Carbohydrate templates for the synthesis of prototype renin inhibitors

Article abstract of DOI:10.1016/j.tetasy.2008.08.007

A concise synthesis of a prototype renin inhibitor and its 7-epimer has been accomplished starting from readily available d-glucose.

Full text of DOI:10.1016/j.tetasy.2008.08.007

Tetrahedron: Asymmetry 19 (2008) 2123–2129
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Carbohydrate templates for the synthesis of prototype renin inhibitors
*
Debendra K. Mohapatra , Gokarneswar Sahoo, Kuppusamy Sankar, Mukund K. Gurjar
Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2008
Accepted 6 August 2008
Available online 11 October 2008
A concise synthesis of a prototype renin inhibitor and its 7-epimer has been accomplished starting from
readily available D-glucose.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Herein, we report a simple synthesis of a prototype analogue 2
and its 7-epimer 19 that could afford divergent entries into the
synthesis of related analogues that differ in the para substituents.
Some of them have been very potent, for example, p-phenyl and
Renin inhibitors have proven efficacy in ameliorating hyperten-
sion and cardiovascular disorders. A variety of stable peptide-like
analogues that can inhibit renin have been developed; intravenous
administration of these results in a dramatic lowering of blood
pressure.1,2 More recently, a new class of non-peptidic renin inhib-
itors has been synthesized. Various analogues of non-peptidic re-
nin inhibitors 1 carrying different substituents at the aromatic
ring, at the amide nitrogen, and at 2,7-alkyls have shown unique
binding affinities to renin (Fig. 1)2,3 and have therefore, attracted
attention from synthetic process chemists wanting to prepare sig-
nificant quantities for bioavailability and related pharmacological
evaluation.
p-tert-butyl analogues of 2 have shown binding affinities (IC50
l
,
M at pH 7.2) of 3 and 2, respectively.4 Recently, Hanessian et al.
have also reported the synthesis of the 2,7-diisopropyl analogue
of 18.2
2. Results and discussion
Retrosynthetic analysis of the target analogue 2 envisages
D
-glucose as an appropriate starting point (Scheme 1). The inherent
stereochemical centers at C-2 and C-3 of -glucose correlate with
those at C-4 and C-5 of 2 via routine transformations. In addition,
the -glucofuranose ring system was expected to provide neces-
D
D
sary off-template stereo control,5 particularly at C-5 of the glucofu-
ranose ring. The aromatic moiety and the C-7 methyl could be
installed by Wittig olefination, followed by stereoselective hydro-
genation. The C-2 stereocenter could be obtained by methylation
of the enolate of the butyrolactone moiety. Finally, the target mol-
ecule 2 could be elaborated from the butyrolactone 3 by replacing
the hydroxyl group with an amine equivalent, followed by aminol-
ysis of the lactone ring with n-butylamine.
OH R5
NHR1
H2N
R3
R2
O
R4
1
R1 = alkyl, amidoalkyl, etc.
The known 5-ulose6 derivative 9 was made from compound 8
by a sequence of oxidative cleavage, methyl Grignard followed by
Swern oxidation. Ketone 9 upon treatment with p-methoxybenzyl-
idene-triphenylphosphorane7 at room temperature yielded an
inseparable mixture (4:1, from 1H NMR) of geometrical isomers
10, which on hydrogenation in the presence of 10% Pd/C at 50 psi
afforded compound 11 as a mixture of C-5 methyl epimers in a
7:3 ratio. Although the furanose ring normally gives good off-tem-
plate selectivity in the hydrogenation of the double bond at C-5
and C-6,8 we obtained rather low stereoselectivity (7:3) presum-
ably due to the absence of functionalities responsible for the stabil-
ity of the rotamers. To introduce the amino group with retention of
R2, R3 = methoxy and methoxy ethoxy, etc.
R4, R5 = methyl, isopropyl
OH Me
H
HCl.H2N
N
1
3
5
4
2
O
7
8
6
Me
2
MeO
Figure 1. General structure 12 and our target molecule 2.
* Corresponding author. Tel.: +91 20 25902586; fax: +91 20 25902629.
E-mail address: dk.mohapatra@ncl.res.in (D.K. Mohapatra).
stereochemistry at
a later stage, the C3 hydroxyl group of
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.007

2124
D. K. Mohapatra et al. / Tetrahedron: Asymmetry 19 (2008) 2123–2129
OH Me
O4
O5
C1
O1
H
C6
HCl.H2N
Me
N
C16
O
C4
C3
C15
C5
C7
C12
C13
C2
C8
MeO
2
C14
O3
C17
O2
C11
O
O
C10
C9
O
O
BnO
N3
Me
Me
Figure 2. ORTEP diagram of 7.
triphenylphosphorane yielded the (E)-a,b-unsaturated ester 6
Me
Me
MeO
MeO
exclusively. The olefinic protons appeared at 6.13 ppm (dd,
J = 15.7, 1.9 Hz) and at 7.15 ppm (dd, J = 15.66, 4.42 Hz). Reduction
of the double bond with Raney nickel and treatment with p-TSA
3
4
O
OH
OH
O
BnO
yielded the
membered lactone. Regioselective formation of the 5-membered
lactone ensures the protection of the -hydroxyl group, leaving
c-butyrolactone derivative 5 in preference to the 7-
OEt
BnO
O
c
OH
the other hydroxyl group unaffected without necessitating any fur-
ther protecting group manipulation. The unwanted hydroxyl group
in compound 5 was removed by using the Barton–McCombie rad-
ical deoxygenation protocol.10 This transformation was confirmed
by the disappearance of the signal for the methine proton at
3.52 ppm. For the introduction of the C-2 methyl stereocenter,
the enolate derived from compound 15 by treatment with LiHMDS
was reacted with MeI at ꢀ78 °C. Exclusive formation of compound
4 was established by NOE studies. As depicted in Figure 3, 3a-H
(1.80 ppm) shows strong NOE interactions with both H4
(4.40 ppm) and the methyl protons (1.22 ppm). Relevant NOE
interactions were also observed between 2b-H (2.72 ppm) and
3b-H (2.44 ppm) confirming the syn relationship of the methyl
group with H4. To introduce the amino functionality at C-5, the
Me
MeO
O
Me
MeO
5
6
MeO
Me
D-Glucose
O
HO
O
7
Scheme 1. Retrosynthetic scheme for 2.
compound 11 was oxidized to a mixture of 3-ulose derivatives,
which were separated by chromatography. Both the ketones 12a
(major isomer) and 12b (minor isomer) were separately reduced
using NaBH4 in MeOH to obtain stereochemically inverted C3–OH
derivatives 7 and 13 as crystalline solids (Scheme 2). Stereochem-
istry at the methyl center in compound 7 was deduced to be (S) by
single crystal X-ray studies9 (Fig. 2).
Our next concern was to design the synthesis of the right half of
the molecule, which includes a methyl stereogenic center and an
alkyl amide. For this, the hydroxyl group in compound 7 was first
protected as its benzyl ether. Cleavage of the isopropylidene group,
two-carbon Wittig homologation with (ethoxycarbonylmethylene)
H4
2a
CH3
H3a
O
BnO
1
H2b
H3b
O
CH3
MeO
MeO
Figure 3. NOE studies of 4.
MeO
b
O
O
Me
Me
O
O
O
O
O
a
c
d
O
O
O
O
BnO
HO
O
O
BnO
O
BnO
O
11
8
9
10
MeO
MeO
Me
Me
O
O
e
O
O
O
O
O
HO
O
12a
7
+
MeO
MeO
Me
Me
O
O
e
O
O
HO
O
O
12b
13
Scheme 2. Reagents and conditions: (a) (i) HIO4ꢁ2H2O, EtOAc, rt, 20 min; (ii) CH3MgI, THF, 0 ° to rt, 2 h, 87% (for two steps); (iii) (COCl)2, DMSO, CH2Cl2, Et3N, ꢀ78 °C, 1 h, 85%;
(b) p-OMeC6H4CH@PPh3, C6H6, rt, 4 h, 70%; (c) Pd/C, H2 (50 psi), rt, 2 h, 95%; (d) PDC, CH2Cl2, 4 Å molecular sieves, Ac2O (cat.), rt, 2 h, 87%, SiO2 chromatography; (e) NaBH4,
MeOH, rt, 2 h, 84%.

D. K. Mohapatra et al. / Tetrahedron: Asymmetry 19 (2008) 2123–2129
2125
O
OH
MeO
Me
O
BnO
OEt
BnO
O
b
c
O
O
OH
OH
RO
7, R = H
O
Me
MeO
Me
MeO
5
6
a
14, R = Bn
O
O
O
O
O
O
HO
Me
BnO
BnO
Me
d
e
f
Me
16
Me
MeO
MeO
Me
MeO
15
4
Scheme 3. Reagents and conditions: (a) NaH, BnBr, THF, 0 °C to rt, 3 h, 94%; (b) (i) 6 M HCl, THF/H2O (3:1), H2SO4 (cat.), reflux, 30 min, 92%; (ii) PPh3@CHCOOEt, toluene,
reflux, 2 h, 88%; (c) Raney Ni, MeOH, 2 h, then filtration, p-TSA, 2 h, 85%; (d) Im2CS, toluene, reflux, 6 h; then Bu3SnH, AIBN, degassing, reflux, 2 h, 80%; (e) LiHMDS, THF,
ꢀ78 °C, MeI, 2 h, 84%; (f) 10% Pd/C, H2 (50 psi), MeOH, 1 h, 92%.
O
O
C13
C17
O
O
O4
C14
C9
Me
C7
HO
N3
Me
C5
O2
C4
a
O1
C12
C11
C6
C8
C15
O3
C10
MeO
Me
16
Me
C1
C2
MeO
C3
3
OH Me
H
N
C16
N3
b
Figure 4. ORTEP diagram of 16.
O
Me
MeO
benzyl ether was cleaved by hydrogenolysis over 10% Pd/C
(Scheme 3). At this juncture the single crystal X-ray crystallo-
graphic study of alcohol 16 assures11 the newly generated stereo-
center beyond doubt (Fig. 4).
17
OH Me
H
N
R
c
Compound 16 was subsequently mesylated, and SN2 displace-
ment with LiN3 in DMF at 60 °C gave 3 (marked by appearance of
a characteristic peak at 2108 cmꢀ1 in IR spectroscopy for the azide
group), which on treatment with n-BuNH2 in ethanol12 yielded 17.
Finally hydrogenation of the azide using 10% Pd/C and in situ Boc-
protection afforded the compound 18, which was characterized by
NMR, IR, and elemental analysis. Treatment of compound 18 with
dry HCl gas in ether/CH2Cl2 culminated in the total synthesis of the
target molecule 2 (Scheme 4).
O
Me
MeO
18, R = NHBoc
2, R = NH2.HCl
d
Scheme 4. Reagents and conditions: (a) (i) MsCl, Et3N, CH2Cl2, rt, 1 h, (ii) LiN3, DMF,
60 °C, 4 h, 82% over two steps; (b) n-BuNH2, EtOH, rt, 2 h, 83%; (c) 10% Pd/C, H2
(1 atm), MeOH, (Boc)2O, 4 h, 95%; (d) dry HCl gas, CH2Cl2/Et2O, 15 min, 92%.
Similarly, the diastereomer 13 was taken through all the 11
steps as described above for 7, leading to the formation of another
diastereomer 19 (Scheme 5). The structure and the absolute config-
uration of 19 were confirmed by single crystal X-ray crystallogra-
phy (Fig. 5).13
OH Me
H
BocHN
N
11 steps
24.3%
13
O
7
3. Conclusions
Me
19
MeO
Scheme 5. Synthesis of the 7-epi compound 19.
In conclusion, we have successfully achieved the synthesis of a
prototype 2,7-dimethyl analogue (8.1% from 7 over 16 steps) of a
renin inhibitor and its 7-epi isomer in a practical, concise, and ster-
4. Experimental
4.1. General
eoselective manner starting from
D-glucose with high yielding
steps. The absolute stereochemistry of some key intermediates
and the 7-epi isomer of the target molecule have been established
by X-ray crystallography. The syntheses of different analogues are
currently in progress in our laboratory for biological investigations
and will be reported in due course.
Air and/or moisture sensitive reactions were carried out in
anhydrous solvents under an atmosphere of argon in an oven/

2126
D. K. Mohapatra et al. / Tetrahedron: Asymmetry 19 (2008) 2123–2129
200 MHz): d 0.82 (d, 0.9H, J = 6.8 Hz), 1.03 (d, 2.1H, J = 6.5 Hz),
C19
1.29–1.30 (2s, 3H), 1.47–1.49 (2s, 3H), 2.09 (m, 1H), 2.32 (dd,
0.7H, J = 8.4, 13.5 Hz), 2.50 (dd, 0.3H, J = 8.6, 13.5 Hz), 2.70 (dd,
0.7H, J = 5.4, 13.5 Hz), 2.97 (dd, 0.3H, J = 3.3, 13.5 Hz), 3.72 (m,
1H), 3.77 (s, 3H), 4.03 (d, 1H, J = 1.9 Hz), 4.45–4.48 (2d, 1H,
J = 3.9 Hz), 5.84 (d, 0.7H, J = 3.9 Hz), 5.92 (d, 0.3H, J = 3.9 Hz),
6.79–7.10 (2ABq, 4H, J = 8.8 Hz). Anal. Calcd for C17H24O5: C,
66.21; H, 7.84. Found: C, 66.05; H, 8.01.
C21
C18
C20
O5
O4
C17
N1
C16
C7
C8
C10
C13
C6
C4
C5
4.1.3. (30R,5R,60S)-5-((S)-1-(4-Methoxyphenyl)propan-2-yl)-2,2-
dimethylfuro[3,2-d][1,3]dioxol-6(30H,5H,60H)-one 12a and
(30R,5R,60S)-5-((R)-1-(4-methoxyphenyl)propan-2-yl)-2,2-
dimethylfuro[3,2-d][1,3]dioxol-6(30H,5H,60H)-one 12b
C11
C22
C24
C2
C3
C9
C14
O1
N2
C12
C1
O2
A suspension of 11 (3.0 g, 9.7 mmol), 4 Å molecular sieves
(7.5 g), PDC (4.4 g, 11.7 mmol), and Ac2O (0.5 mL) in dichlorometh-
ane (60 mL) was stirred for 2 h at room temperature. It was filtered
through a pad of Celite, concentrated, and purified on silica gel
using ethyl acetate/light petroleum (1:19) to afford 12a (1.8 g,
O3
C26
C23
C25
C15
Figure 5. ORTEP diagram of 19.
61%) as a light yellow liquid. ½a D25
ꢂ
¼ þ153:3 (c 1, CHCl3); 1H NMR
(CDCl3, 200 MHz): d 0.82 (d, 3H, J = 6.7 Hz), 1.40 (s, 3H), 1.42 (s,
3H), 2.14 (m, 1H), 2.52 (dd, 1H, J = 7.5, 13.5 Hz), 2.72 (dd, 1H,
J = 8.2, 13.5 Hz), 3.78 (s, 3H), 4.22 (m, 2H), 6.03 (d, 1H, J = 4.3 Hz),
6.80–7.08 (ABq, 4H, J = 8.7 Hz); 13C NMR (CDCl3, 50 MHz): d 14.1
(q), 27.2 (q), 27.3 (q), 37.6 (d), 38.6 (t), 55.1 (q), 76.7 (d), 80.4 (d),
102.6 (d), 113.7 (s), 113.8 (d), 130.1 (d), 131.5 (s), 158.1 (s),
211.4 (s). Anal. Calcd for C17H22O5: C, 66.65; H, 7.24. Found: C,
66.49; H, 7.37. Further elution gave 12b (0.78 g, 26%) as a light yel-
flame-dried glassware. All anhydrous solvents were distilled prior
to use: THF, benzene, toluene, and diethyl ether from Na and ben-
zophenone; CH2Cl2 and N-methyl pyrolidinone from CaH2; MeOH
and EtOH from Mg cake. Commercial reagents were used without
purification. Column chromatography was carried out by using
Spectrochem Silica Gel (60–120 mesh). Specific optical rotations
are given in 10ꢀ1 deg cm2 gꢀ1. Infrared spectra were recorded
low liquid.
½ ꢂ
a 2D5
¼ þ109:9 (c 1.8, CHCl3); 1H NMR (CDCl3,
[a]
D
in CHCl3/neat (as mentioned) and reported in wave number
(cmꢀ1). 1H and 13C NMR chemical shifts are reported in ppm down-
field from tetramethylsilane, and coupling constants (J) are re-
ported in Hertz (Hz). The following abbreviations are used to
designate signal multiplicity: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad.
200 MHz): d 1.02 (d, 3H, J = 6.8 Hz), 1.38 (s, 3H), 1.42 (s, 3H),
2.32 (m, 1H), 2.57 (m, 2H), 3.77 (s, 3H), 3.93 (dd, 1H, J = 0.9,
4.6 Hz), 4.18 (d, 1H, J = 3.4 Hz), 5.98 (d, 1H, J = 4.6 Hz), 6.78–7.03
(ABq, 4H, J = 8.5 Hz); 13C NMR (CDCl3, 50 MHz): d 16.7 (q), 27.2
(q), 27.3 (q), 36.9 (t), 37.7 (d), 55.1 (q), 76.4 (d), 81.5 (d), 102.5
(d), 113.3 (s), 113.7 (d), 130.5 (d), 131.1 (s), 158.2 (s), 211.1 (s).
Anal. Calcd for C17H22O5: C, 66.65; H, 7.24. Found: C, 66.84;
H, 7.12.
4.1.1. (30R,5R,6S,60R)-6-(Benzyloxy)-5-(1-(4-
methoxyphenyl)prop-1-en-2-yl)-2,2-dimethyl-
tetrahydrofuro[3,2-d][1,3]dioxole 10
4.1.4. (30R,5R,6R,60R)-5-((S)-1-(4-Methoxyphenyl)propan-2-yl)-
2,2-dimethyl-tetrahydrofuro[3,2-d][1,3]dioxol-6-ol 7
To a suspension of p-methoxybenzyltriphenylphosphonium
chloride (5.74 g, 13.7 mmol) in dry benzene (50 mL) was added
n-BuLi (6.4 mL, 1.6 M in hexane, 10.3 mmol) dropwise at 0 °C un-
der an argon atmosphere. After 4 h at room temperature, the
supernatant was then slowly cannulated to a solution of ketone 9
(2.0 g, 6.9 mmol) in dry benzene (10 mL) under an argon atmo-
sphere. The reaction mixture was stirred for 4 h at room tempera-
ture, quenched with saturated aqueous ammonium chloride
solution, and the organic layer was separated. The organic layer
was washed with water, brine, dried over Na2SO4, and concen-
trated to give the crude product, which upon purification by silica
gel column chromatography using ethyl acetate/light petroleum
(1:19) afforded 10 (1.9 g, 70%) as a yellow liquid. 1H NMR (CDCl3,
200 MHz): d 1.28 (s, 3H), 1.33 (s, 3H), 1.82 (d, 0.7H, J = 1.0 Hz),
2.08 (d, 2.3H, J = 1.4 Hz), 3.77 (s, 2.3H), 3.8 (s, 0.7H), 3.95 (d, 1H,
J = 3.4 Hz), 4.58 (m, 3H), 5.06 (d, 1H, J = 3.4 Hz), 5.97 (d, 0.78H,
J = 4.1 Hz), 6.03 (d, 0.22H, J = 4.1 Hz), 6.49 (s, 0.78H), 6.63 (s,
0.22H), 6.78–6.96 (ABq, 4H, J = 8.8 Hz), 7.30 (m, 5H). Anal. Calcd
for C24H28O5: C, 72.71; H, 7.12. Found: C, 72.51; H, 7.40.
A
solution of 12a (4.2 g, 13.7 mmol) and NaBH4 (0.62 g,
16.5 mmol) in MeOH (30 mL) at 0 °C was stirred for 2 h. The reac-
tion mixture was then quenched with water and methanol was re-
moved. The aqueous phase was extracted with ethyl acetate,
washed with water, brine, dried over Na2SO4, concentrated, and
purified on silica gel column chromatography by using ethyl ace-
tate/light petroleum (1:6) to give 7 (3.56 g, 84%) as a white solid.
Mp 94.5 °C;
½
a 2D5
ꢂ
¼ þ48:4 (c 1, CHCl3); 1H NMR (CDCl3,
200 MHz): d 0.91 (d, 3H, J = 6.8 Hz), 1.35 (s, 3H), 1.48 (s, 3H),
1.99 (m, 1H), 2.21 (d, 1H, J = 10.2 Hz), 2.43 (dd, 1H, J = 8.6,
13.4 Hz), 2.82 (dd, 1H, J = 6.6, 13.4 Hz), 3.57 (dd, 1H, J = 3.9,
8.9 Hz), 3.77 (s, 3H), 3.81 (m, 1H), 4.51 (t, 1H, J = 4.6 Hz), 5.77 (d,
1H, J = 3.9 Hz), 6.79–7.09 (ABq, 4H, J = 8.5 Hz); 13C NMR (CDCl3,
50 MHz): d 14.0 (q), 26.4 (q), 26.8 (q), 35.9 (d), 38.8 (t), 55.1 (q),
72.7 (d), 78.7 (d), 81.8 (d), 103.6 (d), 112.2 (s), 113.6 (d), 130.1
(d), 132.5 (s), 157.8 (s). Anal. Calcd for C17H24O5: C, 66.21; H,
7.84. Found: C, 65.97; H, 8.03.
4.1.5. (30R,5R,6R,60R)-5-((R)-1-(4-Methoxyphenyl)propan-2-yl)-
2,2-dimethyl-tetrahydrofuro[3,2-d][1,3]dioxol-6-ol 13
4.1.2. (30R,5R,6S,60R)-5-(1-(4-Methoxyphenyl)propan-2-yl)-2,2-
dimethyl-tetrahydrofuro[3,2-d][1,3]dioxol-6-ol 11
Following the above procedure, 12b (3.7 g, 12.1 mmol) was re-
duced with NaBH4 (0.54 g, 14.6 mmol) in MeOH (30 mL) to the cor-
responding alcohol 13 (3.21 g, 86%) as a white solid. Mp 117.1 °C;
A solution of 10 (5.6 g, 14.3 mmol), 10% Pd/C (100 mg), and
methanol (20 mL) was hydrogenated at 50 psi for 2 h. The reaction
mixture was filtered through a bed of Celite, and the clear filtrate
was evaporated. The residue was purified on silica gel column
chromatography by using ethyl acetate/light petroleum (1:6) to
obtain 11 (4.2 g, 95%) as a colorless liquid. 1H NMR (CDCl3,
½
a 2D5
ꢂ
¼ þ37:7 (c 1.1, CHCl3); 1H NMR (CDCl3, 200 MHz): d 0.92 (d,
3H, J = 6.9 Hz), 1.37 (s, 3H), 1.54 (s, 3H), 1.95 (m, 1H), 2.34 (d,
1H, J = 10.4 Hz), 2.43 (dd, 1H, J = 9.2, 13.6 Hz), 2.89 (dd, 1H,
J = 4.1, 13.6 Hz), 3.52 (m, 1H), 3.78 (s, 3H), 3.80 (m, 1H), 4.55 (t,

D. K. Mohapatra et al. / Tetrahedron: Asymmetry 19 (2008) 2123–2129
2127
1H, J = 4.8 Hz), 5.81 (d, 1H, J = 4.0 Hz), 6.80–7.10 (ABq, 4H,
J = 8.5 Hz); 13C NMR (CDCl3, 50 MHz): d 14.4 (q), 26.4 (q), 26.7
(q), 37.6 (d), 38.2 (t), 55.1 (q), 73.7 (d), 78.9 (d), 83.0 (d), 103.4
(d), 112.2 (s), 113.5 (d), 130.3 (d), 132.1 (s), 157.8 (s). Anal. Calcd
for C17H24O5: C, 66.21; H, 7.84. Found: C, 66.04; H, 7.97.
between ethyl acetate (70 mL) and water (30 mL). The organic
layer was separated, dried over Na2SO4, concentrated, and purified
on silica gel column chromatography using ethyl acetate/light
petroleum (1:6) to afford 5 (1.22 g, 85%) as a colorless liquid.
½
a 2D5
ꢂ
¼ ꢀ4:8 (c 3.6, MeOH); IR (neat, cmꢀ1) 3480, 3032, 2962,
2934, 2837, 1771, 1611, 1584, 1512, 1456, 1247, 1179, 1036,
4.1.6. (30R,5R,6R,60R)-6-(Benzyloxy)-5-((S)-1-(4-
752, 700, 682. 1H NMR (CDCl3, 200 MHz):
d 0.84 (d, 3H,
methoxyphenyl)propan-2-yl)-2,2-dimethyl-tetrahydrofuro-
[3,2-d][1,3]dioxole 14
J = 6.8 Hz), 1.84 (m, 1H), 2.12 (m, 2H), 2.28 (m, 1H), 2.47 (m, 3H),
2.63 (dd, 1H, J = 6.7, 13.7 Hz), 3.51 (m, 1H), 3.77 (s, 3H), 3.83 (m,
1H), 4.52–4.68 (ABq, 2H, J = 10.9 Hz), 4.93 (ddd, 1H, J = 2.4, 6.7,
8.2 Hz), 6.80–7.04 (ABq, 4H, J = 8.6 Hz), 7.30 (m, 5H); 13C NMR
(CDCl3, 50 MHz): d 12.5 (q), 21.2 (t), 28.4 (t), 35.8 (d), 39.3 (t),
54.9 (q), 72.7 (d), 74.5 (t), 79.4 (d), 81.5 (d), 113.7 (d), 127.5 (d),
127.7 (d), 127.9 (d), 128.1 (d), 128.2 (d), 129.7 (d), 132.2 (s),
137.6 (s), 157.8 (s), 177.6 (s). Anal. Calcd for C23H28O5: C, 71.85;
H, 7.34. Found: C, 71.83; H, 7.39.
Sodium hydride (0.74 g, 60% in mineral oil, 18.7 mmol) was
added to a stirred solution of 13 (4.8 g, 15.6 mmol) in THF
(40 mL) at 0 °C under nitrogen. After 2 h, BnBr (4.32 mL,
17.0 mmol) was introduced and stirring continued at room tem-
perature for an additional 1 h, at which time cold water was added
and layers separated. The organic layer was dried over Na2SO4,
concentrated, and the crude product was purified on silica gel by
using ethyl acetate/light petroleum (1:9) to afford 14 (5.88 g,
94%) as a colorless liquid. ½a D25
ꢂ
¼ þ72:4 (c 1, CHCl3); 1H NMR
4.1.9. (S)-5-((1R,3S)-1-(Benzyloxy)-4-(4-methoxyphenyl)-3-
methylbutyl)-dihydrofuran-2(3H)-one 15
(CDCl3, 200 MHz): d 0.74 (d, 3H, J = 6.8 Hz), 1.35 (s, 3H), 1.54 (s,
3H), 1.91 (m, 1H), 2.39 (dd, 1H, J = 9.0, 13.6 Hz), 2.76 (dd, 1H,
J = 6.4, 13.6 Hz), 3.57 (dd, 1H, J = 4.4, 9.1 Hz), 3.78 (s, 3H), 3.97
(dd, 1H, J = 3.5, 9.1 Hz), 4.51–4.78 (ABq, 2H, J = 12.2 Hz), 4.54 (t,
1H, J = 4.0 Hz), 5.68 (d, 1H, J = 4.0 Hz), 6.80–7.07 (ABq, 4H,
J = 8.4 Hz), 7.35 (m, 5H); 13C NMR (CDCl3, 50 MHz): d 13.4 (q),
26.7 (q), 35.7 (d), 39.0 (t), 55.0 (q), 71.6 (t), 77.2 (d), 78.2 (d),
79.5 (d), 103.6 (d), 112.5 (s), 113.5 (d), 127.9 (d), 128.3 (d), 130.0
(d), 132.5 (s), 137.5 (s), 157.7 (s). Anal. Calcd for C24H30O5: C,
72.34; H, 7.59. Found: C, 72.38; H, 7.77.
A solution of 5 (1.1 g, 2.9 mmol) and 1,10-thiocarbonyl diimidaz-
ole (0.62 g, 3.4 mmol) in toluene (20 mL) was heated at reflux for
6 h. After completion of the reaction, the reaction mixture was
brought to room temperature. TBTH (1 mL, 3.4 mmol) and catalytic
amount of AIBN (0.02 g) were added to the reaction mixture, de-
gassed with argon, and heated at reflux again for 2 h. The reaction
mixture was concentrated, and partitioned between ethyl acetate
(50 mL) and water (20 mL). The organic layer was separated,
washed with water, brine, dried over Na2SO4, concentrated and
purified on silica gel by using ethyl acetate/light petroleum (1:9)
to give 15 (0.85 g, 80%) as a colorless liquid. ½a D25
¼ þ7:5 (c 1.25,
ꢂ
4.1.7. (4S,5R,6R,7S,E)-Ethyl-5-(benzyloxy)-4,6-dihydroxy-8-
(4-methoxyphenyl)-7-methyloct-2-enoate 6
MeOH); IR (neat, cmꢀ1) 3064, 3018, 2956, 2929, 2871, 1774,
1612, 1583, 1512, 1456, 1248, 1276, 1179, 1036, 756, 698, 667;
1H NMR (CDCl3, 200 MHz): d 0.83 (d, 3H, J = 6.5 Hz), 1.09 (ddd,
1H, J = 3.8, 9.3, 13.5 Hz), 1.59 (ddd, 1H, J = 4.0, 9.3, 13.5 Hz), 1.89
(m, 1H), 2.17 (m, 2H), 2.38–2.59 (m, 4H), 3.77 (s, 3H), 3.84 (m,
1H), 4.45 (m, 1H), 4.50–4.62 (ABq, 2H, J = 11.24 Hz), 6.79–7.10
(ABq, 4H, J = 8.61 Hz), 7.3 (m, 5H); 13C NMR (CDCl3, 50 MHz): d
19.3 (q), 21.5 (t), 28.2 (t), 31.2 (d), 37.9 (t), 43.0 (t), 54.9 (q), 73.7
(t), 77.4 (d), 82.6 (d), 113.6 (d), 127.6 (d), 127.8 (d), 128.2 (d),
129.8 (d), 132.3 (s), 138.1 (s), 157.8 (s), 176.6 (s). Anal. Calcd for
C23H28O4: C, 74.97; H, 7.66. Found: C, 74.86; H, 7.68.
A stirred solution of 14 (2.0 g, 5.03 mmol) in THF/H2O (3:1,
20 mL), 6 M HCl (15 mL), and catalytic amount of H2SO4 (2 drops)
was heated at reflux for 30 min. Solid NaHCO3 was added to
quench the reaction. THF was removed, partitioned between ethyl
acetate (70 mL) and water (30 mL). The organic layer was sepa-
rated, washed with water, brine, dried over Na2SO4, and concen-
trated to give a colorless viscous liquid (1.66 g, 92%), which was
used as such for the next reaction. The crude lactol (1.66 g,
4.2 mmol) was dissolved in anhydrous toluene (30 mL) and to it
was added (ethoxycarbonylmethylene)-triphenylphosphorane
(2.77 g, 5.57 mmol) in toluene (25 mL). The reaction mixture was
refluxed for 2 h. The solvent was evaporated and purified on silica
gel by using ethyl acetate/light petroleum (1:4) to give 6 (1.75 g,
4.1.10. (3R,5S)-5-((1R,3S)-1-(Benzyloxy)-4-(4-methoxyphenyl)-
3-methylbutyl)-3-methyl-dihydrofuran-2(3H)-one 4
88%) as a viscous liquid. ½a D25
¼ þ14:9 (c 3.3, MeOH); IR (neat,
ꢂ
cmꢀ1) 3449, 3064, 3030, 2964, 2934, 1782, 1717, 1655, 1611,
1583, 1512, 1456, 1247, 1178, 1037, 755, 699; 1H NMR (CDCl3,
200 MHz): d 0.83 (d, 3H, J = 6.7 Hz), 1.28 (t, 3H, J = 7.1 Hz), 2.17
(m, 1H), 2.49 (m, 1H), 2.64 (m, 1H), 3.04 (br, 1H), 3.45 (dd, 1H,
J = 5.1, 8.2 Hz), 3.71 (m, 1H), 3.78 (s, 3H), 4.18 (q, 2H, J = 7.2 Hz),
4.59–4.60 (ABq, 2H, J = 11.1 Hz), 4.54 (merged, 1H), 6.13 (dd, 1H,
J = 1.9, 15.7 Hz), 6.78–7.04 (ABq, 4H, J = 8.6 Hz), 7.08 (dd, 1H,
J = 4.4, 15.7), 7.30 (m, 5H); 13C NMR (CDCl3, 50 MHz): d 12.4 (q),
14.0 (q), 35.9 (d), 39.4 (t), 54.9 (q), 60.2 (t), 72.6 (d), 73.5 (t), 74.7
(d), 81.9 (d), 113.6 (d), 120.8 (d), 127.7 (d), 127.9 (d), 128.1 (d),
128.2 (d), 129.8 (d), 132.6 (s), 137.6 (s), 147.5 (d), 157.7 (s),
166.5 (s). Anal. Calcd for C25H32O6: C, 70.07; H, 7.53. Found: C,
69.88; H, 7.67.
To a stirred solution of 15 (0.76 g, 2.06 mmol) in THF (20 mL) at
ꢀ78 °C, was added LiHMDS (2.06 mL, 1 M solution in THF,
2.06 mmol). After 1 h, MeI (0.13 mL, 2.06 mmol) was added and
the reaction mixture was stirred for an additional 1 h at ꢀ78 °C.
The reaction was quenched by saturated aqueous NH4Cl solution
(5 mL) and extracted with ethyl acetate. The organic layer was
dried over Na2SO4, concentrated, and the crude product was puri-
fied on silica gel using ethyl acetate/light petroleum (1:9) to afford
4 (0.66 g, 84%) as a colorless liquid. ½a D25
ꢂ
¼ þ13:3 (c 1, MeOH); 1H
NMR (CDCl3, 500 MHz): d 0.85 (d, 3H, J = 6.6 Hz), 1.09 (ddd, 1H,
J = 3.9, 9.4, 13.4 Hz), 1.23 (d, 3H, J = 7.4 Hz), 1.60 (ddd, 1H, J = 4.1,
9.0, 13.4 Hz), 1.80 (ddd, 1H, J = 8.6, 12.8, 17.2 Hz), 1.88 (m, 1H),
2.38 (dd, 1H, J = 7.9, 13.5 Hz), 2.43 (ddd, 1H, J = 3.8, 9.6, 12.9 Hz),
2.53 (dd, 1H, J = 6.4, 13.5 Hz), 2.72 (m, 1H), 3.77 (s, 3H), 3.81 (dt,
1H, J = 3.4, 6.6, 9.0 Hz), 4.40 (dt, 1H, J = 3.4, 6.4, 8.6 Hz), 4.47–4.58
(ABq, 2H, J = 11.2 Hz), 6.79–7.00 (ABq, 4H, J = 8.5 Hz), 7.3 (m, 5H).
13C NMR (CDCl3, 125 MHz): d 16.5 (q), 19.5 (q), 30.0 (t), 31.4 (d),
34.2 (d), 38.2 (t), 43.2 (t), 55.1 (q), 74.1 (t), 77.8 (d), 80.5 (d),
113.6 (d), 127.8 (d), 128.1 (d), 128.4 (d), 129.9 (d), 132.4 (s),
138.0 (s), 157.9 (s), 180.0 (s). Anal. Calcd for C24H30O4: C, 75.36;
H, 7.91. Found: C, 75.48; H, 8.02.
4.1.8. (S)-5-((1R,2R,3S)-1-(Benzyloxy)-2-hydroxy-4-(4-
methoxyphenyl)-3-methylbutyl)-dihydrofuran-2(3H)-one 5
Compound 6 (1.6 g, 3.7 mmol) in MeOH (15 mL) was hydroge-
nated at balloon pressure using Raney Ni. After 2 h, the reaction
mixture was filtered through a short bed of Celite and treated with
catalytic amount of p-TSA (0.05 g). After 2 h, the reaction mixture
was neutralized with solid NaHCO3, concentrated, and partitioned

2128
D. K. Mohapatra et al. / Tetrahedron: Asymmetry 19 (2008) 2123–2129
4.1.11. (3R,5S)-5-((1R,3S)-1-Hydroxy-4-(4-methoxy-phenyl)-3-
methylbutyl)-3-methyl-dihydrofuran-2(3H)-one 16
4.1.14. tert-Butyl (2S,4S,5S,7R)-8-(butylamino)-5-hydroxy-1-(4-
methoxyphenyl)-2,7-dimethyl-8-oxooctan-4-ylcarbamate 18
Compound 17 (0.065 g, 0.17 mmol) in methanol (5 mL) was
hydrogenated by catalytic amount of 10% Pd/C (0.01 g) at 1 atm
for 3 h. After completion of the reaction, Boc2O (0.05 mL, 0.2 mmol)
was added to the reaction mixture and stirred at room temperature
for 1 h. The reaction mixture was passed through a short Celite
plug, concentrated, and purified on silica gel column chromatogra-
Compound 4 (0.6 g, 1.57 mmol) in MeOH (10 mL) was hydroge-
nated by a catalytic amount of 10% Pd/C (0.03 g) at 50 psi. After 1 h,
the reaction mixture was filtered through a small bed of Celite,
concentrated, and purified on silica gel column chromatography
using ethyl acetate/light petroleum (1:4) to obtain 16 (0.42 g,
92%) as a white solid which on recrystallization (ethyl acetate/
petroleum ether) gave a crystalline solid. Mp 80.5°; ½a D25
ꢂ
¼ þ38:0
phy (1:9) to give 18 (0.071 g, 95%) as a viscous liquid. ½a D25
¼ ꢀ17:6
ꢂ
(c 1.1, CHCl3); 1H NMR (CDCl3, 200 MHz):
d
0.88 (d, 3H,
(c 1, CHCl3); IR (neat, cmꢀ1) 3438, 3346, 3017, 2964, 2933, 1696,
1646, 1512, 1456, 1367, 1247, 1216, 1176, 1039, 756, 668; 1H
NMR (CDCl3, 500 MHz): d 0.78 (2d, 3H, J = 6.8 Hz), 0.86 (2t, 3H,
J = 7.3 Hz), 1.10 (d, 3H, J = 6.9 Hz), 1.2 (m, 2H), 1.27 (m, 2H), 1.39
(s, 9H), 1.40 (m, 4H), 1.59 (m, 2H), 1.68 (br, 1H), 2.10 (dd, 0.8H,
J = 9.3, 13.4 Hz), 2.24 (m, 0.2H), 2.33 (m, 0.2H), 2.48 (m, 0.8H),
2.63 (m, 0.2H), 2.72 (dd, 0.8H, J = 4.5, 13.4 Hz), 2.92 (m, 0.2H),
3.09 (m, 0.8H), 3.19 (m, 1H), 3.55 (m, 0.8H), 3.61 (m, 0.8H), 3.70
(2s, 3H), 3.78 (m, 0.2H), 3.88 (m, 0.2H), 4.43 (d, 0.2H, J = 9.6 Hz),
4.78 (d, 0.8H, J = 9.6 Hz), 6.03 (br s, 1H), 6.72–6.98 (ABq, 4H,
J = 8.1 Hz); 13C NMR (CDCl3, 125 MHz): Major rotamer: d 13.7 (q),
17.1 (q), 19.8 (q), 20.0 (t), 28.4 (q), 31.6 (t), 32.1 (d), 37.6 (d),
38.5 (t), 39.2 (t), 40.0 (t), 41.7 (t), 52.0 (d), 55.1 (q), 70.2 (d), 79.2
(s), 113.4 (d), 130.1 (d), 133.2 (s), 156.5 (s), 157.6 (s), 176.9 (s);
Minor rotamer: d 13.4 (q), 16.6 (q), 19.7 (q), 19.9 (t), 28.3 (q),
32.4 (t), 34.3 (d), 37.0 (d), 38.7 (t), 39.4 (t), 40.1 (t), 41.5 (t), 51.3
(d), 58.9 (q), 70.5 (d), 80.0 (s), 113.5 (d), 130.0 (d), 132.7 (s),
156.0 (s), 157.7 (s), 174.6 (s). Anal. Calcd for C26H44N2O5: C,
67.21; H, 9.54; N, 6.03. Found: C, 67.14; H, 9.59; N, 6.10.
J = 6.6 Hz), 1.07 (ddd, 1H, J = 2.7, 10.2, 13.2 Hz), 1.23 (d, 3H,
J = 7.3 Hz), 1.48 (ddd, 1H, J = 3.7, 10.6, 13.2 Hz), 1.78 (ddd, 1H,
J = 8.2, 12.8, 16.2 Hz), 2.00 (m, 1H), 2.34–2.62 (m, 3H), 2.65 (m,
1H), 3.04 (br s, 1H), 3.77 (s, 3H), 4.00 (d, 1H, J = 10.5 Hz), 4.31 (m,
1H), 6.79–7.04 (ABq, 4H, J = 8.7 Hz); 13C NMR (CDCl3, 50 MHz): d
16.3 (q), 18.8 (q), 29.6 (t), 31.0 (d), 34.4 (d), 38.9 (t), 43.3 (t), 55.0
(q), 69.4 (d), 81.2(d), 113.6 (d), 129.9 (d), 132.6 (s), 157.8 (s),
180.6 (s). Anal. Calcd for C17H24O4: C, 69.84; H, 8.27. Found: C,
69.75; H, 8.15.
4.1.12. (3R,5S)-5-((1S,3S)-1-Azido-4-(4-methoxyphenyl)-3-
methylbutyl)-3-methyl-dihydrofuran-2(3H)-one 3
A solution of 16 (0.4 g, 1.4 mmol), Et3N (0.23 mL, 1.6 mmol), and
MsCl (0.13 mL, 1.6 mmol) in CH2Cl2 (10 mL) was stirred under
nitrogen at 0 °C. After 1 h, the reaction mixture was partitioned be-
tween CH2Cl2 and water. The organic layer was separated, washed
with water, brine, dried over Na2SO4, and concentrated to afford the
mesylated product as a brownish liquid. The crude compound was
taken with LiN3 (0.27 g, 5.6 mmol) in DMF (5 mL), and the reaction
mixture was heated at 60 °C for 4 h. After completion of the reac-
tion, the reaction mixture was partitioned between diethyl ether
and water. The organic layer was separated, washed with water,
brine, dried over Na2SO4, concentrated, and purified on silica gel
using ethyl acetate/light petroleum (1:9) to give 3 (0.36 g, 82%) as
4.1.15. Hydrochloride salt of (2R,4S,5S,7S)-5-amino-N-butyl-4-
hydroxy-8-(4-methoxyphenyl)-2,7-dimethyloctanamide 2
To a stirred solution of 18 (0.028 g, 0.07 mmol) in CH2Cl2/Et2O
(2:2 mL) at rt, dry HCl gas was passed for 15 min. The suspension
was filtered and the residue was washed with CH2Cl2. The com-
pound was dried to get compound 2 as a white solid. (0.022 g,
a light yellow liquid. ½a D25
ꢂ
¼ þ53:6 (c 1, CHCl3); IR (CHCl3, cmꢀ1
)
92%) ½a 2D5
ꢂ
¼ þ6:2 (c 0.5, H2O). 1H NMR (CDCl3, 400 MHz): d 0.89
2932, 2851, 2108, 1778, 1612, 1583, 1513, 1457, 1380, 1248,
1178, 1034, 920, 807, 754; 1H NMR (CDCl3, 200 MHz): d 0.92 (d,
3H, J = 6.6 Hz), 1.27 (d, 3H, J = 7.4 Hz), 1.61 (m, 2H), 1.94 (m, 2H),
2.29 (m, 2H), 2.75 (m, 2H), 3.33 (m, 1H), 3.78 (s, 3H), 4.42 (p, 1H,
J = 4.3, 4.0, 8.3 Hz), 6.80–7.04 (ABq, 4H, J = 8.6 Hz); 13C NMR (CDCl3,
50 MHz): d 16.4 (q), 20.0 (q), 32.1 (d), 32.8 (t), 33.7 (d), 37.2 (t), 42.2
(t), 55.1 (q), 63.0 (d), 78.5 (d), 113.8 (d), 130.0 (d), 132.0 (s), 158.1
(s), 179.0 (s). Anal. Calcd for C17H23N3O3: C, 64.33; H, 7.30; N,
13.24. Found: C, 64.52; H, 7.57; N, 13.20.
(t, 3H, J = 7.4 Hz), 0.93 (d, 3H, J = 6.5 Hz), 1.18 (d, 3H, J = 7.0 Hz),
1.33 (m, 2H), 1.48 (m, 4H), 1.79 (m, 2H), 2.52 (dd, 1H, J = 7.5,
13.6 Hz), 2.64 (m, 2H), 3.21 (m, 3H), 3.52 (ddd, 1H, J = 2.3, 4.5,
10.54 Hz), 3.86 (s, 3H), 7.00–7.25 (ABq, 4H, J = 8.8 Hz). 13C NMR
(CDCl3, 100 MHz): d 14.7 (q), 19.7 (q), 20.3 (q), 21.1 (t), 32.3 (t),
32.9 (d), 37.9 (t), 39.2 (t), 39.3 (d), 40.6 (t), 43.2 (t), 56.1 (d), 57.1
(q), 69.4 (d), 115.7 (d), 132.3 (d), 134.9 (s), 158.9 (s), 179.9 (s). Anal.
Calcd for C21H37N2O3Cl (400.99): Calcd. C, 62.90; H, 9.30, N, 6.99,
Cl, 8.84. Found C, 62.76; H, 9.59, N, 7.16, Cl, 8.69.
4.1.13. (2R,4S,5S,7S)-5-Azido-N-butyl-4-hydroxy-8-(4-
methoxyphenyl)-2,7-dimethyloctanamide 17
4.1.16. tert-Butyl (2R,4S,5S,7R)-8-(butylamino)-5-hydroxy-1-(4-
methoxyphenyl)-2,7-dimethyl-8-oxooctan-4-ylcarbamate 19
Following the same sequence of reaction procedures as of 7, 7-
epi isomer 19 was obtained from 13 in 11 steps (24.3% over all
Compound 3 (0.15 g, 0.47 mmol) was treated with a 33% w/v
solution of n-BuNH2 in dry ethanol (1.7 g. n-BuNH2 in 5 mL dry
ethanol) under nitrogen. After 2 h, the reaction mixture was con-
centrated, partitioned between ethyl acetate and water. The organ-
ic layer was washed with water, brine, dried over Na2SO4,
concentrated, and purified on silica gel column by using ethyl ace-
tate/light petroleum (1:6) to afford 17 (0.153 g, 83%) as a colorless
yield). ½a 2D5
ꢂ
¼ ꢀ17:9 (c 0.3, CHCl3); 1H NMR (CDCl3, 500 MHz): d
0.90 (d, 3H, J = 6.4 Hz), 0.91 (t, 3H, J = 7.3 Hz), 1.17 (d, 3H,
J = 6.9 Hz), 1.26 (m, 2H), 1.33 (m, 2H), 1.43 (s, 9H), 1.48 (m, 2H),
1.59 (m, 1H), 1.66 (m, 1H), 1.77 (m, 1H), 2.39 (dd, 1H, J = 7.7,
13.3 Hz), 2.53 (dd, 1H, J = 6.3, 13.3 Hz), 3.17 (m, 1H), 3.26 (m,
1H), 3.57 (m, 2H), 3.79 (s, 3H), 4.64 (d, 1H, J = 9.5 Hz), 6.01 (b,
1H), 6.81–7.05 (ABq, 4H, J = 8.4 Hz); 13C NMR (CDCl3, 125 MHz):
d 13.7 (q), 17.2 (q), 19.1 (q), 20.0 (t), 28.3 (q), 31.6 (t), 31.8 (d),
37.6 (d), 38.5 (t), 39.2 (t), 39.4 (t), 43.0 (t), 52.4 (d), 55.2 (q), 71.3
(d), 79.2 (s), 113.6 (d), 130.2 (d), 133.0 (s), 156.7 (s), 157.7 (s),
176.9 (s). Anal. Calcd for C26H44N2O5: C, 67.21; H, 9.54; N, 6.03.
Found: C, 67.15; H, 9.65; N, 6.12.
liquid. ½a 2D5
ꢂ
¼ ꢀ10:5 (c 1, CHCl3); IR (neat, cmꢀ1) 3316, 2931, 2873,
2105, 1634, 1549, 1512, 1463, 1376, 1247, 1178, 1037, 850, 805,
754; 1H NMR (CDCl3, 200 MHz): d 0.89 (d, 3H, J = 6.6 Hz), 0.92 (t,
3H, J = 7.0 Hz), 1.19 (d, 3H, J = 6.9 Hz), 1.33 (m, 3H), 1.45 (m, 2H),
1.62 (m, 4H), 1.88 (m, 1H), 2.28 (dd, 1H, J = 8.6, 13.4 Hz), 2.57 (m,
1H), 2.70 (dd, 1H, J = 5.3, 13.4 Hz), 3.20 (m, 3H), 3.55 (m, 1H),
3.79 (s, 3H), 5.91 (br s, 1H), 6.83–7.07 (ABq, 4H, J = 8.6 Hz); 13C
NMR (CDCl3, 50 MHz): d 13.7 (q), 18.1 (q), 20.0 (t), 20.1 (q), 31.6
(t), 32.2 (d), 37.7 (d), 37.8 (t), 38.3 (t), 39.2 (t), 41.9 (t), 55.2 (q),
65.4 (d), 71.1 (d), 113.7 (d), 130.0 (d), 132.6 (s), 157.8 (s), 176.4
(s). Anal. Calcd for C21H34N4O3: C, 64.59; H, 8.78; N, 14.35. Found:
C, 64.46; H, 8.95; N, 14.19.
Acknowledgment
G.S. and K.S. thank CSIR, New Delhi for the financial assistance
in the form of research fellowships.

D. K. Mohapatra et al. / Tetrahedron: Asymmetry 19 (2008) 2123–2129
2129
10. (a) Schmidt, O. T. In Methods in Carbohydrate Chemistry, Vol. 2; Whistler, R. L.,
Wolfrom, M. L., Eds.; Academic Press: New York, 1963; pp 318–325; (b) Barton,
D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–1585.
11. Crystal data for 16: C17H24O4, M = 292.36, crystal dimensions:
0.67 ꢃ 0.60 ꢃ 0.10 mm, crystal system: orthorhombic, space group: P212121,
a = 5.5146(12), b = 9.2177(19), c = 33.537(7) Å, V = 1704.8(6) Å3, Z = 4,
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10085–10089; (e) Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fassler, A.
Tetrahedron Lett. 2000, 41, 10091–10094.
4. (a) Goschke, R.; Cohen, N. C.; Wood, J. M.; Mibuam, J. K. Bioorg. Med. Chem. Lett.
1997, 7, 2735–2740; (b) Goschke, R.; Maibuam, J. K.; Schilling, W.; Stutz, S.;
Rigollier, P.; Yamaguchi, Y.; Cohen, N. C.; Herold, P. U.S. Patent 5,654,445, Aug 5,
1987.
Dc = 1.139 g cmꢀ3
,
l
= 0.080 mmꢀ1
,
F(000) = 632, 2hmax = 51.00°, max. and
min. transmission 0.9917 and 0.9481, 8848 reflections collected, 3165 unique
1931 observed [I > 2 (I)] reflection, 194 refined parameters, S = 1.044, R value
r
0.0502, wR2 = 0.1294 (all data R = 0.0887, wR2 = 0.1453), max. and min.
residual electron densities +0.127 and ꢀ0.119 e Åꢀ3
.
Additional
crystallographic details CCDC 269454 (atomic co-ordinates and equivalent
isotropic displacement coefficients) have been deposited at the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
12. Lawrence, A. J.; Pavey, J. B. J.; Chan, M-Y.; Fairhurst, R. A.; Collingwood, S. P.;
Fisher, J.; Cosstick, R.; O’Neil, I. A. J. Chem. Soc., Perkin Trans. 1 1997, 2761–2767.
13. Crystal data for 19: C26H44N2O5, M = 464.63, crystal dimensions:
0.87 ꢃ 0.09 ꢃ 0.08 mm, crystal system: orthorhombic, space group: P212121,
5. Mohapatra, D. K.; Chaudhury, S. R.; Sahoo, G.; Gurjar, M. K. Tetrahedron:
Asymmetry 2006, 17, 2609–2616.
a = 9.474(4),
Dc = 1.076 g cmꢀ3
min. transmission 0.9943 and 0.9389, 12,036 reflections collected, 5031
unique, 2029 observed [I > 2 (I)] reflection, 307 refined parameters,
b = 10.893(5),
,
c = 27.787(12) Å,
V = 2867(2)
Å3,
Z = 4,
l
= 0.074 mmꢀ1, F(000) = 1016, 2hmax = 50.00°, max. and
6. Liang, D.; Schuda, A. D.; Fraser-Reid, B. Carbohydr. Res. 1987, 164, 229–240.
7. Ketcham, R.; Jambotkar, D.; Martinelli, L. J. Org. Chem. 1962, 27, 4666–4667.
8. Geroges, M.; Tam, T.; Fraser-Reid, B. J. Org. Chem. 1985, 50, 4753–5747.
9. Crystal data for 7: C17H24O5, M = 308.36, crystal dimensions:
0.82 ꢃ 0.26 ꢃ 0.08 mm, crystal system: monoclinic, space group: P21,
r
S = 0.957, R value 0.0670, wR2 = 0.1246 (all data R = 0.1949, wR2 = 0.1575),
maximum and minimum residual electron densities +0.190 and ꢀ0.126 e Åꢀ3
.
Additional crystallographic details CCDC 269452 (atomic co-ordinates and
equivalent isotropic displacement coefficients) have been deposited at the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK. All the data were corrected for Lorentzian, polarization and absorption
a = 10.2759(19),
V = 831.0(3) Å3, Z = 2, Dc = 1.232 g cmꢀ3
2hmax = 51.00°, max. and min. transmission 0.9931 and 0.9299, 4337
reflections collected, 2635 unique 2444 observed [I > 2 (I)] reflection, 295
b = 5.7656(11),
c = 14.152(3)
Å,
b = 97.622
(3)°,
,
l
= 0.090 mmꢀ1
,
F(000) = 332,
r
effects using Bruker’s SAINT and SADABS programs. SHELX-97 (G. M. Sheldrick, SHELX
-
refined parameters, S = 1.050, R value 0.0380, wR2 = 0.0926 (all data R = 0.0411,
wR2 = 0.0944), max. and min. residual electron densities +0.172 and
ꢀ0.123 e Åꢀ3. Additional crystallographic details CCDC 269453 (atomic co-
ordinates and equivalent isotropic displacement coefficients) have been
deposited at the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK.
97 program for crystal structure solution and refinement, University of
Gottingen, Germany, 1997) was used for structure solution and full matrix
least squares refinement on F2. Hydrogen atoms were included in the
refinement as per the riding model.