Asymmetric synthesis of (-)-α-conhydrine

Article abstract of DOI:10.1016/j.tetasy.2005.08.045

The enantioselective synthesis of (-)-α-conhydrine has been achieved by two different synthetic routes. The key steps include Sharpless asymmetric dihydroxylation, regioselective opening of a cyclic sulfate and Wittig olefination.

Full text of DOI:10.1016/j.tetasy.2005.08.045

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3268–3274
Asymmetric synthesis of (ꢀ)-a-conhydrine
Subba Rao V. Kandula and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 9 August 2005; accepted 29 August 2005
Abstract—The enantioselective synthesis of (ꢀ)-a-conhydrine has been achieved by two different synthetic routes. The key steps
include Sharpless asymmetric dihydroxylation, regioselective opening of a cyclic sulfate and Wittig olefination.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
drine have been documented.4 While a number of
auxiliary-supported syntheses or chiral pool approaches
have been reported for unnatural b-conhydrine,4 less
attention has been paid to the enantioselective synthesis
of (ꢀ)-a-conhydrine.5 In connection withour studies on
the enantioselective synthesis of naturally occurring lac-
tones6 and amino alcohols,7 we became interested in
developing a simple and feasible route to (ꢀ)-a-conhy-
drine. Herein, we report a new and highly enantioselec-
tive synthesis of (ꢀ)-a-conhydrine by two different
strategies employing AD, regioselective opening of a
cyclic sulfate and Wittig olefination as the key steps.
Alkaloid mimics witha nitrogen in the ring, especially
those a-substituted by a 1-hydroxyalkyl side chain, con-
stitute a framework frequently encountered in natural
alkaloids.1 This pattern is found in many biologically
active alkaloids suchas conhydrine 1, (ꢀ)-castanosper-
mine 2, (ꢀ)-slaframine 3, and (ꢀ)-swainsonine 4
(Fig. 1).2 Conhydrine is one of the alkaloids of the hem-
lock, isolated from the seeds and leaves of the poisonous
alkaloids plant Conium maculatum, whose extracts were
used in the ancient Greece for the execution of crimi-
nals.3 Various asymmetric syntheses of a- and b-conhy-
2. Results and discussion
OH
HO
OH
H
The synthesis of target molecule (ꢀ)-a-conhydrine 1
involves the preparation of enantiomerically pure diols 7
and 19 by employing the AD reaction and their subse-
quent synthetic manipulations. As shown in Scheme
1,5b the commercially available propionaldehyde 5 was
treated with (methoxycarbonylmethylene)triphenyl-
phosphorane in benzene under reflux to give the Wittig
product trans-6 in 85% yield. Subsequently, olefin 6 was
subjected to a Sharpless asymmetric dihydroxylation8
using osmium tetroxide as oxidant, potassium ferricya-
nide as co-oxidant in the presence of (DHQ)2PHAL
H
OH
N
N
H
OH
(-)-castanospermine
2
(-)-conhydrine
1
OH
H
H2N
H
OH
N
OAc
N
9
ligand to afford 7 in excellent yield and with95% ee.
OH
Diol 7 was then treated with thionyl chloride and tri-
ethyl amine to give the cyclic sulfite, which was oxidized
using RuCl3/NaIO4 to furnishthe corresponding cyclic
sulfate 810 in 88% yield. The essential feature of our syn-
thetic strategy was based on the presumption that the
nucleophilic opening of cyclic sulfate 8 would occur in
a regioselective manner at the a-carbon atom. Thus,
when cyclic sulfate 8 was reacted withNaN 3, it
(-)-slaframine
3
(-)-swainsonine
4
Figure 1.
*
Corresponding author. Tel.: +91 20 2590 2050; fax: +91 20 2589
3614; e-mail: pk.tripathi@ncl.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.045

S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3268–3274
3269
O
OH
O
b
a
CHO
OMe
OMe
6
5
OH
7
O
OH
O
O
O
OH
e
c
d
S
O
OMe
CHO
OMe
OMe
O
O
N3
NHBoc
9
8
10
OH
f
NHBoc
11
Scheme 1. Reaction conditions: (a) Ph3P@CHCOOMe, benzene, reflux, 2 h, 85%; (b) (DHQ)2PHAL, OsO4, CH3SO2NH2, K3Fe(CN)6, K2CO3, t-
BuOH/H2O (1:1), 24 h, 0 ꢁC, 88%; (c) (i) SOCl2, Et3N, dry DCM, 20 min; (ii) RuCl3/NaIO4, 1 h, 88%; (d) NaN3, acetone, 1 h; 20% aq H2SO4, ether,
12 h, 78%; (e) Boc2O, Pd/C, H2, EtOAc, 6 h, 98%; (f) DIBAL-H, ꢀ78 ꢁC, 1 h.
furnished azido alcohol 9 withan apparent complete
selectivity for an attack at the C-2, a-position. The car-
bonyl group must be responsible for the increased reac-
tivity of the a-position.11 Subsequently, azide 9 was
reduced to an amine using 10% Pd/C under hydrogena-
tion conditions, followed by protection of the amine
with(Boc) 2O to give 10, which on reduction with
DIBAL-H afforded the corresponding aldehyde 11 in
good yield.
potassium carbonate to furnish 14 as a white crystalline
solid (Scheme 2).5b With the phosphonium salt 14 in
hand, we then proceeded to carry out the Wittig olefin-
ation. The ylide prepared from the reaction of n-BuLi
and phosphonium salt 14, was reacted withaldehyde
11 to afford olefin 15 in moderate yield (Scheme 3).5b
The olefin reduction by hydrogenation using Pd/C gave
16, which was subjected to cyclization using metha-
nesulfonyl chloride and triethyl amine followed by
deprotection of the Boc group to furnish (ꢀ)-a-conhy-
drine 1.5b The physical and spectroscopic data of 1 were
It was now possible to reachthe target molecule by a
three carbon chain elongation and subsequent
cyclization.
5a
in full agreement withthe literature data.
Although we successfully achieved the synthesis of
target molecule 1 in high ee, the yield obtained at the
Wittig step was not very satisfactory. Therefore, we
looked into an alternative synthetic strategy with an
aim to synthesize the target molecule in high yield and
good enantiomeric excess. As illustrated in Scheme 4,
To this end, we first synthesized the phosphonium salt
14,12 as shown in Scheme 2. Monobromination of 1,3-
propanediol 12 with48% aq HBr using Dean–Stark
water-separator gave the bromo alcohol 13, which was
treated with triphenylphosphine in the presence of
+
-
a
b
Br Ph3P
OH
Br
OH
HO
OH
14
13
12
Scheme 2. Reaction conditions: (a) 48% aq HBr, benzene, 28 h, 79%; (b) PPh3, K2CO3, dry acetonitrile, reflux, 7 h, 26%.
OH
OH
b
a
OH
OH
14
NHBoc
16
NHBoc
15
Boc
HN
N
d
c
OH
OH
1
17
Scheme 3. Reaction conditions: (a) n-BuLi, THF, 0 ꢁC, 30 min then 11, rt, 12 h, 40%; (b) Pd/C, H2, MeOH, 4 h, 95%; (c) MsCl, Et3N, dry DCM,
ꢀ78 ꢁC, 1 h, 84%; (d) CF3COOH, CH2Cl2, 12 h, rt, 74%.

3270
S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3268–3274
Ph
OH
a
b
O
O
OH
OH
OH
18
19
OH
20
Ph
OBn
OBn
O
O
c
d
e
OH
OH
N3
N3
N3
23
22
21
HN
OH
g
f
OH
NHBoc
16
OH
1
Scheme 4. Reaction conditions: (a) (DHQ)2PHAL, OsO4, CH3SO2NH2, K2CO3, t-BuOH/H2O (1:1), 24 h, 0 ꢁC; 75%; (b) C6H5CH(OMe)2, dry
CH2Cl2, p-TSA, rt, 12 h, 74%; (c) (i) CH3SO2Cl, dry CH2Cl2, rt, 6 h; (ii) NaN3, dry DMF, 80 ꢁC, 24 h, 86%; (d) DIBAL-H, ꢀ78 ꢁC to room
temperature, dry CH2Cl2, overnight, 90%; (e) (i) PCC, anhyd CH3COONa, celite; (ii) salt 14, n-BuLi, dry THF, 0 ꢁC–rt, 74%; (f) 10% Pd/C, H2,
Boc2O, EtOAc, 24 h, 86%; (g) steps c and d (Scheme 3).
OH
reductive conditions using DIBAL-H at ꢀ78 ꢁC to room
temperature to afford 22 in 90% yield. PCC oxidation of
alcohol 22 followed by a Wittig reaction using salt 14
gave the required olefin 23 in 75% yield. Reduction of
the olefin and azide with concomitant benzyl deprotec-
tion using 10% Pd/C under hydrogenation conditions
in the presence of Boc2O gave the Boc protected amino
alcohol 16. Subsequent conversion into target com-
pound 1 was carried out following the same reaction
sequence as described in Scheme 3.
AD
OH
R
OH
R
OH
R = Different alkyl chains
Scheme 5.
the commercially available trans-2-pentenol was sub-
jected to asymmetric dihydroxylation8 using osmium
tetroxide and potassium ferricyanide as co-oxidant in
the presence of (DHQ)2PHAL ligand to give (2S,3S)-
triol 19 in excellent yield. Sharpless asymmetric dihydr-
oxylation (AD) on allylic alcohols presented in Scheme
5, with different alkyl chains was reported to give the
two stereogenic centers in 95–97% enantiomeric
excess.13 Thus, by analogy, triol 19 prepared was assumed
to be enantiomerically pure. Furthermore, in order to
achieve the synthesis of (ꢀ)-conhydrine 1 from 19, we
required the transformation of a hydroxyl group into
an azido one, withconcomitant reversal of stereochem-
istry at the 2-position. To this end, the protection of 19
as a benzylidene derivative was effected, using benzalde-
hyde dimethyl acetal in the presence of a catalytic
amount of p-TSA to afford a mixture of 1,3-and 1,2-benz-
ylidene compounds in a 9:1 ratio. The desired major
1,3-benzylidene compound 20 was separated by silica
gel column chromatography. Our initial attempt to
introduce the azido functionality under Mitsunobu con-
ditions using Ph3P/DEAD and freshly prepared hydra-
zoic acid was unsuccessful. Therefore we proceeded
witha two-step reaction sequence. Thus, compound 20
was treated with methanesulfonyl chloride and triethyl-
amine to give O-mesylate derivative, which on reaction
withsodium azide in DMF afforded 21 withthe desired
stereochemistry at the 5-position. The smooth cleavage
of benzylidene protecting group was achieved under
3. Conclusion
In conclusion, we have accomplished the enantioselec-
tive synthesis of (ꢀ)-a-conhydrine by two different syn-
thetic strategies employing Sharpless asymmetric
dihydroxylation, regioselective opening of a cyclic sul-
fate and Wittig olefination as the key steps. The merits
of this synthesis are high enantioselectivity and various
possibilities available for structural modifications. The
other enantiomer can be synthesized by b-dihydroxyl-
ation of olefin 6 and 18 and following the reaction
sequence as shown above.
4. Experimental section
4.1. General information
Solvents were purified and dried by standard procedures
before use; petroleum ether of boiling range 60–80 ꢁC
was used. Optical rotations were measured using a
sodium D line on JASCO-181 digital polarimeter. Infra-
red spectra were recorded on a Perkin–Elmer model 683
grating infrared spectrometer. 1H and 13C NMR spectra
were recorded on Brucker AC-200 spectrometer in
CDCl3 solution withresidual CHCl
as the internal
3

S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3268–3274
3271
standard. Enantiomeric excess was measured using
either the chiral HPLC or by comparison with the spe-
cific rotation. Elemental analyses were carried out with
a Carlo Erba CHNS-O analyzer.
tography of the crude product using EtOAc/pet ether
(2:8) as eluent gave 8 (2.5 g) as a colorless liquid. Yield:
25
88%; ½aŠ ¼ ꢀ15:6 (c 1, CHCl3); IR (neat, cmꢀ1): mmax
D
1
3142, 3022, 2914, 1722; H NMR (200 MHz, CDCl3):
d 1.12 (t, J = 7.4 Hz, 3H), 1.97–2.09 (m, 2H), 3.89 (s,
3H), 4.89–4.93 (m, 1H), 5.30–5.32 (m, 1H); 13C NMR
(50 MHz, CDCl3): d 8.5, 25.8, 52.7, 79.3, 85.2, 164.4.
Anal. Calcd for C6H10SO6 (210.21): C, 34.28; H, 4.80.
Found: C, 34.16; H, 4.72.
4.1.1. Methyl-trans-pent-2-enoate 6. To a solution
of (methoxycarbonylmethylene)triphenylphosphorane
(63.46 g, 0.19 mol) in benzene (200 mL) was added pro-
pionaldehyde 5 (10 g, 0.172 mol). The reaction mixture
was refluxed for 2 hand the solvent concentrated to near
dryness. Column chromatography on silica gel using
EtOAc/pet ether (0.2:9.8) as eluent gave the Wittig
product 6 (16.72 g) as a colorless oil. Yield: 85%; IR
(neat, cmꢀ1): mmax 1617, 1722; 1H NMR (200 MHz,
CDCl3): d 0.98 (t, J = 8 Hz, 3H), 2.08–2.18 (m, 2H),
3.64 (s, 3H), 5.74 (d, J = 16 Hz, 1H), 6.87–6.98 (m,
1H); 13C NMR (50 MHz, CDCl3): d 9.8, 25.1, 53.8,
122.2, 135.5, 174.2.
4.1.4. Methyl (2R,3S)-2-azido-3-hydroxypentanoate
9. To a solution of cyclic sulfate 8 (2.5 g, 11.89 mmol)
in acetone (15 mL) cooled to 0 ꢁC was added NaN3
(3.86 g, 59.46 mmol) and the resulting mixture stirred
for 1 hat room temperature until no cyclic sulfate
remained as indicated by TLC. The solution was then
concentrated, and the residue stirred with 20% aq
H2SO4 and ether (5 mL of each phase/mmol substrate)
for 12 h. The resultant solution was then extracted with
ether. The combined organic phases were washed with
water, brine dried Na2SO4, and concentrated. Silica gel
column chromatography of the crude product using
4.1.2. Methyl (2S,3S)-2,3-dihydroxypentanoate 7. To a
mixture of K3Fe(CN)6 (42.80 g, 0.13 mol), K2CO3
(17.96 g, 0.13 mol), (DHQ)2PHAL (341 mg, 1 mol %)
in t-BuOH/H2O (1:1) were added osmium tetroxide
(1.75 mL, 0.1 M solution in toluene, 0.4 mol %) fol-
lowed by methane sulfonamide (4.16 g, 43.80 mol).
EtOAc/pet ether (1:9) as eluent furnished 9 (1.60 g) as
25
a colorless liquid. Yield: 78%; ½aŠ ¼ ꢀ4:7 (c 1.2,
D
CHCl3); IR (neat, cmꢀ1): mmax 3429, 2112, 1744; 1H
NMR (200 MHz, CDCl3): d 1.0 (t, J = 7.4 Hz, 3H),
1.50–1.69 (m, 2H), 2.33 (br s, 1H, OH), 3.83 (s, 3H),
3.87–3.91 (m, 1H), 3.97 (d, J = 5.9 Hz, 1H); 13C NMR
(50 MHz, CDCl3): d 9.5, 25.6, 51.7, 61.0, 73.0, 168.9.
Anal. Calcd for C6H11N3O3 (173.17): C, 41.61; H,
6.40; N, 24.27. Found: C, 41.59; H, 6.36; N, 24.25.
After stirring for 5 min at 0 ꢁC, olefin
6 (5 g,
43.80 mmol) was added in one portion. The reaction
mixture was stirred at 0 ꢁC for 24 h and then quenched
withsolid sodium sulfite (2.5 g). The stirring was contin-
ued for an additional 45 min and then, the solution
extracted withethyl acetate (5 · 100 mL). The combined
organic phases were washed with 10% aq KOH, brine,
dried over Na2SO4, and concentrated. Silica gel column
chromatography of the crude product using EtOAc/pet
4.1.5. Methyl (2R,3S)-2-tert-butoxycarbonylamino-3-
hydroxypentanoate 10. To a solution of azide 9
(2.0 g, 11.54 mmol) in ethyl acetate (10 mL) was added
10% Pd/C (75 mg) and Boc2O (3.97 mL, 17.32 mmol).
The resulting solution was stirred under a hydrogen
atmosphere at room temperature until disappearance
of the azido alcohol as monitored by TLC. The reaction
mixture was filtered through a celite pad to remove the
catalyst and the filtrate concentrated in vacuo. Silica
gel column chromatography of the crude product using
ether (4:6) as eluent gave 7 (5.71 g) as a viscous liquid.
25
Yield: 88%; ½aŠ ¼ ꢀ5:5 (c 1.0, CHCl3); IR (neat,
D
1
cmꢀ1): mmax 3562, 1722; H NMR (200 MHz, CDCl3):
d 1.0 (t, J = 6 Hz, 3H), 1.57–1.72 (m, 2H), 2.05 (br s,
2H), 3.73–3.78 (m, 1H), 3.83 (s, 3H), 4.14 (d,
J = 4 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 9.8,
26.0, 53.3, 72.8, 73.8, 173.4. Anal. Calcd for C6H12O4
(148.16): C, 48.64; H, 8.16. Found: C, 48.52; H, 8.09.
EtOAc/pet ether (3:7) as eluent gave 10 (2.8 g) as a
25
D
4.1.3. (2S,3S)-5-Ethyl-2,2-dioxo-[1,3,2]dioxathiolane-4-
carboxylic acid methyl ester 8. To a solution of diol 7
(2 g, 13.49 mmol) in dry CH2Cl2 (12 mL) was added
Et3N (5.46 g, 7.52 mL, 53.99 mmol). The mixture was
cooled in an ice bath and thionyl chloride (2.4 g,
1.47 mL, 20.17 mmol) added dropwise. The reaction
mixture was stirred for 20 min and then quenched by
adding water (10 mL). The phases were separated and
aqueous phase extracted with CH2Cl2 (3 · 20 mL). The
combined organic phases were dried over Na2SO4 and
concentrated. Then the solution was cooled with an
ice-water bathand diluted withCH 3CN (32 mL) and
CCl4 (32 mL). RuCl3ÆH2O (15 mg, 0.072 mmol) and
NaIO4 (6.16 g, 28.83 mmol) were added followed by
water (47 mL). The resulting orange mixture was stirred
at room temperature for 1 h. The mixture was then
diluted with ether (50 mL), and the two phases sepa-
rated. The organic layer was washed with water
(40 mL), saturated aq NaHCO3 (30 mL), brine, dried
Na2SO4, and concentrated. Silica gel column chroma-
liquid. Yield: 98%; ½aŠ ¼ ꢀ6:9 (c 2.0, CHCl3); IR (neat,
cmꢀ1): mmax 3522, 3342, 1719; 1H NMR (200 MHz,
CDCl3): d 0.99 (t, J = 8 Hz, 3H), 1.44 (s, 9H), 1.52–
1.63 (m, 2H), 2.54 (br s, OH, 1H), 3.62 (s, 3H), 3.83–
3.86 (m, 1H), 4.38–4.40 (m, 1H), 5.54 (br s, 1H); 13C
NMR (50 MHz, CDCl3): d 10.1, 26.3, 28.1, 52.3, 58.0,
74.3, 80.3, 155.8, 171.2. Anal. Calcd for C11H21NO5
(247.29): C, 53.43; H, 8.56; N, 5.66. Found: C, 53.40;
H, 8.52; N, 5.64.
4.1.6. 3-Bromopropanol 13. To a stirred solution of 1,3-
propanediol 12 (5 g, 65.70 mmol) in benzene (100 mL)
was added 48% aq HBr (12.7 mL, 78.84 mmol) and
the mixture stirred under reflux for 28 h while trapping
the water formed using a Dean–Stark water separator.
The mixture was washed with 6 M NaOH solution
(50 mL), 10% HCl (50 mL), water (2 · 100 mL), and
brine (75 mL). The organic layer was dried over anhy-
drous Na2SO4 and concentrated to near dryness. The
crude product was purified by silica gel column chroma-

3272
S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3268–3274
tography using EtOAc/pet ether (1:9) to give 13 (7.2 g)
as a colorless oil. Yield: 79%; 1H NMR (200 MHz,
CDCl3): d 2.05–2.25 (m, 2H), 2.55 (br s, 1H), 3.54 (t,
J = 6 Hz, 2H), 3.78 (t, J = 8 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d 30.1, 34.6, 59.5.
J = 10 Hz, 3H), 1.23–1.25 (m, 2H), 1.43 (s, 9H), 1.46–
1.49 (m, 4H), 1.55–1.62 (m, 2H), 2.01 (br s, 2H), 3.52
(t, J = 8 Hz, 2H), 3.66–3.83 (m, 2H), 5.56 (br s, 1H);
13C NMR (50 MHz, CDCl3): d 8.2, 19.0, 22.7, 25.6,
28.0, 31.7, 56.2, 62.2, 64.9, 77.8, 153.2. Anal. Calcd for
C13H27NO4 (261.36): C, 59.74; H, 10.41; N, 5.36.
Found: C, 59.72; H, 10.38; N, 5.33.
4.1.7. (3-Hydroxypropyl)-triphenylphosphonium bromide
14.
A
solution of 3-bromopropanol 13 (5 g,
35.97 mmol), triphenylphosphine (9.43 g, 35.97 mmol),
and K2CO3 (4.97 g, 35.97 mmol) in dry CH3CN
(50 mL) was heated at reflux under nitrogen for 7 h.
K2CO3 was filtered off and the filtrate diluted with ether
and the solution allowed to stand, during which, prod-
uct 14 was precipitated out as white crystals. (3.8 g,
26%). Mp 226–227 ꢁC [lit.12 Mp 226–229 ꢁC]; 1H
NMR (200 MHz, CDCl3): d 1.88–1.92 (m, 2H), 3.70–
3.85 (m, 3H), 4.60–4.66 (m, 2H), 7.71–7.79 (m, 15H).
4.1.10. 2-(1-Hydroxypropyl)-piperidine-1-carboxylic acid-
tert-butyl ester 17. To a stirred solution of compound
16 (0.4 g, 1.53 mmol) in dry CH2Cl2 (6 mL) was added
methanesulfonyl chloride (0.14 mL, 1.83 mmol) at
ꢀ78 ꢁC and then triethyl amine (0.25 mL, 1.83 mmol)
was added dropwise. After the mixture was stirred at
ꢀ78 ꢁC for 1 h, aqueous ammonium chloride (3 mL)
was added. The mixture was warmed to room tempera-
ture and diluted withCH 2Cl2 (5 mL), washed with
brine, and dried over Na2SO4. The solvent was removed,
and the residue purified by flash chromatography using
4.1.8. [5-Hydroxy-1-(1-hydroxypropyl)-pent-2-enyl]-car-
bamic acid tert-butyl ester 15. To a solution of 10
EtOAc/pet ether (4:6) to give 17 as a colorless liquid
25
(0.3 g, 1.21 mmol) dissolved in dry DCM (5 mL) was
added DIBAL-H (0.48 mL, 1.21 mmol, 2.5 M solution
of DIBAL-H in toluene) dropwise at ꢀ78 ꢁC. The reac-
tion mixture was stirred for 1 huntil the disappearance
of the starting material as indicated by TLC and then
quenched with saturated sodium potassium tartrate.
The precipitate obtained was filtered off and the com-
bined organic layers dried over Na2SO4 and concen-
trated to near dryness, which was used as such in the
next step without further purification.
(0.31 g). Yield: 84%; ½aŠ ¼ ꢀ12:2 (c 1, CHCl3); IR
(neat, cmꢀ1): mmax 3422,D 1688; 1H NMR (200 MHz,
CDCl3): d 0.96 (t, J = 6 Hz, 3H), 1.32–1.45 (m, 6H),
1.45 (s, 9H), 1.52–1.63 (m, 2H), 2.02 (t, J = 8 Hz, 2H),
2.96 (br s, 1H), 3.32–4.32 (m, 2H); 13C NMR
(50 MHz, CDCl3): d 9.8, 23.3, 24.4, 25.3, 26.2, 27.3,
53.2, 60.2, 70.9, 75.5, 164.9. Anal. Calcd for
C13H25NO3 (243.18): C, 64.16; H, 10.36; N, 5.76.
Found: C, 64.12; H, 10.33; N, 5.72.
4.1.11. Synthesis of (ꢀ)-a- conhydrine 1. To an ice-bath
solution of 17 (23 mg, 0.095 mmol) in dry CH2Cl2
(1 mL) was added trifluoroacetic acid (0.2 mL,
0.095 mmol). The reaction mixture was stirred at room
To a suspension of Wittig salt 14 (0.4 g, 1.01 mmol) in
dry THF (5 mL) was added n-BuLi (1.1 mL, 2.3 mmol)
at 0 ꢁC and stirred for 30 min. To this solution the above
crude aldehyde was added and stirred at rt for 12 h, and
then quenched with satd aq NH4Cl. The aqueous layer
was extracted withEtOAc (4 · 50 mL). The combined
organic extracts were washed with brine, dried over
Na2SO4 and concentrated. Purification of the residue
by silica gel column chromatography using EtOAc/pet
temperature for 12 hand then saturated aq NaHCO
3
added and the mixture extracted with dichloromethane
(3 · 5 mL). The combined organic layers were washed
withbrine, dried over Na SO4, and concentrated under
2
reduced pressure to near dryness. The crude product
was purified by silica gel column chromatography using
ether (6:4) as eluent gave 15 (0.127 g) as a colorless oil.
CH3OH/CH2Cl2 (4:6) as eluent to give 1 (12 mg) as a
25
25
Yield: 40%; ½aŠ ¼ ꢀ10:3 (c 1, CHCl3); IR (neat,
solid. Yield: 74%; ½aŠ ¼ ꢀ8:9 (c 1.0, ethanol). {lit.5a
D
D
25
cmꢀ1): mmax 3511, 3328, 1609; 1H NMR (200 MHz,
CDCl3): d 0.98 (t, J = 10 Hz, 3H), 1.25–1.36 (m, 2H),
1.47 (s, 9H), 2.1 (br s, 2H), 2.15–2.30 (m, 2H), 2.89–
2.97 (m, 2H), 4.20 (q, J = 6 Hz, 1H), 4.30 (t, J = 6 Hz,
1H), 5.42 (br s, 1H), 5.98–5.99 (m, 1H), 6.53 (t,
J = 6 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 12.6,
21.6, 28.0, 30.5, 61.0, 64.9, 71.2, 80.1, 128.5, 132.0,
153.2. Anal. Calcd for C13H25NO4 (259.34): C, 60.21;
H, 9.72; N, 5.40. Found: C, 60.18; H, 9.71; N, 5.38.
½aŠ ¼ ꢀ8:6 (ethanol)}]. The physical and spectroscopic
D
data of 1 were in full agreement withteh literature
data.5a
4.1.12. (2S,3S)-Pent-1,2,3-triol 19. To a mixture of
K3Fe(CN)6 (55.97 g, 0.17 mmol), K2CO3 (23.49 g,
0.17 mmol), and (DHQ)2PHAL (452 mg, 1 mol %) in
t-BuOH–H2O (1:1) cooled at 0 ꢁC was added osmium
tetroxide (2.3 mL, 0.1 M solution in toluene, 0.4
M mol %) followed by methanesulfonamide (5.5 g,
58.09 mmol). After stirring for 5 min at 0 ꢁC, olefin 18
(5 g, 58.09 mmol) was added in one portion. The reac-
tion mixture was stirred at 0 ꢁC for 24 hand tehn
quenched with solid sodium sulfite. Stirring was contin-
ued for an additional 45 min and then the solution
extracted withethyl acetate (5 · 100 mL). The combined
organic phases were washed with 10% aq KOH, brine,
dried over Na2SO4, and concentrated. Silica gel column
chromatography of the crude product using EtOAc/pet
4.1.9. [5-Hydroxy-1-(1-hydroxypropyl)-pentyl]-carbamic
acid tert-butyl ester 16. To a solution of 15 (0.50 g,
1.93 mmol) in methanol (10 mL) was added Pd/C
(50 mg) under a hydrogen atmosphere and mixture stir-
red for 4 h. After completion of the reaction, the mixture
was filtered through a celite pad, and concentrated to
near dryness. The crude product was purified by silica
gel column chromatography using EtOAc/pet ether
(6:4) as eluent to give 16 (0.478 g) as a liquid. Yield:
25
95%; ½aŠ ¼ ꢀ9:8 (c 1, CHCl3); IR (neat, cmꢀ1): mmax
ether (6:4) as eluent gave 19 (5.21 g) as a viscous liquid.
D
25
3520, 3318; 1H NMR (200 MHz, CDCl3): d 0.98 (t,
Yield: 75%; ½aŠ ¼ ꢀ6:7 (c 1, CHCl3); IR (neat, cmꢀ1):
D

S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3268–3274
3273
m
max 3400–3200, 2919, 2851, 1455, 1375, 1074; 1H NMR
(3 mL) and ethyl acetate (5 mL). After being stirred
for 1 hat room temperature, the mixture was filtered
through a celite pad. The filtrate was dried over anhy-
drous Na2SO4 and concentrated under reduced pres-
sure. The crude product was purified by silica gel
column chromatography using EtOAc/pet ether (1:9)
(200 MHz, CDCl3): d 0.9 (t, J = 6 Hz, 3H), 1.42–1.56
(m, 2H), 2.11 (br s, 2H), 3.51–3.59 (m, 2H), 3.67–3.73
(m, 3H). Anal. Calcd for C5H12O3 (120.15): C, 49.98;
H, 10.07. Found: C, 49.96; H, 10.02.
4.1.13.
(2S,3S)-1,3-O-Benzylidenepentane-1,2,3-triol
as eluent to give 22 (0.36 g) as a colorless oil. Yield:
25
20. To a solution of 19 (3 g, 24.96 mmol) in dry
CH2Cl2 (40 mL) were added p-TsOH (80 mg) and benz-
aldehyde dimethyl acetal (4.56 g, 4.49 mL, 29.96 mmol).
The reaction mixture was stirred at room temperature
for 12 h. Subsequently, it was neutralized with saturated
aq NaHCO3. The organic phase was separated and the
aqueous phase extracted with CH2Cl2. The combined
organic extracts were washed with aq NaHCO3, brine,
dried over Na2SO4, and concentrated. Column chroma-
tography over silica gel using EtOAc/pet ether (1:9) as
90%; ½aŠ ¼ ꢀ12:2 (c 1, CHCl3); IR (neat, cmꢀ1): mmax
D
3433, 2126, 1322, 1216, 1156, 1025; 1H NMR
(200 MHz, CDCl3): d 0.96 (t, J = 6.8 Hz, 3H), 1.29–
1.41 (m, 2H), 2.08 (br s, 1H), 2.11–2.14 (m, 1H), 3.37–
3.43 (m, 1H), 3.60 (d, J = 5.9 Hz, 2H), 4.69 (s, 2H),
7.33–7.40 (m, 5H); 13C NMR (50 MHz, CDCl3): d 9.3,
24.4, 59.6, 61.2, 74.2, 76.3, 127.6, 128.3, 129.6, 137.4.
Anal. Calcd for C12H17N3O2 (235.28): C, 61.26; H,
7.28; N, 17.86. Found: C, 61.22; H, 7.25; N, 17.85.
eluent furnished the major product 20 (3.82 g) as a col-
4.1.16. (5R,6S)-5-Azido-6-benzyloxyoct-3-ene-1-ol 23.
To a stirred solution of PCC (0.68 g, 3.19 mmol), anhy-
drous sodium acetate (0.26 g, 3.19 mmol), and celite in
dry CH2Cl2 (5 mL) at 0 ꢁC was added alcohol 22
(0.5 g, 2.12 mmol) in dry CH2Cl2 (3 mL) under an argon
atmosphere and stirring was continued for 4 h at room
temperature until the completion of reaction as indi-
cated by TLC. The reaction mixture was washed thor-
oughly with diethyl ether and concentrated to give an
aldehyde, which was used immediately in the next step
without further purification.
25
orless liquid. Yield: 74%; ½aŠ ¼ ꢀ11:5 (c 0.48, CHCl3);
D
IR (neat, cmꢀ1): mmax 3512, 2922, 2849, 1451, 1377, 1276,
1215; 1H NMR (200 MHz, CDCl3): d 1.0 (t, J = 7.4 Hz,
3H), 1.69–1.87 (m, 2H), 2.52 (br s, 1H, OH), 3.45–3.74
(m, 1H), 3.63–3.72 (m, 1H), 3.93 (dd, J = 2, 12 Hz,
2H), 5.58 (s, 1H), 7.37–7.58 (m, 5H); 13C NMR
(50 MHz, CDCl3): d 9.2, 24.0, 72.7, 79.8, 81.5, 101.3,
125.8, 128.1, 134.3, 137.9. Anal. Calcd for C12H16O3
(208.25): C, 69.21; H, 7.74. Found: C, 69.18; H, 7.71.
4.1.14. (2R,3S)-2-Azido-1,3-O-benzylidenepentane-1,3-
diol 21. To a solution of 20 (2 g, 9.6 mmol) in dry
CH2Cl2 (20 mL) at 0 ꢁC was added methanesulfonyl
chloride (1.65 g, 1.1 mL, 14.40 mmol), Et3N (2.27 mL,
16.32 mmol), and DMAP (cat). The reaction mixture
was stirred at room temperature for 6 hand then poured
into Et2O–H2O mixture. The organic phase was sepa-
rated and the aqueous phase extracted with Et2O. The
combined organic phases were washed with water, brine,
dried over Na2SO4, and concentrated to a white solid,
which was dissolved in dry DMF (20 mL). Sodium azide
(3.4 g, 48.01 mmol) was added and the reaction mixture
stirred at 80 ꢁC for 24 h. It was then cooled and poured
into water and extracted with ethyl acetate. The organic
extracts were washed with water, brine, dried over
Na2SO4, and concentrated. Column chromatography
on silica gel using EtOAc/pet ether (0.7:9.3) as eluent
To a stirred solution of salt 14 (1.70 g, 4.25 mmol) in dry
THF (20 mL) was added n-BuLi (2.12 mL, 2 M solution
in hexane, 4.25 mmol) at 0 ꢁC and stirring continued for
further 30 min. The above aldehyde was added to the
reaction mixture and stirred for 12 hat ambient temper-
ature and quenched with saturated ammonium chloride
solution. The organic layer was separated and the aque-
ous layer extracted withethyl acetate (3 · 20 mL), dried
over Na2SO4, and concentrated to near dryness. Purifi-
cation by silica gel column chromatography using
EtOAc/pet ether (7:3) as eluent gave 23 (0.35 g) as a vis-
25
cous liquid. Yield: 74%; ½aŠ ¼ ꢀ19:3 (c 0.52, CHCl3);
D
IR (neat, cmꢀ1): mmax 3429, 2133, 1616, 1221, 1156,
1025; 1H NMR (200 MHz, CDCl3):
d 0.96 (t,
J = 6.0 Hz, 3H), 1.32–1.46 (m, 2H), 2.02 (s, 1H), 2.15–
2.23 (m, 2H), 2.62–2.66 (m, 1H), 3.01 (q, J = 8.2 Hz,
1H), 3.62 (t, J = 10.5 Hz, 2H), 4.69 (s, 2H), 5.48 (t,
J = 12.6 Hz, 1H), 5.55 (q, J = 12.6 Hz, 1H), 7.15–7.28
(m, 5H); 13C NMR (50 MHz, CDCl3): d 9.4, 24.6,
36.5, 62.2, 64.6, 73.9, 81.2, 126.4, 127.6, 128.4, 129.3,
132.6, 137.5. Anal. Calcd for C15H21N3O2 (275.35): C,
65.43; H, 7.69; N, 15.26. Found: C, 65.40; H, 7.63; N,
15.21.
gave 21 (1.92 g) as a colorless liquid. Yield: 86%;
25
½aŠ ¼ ꢀ8:8 (c 1, CHCl3); IR (neat, cmꢀ1): mmax 2122,
D
2752, 1432, 1327, 1256, 1225; 1H NMR (200 MHz,
CDCl3): d 1.09 (t, J = 4 Hz, 3H), 1.62–1.76 (m, 2H),
3.50–3.62 (m, 2H), 3.99–4.01 (m, 2H), 5.97 (s, 1H),
7.39–7.53 (m, 5H); 13C NMR (50 MHz, CDCl3): d 9.8,
25.4, 51.7, 69.0, 80.0, 103.2, 126.4, 128.4, 129.2, 137.3.
Anal. Calcd for C12H15N3O2 (233.27): C, 61.79; H,
6.48; N, 18.01. Found: C, 61.76; H, 6.44; N, 17.98.
4.1.17. [5-Hydroxy-1-(1-hydroxypropyl)-pentyl]-carbamic
acid tert-butyl ester 16. To a solution of azide 23 (0.3 g,
1.09 mmol) in ethyl acetate was added 10% Pd/C
(75 mg) and Boc2O (0.3 mL, 1.3 mmol). The resulting
solution was stirred under a hydrogen atmosphere for
24 hat room temperature until disappearance of the azido
alcohol as monitored by TLC. The reaction mixture was
filtered through a celite pad to remove the catalyst and
the filtrate was concentrated in vacuo. Silica gel column
chromatography of the crude product using EtOAc/pet
4.1.15. (2R,3S)-2-Azido-3-benzyloxypentan-1-ol 22. To
a solution of 21 (0.4 g, 1.71 mmol), in dry CH2Cl2
(10 mL) was added dropwise DIBAL-H (2.57 mL, 2 M
solution in toluene, 5.14 mmol) at ꢀ78 ꢁC under an
argon atmosphere. The mixture was gradually allowed to
warm to room temperature and the stirring continued
overnight. The reaction mixture was cooled to 0 ꢁC
and to this was added successively saturated NH4Cl

3274
S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3268–3274
Rao, K. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 1957–
1958.
ether (3:7) as eluent gave 16 (0.24 g) as a colorless liquid.
25
yield: 86%; ½aŠ ¼ ꢀ8:9 (c 0.86, CHCl3). The physical
D
6. (a) Pais, G. C. G.; Fernandes, R. A.; Kumar, P.
Tetrahedron 1999, 55, 13445–13450; (b) Fernandes, R.
A.; Kumar, P. Tetrahedron: Asymmetry 1999, 10, 4349–
4356; (c) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem.
2002, 2921–2923; (d) Gupta, P.; Naidu, S. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 849–851; (e) Naidu, S. V.;
Gupta, P.; Kumar, P. Tetrahedron Lett. 2005, 46, 2129–
2131; (f) Kumar, P.; Naidu, S. V.; Gupta, P. J. Org. Chem.
2005, 70, 2843–2846; (g) Kumar, P.; Naidu, S. V. J. Org.
Chem. 2005, 70, 4207–4210.
7. (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000,
3447–3449; (b) Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2000, 41, 10309–10312; (c) Subba Rao, K. V.;
Kumar, P. Tetrahedron Lett. 2003, 44, 6149–6151; (d)
Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2002, 43, 4425–4426; (e) Fernandes, R. A.; Kumar,
P. Synthesis 2003, 129–135; (f) Naidu, S. V.; Kumar, P.
Tetrahedron Lett. 2003, 44, 1035–1037; (g) Kondekar, N.
B.; Subba Rao, K. V.; Kumar, P. Tetrahedron Lett. 2004,
45, 5477–5479; (h) Pandey, S. K.; Subba Rao, K. V.;
Kumar, P. Tetrahedron Lett. 2004, 45, 5877–5879; (i)
Bodas, M. S.; Kumar, P. Tetrahedron Lett. 2004, 45, 8461–
8463; (j) Kumar, P.; Bodas, M. S. J. Org. Chem. 2005, 70,
360–363.
8. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 448–481; (b) Torri, S.; Liu, P.; Bhuvanes-
wari, N.; Amatore, C.; Jutand, A. J. Org. Chem. 1996, 61,
3055–3060; For a review on asymmetric dihydroxylation,
see: (c) Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K.
B. Chem. Rev. 1994, 94, 2483–2547.
9. Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yama-
guchi, S.; Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya,
H.; Osada, H. J. Am. Chem. Soc. 2002, 124, 12078–
12079.
and spectroscopic data were in accord withtohse
described in Section 4.1.9. The transformation of 16 to
the target compound 1 is already described in Sections
4.1.10 and 4.1.11.
Acknowledgments
Subba Rao thanks CSIR, New Delhi for senior research
fellowship. We are grateful to Dr. M. K. Gurjar for his
support and encouragement. Financial support from
DST, New Delhi (Grant No. SR/S1/OC-40/2003) is
gratefully acknowledged.
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