A novel stereoselective synthesis of (-)-β-conhydrine from (R)-2,3-O-cyclohexylidine glyceraldehyde

Article abstract of DOI:10.1016/j.tet.2009.06.060

A novel stereoselective synthesis of (-)-β-conhydrine is achieved. Stereoselective Grignard reaction of (R)-2,3-O-cyclohexylidine glyceraldehyde with ethyl magnesium bromide, chelation controlled stereoselective Grignard reaction of allyl imine derivative

Full text of DOI:10.1016/j.tet.2009.06.060

Tetrahedron 65 (2009) 6950–6952
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A novel stereoselective synthesis of (ꢀ)-
b-conhydrine from
(R)-2,3-O-cyclohexylidine glyceraldehyde
*
Mallam Venkataiah, Nitin W. Fadnavis
Biotransformation Laboratary; Indian Institute of Chemical Technology, Uppal Road, 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 novel stereoselective synthesis of (ꢀ)-
b-conhydrine is achieved. Stereoselective Grignard reaction of
(R)-2,3-O-cyclohexylidine glyceraldehyde with ethyl magnesium bromide, chelation controlled stereo-
Received 16 January 2009
Received in revised form 15 June 2009
Accepted 16 June 2009
selective Grignard reaction of allyl imine derivative with allyl magnesium bromide, and ring-closing
metathesis (RCM) of the diallyl product provides (ꢀ)-
b-conhydrine in high yield.
Available online 21 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
a
b
c
O
O
(D)-Mannitol
O
Biologically active alkaloids containing
a
2-(1-hydroxy-
CHO
alkyl)piperidine unit such as 1 and 2 have attracted much attention
due to their antiviral and antitumor properties.1,2 Several routes for
the synthesis of these alkaloids along with their epimers and en-
antiomers (Fig. 1) have been reported.3–5
4 (de 94%)
3
OBn
OH
5
d
N
O
H
OH
f
HO
e
NH
NH
H
OBn
OBn
OBn
8
6
7
OH
OH
g
(+)-α-Conhydrine ent-1
(-)-α-Conhydrine 1
NBoc
NH
OBn
NH
NH
NBoc
OBn
h
i
OBn
OH
OH
11
9
10
(+)-β-Conhydrine ent-2
(-)-β-Conhydrine 2
j
Figure 1.
NH
NBoc
k
However, the strategies involving diastereoselective NaBH4-
mediated reduction of Weinreb amide derived from (S)-phenyl-
glycine3b,c or stereoselective addition of diethylzinc to an aldehyde
derived from (S)-glutamic acid3a produce the key chiral in-
termediates in low diastereoselectivities3b,c (de 72%). Herein, we
OH
OH
2
12
Scheme 1. Reagents and conditions: (a) Ref. 8; (b) EtMgBr, Et2O, 0 ꢁC, 2 h, 76%; (c) NaH,
BnBr, DMF, 0 ꢁC to rt, 1 h, 83%; (d) 90% CF3COOH in water, 0 ꢁC, 2 h, 80%; (e) NaIO4, 60%
CH3CN in water, 0 ꢁC to rt, 1 h, 90%; (f) allyl amine, anhydrous MgSO4, Et2O 0 ꢁC to rt,
2 h, 85%; (g) allyl magnesium bromide, Et2O, 0 ꢁC to rt, 6 h, 78%; (h) Boc2O, Et3N, DCM,
rt, 1 h, 90%; (i) Grubbs I, DCM, rt, 12 h, 92%; (j) H2/Pd–C, EtOAc, rt, 4 h, 98%; (k) 85%
H3PO4, 0 ꢁC, 4 h, 92%.
report an efficient stereoselective synthesis of (ꢀ)-
b-conhydrine 2,
a natural product obtained from seeds and leaves of the poisonous
plant Canium maculatum L,6 employing the strategy of chelation
controlled, stereoselective Grignard reaction (Scheme 1).
2. Results and discussion
Our strategy for synthesis of 2 is shown in Scheme 1. (R)-2,3-O-
* Corresponding author. Fax: þ91 40 27160512.
E-mail addresses: fadnavis@iict.res.in, fadnavisnw@yahoo.com (N.W. Fadnavis).
Cyclohexylidine glyceraldehyde
3
readily prepared from
D-
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.060

M. Venkataiah, N.W. Fadnavis / Tetrahedron 65 (2009) 6950–6952
6951
mannitol7 was treated with ethyl magnesium bromide in diethyl
ether at 0 ꢁC to yield anti-4 (76%, de 94%).8 The preferred formation
of anti-diastereomer 4 predicted on the basis of Felkin–Anh model
is well known.8,9 The diastereomers were separated by column
chromatography and the hydroxy group of 4 was protected as its
benzyl ether 5. The cyclohexylidene protecting group was then
removed using 90% trifluoroacetic acid in water and the corre-
sponding diol 6 was cleaved by sodium periodate to give aldehyde
7. Reaction of allylamine with 7 gave the imine 8 which was sub-
jected to Grignard reaction with allylmagnesium bromide in diethyl
ether. The reaction proceeds with excellent stereoselectivity and
provides the corresponding diallyl amine 9 in 78% yield as a single
diastereomer. The formation of the syn-diastereomer 9 during the
Grignard reactions can be predicted on the basis of Cram’s chelation
bromide 0.5 M in diethyl ether (59 mL, 29.5 mmol) at 0 ꢁC under
nitrogen atmosphere. After being stirred for 2 h at room tempera-
ture, the reaction mixture was quenched with saturated aqueous
NH4Cl (20 mL) and extracted with ether (2ꢂ100 mL) the combined
organic layers were dried over Na2SO4 and concentrated in vacuo.
The diastereomers (de 94%) were separated and purified through
silica gel column chromatography (EtOAc–PE, 1:9, Rf¼0.5 in 20%
25
EtOAc–PE) to afford 3 (1.79 g, 76%) as a yellow oil. [
a]
þ17.4 (c 1.5,
D
CHCl3); IR (neat): 3438, 2935, 2860, 1451, 1367, 1279, 1100,
930 cmꢀ1 1H NMR (300 MHz, CDCl3):
¼1.03 (t, J¼7.5 Hz, 3H),
1.31–1.63 (m, 12H), 1.86 (d, J¼3.0 Hz, 1H), 3.69 (m, 1H), 3.83–4.05
;
d
(m, 3H); 13C NMR (75 MHz, CDCl3):
d
¼10.1, 23.7, 23.9, 25.1, 25.6,
34.8, 36.1, 64.1, 72.1, 78, 109.4; EIMS: m/z¼223.7 [MþNa]þ. HRMS
(EI): m/z calcd for C11H20O3Na: 223.1310; found: 223.1316.
4.1.2. (2R)-2-[(1S)-1-(Benzyloxy)propyl]-1,4-dioxaspiro[4.5]-
decane (5)
Nu
H
H
A solution of 4 (1.5 g, 7.5 mmol) in dry DMF (10 mL) was added
dropwise to a stirred suspension of NaH (0.36 g, 15 mmol) in dry
DMF (10 mL) at 0 ꢁC under a nitrogen atmosphere. After stirring at
room temperature for 15 min, benzyl bromide (0.87 mL, 7.5 mmol)
was added and the reaction mixture was stirred for 1 h, quenched
with saturated aq NH4Cl at 0 ꢁC and extracted with ether
(2ꢂ50 mL). The combined organic extracts were washed with brine
(30 mL), dried over anhydrous Na2SO4, concentrated under reduced
pressure and purified by column chromatography (EtOAc–PE, 3:97,
N
N
H
Bn
H
O
O
M
M
Bn
NH
H
N
H
H
Bn
OBn
O
9
Scheme 2. Stereoselectivity control during Grignard reaction of imine 8.
Rf¼0.4 in 5% EtOAc–PE). The benzyl protected product 5 was
25
model10,11a wherein the chelation of O-benzyl lone pair of imine 8
gives the syn-diastereomer 9 (Scheme 2).
obtained as a yellow oil (1.81 g, 83%). [
a
]
þ19.5 (c 1, CHCl3); IR
D
(neat): 3030, 2935, 2860, 1453, 1365, 1279, 1103, 931, 737,
697 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
¼0.97 (t, J¼7.3 Hz, 3H),
Our results are in agreement with those observed by Cativiela
et al.11b,c who have reported high stereoselectivity during Grignard
1.32–1.69 (m, 12H), 3.42 (q, J¼4.39, 5.85 Hz, 1H), 3.76–3.90 (m, 1H),
3.95–4.10 (m, 2H), 4.53–4.58 (m, 2H), 7.20–7.39 (m, 5H); 13C NMR
reaction of N-benzylimine derived from 2-O-benzyl (D)-glyceral-
(75 MHz, CDCl3):
d
¼10.3, 23.2, 24.4, 25.3, 25.7, 34.2, 35.6, 64.2,
dehyde and phenyl magnesium bromide under similar conditions.
Protection of the amine with (Boc)2O followed by ring-closing
metathesis12 of 11 using Grubbs first generation catalyst,
Cl2Ru(]CHPh)(PCy3)2 (5 mol %) in DCM at rt gave 12 in 90% yield.
Hydrogenation over Pd–C in EtOAc followed by Boc-deprotection
with 85% aquous phosphoric acid13 gave 2. The physical and
spectroscopic data of 2 were in agreement with the literature
data.4b
71.2, 81.6, 83.2, 106.0, 128.2 (ꢂ2), 128.3, 128.6 (ꢂ2), 136.6. EIMS:
m/z¼313.2 [MþNa]þ. HRMS (EI): m/z calcd for C18H26O3Na:
313.1779; found: 313.1785.
4.1.3. (2R,3S)-3-(Benzyloxy)pentane-1,2-diol (6)
Compound 5 (1.5 g, 5.17 mmol) was dissolved in 90% aq
CF3COOH (10 mL) at 0 ꢁC and the mixture was stirred at the same
temperature for 2 h. The reaction mixture was then extracted with
CH2Cl2 (3ꢂ50 mL). The collected organic layers were combined,
washed with 10% NaHCO3 (3ꢂ50 mL), water and brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
3. Summary
We have employed the high stereoselectivity in the Grignard
silica gel column chromatography (EtOAc–PE, 3:7, Rf¼0.4 in 60%
reactions involving
D-glyceraldehyde template for synthesis of
25
EtOAc–PE) to obtain 6 (0.869 g, 80%) as a syrup. [
a
]
þ21 (c 1,
D
(ꢀ)- -conhydrine. This strategy can be used for making analogues
b
CHCl3); IR (neat): 3410, 2966, 2931, 2877, 1713, 1455, 1274, 1070,
by changing the Grignard reagent. Most of the steps are simple and
high yielding and the product is obtained in 22% overall yield.
1024, 701 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.00 (t, J¼7.5 Hz,
3H), 1.50–1.82 (m, 2H), 2.01–2.74 (br, 2H), 3.39–3.54 (m, 1H), 3.55–
3.79 (m, 3H), 4.45–4.72 (m, 2H), 7.25–7.39 (m, 5H); 13C NMR
4. Experimental
4.1. General
(75 MHz, CDCl3):
d
¼9.6, 23.0, 63.6, 72.2, 72.6, 82.3,127.7 (ꢂ2),127.9,
128.4 (ꢂ2), 138.2; EIMS: m/z¼233.2 [MþNa]þ. HRMS (EI): m/z calcd
for C12H18O3Na: 233.1153; found: 233.1158.
All reagents were purchased from Aldrich. IR spectra were
recorded on a Perkin–Elmer RX-1 FT-IR system. 1H NMR (200 MHz)
spectra were recorded on a Varian Gemini-200 MHz spectrometer.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded
on Bruker Avance-300 MHz spectrometer. Optical rotations were
measured with Horiba-SEPA-300 digital polarimeter. Mass mea-
surement were performed on Q STAR mass spectrometer (Applied
Biosystems, USA).
4.1.4. N-Allyl-N-{(1S)-1-[(1S)-1-(benzyloxy)propyl]-3-
butenyl}amine (9)
To a solution of 6 (0.8 g, 3.81 mmol) in 60% aq CH3CN (20 mL) was
added NaIO4 (1.63 g, 7.6 mmol) in one portion. The mixture was
stirred at room temperature for 1 h and filtered. The reaction mix-
ture was extracted with CH2Cl2 and the combined organic layers
were washed with brine, dried over Na2SO4 and concentrated in
vacuo to give aldehyde 7 (0.61 g, 90%) as a colourless oil. The crude
aldehyde 7 (0.61 g, 3.42 mmol) was dissolved in cold dry diethyl
ether (15 mL). MgSO4 (1.5 g) and allyl amine (0.266 mL, 3.42 mmol)
were added in cold, the reaction mixture was slowly allowed to
reach room temperature (0.5 h) and stirring was continued at room
4.1.1. (1S)-1-[(2R)-1,4-Dioxaspiro[4.5]dec-2-yl]propan-1-ol (4)
The aldehyde 2 (2 g, 11.8 mmol) in dry ether (20 mL) was added
dropwise over 30 min to a stirred solution of ethyl magnesium

6952
M. Venkataiah, N.W. Fadnavis / Tetrahedron 65 (2009) 6950–6952
temperature for 2 h more. After completion of the reaction, the re-
action mixture was filtered and the filtrate was concentrated in
vacuo to give imine 8 (0.632 g, 85%) as a yellow syrup. The crude
imine 8 (0.632 g, 2.91 mmol) in dry ether (10 mL) was added drop
wise over 30 min to a stirred solution of allyl magnesium bromide in
diethyl ether (0.5 M, 14.56 mL, 7.2 mmol) at 0 ꢁC under nitrogen
atmosphere. After stirring for 6 h at room temperature, the reaction
mixture was poured in to saturated aqueous NH4Cl (20 mL), the
organic layer was dried over Na2SO4, concentrated in vacuo and the
residue was purified by silica gel column chromatography (EtOAc–
chromatography (EtOAc–PE, 4:6, Rf¼0.5 in 30% EtOAc–PE) to obtain
25
12 as a viscous liquid (0.086 g, 98%). [
(neat): 3460, 2932, 2870, 2357,1671,1421,1269,1167 cmꢀ1; 1H NMR
(300 MHz, CDCl3):
¼1.01 (t, J¼7.5 Hz, 3H), 1.2–1.45 (m, 2H), 1.46 (s,
9H), 1.46–1.75 (m, 6H), 2.9–3.02 (br s, 1H), 3.68–3.76 (m, 1H), 3.77–
a
]
ꢀ26.8 (c 1, CHCl3); IR
D
d
4.15 (m, 3H); 13C NMR (75 MHz, CDCl3):
d
¼9.3, 19.5, 25.1, 25.6, 27.2,
28.4 (ꢂ3), 40.2, 55.6, 70.2, 79.8, 152.0; EIMS: m/z¼266.2 [MþNa]þ.
HRMS (EI): m/z calcd for C13H25NO3Na: 266.1732; found: 266.1738.
4.1.8. (1S,2S)-Piperidine-2-yl-propan-1-ol (2)
PE,1:9, Rf¼0.5 in 25% EtOAc–PE) to give 9 (0.588 g, 78%) as yellow oil.
To a solution 12 (50 mg, 0.21 mmol) in DCM (1 mL) at room
temperature, aqueous phosphoric acid (85 wt %, 2.8 mL) was added
drop wise. The mixture was stirred for 4 h and cooled in ice after
addition of water (5 mL). The reaction mixture was then slowly
neutralized with 10 N NaOH. The mixture was then extracted with
DCM (2ꢂ20 mL). The combined DCM extracts were dried over
25
[
a]
þ22 (c 0.25, CHCl3); IR (neat): 3369, 2980, 2943, 2832, 2246,
D
1635, 1450, 1376, 1248, 1101, 1033, 918, 787 cmꢀ1
(300 MHz, CDCl3):
;
1H NMR
d
¼0.96 (t, J¼7.5 Hz, 3H), 1.47–1.64 (m, 1H), 1.66–
1.84 (m,1H), 2.08–2.12 (m,1H), 2.31–2.48 (m, 2H), 2.75 (q, J¼11.3 Hz,
1H), 3.16–3.39 (m, 3H), 4.54 (m, 2H), 5.01–5.21 (m, 4H), 5.72–5.93
(m, 2H), 7.23–7.38 (m, 5H); 13C NMR (75 MHz, CDCl3):
d
¼10.1, 22.4,
Na2SO4 and concentrated in vacuo to give the desired product 2 as
25
34.7, 50.5, 57.8, 72.1, 81.9, 115.6, 116.8, 127.4, 127.7 (ꢂ2), 128.3 (ꢂ2),
136.2, 137.3, 139.0; EIMS: m/z¼260.2 [MþH]þ. HRMS (EI): m/z calcd
for C17H26NO: 260.2014; found: 260.2010.
a white solid (27 mg, 92%). Mp: 67–68 ꢁC (lit.4b mp. 67 ꢁC); [
a]
D
20
ꢀ34.5 (c 1, CHCl3), lit.4b
[
a
]
D
ꢀ31.1 (c 1, CHCl3); IR (neat): 3285,
2928, 2855, 1726, 1635, 1455, 1269, 1114, 976 cmꢀ1 1H NMR
;
(200 MHz, CDCl3):
d
¼0.93 (t, J¼7.5 Hz, 3H), 1.04–1.55 (m, 8H), 2.3
4.1.5. tert-Butyl N-allyl-N-{(1S)-1-[(1S)-1-(benzyloxy)propyl]-
3-butenyl}carbamate (10)
(ddd, J¼2.5, 7.5, 10.2 Hz, 1H), 2.52 (td, J¼2.7, 11.5 Hz, 1H), 3.0–3.08
(m, 1H), 3.18 (td, J¼3.5, 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3):
Triethylamine (0.09 mL, 0.675 mmol) followed by Boc2O
(0.39 mL, 1.69 mmol) were added to a solution of 9 (0.175 g,
0.675 mmol) in dry DCM (10 mL) at 0 ꢁC. The reactants were then
stirred at room temperature for 1 h. Aftercompletion of the reaction,
the reaction mixture was washed with saturated NH4Cl (5 mL) and
extracted with CH2Cl2 (2ꢂ10 mL). The combined organic extracts
were washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by silica gel column chromatogra-
d
¼10.4, 25, 26.9, 29.7, 47, 61.3, 76; EIMS: m/z¼144.1 [MþH]þ. HRMS
(EI): m/z calcd for C8H18NO3: 144.1025; found: 144.1022.
Acknowledgements
We thank CSIR, New Delhi, for financial support and Dr. B
Venkateswara Rao, Organic Division-III, IICT Hyderabad, for helpful
discussions.
phy (EtOAc–PE, 2:98, Rf¼0.4 in 5% EtOAc–PE) to obtain 10 as a syrup
25
(0.218 g, 90%). [
a
]
þ25.5 (c 1, CHCl3); IR (neat): 3050, 2990, 2836,
D
1626, 1435, 1240, 1053, 925, 725 cmꢀ1; 1H NMR (200 MHz, CDCl3):
References and notes
d
¼0.97 (t, J¼7.3 Hz, 3H),1.46 (s, 9H),1.55–1.80 (m, 2H), 2.27–2.58 (m,
1. Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. Rev. 1995, 95, 1677–1716.
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2H), 3.43–3.58 (m, 1H), 3.74–4.01 (m, 2H), 4.09–4.27 (m, 1H), 4.4–
4.65 (m, 2H), 4.95–5.16 (m, 4H), 5.63–5.93 (m, 2H), 7.21–7.44 (m,
5H); 13C NMR (75 MHz, CDCl3):
d
¼9.8, 23.9, 28.4 (ꢂ3), 34.3, 48.4,
57.7, 72.3, 79.2, 82.3, 115.3, 116.7, 127.4 (ꢂ2), 127.9, 128.2 (ꢂ2), 135.7,
136.2, 136.6, 153; EIMS: m/z¼382.2 [MþNa]þ. HRMS (EI): m/z calcd
for C22H33NO3Na: 382.2358; found: 382.2355.
4.1.6. tert-Butyl (2S)-2-[(1S)-1-(benzyloxy)propyl]-1,2,3,6-
tetrahydro-1-pyridinecarboxylate (11)
The diene 10 (0.18 g, 0.5 mmol) was dissolved in dry CH2Cl2
(50 mL). Grubbs’ first generation catalyst (41 mg, 0.05 mmol) was
added and the reaction mixture was stirred at room temperature
for 12 h. The dark brown solution was concentrated in vacuo and
the residue was purified by column chromatography (EtOAc–PE,
6. Wertheim, T. Liebigs Ann. Chem. 1856, 100, 328–330.
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25
colorless oil (0.152 g, 92%). [
a]
ꢀ35 (c 1.5, CHCl3); IR (neat): 2965,
D
2927, 2855, 1693, 1457, 1411, 1365, 1219, 1173, 1109, 770 cmꢀ1
;
1H
NMR (300 MHz, CDCl3):
d
¼0.98 (t, J¼7.5 Hz, 3H), 1.42 (s, 9H), 1.43–
10. (a) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828–5835; (b) Cram,
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1.50 (m, 2H),1.50–1.79 (m,1H),1.99–2.18 (m,1H), 2.35–2.51 (m,1H),
3.39–3.53 (m, 2H), 4.04–4.27 (m, 1H), 4.27–4.65 (m, 3H), 5.54–5.79
11. For chelation controlled reactions of chiral imine derivatives see: (a) Bloch, R.
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M. D.; Galvez, J. A. Tetrahedron 1997, 53, 1411–1416; (c) Cativiela, C.; Diaz-de-
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A. P.; Smith, A. D.; Rodriguez-Solla, H. Synlett 2002, 1146–1148; (h) Felpin, F.-X.;
Lebreton, J. Curr. Org. Synth. 2004, 1, 83–109.
(m, 2H), 7.19–7.34 (m, 5H); 13C NMR (75 MHz, CDCl3):
d
¼11.3, 28.3
(ꢂ3), 30.3, 34.6, 42.2, 59.3, 72.2, 78.6, 82.1, 124.0, 127.1 (ꢂ2), 127.5
(ꢂ2), 128.2, 129.9, 136.7, 153.5; EIMS: m/z¼354.2 [MþNa]þ. HRMS
(EI): m/z calcd for C20H30NO3: 332.2225; found: 332.2229.
4.1.7. tert-Butyl (2S)-2-[(1S)-1-hydroxypropyl]hexahydro-1-
pyridine carboxylate (12)
A solution of 11 (0.12 g, 0.362 mmol) in ethyl acetate (10 mL) was
stirred with 20 mg of 10% Pd/C under hydrogen atmosphere for 4 h.
The reaction mixture was filtered and the filtrate was concentrated.
The crude product was purified on silica gel column
13. Li, B.; Bemish, R.; Buzon, R. A.; Chiu, C. K. F.; Colgan, S. T.; Kissel, W.; Le, T.;
Leeman, K.; Newell, L.; Roth, J. Tetrahedron Lett. 2003, 44, 8113–8115.