Synthesis of (-)-hygrine, (-)-norhygrine, (-)-pseudohygroline and (-)-hygroline via Nef reaction

Article abstract of DOI:10.1016/j.tetlet.2011.09.118

Synthesis of tropane alkaloids (-)-hygrine, (-)-norhygrine and sedum alkaloids (-)-pseudohygroline and (-)-hygroline is described from l-proline via Henry and Nef reactions.

Full text of DOI:10.1016/j.tetlet.2011.09.118

Tetrahedron Letters 52 (2011) 6566–6568
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Synthesis of (ꢀ)-hygrine, (ꢀ)-norhygrine, (ꢀ)-pseudohygroline and
(ꢀ)-hygroline via Nef reaction
⇑
Chinmay Bhat, Santosh G. Tilve
Department of Chemistry, Goa University, Taleigao-Plateau, Goa 403 206, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of tropane alkaloids (ꢀ)-hygrine, (ꢀ)-norhygrine and sedum alkaloids (ꢀ)-pseudohygroline and
Received 8 August 2011
Revised 22 September 2011
Accepted 24 September 2011
Available online 2 October 2011
(ꢀ)-hygroline is described from
L-proline via Henry and Nef reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Nef reaction
Henry reaction
Diastereoselective
Tropane alkaloid
Sedum alkaloid
The pyrrolidine members of tropane alkaloids1a–h and of sedum
alkaloids1i,j have been the target of synthesis due to their intriguing
biological activities, hallucinogenic characteristics and their utility
as pharmacological probes. The representative members of these
families include ketone derivatives hygrine 1 and norhygrine 2
which differ only in the substituent on pyrrolidine nitrogen atom
and pseudohygroline 3 and hygroline 4 which differ in the stereo-
chemistry of the secondary alcoholic group. The other examples
include pyrrolsedamine 5, pyrrolallosedamine 6, ruspolinone 7
and cuscohygrine 8, a bispyrrolidine alkaloid (Fig. 1).
and co-workers based on asymmetric phase transfer alkylation,3
the second is by Arévalo-Garcia and Colmenares from
-proline,6a
the third and the last is from our own laboratory starting from
-proline using regioselective Wacker oxidation.6b This report also
D
L
includes the first synthesis of (ꢀ)-norhygrine.
Pseudohygroline 3 and hygroline 4 have been synthesized by
Takahata et al. using Sharpless asymmetric dihydroxylation7a and
by Knight and Salter via reverse Cope elimination.7b The synthesis
of hygroline 4 is reported by Murahashi et al. using [1,3]-dipolar
cycloaddition of cyclic nitrones to crotonic acid derivatives bearing
chiral auxilliaries7c and by Louis and Hootelé using asymmetric ni-
tro-vinyl sulfoxide cycloadditions.7d Vanucci-Bacqué et al. have
achieved the synthesis of 4 by the condensation of (S)-phenylgly-
cinol with oxo alkynones.7e Pseudohygroline 3 is synthesized by
Enierga et.al. using intramolecular oxymercuration.7f Recently
Davies et al. have synthesized pseudohygroline 3 through a diaste-
reoselective lithium amide conjugate addition,7g while Yadav et al.
have approached it through stereoselective Prins cyclisation.7h
Hygrine 1, which serves as a biosynthetic precursor for the tro-
pane skeleton, is isolated from several plants2 and appears to have
no detectable optical activity when isolated. ( )-Hygrine was
resolved with D-(+)-tartarate to give diastereomeric purity of max-
imum 80% after several crystallizations. The absolute configura-
tions1a of (+)-hygrine and (ꢀ)-hygrine were determined by the
relative correlations with those of D-proline and L-proline. Later,
Park & co-workers confirmed the absolute configuration of (+)-hy-
grine as ‘R’ by its first asymmetric synthesis.3 The compound
norhygrine 2 is found to co-occur with hygrine 1. Hygroline 3
and pseudohygroline 4 were isolated from Carallia brachiata,4a
Erythroxylon coca4b and Schizanthus hookeri.4c
OH
OH
O
H
O
H
H
H
N
N
N
N
H
There are seven reports on the synthesis of ( )-hygrine,5a–g
including the shortest synthesis by Klussmann and co-workers
3
1
4
2
OH
O
H
OH
by
L
a direct oxidative coupling using vanadium acetate and
O
H
H
H
H
-proline.5f Among the chiral syntheses, the first one is by Park
O
O
N
N
H
N
Ph
Ph
N
N
5
8
6
7
⇑
Corresponding author. Tel.: +91 832 6519317; fax: +91 832 2452886.
E-mail address: stilve@unigoa.ac.in (S.G. Tilve).
Figure 1. Selected natural pyrrolidine alkaloids.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.118

C. Bhat, S. G. Tilve / Tetrahedron Letters 52 (2011) 6566–6568
6567
O
OH
O
O
H
H
H
1, 2, 3, 4
H
H
DMP/ DCM
00C, 95%
LAH/THF
H
NO2
N
N
P
N
N
N
Reflux, 90%
P
9
COOEt
10
9c
12
1
+
NO2
CHO
N
Scheme 3. Synthesis of (ꢀ)-hygrine.
P
11
O
O
Scheme 1. Retrosynthetic analysis.
H2/ Pd(C)
H
H
N
H
N
EtOH, rt, 95%
Our continuing interest in the synthesis of small molecules8a–e
prompted us to devise the synthesis of these alkaloids via Henry
and Nef reactions. The versatility of the nitro group to be manipu-
lated to carbonyl functionality is well demonstrated9a–d in the lit-
erature. Our retro synthetic approach is shown in Scheme 1. The
required alkaloids could be approached via functional group
manipulation of the N-protected pyrrolidine ketone 9, which in
turn can be obtained from the unsaturated nitro compound 10
via Nef reaction. The compound 10 could be realized via Henry
reaction between N-protected prolinal and nitroethane. Thus, we
Cbz
9a
2
Scheme 4. Synthesis of (ꢀ)-norhygrine.
O
HO
HO
H
Reduction
H
H
+
N
N
N
P
P
SR
P
SS
9
13a, P=-Cbz
b, P=-Boc
14a, P=-Cbz
b, P=-Boc
started our synthesis from the cheaply available
L-proline (Scheme
2). -Proline was reduced with LAH followed by protection of nitro-
L
c, P=-COOEt
c, P=-COOEt
gen with suitable protecting groups. The Swern oxidation of the
prolinols gave N-protected prolinal 11 in a quantitative yield. The
Henry reaction with nitroethane gave the corresponding nitro alco-
hols as diastereomeric mixtures which as such were converted to
unsaturated nitro compounds 10. Of the different methods9b tried
for Nef reaction, NaBH4/MeOH/H2O2 method9a worked well in our
hands to give moderate yields of the keto pyrrolidines 9a–c.
Having obtained the key intermediate 9 through Nef reaction,
we proceeded on to the synthesis of alkaloids 1–4. For the synthe-
sis of alkaloid (ꢀ)-hygrine 1, we reduced 9c (Scheme 3) with LAH
to give a mixture of diastereomers of the corresponding N-methyl
alcohol 12 in 90% yield. The substrate 9c was preferred to 9a and
9b for the reduction, as latter would have given the side products
benzyl alcohol and tert-butanol which would have required an
additional purification step. The alcohol 12 was then oxidized with
Dess-Martin periodinane (DMP) to give (ꢀ)-hygrine 1 in 95% yield.
The optical activity of our synthetic (ꢀ)-hygrine. HCl matched very
Reducing Agents
Li(t-OBu)3AlH
Zn(BH4)2
P=-Cbz
P=-Boc
P=-COOEt
91.57 : 8.43
44.69 : 55.31
50.16 : 49.86
98.62 : 1.38
14.68 : 85.32
78.90 : 21.10
80.88 : 19.12
53.50 : 46.50
57.47 : 42.53
NaBH4
: - diastereomeric ratio of 13:14 was determined by HPLC using kromasil
column, Flow rate 1mL/min, eluent 10% IPA + n-hexane
Scheme 5. Diastereoselective reduction of carbonyls.
the reduction of keto group. ½a D30
ꢁ
ꢀ30.2 (c 0.2, CHCl3); Lit.6a
½ ꢁ
a 3D3
ꢀ29.6 (c 0.14, CHCl3).
For the synthesis of sedum alkaloids (ꢀ)-pseudohygroline 3 and
(ꢀ)-hygroline 4 which differ in their hydroxyl configuration, we
probed the selective reduction of 9a–c with different reducing
agents (Scheme 5). Results of these studies show that there is very
little diastereoselectivity protecting groups for the ethoxycarbonyl
and benzyloxycarbonyl when NaBH4 was used as a reducing agent,
while when the tert-butoxycarbonyl is the protecting group there
was 80% cis (SR) diastereoselectivity. The cis (SR) diastereoselectiv-
ity is found to increase for all the protecting groups when bulky
lithium tri-tert-butoxyaluminium hydride was used, the maximum
(98%) being for the tert-butoxy protecting group. Interestingly,
trans (SS) selectivity of 85% was observed for the tert-butoxy
protected 9 when Zn(BH4)2 was used as the reducing agent. The
well with the literature values. ½a D30
ꢁ
ꢀ33.2 (c 0.2, H2O); Lit.3
½ ꢁ
a 3D0
+34.5 (c 0.5, H2O) for R isomer; Lit.6b
S isomer.
½
a 3D0
ꢁ
ꢀ32.1 (c 0.25, H2O) for
Synthesis of (ꢀ)-norhygrine was achieved in a straightforward
manner (Scheme 4) by selective hydrogenolysis of 9a without
H
H
CHO
H
a, b, c
d
COOH
N
H
N
P
N
NO2
P
10a-c
11a-c
O
tert-butoxycarbonyl group shows a better discrimination for
e
H
diastereoselective reduction with bulky reducing agent Li(t-
OBu)3AlH giving maximum syn (SR) diastereoselectivity while with
Zn(BH4)2, it gave maximum trans (SS) diastereoselectivity. The nor-
mally difficult trans (SS) selectivity obtained by Zn(BH4)2 is note-
worthy.7g,10 For the synthesis of pure (ꢀ)-pseudohygroline 3, the
N
P
9a-c
9, 10, 11
a, P= -Cbz,
b, P= -Boc
c, P= -COOEt
HO
HO
H
H
LAH/THF
95%
Scheme 2. General synthetic route from L-proline. Reagents and conditions: (a)
N
N
LAH, THF, reflux, 8 h, 90%; (b) For P = –Cbz: Cbz–Cl, K2CO3, CH3CN, 0 °C, 6 h, 95%; For
P = –Boc: (Boc)2O, Et3N, DCM, 0 °C, 95%; For P = –COOEt: ClCOOEt, K2CO3, CH3CN,
0 °C, 90%; (c) COCl2, DMSO, Et3N, DCM, –78 °C, 95%; (d) (i) CH3CH2NO2, 2 mL of 3 N
KOH, two drops of conc. H2SO4; (ii) MeSO2Cl, Et3N, DCM, (85%, two steps); (e)
NaBH4, MeOH, K2CO3, H2O2, rt. 18 h (P = –Cbz, 65%; P = –Boc, 56%; P = –COOEt, 56%).
COOEt
13c
3
Scheme 6. Synthesis of (ꢀ)-pseudohygroline.

6568
C. Bhat, S. G. Tilve / Tetrahedron Letters 52 (2011) 6566–6568
1996, 41, 1319; For a review see: (j) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002,
HO
HO
H
H
LAH/THF
95%
58, 5957.
2. (a) McGaw, B. A.; Woolley, J. G. Phytochemistry 1978, 17, 257–259; (b) Witte, L.;
Mular, K.; Arfermann, H. A. Planta Med. 1987, 53, 192–197; (c) Leete, E. Planta
Med. 1979, 36, 97–112; (d) Parr, A. J. Plant Cell Rep. 1992, 11, 270–273; (e) Kim,
J. H.; Hart, H. T.; Stevens, J. F. Phytochemistry 1996, 41, 1319–1324; (f) Lansky, E.
P.; Newman, R. A. J. Ethnopharmacol. 2006, 103, 311–318.
N
N
COOEt
14c
4
Scheme 7. Synthesis of (ꢀ)-hygroline.
3. Lee, J.-H.; Jeong, B.-S.; Ku, J.-M.; Jew, S.-s.; Park, H.-g. J. Org. Chem. 2006, 71,
6690–6692.
4. (a) Platonava, T. F.; Kuzovkov, A. D. Med. Prom. SSSR 1963, 17, 19; (b) Fitzgerald,
J. S. Aust. J. Chem. 1965, 18, 589; (c) Martin, S. A.; Rovirosa, J.; Gambaro, V.;
Castillo, M. Phytochemistry 1980, 19, 2007.
5. (a) Sorm, F. Coll. Czech CC 1947, 12, 245–250; (b) Galinovsky, F.; Zuber, H.
Monatsh. Chem. 1953, 84, 798–808; (c) Shono, T.; Matsumura, Y.; Tsubata, K. J.
Am. Chem. Soc. 1981, 103, 1172–1176; (d) Langeskiold, T.; Lounasmaa, M.
Heterocycles 1983, 29, 671–675; (e) Nagasaka, T.; Yamamoto, H.; Hayashi, H.
Heterocycles 1989, 29, 155–164; (f) Sud, A.; Sureshkumar, D.; Klussmann, M.
Chem. Commun. 2009, 3169–3171; (g) Ponpandian, T.; Muthusubramanian, S.
Tetrahedron Lett. 2011, 52, 1520–1522.
cis (SR) diastereomer 13c was reduced with LAH (Scheme 6) and
the trans (SS) 14c for (ꢀ)-hygroline 4 (Scheme 7). The optical
rotation of our synthetic products matched well with the literature
values. For (ꢀ)-pseudohygroline ½a D28
ꢁ
ꢀ90 (c 0.2, EtOH; Lit.7f aD
+70.7 (c 2.0, EtOH); Lit.7a
½
a 2D5
+97.0° (c 3.4, EtOH) for RS isomer;
ꢁ
for (ꢀ)-hygroline, ½a D23
ꢁ
ꢀ50 (c 0.2, EtOH); Lit.7a
ꢀ49 (c 0.4, EtOH).
½
a 2D0
ꢁ
ꢀ50.2 (c
0.466, EtOH), Lit.7a
½ ꢁ
a 2D2
6. (a) Arévalo-Garcia, E. B.; Colmenares, J. C. Q. Tetrahedron Lett. 2008, 49,
3995–3996; (b) Majik, M. S.; Tilve, S. G. Tetrahedron Lett. 2010, 51, 2900–
2902.
In summary, tropane alkaloids (ꢀ)-hygrine, (ꢀ)-norhygrine and
sedum alkaloids (ꢀ)-pseudohygroline and (ꢀ)-hygroline have been
7. (a) Takahata, H.; Kubota, M.; Momose, T. Tetrahedron: Asymmetry 1997, 8, 2801;
(b) Knight, D. W.; Salter, R. Tetrahedron Lett. 1999, 40, 5915; (c) Murahashi, S.-I.;
Imada, Y.; Kohno, M.; Kawakami, T. Synlett 1993, 395; (d) Louis, C.; Hootele, C.
Tetrahedron: Asymmetry 1997, 8, 109–131; (e) Vanucci-Bacqué, C.; Calvet-
Vitale, S.; Bellassoued, M. C.; Lhommet, G. ARKIVOC 2007, 148–161; (f) Enierga,
G.; Hockless, D. C. R.; Perlmutter, P.; Rose, M.; Sjoberg, S.; Wong, K. Tetrahedron
Lett. 1998, 39, 2813; (g) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Tetrahedron 2009, 65, 10192; (h) Yadav, J. S.; Narasimhulu, G.; Reddy, N. M.;
Reddy, B. V. S. Tetrahedron Lett. 2010, 51, 1574–1577.
synthesized successfully from L-proline via Henry and Nef reac-
tions. The trans (SS) diastereoselectivity observed for the reduction
of tert-butyl-(2S)-2-(2-oxopropyl)pyrrolidine-1-carboxylate 9b
using Zn(BH4)2 is noteworthy. Further application of this method-
ology for the synthesis of piperidine alkaloids is underway.
Acknowledgments
8. (a) Shet, J. B.; Desai, V.; Tilve, S. G. Synthesis 2004, 11, 1859; (b) Majik, M. S.;
Shet, J.; Tilve, S. G.; Parameswaran, P. S. Syntheis 2007, 663–665; (c) Majik,
M. S.; Parameswaran, P. S.; Tilve, S. G. Helv. Chim. Acta 2008, 91, 1500–1504;
(d) Majik, M. S.; Parameswaran, P. S.; Tilve, S. G. J. Org. Chem. 2009, 74,
3591–3594; (e) Majik, M. S.; Parameswaran, P. S.; Tilve, S. G. J. Org. Chem.
2009, 74, 6378–6381.
We thank IISc (Bangalore) for HRMS and NMR facility and DST
for the financial support. One of the authors (CB) is thankful to
CSIR, New Delhi, for awarding Senior Research Fellowship.
9. (a) Ballini, R.; Bosica, G. Synthesis 1994, 723–726; (b) Ballini, R.; Petrini, M.
Tetrahedron 2004, 1017–1047; (c) Ballini, R.; Petrini, M. ARKIVOC 2009,
195–223; (d) Aginagalde, M.; Bello, T.; Masdeu, C.; Vara, Y.; Arrieta, A.;
Cossio, F. P. J. Org. Chem. 2010, 75, 7435–7438.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.118.
10. (a) Irie, K.; Aoe, K.; Tanaka, T.; Saito, S. J. Chem. Soc., Chem. Commun. 1985, 633;
(b) Ibuka, T.; Chu, G. N. Chem. Pharm. Bull. 1986, 34, 2380; (c) Wanner, K. T.;
Kaertner, A. Heterocycles 1987, 26, 921; (d) Driessens, F.; Hootele´, C. Can. J.
Chem. 1991, 69, 211; (e) Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenaender, F.
Liebigs Ann. 1995, 1295; (f) McAlpine, I. J.; Armstrong, R. W. Tetrahedron Lett.
2000, 41, 1849; (g) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am.
Chem. Soc. 2001, 123, 12510; (h) Heydenreich, M.; Koch, A.; Lazar, L.; Szatmari,
I.; Sillanpaa, R.; Kleinpeter, E.; Fulop, F. Tetrahedron 2003, 59, 1951; (i)
Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126,
3734; (j) Dooms, C.; Laurent, P.; Daloze, D.; Pasteels, J.; Nedved, O.; Braekman,
J.-C. Eur. J. Org. Chem. 2005, 1378; (k) Birman, V. B.; Jiang, H.; Li, X. Org. Lett.
2007, 9, 3237; (l) Al-Sarabi, A. E.; Bariau, A.; Gabant, M.; Wypych, J.-C.; Chalard,
P.; Troin, Y. ARKIVOC 2007, 119; (m) Chen, L.-J.; Hou, D.-R. Tetrahedron:
Asymmetry 2008, 19, 715; (n) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.;
Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745.
References and notes
1. (a) Cignarella, G.; Gallo, C. G.; Testa, E. J. Am. Chem. Soc. 1961, 83, 4999–
5003; (b) Noyori, R.; Baba, Y.; Hayakawa, H. J. Am. Chem. Soc. 1974, 96,
3336–3338; (c) Forder, G.; Dharanipragada, R. Nat. Prod. Rep. 1993, 199–206;
(d) Majewski, M.; Lazny, R. J. Org. Chem. 1995, 60, 5825–5830; (e) Jordan, M.;
Human, M.; Bieri, S.; Christen, C.; Poblete, E.; Munoz, O. Phytochemistry 2006,
67, 570–578; (f) Yamauchi, T.; Hagiwara, S.; Higashiya, K. J. Org. Chem. 2008,
73, 9784–9787; (g) Sandala, G. M.; Smith, D. M.; Radom, L. J. Am. Chem. Soc.
2008, 130, 10684–10690; (h) Davis, F. A.; Theddu, N.; Gaspari, P. M. Org. Lett.
2009, 11, 1647–1650; (i) Kim, J. H.; t’Hart, H.; Stevens, J. F. Phytochemistry