Stereoselective synthesis of (-)-α-conhydrine

Article abstract of DOI:10.1016/j.tetasy.2011.10.008

(-)-α-Conhydrine was synthesized from propargyl alcohol in 20% overall yield in nine steps. The key intermediates were obtained via a regioselective epoxide opening, cross-metathesis, tandem hydrogenation and hydrogenolysis, and stereoselective dihydroxyl

Full text of DOI:10.1016/j.tetasy.2011.10.008

Tetrahedron: Asymmetry 22 (2011) 1778–1783
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (ꢀ)-
a-conhydrine
⇑
Gowrisankar Reddipalli, Mallam Venkataiah, Nitin W. Fadnavis
Biotransformations Laboratory, Organic Division-I, Indian Institute of Chemical Technology, Habsiguda, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
(ꢀ)-
a-Conhydrine was synthesized from propargyl alcohol in 20% overall yield in nine steps. The key
Received 20 September 2011
Accepted 18 October 2011
Available online 17 November 2011
intermediates were obtained via a regioselective epoxide opening, cross-metathesis, tandem hydrogena-
tion and hydrogenolysis, and stereoselective dihydroxylaton. The side product from the epoxide ring
opening was used to synthesize the seven-membered amino sugar DMJ analogue.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
(+)-b-conhydrine started from the enantiopure benzyl protected
2-hydroxypropionaldehyde 15 (obtained in three steps, 77%),
Alkaloids that possess hydroxyalkyl piperidine and polyhydr-
oxylated piperidine units have attracted considerable attention
from the synthetic community due to their potent glycosidase
inhibitor, antiviral, and antitumor properties.1,2 Conhydrine is
one of the alkaloids isolated from the seeds and leaves of the poi-
sonous plant Conium maculatum L., and its structure was eluci-
dated in 1933.3
which was converted into the hydrazone of (S)-(ꢀ)-1-amino-2-
(methoxymethyl)pyrrolidine 14. The hydrazone 16 was then
converted to (+)-b-conhydrine 3 via allylation and ring closing
metathesis of 17 in overall 11% yield (Scheme 1).
NH
NH
NH
NH
Several routes for the synthesis of these alkaloids along with
their epimers and enantiomers 1–4 (Fig. 1) have been reported.4
For example, Pilard et al.4a have synthesized racemic b-conhydrine
from 8-chlorooct-3-yne 5, which was partially hydrogenated to a
cis-olefin; the chloro-olefin was transformed into azido compound
6 and the olefinic group was converted to an epoxy group. The azi-
do compound was reduced to amino compound 7 wherein the ami-
no group internally attacked the epoxide in refluxing benzene to
give ( )-b-conhydrine in 57% overall yield (five steps). In another
approach, Ratovelomanana et al.4b used 2-cyano-6-oxazolopiperi-
dine 8 as a starting reagent which was condensed with propional-
dehyde to obtain 9. A stereospecific reaction with NaBH4 to 10 and
debenzylation gave (+)-b-conhydrine. The product was thus
obtained in 24% yield in four steps based on 8 as a starting material
which itself was prepared in 68% overall yield in three steps. The
approach of Comins et al.4c involves the synthesis of (+)-b-conhy-
drine starting with the addition of cis-propenylmagnesium bro-
mide to a mixture of 4-methoxy-3-(triisopropylsilyl)pyridine 11
and the chloroformate of (+)-TCC to obtain 12. The one-pot
removal of the chiral auxiliary and TIPS group gave enantiopure
dihydropyridone 13, which was then converted to (+)-b-conhy-
drine in several steps. The overall yield of the product thus
obtained was 17%. Lebrun’s approach4d toward the synthesis of
OH
OH
OH
OH
4
(-)-β-Conhydrine
1
2
3
(+)-β-Conhydrine
(+)-α-Conhydrine
(-)-α-Conhydrine
Figure 1.
The synthesis of (ꢀ)-b-conhydrine has been carried out by
employing a phenyl glycinol derived Weinreb amide 18 by Agami
et al. (Scheme 2).5a The reaction of ethylmagnesium bromide with
amide 18 and the NaBH4 mediated reduction of the resulting
ketone gave
a-hydroxy oxazolidine 19. Reductive debenzylation
with sodium gave an oxazolidinone 20, which was allylated and
converted into a di-olefin oxazolidinone 21. Ring-closing metathe-
sis followed by hydrogenation of the bicyclic oxazolidinone and
alkaline hydrolysis gave (ꢀ)-b-conhydrine 4 with 9% overall yield
in seven steps. Pandey and Pradeep Kumar have used commer-
cially available L-aspartic acid 22 to prepare a single isomer of
syn-amino alcohol 23 which was the key intermediate for the
synthesis of 24 which was then converted to (ꢀ)-b-conhydrine in
an overall yield of 19% in 10 steps.5b Saikia et al.5c have subjected
4-nitro-1-butene 25 to Shibasaki’s asymmetric Henry reaction
with propionaldehyde in the presence of a La-(R)-BINOL catalyst
to obtain 2-nitroalcohol 26, which was converted into a b-hydroxy
amine. Protection and allylation of the amine function gave 27.
Ring closing metathesis with Grubbs’ second generation catalyst
gave the expected cyclic enamine, which was further converted
to (ꢀ)-b-conhydrine in 21% yield.
⇑
Corresponding author. Tel.: +91 40 27191631; fax: +91 40 27160512.
E-mail addresses: fadnavis@iict.res.in, fadnavisnw@yahoo.com (N.W. Fadnavis).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.008

G. Reddipalli et al. / Tetrahedron: Asymmetry 22 (2011) 1778–1783
1779
H
H
NH
O
Cl
H
H
NH2
5
6
7
OH
N3
β
racemic -Conhydrine
BnO
Ph
NC
Ph
Ph
N
N
O
N
N
H
NH
HO
H
HO
H
H
N
O
NC
N
O
N
O
OH
OMe
OMe
OH
9
8
10
17
16
(+)-β-Conhydrine 3
O
N
OTf
TIPS
OMe
NH2
N
H
TIPS
I
OBn
N
O
N
OMe
+
O
*RO
O
O
15
11
12
13
14
Scheme 1.
In a noteworthy approach, Liu et al.6 have synthesized a racemic
mixture of conhydrines 29 from piperidine 28. Oxidation with
Jones’ reagent produced amino ketone 30. Ruthenium-catalyzed
2. Results and discussion
2.1. Synthesis of (ꢀ)- -conhydrine 2
a
asymmetric hydrogenation of the ketone gave (ꢀ)-a-conhydrine
2 in 26% overall yield. It was possible to convert 2 into (+)-b-con-
Commercially available propargyl alcohol 31 was treated with
allyl bromide in the presence of copper iodide, sodium iodide and
K2CO3 in acetone at room temperature to give allylated propargyl
alcohol 32 (85%). Alkyne 32 was reduced with LiAlH4 in dry THF to
give allylic dienol 33 (87%). Dienol 33 was treated under Sharpless
asymmetric epoxidation conditions by using TBHP, titanium iso-
propoxide and (+)-DET in dry DCM at ꢀ20 °C to obtain (S,S)-epoxy
alcohol 34 (85%).8 Opening of the epoxy alcohol with allylamine un-
der Chini’s conditions using lithium perchlorate9 gave a mixture of
N-allyl diols, which was immediately sonicated with (Boc)2O and
NaHCO3 in methanol to give an inseparable mixture of amino pro-
tected allyl diols 35 and 36. The mixture was treated with dimethyl
hydrine 3 via its cyclic sulfate and SN2 inversion with sodium
acetate. By using the same procedure, (+)-a-conhydrine 1 was con-
verted to (+)-b-conhydrine 3 (Scheme 3).
In addition to the routes mentioned above, there are other
approaches which have been reported in the literature for the
synthesis of conhydrines.7 Many of the approaches above suffer
from long reaction sequences, require expensive chiral catalysts,
and provide low overall yields. Herein we report the synthesis of
(ꢀ)-
a-conhydrine 2 from inexpensive and commercially available
propargyl alcohol via regioselective epoxy opening and cross
metathesis.
O
O
OH
O
N
O
HN
O
N
Me
N
N
Ph
Ph
Boc
Boc
OMe
O
20
O
21
18
19
O
OH
OEt
HOOC
OTBS
COOH
NO2
NBoc
O
N
H
NH2
NBn2
23
OH
22
24
(-)-β-Conhydrine 4
NO2
NBoc
OH
25
27
26
OAc
Scheme 2.
N
H
N
H
N
H
N
N
H
N
H
N
H
OH
OH
O
O
S
O
OAc
OH
29
30
28
α
2
(-)- -Conhydrine
3
(+)-b-Conhydrine
O
Scheme 3.

1780
G. Reddipalli et al. / Tetrahedron: Asymmetry 22 (2011) 1778–1783
O
c
a
b
OH
OH
OH
85%
87%
OH
85%
33
31
32
34
Ph
O
O
OH
NBoc
NBoc
O
d
e
+
OH
OH
+
O
64%
NBoc
(20%)
98%
NBoc
OH
Ph
35
36
38
37 (80%)
f (96%)
g
i
h
NBoc
NBoc
NBoc
NH
93%
92%
77%
OH
OH
OBn
OBn
41
OBn
40
OH
2
(-)-α-Conhydrine
39
Scheme 4. Reagents and conditions: (a) allyl bromide, NaI, K2CO3, CuI, acetone, 3 h; (b) LAH, THF, 4 h; (c) (+)-DET, TBHP, Ti (OiPr)4, dry DCM, ꢀ20 °C, 12 h; (d) (i) LiClO4, allyl
amine, CH3CN, 10 h, (ii) (Boc)2O, NaHCO3, MeOH, 16 h; (e) benzaldehyde dimethyl acetal, PTSA, DCM, 10 h; (f) DIBAL-H, DCM, 0 °C–rt, 1 h; (g) 5 mol % Grubbs’s first
generation catalyst, DCM, 40 °C, 5 h; (h) (i) DMSO, (COCl)2, DCM, ꢀ78 °C, 45 min; (ii) CHþ3 PPh3Iꢀ, KOtBu, THF, 0 °C, 6 h; (i) 10% Pd/C, methanolic HCl, 20 h.
benzaldehyde acetal to give 1,2-benzylidine derivative 37 and
1,3-benzylidine derivative 38 in an 8:2 ratio. which was easily sep-
arated by column chromatography. In the 13C NMR spectrum of 37
the C-2 carbon of the 1,3-dioxalane ring resonated at 104.7 ppm
indicating the formation of a five-membered ring. In the case of 38
this carbon resonated at 100.9 ppm indicating the formation of a
six-membered ring. This also indicated that epoxide opening at
the C-3-position was the major reaction.
The treatment of 37 with DIBAL-H in dry DCM at 0 °C for 1 h
gave benzylated alcohol 39. Ring closing metathesis (RCM) of 39
using Grubbs’s 1st generation catalyst in DCM at 40 °C for 5 h gave
product 40 (93%). The RCM product 40 was oxidized under Swern
conditions followed by Wittig olefination with methyl phospho-
nium salt in dry THF at ꢀ78 °C to obtain olefin product 41 (77%).
Tandem hydrogenation and hydrogenolysis of compound 41 with
such as DMJ and DNJ analogues have received much attention.1,2
Seven membered iminocyclitols have several properties that make
them potentially useful as drug candidates. The flexibility of the
seven-membered ring compared with five or six-membered rings
allows the hydroxyl groups to adopt a variety of positions increas-
ing the probability of forming hydrogen bonds with structural
motifs found within a DNA framework, or within the active sites
of various proteins leading to better inhibiting activity..10 During
our studies, we discovered that the 1,3-benzaldehyde acetal deriv-
ative 38 obtained as a side product in Scheme 4 could be
conveniently used for the synthesis of the seven membered imino-
cyclitol DMJ analogue 45. Compound 45 has been found to be a
good inhibitor of
and b-mannosidase with Ki values ranging between 30 and
60
M.11 Compound 38 was treated with Grubbs’s 1st generation
a-galactosidase, a-mannosidase, b-glucosidase
l
Pd/C in methanolic HCl gave (ꢀ)-
a
-conhydrine 2. Thus starting
catalyst in DCM at 40 °C for 8 h to obtain ring closing metathesis
product 42 (96%). Compound 42 was treated with osmium tetrox-
ide and NMO in acetone and water to obtain anti-cyclic diol 43 as
the major product (89%, de 94%). Cyclic diol 43 was treated with
methanolic HCl solution to give the hydrochloride salt of tetra-
hydroxy 44, which was subsequently adsorbed on a DOWEX
50W X8 resin and treated with ammonia to give the seven mem-
bered analogue of DMJ 45 (95%, 81% overall in three steps starting
from propargyl alcohol, compound 2 was obtained in 20% overall
yield in nine steps.
2.2. Synthesis of iminocyclitol, DMJ analogue 42
Among the many glycosidase inhibitors, nojirimycin, 1-deoxy-
nojirimycin, mannozirimycin and seven membered iminocyclitols
Ph
Ph
Ph
O
Ph
HO
O
HO
O
O
O
j
k
O
+
O
O
HO
HO
96%
NBoc
NBoc
89%
NBoc
NBoc
42
38
43 (97%)
44
(3%)
95%
l
HO
OH
OH
HO
NH
45
Scheme 5. Reagents and conditions: (j) 5 mol % Grubbs’s first generation catalyst, DCM, 40 °C, 8 h; (k) OsO4, NMO, H2O/acetone (4:2), rt, 5 h; (l) methanolic HCl, 1 h, DOWEX
50W X8.

G. Reddipalli et al. / Tetrahedron: Asymmetry 22 (2011) 1778–1783
1781
from 38). The structure was confirmed by comparison of the spec-
raphy on silica gel (60–120 mesh, EtOAc/hexane, 2:8) to yield com-
troscopic data with the literature values (Scheme 5).11
pound 34 (0.75 g, 85%) as a colorless oil 94.5% ee ½a D25
¼ ꢀ34:6 (c 1,
ꢂ
CHCl3). {Lit9
½
a 2D0
ꢂ
¼ ꢀ36:0 (c 1.15, CHCl3)}.
The enantiomeric excess of epoxide 34 was determined after
derivatizing to a p-toluenesulfonate ester. Analysis was carried
out by HPLC on chiral stationary phase using Chiralcel OD column
(250 ꢁ 5 mm). Detection wavelength 254 nm, mobile phase 10%
2-propanol in hexane, flow rate 0.5 ml/min. Retention times:
3. Conclusion
In conclusion, we have synthesized the (ꢀ)-
a-conhydrine in
nine simple steps with an overall yield of 20%. The isomer obtained
as a result of the C-2 attack by allylamine is also used to synthesize
a b-glucosidase inhibitor DMJ analogue.
(2R,3R) 17.4 min; (2S,3S) 18.8 min. IR(neat)
mmax: 1229, 1743,
2982, 3404 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.53 (br, 1H), 2.34
.
(t, J = 6.60 Hz, 2H), 2.91 (qn, J = 2.66 Hz, 1H), 3.02 (td, J = 2.66 Hz,
1H), 3.55–3.65 (m, 1H), 3.83–3.94 (m, 1H), 5.06–5.19 (m, 2H),
5.75–5.90 (m, 1H). 13C NMR (75 MHz, CDCl3): d 35.4, 54.8, 58.0,
62.2, 117.6, 132.4. GCMS: m/z 114(M)+.
4. Experimental
4.1. General
All reagents were purchased from Aldrich. IR spectra were
4.1.4. tert-Butyl allyl((2R,3R)-1,2-dihydroxyhex-5-en-3-yl)car-
bamates 35 and 36
recorded on
a
Perkin–Elmer RX-1 FT-IR system. 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were recorded on a
Bruker Avance-300 MHz spectrometer. Optical rotations were mea-
sured with a Horiba-SEPA-300 digital polarimeter. Mass spectra
were recorded on a Q STAR mass spectrometer (Applied Biosystems,
USA).
To a solution of the epoxide 34 (0.32 g, 2.77 mmol) in CH3CN
(20 mL) was added allyl amine (0.47 g, 8.31 mmol) and LiClO4
(0.59 g, 5.54 mmol) and the reaction mixture was stirred at ambi-
ent temperature for 10 h. The organic layer was then evaporated
under reduced pressure and the crude diol was sonicated with
(Boc)2O (0.91 g, 4.15 mmol) and NaHCO3 (0.70 g, 3.76 mmol) in
methanol (10 mL) for 16 h. The reaction mixture was filtered, after
which the filtrate was evaporated under reduced pressure and the
residue was purified by column chromatography over silica gel
(60–120 mesh, EtOAc/hexane, 2:3) to yield a mixture of com-
pounds 35 and 36 (0.49 g, 65%) as a colorless oil. IR(neat) mmax:
4.1.1. Hex-5-en-2-yn-1-ol 32
To a solution of propargyl alcohol 31 (2 g, 35.7 mmol) in ace-
tone (100 mL) was added sodium iodide (5.35 g, 35.7 mmol), cop-
per iodide (0.136 g, 0.7 mmol) and K2CO3 (7.40 g, 49.3 mmol)
followed by allyl bromide (4.75 g, 39.3 mmol). The reaction mix-
ture was stirred for 3 h at room temperature. The reaction mixture
was filtered and the residue was extracted with EtOAc
(2 ꢁ 100 mL) and dried over anhydrous Na2SO4. After evaporation
of the solvent, the residue was chromatographed over silica gel
(60–120 mesh, EtOAc/hexane, 3:7) yielding 32 (2.92 g, 85%) as an
1165, 1406, 1668, 2976, 3414 cmꢀ1 1H NMR (300 MHz, CDCl3): d
.
1.46 (br, 9H), 2.21–2.70 (m, 2H), 3.00 (br, 1H), 3.23 (br, 1H),
3.41–3.60 (m, 1H), 3.64–3.80 (m, 2H), 3.83–3.99 (m, 1H),
4.97–5.23 (m, 4H), 5.62–5.92 (m, 2H). ESIMS: m/z 294 (M+Na)+.
oil. IR(neat) mmax
: .
1010, 1419, 2871, 3351 cmꢀ1 1H NMR
4.1.5. tert-Butyl allyl((1R)-1-((4R)-2-phenyl-1,3-dioxolan-4-
yl)but-3-en-1-yl)carbamate 37 and tert-butyl allyl((4S,5R)-4-
allyl-2-phenyl-1,3-dioxan-5-yl)carbamate 38
(300 MHz, CDCl3): d 1.76 (br, 1H), 3.01 (d, J = 3.16, 2H), 4.26 (s,
2H), 5.11 (d, J = 9.93, 1H), 5.25–5.34 (m, 1H), 5.65–5.84 (m, 1H).
13C NMR (75Mz, CDCl3): d 22.8, 50.6, 80.5, 82.5, 116.0, 132.2.
GCMS: m/z 96 (M)+.
Benzaldehyde dimethyl acetal (0.21 g, 1.38 mmol) and PTSA
(32 mg, 0.14 mmol) were added to a solution of a mixture of the
N-Boc-protected diols 35 and 36 (0.312 g, 1.15 mmol) in dry CH2Cl2
(20 mL). The reaction mixture was stirred at ambient temperature
for 10 h. The organic layer was evaporated under reduced pressure
to afford the crude acetonide, which was purified by column chro-
matography over silica gel (60–120 mesh, EtOAc/hexane, 1:8) to
yield 37 (0.304 g) and 38 (0.101 g) (combined yield 98%) as a col-
4.1.2. Hexa-2,5-dien-1-ol 33
To a solution of lithium aluminum hydride (0.73 g, 19.7 mmol)
in dry THF (25 mL) was added dropwise alcohol 32 (0.95 g,
9.9 mmol) in dry THF at 0 °C for 20 min, after which the reaction
mixture was refluxed for 4 h. The reaction was quenched with a
cold saturated NH4Cl solution (10 mL) and stirred for 30 min. The
reaction mixture was filtered and the solvent was evaporated
under reduced pressure. The residue was extracted with EtOAc
(2 ꢁ 20 mL) and dried over anhydrous Na2SO4. After evaporation
of the solvent, the residue was chromatographed over silica gel
(60–120 mesh, EtOAc/hexane, 1:4) yielding 33 (0.85 g, 87%) as an
orless oil. 37 ½a D25
ꢂ
¼ ꢀ32:3 (c 1, CHCl3). IR(neat) mmax: 1154, 1271,
1402, 1693, 2975 cmꢀ1
.
1H NMR (300 MHz, CDCl3): 1.44 (s, 9H),
2.33–2.61 (m, 2H), 3.60–4.40 (m, 6H), 4.96–5.17 (m, 4H),
5.61–5.88 (m, 3H), 7.30–7.37 (m, 3H), 7.38–7.47 (m, 2H). 13C
NMR (75 MHz, CDCl3): d 28.3, 29.6, 32.9, 47.5, 58.0, 68.8, 78.2,
79.8, 80.4, 104.7, 116.3, 117.0, 117.3, 126.5, 126.7, 128.3, 129.3,
134.6, 135.0, 135.6, 137.1, 155.8. ESIMS: m/z 360 (M+1)+,
382(M+Na)+. HRMS calcd for C21H29NO4Na: [M+Na]+ 382.1994,
oil. IR(neat) m .
max: 1088, 1428, 2924, 3353 cmꢀ1 1H NMR (300Mz,
CDCl3): d 1.62 (br, 1H), 2.77–2.84 (m, 2H), 4.09–4.14 (m, 2H),
5.01–5.21 (m, 2H), 5.62–5.80 (m, 3H). 13C NMR (75 MHz, CDCl3):
d 36.1, 63.2, 115.4, 129.9, 130.2, 136.2. GCMS: m/z 98 (M)+.
found 382.1985. Compound 38 ½a D25
ꢂ
¼ ꢀ29:3 (c 1, CHCl3). IR(neat)
mmax: 1154, 1271, 1402, 1693, 2975 cmꢀ1
.
1H NMR (300 MHz,
CDCl3): d 1.44 (s, 9H), 2.33–2.61 (m, 2H), 3.60–4.40 (m, 6H),
4.96–5.17 (m, 4H), 5.61–5.88 (m, 3H), 7.30–7.37 (m, 3H),
7.38–7.47 (m, 2H). 13C NMR (75 MHz, CDCl3): d 28.3, 28.5, 33.8,
36.4, 36.8, 68.9, 77.7, 78.5, 100.9, 116.6, 117.1, 126.1, 126.5,
128.2, 128.4, 128.8, 129.3, 134.3, 134.9, 135.5, 137.9, 154.7. ESIMS:
m/z 360 (M+1)+, 382 (M+Na)+. HRMS calcd for C21H29NO4Na:
[M+Na]+ 382.1994, found 382.1991.
4.1.3. ((2S,3S)-3-Allyloxiran-2-yl)methanol 34
To a stirred solution of (+)-diethyl tartrate (0.58 g, 2.8 mmol)
and 4 Å molecular sieves (1 g) in dry CH2Cl2 (25 mL), titanium
isopropoxide (0.54 g, 1.9 mmol) was added and stirred at ꢀ25 °C
for 30 min. Alcohol 33 (0.92 g, 9.4 mmol) was added to the reaction
mixture and stirred at the same temperature for 30 min. Next,
TBHP (1.0 g, 11.3 mmol) was added and stirred for 12 h at the same
temperature. The reaction was then quenched with 30% NaOH
(2 mL), filtered and the reaction mixture was extracted with CH2Cl2
(2 ꢁ 20 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
4.1.6. tert-Butyl allyl((2S,3S)-2-(benzyloxy)-1-hydroxyhex-5-en-
3-yl)carbamate 39
To a stirred solution of compound 37 (0.27 g, 0.76 mmol) in dry
THF (20 mL), DIBAL-H (0.16 g, 1.13 mmol) was added at 0 °C and

1782
G. Reddipalli et al. / Tetrahedron: Asymmetry 22 (2011) 1778–1783
the solution was stirred for 1 h. After the completion of the reac-
tion, a saturated solution of sodium potassium tartrate in water
(2 mL) was added to quench the reaction. The solvent was then
evaporated under reduced pressure, after which the reaction mix-
ture was extracted with EtOAc (2 ꢁ 15 mL), dried over anhydrous
Na2SO4 and concentrated. After evaporation of ethyl acetate the
residue was chromatographed (silica gel, 60–120 mesh, EtOAc/
127.4, 127.6, 128.3, 138.2, 143.2, 154.9. ESIMS: m/z 352 (M+Na)+.
HRMS calcd for C20H27NaNO3: [M+Na]+ 352.1888, found 352.1885.
4.1.9. (ꢀ)-
a-Conhydrine 2
To a stirred solution of compound 41 (0.09 g, 0.273 mmol) in
4 M methanolic HCl (10 mL) palladium/C (15 mg) was added. The
reaction mixture was stirred under a hydrogen atmosphere at rt
for 20 h. The reaction mixture was filtered through a pad of Celite,
and the filtrate was evaporated to dryness. The residue was
neutralized with saturated NaHCO3 (4 mL), and the compound
extracted with CH2Cl2 (2 ꢁ 8 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated under
reduced pressure to give the desired product 2 as a white solid
hexane, 2:8) to obtain 39 (0.26 g, 96%) as
¼ ꢀ8:9 (c 1, CHCl3). IR(neat) mmax 1365, 1700, 2923,
3415 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.43 (s, 9H), 2.20–2.67
a colorless oil.
½
a 2D5
ꢂ
:
.
(m, 2H), 3.31–4.01 (m, 6H), 4.43–4.58 (m, 2H), 4.92–5.14 (m,
4H), 5.61–5.81 (m, 2H), 7.20–7.33 (m, 5H). 13C NMR (75 MHz,
CDCl3): d 28.3, 28.4, 31.2, 51.5, 60.3, 71.6, 73.1, 80.1, 116.6,
117.0, 127.7, 127.9, 128.4, 128.5, 135.0, 135.8, 138.1, 156.5. ESIMS:
m/z 384 (M+Na)+. HRMS calcd for C21H31NO4Na: [M+Na]+
384.2151, found 384.2159.
(0.080 g, 92%). ½a D25
ꢂ
¼ ꢀ9:1 (c 1, EtOH) {Lit4a
½
a 2D5
ꢂ
¼ ꢀ8:6 (EtOH)}.
IR(KBr)
m .
max: 1455, 2854, 2928, 3285 cmꢀ1 1H NMR (300 MHz,
CDCl3): d 0.98 (t, J = 7.5 Hz, 3H), 1.22–1.98 (m, 8H), 2.56 (td,
J = 2.7, 10.9 Hz, 1H), 2.72 (m, 1H), 3.06 (br, 2H), 3.11 (m, 1H),
3.43 (m, 1H). 13C NMR (75 MHz, CDCl3): d 10.6, 24.3, 25.1, 25.6,
26.5, 47, 60.3, 75.8. ESIMS: m/z 144 (M+1)+.
4.1.7. (S)-tert-Butyl 6-((S)-1-(benzyloxy)-2-hydroxyethyl)-5,6-
dihydropyridine-1(2H)-carboxylate 40
Alcohol 39 (0.22 g, 0.60 mmol) was dissolved in dry CH2Cl2
(50 mL). Grubbs’s 1st generation catalyst (25 mg, 0.03 mmol) was
added and the reaction mixture was stirred at 40 °C for 5 h. The
dark brown solution was concentrated in vacuo and the residue
was chromatographed (silica gel, 60–120 mesh, EtOAc/hexane,
4.1.10. (4aR,9aS)-tert-Butyl 2-phenyl-4,4a,9,9a-tetrahydro-
[1,3]dioxino[5,4-b]azepine-5(6H)-carboxylate 42
Diene 38 (0.21 g, 0.57 mmol) was dissolved in dry CH2Cl2
(50 mL). Grubbs’s 1st generation catalyst (28 mg, 0.03 mmol) was
added and the reaction mixture was stirred at 40 °C for 8 h. The
dark brown solution was concentrated in vacuo and the residue
was chromatographed (silica gel, 60–120 mesh, EtOAc/hexane,
2:8) to obtain 40 (0.188 g, 93%) as a colorless oil. ½a D25
¼ ꢀ3:3 (c
ꢂ
1, CHCl3). IR(neat) mmax: 1167, 1293, 1408, 1724, 2930,
3428 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.41 (s, 9H), 2.17–2.59
.
2:8) to obtain 42 (0.182 g, 96%) as a white solid. ½a D25
ꢂ
¼ ꢀ72:0 (c
(m, 2H), 3.28–3.50 (m, 2H) 3.82 (br, 1H), 3.99–4.36 (m, 2H),
4.42–4.60 (m, 2H), 5.27–5.82 (m, 2H), 7.26–7.37 (m, 5H). 13C
NMR (75 MHz, CDCl3): d 24.4, 28.5, 40.2, 48.9, 50.0, 68.0, 72.3,
79.9, 116.5, 117.0, 123.0, 123.3, 127.8, 128.5, 137.7, 154.7. ESIMS:
m/z 356 (M+Na)+. HRMS calcd for C19H27NO4Na: [M+Na]+
356.1836, found 356.1815.
1, CHCl3). IR(KBr)
m .
max: 1127, 1323, 1599, 1745 cmꢀ1 1H NMR
(300 MHz, CDCl3): d 1.48 (s, 9H), 2.58 (br, 2H), 3.36–3.53 (m, 1H),
3.59–3.70 (m, 1H), 3.80–4.44 (m, 4H), 5.46 (s, 1H), 5.72 (m, 2H),
7.29–7.40 (m, 3H), 7.41–7.52 (m, 2H). 13C NMR (75 MHz, CDCl3):
d 28.2, 29.5, 36.0, 40.0, 41.4, 56.0, 68.4, 77.9, 80.4, 101.4, 126.0,
127.8, 128.2, 128.4, 128.9, 137.9,154.9. ESIMS: m/z 332 (M+1)+,
354 (M+Na)+. HRMS calcd for C19H25NO4Na: [M+Na]+ 354.1681,
found 354.1682.
4.1.8. (S)-tert-Butyl 6-((R)-1-(benzyloxy)allyl)-5,6-dihydropyr-
idine-1(2H)-carboxylate 41
To a stirred solution of DMSO (0.12 g, 1.48 mmol), oxalyl chlo-
ride (0.13 g, 1 mmol) in dry DCM (20 mL) was added at ꢀ78 °C
and the solution was stirred for 30 min. Then compound 40
(0.17 g, 0.5 mmol) in DCM (5 mL) was added dropwise. After com-
pletion of the reaction (TLC), triethylamine (2 mL) was added to
quench the reaction. The solvent was then evaporated under
reduced pressure. The reaction mixture was extracted with DCM
(2 ꢁ 15 mL), dried over anhydrous Na2SO4 and concentrated to
obtain the crude aldehyde product which was used as such with-
out further purification due to its instability on a silica gel column.
To a stirred solution of methyl triphenylphosphonium bromide
(0.52 g, 1.48 mmol) in dry THF (20 mL) at 0 °C was added potas-
sium tert butoxide (0.14 g, 1.23 mmol) and the resulting solution
was stirred for 3 h. The crude aldehyde obtained above was dis-
solved in dry THF (5 mL) and added dropwise with stirring to the
ylide solution at ꢀ0 °C. Cooling was then removed and the reaction
mixture was stirred at room temperature for 3 h. The reaction was
quenched with a saturated NH4Cl (6 mL) solution at 0 °C, and the
solvent was evaporated under reduced pressure. The residue was
extracted with EtOAc (2 ꢁ 15 mL) and dried over anhydrous
Na2SO4. After evaporation of ethyl acetate, the residue was chro-
matographed (silica gel, 60–120 mesh, EtOAc/hexane, 2:98) to
4.1.11. (4aR,7R,8S,9aS)-tert-Butyl 7,8-dihydroxy-2-phenylhexa-
hydro-[1,3]dioxino[5,4-b]azepine-5(6H)-carboxylate 43
To a stirred solution of compound 42 (0.15 g, 0.46 mmol) water
and acetone 4:1 (20 mL) was added osmium tetroxide in toluene
(25 mM in toluene, 1 mL) and NMO (0.18 g, 1.35 mmol) at rt and
the solution was stirred for 5 h. The reaction mixture was extracted
with EtOAc (2 ꢁ 15 mL), dried over anhydrous Na2SO4 and concen-
trated. The residue was chromatographed (silica gel, 60–120 mesh,
EtOAc/hexane, 1:1) to obtain 43 (0.148 g, 89%) as a white solid.
½
a 2D5
ꢂ
¼ ꢀ42:1 (c 1, CHCl3). IR(KBr) mmax: 1170, 1459, 1739, 2856,
2927, 3456 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.45 (s, 9H),
.
1.80–2.80 (m, 5H), 3.04–3.17 (m, 1H), 3.44–3.92 (m, 3H),
4.02–4.11 (m, 1H), 4.18–4.36 (m, 2H), 5.51 (s, 1H), 7.27–7.38 (m,
3H), 7.41–7.52 (m, 2H). 13C NMR (75 MHz, CDCl3): d 28.4, 29.7,
36.7, 42.8, 56.6, 67.1, 69.0, 72.8, 73.4, 81.3, 101.8, 126.0, 128.3,
128.9, 137.6, 155.8. ESIMS: m/z 388 (M+Na)+. HRMS calcd for
C
19H27NO6Na: [M+Na]+ 388.1736, found 388.1743.
4.1.12. (3R,4S,6S,7R)-7-(Hydroxymethyl)azepane-3,4,6-triol 45
To a stirred solution of compound 43 (0.12 g, 0.33 mmol), 4 M
methanolic HCl (10 mL) was added at rt for 1 h. The reaction mix-
ture was poured on a DOWEX 50W X8 resin (4 g), and washed with
distilled water. The product was eluted with 30% ammonia solu-
tion and the ammonia solution was lyophilized to obtain tetrol
obtain 41 (0.125 g, 77%) as a colorless oil. ½a D25
ꢂ
¼ þ4:5 (c 1, CHCl3).
IR(neat) mmax: 1165, 1240, 1458, 1738, 2858, 2928 cmꢀ1
.
1H NMR
45 (0.056 g, 95%) as a white solid. ½a D25
ꢂ
¼ ꢀ15:5 (c 1, MeOH).
(300 MHz, CDCl3): d 1.44 (s, 9H), 2.26–2.55 (m, 2H), 3.42 (m, 1H),
3.89–3.93 (m, 2H), 4.05–4.25 (m, 1H), 4.41–4.54 (m, 2H),
4.82–4.95 (m, 1H), 4.98–5.24 (m, 2H), 5.52–5.65 (m, 1H),
5.71–5.82 (m, 1H), 7.22–7.33 (m, 5H). 13C NMR (75 MHz, CDCl3):
d 26.5, 28.4, 40.3, 49.4, 71.2, 72.1, 79.8, 113.1, 123.0, 123.9,
IR(KBr) mmax: 1031, 2927, 3132, 3444 cmꢀ1
.
1H NMR (300 MHz,
CDCl3): d 1.68 (dd, J = 5.28, 15.10 Hz, 1H), 2.38–2.50 (m, 1H),
2.52–2.61 (m, 1H), 2.78 (dd, J = 2.2, 14.3 Hz, 1H), 3.13 (dd, J = 3.7,
10.6 Hz, 1H), 3.41 (dd, J = 3.7, 10.6 Hz, 1H), 3.65–3.72 (m, 1H),

G. Reddipalli et al. / Tetrahedron: Asymmetry 22 (2011) 1778–1783
1783
Tezuka, K.; Compain, P.; Martin, O. R. Synlett 2000, 1837; (l) Gallos, J. K.;
Demeroudi, S. C.; Stathopoulou, C. C.; Dellios, C. C. Tetrahedron Lett. 2001, 42,
7497.
3.73 (dd, J = 3.7, 11.2 Hz, 1H), 3.79–3.86 (m, 1H), 4.02 (dd, J = 2.2,
10.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 37.1, 52.4, 64.6, 68.5,
68.7, 69.4, 73.5. ESIMS: m/z 178 (M+1)+.
3. Isolation: (a) Wertheim, T. Liebigs Ann. Chem. 1856, 100, 328; Elucidation of the
conhydrine structure: (b) Späth, E.; Adler, E. Monatsh. Chem. 1933, 63, 127;
Review on the poison hemlock Conium maculatum L.: (c) Vetter, J. Food Chem.
Toxicol. 2004, 42, 1373.
Acknowledgments
4. (a) Pilard, S.; Vaultier, M. Tetrahedron Lett. 1984, 25, 1555; (b) Ratovelomanana,
V.; Royer, J.; Husson, H.-P. Tetrahedron Lett. 1985, 26, 3803; (c) Comins, D. L.;
Williams, A. L. Tetrahedron Lett. 2000, 41, 2839; (d) Lebrun, S.; Deniau, E.;
Grandclaudon, P.; Couture, A. Tetrahedron: Asymmetry 2008, 19, 1245.
5. (a) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron 2001, 57, 5393; (b) Pandey, S.
K.; Kumar, P. Tetrahedron Lett. 2005, 46, 4091; (c) Saikia, P. P.; Baishya, G.;
Goswami, A.; Barua, N. C. Tetrahedron Lett. 2008, 49, 6508.
We are thankful to UGC-New Delhi, and CSIR-New Delhi for the
financial assistance.
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