3.85–3.76 (m, 1 H), 3.66–3.58 (m, 1 H), 3.42–3.28
(m, 2 H), 2.89 (t, J = 14.1 Hz, 1 H), 2.62 (br. d, J = 21.0 Hz, 1 H),
2.49 (br. d, J = 21.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3,
mixture of rotamers): δ = 156.5, 156.4, 143.7, 137.1, 136.7, 136.3,
128.5, 128.0, 127.8, 126.9, 86.9, 75.8, 75.7, 72.2, 72.0, 70.2, 67.8,
67.5, 58.1, 57.7, 53.1, 53.0, 52.4, 52.3, 43.4, 43.2 ppm. HRMS
(ESI): calcd. for C40H39NO6 [M + Na]+ 630.2855; found 630.2856.
Benzyl (2S,3S)-[3-(Benzyloxy)-1-(trityloxy)pent-4-en-2-yl]carbamate
(28): The same experimental procedure was followed for converting
13 (1.0 g, 2.10 mmol) to 28 (1.0 g, 81.5% yield over two steps) as
was followed for the conversion of 13 to 14 with CbzCl being used
instead of Boc2O. Rf = 0.5 (hexane/ethyl acetate, 9:1). [α]2D5 = +10.7
(c = 1.0, CH Cl ). IR (neat): ν = 3440, 2926, 1724, 1499, 1053 cm–1.
˜
2
2
1H NMR (400 MHz, CDCl3): δ = 7.40–7.10 (m, 25 H, ArH), 5.79
(ddd, J = 17.3, 10.2, 7.3 Hz, 1 H, olefinic), 5.31–5.25 (m, 2 H,
olefinic), 5.06 (s, 2 H, CO2CH2Ph), 5.03 (m, 1 H), 4.51 (d, J =
11.7 Hz, 1 H, OCH2Ph), 4.22 (d, J = 11.7 Hz, 1 H, OCH2Ph), 4.18
(m, 1 H), 3.99 (m, 1 H), 3.28 (dd, J = 8.8, 5.3 Hz, 1 H), 3.19 (t, J
= 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.1,
143.8, 138.0, 136.5, 135.3, 128.6, 128.4, 128.2, 127.9, 127.7, 127.6,
127.5, 126.9, 118.7, 86.7, 78.3, 70.6, 66.6, 62.6, 54.4 ppm. HRMS
(ESI): calcd. for C39H37NO4 [M + Na]+ 606.2621; found 606.2621.
(2S,3R,4R,5R)-3-(Benzyloxy)-2-(trityloxymethyl)piperidine-4,5-diyl
Diacetate (32): Diol 31 (0.050 g, 0.08 mmol) was acetylated follow-
ing the general procedure C. The acetylated compound was filtered
through a short pad of silica gel and dissolved in ethyl acetate
(2 mL) and treated with 10 mol-% Pd/C. The reaction mixture was
stirred under hydrogen for 4 h, filtered through Celite and purifica-
tion by column chromatography gave amine 32 (0.040 g, 87% yield)
Benzyl Allyl[(2S,3S)-3-(benzyloxy)-1-(trityloxy)pent-4-en-2-yl]carb-
amate (29): Anhydrous DMF (5 mL) was added to NaH (0.103 g,
2.565 mmol, 60% dispersion in mineral oil) at 0 °C. Compound 28
(1.0 g, 1.71 mmol) dissolved in dry DMF (5 mL) was then added
dropwise and the mixture was stirred for 15 min at the same tem-
perature. Allyl bromide (0.44 mL, 0.620 g, 5.13 mmol) was then
added and the reaction mixture was stirred for 2 h. After comple-
tion of the reaction, it was quenched with saturated NH4Cl solu-
tion and extracted with diethyl ether (3ϫ20 mL). The combined
extracts was washed with water and brine and dried with anhydrous
Na2SO4. Evaporation of the solvent and purification by column
chromatography afforded the pure compound 29 (0.982 g, 92%
yield) as a colourless liquid. Rf = 0.6 (hexane/ethyl acetate, 9:1).
as a colourless liquid. Rf = 0.4 (hexane/ethyl acetate, 1:1). [α]2D5
–8.5 (c = 1.2, CH Cl ). IR (neat): ν = 3448, 2926, 1743, 1243,
=
˜
2
2
1
1052 cm–1. H NMR (400 MHz, CDCl3): δ = 7.44–7.13 (m, 20 H,
ArH), 5.49 (br. s, 1 H, 4-H), 5.10 (ddd, J = 10.6, 5.4, 3.1 Hz, 1 H,
5-H), 4.65 (d, J = 11.2 Hz, 1 H, OCH2Ph), 4.42 (d, J = 11.2 Hz, 1
H, OCH2Ph), 3.73 (m, 1 H, 3-H), 3.33 (dd, J = 8.3, 5.7 Hz, 1 H,
7-H), 3.07–3.03 (m, 2 H, 7Ј-H, 2-H), 2.95 (dd, J = 13.6, 5.4 Hz, 1
H, 6-H), 2.89 (m, 1 H, 6Ј-H), 2.16 (s, 3 H, CH3), 2.00 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1, 170.0, 143.8,
137.5, 128.5, 128.2, 127.9, 127.7, 126.9, 86.7, 74.4, 72.4, 67.9, 67.3,
62.8, 54.1, 43.5, 21.0, 20.8 ppm. HRMS (ESI): calcd. for
C36H37NO6 [M + H]+ 580.2699; found 580.2699.
Eur. J. Org. Chem. 2011, 1166–1175
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1173

P. Gupta, A. P. J. Pal, Y. S. Reddy, Y. D. Vankar
FULL PAPER
Benzyl
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-2-(trityloxymethyl)-
tion mixture was heated at reflux for 10 h. The solvent was evapo-
rated and the residue extracted with ethyl acetate (3ϫ20 mL). The
combined organic extracts were washed with water and brine and
dried with Na2SO4. Evaporation of the solvent in vacuo and purifi-
piperidine-1-carboxylate (33): A solution of alcohol 31 (0.500 g,
0.79 mmol) in DMF (4 mL) was added to a stirred suspension of
NaH (0.079 g, 60% in mineral oil, 1.975 mmol) in DMF (2 mL) at
0 °C. After 30 min, benzyl chloride (2.607 mmol) was added drop- cation by column chromatography gave the lactam 36 (0.102 g,
wise at 0 °C and the reaction mixture was stirred for 8 h at room
temperature. Excess NaH was quenched by pouring the reaction
mixture into ice and then extracting it with diethyl ether (30 mL)
followed by washing with water and brine solution. The organic
layer was dried with Na2SO4 and concentrated in vacuo. Purifica-
tion by column chromatography afforded compound 33 (0.546 g,
85% yield) as a white solid. M.p. 100 °C. Rf = 0.6 (hexane/ethyl
70.8%) as a colourless syrup. Rf = 0.6 (hexane/ethyl acetate, 1:1).
[α]2D5 = –23.5 (c = 0.2, CH Cl ). IR (neat): ν = 3030, 2923, 1681,
˜
2
2
1
1101 cm–1. H NMR (400 MHz, CDCl3): δ = 7.36–7.28 (m, 13 H,
ArH), 7.13–7.11 (m, 2 H, ArH), 4.84 (d, J = 11.9 Hz, 1 H,
OCH2Ph), 4.62 (d, J = 11.9 Hz, 1 H, OCH2Ph), 4.57 (d, J =
11.9 Hz, 1 H, OCH2Ph), 4.45 (d, J = 11.9 Hz, 1 H, OCH2Ph), 4.41
(d, J = 11.9 Hz, 1 H, OCH2Ph), 4.32 (d, J = 11.9 Hz, 1 H,
OCH2Ph), 4.25 (dd, J = 11.2, 5.6 Hz, 1 H, 5Ј-H), 3.96 (ddd, J =
8.8, 4.1, 2.4 Hz, 1 H, 8a-H), 3.88 (t, J = 2.4 Hz, 1 H, 7-H), 3.74
(ddd, J = 11.2, 5.6, 2.4 Hz, 1 H, 6-H), 3.41 (dd, J = 4.1, 2.4 Hz, 1
H, 8-H), 3.07 (t, J = 11.2 Hz, 1 H, 5-H), 2.48–2.39 (m, 1 H, 2-H),
2.33–2.25 (m, 1 H, 2Ј-H), 1.96–1.91 (m, 1 H, 1Ј-H), 1.90–1.80 (m,
1 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.7, 138.5,
138.1, 137.9, 128.5, 128.2, 128.1, 127.9, 127.8, 127.7, 83.4, 79.5,
75.9, 71.8, 70.9, 70.6, 59.9, 39.8, 29.9, 22.3 ppm. HRMS (ESI):
calcd. for C29H31NO4 [M + H]+ 458.2332; found 458.2334.
acetate, 4:1). [α]2D5 = –41.3 (c = 1.2, CH Cl ). IR (neat): ν = 3030,
˜
2
2
2877, 1699, 1107 cm–1. 1H NMR (400 MHz, CDCl3, mixture of
rotamers): δ = 7.38–7.18 (m, 35 H, ArH), 5.20–5.13 (m, 2 H), 4.76–
4.55 (m, 8 H), 4.12 (m, 1 H), 3.65 (br. s, 2 H), 3.46–3.37 (m, 2
H), 2.77 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3, mixture of
rotamers): δ = 156.0, 143.7, 138.4, 138.2, 138.0, 136.5, 128.5, 128.3,
128.2, 128.1, 127.6, 127.5, 127.4, 127.3, 126.7, 86.9, 78.5, 75.5, 73.2,
72.4, 72.2, 70.5, 70.4, 67.3, 59.2, 58.8, 53.8, 53.2, 41.4, 40.5 ppm.
HRMS (ESI): calcd. for C54H51NO6 [M + Na]+ 832.3614; found
832.3614.
(6R,7R,8R,8aR)-6,7,8-Tris(benzyloxy)hexahydroindolizin-3(5H)-one
(37): Compound 37 (0.010 g, 14% yield) was obtained along with
compound 36 (0.037 g, 51%yield) when chromium trioxide based
oxidation (CrO3, Ac2O, pyridine system) was performed on 34, fol-
lowing the procedure used for the oxidation of compound 15, fol-
lowed by the Wittig reaction, hydrogenolysis and cyclisation. Rf =
Benzyl
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-2-(hydroxymethyl)-
piperidine-1-carboxylate (34): Trifluoroacetic acid (0.14 mL,
1.851 mmol) was added to a solution of compound 33 (0.500 g,
0.617 mmol) in DCM (5 mL) cooled to 0 °C. The reaction mixture
was stirred for 1 h at room temperature and then quenched by the
addition of a saturated NaHCO3 solution. It was extracted with
CH2Cl2 (3ϫ15 mL) and the combined organic extracts were
washed with water and brine and dried with anhydrous Na2SO4.
Evaporation of the solvent and purification by column chromatog-
raphy afforded pure compound 34 (0.301 g, 86% yield) as a colour-
less liquid. Rf = 0.3 (hexane/ethyl acetate, 4:1). [α]2D5 = –36.7 (c =
0.5 (hexane/ethyl acetate, 1:1). [α]2D5 = –17.6 (c = 0.3, CH2Cl2). IR
1
(neat): ν = 2925, 1669, 1122 cm–1. H NMR (500 MHz, CDCl ): δ
˜
3
= 7.40–7.24 (m, 15 H, ArH), 5.01 (d, J = 11.4 Hz, 1 H, OCH2Ph),
4.77 (d, J = 12.2 Hz, 1 H, OCH2Ph), 4.67 (d, J = 11.1 Hz, 1 H,
OCH2Ph), 4.59 (d, J = 11.4 Hz, 1 H, OCH2Ph), 4.55 (d, J =
12.2 Hz, 1 H, OCH2Ph), 4.52 (d, J = 12.2 Hz, 1 H, OCH2Ph), 4.39
(dd, J = 14.5, 2.7 Hz, 1 H, 5Ј-H), 3.83 (s, 1 H, 6-H), 3.69 (t, J =
9.2 Hz, 1 H, 8-H), 3.51 (dd, J = 9.2, 2.5 Hz, 1 H, 7-H), 3.39–3.35
(m, 1 H, 8a-H), 2.53 (d, J = 14.5 Hz, 1 H, 5-H), 2.43–2.34 (m, 2
H, 2-H, 2Ј-H), 2.32–2.20 (m, 1 H, 1-H), 1.81–1.75 (m, 1 H, 1Ј-
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 178.0, 142.0, 141.7,
141.0, 132.0, 131.9, 131.5, 131.3, 131.2, 131.1, 80.5, 77.0, 76.9, 76.2,
76.0, 75.0, 58.8, 42.0, 34.6, 22.0 ppm. HRMS (ESI): calcd. for
C29H31NO4 [M + H]+ 458.2332; found 458.2335.
1.3, CH Cl ). IR (neat): ν = 3449, 2920, 1691, 1108 cm–1. 1H NMR
˜
2
2
(400 MHz, CDCl3, mixture of rotamers): δ = 7.29–7.21 (m, 20 H,
ArH), 5.12 (br. s, 2 H), 4.80 (br. d, J = 11.2 Hz, 1 H), 4.70–4.50
(m, 8 H), 4.18 (dd, J = 10.0, 6.6 Hz, 1 H), 3.96 (br. s, 1 H), 3.72
(br. s, 2 H), 3.66 (dd, J = 10.0, 3.2 Hz, 1 H), 2.31 (br. s, 1 H,
OH) ppm. 13C NMR (100 MHz, CDCl3, mixture of rotamers): δ =
156.6, 156.4, 138.4, 138.2, 138.0, 136.6, 136.3, 128.5, 128.4, 128.3,
128.1, 127.8, 127.6, 78.8, 76.3, 74.1, 73.9, 72.3, 70.8, 67.7, 59.7,
55.1, 54.8, 41.4, 40.6 ppm. HRMS (ESI): calcd. for C35H37NO6 [M
+ Na]+ 590.2519, [M + H]+ 568.2699; found 590.2516, 568.2698.
(6R,7R,8R,8aS)-6,7,8-Trihydroxyhexahydroindolizin-3(5H)-one (38):
Compound 36 (0.050 g, 0.109 mmol) was dissolved in MeOH
(2 mL) and treated with 20% of Pd(OH)2/C (0.025 g). The mixture
was stirred under hydrogen for 12 h. The catalyst was filtered off
through Celite and concentrated in vacuo to obtain the debenzyl-
ated product 38 (0.018 g, 90% yield) as a colourless liquid. Rf =
0.3 (ethyl acetate/methanol, 4:1). [α]2D5 = +14.3 (c = 0.15, MeOH).
1H NMR (500 MHz, D2O): δ = 3.85–3.83 (m, 2 H, 7-H, 8a-H),
3.72–3.68 (m, 3 H, 5Ј-H, 6-H, 8-H), 2.76 (t, J = 13.5 Hz, 1 H, 5-
H), 2.28 (m, 2 H, 2-H, 2Ј-H), 1.99–1.91 (m, 1 H, 1-H), 1.83–1.76
(m, 1 H, 1Ј-H) ppm. 13C NMR (125 MHz, D2O): δ = 177.4, 70.4,
70.0, 63.3, 55.7, 39.7, 30.8, 17.2 ppm. HRMS (ESI): calcd. for
C8H13NO4 [M + H]+ 180.0923; found 180.0920.
Benzyl (2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-2-[(E/Z)-3-ethoxy-3-
oxoprop-1-enyl]piperidine-1-carboxylate (35b): Alcohol 34 (0.300 g,
0.528 mmol) was dissolved in CH2Cl2 (4 mL) at 0 °C and pyridi-
nium chlorochromate (0.341 g, 1.584 mmol) was added. The reac-
tion mixture was stirred for 4 h and then filtered through a sintered
funnel and passed through a short pad of silica gel. The aldehyde
was immediately subjected to further reaction. (Ethoxycarbonyl)
methylenetriphenylphosphorane (0.368 g, 1.056 mmol) was added
to a solution of the aldehyde in CH2Cl2 (5 mL) and the reaction
mixture was heated at reflux for 6 h. After concentration, the resi-
due was purified through a column of silica gel to give 35b (0.270 g,
80.3%) as a viscous liquid. HRMS (ESI): calcd. for C39H41NO7
[M + H]+ 636.2961; found 636.2964.
CCDC-772824 (for 20) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(6R,7R,8R,8aS)-6,7,8-Tris(benzyloxy)hexahydroindolizin-3(5H)-one
(36): Compound 35b (0.200 g, 0.315 mmol) was dissolved in etha-
nol and hydrogenated at atmospheric pressure in the presence of
10% Pd/C (0.030 g) for 12 h. The catalyst was filtered off through
Celite and concentrated in vacuo. The residue was dissolved in ab-
solute ethanol and sodium acetate (0.100 g) was added. The reac-
Supporting Information (see the footnote on the first page of this
article): X-ray data for compound 20 and spectra for all new com-
pounds 11–14 and 16–38.
1174
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1166–1175

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Acknowledgments
We thank the Council of Scientific and Industrial Research (CSIR),
New Delhi for financial support [grant number 01(2298)/09/EMR-
II]. We thank the University Grants Commission (UGC), New
Delhi for a fellowship to P. G. and A. P. J. P. and also the CSIR,
New Delhi for a fellowship to Y. S. R.
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