A concise diastereoselective approach to (+)-dexoxadrol, (-)-epi-dexoxadrol, (-)-conhydrine and (+)-lentiginosine from (-)-pipecolinic acid

Article abstract of DOI:10.1016/j.tet.2013.10.082

A new diastereoselective pathway for the total synthesis of (+)-dexoxadrol, first asymmetric synthesis of (-)-epi-dexoxadrol and formal synthesis of conhydrine and (+)-lentiginosine is presented using commercially available (-)-pipecolinic acid. The key reactions utilized are Sharpless asymmetric dihydroxylation and Wittig reaction. The paper further describes the study of effect of protecting groups on dihydroxylation of a terminal olefin in piperidine ring system.

Full text of DOI:10.1016/j.tet.2013.10.082

Tetrahedron 69 (2013) 10876e10883
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A concise diastereoselective approach to (þ)-dexoxadrol, (ꢀ)-epi-
dexoxadrol, (ꢀ)-conhydrine and (þ)-lentiginosine from
(ꢀ)-pipecolinic acid
*
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:
Received 14 August 2013
Received in revised form 24 October 2013
Accepted 25 October 2013
Available online 31 October 2013
A new diastereoselective pathway for the total synthesis of (þ)-dexoxadrol, first asymmetric synthesis of
(ꢀ)-epi-dexoxadrol and formal synthesis of conhydrine and (þ)-lentiginosine is presented using com-
mercially available (ꢀ)-pipecolinic acid. The key reactions utilized are Sharpless asymmetric dihydrox-
ylation and Wittig reaction. The paper further describes the study of effect of protecting groups on
dihydroxylation of a terminal olefin in piperidine ring system.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Piperidines
Sharpless dihydroxylation
Wittig reaction
Alkaloids
1. Introduction
chain homologues of dexoxadrol 1 are synthesized and tested for
different biological responses.6
2-Substituted piperidine alkaloids are widely dispersed among
the natural products and found to play vital role in various bi-
ological and medicinal applications.1 The presence of active func-
tional groups on the side chain and piperidine nucleus together
plays a crucial role for their potent biological activities. Due to their
unique and interesting structures, chemists are attracted towards
the syntheses of these motifs as new drugs for the clinical trials.2 As
a result, over the last few decades many such synthetic drugs are
produced and tested for the treatment of various diseases. Dexox-
adrol 1 is one such alkaloid, first synthesized by Hardie et al. in 1960
as an anaesthetic drug along with etoxadrol 3.3 The subsequent
clinical trials revealed that these compounds are efficient NMDA
receptor antagonist by binding with the PCP cites and found to be
more efficient than the available drugs memantine 4 and amanta-
dine 5 (Fig. 1).4 The detailed study on the biological behaviour of
these molecules realized that, the presence of secondary amine,
piperidine ring, five member oxygenated ring and the (S, S) ste-
reochemistry altogether plays a crucial role for its enhanced ac-
tivity.5 The interesting structure and its potent biological activity
prompted the synthetic chemists to design newer methods for
different analogues of 1. In recent years various substituted side-
There are three synthetic reports available for the synthesis of
dexoxadrol so far (Scheme 1).3,7 The Hardie’s and Thukauf’s
methods involve substituted pyridines as starting materials, which
eventually produce (þ)-dexoxadrol 1 after racemic separation at
the final stage.3,7a The first asymmetric synthesis developed by
Etayo et al. manipulates mannitol successfully to convert to 1 dia-
stereoselectively, using RCM as a key step.7b
2. Results and discussion
In continuation of our research directed towards the synthesis of
2-substituted piperidine and pyrrolidine alkaloids,8 we undertook
the synthesis of dexoxadrol 1 and its possible epi isomer 2 using
commercially available (ꢀ)-pipecolinic acid. Our retrosynthetic
approach is outlined in Scheme 2. Accordingly, our synthesis in-
volves the formation of alkene 6 and diol 7 through Wittig and
Sharpless asymmetric dihydroxylation (SAD), respectively.
The synthesis commenced with LAH reduction of commercially
available (ꢀ)-pipecolinic acid to pipecolinol 9 in good yield
(Scheme 3). The pipecolinol 9 obtained as a pale yellow solid was
converted to benzyl carbamate 10a. The aldehyde 11a prepared by
Swern oxidation of 10a was immediately converted to alkene 6a in
90% yield by carrying out Wittig reaction using þPPh3CH3Brꢀ/
NaHMDS. The dihydroxylation of alkene 6a using OsO4/NMO pro-
duced diols 7a and 8a. The stereochemistry of the diols 7a and 8a
* Corresponding author. Tel.: þ91 832 6519317; e-mail addresses: santoshtilve@
yahoo.com, stilve@unigoa.ac.in (S.G. Tilve).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.082

C. Bhat, S.G. Tilve / Tetrahedron 69 (2013) 10876e10883
10877
Fig. 1. Some of the NMDA receptor antagonists.
Scheme 1. Synthetic reports of dexoxadrol.
Scheme 2. Retrosynthetic approach.
was arbitrarily assigned as shown in Scheme 3. The exact ratio of
7a/8a was determined based on HPLC method and it showed that
they were formed in the proportions of 3:2.
not hold good for the system involving monosubstituted terminal
double bond.9 For achieving the required differential double dia-
stereoselection, a different rule popularly called ‘binding pocket’
Scheme 3. General synthetic approach.
In order to achieve better diastereoselectivity, it was necessary
for us to employ Sharpless asymmetric dihydroxylation (SAD) using
Sharpless ligands. The general elegant Sharpless rule for predicting
the differential diastereoselectivity for the substituted olefin does
mnemonic is proposed by Sharpless where the reversal of
facial selectivity for asymmetric dihydroxylation of terminal
olefins is obtained.9,10 Accordingly, the reversed facial selectivity
could be achieved by selection of appropriate ligands for the

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C. Bhat, S.G. Tilve / Tetrahedron 69 (2013) 10876e10883
monosubstituted terminal olefins. Very few systems have been
reported for manifesting this kind of unusual behaviour. Smith and
co-workers observed this kind of same sense of diastereoselectivity
while synthesizing calyculin.11 During the synthesis of zaragozic
acids similar unexpected diastereomeric outcomes were observed
by Carreira’s group.12 It was also explained by Gardiner and Bruce
by conducting the similar experiments for pyrrolidine system.13
Recently, once again this abnormal behaviour was noticed by
Díez and co-workers while synthesizing new proline analogues for
organocatalysis.14
We thought of studying the Sharpless ‘binding pocket’ effect for
our novel monosubstituted terminal olefin attached to piperidine
system. The dihydroxylation was initially carried out in PHAL
spacer using (DHQ)2PHAL and (DHQD)2PHAL (Scheme 4). Only one
diastereomer was preferred by both the ligands. We then switched
to AQN spacer and the similar results were noticed with further
improvement in the formation of the same isomer. The same re-
action was then studied shifting to ligands of PYR spacer. A re-
markable diastereoselective differentiation was observed with
enhancement of the other isomer with (DHQD)2PYR. The HPLC
chromatogram showed the formation of 8a and 7a with diaster-
eoselective ratio of 7:3.
due to failure of 7a to undergo acetalization. Thus 7a on hydro-
genolysis of eCbz group afforded 12. The amino diol 12 was then
reacted with dimethoxybenzophenone in refluxing IPA to produce
dexoxadrol 1. The spectroscopic data were well matching with the
reported values. The optical activity of 1$HCl was recorded and
further confirmed the formation of (þ)-dexoxadrol and the as-
signment of stereochemistry of diols 7 and 8. Similarly the first
asymmetric synthesis of (ꢀ)-epi-dexoxadrol 2 was achieved from
8a.
Moyano and co-workers have reported the synthesis of an im-
portant alkaloid conhydrine 13 by synthesizing epoxide 14 starting
from an open chain molecule in several synthetic steps.15 Conhy-
drine 13 is an alkaloid of hemlock family isolated basically from the
leaves and seeds of the plant Conium maculatum L.16 whose struc-
ture was first elucidated in 1933.17 The (þ)-conhydrine 13a has
attracted considerable synthetic interests due to its potent anti-
tumour, antiviral and glycosidase inhibitory activities.18 As a con-
sequence, several synthetic routes have been manifested in the
literature15,19 for the synthesis of all different isomers and actively
studied for numerous biological activities.
We envisioned that similar epoxides can be synthesized by
simple synthetic transformation on either of alkene 6 or diol 7. The
Scheme 4. Study of SAD on piperidine olefinic system.
The stereochemistry of diols 7a and 8a was assigned at this stage
based on Sharpless mnemonic.14
epoxidation of alkenes 6 using m-CPBA was found to be un-
satisfactory due to the formation of isomers and decomposition.
Then the diol 8a was subjected for monotosylation. Even though
the synthesis of monotosylated compound 15b appeared to be
simple, the initial experimentations using different stoichiometric
ratio of pyridine or Et3N resulted either in getting ditosylated
product or in poor yield. The other alternate methods tried for this
were also not encouraging. Most of the times it ended in substantial
amount of ditosylated compound with a very less formation of the
anticipated 14b. Recently Zhu et al. described the selective mono-
tosylation of vicinal diols and cyclisation to corresponding epoxide
for the synthesis of several antimalarial drugs by using catalytic
amount of K2CO3.20 Inspired by this, we adopted the same pro-
cedure in our case to furnish the synthesis of epoxide 14b from 8a
by reacting with TsCl followed by treatment with 0.2 equiv of
K2CO3. However for the synthesis of epoxide 14a from diol 7a,
1.0 equiv of K2CO3 had to be used. The synthesis of epoxides 14a
Next, we studied the effect of protecting groups on this reversal
of double diastereoselection in piperidine system using PYR spacer.
In this context, we prepared the Boc and COOEt protected alkenes
6b and 6c and subjected for dihydroxylation using PYR-based li-
gands (Scheme 5). Though there was not much difference in the
diastereoselection by changing to eBoc group (6b) from eCbz (6a),
a considerable change was observed with eCOOEt group (6c). The
COOEt being sterically less hindered compared to eCbz and eBoc
offered a better reversal of facial selectivity to give predominantly
7c and 8c with (DHQ)2PYR and (DHQD)2PYR, respectively.
The present results are in agreement with the Gardiner’s view
that the extent of differential diastereoselectivity also depends on
the steric bulkiness of the substituent present on the double
bond.13
The planned synthetic approach was then proceeded to ac-
complish the total synthesis of dexoxadrol 1 (Scheme 6). It was
necessary for us to deprotect Cbz prior to required acetal formation
and 14b accomplished the formal synthesis of (þ)-
a-conhydrine
13a and (ꢀ)- -conhydrine 13b (Scheme 7).
b

C. Bhat, S.G. Tilve / Tetrahedron 69 (2013) 10876e10883
10879
Scheme 5. The effect of protecting groups on diastereoselectivity.
Scheme 6. Synthesis of dexoxadrol and epi-dexoxadrol.
Scheme 7. Formal synthesis of conhydrine.
The recent synthetic report by Vankar and co-workers describes
3. Conclusion
a total synthesis of (þ)-lentiginosine 16 from diol 7a prepared by
synthetic manoeuvring of
D
-mannitol.21 (þ)-Lentiginosine 16,
In summary we have successfully synthesized (þ)-dexoxadrol
and (ꢀ)-epi-dexoxadrol starting from chiral source (ꢀ)-pipecolinic
acid. Incidentally, this is the first asymmetric synthesis of (ꢀ)-epi-
dexoxadrol. The results also uncovered the study of Sharpless
dihydroxylation on terminal olefins for the hitherto unreported
olefinic piperidine system and the effect of protecting groups on
mismatching double diastereoselection. The paper also presents
short and facile synthetic routes for the formal synthesis of con-
hydrine and (þ)-lentiginosine.
a naturally occurring isomer was isolated from Astragalus lentigi-
nosus in 1990.22 Being a hydroxylated alkaloid, serves as sugar
mimics by acting as a potent selective inhibitor of a-glucosidase
and amyloglucosidase.23 Due to its unique structure and interesting
biological activities, various synthetic routes have been established
involving mainly chiral pool, organocatalytic and chiral auxiliary
methods.19e,21,23b,24
Incidentally during our synthetic manoeuvring of dexoxadrol,
the same diol 7a is obtained from another chiral source (ꢀ)-pipe-
colic acid. Thus the synthesis of diol 7a provides a straightforward
formal synthetic approach to (þ)-lentiginosine 16 (Scheme 8).
4. Experimental
4.1. General remarks
Chemicals and solvents were purchased from commercial
suppliers and purified by standard techniques whenever necessary.
Column chromatography was performed on silicagel (60e120 mesh).
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on
a Bruker AVANCE 400 instrument. Chemical shifts are expressed in
d
relative to tetramethylsilane (TMS). The spectra were recorded in
¼7.28 ppm for 1H,
d
¼77.0 ppm for 13C). The
Scheme 8. Formal synthesis of (þ)-lentiginosine.
CDCl3 as solvent (
d

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C. Bhat, S.G. Tilve / Tetrahedron 69 (2013) 10876e10883
multiplicities of carbon signals were obtained from DEPT 135 ex-
periment. Optical rotations (concentration in grams/100 mL solvent)
were measured using sodium D line on a ADP 220 polarimeter. In-
frared spectra (IR) were recorded on a Shimadzu FTIR instrument.
High-resolution mass spectra (HRMS) were recorded on a Micro Mass
ES-QTOF Mass spectrometer.
3.52e3.55 (m, 1H, H-6B), 3.71e3.76 (m, 1H, H-2), 3.85e3.88 (m, 1H,
H-10A), 4.20e4.23 (m, 1H, H-10B); 13C NMR (CDCl3, 100 MHz):
d 19.6
(C-4), 25.2 (C-5, C-3), 28.4 (tBuC), 39.9 (C-6), 52.4 (C-2), 61.6 (C-10),
79.8 (OC-tBu), 156.3 (NCO).25b
Compound 10c: To a mixture of pipecolinol (2.0 g, 17 mmol) and
K2CO3 (2.8 g, 20 mmol) in CH3CN cooled to 0 ꢁC, was added eth-
ylchloroformate (2.0 mL, 21 mmol) over a period of 10 min. The
reaction mixture was further stirred at the same temperature for
6 h. It was then concentrated under reduced pressure and diluted
with DCM (30 mL). The organic layer was further treated with dil
HCl (20 mLꢂ2) followed by brine solution (20 mL) and dried over
anhyd Na2SO4 and concentrated in vacuo. The crude mixture was
column chromatographed (SiO2, hexane/EtOAc, 9:1) to give 10c as
4.2. General procedures and characterization
4.2.1. LAH reduction of (ꢀ)-pipecolinic acid to (ꢀ)-pipecolinol 9. To
a well stirred suspension of LAH (2.0 g, 50 mmol) in anhyd THF
under N2 atm was added pipecolinic acid (5.0 g, 40 mmol) at 0 ꢁC in
three portions over a period of 40 min. The reaction mixture was
slowly brought to rt, stirred for 6 h and then refluxed for 8 h. It was
then cooled in an ice bath and a solution of 10% KOH (5 mL) was
added drop wise over a period of 1 h. H2O (5 mL) was then added
and brought to rt in 30 min. The residue was then filtered to get rid
of white precipitate of Al(OH)3 and the filtrate was concentrated
under vacuum. The pale yellow colour residual liquid was diluted
with DCM (100 mL) and dried over anhyd Na2SO4 (if a thin layer of
water persists over DCM, should be separated before drying over
anhyd Na2SO4). It was then concentrated under reduced pressure to
give essentially pure pale yellow thick liquid of pipecolinol 9 (4.2 g,
95%), which should immediately be preserved at 0 ꢁC or consumed
for the next reaction. IR (neat): nmax¼3500 cmꢀ1 (broad peak).
(Note: The pipecolinol thus formed is essentially pure and
should be utilized as soon as possible in order to achieve better
yield in the next reaction. The storage of it at rt should be avoided
since it turns dark yellow and the yield of the subsequent reaction
would substantially go down).
a pale yellow thick liquid (2.7 g, 82%).
26
Rf¼0.30 (hexane/EtOAc, 8.5:1.5); [
a
]
ꢀ39.5 (c 1.0, CHCl3);
D
20
{lit.25c
[a
]
ꢀ36.6 (c 0.40, CHCl3)}; IR (neat): nmax¼3410, 2955,
D
1675 cmꢀ1
;
1H NMR (CDCl3, 400 MHz): 1.19 (t, J¼7.2 Hz, 3H,
OCH2CH3), 1.32e1.68 (m, 6H, H-4, H-5, H-3), 2.80e2.86 (m, 2H, H-
6A and OH), 3.53e3.57 (m, 1H, H-6B), 3.70e3.75 (m, 1H, H-2),
3.90e3.94 (m, 1H, H-10A), 4.05 (q, J¼7.2 Hz, 2H, OCH2CH3),
4.22e4.27 (m, 1H, H-10B); 13C NMR (CDCl3, 100 MHz):
d 14.6
(OCH2CH3), 19.4 (C-4), 25.0 (C-5), 25.2 (C-3), 39.9 (C-6), 52.5 (C-2),
61.0 (C-10), 61.4 (OCH2CH3), 156.8 (NCO).25c
4.2.3. General procedure for the synthesis of 11 (a, b, c) by Swern
oxidation. To a solution of (COCl)2 (1.2 mmol) in DCM (10 mL) cooled
to ꢀ78 ꢁC was added DMSO (1.5 mmol). The carbamate protected
pipecolinol 10 (a, b, c) (1 mmol) was then added drop wise over
a period of 5 min. The reaction mixture was brought to ꢀ50 ꢁC in
15 min and Et3N (3 mmol) was added over a period of 5 min. It was
then stirred for 10 min at the same temperature and further stirred
at rt for 15 min. The reaction mixture was further diluted with DCM
(10 mL) and the organic layer was washed with very dil HCl (0.1 N,
10 mLꢂ2) and brine solution (10 mLꢂ2). It was then dried over
anhyd Na2SO4 and concentrated under reduced pressure to afford
aldehyde 11 (a, b, c) as a thick liquid, which without any further
purification was immediately consumed for the next reaction.
4.2.2. Synthesis of 10a, 10b and 10c. Compound 10a: To a mixture
of pipecolinol (2.0 g,17 mmol) and K2CO3 (4.7 g, 34 mmol) in CH3CN
(20 mL) cooled to 0 ꢁC, was added benzylchloroformate (50% in
toluene) (6.5 mL, 19 mmol) over a period of 15 min. The reaction
mixture was further stirred at the same temperature for 6 h. It was
then concentrated under reduced pressure and diluted with DCM
(50 mL). The water was added (30 mL) and the organic compound
was separated. The organic layer was further washed with dil HCl
(20 mLꢂ2) followed by brine solution (20 mL), dried over anhyd
Na2SO4 and concentrated in vacuo. The crude mixture was column
chromatographed (SiO2, hexane/EtOAc, 7:3) to give Cbz-pipecolinol
4.2.4. General procedure of Wittig reaction for the synthesis of al-
kenes 6a, 6b and 6c. The commercially available salt þPPh3CH3Brꢀ
(1.07 g, 3.0 mmol) was stirred at 0 ꢁC with dry THF (10 mL) in
a three-necked 50 mL round bottom flask under N2 atm sealed with
a septum at one end. NaHMDS (1 M in THF) (1.5 mL, 1.5 mmol) was
purged with the help of a syringe into the reaction mixture and
appearance of the pale yellow colour was noticed. The stirring was
continued for further 10 min and the corresponding aldehyde 11
(1 mmol) was added. The disappearance of the yellow colour was
observed. The reaction mixture was then brought to rt and stirred
for 2 h. It was concentrated in vacuo and quenched with saturated
aq NH4Cl (5 mL). The solution was diluted with DCM (25 mL) and
the organic layer was separated. It was then washed with saturated
aq NH4Cl solution (10 mLꢂ3) and dried over anhyd Na2SO4, con-
centrated under vacuum and purified by column chromatography
(SiO2, hexane/EtOAc, 9.5:0.5) to afford 6.
10a as a pale yellow thick liquid (3.9 g, 90%).
26
Rf¼0.25 (hexane/EtOAc, 7:3); [
a]
ꢀ36.5 (c 1.0, CHCl3) {lit.25a
D
[
a]
ꢀ30.2 (c 1.1, CHCl3) for 85% ee}; IR (neat): nmax¼3500, 2995,
D
1690,1680 cmꢀ1; 1H NMR (CDCl3, 400 MHz): 1.34e1.64 (m, 6H, H-4,
H-5, H-3), 2.02 (br s, 1H, OH), 2.85e2.90 (m, 1H, H-6A), 3.52e3.56
(m, 1H, H-6B), 3.71e3.76 (m, 1H, H-2), 3.94e3.96 (m, 1H, H-10A),
4.25e4.30 (m, 1H, H-10B), 5.05 (s, 2H, CH2Ph), 7.20e7.28 (m, 5H,
PhH); 13C NMR (CDCl3, 100 MHz):
d 19.5 (C-4), 25.1 (C-5), 25.2 (C-3),
40.1 (C-6), 52.8 (C-2), 61.2 (C-10), 67.2 (CH2Ph), 127.8 (PhCH), 127.9
(PhCH), 128.5 (PhCH), 136.7 (PhC), 156.6 (NCO).25a
Compound 10b: To a mixture of pipecolinol (2.0 g, 17 mmol) and
Et3N (4.7 mL, 34 mmol) cooled to 0 ꢁC in DCM (30 mL), was added
(Boc)2O (4.4 mL, 20 mmol) drop wise over a period of 10 min. The
reaction mixture was further stirred at the same temperature for
6 h. It was then treated with dil HCl (20 mL) and the organic layer
was separated, washed with brine (20 mLꢂ2), dried over anhyd
Na2SO4 and then concentrated under reduced pressure. The crude
mixture was purified by column chromatography (SiO2, hexane/
EtOAc, 8:2) to afford 10b as a colourless thick liquid (3.2 g, 85%),
4.2.4.1. (S)-Benzyl-2-vinylpiperidine-1-carboxylate 6a. Obtained
as a pale yellow thicky liquid (90%); Rf¼0.80 (hexane/EtOAc,
28
9.5:0.5); [
a
]
ꢀ17.5 (c 0.2, CHCl3); IR (neat): nmax¼1690, 1675,
D
1660 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d 1.45e1.80 (m, 6H, H-4, H-
5, H-3), 2.91e2.98 (m, 1H, H-6A), 4.06e4.09 (m, 1H, H-6B),
4.91e4.92 (m, 1H, H-2), 4.92e5.24 (m, 2H, H-20), 5.17 (s, 2H, CH2Ph),
5.76e5.84 (m, 1H, H-10), 7.32e7.38 (m, 5H, PhH); 13C NMR (CDCl3,
which slowly turned to a crispy solid on prolonged cooling.
26
Rf¼0.30 (hexane/EtOAc, 8:2); [
a
]
D
ꢀ40.0 (c 1.0, CHCl3) {lit.25b
100 MHz): d 19.4 (C-4), 25.2 (C-5), 28.9 (C-3), 40.1 (C-6), 52.7 (C-2),
25
[
a]
ꢀ40.1 (c 1.0, CHCl3) for 98% ee}; IR (neat): nmax¼3450, 2995,
67.0 (CH2Ph), 115.9 (C-20), 127.7 (PhCH), 127.9 (PhCH), 128.5 (PhCH),
136.5 (C-10), 136.9 (PhCH), 155.8 (NCO); HRMS: m/z calcd for
D
1685 cmꢀ1; 1H NMR (CDCl3, 400 MHz): 1.33e1.64 (m, 6H, H-4, H-5,
H-3), 1.39 (s, 9H, tBuH), 1.95 (br s, 1H, OH), 2.76e2.82 (m, 1H, H-6A),
C
15H19NO2Na [MþNa]þ:268.1313; found: 268.1313.

C. Bhat, S.G. Tilve / Tetrahedron 69 (2013) 10876e10883
10881
4.2.4.2. tert-Butyl-(2S)-2-vinylpiperidine-1-carboxylate
2 mmol) afforded 7a as a colourless thick liquid (0.34 g, 75%) (SiO2,
6b. Obtained as a pale yellow thicky liquid (70%); Rf¼0.85 (hexane/
hexane/EtOAc, 7:3); Rf¼0.4 (hexane/EtOAc, 1:1); [
a
[a]
D
]
28 ꢀ26.2 (c 0.07,
Dꢀ36.15 (c 1.3,
28
28
EtOAc, 9.5:0.5); [
a
]
27 ꢀ32.8 (c 0.2, CHCl3) {lit.25d
[
a
;
]
20 ꢀ30.9 (c 0.24,
CHCl3), [
a
]
ꢀ24.2 (c 0.05, CH2Cl2) {lit.21
D
D
D
CHCl3)}; IR (neat): nmax¼1700, 1670, 1650 cmꢀ1
1H NMR (CDCl3,
CH2Cl2)}; IR (neat): nmax¼3500, 1699, 1650, 1640 cmꢀ1
;
1H NMR
t
400 MHz):
d
1.18e1.69 (m, 6H, H-4, H-5, H-3), 1.38 (s, 9H, BuH),
(CDCl3, 400 MHz): d 1.43e1.66 (m, 6H, H-5, H-4, H-3), 2.19 (br s, 1H,
2.72e2.79 (m, 1H, H-6A), 3.85e3.89 (m, 1H, H-6B), 4.70e4.71 (m,
1H, H-2), 5.04 (dd J¼58.8 and 10.4 Hz, 2H, H-20), 5.64e5.72 (m, 1H,
eOH), 2.70e2.76 (m,1H, H-6A), 3.10 (br s, OH), 3.48e3.51 (m,1H, H-
6B), 3.59e3.62 (m, 1H, H-2), 3.72e3.83 (m, 1H, H-10), 4.06e4.12 (m,
2H, H-20), 5.11e5.20 (m, 2H, CH2Ph), 7.33e7.40 (m, 5H, PhH); 13C
H-10); 13C NMR (CDCl3, 100 MHz):
d 18.4 (C-4), 24.5 (C-5), 27.4
(OC(CH3)3), 27.9 (C-3), 38.7 (C-6), 51.4 (C-2), 76.2 (CH2Ph), 114.4 (C-
20), 135.8 (C-10), 154.4 (NCO); HRMS: m/z calcd for C12H21NO2Na
[MþNa]þ: 234.1470; found: 234.1470.25d
NMR (CDCl3, 100 MHz): d 18.9 (C-4), 24.2 (C-5), 25.1 (C-3), 40.9 (C-
6), 50.1 (C-2), 62.5 (C-20), 67.7 (CH2Ph), 67.8 (C-10), 127.1 (PhCH),
128.1 (PhCH), 129.0 (PhCH), 136.1 (PhC), 155.1 (NCO).21
4.2.4.3. Ethyl-(2S)-2-vinylpiperidine-1-carboxylate 6c. Obtained
4.2.6.4. Benzyl (2S)-2-[(1R)-1,2-dihydroxyethyl] piperidine-1-
carboxylate 8a. After following the standard procedure of SAD us-
ing the ligand [DHQD]2PYR (0.17 g, 10 mol %), compound 6a (0.5 g,
2 mmol) afforded 8a as a colourless thick liquid (0.25 g, 55%) (SiO2,
as a pale yellow thicky liquid (68%); Rf¼0.83 (hexane/EtOAc,
26
9.5:0.5);
[
a
;
]
ꢀ33.9 (c 0.2, CHCl3); IR (neat): nmax¼1695,
D
1640 cmꢀ1
1H NMR (CDCl3, 400 MHz):
d
1.18 (t, J¼7.2 Hz, 3H,
OCH2CH3), 1.32e1.71 (m, 6H, H-4, H-5, H-3), 2.77e2.84 (m, 1H, H-
6A), 3.91e3.95 (m, 1H, H-6B), 4.04e4.09 (m, 2H, OCH2CH3),
4.70e4.80 (m, 1H, H-2), 4.97e5.14 (m, 2H, H-20), 5.65e5.74 (m, 1H,
hexane/EtOAc, 7:3); Rf¼0.4 (hexane/EtOAc, 1:1); [
a
]
21 ꢀ17.4 (c 0.05,
D
CHCl3), [
a
]
21 ꢀ11.4 (c 0.6, CH2Cl2) {lit.25g
[a
]
D þ41.8 (c 0.5, CH2Cl2)};
D
IR (neat): nmax¼3400, 1699, 1650, 1640 cmꢀ1
;
1H NMR (CDCl3,
H-10); 13C NMR (CDCl3, 100 MHz):
d
14.7 (OCH2CH3), 19.4 (C-4), 25.5
400 MHz): d 1.46e1.68 (m, 6H, H-5, H-4, H-3), 2.90e3.11 (br s, 2H,
(C-5), 28.8 (C-3), 39.8 (C-6), 52.5 (C-2), 61.2 (OCH2CH3), 115.8 (C-20),
136.6 (C-10), 155.1 (NCO); HRMS: m/z calcd for C10H17NO2Na
[MþNa]þ: 206.1157; found: 206.1157.
eOH), 3.50e3.61 (m, 1H, H-6A), 3.73e3.76 (m, 1H, H-6B), 3.99e4.01
(m, 1H, H-2), 4.01e4.20 (m, 2H, H-20), 4.30e4.32 (m, 1H, H-10), 5.16
(s, 2H, CH2Ph), 7.33e7.37 (m, 5H, PhH); 13C NMR (CDCl3, 100 MHz):
d
19.6 (C-4), 25.0 (C-5), 25.9 (C-3), 40.7 (C-6), 51.2 (C-2), 64.3 (C-20),
67.4 (CH2Ph), 71.1 (C-10), 127.8 (PhCH), 128.0 (PhCH), 128.5 (PhCH),
4.2.5. Procedure for Upjohn method of dihydroxylation of 6a for the
synthesis of 7a and 8a. To stirred solution of 6a (0.24 g, 1 mmol) in
10 mL of acetone and water (1:1), was added NMO (0.12 g,
1.0 mmol) followed by OsO4 (1.3 mL, 5 mol %, 1% aq solution). The
reaction mixture was stirred at rt for 6 h and quenched by saturated
aq Na2SO3 (10 mL). The organic compound was extracted in ethyl
acetate (25 mLꢂ3), dried over anhyd Na2SO4 and concentrated in
vacuo to furnish the mixture of diols 7a and 8a (0.24 g, 85%). The
ratio of 7a/8a was found using HPLC (Kromasil, IPA/hexane 1:4,
flow rate 1.5 mL/min). The separation of 7a and 8a was achieved by
slow elution on column chromatography (SiO2, hexane/EtOAc, 7:3).
136.6 (PhC), 155.5 (NCO).25g
Compound 7b: After following the standard procedure of SAD
using the ligand [DHQ]2PYR (0.17 g, 10 mol %), compound 6b
(0.42 g, 2 mmol) afforded 7b as a colourless thick liquid (0.28 g,
26
72%) (SiO2, hexane/EtOAc, 7:3); Rf¼0.4 (hexane/EtOAc, 2:3); [
a]
D
ꢀ55.7 (c 0.2, CHCl3) {lit.25f
[
a
]
ꢀ59.5 (c 0.9, CHCl3)}; IR (neat):
nmax¼3400, 1688, 1423 cmꢀ1D
;
1H NMR (CDCl3, 400 MHz):
d
1.18e1.57 (m, 6H, H-5, H-4, H-3), 1.39 (s, 9H, tBuH), 2.01e2.09 (m,
1H, H-6A), 2.53e2.60 (m, 1H, H-6B), 3.40e3.56 (m, 3H, H-2, H-20),
3.60e3.73 (m, 1H, H-10), 3.88e3.97 (m, 2H, eOH); 13C NMR (CDCl3,
100 MHz): d 17.9 (C-4), 23.0 (C-5), 24.1 (C-3), 27.3 (C(CH3)3), 40.0 (C-
6), 49.6 (C-2), 63.2 (C-20), 66.8 (C-10), 79.6 (tBuCO), 155.5 (NCO)
(extra signals appeared due to the presence of rotamers); HRMS: m/
z calcd for C12H23NO4Na [MþNa]þ: 268.1585; found: 268.1525.25f
Compound 8b: After following the standard procedure of SAD
using the ligand [DHQD]2PYR (0.17 g, 10 mol %), compound 6b
4.2.6. Procedure for SAD of 6 for the synthesis of 7 and 8
4.2.6.1. Preparation of AD-mix a. Prepared by premixing K2CO3
(0.41 g, 3 mmol), K3Fe(CN)6 (0.98 g, 3 mmol), CH3SO2NH2 (0.09 g, 1
mmol), K2OsO4$2H2O (4 mol %), Ligand [(DHQ)2PYR/(DHQ)2AQN/
(DHQ)2PYR] (10 mol %).
(0.42 g, 2 mmol) afforded 8b as a colourless thick liquid (0.2 g, 50%)
21
(SiO2, hexane/EtOAc, 7:3); Rf¼0.4 (hexane/EtOAc, 2:3); [
a]
ꢀ40.6
D
27
(c 0.05, CHCl3) {lit.19e
[
a]
þ27.1 (c 1.0, CHCl3) for RS isomer}; IR
4.2.6.2. Preparation of AD-mix b. Prepared by premixing K2CO3
D
(neat): nmax¼3400, 1670, 1423 cmꢀ1
;
1H NMR (CDCl3, 400 MHz):
(0.41 g, 3 mmol), K3Fe(CN)6 (0.98 g, 3 mmol), CH3SO2NH2 (0.09 g, 1
mmol), K2OsO4$2H2O (4 mol %), Ligand [(DHQD)2PYR/
(DHQD)2AQN/(DHQD)2PYR] (10 mol %).
d
1.30e1.57 (m, 6H, H-5, H-4, H-3), 1.39 (s, 9H, tBuH), 2.89 (br s, 2H,
OH), 3.01e3.02 (m, 1H, H-6A), 3.44e3.46 (m, 1H, H-6B), 3.47e3.49
A solution of AD-mix a/AD-mix b
in 10 mL tBuOH/H2O (1:1) was
(m, 1H, H-2), 3.80e3.88 (m, 2H, H-20), 4.10e4.15 (m, 1H, H-10); 13C
stirred for 30 min at rt. The reaction mixture was cooled to 0 ꢁC,
NMR (CDCl3, 100 MHz):
d 18.6 (C-4), 24.0 (C-5), 24.8 (C-3), 27.4
t
(tBuC), 39.8 (C-6), 42.3 (C-2), 51.0 (C-10), 63.2 (C-20), 70.2 (tBuCO),
added requisite alkene 6 (1 mmol) in 1 mL BuOH and the stirring
155.8 (NCO); HRMS: m/z calcd for
C
12H23NO4Na [MþNa]þ:
was continued for 30 min at the same temperature. It was then
brought to rt and further stirred till the completion of reaction
indicated by TLC. The reaction mixture was then quenched by
saturated aq Na2SO3 (5 mL) and extracted with EtOAc (15 mLꢂ2).
The combined organic layer was dried over anhyd Na2SO4, con-
centrated and subjected to column chromatography to remove the
impurities without separating the isomers 7 and 8 (Silica gel, 100%
EA). The diastereomeric mixture was then subjected to HPLC to find
the diastereomeric ratio of 7 and 8 (Kromasil, eluent IPA/n-hexane
1:4, flow rate 1.5 mL/min). The separation of diastereomers 7 and 8
was then achieved by very slow elution through column chroma-
tography (SiO2, hexane/EtOAc, 7:3).
268.1585; found: 268.1525.25e
Compound 7c: After following the standard procedure of SAD
using the ligand [DHQ]2PYR (0.17 g,10 mol %), compound 6c (0.36 g,
2 mmol) afforded 7c as a colourless thick liquid (0.30 g, 85%) (SiO2,
21
hexane/EtOAc, 7:3); Rf¼0.35 (hexane/EtOAc, 2:3); [
a
]
ꢀ49.2 (c
D
0.04, CHCl3); IR (neat): nmax¼3500, 1668 cmꢀ1
;
1H NMR (CDCl3,
400 MHz):
d
1.19 (t, J¼6.8 Hz, 3H, OCH2CH3), 1.35e1.58 (m, 6H, H-5,
H-4, H-3), 2.09e2.11 (m, 1H, H-6A), 2.59e2.66 (m, 1H, H-6B),
3.01e3.02 (m, 1H, H-2), 3.44e3.57 (m, 2H, H-20), 3.75e3.76 (m, 1H,
H-10), 3.95e4.01 (m, 2H, OH), 4.07e4.09 (m, 2H, OCH2CH3); 13C
NMR (CDCl3,100 MHz): d 14.6 (OCH2CH3),18.9 (C-5), 24.1 (C-4), 25.1
(C-3), 40.7 (C-6), 43.3 (C-2), 51.3 (C-20), 61.9 (C-10), 67.8 (OCH2CH3),
156.1 (NCO) (extra signals are appeared due to the presence of
rotamers); HRMS: m/z calcd for C10H19NO4Na [MþNa]þ: 240.1212;
found: 240.1212.
4.2.6.3. Benzyl-(2S)-2-[(1S)-1,2-dihydroxyethyl] piperidine-1-
carboxylate 7a. After following the standard procedure of SAD us-
ing the ligand [DHQ]2PYR (0.17 g, 10 mol %), compound 6a (0.5 g,

10882
C. Bhat, S.G. Tilve / Tetrahedron 69 (2013) 10876e10883
Compound 8c: After following the standard procedure of SAD
nmax¼1700, 1690 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d 1.58e1.75 (m,
using the ligand [DHQD]2PYR (0.17 g, 10 mol %), compound 6c
(0.36 g, 2 mmol) afforded 8c as a colourless thick liquid (0.23 g, 80%)
6H, H-4, H-5, H-3), 2.65e2.67 (m, 1H, H-6A), 2.95e3.01 (m, 1H, H-
6B), 3.08e3.11 (m, 1H, H-2), 3.80e4.03 (m, 1H, H-20A), 4.23e4.30
(m, 1H, H-20B), 4.62e4.63 (m, 1H, H-10), 5.01e5.08 (m, 2H, PhCH2),
(SiO2, hexane/EtOAc, 7:3); Rf¼0.35 (hexane/EtOAc, 2:3); [
a
]
21 ꢀ36.3
D
(c 0.03, CHCl3); IR (neat): nmax¼3500, 1668 cmꢀ1
;
1H NMR (CDCl3,
7.19e7.30 (m, 5H, PhH); 13C NMR (100 MHz, CDCl3):
d 21.7 (C-4),
400 MHz):
d
1.18e1.22 (m, 3H, OCH2CH3), 1.35e1.59 (m, 6H, H-5, H-
24.2 (C-5), 30.4 (C-3), 41.3 (C-6), 54.2 (C-2), 69.0 (C-20), 71.9
(CH2Ph), 76.5 (C-10), 127.9 (PhCH),128.0 (PhCH),128.6 (PhCH),128.7
(PhCH), 129.0 (PhCH), 136.8 (PhC), 144.5, 155.8 (NCO) (some extra
signals are observed due to the presence of rotamers).
4, H-3), 2.10e2.11 (m, 1H, H-6A), 2.58e2.65 (m, 1H, H-6B),
3.01e3.03 (m, 1H, H-2), 3.43e3.56 (m, 2H, H-20), 3.70e3.75 (m, 1H,
H-10), 3.94e3.98 (m, 2H, OH), 4.00e4.09 (m, 2H, OCH2CH3); 13C
NMR (CDCl3, 100 MHz):
d
13.6 (OCH2CH3), 17.9 (C-5), 23.1 (C-4), 24.1
Similar procedure was repeated for the synthesis of 14a (0.18 g,
28
(C-3), 39.7 (C-6), 42.3 (C-2), 50.3 (C-20), 60.9 (C-10), 66.8 (OCH2CH3),
60%); Rf¼0.85 (hexane/EtOAc, 9:1); [
a
]
ꢀ25.0 (c 0.05, CHCl3); IR
D
156.1 (NCO); HRMS: m/z calcd for
240.1212; found: 240.1212.
C
10H19NO4Na [MþNa]þ:
(neat): nmax¼1700, 1690 cmꢀ1
;
1H NMR (CDCl3, 400 MHz):
d 1.17e1.84 (m, 6H, H-4, H-5, H-3), 2.43 (br s, 1H), 2.65e2.66 (m,
1H), 2.94e2.98 (m, 1H), 3.05e3.08 (m, 1H), 3.99e4.02 (m, 1H),
4.20e4.23 (m, 1H), 4.62 (s, 1H), 5.04 (s, 1H), 7.23e7.28 (5H, PhH);
4.2.6.5. (þ)-Dexoxadrol 1. To a solution of 7a (0.28 g, 1 mmol) in
EtOH (10 mL) was added 10% Pd/C (0.028 g, 10% w/w) and hydro-
genated using Parr hydrogenator (2.5 atm) at rt for 6 h. The solution
was filtered and concentrated under reduced pressure to afford
essentially pure 12 (0.13 g, 95%). The disappearance of carbonyl
stretching in IR indicated the formation of product;26 IR (neat):
13C NMR (100 MHz, CDCl3):
d 20.2 (C-4), 25.1 (C-5), 27.5 (C-3), 41.5
(C-6), 44.5 (C-20), 53.4 (C-10), 65.3 (C-20), 67.1 (CH2Ph, C-10), 126.9
(PhCH), 127.6 (PhCH), 127.8 (PhCH), 127.9 (PhCH), 128.5 (PhCH),
136.8 (PhC), 155.8 (NCO) (some extra signals are observed due to
the presence of rotamers).
nmax¼3300, 3000, 1440 cmꢀ1
.
To a refluxing solution of 12 (0.14 g, 1 mmol) in IPA with PTSA
(cat), was added dimethoxybenzophenone (1.61 g, 7 mmol) and
refluxed further for 1 h. The reaction mixture was cooled, con-
centrated and as such subjected to column purification to give pure
1 (SiO2, hexane/EtOAc, 7:3) (0.18 g, 60%). To compound 1 (0.31 g,
1 mmol) in EtOAc (5 mL), passed dry HCl gas liberated from the
reaction of concd H2SO4 over NaCl. The reaction mixture was
Acknowledgements
We are thankful to DST, New Delhi, for the financial support and
NIO, Goa, for optical activity measurements. One of authors (C.B.) is
thankful to CSIR, New Delhi, for awarding NET Senior Research
Fellowship. We also thank IISc, Bangalore for HRMS analysis.
concentrated to dryness to give pure 1$HCl (0.27 g, 80%).
Supplementary data
26
Rf¼0.3 (CHCl3/MeOH, 9:1); [
a
]
þ34.5 (c 0.05, MeOH) (of HCl
D
25
salt); {lit.3
[
a]
þ33.9 (c 2.0, MeOH)}; IR (neat): nmax¼3330 cmꢀ1
;
D
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.10.082.
1H NMR (CDCl3, 400 MHz):
d 1.10e1.13 (m, 1H), 1.27e1.49 (m, 3H),
1.60e1.63 (m, 1H), 1.72e1.75 (m, 2H), 1.82e1.85 (m, 1H), 2.59e2.65
(m, 1H), 2.85e2.88 (m, 1H), 3.09e3.12 (br d, J¼11.6 Hz, 1H),
3.94e3.97 (m, 1H), 4.09e4.10 (m, 1H), 4.14e4.15 (m, 1H), 7.28e7.37
(m, 6H), 7.48e7.50 (m, 2H), 7.54e7.55 (m, 2H); 13C NMR (100 MHz,
References and notes
1. (a) Buckingham, J.; Baggaley, K. H.; Roberts, A. D.; Szab, L. F. Dictionary of Al-
kaloids, 2nd ed.; CRC: Boca Raton, FL, 2010; (b) The Alkaloids: Chemistry and
Biology; Cordell, G. A., Ed.; Academic: San Diego, CA, 2000; Vol. 54; (c) Galliford,
C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748 for reviews on piper-
idines and piperidine alkaloids see: (d) Pinder, A. R. Nat. Prod. Rep. 1992, 9, 17;
(e) Pinder, A. R. Nat. Prod. Rep. 1992, 9, 491; (f) Rodrígez, D.; Wang, C. L. J.;
Wuonola, M. A. Org. Prep. Proceed. Int. 1992, 583; (g) Plunkett, A. O. Nat. Prod.
Rep. 1994, 11, 581; (h) Harrison, T. Cont. Org. Synth. 1995, 2, 209.
2. (a) Over 5000 Compounds Containing These Pharmacophores Are Currently in
Advanced Stages of Biological Testing; MDL Information Systems: San Leandro,
CA, 2010; MDL Drug Data Report; (b) Elliott, R. L.; Ryther, K. B.; Anderson, D. J.;
Piattoni-Kaplan, M.; Kuntzweiler, T. A.; Donnelly-Roberts, D.; Arneric, S. P.;
Holladay, M. W. Bioorg. Med. Chem. Lett. 1997, 7, 2703; (c) Elliott, R. L.; Kopecka,
H.; Lin, N.-H.; He, Y.; Garvey, D. S. Synthesis 1995, 772; (d) Hubbard, R. D.;
Dickerson, S. H.; Emerson, H. K.; Griffin, R. J.; Reno, M. J.; Hornberger, K. R.;
Rusnak, D. W.; Wood, E. R.; Uehling, D. E.; Waterson, A. G. Bioorg. Med. Chem.
Lett. 2008, 18, 5738; (e) Lin, N.-H.; Carrera, G. M.; Anderson, D. J. J. Med. Chem.
2002, 37, 3542; (f) Corbett, J. W.; Dirico, K.; Song, W.; Boscoe, B. P.; Doran, S. D.;
Boyer, D.; Qiu, X.; Ammirati, M.; VanVolkenburg, M. A.; McPherson, R. K.;
Parker, J. C.; Cox, E. D. Bioorg. Med. Chem. Lett. 2007, 17, 6707.
CDCl3):
d 24.3, 26.1, 28.1, 46.5, 57.9, 65.9, 79.3, 109.5, 126.1, 126.2,
128.0, 128.2, 141.9, 142.1.7b
4.2.6.6. (ꢀ)-epi-Dexoxadrol 2. Similar procedure was followed
for the synthesis of (ꢀ)-epi-dexoxadrol 2 (0.15 g, 50%); Rf¼0.3
26
(CHCl3/MeOH, 9:1); [
a
]
D
ꢀ42.5 (c 0.04, CHCl3) (of HCl salt); IR
(neat): nmax¼3330 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d 1.14e1.17 (m,
1H), 1.25e1.35 (m, 1H), 1.36e1.51 (m, 2H), 1.60e1.63 (m, 1H),
1.78e1.81 (m, 1H), 2.39 (br s, 2H), 2.59e2.65 (m, 2H), 3.11e3.14 (m,
1H), 3.85 (br s, 1H), 4.04 (s, 2H), 7.28e7.33 (m, 6H), 7.49e7.54 (m,
4H); 13C NMR (100 MHz, CDCl3):
d 23.9, 25.6, 27.9, 46.2, 59.9, 67.3,
80.1, 109.8, 126.1, 126.3, 128.0, 128.1, 128.2, 142.0, 142.3.
4.2.6.7. Synthesis of 14b. To a mixture of 8a (0.26 g, 1 mmol),
Et3N (0.2 mL, 1.4 mmol) and DMAP (0.007 g, 0.06 mmol) in DCM
(10 mL) was added TsCl (0.19 g, 1 mmol) at 0 ꢁC. The reaction
mixture was brought to rt in 30 min and further stirred for 2 h at rt.
It was then diluted with DCM (20 mL), washed with saturated aq
NaHCO3 (10 mLꢂ3) and 1 N HCl (10 mLꢂ3). The combined organic
layer was dried over anhyd Na2SO4 and concentrated under re-
duced pressure to give essentially pure monotosylate 15b. The
crude compound 15b was stirred in MeOH (10 mL) at rt, added
K2CO3 (0.03 g, 0.2 mmol). The reaction mixture was further stirred
for 30 min and then concentrated to dryness. It was diluted with
DCM (25 mL), washed with H2O and saturated aq NaHCO3
(15 mLꢂ3). The organic layer was dried over anhyd Na2SO4 and
purified by column chromatography (SiO2, hexane/EtOAc, 9:1) to
afford 14b (0.15 g, 58%).
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€
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Kohler, J.; Wurthwein, E.-U.; Wunsch, B. Bioorg. Med. Chem. 2010, 18, 7855.
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ꢀ
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1323; (b) Etayo, P.; Badorrey, R.; Díaz-de-Villegas, M. D.; Galvez, J. A.; Lopez-
Ram-de-Víu, P. Synlett 2010, 1775.
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The spectroscopic data were comparable with the literature.15
28
Rf¼0.8 (hexane/EtOAc, 9:1); [
a]
ꢀ30.3 (c 0.04, CHCl3); IR (neat):
D

C. Bhat, S.G. Tilve / Tetrahedron 69 (2013) 10876e10883
10883
11. Iwashima, M.; Kinsho, T.; Smith, A. B., III. Tetrahedron Lett. 1995, 36, 2199.
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ꢀ
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