Stereoselective total synthesis of alkaloid caulophyllumine B using iterative olefin cross-metathesis protocol

Article abstract of DOI:10.1016/j.tetlet.2010.09.079

Herein we report the first total synthesis of alkaloid caulophyllumine B in 14 steps by an iterative olefin cross-metathesis strategy from l-glutamic acid.

Full text of DOI:10.1016/j.tetlet.2010.09.079

Tetrahedron Letters 51 (2010) 6262–6264
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective total synthesis of alkaloid caulophyllumine B using
iterative olefin cross-metathesis protocol
⇑
Palakodety Radha Krishna , Bonepally Karunakar Reddy
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the first total synthesis of alkaloid caulophyllumine B in 14 steps by an iterative olefin
Received 9 August 2010
Revised 15 September 2010
Accepted 19 September 2010
Available online 15 October 2010
cross-metathesis strategy from L-glutamic acid.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Piperidine alkaloids
Cytochrome P450
Grubbs-II catalyst
Iterative olefin cross-metathesis
Caulophyllumine A and B (Fig. 1) are the two new piperidine
alkaloids isolated by Ali and Khan1a from Blue Cohosh, Caulophyl-
lum thalictroides (L.) Michx (Berberidaceae), an indigenous peren-
nial plant found in north-eastern North America. It is a well
known dietary supplement used for regulation of the menstrual cy-
cle and to ease childbirth and painful cramps. Native Americans
used this plant for various ailments like rheumatism, dropsy, colic,
sore throat, cramp, epilepsy, hysterics, and inflammation of the
uterus.1b Among the isolated alkaloids, caulophyllumine B inhib-
ited major drug metabolizing cytochrome P450 (CYP450) enzymes
showed strong inhibition of CYP 2C19, 3A4, 2D6, and 1A2 enzymes
deblocking of the acetyl group in one-pot. The advanced interme-
diate 2 in turn could be realized from the cross-metathesis reaction
of 3 and 4-acetoxy styrene. Though piperidine derivative 3 was
synthesized previously,4 herein we propose a strategically different
route to access it from naturally occurring L-glutamic acid as start-
ing material involving an olefin cross-metathesis protocol. It is per-
tinent to mention that (S)-2-vinyl-N-Boc-piperidine 3 is a key
building block in the synthesis of natural products like epilupinine
and (ꢀ)-aloperine.4
Accordingly, synthesis of 1b commenced with the known5 N-
Boc-allyloxazolidine 5 (Scheme 2). Thus, compound 5 was accessed
to various extents (IC50: 2.5–50
l
M).2
by a modified literature route from L-glutamic acid and the struc-
Caulophyllumine B (1b) attracted our attention primarily due to
the interest we harbor in the synthesis of piperidine-based natural
products.3 Additionally, caulophyllumine B has impressive biolog-
ical profile as well as the presence of a rare 2-vinyl-piperidine moi-
ety as part of the structure. The above mentioned features led us to
undertake its synthesis. Toward the synthesis of 1b, we envisaged
that olefin cross-metathesis could be the key reaction in assem-
bling the piperidine skeleton. In fact, herein we propose to perform
two cross-metathesis reactions; the first one to access the crucial
intermediate (S)-2-vinyl-N-Boc-piperidine 3 and the other one
during the coupling of 3 with commercially available 4-acetoxy
styrene (Aldrich) en route the target compound. Thus in essence
the retrosynthetic strategy (Scheme 1) proposed is as follows: 1b
could be obtained by the exhaustive reduction of 2 wherein the
Boc group manifests into a ‘methyl’ group with the simultaneous
ture was confirmed by comparing its analytical data with reported
values.
After having the N-Boc-allyloxazolidine 5 in hand, Grubbs cata-
lyst assisted cross-metathesis6 reaction of 5 (1.0 equiv) with its
olefin partner, methyl acrylate {2.5 equiv; G-II (8 mol %)/CH2Cl2/
6 h} was conducted to afford
a
,b-unsaturated ester (4, 80%)7 as
an exclusive E-isomer (Scheme 2). Compound 4 was characterized
by its spectroscopic data, for instance, the 1H NMR spectrum re-
vealed a peak at d 5.85 ppm (J = 15.8 Hz) indicating the trans-
geometry of the olefin and the optical rotation value was found
O
OMe
OMe
OH
N
N
H
1a
1b
Caulophyllumine B
OH
Caulophyllumine A
⇑
Corresponding author. Tel.: +91 40 27160123; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
Figure 1. New alkaloids from blue cohosh.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.079

P. Radha Krishna, B. K. Reddy / Tetrahedron Letters 51 (2010) 6262–6264
6263
O
2nd Cross
+
N
N
N
O
O
metathesis
Boc
Boc
1b
3
2
OH
O
1st Cross
O
O
+
O
O
BocN
metathesis
O
O
BocN
4
5
L-glutamic acid
Scheme 1. Retrosynthetic analysis of caulophyllumine B.
3
Synthesis of (S)-2-vinyl-N-Boc-piperidine
O
O
a
b
+
O
O
BocN
O
O
BocN
5
4
c
HO
HO
HO
d
O
+
O
BocN
BocN
NHBoc
8
7
6
e
N
Boc
3
Scheme 2. Reagents and conditions: (a) G-II (8 mol %), rt, 6 h, 80%; (b) (i) LiAlH4, THF, 0 °C to rt, 2.5 h, (compound 6, 32%, compound 7, 51%); (c) Pd/C, H2, EtOAc, 4 h, 78%; (d)
(i) TBDPSCl, imidazole, CH2Cl2, rt, 2 h, 94%; (ii) CuCl2ꢂ2H2O, CH3CN, rt, 0.5 h, 89%; (iii) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 1.5 h; (iv) Ph3P+CH3Iꢀ, KOtBu, THF, ꢀ5 °C, 6 h, then
aldehyde, rt, 2 h, 83% over two steps; (v) TBAF, THF, rt, 1.5 h, 88%; (e) (i) MsCl, Et3 N, CH2Cl2, rt, 0.5 h; (ii) KOtBu, THF, 0 °C to rt, 4 h (for two steps overall yield 93%).
to be ½a 2D5
ꢁ
+25.3 (c 0.85, CHCl3). Incidentally, an enantiomer of 4
Synthesis of caulophyllumine B
was reported in the literature7 {½a D25
ꢀ27.9 (c 1.15, CHCl3)}.
ꢁ
O
Further, the trans-a,b-unsaturated ester (4) on reduction with
a
LAH resulted in a chromatographically separable mixture of satu-
rated alcohol 6 (32%) and unsaturated alcohol 7 (51%).7b After sep-
aration of this mixture into individual components, compound 7
was hydrogenated (Pd-C/H2/rt/EtOAc/78%) to furnish an additional
crop of saturated alcohol 6. Later, the pooled alcohol 6 was pro-
tected as its silyl ether (TBDPSCl/imidazole/CH2Cl2/rt/2 h/94%),
which on acetonide group deprotection8 (CuCl2ꢂ2H2O/CH3CN/rt/
89%) gave the corresponding primary alcohol that was oxidized un-
der Swern conditions and the ensuing aldehyde was exposed to a
Wittig olefination reaction (Ph3P+CH3Iꢀ/KOtBu/THF/ꢀ5 °C to rt/
8 h, 83%). It furnished an olefin without any epimerization as ascer-
tained at a later stage of the synthesis of 3 by comparing the spe-
cific rotation values. Next, the silyl group was deblocked (TBAF/
N
O
N
O
+
Boc
Boc
3
2
O
b
N
1b
OH
Scheme 3. Reagents and conditions: (a) G-II (10 mol %), CH2Cl2, rt, 1.5 h, 76%; (b)
LiAlH4, THF, reflux, 3 h, 68%.
THF/rt/1.5 h) to afford the corresponding primary alcohol
8
(88%). Further, alcohol 8 was converted into its corresponding mes-
ylate (MsCl/Et3N/CH2Cl2/rt), which on immediate base induced
intramolecular SN2 reaction (KOtBu/THF/0 °C to rt) furnished (S)-
2-vinyl-N-Boc-piperidine 3 (93% over two steps, Scheme 2). Com-
pound 3 was characterized by comparing its spectral data with
the reported values.4,9
During the crucial cross-metathesis reaction (Scheme 3), 2.5-
folds of 4-acetoxy styrene was reacted with 1.0 fold of (S)-2-vi-
nyl-N-Boc-piperidine 3 {G-II (10 mol %)/CH2Cl2/rt/1.5 h} to afford
the (E)-olefin 2 (76%) as the major product albeit a small amount
of homo dimer of 4-acetoxy styrene (10%) was also observed as a
separable mixture. (E)-Olefin 2 was characterized by its spectro-
scopic data, wherein the 1H NMR spectrum displayed the olefinic
protons at d 6.33 ppm (J = 16.2 Hz) and at d 6.09 ppm (J = 16.2 Hz)
indicating the trans disposition of the olefinic protons. (E)-Olefin 2
on reaction with LAH in THF at reflux resulted in the one-pot depro-
tection of the acetyl group as well as the transformation of Boc
group into the methyl functionality to furnish the natural product
caulophyllumine B 1b (68%) as a brown powder. The spectral data
matched with the reported values.1,9

6264
P. Radha Krishna, B. K. Reddy / Tetrahedron Letters 51 (2010) 6262–6264
9. Spectral data for selected compounds. Compound 5: Colorless liquid; (two
In conclusion, a method for the synthesis of (S)-2-vinyl-N-Boc-
rotamers). ½a 2D5
ꢁ
+19.8 (c 0.85, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.73 (br s,
piperidine 3, a versatile intermediate in the synthesis of piperidine
based natural products was accomplished and its use was exempli-
fied in the first stereoselective total synthesis of caulophyllumine B
(1b) via an iterative olefin cross-metathesis reaction. The combina-
torial advantage of this synthetic strategy lies in the second cross-
metathesis wherein various styrenes/designed olefins could be
coupled for generating a diverse library of compounds.10
1H), 5.12–5.16 (m, 2H), 3.95–3.75 (m, 3H), 2.59–2.43 (m, 1H), 2.30–2.20 (m,
1H), 1.60–1.47 (m, 15H); 13C NMR (75 MHz, CDCl3): d 157.5, 134.6, 117.7, 96.1,
93.9, 66.4, 66.1, 56.9, 38.1, 37.1, 28.5, 27.5, 26.7, 24.6, 23.3; ESI-MS (m/z): 242
[M+H]+, 264 [M+Na]+; HRMS (m/z) calcd for: C13H23NO3Na 264.1575 [M+Na]+,
found 264.1574. Compound 4: Colorless liquid; (two rotamers). ½a D25
ꢁ
+25.3 (c
0.63, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.86 (ddd, J = 7.9, 14.3 Hz, 1H), 5.85
(d, J = 15.9 Hz, 1H), 3.72–3.68 (m, 4H), 2.70–2.39 (m, 2H), 1.55 (d, J = 15.9 Hz,
2H), 1.55–1.46 (m, 15H); 13C NMR (75 MHz, CDCl3): d 170.4, 159.0, 137.4,
135.7, 130.7, 129.9, 129.2, 118.8, 117.9, 113.6, 81.7, 77.9, 76.8, 72.8, 71.5, 70.1,
55.2, 41.2, 35.8, 35.1, 31.7, 29.1, 25.1, 22.4; ESI-MS (m/z): 300 [M+H]+, 322
[M+Na]+. Compound 6: Colorless syrup; (two rotamers). ½a 2D5
ꢁ
+24.3 (c 0.74,
Acknowledgment
CHCl3); 1H NMR (300 MHz, CDCl3): d 3.92–3.61 (m, 5H), 1.71–1.25 (m, 21H);
13C NMR (75 MHz, CDCl3): d 152.2, 151.3, 96.2, 66.7, 64.8, 62.0, 57.5, 52.5, 33.5,
32.4, 31.1, 28.6, 27.7, 26.0, 24.6, 23.3, 22.6, 22.1; ESI-MS (m/z): 274 [M+H]+, 296
[M+Na]+; HRMS (m/z) calcd for: C14H27NO4Na, 296.1837 [M+Na]+, found (m/z):
One of the authors (B.K.R.) thank the CSIR, New Delhi for finan-
cial assistance in the form of a fellowship.
296.1845. Compound 8: Colorless thick liquid; ½a D25
ꢁ
+2.3 (c 0.74, CHCl3); 1H
NMR (300 MHz, CDCl3): d 5.82–5.68 (m, 1H), 5.1 (tq, J = 1.2, 17.2 Hz, 2H), 4.38
(d, J = 7.7 Hz, 1H), 4.1 (d, J = 6.8 Hz, 1H), 3.62 (t, J = 5.8 Hz, 2H), 1.65–1.38 (m,
15H); 13C NMR (75 MHz, CDCl3): d 155.5, 139.0, 114.5, 79.4, 62.6, 52.5, 34.9,
32.5, 28.5, 21.9; ESI-MS (m/z): 230 [M+H]+, 252 [M+Na]+. Compound 3:
References and notes
1. (a) Ali, Z.; Khan, I. A. Phytochemistry 2008, 69, 1037–1042; (b) Jhoo, J.; Sang, S.;
He, K.; Cheng, X.; Zhu, N.; Stark, R. E.; Zheng, Q. Y.; Rosen, R. T.; Ho, C. T. J. Agric.
Food. Chem. 2001, 49, 5969–5974.
2. Madgula, V. L. M.; Ali, Z.; Smillie, T.; Khan, I. A.; Walker, L. A.; Khan, S. I. Planta
Med. 2009, 75, 329–332.
Colorless liquid; ½a D25
ꢁ
ꢀ38.2 (c 1.25, CHCl3); 1H NMR (300 MHz, CDCl3): d
5.73 (ddd, J = 4.1, 10.6, 17.4 Hz, 1H), 5.16 (ddd, J = 1.5, 2.3, 10.6 Hz, 1H), 5.03
(ddd, J = 1.9, 2.3, 17.4 Hz, 1H), 4.75 (br s, 1H), 3.92 (br d, J = 13.5 Hz, 1H), 2.80
(dt, J = 2.6, 12.8 Hz, 1H), 1.74–1.54 (m, 4H), 1.52–1.40 (m, 11H); 13C NMR
(75 MHz, CDCl3): d 155.3, 136.8, 115.4, 79.2, 52.4, 39.6, 28.9, 28.4, 25.5, 19.4;
3. (a) Radha Krishna, P.; Srishailam, A. Tetrahedron Lett. 2007, 48, 6924–6927; (b)
Radha Krishna, P.; Dayaker, G. Tetrahedron Lett. 2007, 48, 7279–7282; (c) Radha
Krishna, P.; Lopinti, K. Synlett 2007, 1742–1744; (d) Radha Krishna, P.; Reddy, P.
S. J. Comb. Chem. 2008, 10, 426–435.
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1911–1916; (b) Yamouchi, S.; Omi, Y. Biosci. Biotechnol. Biochem. 2005, 69,
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ESI-MS (m/z): 212 [M+H]+, 234 [M+Na]+. Compound 2: Colorless syrup; ½a 2D5
ꢁ
ꢀ34.2 (c 0.25, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.34 (d, J = 8.6 Hz, 2H), 6.99
(d, J = 8.3 Hz, 2H), 6.33 (dd, J = 1.1, 16.6 Hz, 1H), 6.09 (dd, J = 4.5, 15.8 Hz, 1H),
4.92 (br s, 1H), 3.97 (d, J = 13.6 Hz, 1H), 2.87 (t, J = 12.8 Hz, 1H), 2.27 (s, 3H),
1.80–1.62 (m, 3H), 1.47 (s, 9H), 1.25 (m, 3H); 13C NMR (75 MHz, CDCl3): d
169.5, 155.4, 149.9, 134.9, 129.7, 129.1, 127.2, 121.7, 79.6, 52.2, 39.9, 29.6, 28.5,
25.5, 21.1, 19.7; ESI-MS (m/z): 346 [M+H]+, 368 [M+Na]+; HRMS (m/z) calcd for:
C
20H27NO4Na 368.1837 [M+Na]+, found 368.1855. Compound 1b: Brown
powder; ½a 2D5
ꢁ
ꢀ8.5 (c 0.27, MeOH); 1H NMR (300 MHz, CDCl3): d 7.17 (d,
J = 8.3 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.43 (d, J = 15.9 Hz, 1H), 5.95 (dd, J = 9.0,
15.9 Hz, 1H), 3.12 (br d, J = 11.0 Hz, 1H), 2.67 (ddd, J = 4.9, 9.1, 13.2 Hz, 1H),
2.37 (s, 3H), 2.22 (ddd, J = 4.2, 11.3, 15.1 Hz 1H), 1.84–1.60 (m, 5H), 1.43–1.22
(m, 2H); 13C NMR (75 MHz, CDCl3): d 157.1, 132.2, 128.2, 127.8, 127.3, 116.2,
68.5, 56.4, 43.5, 32.5, 24.9, 23.6; ESI-MS (m/z): 218 [M+H]+; HRMS (m/z) calcd
for: C14H20NO 218.1544 [M+H]+, found 218.1541.
7. (a) Blackburn, L.; Wei, X.; Taylor, R. J. K. Chem. Commun. 1999, 1337–1338; (b)
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10. The authors are thankful to the referee for asking us to bring out this
importance.