Stereocontrolled synthesis of piperidine alkaloids, (-)-241D and (-)-isosolenopsin

Article abstract of DOI:10.1016/j.tetlet.2012.04.115

Highly diastereocontrolled synthesis of alkaloids, (-)-241D and (-)-isosolenopsin was achieved in 7.7% and 5.3% yields, respectively, using a Barbier-type allylation of a chiral imine and d-proline catalyzed aldol addition reaction of a β-amino aldehyde with acetone as the key steps. The synthesis involves a nine-step sequence using (S)-valinate imine in a Barbier-type allylation for the first time.

Full text of DOI:10.1016/j.tetlet.2012.04.115

Tetrahedron Letters 53 (2012) 3467–3470
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Stereocontrolled synthesis of piperidine alkaloids, (ꢀ)-241D and
(ꢀ)-isosolenopsin
⇑
R.V.N.S. Murali, S. Chandrasekhar
Division of Natural Products Chemistry, CSIR–Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly diastereocontrolled synthesis of alkaloids, (ꢀ)-241D and (ꢀ)-isosolenopsin was achieved in 7.7%
Received 1 March 2012
Revised 22 April 2012
Accepted 25 April 2012
Available online 1 May 2012
and 5.3% yields, respectively, using a Barbier-type allylation of a chiral imine and D-proline catalyzed
aldol addition reaction of a b-amino aldehyde with acetone as the key steps. The synthesis involves a
nine-step sequence using (S)-valinate imine in a Barbier-type allylation for the first time.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Isosolenopsin
Barbier-type allylation
Aldol addition
b-Amino aldehyde
(S)-Valinate imine
2,6-cis-Disubstituted piperidines and 2,6-cis-disubstituted
4-piperidinols possess biological as well as pharmaceutical impor-
tance.1 (ꢀ)-241D (1a), a cis, cis-2-nonyl-6-methyl-4-hydroxypiper-
idine is isolated from the skin of poison dart Dendrobate frog.
Racemic piperidine,2 ( )-241D has been found to block the action
of acetylcholine by a noncompetitive blockade of nicotinic receptor
channels.2c Similarly, 2-methyl 6-alkylated cis-piperidines, isosole-
nopsins,3 extracted from fire ant’s venom of the genus ‘Solenopsis’,
were found to be responsible for various hemolytic, necrotoxic,
phytotoxic, antibiotic, insecticidal, antifungal, and anti-HIV proper-
ties.3c,3d Isosolenopsin A (2b) was found to block neuromuscular
transmissions while isosolenopsin 2d, at low concentrations, re-
duced mitochondrial respiration through the inhibition of Na+
and K+ ATPases.3c,3d These interesting biological properties and
availability of minute quantities from natural sources inspired
chemists to explore new and efficient approaches for the synthesis
of 1a and 2a (Fig. 1).
a Barbier-type allylation5 of a chiral imine and an organo-catalyzed al-
dol reaction6 as key steps. The synthetic utility of this approach has
been fully exploited in enantioselective syntheses of alkaloids (ꢀ)-
241D and (ꢀ)-isosolenopsin as their hydrochloride salt forms, based
on asymmetric syntheses of d-amino b-hydroxy ketone 4a and d-ami-
no
and 3.
Our synthetic strategy starts from commercially available mate-
a,b-unsaturated ketone 4b, respectively, as depicted in Schemes 2
rials decanal (8) and methyl (S)-valinate hydrochloride salt. In the
first step decanal (8) was treated with methyl (S)-valinate hydro-
chloride in the presence of triethylamine and anhydrous Na2SO4
OH
OH
C9H19
N
H
C9H19
N
H
Various synthetic efforts have been reported4 for asymmetric
synthesis of 2,6-cis-disubstituted piperidine skeleton in enantiopure
form. Although, these synthetic approaches offer certain advantages,
they have a few drawbacks, such as longer synthetic operations and
expensive chiral reagents or starting materials. Thus more efficient
strategies are welcome.
(-)-241D (1a)
epi-(-)-241D (1b)
R
N
H
R
N
H
2a, Isosolenopsin
3a, Solenopsin
If R=C9H19,
If R=C9H19
,
Herein, we wish to report a new strategy for a stereoselective asym-
metric synthesis of 2,6-cis-disubstituted piperidines (Scheme 1), using
If R=C11H23, 2b, Isosolenopsin A
If R=C13H27, 2c, Isosolenopsin B
If R=C15H31, 2d, Isosolenopsin C
If R=C11H23, 3b, Solenopsin A
If R=C13H27, 3c, Solenopsin B
If R=C15H31, 3d, Solenopsin C
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Figure 1. Structures of the alkaloids 241D and isosolenopsins.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.115

3468
R. V. N. S. Murali, S. Chandrasekhar / Tetrahedron Letters 53 (2012) 3467–3470
OH
Cbz
NH OH
O
C9H19
C9H19
N
H
Cbz
NH
(-)-241D (1a)
4a
Decanal (8)
COOMe
C9H19
N
H
C9H19
O
Cbz
5
7
O
NH
C9H19
N
C9H19
H
Isosolenopsin (2a)
4b
Scheme 1. Retrosynthesis of (ꢀ)-241D and (ꢀ)-isosolenopsin.
CO2Me
Br, Zn
dry THF
NH2 HCl
O
•
N
CO2Me
anhydrous Na2SO4
H
H
NEt3, 3 h, dry CH2Cl2,
0 °C to r.t., 88.7%
0 °C to r.t., 12 h, 79%
8
9
OMe
O
OMe
N
N
H
H
O
7
7a
4:1 separable diastereomers
1. Pb(OAc)4,
NH2OH • HCl,
CH2Cl2:MeOH
LiAlH4,
dry THF
NHCbz
7
OH
2. CbzCl, K2CO3
THF, 72% (overall)
0 °C to r.t.,
1 h, 74%
N
C9H19
H
11
10
Scheme 2. Synthesis of Cbz-homoallyl amine.
OsO4, NaIO4
2,6-lutidine
Cbz
Cbz
NHCbz
NHCbz
O
D-proline (20 mol%)
NH OH
O
NH OH
O
11
O
dioxane-H2O
in 3:1 ratio,
12 h, 65%,
C9H19
C9H19
O
C9H19
C9H19
5
4a (42%)
4a'(14%)
4b (29%)
0
oC; 16 h,
80% (based on starting
material recovery)
85% (overall)
3:1 separable diastereomers
OH
H2-Pd (10% on C)
ether, 12 h
4a
4b
OH
1 M HCl in ether
95%
C9H19
N
H · HCl
(-) 241D · HCl
4a'
ref. 2j
C9H19
N
H
H2-Pd (10% on C)
ether, 12 h
(-)-epi-241D
C9H19
N
1 M HCl in ether
95%
H · HCl
(-)-Isosolenopsin · HCl
Scheme 3. Syntheses of (ꢀ)-241DꢁHCl and (ꢀ)-isosolenopsinꢁHCl and a formal synthesis of (ꢀ)-epi-241D.
to generate the corresponding (S)-valinate imine 9. This unstable
imine 9, was immediately subjected to Barbier-type allylation,5
that is, allyl bromide in the presence of activated zinc dust, to ste-
of this novel methodology in a total synthesis of natural product
alkaloid.
Homoallyl amine 11 was subjected to a one-pot oxidative cleav-
age, using OsO4-NaIO4 in the presence of 2,6-lutidine, to afford
b-amino aldehyde 5 in 65% yield.8 This b-amino aldehyde 5,
underwent an organo-catalyzed aldol reaction with acetone in the
reoselectively furnish a separable mixture of a-amino esters 7 and
7a in a 4:1 ratio. The ester functionality of the major isomer 7 was
reduced to the corresponding primary alcohol 10 in 74% yield using
LiAlH4. 1,2-Amino alcohol 10, was treated with Pb(OAc)4 and
H2NOHꢁHCl, which removed the isopentyl alcohol moiety,5a to ob-
tain the free amine, which was subsequently protected as its Cbz
derivative 11 in 72% yield with an enantioselectivity of 83% using
Cbz-Cl/K2CO3 (Scheme 2).7 Thus, the desired amino group was
introduced by using a stereoselective addition to the (S)-valinate
imine 9. To the best of our knowledge, this is the first application
presence of
graphically separable diastereomeric pair of 1,3-amino alcohols 4a
(42%) and 4a0 (14%) in 3:1 ratio along with
,b-unsaturated ketone
,b-unsaturated ketone 4b was found to
D-proline (20 mol %) to furnish a column chromato-
a
4b (29%) (Scheme 3). The
a
be the E stereoisomer, by 1H NMR spectroscopy. Hydrogenation
(10% Pd/C) of compound 4a under an H2 atmosphere removed the
Cbz protecting group to give free amine, which underwent a smooth

R. V. N. S. Murali, S. Chandrasekhar / Tetrahedron Letters 53 (2012) 3467–3470
3469
Higashiyama, K.; Yamauchi, T.; Kubo, H.; Ohmiya, S.; Takahashi, H. Tetrahedron
1998, 54, 13955–13970; (f) Ciblat, S.; Besse, P.; Papastergiou, V.; Veschambre,
H.; Canet, J.-L.; Troin, Y. Tetrahedron: Asymmetry 2000, 11, 2221–2229; (g)
Monfray, J.; Gelas-Mialhe, Y.; Gramain, J. C.; Remuson, R. Tetrahedron:
Asymmetry 2005, 16, 1025–1034; (h) Wang, X.; Dong, Y.; Sun, J.; Xu, X.; Li, R.;
Hu, Y. J. Org. Chem. 2005, 70, 1897–1900; (i) Kumar, R. S. C.; Sreedhar, E.; Reddy,
G. V.; Babu, K. S.; Rao, J. M. Tetrahedron: Asymmetry 2009, 20, 1160–1163; (j)
Reddy, C. R.; Latha, B. Tetrahedron: Asymmetry 2011, 22, 1849–1854.
OH
H
+
N
+
C9H19
C9H19
N
H
H
H2
H
H
H2
Cl-
Cl-
(-)-Isosolenopsin • HCl
2a • HCl
1a • HCl
4. (a) Kartritzky, A. R.; Qui, G.; Yang, B.; Steel, P. J. J. Org. Chem. 1998, 63, 6699–
6703; (b) Amat, M.; Hidalgo, J.; Llor, N.; Bosch, J. Tetrahedron: Asymmetry 1998, 9,
2419–2422; (c) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1–8. and
references cited there in; (d) Weymann, M.; Pfrengel, W.; Schollmeyer, D.; Kunz,
H. Synthesis 1997, 1151–1160; (e) Comins, D. L.; Benjelloun, N. R. Tetrahedron
Lett. 1994, 35, 829–832; (f) Grierson, D. S.; Royer, J.; Guerrier, L.; Husson, H.-P. J.
Org. Chem. 1986, 51, 4475–4477; (g) Royer, J.; Husson, H.-P. J. Org. Chem. 1985,
50, 670–673; (h) Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem.
Soc. 1983, 105, 7754–7755; (i) Davis, F. A.; Chao, B.; Fang, T.; Szenczyck, J. M. Org.
Lett. 2000, 2, 1041–1043; (j) Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28,
383–394; (k) Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1998, 39, 3505–
3508; (l) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712; (m)
Chandrasekhar, S.; Murali, R. V. N. S.; Reddy, Ch. R. Tetrahedron Lett. 2009, 50,
5686–5688; (n) Molander, G. A.; Dowdi, E. D.; Pack, S. K. J. Org. Chem. 2001, 66,
4344–4347; (o) Kuethe, J. T.; Comins, D. L. Org. Lett. 2000, 2, 855–857; (p)
Carbonnel, S.; Troin, Y. Heterocycles 2002, 10, 1807–1830.
5. For the preparation of (S)-valinate imine, see: (a) Basile, T.; Bocoum, A.; Savoia,
D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59, 7766–7773; (b) Bocoum, A.; Savoia,
D.; Umani-Ronchi, A. J. Chem. Soc., Chem. Commun. 1993, 1542–1544.
6. (a) Chandrasekhar, S.; Narasimhulu, Ch.; Reddy, N. R.; Sultana, S. S. Chem.
Commun. 2004, 1, 2450–2451; (b) Chandrasekhar, S.; Narasimhulu, Ch.; Reddy,
N. R.; Sultana, S. S. Tetrahedron Lett. 2004, 45, 4581–4582; (c) Chandrasekhar, S.;
Reddy, N. R.; Sultana, S. S.; Narasimhulu, Ch.; Reddy, K. V. Tetrahedron 2006, 62,
338–345; (d) Chandrasekhar, S.; Tiwari, B.; Parida, B. B.; Reddy, C. R.
Tetrahedron: Asymmetry 2008, 19, 495–499; (e) Chandrasekhar, S.; Johny, K.;
Reddy, C. R. Tetrahedron: Asymmetry 2009, 20, 1742–1745.
= nOe enhancement
Figure 2. nOe enhancements of (ꢀ)-241DꢁHCl and (ꢀ)-isosolenopsinꢁHCl.
intramolecular cyclization,2j followed by reduction of the imine
which accomplished (ꢀ)-241D (1a) in its crude form. This was fur-
ther treated with 1 N HCl diluted in ether to furnish, (ꢀ)-241D as its
hydrochloride salt. Similarly, compound 4b was subjected to hydro-
genation conditions, followed by acid treatment to furnish (ꢀ)-iso-
solenopsinꢁHCl (2aꢁHCl). Compound 4a0 could be transformed into
(ꢀ)-epi-241D (1b) by a known procedure.2j,2k
The optical rotations observed for (ꢀ)-241DꢁHCl and (ꢀ)-iso-
solenopsinꢁHCl were (ꢀ)-241DꢁHCl ((½a D20
ꢀ15.1, c 0.26 MeOH), [lit-
ꢂ
erature value2c for (+)-241DꢁHCl is ½a 2D0
ꢂ
+15.8, c 1.30 EtOH]) and for
(ꢀ)-isosolenopsinꢁHCl ((½a D21 ꢀ11.1, c 0.7 CHCl3), [literature va-
ꢂ
lue,3h
½
a 2D0
ꢂ
ꢀ12.5, c 0.2 CHCl3]). The stereochemistry of these piper-
idines, (ꢀ)-241DꢁHCl and (ꢀ)-isosolenopsinꢁHCl was exclusively
2,6-cis-cis-piperidin-4-ol and 2,6-cis-piperidine, respectively,
which was further confirmed from nOe studies performed on the
alkaloids (Fig. 2). It is noteworthy that the present synthetic route
involves only nine-steps9 to prepare both the alkaloids (ꢀ)-
241DꢁHCl and (ꢀ)-isosolenopsinꢁHCl in 7.7% and 5.3% yields,
respectively, and accompanies a formal synthesis of (ꢀ)-epi-241D
in enantiopure manner starting from a common b-amino aldehyde
5 with nine-steps which makes this procedure amenable for scale-
up.
7. (a) The enantiomeric excess of the compound 11 was determined from the
following chiral HPLC method. The ee was determined as 83%; HPLC chiral peak
OJ-H (46 ꢃ 25 cm), flow rate 1.0 mL/min (2% 2-propanol in hexane), retention
time 5.29 (91.64%), 6.56 (8.3%). (b) The lower enantioselectivity is may be due to
retroallylation-allylation of the intermediate aluminium salt formed during the
LiAlH4 reduction of 7.
8. Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–3219.
9. Spectral data for representative compounds:
Methyl (S)-3-methyl-2-((R)-tridec-1-en-4-ylamino)butanoate (7):
½
a 2D0
ꢂ
ꢀ11 (c 1.5, CHCl3); IR (KBr):
tmax 3328, 2925, 2855, 1733, 1464, 1376, 1255,
1162, 914, 725 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 5.80–5.59 (m, 1H), 5.18–4.92
;
In conclusion, we have described a new strategy for enantiose-
lective syntheses of the alkaloids (ꢀ)-241DꢁHCl and (ꢀ)-isosole-
(m, 2H), 4.10–3.91 (m, 1H), 3.68 (s, 3H), 2.95 (dd, J = 22.3, 6.2 Hz, 1H), 2.76 (dd,
J = 8.7, 4.7 Hz, 1H), 2.43–2.12 (m, 2H), 2.12–1.90 (m, 1H), 1.90–1.70 (m, 1H),
1.68–1.44 (m, 2H), 1.43–1.15 (m, 19H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR NMR
(CDCl3, 75 MHz): d 176.2, 136.1, 116.9, 64.0, 62.4, 51.0, 40.6, 31.9, 31.8, 30.3,
29.9, 29.6, 29.3, 27.9, 27.6, 22.7, 19.4, 18.9, 14.1; ESI-MS: m/z 312.5 (M+H)+.
nopsinꢁHCl and
a
formal synthesis of (ꢀ)-epi-241D using
a
Barbier-type allylation of a novel chiral imine and an organo-cata-
lyzed aldol reaction using -proline. Further, applications of this
a 2D0
ꢂ
ꢀ8 (c 0.08,
D
(S)-3-Methyl-2-((R)-tridec-1-en-4-ylamino)butan-1-ol (10):
½
CHCl3); IR (KBr): tmax 2957, 2917, 2873, 1640, 1466, 1219, 914, 772 cmꢀ1
;
1H
methodology to the synthesis of enantiopure cis-piperidine rings
NMR (CDCl3, 300 MHz): d5.87–5.68 (m, 1H), 5.13–4.98 (m, 2H), 3.49 (dd,
J = 10.6, 4.5 Hz, 1H), 3.27 (dd, J = 10.6, 6.0 Hz, 1H), 2.70–2.57 (dt, J = 11.3, 6.0 Hz,
1H), 2.51–2.41 (ddd, J = 6.0, 3.8, 2.3 Hz, 1H), 2.26 (br. S, 1H), 2.14 (t, J = 5.3 Hz,
2H), 1.79 (m, 1H), 1.46–1.18 (m, 17H), 0.97 (d, J = 6.8 Hz, 3H), 0.89 (distorted t,
J = 6.8 Hz, 6H); 13C NMR (CDCl3, 75 MHz): d 135.5, 117.1, 61.4, 60.5, 54.7, 44.2,
38.9, 34.4, 31.9, 29.9, 29.8, 29.5, 29.3, 25.9, 22.6, 19.7, 18.1, 14,1; ESI-MS: m/z
284.0 (M+H)+.
are currently being pursued in our laboratory.
Acknowledgments
R.V.N.S.M. thanks the UGC, New Delhi for research fellowship
and S.C. is thankful to the DST New Delhi for funding a research
grant (SR/ S1/OC-65/2009).
Benzyl N-((R)-tridec-1-en-4-yl)carbamate (11): ½a D20
ꢂ
+11 (c 0.5, CHCl3); IR (KBr):
tmax 3329, 3072, 3035, 2927, 2856, 1700, 1534, 1460, 1253, 1060, 913, 735,
697 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.43–7.27 (m, 5H), 5.93–5.67 (m, 1H),
;
5.19–4.96 (m, 4H), 4.56 (d, J = 8.2 Hz, 1H), 3.70 (m, 1H), 2.40–1.92 (m, 2H), 1.54–
1.14 (m, 16 H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR NMR: (CDCl3, 75 MHz): d 155.9,
136.6, 134.2, 128.4, 127.9, 117.9, 117.7, 66.4, 50.6, 39.4, 34.6, 31.8, 29.8, 29.5,
29.3, 25.8, 22.6, 14.1.; ESI-MS: m/z 354.3 (M+Na)+.
References and notes
1. (a) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 1999, 2553–2581; (b)
Bailey, P. D.; Millwood, P. A.; Smith, P. D. J. Chem. Soc., Perkin Trans. 1 1998, 633–
640; (c) Schneider, M. J. In Alkaloids: Chemical and Biological perspectives;
Pelletier, S. W., Ed.; Pergamon: Oxford, 1996; Vol. 10, pp 155–299.
Benzyl N-((R)-1-oxododecan-3-yl)carbamate (5): IR (KBr):
tmax 3325, 2925, 2855,
1710, 1518, 1458, 1221, 1063, 773, 697 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 9.71
;
(s, 1H), 7.37–7.21 (m, 5H), 5.13–4.95 (m, 3H), 4.09–3.89 (m, 1H), 2.69–2.44 (m,
2H), 1.63–1.40 (m, 2H), 1.40–1.13 (m, 14H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR
NMR (CDCl3, 75 MHz): d 200.9, 155.9, 136.5, 136.3, 128.5, 128.1, 128.0, 66.7,
48.7, 47.1, 34.8, 31.8, 29.6, 29.4, 29.2, 26.1, 26.0, 22.6, 14.0; ESI-MS: m/z 356.2
(M+Na)+.
2. Isolation: (a) Edwards, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188–1197. For
Racemic synthesis, see; (b) Edwards, M. W.; Garraffo, H. N.; Daly, J. W. Synthesis
1994, 1167–1170. For asymmetric Syntheses, see; (c) Chenevert, R.; Dickmann,
M. J. Org. Chem. 1996, 61, 3332–3341; (d) Ciblat, S.; Calinaud, P.; Canet, J.-L.;
Troin, Y. J. Chem. Soc. Perkin Trans 2000, 1, 353–357; (e) Ma, D.; Sun, H. Org. Lett.
2000, 2, 2503–2505; (f) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169–
3171; (g) Girard, N.; Hurvois, J.-P. Tetrahedron Lett. 2007, 48, 4097–4099; (h)
Gnamm, C.; Krauter, C. M.; Brödner, K.; Helmchen, G. Chem. Eur. J. 2009, 15,
2050–2054; (i) Gnamm, C.; Brödner, K.; Krauter, C. M.; Helmchen, G. Chem. Eur.
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K. S.; Rao, J. M. Tetrahedron Lett. 2010, 51, 1114–1116; (k) Damodar, K.; Das, B.
Synthesis 2012, 43, 83–86.
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J. C. Tetrahedron 1994, 50, 8465–8478; (b) Jefford, C. W.; Wang, J. B. Tetrahedron
Lett. 1993, 34, 2911–2914; (c) Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: New York, 1987; Vol. 31, pp 193–317; (d) Jones, T. H.;
Blum, M. S.; Fales, H. M. Tetrahedron 1982, 38, 1949–1958; (e) Poerwono, H.;
Benzyl N-((4S,6R)-4-hydroxy-2-oxopentadecan-6-yl)carbamate (4a): ½a D20
ꢂ
+2.8 (c
0.75, CHCl3); IR (KBr): t ;
max 3332, 2924, 2853, 1709, 1460, 1250, 773, 694 cmꢀ1
1H NMR (CDCl3, 300 MHz): d 7.40–7.22 (m, 5H), 5.17–5.00 (m, 3H), 4.83 (d,
J = 8.9 Hz, 1H), 4.12–3.97 (m, 1H), 3.93–3.63 (m, 2H), 2.62 (dd, J = 16.6, 4.3 Hz,
1H), 2.41 (dd, J = 16.6, 4.3 Hz, 1H), 2.16 (s, 3H), 1.64–1.08 (m, 16H), 0.89 (t,
J = 6.9 Hz, 3H); 13C NMR NMR (CDCl3, 75 MHz): d 208.7, 157.2, 129.7, 128.5,
128.2, 128.0, 114.3, 66.9, 64.4, 50.2, 48.4, 42.8, 35.3, 31.8, 31.0, 29.7, 29.5, 29.4,
29.3, 26.1, 22.7, 14.1.; ESI-MS: m/z 414.3 (M+Na)+; HRMS: Calcd for
C
23H37NNaO4 (M+Na)+: 414.2615, found: 414.2630.
Benzyl N-((4R,6R)-4-hydroxy-2-oxopentadecan-6-yl)carbamate (4a0): ½a D20
ꢂ
: ꢀ7.6
(c 0.3, CHCl3); IR (neat): tmax 3345, 2924, 2853, 1458, 1220, 773 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz): d 7.38–7.24 (m, 5H), 5.12–4.98 (m, 2H), 4.72 (d, J = 8.3 Hz,
1H), 4.12–3.98 (dt, J = 9.1, 6.8, 2.3 Hz, 1H), 3.72–3.58 (dt, J = 13.6, 7.6, 6.8 Hz,

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R. V. N. S. Murali, S. Chandrasekhar / Tetrahedron Letters 53 (2012) 3467–3470
1H), 2.75 (d, J = 17.4 Hz, 1H), 2.47 (dd, J = 9.3, 9.1 Hz, 1H), 2.14 (s, 3H), 1.57 (t,
+15.8 (c 1.30, MeOH) for it0s enantiomer2c].; IR (KBr): tmax 3318, 2927, 2856,
1714, 1527, 1458, 1355, 1251, 1220, 772 cmꢀ1 1H NMR (CD3OD, 300 MHz): d
J = 6.8 Hz, 2H), 1.53–1.38 (m, 2H), 1.37–1.14 (m, 13H), 0.89 (t, J = 7.6 Hz, 3H).;
13C NMR NMR (CDCl3, 75 MHz): d 209.9, 156.3, 129.8, 128.4, 128.0, 127.9, 66.6,
65.6, 49.6, 49.1, 41.9, 35.9, 31.8, 30.6, 29.6, 29.5, 29.4, 29.2, 25.7, 22.6, 14.1.; ESI-
MS: m/z 414.6 (M+Na)+. HRMS: Calcd for C23H38NO4 (M+H)+: 392.2715, found
392.2812.
;
3.82–3.62 (m, 1H), 3.28–3.13 (m, 2H), 3.13–2.97 (m, 1H), 2.21–1.98 (m, 2H),
1.73–1.56 (m, 1H), 1.56–1.40 (m, 1H), 1.40–1.08 (m, 19H), 0.80 (t, J = 6.9 Hz,
3H);. 13C NMR NMR (CD3OD, 75 MHz): d 69.0, 59.3, 55.4, 43.1, 41.0, 36.9, 35.5,
33.0, 32.9, 32.8, 28.7, 26.2, 21.6, 16.9.; ESI-MS: m/z 242.1 (M+H)+; HRMS: Calcd
for C15H32NO (M+H)+: 242.2478, found: 242.2499.
Benzyl N-((R,E)-2-oxopentadec-3-en-6-yl)carbamate (4b):
CHCl3); IR (KBr): tmax. 3328, 2927, 2856, 1699, 1678, 1534, 1458, 1361, 1253,
1057, 979, 698 cmꢀ1 1H NMR (CDCl3, 300 MHz); d 7.38–7.17 (m, 5H), 6.76–6.58
½ ꢂ +17.5 (c 0.4,
a 2D0
(ꢀ)-Isosolenopsin hydrochloride or (ꢀ)-2aꢁHCl: mp = 175 °C; ½a D21
ꢀ11.1 (c 0.7,
ꢂ
;
CHCl3) [lit.3h ꢀ12.5 (c 0.2, CHCl3)]; IR (KBr):
tmax 3312, 2924, 2853, 1683, 1622,
(m, 1H), 6.02 (d, J = 15.9 Hz, 1H), 5.04 (dd, J = 12.3, 12.1 Hz, 2H), 4.58 (d,
J = 8.5 Hz, 1H), 3.84–3.67 (br.s, 1H), 2.54–2.35 (m, 1H), 2.35–2.22 (m, 1H), 2.16
(s, 3H), 1.68–1.15 (m, 16H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR NMR (CDCl3,
75 MHz): d 198.3, 162.1, 155.9, 143.7, 136.4, 133.6, 128.5, 128.1, 128.0, 66.7,
50.5, 38.6, 34.9, 31.8, 29.7, 29.5, 29.2, 26.9, 25.9, 22.7, 14.1.; ESI-MS: m/z 396
(M+Na)+. HRMS: Calcd for C23H36NO3 (M+H)+: 374.2690. Found: 374.2699.
1464, 1364, 1125, 1038, 723 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 3.21–3.01 (m,
;
1H), 2.92 (t, J = 9.8 Hz, 1H), 2.17–1.86 (m, 3H), 1.86–1.68 (m, 2H), 1.68–1.40 (m,
4H), 1.3–1.13 (m, 17H), 0.87 (t, J = 6.7 Hz, 3H).; 13C NMR NMR (CDCl3, 75 MHz): d
58.0, 54.0, 33.4, 31.9, 30.5, 29.7, 29.5, 29.4, 29.3, 27.6, 25.3, 22.9, 22.7, 19.2, 14.0;
ESI-MS: m/z 226 (M+H)+; HRMS: Calcd for C15H32N (M+H)+: 226.2529. Found:
226.2561.
(ꢀ)-241D Hydrochloride or (ꢀ)-1aꢁHCl: ½a D20
ꢂ
ꢀ15.1 (c 0.26, MeOH) [lit.2c a 2D0
½ ꢂ