An asymmetric aminohydroxylation route to cis-2,6-disubstituted piperidine-3-ol: application to the synthesis of (-)-deoxocassine

Article abstract of DOI:10.1016/j.tet.2006.08.014

A highly efficient, flexible, and convergent route to cis-2,3,6-trisubstituted piperidines has been developed employing the Sharpless asymmetric aminohydroxylation and stereoselective reductive amination by catalytic hydrogenation as the key steps. Its usage is illustrated by the short synthesis of the piperidine-3-ol alkaloid, (-)-deoxocassine.

Full text of DOI:10.1016/j.tet.2006.08.014

Tetrahedron 62 (2006) 9942–9948
An asymmetric aminohydroxylation route to cis-2,6-disubstituted
piperidine-3-ol: application to the synthesis of (L)-deoxocassine
*
Subba Rao V. Kandula and Pradeep Kumar
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, Maharashtra, India
Received 13 April 2006; revised 18 July 2006; accepted 3 August 2006
Available online 22 August 2006
Abstract—A highly efficient, flexible, and convergent route to cis-2,3,6-trisubstituted piperidines has been developed employing the
Sharpless asymmetric aminohydroxylation and stereoselective reductive amination by catalytic hydrogenation as the key steps. Its usage
is illustrated by the short synthesis of the piperidine-3-ol alkaloid, (ꢀ)-deoxocassine.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In connection with our ongoing program aimed at devel-
oping enantioselective syntheses of naturally occurring
lactones8 and amino alcohols,9 we became interested in
developing a simpleand feasible route to cis-2,6-disubstituted
piperidine-3-ols. Here, we present an enantioselective syn-
thesis of (ꢀ)-deoxocassine as a representative example for
a general synthetic strategy to all 2,6-dialkyl 3-piperidinols.
Functionalized piperidines are among the most ubiquitous
heterocyclic building blocks in natural products and syn-
thetic compounds with important activities.1 Hydroxylated
piperidine alkaloids are frequently found in living systems
and display a wide range of biological activities due to their
ability to mimic carbohydrates in a variety of enzymatic
processes.2 Selective inhibition of a number of enzymes
involved in the binding and processing of glycoproteins
has rendered piperidine alkaloids as important tools in the
study of biochemical pathways.3 2,6-Disubstituted 3-piperi-
dinols are abundantly found in nature and have received
much attention from the synthetic community.4 Typical
representative of this class of compounds includes deoxocas-
sine (1), prosafrinine (2), cassine (3), spectaline (4), azimic
acid (5), and carpamic acid (6) etc. (Fig. 1). Consequently,
much effort has been directed to the syntheses of these
alkaloids including cassine5 and deoxocassine.6 Besides
the interesting structural features, these compounds are
also of pharmaceutical interest as they exhibit a wide range
of biological activities.7
2. Results and discussion
Our approach for a general synthetic strategy to cis-2,6-
disubstituted 3-piperidinols was envisioned via the synthetic
route as shown in Scheme 1. Compound 7 was visualized
as an immediate precursor for the basic alkaloid skeleton,
which in turn would be obtained by the coupling of frag-
ments 8 and 12. Lactone 8 could be derived from amino-
hydroxy ester 9, which in turn would be prepared from the
Sharpless asymmetric aminohydroxylation of tert-butyl
crotonoate 11. The sulfone fragment 12 could be easily
derived from alcohol 13.
In order to demonstrate the application of this general strat-
egy for the cis-2,6-disubstituted 3-piperidinols, we first
attempted at the total synthesis of (ꢀ)-deoxocassine (1).
The synthesis of the target compound 1 started from com-
mercially available tert-butyl crotonoate 11. As shown in
Scheme 2, compound 11 was subjected to Sharpless asym-
metric aminohydroxylation10 using benzyl carbamate as a
nitrogen source, potassium osmate as an oxidant, and
(DHQD)2PHAL as a chiral ligand in n-propanol/water
(1:1) to give the amino alcohol 10 in high regioselectivity
as well as in excellent enantioselectivity. The ratio of the
HO
R = -(CH2)10CH2CH3 deoxocassine (1)
R = -(CH2)9COCH3 Prosafrinine (2)
R = -(CH2)10COCH3 Cassine (3)
N
H
R
R
HO
R = -(CH2)12COCH3 Spectaline (4)
R = -(CH2)5COOH Azimic acid (5)
R = -(CH2)7COOH Carpamic acid (6)
N
H
Figure 1.
1
regioisomer was about 9:1 based on H NMR spectrum of
the crude product, and the initial ee of 90% could be
easily raised to >99% by a single recrystallization from
* Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629;
e-mail: pk.tripathi@ncl.res.in
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.014

S. R. V. Kandula, P. Kumar / Tetrahedron 62 (2006) 9942–9948
9943
NHCbz
NHCbz
OH
O
HO
RCH2SO2Ph
R
+
N
H
R
12
O
SO2Ph
O
7
8
NHCbz
OH
O
RCH2OH
13
OEt
9
NHCbz
COOBu
-t
OH
10
COOBu
-t
11
Scheme 1. Retrosynthetic analysis for a general synthetic strategy to cis-2,6-disubstituted piperidin-3-ol.
NHCbz
NHCbz
b
COOBu
-t
a
COOBu-t
COOBu
-t
OTBS
14
OH
10
11
NHCbz
O
NHCbz
O
d
c
OEt
OTBS
SO2Ph
OTBS
15
19
e
NHCbz
NHCbz
O
f
OEt
O
OH
O
8
9
Scheme 2. Reagents and conditions: (a) K2OsO2(OH)4, t-BuOCl, NaOH, benzyl carbamate, (DHQD)2PHAL, n-PrOH/H2O, 5 h, 67%, 9:1 regioisomer, >99%
ee; (b) TBSCl, imidazole, DMAP (cat), dry DCM, 67%; (c) (i) DIBAL-H, dry DCM, ꢀ78 ꢁC, 1 h; (ii) Ph3P]CHCOOEt, dry THF, rt, 24 h, 73%; (d)
C12H25SO2Ph (18), n-BuLi, dry THF, ꢀ78 ꢁC; (e) (i) 10% Pd/C, MeOH, H2, 6 h; (ii) CbzCl, Et3N, dry DCM, 12 h, 78%; (f) p-TSA, MeOH, 30 min, 76%.
hexane/ethyl acetate.10a,11 Subsequently, the free hydroxyl
group of 10 was protected as silyl ether using TBSCl, imida-
zole, and catalytic amount of DMAP to give 14 in good
yield. The ester group of 14 was then reduced to the corre-
sponding aldehyde using 1 equiv of DIBAL-H at ꢀ78 ꢁC
followed by Wittig olefination to give the a,b-unsaturated
ester 15 in 73% yield.12
and TPP to give the bromo compound 17, which was reacted
with PhSO2Na13 in dry DMF to furnish the sulfone 18 in
excellent yield.
b
a
C12H25SO2Ph
C12H25Br
C12H25OH
16
17
18
The sulfone moiety, another fragment required in the synthe-
sis of (ꢀ)-deoxocassine 1, was synthesized as shown in
Scheme 3. Thus, dodecane-1-ol 16 was treated with CBr4
Scheme 3. Reagents and conditions: (a) CBr4, TPP, dry DCM, 2 h, 85%;
(b) PhSO2Na, dry DMF, 8 h, 98%.

9944
S. R. V. Kandula, P. Kumar / Tetrahedron 62 (2006) 9942–9948
With substantial amount of both the fragments in hand, we
then attempted at the coupling reaction of ester 15 with sul-
fone 18 under varied reaction conditions using different
types of bases such as n-BuLi, NaH, and LDA in dry THF,
however, the desired coupled product 19 could not be
obtained14 (Scheme 2). The reason for reaction failure could
probably be attributed to the less reactivity of the a,b-
unsaturated ester 15 as an electrophile. We then decided to
use a more reactive electrophile such as 8 as a coupling part-
ner instead of a,b-unsaturated ester 15. The lactone 8 can be
easily obtained from 15 simply by double bond reduction
and subsequent cyclization. Accordingly, the double bond
of 15 was reduced using H2-10% Pd/C in methanol under
hydrogenation conditions, which led to an intermediate
resulting through concomitant deprotection of TBS and
Cbz group. The free amine was subsequently protected using
benzyloxycarbonyl chloride and triethyl amine to give 9,
which on treatment with 10 mol % p-TSA in methanol
afforded the lactone 8 in 76% yield.
the azido group with retention of configuration, we carried
out double inversion following a two-step reaction sequence
as shown in Scheme 4.
Thus the lactone 23 was first reacted with methanesulfonyl
chloride to give the O-mesyl derivative, which was subse-
quently treated with NaI under reflux conditions to furnish
the iodide 24 with inversion of configuration. The introduc-
tion of azido group in SN2 fashion led to the formation of
desired syn-azido lactone 25 in good yield. Subsequent
treatment with TPP in THF/H2O afforded the free amine,
which was protected with benzyloxycarbonyl chloride and
triethyl amine to give the desired lactone 8. The physical
and chemical properties of 8 exactly matched with the one
prepared earlier through aminohydroxylation approach
(Scheme 2). The advantage of the aminohydroxylation
over the dihydroxylation approach is that the desired frag-
ment 8 could be prepared in relatively less number of steps.
Having completed the synthesis of both fragments 8 and 18,
we needed to couple the two fragments by lactone ring open-
ing and subsequent reductive cyclization (Scheme 5). To this
end the opening of the lactone 8 (prepared through the ami-
nohydroxylation method) was carried out with a carbanion
derived from 18 using n-BuLi at ꢀ78 ꢁC to give the coupled
product 26. Reductive removal of the sulfonyl group with
6% Na/Hg in dry methanol at ꢀ10 ꢁC furnished 27, which
was subjected to cyclization under hydrogenation conditions
using H2-20% Pd(OH)2. This reaction proceeded through
the formation of imine 28 as an intermediate, the catalytic
hydrogenation of which under standard conditions afforded
stereoselectively the target compound 1 as the only product.
Alternatively, the lactone 8 could be prepared starting from
easily available starting material sorbate 20 following a
sequence of reaction as illustrated in Scheme 4. Thus, selec-
tive dihydroxylation of 2015 using osmium tetraoxide as
oxidant and (DHQD)2PHAL as chiral ligand gave the diol
21 in good yield as well as in good enantioselectivity [a]D25
+51.87 (c 1.1, EtOH) [lit.15 [a]D25 ꢀ52.0 (c 1.17, EtOH) for
S-enantiomer]. Subsequently, the olefinic double bond was
reduced to the corresponding saturated system 22 using
H2-10% Pd/C in methanol under hydrogenation conditions
followed by treatment with 10 mol % p-TSA in methanol
to give the lactone 23 in excellent yield. In order to introduce
O
OH
O
OH
O
b
a
OEt
OEt
OEt
20
OH
OH
21
22
OH
I
NHCbz
N3
c
e
f
d
O
O
O
O
O
O
O
O
23
25
8
24
Scheme 4. Reagents and conditions: (a) (DHQD)2PHAL, OsO4, CH3SO2NH2, K3Fe(CN)6, K2CO3, t-BuOH/H2O (1:1), 12 h, 0 ꢁC, 84%; (b) 10% Pd/C, H2,
MeOH, 1 h, 99%; (c) 10% p-TSA, MeOH, 30 min, rt, 83%; (d) (i) CH3SO2Cl, Et3N, DMAP, dry DCM, rt, 30 min; (ii) NaI, acetone, reflux, 24 h, 60%;
(e) NaN3, dry DMF, 24 h, 70 ꢁC, 74%; (f) (i) TPP, THF/H2O (5:2), 24 h; (ii) CbzCl, Et3N, dry DCM, 12 h, 73%.
NHCbz
OH
O
b
a
8
18
+
SO2Ph
26
H
O
HO
H
H
N
R
HO
OH
c
C12H25
H
H
N
H
C12H25
NHCbz
27
1
R= C12H25
28
Scheme 5. Reagents and conditions: (a) n-BuLi, dry THF, ꢀ78 ꢁC, 50 min, 80%; (b) 6% Na/Hg, dry MeOH, ꢀ10 ꢁC, 4 h, 68%; (c) 20% Pd(OH)2, H2, dry
MeOH, 24 h, 100%.

S. R. V. Kandula, P. Kumar / Tetrahedron 62 (2006) 9942–9948
9945
The assigned stereochemistry at the newly created center
was based on the assumption that the hydrogenation of imine
28 will occur from the less hindered b-face of the molecule,
resulting in the all syn-configuration.16 The physical and
spectroscopic data of 1 were in accord with those described
in literature.6c
with brine, dried (Na2SO4), and concentrated to near dryness
to afford the crude product, which was contaminated with
excess of benzyl carbamate. Purification by flash chromato-
graphy using petroleum ether/EtOAc (6:4) as eluant pro-
vided 10 (2.92 g, 67%) as a white solid. The enantiomeric
excess was found to be >99%.11 Mp: 82–85 ꢁC [lit.10a mp:
82–85 ꢁC]; [a]2D5 ꢀ9.7 (c 0.34, CHCl3); IR (CHCl3, cmꢀ1
)
1
nmax 3522, 3311, 1721, 1692; H NMR (200 MHz, CDCl3)
d 1.26 (d, J¼6.6 Hz, 3H), 1.45 (s, 9H), 3.20 (br s, 1H,
OH), 3.92–4.01 (m, 1H), 4.23–4.31 (m, 1H), 4.70 (s, 2H),
5.20 (br s, 1H, NH), 7.33–7.39 (m, 5H); 13C NMR
(50 MHz, CDCl3) d 18.1, 27.6, 48.9, 66.4, 73.2, 83.3,
126.8, 127.4, 127.9, 128.3, 136.3, 155.5, 172.2.
3. Conclusion
In summary, we have achieved the synthesis of (ꢀ)-deoxo-
cassine using Sharpless asymmetric aminohydroxylation/
dihydroxylation and stereoselective reductive amination as
the key steps. The synthetic strategy described would allow
an easy access to a wide variety of related 2,6-disubstituted
3-piperidinols, for example, 2–6.
4.1.2. (2S,3R)-tert-Butyl-2-(tert-butyldimethylsilanyl-
oxy)-3-(N-benzyloxycarbonyl)-aminobutanoate (14). To
a stirred solution of alcohol 10 (0.5 g, 1.61 mmol) in dry
DCM (10 mL), imidazole (0.11 g, 1.61 mmol), TBSCl
(0.36 g, 2.42 mmol), and catalytic amount of DMAP were
added sequentially. The reaction mixture was stirred at
ambient temperature. After TLC diagnosis, water was added
to the reaction mixture and aqueous layer was extracted with
dichloromethane (3ꢂ10 mL) and combined organic layers
were washed with brine solution and dried over Na2SO4.
The crude product was purified on silica gel column chroma-
tography using petroleum ether/EtOAc (9:1) as eluant to
give 14 (0.42 g, 67%) as a colorless liquid. [a]2D5 ꢀ14.6
(c 0.56, CHCl3) [lit.10b [a]D25 ꢀ14.6 (c 0.8, CH2Cl2)]; IR
4. Experimental
4.1. General methods
All reactions requiring anhydrous conditions were per-
formed under positive pressure of argon using oven-dried
glassware (110 ꢁC), which was cooled under argon. DCM
and triethyl amine were distilled from CaH2 and stored
over molecular sieves and KOH, respectively. THF was dis-
tilled over sodium benzophenone ketyl. Solvents used for
chromatography were distilled at respective boiling points
using known procedures. Infrared spectra were recorded
(CHCl3, cmꢀ1
)
nmax 3392, 1702, 1682; 1H NMR
(200 MHz, CDCl3) d 0.12 (s, 3H), 0.13 (s, 3H), 0.89 (d,
J¼5.4 Hz, 3H), 0.96 (s, 9H), 1.46 (s, 9H), 4.13 (t, J¼
6.6 Hz, 1H), 4.76 (s, 2H), 4.83–4.89 (m, 1H), 5.17 (s, 1H),
7.33–7.38 (m, 5H); 13C NMR (50 MHz, CDCl3) d ꢀ5.4,
ꢀ5.3, 10.1, 25.3, 25.5, 25.7, 25.9, 64.9, 69.3, 69.6, 125.9,
126.8, 127.5, 128.1, 128.2, 128.3, 128.5, 158.0, 170.2.
1
with an ATI MATTSON RS-1 FT-IR spectrometer. H and
13C NMR spectra were recorded on Bruker AC-200, Bruker
MSL-300, and Brucker DRX-500 instruments using deuter-
ated solvent. Chemical shifts are reported in parts per mil-
lion. All melting points are uncorrected in degree celsius
and recorded on a Thermonik melting point apparatus. Opti-
cal rotations were measured using the sodium D line of a
JASCO-181 digital polarimeter. Elemental analyses were
carried out with a Carlo Erba CHNS-O analyzer. Enantio-
meric excess was determined using chiral HPLC and
Mosher’s analyses.
4.1.3. 5-Benzyloxycarbonylamino-4-(tert-butyldimethyl-
silanyloxy)-hex-2-enoic acid ethyl ester (15). To a stirred
solution of 14 (1.0 g, 2.36 mmol) in dry DCM (10 mL)
was added DIBAL-H (2.36 mL, 1 M solution in toluene,
2.36 mmol) at ꢀ78 ꢁC and the mixture was stirred for 1 h
at the same temperature. After completion of the reaction,
the reaction mixture was quenched with saturated sodium
potassium tartrate (5 mL) and filtered through Celite pad,
dried over Na2SO4, and concentrated to near dryness. The
crude product was used as such in the next Wittig reaction.
4.1.1. (2S,3R)-tert-Butyl-2-hydroxy-3-(N-benzyloxycar-
bonyl)-aminobutanoate (10). Benzyl carbamate (6.6 g,
43.60 mmol) was dissolved in 56 mL of n-propyl alcohol
in a single-necked round bottom flask (250 mL) equipped
with a magnetic stir bar. To this stirred solution was added
a freshly prepared solution of NaOH (1.71 g, 42.89 mmol)
in 105 mL of water followed by freshly prepared tert-butyl
hypochlorite (4.7 mL, 42.89 mmol). Next, a solution of
the ligand (DHQD)2PHAL (0.54 g, 5 mol %) in 49 mL of
n-propyl alcohol was added. The reaction mixture was
homogeneous at this point. Then the reaction mixture was
immersed in a room temperature water bath and stirred for
3 min, and the tert-butyl crotonoate 11 (2.0 g, 14.06 mmol)
was added followed by the osmium catalyst (K2OsO2(OH)4)
(0.20 g, 4 mol %). The reaction mixturewas stirred until con-
sumption of the starting material, when the light green color
turned to light yellow. After completion of reaction, 30 mL
of ethyl acetate was added and the phases were separated.
The lower aqueous phase was extracted with ethyl acetate
(4ꢂ60 mL). The combined organic layers were washed
To a stirred solution of (ethoxycarbonylmethylene)-triphe-
nylphosphorane (0.98 g, 2.83 mmol) in dry THF (10 mL)
was added the crude aldehyde in dry THF (3 mL) and the
reaction mixture was stirred for 24 h at room temperature
andconcentratedtoneardryness. Thecrudeproductwaspuri-
fied on silica gel column chromatography using petroleum
ether/EtOAc (8:2) as eluant to give 15 (0.62 g, 73%) as a light
yellow liquid. [a]D25 ꢀ12.4 (c 1.0, CHCl3); IR (CHCl3, cmꢀ1
)
1
nmax 3369, 1723, 1682, 1603; H NMR (200 MHz, CDCl3)
d 0.06 (s, 3H), 0.08 (s, 3H), 1.12 (s, 9H), 1.23 (t, J¼
6.4 Hz, 3H), 1.30 (d, J¼7.1 Hz, 3H), 3.70 (qn, J¼6.2 Hz,
1H), 4.03–4.05 (m, 1H), 4.20 (q, J¼7.2 Hz, 2H), 6.10 (dd,
J¼15.7, 1.6 Hz, 1H), 6.94 (dd, J¼15.8, 5.2 Hz, 1H), 4.72
(s, 2H), 4.98 (s, 1H), 7.28–7.31 (m, 5H); 13C NMR
(50 MHz, CDCl3) d ꢀ4.3, ꢀ3.4, 13.9, 18.7, 20.7, 52.3,
60.5, 70.0, 75.3, 122.0, 126.5, 127.3, 127.9, 140.9, 146.8,

9946
S. R. V. Kandula, P. Kumar / Tetrahedron 62 (2006) 9942–9948
1
157.2, 166.6. Anal. Calcd for C22H35NO5Si (421.60): C,
62.67; H, 8.37; N, 3.32. Found: C, 62.63; H, 8.31; N, 3.30.
eluant to give 17 (6.24 g, 85%) as a colorless oil. H NMR
(200 MHz, CDCl3) d 0.89 (t, J¼6.3 Hz, 3H), 1.17–1.43
(m, 20H), 3.90 (t, J¼6.6 Hz, 2H); 13C NMR (50 MHz,
CDCl3) d 14.0, 22.6, 26.9, 28.1, 28.7, 29.3, 29.4, 29.5,
29.6, 31.9, 32.8, 33.8.
4.1.4. 5-Benzyloxycarbonylamino-4-hydroxyhexanoic
acid ethyl ester (9). To a stirred solution of 15 (0.5 g,
1.18 mmol) in dry methanol (10 mL) was added 10% Pd/C
(50 mg) and the reaction mixture was stirred under hydrogen
atmosphere for 6 h. The reaction mixture was filtered
through Celite pad and concentrated to near dryness. The
crude product thus obtained was dissolved in dry DCM
(10 mL). Et3N (0.25 mL, 1.78 mmol) and benzyloxycar-
bonyl chloride (0.22 mL, 1.54 mmol) were added at 0 ꢁC.
After consumption of the starting material (12 h), the reac-
tion mixture was quenched with water (5 mL) and organic
layer was extracted with dichloromethane (3ꢂ10 mL), dried
over Na2SO4, and concentrated to near dryness. The crude
product was purified on silica gel column chromatography
using petroleum ether/EtOAc (4:5) as eluant to give 9
(0.28 g, 78%) as a viscous liquid. [a]2D5 ꢀ32.4 (c 0.76,
CHCl3); IR (CHCl3, cmꢀ1) nmax 3522, 3306, 1712, 1682;
1H NMR (200 MHz, CDCl3) d 1.18 (t, J¼6.9 Hz, 3H),
1.20 (d, J¼6.4 Hz, 3H), 1.99–2.23 (m, 2H), 2.47–2.58 (m,
2H), 2.99 (br s, 1H), 3.69 (q, J¼7.1 Hz, 1H), 3.70–3.76
(m, 1H), 4.29 (q, J¼7.3 Hz, 2H), 4.76 (s, 2H), 4.88 (s,
1H), 7.22–7.29 (m, 5H); 13C NMR (50 MHz, CDCl3)
d 13.7, 18.7, 27.8, 28.3, 52.5, 57.3, 70.1, 74.6, 127.3,
127.8, 128.8, 140.4, 155.2, 173.8. Anal. Calcd for
C16H23NO5 (309.36): C, 62.12; H, 7.49; N, 4.53. Found:
C, 62.08; H, 7.43; N, 4.51.
4.1.7. (Dodecane-1-sulfonyl)-benzene (18). To a stirred
solution of 17 (1 g, 4 mmol) in dry DMF (10 mL) was added
PhSO2Na (0.98 g, 6 mmol) and then the reaction mixture
was stirred for 8 h at ambient temperature. To the reaction
mixture were added water (10 mL) and ethyl acetate
(10 mL) and organic layer was separated. The aqueous layer
was extracted with ethyl acetate (3ꢂ10 mL) and combined
organic layers were washed thoroughly with water and dried
over Na2SO4. The crude product was purified on silica
gel column chromatography using petroleum ether/EtOAc
(9.5:0.5) to give 18 (1.21 g, 98%) as a light yellow solid.
Mp: 62 ꢁC; 1H NMR (200 MHz, CDCl3) d 0.87 (t, J¼
5.9 Hz, 3H), 1.12–1.33 (m, 20H), 3.04–3.12 (m, 2H), 7.53–
7.68 (m, 3H), 7.91 (d, J¼6.6 Hz, 2H); 13C NMR (50 MHz,
CDCl3) d 13.8, 22.4, 28.0, 28.7, 28.9, 29.1, 29.2, 29.3,
31.6, 56.0, 127.8, 129.0, 133.4, 139.0.
4.1.8. (6-Benzenesulfonyl-2-hydroxy-1-methyl-5-oxo-
heptadecyl)-carbamic acid benzyl ester (26). To a stirred
solution of sulfone 18 (0.7 g, 2.28 mmol) in dry THF
(10 mL) was added n-BuLi (1.4 mL, 2.28 mmol, 1.6 M solu-
tion in hexane) at ꢀ78 ꢁC and stirring was continued for
20 min. Then, the lactone 8 (0.3 g, 1.14 mmol) in dry THF
(3 mL) was added dropwise at the same temperature and stir-
ring was continued for further 30 min. After TLC diagnosis,
the reaction mixture was quenched with saturated NH4Cl
(5 mL) and aqueous layer was extracted with ethyl acetate
(3ꢂ20 mL) and washed with brine solution, dried over
Na2SO4, and concentrated to near dryness. The crude prod-
uct was purified on silica gel column chromatography using
petroleum ether/EtOAc (4:6) as eluant to give 26 (0.52 g,
80%) as a light yellow solid. Mp: 165 ꢁC; [a]D25 ꢀ6.3 (c
0.7, CHCl3); IR (CHCl3, cmꢀ1) nmax 3492, 3352, 1734,
4.1.5. [1-(5-Oxo-tetrahydrofuran-2-yl)-ethyl]-carbamic
acid benzyl ester (8). Compound 9 (0.5 g, 1.62 mmol)
was dissolved in bottle grade methanol (10 mL) and cata-
lytic amount of p-TSA was added to this. The reaction mix-
ture was stirred till completion of the reaction. Saturated
sodium bicarbonate solution (3 mL) was added to the reac-
tion mixture and stirred for 5 min. Methanol was removed
in vacuo and the aqueous layer was extracted with dichloro-
methane (3ꢂ10 mL), washed with brine solution, dried over
Na2SO4, and concentrated to near dryness. The crude prod-
uct was purified on silica gel column chromatography using
petroleum ether/EtOAc (1:1) as eluant to give the lactone 8
(0.32 g, 76%) as a light yellow solid. Mp: 122–124 ꢁC; [a]D25
ꢀ28.61 (c 0.92, CHCl3); IR (CHCl3, cmꢀ1) nmax 3323, 1721,
1696, 1321, 1225, 1032; 1H NMR (200 MHz, CDCl3) d 1.20
(d, J¼6.8 Hz, 3H), 1.92–2.11 (m, 2H), 2.55 (t, J¼8.5 Hz,
2H), 3.84–3.98 (m, 1H), 4.50 (q, J¼7.1 Hz, 1H), 5.10 (s,
2H), 5.03 (br s, 1H), 7.31–7.40 (m, 5H); 13C NMR
(50 MHz, CDCl3) d 15.3, 23.9, 28.0, 49.4, 66.5, 82.3,
127.7, 128.2, 131.7, 155.7, 176.7. Anal. Calcd for
C14H17NO4 (263.29): C, 63.87; H, 6.51; N, 5.32. Found:
C, 63.84; H, 6.50; N, 5.29.
1
1432; H NMR (200 MHz, CDCl3) d 0.89 (t, J¼4.3 Hz,
3H), 1.22 (d, J¼6.6 Hz, 3H), 1.13–1.26 (m, 20H), 1.76–
1.88 (m, 2H), 2.02 (s, 1H), 2.24 (t, J¼10.5 Hz, 2H), 3.06
(t, J¼9.1 Hz, 1H), 3.81–3.95 (m, 1H), 4.35 (q, J¼6.6 Hz,
1H), 4.79 (d, J¼7.9 Hz, 1H), 5.11 (s, 2H), 7.36–7.38 (m,
5H), 7.49–7.60 (m, 3H), 7.85 (dd, J¼7.7, 1.4 Hz, 2H); 13C
NMR (50 MHz, CDCl3) d 14.0, 22.5, 26.3, 26.7, 27.1,
28.5, 29.1, 29.4, 29.9, 31.7, 49.3, 66.8, 85.8, 111.3, 126.7,
127.9, 128.9, 128.4, 129.2, 132.3, 134.2, 136.3, 142.6,
155.6, 167.8. Anal. Calcd for C32H47NO6S (573.78): C,
66.98; H, 8.26; N, 2.44. Found: C, 66.96; H, 8.23; N, 2.42.
4.1.9. (4R,5R,E)-Ethyl 4,5-dihydroxyhex-2-enoate (21).
To a mixture of K3Fe(CN)6 (35.20 g, 0.1 mol), K2CO3
(14.76 g, 0.1 mol), and (DHQD)2PHAL (278 mg, 1 mol %)
in t-BuOH/H2O (1:1) cooled at 0 ꢁC was added osmium tet-
raoxide (1.43 mL, 0.1 M solution in toluene, 0.4 mol %)
followed by methane sulfonamide (3.38 g, 35.66 mmol).
After stirring for 5 min at 0 ꢁC, olefin 20 (5 g, 35.66 mmol)
was added in one portion. The reaction mixture was stirred at
0 ꢁC for 12 h and then quenched with solid sodium sulfite
(5 g). The stirring was continued for an additional 45 min
and then the solution was extracted with ethyl acetate
(5ꢂ100 mL). The combined organic phases were washed
4.1.6. 1-Bromododecane (17). To a solution of alcohol 16
(5.5 g, 29.51 mmol) in dry DCM (50 mL) were added TPP
(15.48 g, 59.03 mmol) and CBr4 (14.68 g, 44.27 mmol)
sequentially at 0 ꢁC. The reaction mixture was stirred (2 h)
until disappearance of the starting material. Then, water
was added to the reaction mixture and the aqueous layer
was extracted with dichloromethane. The combined organic
layers were dried over Na2SO4 and concentrated to near dry-
ness. The crude product was purified on silica gel column
chromatography using petroleum ether/EtOAc (9.9:0.1) as

S. R. V. Kandula, P. Kumar / Tetrahedron 62 (2006) 9942–9948
9947
with 10% aq KOH, brine, dried (Na2SO4), and concentrated.
Silica gel column chromatography of the crude product
using petroleum ether/EtOAc (7:3) as eluant gave the diol
21 (5.2 g, 84%) as a light yellow oil. [a]2D5 +51.87 (c 1.1,
EtOH) [lit.15 [a]2D5 ꢀ52.0 (c 1.17, EtOH) for S-enantiomer];
into water and extracted with ethyl acetate. The organic
extracts were washed with water, brine, dried (Na2SO4), and
concentrated. Column chromatography on silica gel using
petroleum ether/EtOAc (9.3:0.7) as eluant gave 24 (2.2 g,
60%) as a light yellow liquid. [a]2D5 ꢀ28.36 (c 0.98,
CHCl3); IR (CHCl3, cmꢀ1) nmax 1722, 1519; 1H NMR
(200 MHz, CDCl3) d 1.98 (d, J¼7.1 Hz, 3H), 2.02–2.06 (m,
2H), 2.28–2.31 (m, 1H), 4.19 (qn, J¼6.6 Hz, 1H), 4.33 (q,
J¼7.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 17.8, 20.8,
26.1, 34.9, 91.5, 172.0. Anal. Calcd for C6H9IO2 (240.04):
C, 30.02; H, 3.78; I, 52.87. Found: C, 30.01; H, 3.76; I, 52.85.
1
IR (CHCl3, cmꢀ1) nmax 3544, 3469, 1720, 1619; H NMR
(200 MHz, CDCl3) d 1.2 (d, J¼6.5 Hz, 3H), 1.27 (t, J¼
7.1 Hz, 3H), 3.25 (br s, 2H), 3.63–3.76 (m, 1H), 4.03 (ddd,
J¼11.4, 6.3, 1.6 Hz, 1H), 4.20 (q, J¼7.2 Hz, 2H), 6.06–
6.15 (dd, J¼15.6, 1.6 Hz, 1H), 6.92 (dd, J¼15.7, 5.2 Hz,
1H); 13C NMR (50 MHz, CDCl3) d 13.9, 18.7, 60.5, 70.1,
75.3, 122.0, 146.8, 166.6. Anal. Calcd for C8H14O4
(174.19): C, 55.16; H, 8.10. Found: C, 55.14; H, 8.18.
4.1.13. 5-(1-Azidoethyl)-dihydrofuran-2-one (25). Com-
pound 24 (1.0 g, 4.16 mmol) was dissolved in dry DMF
(10 mL). Sodium azide (1.62 g, 25 mmol) was added to
the above solution and stirred at 80 ꢁC for 24 h. The solution
was then cooled and poured into water and extracted with
ethyl acetate. The organic extracts were washed with water,
brine, dried (Na2SO4), and concentrated. Column chromato-
graphy on silica gel using petroleum ether/EtOAc (1:9) as
eluant gave 25 (0.48 g, 74%) as a colorless liquid. [a]D25
ꢀ32.3 (c 1.1, CHCl3); IR (CHCl3, cmꢀ1) nmax 2122, 1738;
1H NMR (200 MHz, CDCl3) d 1.30 (d, J¼6.7 Hz, 3H), 2.12–
2.35 (m, 2H), 2.51–2.62 (m, 2H), 3.76–3.84 (m, 2H), 4.34–
4.43 (m, 2H); 13C NMR (50 MHz, CDCl3) d 14.9, 22.3, 27.8,
59.2, 81.3, 176.3. Anal. Calcd for C6H9N3O2 (155.15): C,
46.45; H, 5.85; N, 27.08. Found: C, 46.41; H, 5.83; N, 27.05.
4.1.10. (4R,5R)-Ethyl 4,5-dihydroxyhexanoate (22). To
a stirred solution of 21 (2.5 g, 14.35 mmol) in dry methanol
(20 mL) was added 10% Pd/C (150 mg) and the reaction
mixture was stirred under hydrogen atmosphere for 1 h.
The reaction mixture was filtered through Celite pad and
concentrated to near dryness. Silica gel column chromato-
graphy of the crude product using petroleum ether/EtOAc
(7:3) as eluant gave the diol 22 (2.51 g, 99%) as a colorless
oil. [a]2D5 +8.56 (c 1.1, CHCl3); IR (CHCl3, cmꢀ1) nmax 3533,
1719; 1H NMR (200 MHz, CDCl3) d 1.15 (t, J¼6.9 Hz, 3H),
1.20 (d, J¼6.4 Hz, 3H), 1.99–2.23 (m, 2H), 2.47–2.58 (m,
2H), 2.99 (br s, 2H), 3.60 (q, J¼7.1 Hz, 2H), 3.69–3.76
(m, 1H), 4.30 (q, J¼7.3 Hz, 1H); 13C NMR (50 MHz,
CDCl3) d 13.7, 18.7, 27.8, 30.2, 60.1, 70.1, 74.6, 173.8.
Anal. Calcd for C8H16O4 (176.21): C, 54.53; H, 9.15. Found:
C, 54.50; H, 9.13.
4.1.14. [1-(5-Oxo-tetrahydrofuran-2-yl)-ethyl]-carbamic
acid benzyl ester (8). To a stirred solution of 25 (0.5 g,
3.2 mmol) in THF/H2O (5:2) was added TPP (0.76 g,
2.9 mmol). The reaction mixture was stirred at ambient tem-
perature for 24 h. The reaction mixture was concentrated to
near dryness. The crude product thus obtained was dissolved
in dry DCM (10 mL). Et3N (0.65 mL, 4.64 mmol) and ben-
zyloxycarbonyl chloride (0.60 mL, 4.02 mmol) were added
at 0 ꢁC. After consumption of the starting material (12 h),
the reaction mixture was quenched with water (5 mL) and
organic layer was extracted with dichloromethane (3ꢂ
10 mL), dried over Na2SO4, and concentrated to near dry-
ness. The crude product was purified on silica gel column
chromatography using petroleum ether/EtOAc (6:4) as
eluant to give 8 (0.62 g, 73%) as a light yellow solid. The
physical and spectroscopic data were in accord with those
described earlier.
4.1.11. 5-(1-Hydroxyethyl)-dihydrofuran-2-one (23).
Compound 22 (2.0 g, 11.35 mmol) was dissolved in bottle
grade methanol (20 mL) and catalytic amount of p-TSA
was added to this. The reaction mixture was stirred at
room temperature till completion of the reaction. Saturated
sodium bicarbonate solution (10 mL) was added to the reac-
tion mixture and stirred for 5 min. Methanol was removed in
vacuo and the aqueous layer was extracted with dichloro-
methane (3ꢂ10 mL), washed with brine solution, dried over
Na2SO4, and concentrated to near dryness. The crude prod-
uct was purified on silica gel column chromatography using
petroleum ether/EtOAc (1:1) as eluant to give the lactone 23
(1.22 g, 83%) as a light yellow solid. Mp: 92 ꢁC; [a]D25 ꢀ52.8
(c 1.1, CHCl3); IR (CHCl3, cmꢀ1) nmax 3463, 1699; 1H NMR
(200 MHz, CDCl3) d 1.20 (d, J¼6.6 Hz, 3H), 1.97–2.29 (m,
2H), 2.47–2.57 (m, 2H), 3.03 (br s, 1H), 3.71–3.83 (m, 1H),
4.29–4.38 (m, 1H); 13C NMR (50 MHz, CDCl3) d 18.0, 23.5,
28.2, 68.9, 83.9, 177.6. Anal. Calcd for C6H10O3 (130.14):
C, 55.37; H, 7.74. Found: C, 55.34; H, 7.72.
4.1.15. (2-Hydroxy-1-methyl-5-oxo-heptadecyl)-carbamic
acid benzyl ester (27). To a stirred solution of 26 (0.25 g,
0.43 mmol) in dry methanol (5 mL) were added 6% Na/Hg
(1.3 g) and Na2HPO4 (0.12 g, 0.87 mmol) at ꢀ10 ꢁC and
stirring was continued at the same temperature for further
4 h. After disappearance of the starting material the reaction
mixture was quenched with water and methanol was
removed in vacuo, water layer was extracted with ethyl
acetate (3ꢂ5 mL) and washed with brine solution, dried
over Na2SO4, and concentrated to near dryness. The crude
product was purified on silica gel column chromatography
using petroleum ether/EtOAc (7:3) as eluant to afford 27
(0.13 g, 68%) as a white solid. Mp: 141 ꢁC; [a]D25 ꢀ28.6 (c
0.92, CHCl3); IR (CHCl3, cmꢀ1) nmax 3499, 3296, 1696;
1H NMR (200 MHz, CDCl3) d 0.88 (t, J¼6.6 Hz, 3H),
1.12 (d, J¼6.6 Hz, 3H), 1.18–1.34 (m, 20H), 1.56–1.59
(m, 2H), 1.66–1.71 (m, 2H), 2.42 (t, J¼7.3 Hz, 2H), 2.5
4.1.12. 5-(1-Iodoethyl)-dihydrofuran-2-one (24). To a so-
lution of 23 (2 g, 15.36 mmol) in dry CH2Cl2 (20 mL) at
0 ꢁC were added methanesulfonyl chloride (1.43 mL,
18.44 mmol), Et3N (3.2 mL, 23.0 mmol), and DMAP (cat).
The reaction mixture was stirred at room temperature for
30 min and then poured into Et2O/H2O mixture. The organic
phase was separated and the aqueous phase was extracted
with Et2O. The combined organic phases were washed
with water, brine, dried (Na2SO4), and concentrated to
a white solid, which was dissolved in dry acetone (20 mL).
Sodium iodide (21.6 g, 0.14 mol) was added and the reaction
mixture was refluxed for 24 h. It was then cooled and poured

9948
S. R. V. Kandula, P. Kumar / Tetrahedron 62 (2006) 9942–9948
(g) Zhou, W.-S.; Lu, Z.-H. Tetrahedron 1993, 49, 4659; (h)
Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994,
59, 3575; (i) Zhou, W.-S.; Liao, L.-X.; Xu, Y.-M.; Yang,
C.-F. Tetrahedron Lett. 1998, 39, 9227; (j) Datta, A.; Kumar,
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Kibayashi, C. Org. Lett. 2003, 5, 3839.
(br s, 1H), 3.56–3.73 (m, 1H), 4.08–4.10 (m, 1H), 4.71 (br s,
1H), 5.10 (s, 2H), 7.35–7.52 (m, 5H); 13C NMR (50 MHz,
CDCl3) d 13.9, 15.5, 22.4, 23.8, 24.1, 24.5, 29.0, 29.1,
29.3, 29.4, 31.5, 33.3, 44.9, 53.6, 69.5, 71.9, 126.6, 127.8,
128.8, 128.9, 142.4, 155.7, 210.8. Anal. Calcd for
C26H43NO4 (433.62): C, 72.02; H, 10.00; N, 3.23. Found.
C, 72.0; H, 9.96; N, 3.20.
6. (a) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029; (b) Liu,
L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem.
2004, 69, 6001; (c) Kurihara, K.; Sugimoto, T.; Saitoh, Y.;
Igarashi, Y.; Hirota, H.; Moriyama, Y.; Tsuyuki, T.;
Takahashi, T. Bull. Chem. Soc. Jpn. 1985, 58, 3337; (d)
Ma, D.; Ma, N. Tetrahedron Lett. 2003, 44, 3963.
4.1.16. Synthesis of (L)-deoxocassine (1). In a single neck
round bottom flask was placed 27 (0.1 g, 0.23 mmol) in
methanol (2 mL) followed by addition of 20% Pd(OH)2
(20 mg). The reaction mixture was stirred under hydrogen
atmosphere for 24 h and filtered through Celite pad, and con-
centrated to near dryness. The crude product was purified on
silica gel column chromatography using petroleum ether/
EtOAc (7:4) as eluant to give 1 (65 mg, 100%) as a white
solid. Mp: 48 ꢁC [lit.6b Mp: 47–48 ꢁC]. The physical and
spectroscopic data of 1 were in full agreement with those
reported.6c [a]2D5 ꢀ12.2 (c 0.68, CHCl3) [lit.6c [a]2D5 ꢀ12.3
7. Schneider, M. J. Pyridine and Piperidine Alkaloids: An Update.
In Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Pergamon: Oxford, 1996; Vol. 10, pp 155–299.
8. (a) Pais, G. C. G.; Fernandes, R. A.; Kumar, P. Tetrahedron
1999, 55, 13445; (b) Fernandes, R. A.; Kumar, P. Tetrahedron:
Asymmetry 1999, 10, 4349; (c) Fernandes, R. A.; Kumar, P. Eur.
J. Org. Chem. 2002, 2921; (d) Kandula, S. V.; Kumar, P. Tetra-
hedron Lett. 2003, 44, 6149; (e) Gupta, P.; Naidu, S. V.; Kumar,
P. Tetrahedron Lett. 2004, 45, 849; (f) Naidu, S. V.; Gupta, P.;
Kumar, P. Tetrahedron Lett. 2005, 46, 2129; (g) Kumar, P.;
Naidu, S. V.; Gupta, P. J. Org. Chem. 2005, 70, 2843;
(h) Kumar, P.; Naidu, S. V. J. Org. Chem. 2005, 70, 4207; (i)
Pandey, S. K.; Kumar, P. Tetrahedron Lett. 2005, 46, 6625; (j)
Kumar, P.;Gupta, P.;Naidu, S. V. Chem.—Eur. J. 2006, 12, 1397.
9. (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000, 3447;
(b) Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2000, 41,
10309; (c) Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003,
44, 1957; (d) Pandey, R. K.; Fernandes, R. A.; Kumar, P.
Tetrahedron Lett. 2002, 43, 4425; (e) Fernandes, R. A.;
Kumar, P. Synthesis 2003, 129; (f) Naidu, S. V.; Kumar, P.
Tetrahedron Lett. 2003, 44, 1035; (g) Kondekar, N. B.;
Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2004, 45, 5477;
(h) Pandey, S. K.; Kandula, S. V.; Kumar, P. Tetrahedron
Lett. 2004, 45, 5877; (i) Bodas, M. S.; Kumar, P. Tetrahedron
Lett. 2004, 45, 8461; (j) Kumar, P.; Bodas, M. S. J. Org.
Chem. 2005, 70, 360.
1
(c 0.19, CHCl3)]; H NMR (200 MHz, CDCl3) d 0.75 (t,
J¼6.8 Hz, 3H), 1.0 (d, J¼6.5 Hz, 3H), 1.12–1.17 (m,
22H), 1.34–1.42 (m, 2H), 1.83–1.95 (m, 2H), 2.44–2.55
(m, 2H), 2.72–2.74 (m, 1H), 3.90 (d, J¼6.5 Hz, 1H); 13C
NMR (50 MHz, CDCl3) d 14.3, 16.3, 23.5, 26.2, 27.9,
30.2, 30.4, 30.5, 39.2, 56.5, 58.0, 58.2, 68.3.
Acknowledgements
S.R.V.K. thanks CSIR, New Delhi for senior research fellow-
ship. Financial support from DST, New Delhi (Grant no. SR/
S1/OC-40/2003) is gratefully acknowledged. We are grateful
to Dr. M. K. Gurjar for his support and encouragement. This
is NCL communication no. 6695.
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