A concise enantioselective synthesis of (+)-lentiginosine

Article abstract of DOI:10.1016/j.tetasy.2009.08.027

A high yielding enantioselective synthesis of the indolizidine alkaloid, (+)-lentiginosine, has been described based on asymmetric aza-Cope rearrangement and the l-proline catalyzed α-aminooxylation of aldehydes. The strategy also makes use of ring-closin

Full text of DOI:10.1016/j.tetasy.2009.08.027

Tetrahedron: Asymmetry 20 (2009) 2287–2292
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A concise enantioselective synthesis of (+)-lentiginosine
*
Tanveer Mahamadali Shaikh, Arumugam Sudalai
Chemical Engineering & Process Development Division National Chemical Laboratory, Pashan Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2009
Accepted 27 August 2009
Available online 26 September 2009
A high yielding enantioselective synthesis of the indolizidine alkaloid, (+)-lentiginosine, has been
described based on asymmetric aza-Cope rearrangement and the L-proline catalyzed a-aminooxylation
of aldehydes. The strategy also makes use of ring-closing metathesis for the construction of piperidine
core.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
lective dihydroxylation. We further considered that the
piperidine core in 4 could be constructed from 5 by ring-closing
Polyhydroxylated alkaloids such as (+)-lentiginosine 1, (ꢀ)-
swainsonine 2 and (+)-catanospermine 3 constitute a class of aza-
sugars exhibiting potent and selective glycosidase inhibitory activ-
ities and are found to be useful as anti-cancer, anti-diabetic and
anti-viral agents and immune stimulants.1 For instance, (+)-lentig-
inosine 1, a dihydroxylated indolizidine alkaloid isolated from the
leaves of Astragalus lentiginosis2 was shown to be a selective inhib-
itor of amyloglucosidase, an enzyme that hydrolyses 1,4- and 1,6-
metathesis (RCM), which in turn may be obtained from the key
intermediate 6. The key intermediate 6 was planned to be synthe-
sized by two routes involving proline-catalyzed a
-aminooxylation5
as well as via aza-Cope rearrangement.6
Firstly, our synthesis of (+)-lentiginosine 1 started with the pro-
tected aldehyde 7 prepared from the corresponding monoprotect-
ed 1,3-propanediol followed by selective oxidation with IBX in
DMSO. The proline-catalyzed
a-aminooxylation of aldehyde 7
a
-glycosidic linkages.3 Due to the enormous biological importance
involved a two-step reaction sequence: (i) reaction of aldehyde 7
as well as structural complexities of this class of compounds,
numerous reports describing the synthesis of these natural prod-
ucts and their analogues have been published.4 Although the
majority of the reported enantiospecific synthesis of (+)-lentigino-
with nitrosobenzene as electrophile in the presence of L-proline
(25 mol %) in CH3CN at ꢀ20 °C5a followed by treatment with NaBH4
in MeOH to give crude aminooxy alcohol (ii) subsequent cleavage
7
of aminooxy moiety with 30% CuSO4 to yield chiral diol 9 in 54%
sine relies mostly upon the chiral pool, the low-cost
L
-tartaric acid
yield. Selective protection of primary alcohol in 9 with mesyl chlo-
is the most widely employed since it allows the direct construction
of the (1S,2S)-configuration of (+)-lentiginosine (Fig. 1).
ride gave the corresponding mesylate which on treatment with
K2CO3 in MeOH yielded the terminal epoxide 11; ½a D25
¼ ꢀ5:3 (c
ꢁ
4.5, toluene). Regioselective ring opening of epoxide 11 with vinyl
magnesium bromide in the presence of CuI (40 mol %)8 in THF at
ꢀ40 °C gave homoallylic alcohol 12, which was converted into
mesylate 13. The nucleophilic displacement of mesylate 13 with
NaN3 in DMF at 80 °C yielded the corresponding azide 14 in 87%
yield. The selective reduction of azide function in 14 using LiAlH4
gave homoallylic amine 6 in 93% yield and >95% ee (by HPLC)6;
OH
OH
OH
OH
OH
H
H
H
HO
HO
OH
OH
OH
N
N
N
½
a 2D5
ꢁ
¼ þ7:4 (c 1, CHCl3). Since the
L-proline-based route for obtain-
3
1
2
ing key intermediate 6 involved several steps, an alternative strat-
egy was developed, which focused on asymmetric aza-Cope
rearrangement6 of aldehydes leading to the synthesis of homoal-
lylic amines (Scheme 2).
Figure 1. Structures of polyhydroxylated alkaloids.
2. Results and discussion
In the second route, the synthesis of (+)-lentiginosine 1 com-
menced with benzyl-protected acetaldehyde 8, which was sub-
jected to an asymmetric aza-Cope rearrangement using the
Kobayashi protocol6 [(CSA (10 mol %), 20 (1 equiv), NH2OHꢂAcOH,
1,2-dichloroethane] to give exclusively (S)-homoallylic amine 6
in 87% yield and 96% ee (Scheme 3). Homoallylic amine 6 was
protected as its Boc derivative 15 [(Boc)2O, DMAP, Et3N, and
A retrosynthetic analysis of (+)-lentiginosine 1 is outlined in
Scheme 1. Accordingly, (+)-lentiginosine 1 is envisaged to be pre-
pared from
a,b-unsaturated ester 4 via Os-catalyzed diastereose-
* Corresponding author. Tel.: +91 02025902547; fax: +91 02025902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.027

2288
T. M. Shaikh, A. Sudalai / Tetrahedron: Asymmetry 20 (2009) 2287–2292
N
BocN
BocN
HO
EtO
BnO
HO
O
5
1
4
NH2
α-aminooxylation
BnO
CHO
BnO
7
6
aza-Cope
rearrangement
BnO
CHO
8
Scheme 1. Retrosynthetic analysis of (+)-lentiginosine.
OH
i
iii
iv
O
BnO
BnO
BnO
CHO
OR
7
11
9, R = H
ii
10, R = Ms
OR
N3
NH2
vii
vi
BnO
v
BnO
BnO
12, R = H
14
6
13, R = Ms
Scheme 2. Reagents and conditions: (i) (a)
Et3N, CH2Cl2, 0 °C; (iii) K2CO3, MeOH, 91% for two steps; (iv) CH2@CHMgBr, CuI (40 mol %), THF, ꢀ40 °C, 92%; (v) (a) MsCl, Et3N, CH2Cl2, 45 min, 94%; (vi) NaN3, DMF, 85 °C,
87%; (vii) LiAlH4, THF, 0–25 °C, 93%.
L
-Proline (25 mol %), PhNO, CH3CN, ꢀ23 °C, 24 h; then NaBH4, MeOH, 0 °C, 1 h; (b) CuSO4 (30 mol %), MeOH, 12 h, 54%; (ii) MsCl,
Boc
NHR
N
i
iii
iv
BnO
CHO
BnO
BnO
5
8
6, R = H
15, R = Boc
ii
Boc
Boc
Boc
N
N
N
v
vii
viii
BnO
EtO2C
R
16
17, R = CH2OH
18, R = CHO
4
vi
O
N
N
ix
NH2
HO
HO
O
HO
HO
1
20
19 (dr = 3.1:2)
Scheme 3. Reagents and conditions: (i) Camphorsulfonic acid (10 mol %), (1R,3R,4S)-3-allyl-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 20 (1 equiv), 1,2-dichloro-
ethane, NH2OHꢂAcOH, 25 °C, 24 h, 87%; (ii) (Boc)2O, DMAP (10 mol %), Et3N, CH2Cl2, 25 °C, 10 h, 95%; (iii) NaH, allylbromide, dry DMF, 0–25 °C, 5 h, 88%; (iv) Grubbs’ 2nd
generation catalyst (10 mol %), dry CH2Cl2, 20 h, reflux, 78%; (v) 10% Pd/C, H2 (20 psi), MeOH, 25 °C, 8 h, 88%; (vi) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 93%; (vii)
Ph3P@CHCO2Et, benzene, 50 °C, 14 h, 90%; (viii) OsO4, NMO, tBuOH:H2O, 25 °C, 24 h; then TFA, 18 h, EtOH, reflux, 58%; (ix) LiAlH4, THF, reflux, 12 h, 82%.

T. M. Shaikh, A. Sudalai / Tetrahedron: Asymmetry 20 (2009) 2287–2292
2289
CH2Cl2] followed by N-allylation with allylbromide and NaH to
4.2. (R)-2-(Benzyloxymethyl)oxirane 11
give the RCM precursor 5 in 88% yield. Ring-closing metathesis9
of 5 using Grubbs’ 2nd generation catalyst, (10 mol %) in refluxing
dichloromethane proceeded smoothly to give dihydropyridine 16
in 78% yield. Catalytic hydrogenation of the resulting olefin cou-
pled with the removal of the benzyl group resulted in piperidine
alcohol 17 in 88% yield. The enantiomeric purity of 17 was deter-
mined to be 98% ee by HPLC analysis. The Swern oxidation of piper-
idine alcohol 17 produced piperidine carboxaldehyde 18 in 93%
yield, which underwent Wittig olefination with stabilized salt
A solution of diol 9 (1.5 g, 8.2 mmol) in CH2Cl2 (40 mL) was
treated with methane sulfonyl chloride (0.98 mL, 12.3 mmol)
and Et3N (2.29 mL, 16.48 mmol) at 0 °C. After being stirred for
35 min, the mixture was extracted with CH2Cl2 (3 ꢃ 100 mL),
washed with water and the combined organic phases were dried
over anhyd Na2SO4 and concentrated to give the crude mesylate
10, which was subjected to epoxidation without further purifica-
tion. To a solution of mesylate 10 (1.96 g, 7.5 mmol) in MeOH
(40 mL) was added anhyd K2CO3 (1.03 g, 7.5 mmol) and the mix-
ture was stirred at 25 °C for 1 h. After the reaction was completed
(monitored by TLC), the mixture was evaporated and the residue
was extracted with diethyl ether (3 ꢃ 80 mL). The combined or-
ganic phases were dried over anhyd Na2SO4 and concentrated to
give the crude product, which was then purified by column chro-
matography over silica gel using petroleum ether/EtOAc (8:2) to
(Ph3P@CHCO2Et) to give
a
,b-unsaturated ester 4 in 90% yield. The
,b-unsatu-
Os-catalyzed diastereoselective dihydroxylation10 of
a
rated ester 4 furnished the corresponding diol in 87% yield, which
on in situ Boc deprotection followed by refluxing the crude mixture
in EtOH produced indolizidinone 19 (dr = 60:40) which was puri-
fied by chromatography followed by recrystallization4o to give a
single diastereomer 19 in 58% yield. Finally, LiAlH4 reduction of
indolizidinone carbonyl in 19 was carried out that produced (+)-
lentiginosine 1 in 82% yield, whose stereogenic values (mp, 1H
give epoxide 11 (1.6 g, 91%) as a colourless oil. ½a D25
¼ ꢀ5:3 (c 4.5,
ꢁ
toluene) 1H NMR (200 MHz, CDCl3): d 2.60–2.63 (dd, J = 2.6,
5.0 Hz, 1H), 2.77–2.82 (dd, J = 4.2, 1.0 Hz, 1H), 3.15–3.22 (m, 1H),
3.39–3.47 (dd, J = 5.8, 5.5 Hz, 1H), 3.73–3.80 (dd, J = 2.9, 8.5 Hz,
1H), 4.51–4.65 (d, J = 3.8 Hz, 2H), 7.27–7.36 (m, 5H); 13C NMR
(50 MHz, CDCl3): d 44.1, 50.7, 70.6, 73.2, 127.6, 127.9, 128.3,
137.8; IR (CHCl3 cmꢀ1): 877, 985, 1216, 1387, 1452, 1476, 3018,
3435. Anal. Calcd for C10H12O2: C, 73.15; H, 7.37. Found: C, 73.20,
H, 7.29.
and 13C NMR, [
a]D, etc.) are in complete agreement with the re-
ported synthesis.4c,h,p,x,y
3. Conclusion
In conclusion, a short enantioselective synthesis of (+)-lentig-
inosine 1 has been described based on asymmetric aza-Cope
rearrangement and
hydes. Our route to (+)-lentiginosine emphasizes on an organo-
catalytic and metal-free approach demonstrating shortest
route to key intermediate homoallylic amine 6 and should hold
promise for the synthesis of similar such alkaloids. The synthesis
also involves RCM strategy for the construction of piperidine
core.
L-proline-catalyzed a-aminooxylation of alde-
4.3. (R)-1-(Benzyloxy)pent-4-en-2-ol 12
a
Vinyl bromide (6.44 M in THF, 6 mL, 38.36 mmol) was added
slowly to Mg (0.4 g, 19.1 mmol) in THF (20 mL) at 0 °C and the mix-
ture was stirred for 10 min; then cooled to ꢀ40 °C and CuI (0.52 g,
30 mol %) was added. The resulting reaction mixture was stirred
for 30 min at ꢀ40 °C and a solution of epoxide 11 (1.5 g, 9.14 mmol)
in THF (25 mL) was added. After being stirred for 3 h, the mixture
was quenched with saturated aq NH4Cl solution, extracted with
diethyl ether (3 ꢃ 80 mL), washed with brine and the combined or-
ganic phases were dried over anhyd Na2SO4 and concentrated togive
the crude product, which was then purified by column chromatogra-
phy over silica gel using petroleum ether/EtOAc (7:3) to give alcohol
4. Experimental
4.1. (R)-3-(Benzyloxy)propane-1,2-diol 9
12 (1.6 g, 92%) as a colourless oil. ½a D25
ꢁ
¼ ꢀ2 (c 1, CHCl3); 1H NMR
To a pre-cooled (ꢀ20 °C) acetonitrile (50 mL) solution of alde-
hyde 7 (5.0 g, 30.4 mmol) and nitrosobenzene (1.68 g, 15.7 mmol)
was added L-proline (0.49 g, 25 mol %). The reaction mixture was
(200 MHz, CDCl3): d 2.21–2.29 (m, 1H), 2.34 (br s, 1H), 3.31–3.34
(dd, J = 7.3, 2.0 Hz, 1H), 4.5 (s, 2H), 5.06–5.16 (m, 2H), 5.71–5.92
(m, 1H), 7.27–7.38 (m, 5H); 13C NMR (50 MHz, CDCl3): d 37.8, 69.5,
73.2, 73.8, 117.5, 127.6, 128.3, 134.2, 137.8; IR (CHCl3 cmꢀ1):
1243, 1670, 2930, 3010, 3415. Anal. Calcd for C12H16O2: C, 74.97;
H, 8.39. Found: C, 74.88, H, 8.27.
allowed to stir at the same temperature for 24 h, followed by the
addition of MeOH (20 mL) and NaBH4 (2.31 g, 60.9 mmol), which
was stirred for 20 min. After the addition of saturated aq NH4Cl,
the resulting mixture was extracted with EtOAc (3 ꢃ 60 mL) and
the combined organic phases were dried over anhyd Na2SO4 and
concentrated to give the crude aminooxy alcohol, which was di-
rectly used for the next step without purification. To a MeOH
(50 mL) solution of the crude aminooxyalcohol was added Cu-
SO4ꢂ5H2O (1.28 g, 5.1 mmol) at 0 °C. The reaction mixture was al-
lowed to stir for 10 h at this temperature. After the addition of
the phosphate buffer, the resulting mixture was extracted with
CHCl3 (3 ꢃ 60 mL) and the combined organic phases were dried
over anhyd Na2SO4 and concentrated to give the crude diol, which
was then purified by column chromatography over silica gel using
petroleum ether/EtOAc (6:4) to give diol 9 (1.5 g, 54%) as a colour-
4.4. (R)-1-(Benzyloxy)pent-4-en-2-yl methanesulfonate 13
To a stirred solution of alcohol 12 (2.5 g, 13 mmol) in CH2Cl2
(40 mL) was added Et3N (3.6 g, 26.0 mmol) at 0 °C. After 10 min,
methanesulfonyl chloride (1.5 g, 19.5 mmol) was added dropwise.
The reaction mixture was then stirred for another 1 h at 0 °C and
brought to room temperature. After completion of the reaction as
monitored by TLC, it was quenched with water and extracted with
CH2Cl2 (3 ꢃ 50 mL) washed with water, brine and dried over anhyd
Na2SO4. The combined organic layer was concentrated under re-
duced pressure to obtain crude mesylate 13, which was purified
by column chromatography using petroleum ether/ethyl acetate
(6:4) to give pure mesylate 13 (3.3 g, 94%) as a viscous liquid.
less oil. ½a 2D5
ꢁ
¼ þ5:5 (c 10, CHCl3); 1H NMR (200 MHz, CDCl3): d
2.19–2.25 (dd, J = 5.4, 1.2 Hz, 1H), 2.69–2.72 (d, J = 4.8 Hz, 1H),
3.59–3.60 (m, 2H), 3.62–3.74 (m, 2H), 3.83–3.95 (m, 1H), 4.55 (s,
2H), 7.29–7.39 (m, 5H); 13C NMR (50 MHz, CDCl3): d 63.7, 70.7,
71.3, 73.2, 127.7, 128.3, 137.5; IR (CHCl3 cmꢀ1): 3684, 3615,
3472, 3020, 2927, 2400, 1602, 1521, 1455, 1424, 1216, 1094,
1051, 929, 850, 770, 660. Anal. Calcd for C10H14O3: C, 65.91; H,
7.74. Found: C, 65.89, H, 7.68.
½
a 2D5
ꢁ
¼ ꢀ4:8 (c 0.84, CHCl3); 1H NMR (200 MHz, CDCl3): d 2.47–
2.50 (t, J = 6.6, 13.3 Hz, 2H), 3.0 (s, 3H), 3.60–3.62 (t, J = 3.7 Hz, 2H),
4.51–4.58 (q, J = 11.7 Hz, 2H), 4.80–4.85 (m, 1H), 5.14–5.18 (m,
2H), 5.74–5.82 (m, 1H), 7.28–7.36 (m, 5H); 13C NMR (50 MHz,
CDCl3): d 36.2, 38.4, 70.8, 73.2, 81.0, 119.1, 127.6, 127.7, 128.3,

2290
T. M. Shaikh, A. Sudalai / Tetrahedron: Asymmetry 20 (2009) 2287–2292
131.7, 137.2; IR (CHCl3 cmꢀ1): 3085, 3031, 2867, 2360, 1647, 1456,
1357, 1174, 1116, 910, 781, 705, 649. Anal. Calcd for C13H18O4S: C,
57.76; H, 6.71; S, 11.86. Found: C, 57.80, H, 6.69; S, 11.79.
25.2 mmol) and DMAP (0.255 g, 10 mol %), and the reaction mixture
wasstirred for10 h. Aftercompletionof thereactionasmonitoredby
TLC, it was extracted with CH2Cl2 (3 ꢃ 60 mL), washed with brine
and dried over anhyd Na2SO4 and concentrated to give the crude
product, which was then purified by column chromatography over
silica gel using petroleum ether/EtOAc (7:3) to give carbamate 15
4.5. 1-{[(S)-2-Azidopent-4-enyloxy]methyl} benzene 14
To a stirred mixture of crude methane sulfonate ester 13 (2 g,
7.3 mmol) in DMF (30 mL) was added sodium azide (2.4 g,
37 mmol), and the reaction mixture was heated at 80 °C for 15 h.
After completion of the reaction as monitored by TLC, it was ex-
tracted with EtOAc (3 ꢃ 50 mL), washed with water, brine and
dried over anhyd Na2SO4. The combined organic layer was concen-
trated under reduced pressure to give the crude homoallylic azide,
which was purified by column chromatography using petroleum
(5.8 g, 95%) as a colourless oil. ½a D25
ꢁ
¼ ꢀ5:8 (c 0.86, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.42 (s, 9H), 1.64 (br s, 1H), 2.29–2.36 (m, 2H),
3.40–3.53 (m, 2H), 4.49–4.51 (d, J = 2.4 Hz, 2H), 5.01–5.12 (m, 2H),
5.65–5.86 (m, 1H), 7.27–7.35 (m, 5H); 13C NMR (50 MHz, CDCl3): d
28.2, 36.3, 49.8, 71.0, 73.0, 79.1, 117.5, 127.5, 128.2, 134.4, 138.0,
155.4; IR (CHCl3 cmꢀ1): 3750, 3690, 3021, 2928, 2357, 1708, 1425,
1216, 764, 670. Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65; N,
4.81. Found: C, 70.11, H, 8.59; N, 4.78.
ether/ethyl acetate (9:1) to give 14 (1.4 g, 87%). ½a D25
¼ ꢀ7:3 (c
ꢁ
1.1, CHCl3); 1H NMR (200 MHz, CDCl3): d 2.26–2.33 (m, 2H),
3.48–3.61 (m, 3H), 4.56 (s, 2H), 5.08–5.18 (m, 2H), 5.68–5.89 (m,
1H), 7.28–7.36 (m, 5H); 13C NMR (50 MHz, CDCl3): d 35.2, 60.9,
72.06, 73.2, 118.1, 127.4, 127.6, 128.3, 133.4, 137.7; IR (CHCl3
cmꢀ1): 2959, 2112, 1650, 1216, 640. Anal. Calcd for C12H15N3O:
C, 66.34; H, 6.96; N, 19.34. Found: C, 66.29, H, 6.89; N, 19.30.
4.9. tert-Butyl allyl-(S)-1-(benzyloxy)pent-4-en-2-ylcarbamate 5
To a solution of NaH (0.494 g, 12.35 mmol) in dry DMF (30 mL)
was added Boc-protected amine 15 (3 g, 10.29 mmol) at 0 °C. After
15 min, allylbromide (1 mL, 12.35 mmol) was added dropwise. The
reaction mixture was then stirred for 6 h at 25 °C. After completion
of the reaction as monitored by TLC, it was extracted with CH2Cl2
(3 ꢃ 50 mL), washed with brine and dried over anhyd Na2SO4
and concentrated to give the crude product, which was then
purified by column chromatography over silica gel using petro-
leum ether/EtOAc (9:1) to give 5 (3 g, 88%) as a colourless oil.
4.6. Proline route: (S)-1-(benzyloxy)pent-4-en-2-amine 6
To a stirred mixture of LiAlH4 (0.350 g, 9.21 mmol) in anhyd
THF (20 mL) was added homoallylic azide 14 (1 g, 4.60 mmol) in
THF (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for
10 h. After completion of the reaction as monitored by TLC, it
was quenched with ice-cold water and 20% aq NaOH. This crude
mixture was passed through anhyd Na2SO4 and washed thor-
oughly with EtOAc (3 ꢃ 50 mL) and the solvent was evaporated un-
der reduced pressure to give the crude homoallylic amine, which
was purified by column chromatography using CHCl3/MeOH
½
a 2D5
ꢁ
¼ þ2:05 (c 1.46, CHCl3); 1H NMR (200 MHz, CDCl3): d 1.43
(s, 9H), 2.29–2.37 (t, J = 7.0 Hz, 2H), 3.44–3.61 (m, 2H), 3.71–3.81
(m, 2H), 4.05–4.31 (m, 1H), 4.46–4.48 (d, J = 5.0 Hz, 2H), 4.99–
5.11 (m, 4H), 5.63–5.88 (m, 2H), 7.30 (s, 5H); 13C NMR (50 MHz,
CDCl3): d 28.2, 34.1, 47.2, 55.1, 70.9, 72.7, 79.2, 115.1, 116.1,
127.3, 128.1, 135.0, 136.0, 138.1, 155.4; IR (CHCl3 cmꢀ1): 3780,
3697, 3633, 3019, 2932, 2361, 1682, 1216, 1104, 762, 670. Anal.
Calcd for C20H29NO3: C, 72.47; H, 8.82; N, 4.23. Found: C, 72.50,
H, 8.79; N, 4.19.
(9:1) to give 6 (0.820 g, 93%) as colourless oil. ½a D25
¼ þ7:4 (c 1,
ꢁ
CHCl3) {lit.6
½
a 2D5
ꢁ
¼ þ7:1 (c 1.14, CHCl3)}.
4.7. Aza-Cope rearrangement: (S)-1-(benzyloxy)pent-4-en-2-
amine 6
4.10. (S)-tert-Butyl-6-(benzyloxymethyl)-5,6-dihydropyridine-
1(2H)-carboxylate 16
To a solution of chiral amine 206 (2.072 g, 10 mmol) and alde-
hyde 8 (1.5 g, 10 mmol) in 1,2-dichloroethane (20 mL) was added
camphorsulfonic acid (0.232 g, 10 mol %) at 0 °C. The mixture
was stirred at the 0 °C for 24 h. Then, a solution of HONH2ꢂAcOH
in methanol [0.5 M, 2 mL, prepared from HONH2ꢂHCl, NaOH (solid,
1 equiv), and AcOH (1 equiv) in methanol] was added to the solu-
tion. After being stirred at 50 °C for 3 h, the mixture was cooled to
25 °C, acidified with 1 N aq HCl (pH 1). The mixture was washed
with dichloromethane (3 ꢃ 50 mL), basified with 6 N aq NaOH
(pH 10), and extracted with dichloromethane (3 ꢃ 50 mL). The
combined solvent layers were dried over anhyd Na2CO3, filtered,
and evaporated to give amine 6. The crude product was purified
by column chromatography (petroleum ether/EtOAc = 1:1) to give
Olefin 5 (1 g, 3 mmol) was dissolved in dry CH2Cl2 (40 mL) and
the solution was degassed by bubbling with argon for 10 min.
Then, Grubbs’ 2nd generation ruthenium catalyst (256 mg,
0.30 mmol) was added. The reaction mixture was stirred for 22 h
at 50 °C and then cooled and the solvent was evaporated to give
the residue, which was then directly purified by column chroma-
tography over silica gel using petroleum ether/EtOAc (8:2) to give
dihydropyridine 16 (0.720 g, 78%) as a colourless oil. ½a D25
¼ þ20 (c
ꢁ
1, CHCl3); 1H NMR (200 MHz, CDCl3): d 1.45 (s, 9H), 1.66–1.70 (m,
1H), 2.01–2.16 (m, 1H), 2.31–2.48 (m, 1H), 3.34–3.50 (m, 3H), 4.05-
.24 (m, 1H), 4.49–4.53 (d, J = 5.4 Hz, 2H), 5.56–5.74 (m, 2H), 7.29–
7.32 (m, 5H); 13C NMR (50 MHz, CDCl3): d 25.2, 28.2, 40.4, 45.9,
68.7, 72.5, 72.9, 79.4, 122.4, 123.1, 127.3, 128.1, 128.9, 138.1,
155.0; IR (CHCl3 cmꢀ1): 3443, 2978, 1685, 1413, 1227, 1115,
1028, 909, 698, 648. Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31;
N, 4.62. Found: C, 71.30, H, 8.29; N, 4.58.
pure amine 6 (1.65 g, 87%). ½a D25
ꢁ
¼ þ7:1 (c 1.46, CHCl3), {lit.6
½
a 2D5
ꢁ
¼ þ7:1 (c 1.14, CHCl3)}; 1H NMR (200 MHz, CDCl3): d 1.6 (s,
2H), 1.96–2.10 (m, 1H), 2.16–2.30 (m, 1H), 3.0–3.12 (m, 1H),
3.23–3.31 (t, J = 3.0 Hz, 1H), 3.42–3.48 (dd, J = 4.3, 4.8 Hz, 1H),
4.52 (s, 1H), 4.97–5.13 (t, J = 10.3 Hz, 2H), 5.67–5.87 (m, 1H),
7.31–7.38 (m, 5H); 13C NMR (50 MHz, CDCl3): d 38.6, 50.2, 73.1,
75.1, 117.3, 127.5, 128.2, 135.0, 138.1; IR (CHCl3 cmꢀ1): 3418,
3297, 3020, 1618, 761, 670. Anal. Calcd for C12H17NO: C, 75.35;
H, 8.96; N, 7.32. Found: C, 75.29, H, 8.91, N, 7.28.
4.11. (S)-tert-Butyl 2-(hydroxymethyl)piperidine-1-carboxylate 17
Dihydropyridine 16 (0.5 g, 1.65 mmol) was dissolved in MeOH
(25 mL), 10% Pd/C (38 mg) was added and the mixture was stirred
under H2 (20 psi) atmosphere for 8 h. The mixture was then fil-
tered over Celite, washed with MeOH (2 ꢃ 20 mL) and the solvent
was evaporated under reduced pressure to afford alcohol 17, which
was then purified by column chromatography over silica gel using
petroleum ether/EtOAc (7:3) to give 17 (0.320 g, 88%).
4.8. tert-Butyl (S)-1-(benzyloxy)pent-4-en-2-ylcarbamate 15
To a solution of amine 6 (4 g, 20.9 mmol) in dry CH2Cl2
(40 mL) were added dry Et3N (4.3 mL, 31.38 mmol, (Boc)2O (5.47 g,

T. M. Shaikh, A. Sudalai / Tetrahedron: Asymmetry 20 (2009) 2287–2292
2291
Chiral column: CHIRALCEL OD-H, length 25 cm, wavelength:
230 nm, flow rate 1.0 mL/min. Mobile phase: 5% isopropyl alco-
2H); 13C NMR (50 MHz, CD3OD): d 25.0, 25.9, 30.4, 41.8, 64.2,
71.2, 72.5, 172.0; IR (CHCl3 cmꢀ1): 1685, 1450, 1365, 1280, 640.
Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65; N, 8.18. Found: C,
56.20, H, 7.59, N, 8.20.
hol in hexane; ee = 98.4%;
½
a 2D5
ꢁ
¼ ꢀ40:1 (c 1, CHCl3), {lit.11
½
a 2D5
ꢁ
¼ ꢀ40:5 (c 1, CHCl3)}; 1H NMR (200 MHz, CDCl3): d 1.45 (s,
9H), 1.51–1.76 (m, 6H), 2.11 (br s, 1H), 2.78–2.92 (m, 1H), 3.5–
3.6 (m, 1H), 3.74–3.96 (m, 2H), 4.23–4.34 (m, 1H); 13C NMR
(50 MHz, CDCl3): d 18.9, 24.4, 24.9, 28.0, 39.5, 51.7, 60.0, 79.1,
155.5; IR (CHCl3 cmꢀ1): 3442, 2940, 2890, 1655, 1422, 1370,
1280, 1170, 1150, 1060, 1050, 870. Anal. Calcd for C11H21NO3: C,
61.37; H, 9.83, N, 6.51. Found: C, 61.40, H, 9.79, N, 6.49.
4.14. (+)-Lentiginosine 1
To a stirred solution of (0.1 g, 0.584 mmol) of indolizidinone 19
in THF (10 mL) at 0 °C was added lithium aluminum hydride
(0.044 g, 1.16 mmol). The suspended mixture was stirred at 65 °C
for 12 h, cooled to 0 °C, diluted with 2 mL of THF, and then care-
fully treated successively with water, 10% aq NaOH. The resulting
mixture was stirred for 1 h and filtered through pad of sodium sul-
fate and filtrate was concentrated under reduced pressure. The
crude residue was then purified by column chromatography on sil-
ica gel (CHCl3/MeOH, 8:2) to give 0.075 g of pure lentiginosine 1 as
a colourless solid 82%. Mp 103–105 °C [lit.4p mp 103–104 °C];
4.12. (S)-tert-Butyl 2-[E-2-(ethoxycarbonyl)vinyl] piperidine-1-
carboxylate 4
To a stirred solution of oxalyl chloride (0.825 g, 6.48 mmol) in
CH2Cl2 (20 mL) at ꢀ78 °C was added a solution of DMSO (0.760 g,
9.72 mmol). The reaction mixture was stirred for 20 min. followed
by the addition of a solution of alcohol 17 (0.7 g, 3.24 mmol) in
CH2Cl2 (10 mL). After stirring for 1 h at ꢀ78 °C, the reaction was
quenched by the addition of Et3N (1.8 mL, 12.96 mmol). The reac-
tion mixture was then stirred for 20 min. followed by the addition
of water (20 mL). The organic phase was separated and the aque-
ous phase was extracted with CH2Cl2 (3 ꢃ 30 mL), dried over anhyd
Na2SO4 and concentrated to give the corresponding crude aldehyde
18 in 0.650 g (93%), which was subjected to Wittig olefination
without purification as follows. To a solution of aldehyde 18 in
dry benzene (20 mL) was added Ph3P@CHCO2Et (1 g, 3.0 mmol)
and the reaction mixture was heated at 50 °C for 12 h. After com-
pletion of the reaction as monitored by TLC, it was cooled to
25 °C, extracted with EtOAc (3 ꢃ 50 mL), washed with water, brine
and dried over anhyd Na2SO4 and concentrated to give the crude
product, which was then purified by column chromatography over
silica gel using petroleum ether/EtOAc (8:2) to give the unsatu-
½
a 2D5
ꢁ
¼ þ3:0 (c 0.4, MeOH) {lit.4j
½
a 2D4
ꢁ
¼ þ3:1 (c 0.31, MeOH); 1H
NMR (200 MHz, D2O): d 1.15–1.89 (m, 7H), 1.99–2.07 (m, 1H),
2.48–2.62 (dd, J = 11.0, 7.4 Hz, 1H), 2.68–2.79 (dd, J = 11.0, 2.0 Hz,
1H), 2.90–2.93 (br d, J = 11.0 Hz, 1H), 3.46–3.60 (dd, J = 8.0,
4.0 Hz, 1H), 4.03–4.20 (m, 1H); 13C NMR (50 MHz, D2O): d 23.9,
24.8, 28.4, 53.5, 61.1, 69.4, 76.5, 83.8; IR (CHCl3 cmꢀ1): 3525,
3515, 3021, 3012, 2932, 2857, 1443, 1210, 1130. Anal. Calcd for
C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.20, H, 9.57, N,
8.78.
Acknowledgements
TMS thanks CSIR, New Delhi, for the award of senior research
fellowships. The authors are also thankful to Dr. B. D. Kulkarni,
Head, CEPD for his constant support and encouragement.
rated ester 4 (0.6 g, 90%) as a gum. ½a D25
¼ ꢀ77:5 (c 1.3, CHCl3);
ꢁ
References
1H NMR (200 MHz, CDCl3): d 1.25–1.32 (t, J = 7.0 Hz, 3H), 1.44 (s,
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5.82 (dd, J = 2.1, 13.7 Hz, 1H), 6.79–6.89 (dd, J = 4.0, 12.0 Hz); 13C
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8.89; N, 4.94. Found: C, 63.60, H, 8.90, N, 4.89.
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ꢁ
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