Formal synthesis of (-)-stemoamide using a useful epimerization at C-8

Article abstract of DOI:10.1016/j.tetlet.2012.03.054

The formal synthesis of (-)-stemoamide was achieved starting from l-pyroglutamic acid. The key steps used are the allylation using BF ₃·OEt₂, ring closing metathesis, allylic oxidation and a novel epimerization at C8.

Full text of DOI:10.1016/j.tetlet.2012.03.054

Tetrahedron Letters 53 (2012) 2647–2650
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Tetrahedron Letters
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Formal synthesis of (ꢀ)-stemoamide using a useful epimerization at C-8
Subhash P. Chavan a, , Kishor R. Harale a, Vedavati G. Puranik b, Rupesh L. Gawade b
⇑
a Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
b Centre for Materials Characterization, National Chemical Laboratory, Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal synthesis of (ꢀ)-stemoamide was achieved starting from
L-pyroglutamic acid. The key steps
used are the allylation using BF3ꢁOEt2, ring closing metathesis, allylic oxidation and a novel epimerization
Received 14 December 2011
Revised 14 March 2012
Accepted 18 March 2012
Available online 23 March 2012
at C8.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Stemoamide
Ring closing metathesis
Allylation
Allylic oxidation
Pyroglutamic acid
The ancient people had great sense of using plant extracts for
the treatment of various diseases, based on their traditional knowl-
edge of these plants possessing biologically active molecules
responsible for cure. One such root extract used for the treatment
of tuberculosis, pertussis and throat infections in traditional
Chinese and Japanese medicines belongs to the Stemonaceae fam-
ily.1 The root extracts of Stemonaceae family consist of more than
hundred and thirty stemona alkaloids.2 The common structural
feature encountered in stemona alkaloids is the presence of perhy-
tion of stemoamide structure. Herein we describe our efforts
towards the enantioselective synthesis of (ꢀ)-stemoamide starting
from L-pyroglutamic acid.
According to our retrosynthetic plan (Scheme 1), the key inter-
mediate is butenolide 2. Elaboration of the intermediate 2 to 1 is
well documented.5f,g In turn our focus was the construction of but-
enolide ring 2 based on our previously reported strategy for bute-
nolide synthesis,6 which includes the Reformatsky reaction on
ketone 5 to furnish the corresponding hydroxy ester which on
dropyrrolo azepine as well as
c
-butyrolactone core. Taking into
dehydration furnishes b,
lation and treatment with acid would provide butenolide. The ke-
tone could be constructed by two routes, one by taking
c-unsaturated ester which on dihydroxy-
account the interesting structure and important biological activity
of stemona alkaloids, there is a need to develop novel synthetic
routes to this class of compounds.1
5
advantage of RCM strategy and another route by taking advantage
(ꢀ)-Stemoamide 1 (Fig. 1), one of the stemona alkaloids was
isolated by Xu and co-workers in 1992 from Stemona tuberosa Lour
and related stemona species.3 Amongst the stemona alkaloid fam-
ily, (ꢀ)-stemoamide is the simplest and structurally attractive mol-
ecule.4 To date eight different routes are reported for the synthesis
of (ꢀ)-stemoamide, so there is a considerable scope for its synthe-
sis.5 Besides this, ten various other strategies are reported for the
synthesis of stemoamide, six of them describe different routes
leading to racemic syntheses while rest of them describe the
syntheses of its unnatural isomers. Jacobi et al. in their seminal
manuscript5c disclosed the interesting steric bias of the tricyclic
skeleton of stemoamide leading to a high degree of diastereoselec-
tivity by computational studies which was backed by experimental
observations and it was attributed to the thermodynamic stabiliza-
of Grignard reaction on aldehyde 10. The di-allylated precursor 6
could be constructed from
L
-pyroglutamic acid 11.
-pyroglutamic acid 11 (Scheme 2)
Our synthesis started from
L
wherein the N-allyl alcohol 12 was prepared using the reported
method with no loss in chirality.7 The resulting N-allyl alcohol 12
was oxidized to aldehyde 7 using IBX in refluxing ethyl acetate.
The crude aldehyde 7, as such, was subjected to allylation using
allyltrimethylsilane and TBAF in THF but we were unable to get
di-allylated product 6 in good yields despite modifications in the
Me
H
9a
O
10
N
O
9
H
8
O
H
⇑
Corresponding author. Tel.: +91 020 25902289; fax: +91 020 25902629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
Figure 1. (ꢀ)-Stemoamide 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.054

2648
S. P. Chavan et al. / Tetrahedron Letters 53 (2012) 2647–2650
Me
10
OBn
THF, -50 oC, 89%
H
H
H
OH
BrMg
O
IBX,
9a
O
O
O
H
N
O
N
N
O
O
O
N
9
N
H
H
H
8
EtOAc,
reflux
O
10
O
O
O
Ref. 5b
Epimerisation
Ph
H
H
H
Ph
13
(over 2 steps)
3
2
H
1
H
(-)-Stemoamide,
MOMO
HO
1. MOMCl, DIPEA,
DCM, reflux, 90%
O
N
H
O
N
O
O
O
EtO
N
N
Ph
2. Na, NH3, THF,
-78 oC, 87%
H
H
O
di-hydroxylation
and elimination
14
9
OH
O
4
5
OBn
1. MsCl, Et3N, DCM
2. NaH, THF
H
O
HO
HO
N
N
O
O
O
H
3. HCl (trace), MeOH, reflux
(60% over three steps)
N
N
OHC
H
H
15
7
6
5
H
O
IBX, EtOAc,
O
N
reflux, 65%
O
O
Grignard
MOMO
HO
O
N
H
N
N
Bn
10
OHC
H
H
Bn
5
H
OMs
OBn
9
Scheme 3. Alternate route to ketone 5.
8
Scheme 1. Retrosynthetic analysis of (ꢀ)-stemoamide.
provide aldehyde 10 with no loss in chirality. The required Grig-
nard reagent was prepared from 4-benzyloxybutyl bromide and
activated Mg in THF. The crude aldehyde 10 was initially treated
with 2 equiv of Grignard reagent at room temperature in THF
which resulted in complex reaction mixture. After optimization
of reaction conditions, the Grignard reaction was performed at
ꢀ50 °C in the presence of THF as the solvent, furnishing alcohol 9
in 89% yield. Alcohol 9 was reacted with methoxymethyl chloride
in the presence of Hünig’s base in DCM under reflux condition to
afford the corresponding MOM ether in 90% yield. Subsequently
the MOM protected compound was subjected to Birch reduction
using Na and ammonia in THF at ꢀ78 °C for one hour to provide
amido alcohol 14 in 87% yield. Mesylation of 14 was carried out
using MsCl and triethylamine in DCM at room temperature. The
mesyl compound was then subjected to react with NaH in THF to
provide cyclized compound which was subsequently subjected to
MOM deprotection using trace amount of conc. HCl in methanol
under reflux conditions to provide alcohol 15 in 60% yield over
three steps. The bicyclic alcohol 15 was oxidized to ketone 5 using
IBX (2 equiv) in ethyl acetate under reflux condition for 3 hours, in
65% yield.
amounts of allyltrimethylsilane and of TBAF. However, by perform-
ing the reaction under Lewis acidic conditions employing BF3.OEt2
as catalysts in DCM we got the di-allylated product 6 in 87% yield.
The 1H NMR of di-allylated compound 6 showed it to be a mixture
of diastereomers, which did not matter to us because the alcohol
functionality in 6 was to be oxidized at a later stage.
The di-allylated product 6 was subjected to RCM reaction using
Grubbs’ 1st generation catalyst (2 mol %) in DCM, which resulted in
cyclic olefin product but low yields (34%) were obtained at room
temperature as well as under reflux conditions. Varying the
amount of Grubbs’ catalyst up to 8 mol % also resulted in unsatis-
factory yield, up to a maximum of 40%. However switching over
to the use of Grubbs’ 2nd generation catalyst (2 mol %) in DCM at
room temperature furnished good yield (85%) of ring closed prod-
uct.8 The subsequent oxidation of alcohol using IBX in ethyl acetate
under reflux conditions and reduction of double bond by hydroge-
nation using 10% Pd over carbon in methanol under hydrogen
(60 psi) provided ketone 5 in 92% yield. Ketone 5 was also prepared
by another route (Scheme 3). Alcohol 13 was prepared according to
the reported procedure from L
-pyroglutamic acid.9 Alcohol 13 was
oxidized using IBX in ethyl acetate under reflux conditions to
Ketone 5 was subjected to Reformatsky reaction (Scheme 4)
using ethyl 2-bromopropionate in the presence of zinc and cata-
lytic iodine to give alcohol 16 in 78% yield almost as a single diaste-
reomer as judged by the examination of the spectral data (1H NMR,
13C NMR). The next job was to eliminate the hydroxy group to ob-
tain the alkene 4. We subjected the alcohol 16 to elimination using
thionyl chloride and pyridine in DCM to furnish isomeric mixture
of olefins including the desired olefin 4.
IBX, EtOAc
O
HO
reflux,
Ref. 7
N
O
HO
H
H
N
H
H
O
11
12
O
O
HO
TMS
N
N
OEt
H
H
H
Br
O
O
BF3.OEt2, DCM,
87% (over two steps)
EtO
N
SOCl2, Pyridine,
DCM
O
5
OH
7
6
O
Zn, I2, benzene: ether
(1:1), reflux, 78%
16
1. Grubbs' 2nd gen. cat.
DCM, rt, 85%
H
O
O
O
EtO
N
N
H
2. IBX, EtOAc, reflux, 82%
3. H2, Pd/C, MeOH, 92%
O
5
4
Scheme 2. Synthesis of ketone 5.
Scheme 4. Synthesis of 1.

S. P. Chavan et al. / Tetrahedron Letters 53 (2012) 2647–2650
2649
O
P
OEt
O
O
OEt
H
O
O
EtO
OEt
O
SeO2, AcOH,
reflux, 45%
EtO
O
N
N
N
H
H
NaH, benzene, 88%
O
HO
17
18
5
PhSe
1. NiCl2, NaBH4,
THF, 78%
O
H
O
H
Et3N, DCM,
2 days
30% H2O2,
DCM, 92%
N
N
O
O
O
H
2. LiHMDS, PhSeBr, THF, 95%
8
O
19
20 (a, b)
H
H
O
O
H
N
N
O
O
H
Ref. 5e
O
O
H
(-)-1
20 (b)
Scheme 5. Synthesis of 1 using alternate route to proposed plan.
Alkene 4 was obtained as an inseparable mixture of 3 isomeric
olefins in equal proportions, which was confirmed by LCMS
although the exact identity of the olefins could not be rigorously
established.10 In spite of several modifications, we were not able
to obtain the required alkene 4 exclusively and it was very difficult
to proceed with the mixture.
The undesired results obtained during elimination forced us to
change our route to (ꢀ)-stemoamide 1. The ketone 5 was subjected
to Horner-Wadsworth–Emmons reaction (Scheme 5) using triethyl
phosphonoacetate, to furnish a,b-unsaturated ester 17 in 88% yield
as a (4:1) mixture of olefins with E isomer predominating. This was
confirmed by X-ray analysis of the corresponding acid 17a
(Fig. 2).11
It was surmised that the butenolide 20 could be readily ob-
tained by performing allylic oxidation on substrate 17 according
to the literature report.12 Accordingly we carried out allylic oxida-
tion using selenium dioxide under reflux conditions in acetic acid,
but unfortunately instead of butenolide 20, the uncyclized hydroxy
ester 18 was obtained as a single diastereomer. We were unable to
isolate any other isomeric product from the remaining intractable
residue.13 Failure to obtain butenolide was attributed to the Z con-
figuration at double bond in hydroxy olefin 18, in which ester is
away from the hydroxy group, which indeed was later confirmed
by single crystal X-ray analysis of 18 (Fig. 3).14 The isomerization
of the olefin could be explained based on the literature precedence
which involves [2,3]-rearrangement of the seleno ester intermedi-
ate during allylic oxidation in acidic conditions.15 It may be pointed
out that the hydroxy group installed had the opposite stereochem-
istry than what is required for (ꢀ)-stemoamide. Hydroxy olefin 18
was treated with various reagents like PTSA, H2SO4, HCl, thiophe-
nol-triethylamine and thiophenol-sodium hydride but none of
the above conditions resulted in the formation of butenolide 20
(b).
Figure 3. The X-ray structure of ester 18.
unsuccessful attempts to cyclize the hydroxy olefin 18, we reduced
the double bond using NiCl2:NaBH4 in THF which furnished cy-
clized butyrolactone product in 78% yield. But the stereochemistry
of cyclized product disappointed us because the NMR spectrum
showed it to be a diastereomeric mixture in which C8 was not of
desired stereochemistry.
In order to fix these two centres, we converted cyclized product
a-phenyl selenolactone derivative using LiHMDS and PhSeBr
into
in THF to give selenyl compound 19 in 95% yield, according to Sibi’s
protocol.5e The selenolactone 19 was subjected to elimination
using hydrogen peroxide in DCM at 0 °C, to furnish butenolide 20
(a, b) in 92% yield. The butenolide 20 (a, b) was obtained as a dia-
stereomeric mixture in the ratio 70:30 which was evident from 1H
NMR spectrum. The major diastereomer was with undesired
stereochemistry. Although compounds 19 and 20 (a, b) were the
mixture of diastereomers, they were almost homogenous by TLC
and were carried forward to eventually obtain butenolide 20(b)
as a single diastereomer.
As we were unable to transform the hydroxy ester 18 directly
into butenolide 20, we had to take a circuitous route. After the
Careful observation revealed that these two diastereomers of
20(a,b) have a very small difference in Rf values. We treated this
diastereomeric mixture with triethylamine in DCM and to our de-
light we observed that the concentration of the faster moving (less
polar) spot increased when the reaction was monitored by TLC.
After prolonging this reaction by stirring the reaction mixture for
almost two days, we observed that the mixture was completely
transformed in to the desired butenolide 20(b).
O
HO
N
H
O
After characterization, it was confirmed that the observed prod-
uct was the desired diastereomer butenolide 20(b) whose melting
point, spectral data and [
Hence for the first time we have successfully converted the
a]
value agreed with those reported.5f
D
Figure 2. The X-ray structure of acid 17a.

2650
S. P. Chavan et al. / Tetrahedron Letters 53 (2012) 2647–2650
Somfai, P. J. Org. Chem. 2007, 72, 4246; (h) Honda, T.; Matsukawa, T.; Takahashi,
K. Org. Biomol. Chem. 2011, 9, 673.
6. (a) Chavan, S. P.; Zubaidha, P. K.; Ayyangar, N. R. Tetrahedron Lett. 1992, 33,
4605; (b) Scherkenbeck, T.; Siegel, K. Org. Process Res. Dev. 2005, 9, 216.
7. Keusenkothen, P. F.; Smith, M. B. J. Chem. Soc., Perkin Trans. 1 1994, 2485.
8. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
9. Mavromoustakos, T.; Moutevelis-Minakakis, P.; Kokotos, C. G.; Kontogianni, P.;
Politi, A.; Zoumpoulakis, P.; Findlay, J.; Cox, A.; Balmforth, A.; Zoga, A.;
Iliodromitis, E. Bioorg. Med. Chem. 2006, 14, 4353.
10. The LCMS revealed three peaks with equal integration and same mass.
11. CCDC 866111 (17a) contains the Supplementary crystallographic data for this
Letter. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
12. Kagabu, S.; Shimizu, Y.; Ito, C.; Moriya, K. Synthesis 1992, 830.
13. Allylic oxidation, synthesis of 18
diastereomeric mixture 20 (a, b) into the required isomer 20(b) in
good yields.16 The conversion of butenolide 20(b) into (ꢀ)-stemoa-
mide is well documented in the literature in two steps,5g hence this
constitutes the formal total synthesis of (ꢀ)-stemoamide. By per-
forming this sequence of reactions we were able to convert ketone
5 into butenolide 20(b) in 27% overall yields.
In conclusion, the formal total synthesis of (ꢀ)-stemoamide was
achieved by taking advantage of RCM and allylic oxidation in 11
steps in 15% overall yield. The alternate route to seven membered
ring construction was developed using Grignard reaction and base
induced cyclization to furnish butenolide 20(b) in 14 steps in 11%
overall yield. Complete novel epimerization of 20(a, b) to expected
isomer 20(b) was achieved successfully.
To the a,b-unsaturated ester 14 (400 mg, 1.7 mmol) in acetic acid (10 mL), was
added selenium dioxide (284 mg, 2.5 mmol) and the resulting reaction mixture
was heated at reflux for 5 h. The reaction mixture was filtered on celite and the
residue was washed with ethyl acetate (50 mL). The collected filtrates were
concentrated in vacuo and purified using flash chromatography (EtOAc) to
afford hydroxy compound 15 (272 mg, 45%) as a crystalline solid (mp 104–
Acknowledgments
105 °C). IR (CHCl3) mmax
: 3367, 2925, 2800, 1706, 1663, 1402, 1223,
K.R.H. thanks the CSIR, New Delhi, India for the financial
support in the form of fellowship and Dr. H.B. Borate and Dr. U.
R. Kalkote for their help.
1175 cmꢀ1.1H NMR (400 MHz, CDCl3): d 5.80 (s, 1H), 5.41 (t, J = 7.2 Hz, 1H),
4.60 (d, J = 6.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.11 (br d, J = 14 Hz, 1H), 2.34–
2.65 (m, 4H), 2.20–2.25 (m, 1H), 1.88–2.09 (m, 2H), 1.54–1.61 (m, 2H), 1.30 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.7, 165.6, 163.9, 117.5, 77.2,
60.4, 60.2, 42.8, 35.3, 30.3, 25.6, 21.9, 14.2; ESIMS (m/z): 254 (M+H)+, 276
(M+Na)+.
References and notes
14. CCDC 866112 (18) contains the supplementary crystallographic data for this
Letter. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
15. (a) Stephenson, L. M.; Speth, D. R. J. Org. Chem. 1979, 44, 4683; (b) Patel, R. M.;
Puranik, V. G.; Argade, N. P. Org. Biomol. Chem. 2011, 9, 6312; (c) Gyoosoon, P.;
Jang, C. H.; Woo, S. J.; Choon, S. R. Bull. Korean Chem. Soc. 1856, 2005, 26.
16. Epimerization of 20(a, b) to 20(b).
1. (a) Götz, M.; Strunz, G. M. Tuberostemonine and Related Compounds: The
Chemistry of Stemona Alkaloids’. In Alkaloids; Wiesner, G., Ed.; Vol. 9;
Butterworths: London, 1975; MTP, International Review of Sciences Organic
Chemistry, Series One, pp 143–160; (b) Sakata, K.; Aoki, K.; Chang, C.-F.;
Sakurai, A.; Tamura, S.; Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457.
2. Kongkiatpaiboon, S.; Schinnerl, J.; Felsinger, S.; Keeratinijakal, V.; Vajrodaya, S.;
Gritsanapan, W.; Brecker, L.; Greger, H. J. Nat. Prod. 1931, 2011, 74.
To the diastereomeric mixture of butenolide 20(a, b) (30 mg, 0.15 mmol) in
anhydrous DCM (5 mL), was added triethylamine (0.04 ml, 2.9 mmol) and the
reaction mixture was stirred for 2 days. The reaction mixture was concentrated
in vacuo and the residue purified using flash chromatography (2:98
3. Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571.
4. Reviews: (a) Alibés, R.; Figueredo, M. Eur. J. Org. Chem. 2009, 15, 2421; (b) Jezek,
E.; Reiser, O. Chemtracts 2005, 18, 200; (c) Pilli, R. A.; Ferreira de Oliveira, M. C.
Nat. Prod. Rep. 2000, 17, 117; (d) Pilli, R. A.; Rosso, G. B.; Ferreira de Oliveira, M.
C. Nat. Prod. Rep. 1908, 2010, 27.
5. Total and formal syntheses of (ꢀ)-stemoamide: (a) Williams, D. R.; Reddy, J. P.;
Amato, G. S. Tetrahedron Lett. 1994, 35, 6417; (b) Kinoshita, A.; Mori, M. J. Org.
Chem. 1996, 61, 8356; (c) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295;
(d) Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295; (e) Sibi, M. P.;
Subramanian, T. Synlett 2004, 1211; (f) Olivo, H. F.; Tovar-Miranda, R.;
MeOH:EtOAc) to afford diastereomerically pure butenolide 20(b) (24 mg,
80%) as a white solid (mp 158–159 °C, lit.5g mp 157–158 °C) ½a 2D5
ꢂ
227 (, 0.4
_
CHCl3), lit.5g-½a D20
ꢂ
– 224 (c, 0.4 CHCl3), IR (CHCl3) mmax: 2928, 2850, 1753, 1665,
1454, 1223, 911, 750 cmꢀ1 1H NMR (500 MHz, CDCl3): d 5.98 (s, 1H), 5.00–5.03
.
(m, 1H), 4.77–4.81 (m, 1H), 4.29–4.32 (m, 1H), 2.49–2.58 (m, 5H), 1.84–1.94
(m, 2H), 1.68–-1.76 (m, 1H), 1.40–1.48 (m, 1H); 13C NMR (125 MHz, CDCl3) d
174.5, 174.1, 171.7, 115.9, 82.9, 58.1, 43.4, 34.5, 30.2, 27.7, 25.7; ESIMS (m/z):
208 (M+H)+, 230 (M+Na)+.
´
Barragan, E. J. Org. Chem. 2006, 71, 3287; (g) Torssell, S.; Wanngren, E.;