The first stereoselective total synthesis of nicotlactone A

Article abstract of DOI:10.1016/j.tetlet.2012.12.003

Herein we report the first stereoselective total synthesis of nicotlactone A via acid catalyzed acetonide deprotection followed by intramolecular lactonization in one pot as the key step.

Full text of DOI:10.1016/j.tetlet.2012.12.003

Tetrahedron Letters 54 (2013) 669–671
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Tetrahedron Letters
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The first stereoselective total synthesis of nicotlactone A
⇑
Palakodety Radha Krishna , Sunchu Prabhakar, Chittela Sravanthi
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR–Indian Institute of Chemical Technology, Hyderabad 500007, 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 stereoselective total synthesis of nicotlactone A via acid catalyzed acetonide
deprotection followed by intramolecular lactonization in one pot as the key step.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 3 October 2012
Revised 29 November 2012
Accepted 1 December 2012
Available online 7 December 2012
Keywords:
Nicotlactone A
c
-Lactone
Anti-tobacco-mosaic (ATM) virus activity
Anti-HIV-1 activity
Rychnovsky anology
Intramolecular lactonization
Nicotlactone A 1 (Fig. 1), a lignan derivative was recently iso-
lated from the leaves of Nicotiana tabaccum by Yang et al.1 Num-
ber of bioactive compounds such as alkaloids, sesquieterpenes,
diterpenoids, phenols, and lignan derivatives2 were isolated from
the Nicotiana tabacum (for e.g. 2–4). Compound 1 showed anti-
TMV activity and modest anti-HIV-1 activity. In anti-TMV activity
by Sharpless asymmetric epoxidation and Gilman’s reaction of
the corresponding epoxide, while allylic alcohol 7 could be ob-
tained from commercially available hydroxy acetone.
Our synthesis (Scheme 2) began from the inexpensive commer-
cially available starting material hydroxy acetone. Accordingly,
Wittig olefination (Ph3P@CHCO2Et/benzene/reflux/8 h) of the hy-
droxyl acetone provided the desired hydroxy ester 8 (92%) as an
exclusive E-isomer. The alcohol functionality in 8 was protected
as its PMB ether {PMBO(C@NH)CCl3/cat.PTSA/CH2Cl2/0 °C to rt/
test, the anti-viral inhibition rate of nicotlactone A (1) at 20 lM
concentration was 58.4%. This shows that nicotlactone A 1 exhib-
ited high anti-TMV activity; its inhibition rate was higher than that
of a positive control. As part of our interest in the total synthesis of
biologically active lactones using acid catalyzed lactonization3 we
chose nicotlactone A 1 as our next target. Apart from possessing
an impressive bioactivity profile, structurally compound 1 is un-
ique due to its sensitive benzylic alcohol moiety and a tertiary ste-
reogenic centre containing the hydroxyl group next to the lactone
ketone. Herein we report the first stereoselective total synthesis of
nicotlactone A 1.
The envisaged retrosynthetic strategy for nicotlactone A 1 is
delineated in Scheme 1. A linear synthetic strategy was invoked
wherein alcohol 5 was conceived as the ideal precursor to 1. Alco-
hol 5 upon oxidation–deprotection–lactonization would lead to
nicotlactone A 1 in one pot. While alcohol 5 in turn could be ac-
cessed from diol 6 involving functional group transformations like
Grignard reaction of the aldehyde generated from 6 with commer-
cially available aryl bromide namely 4-bromo-1,2-(methylenedi-
oxy)benzene followed by protection/deprotection reaction
sequence. Diol 6 in turn could be accessed from allylic alcohol 7
3 h}. Next,
a,b-conjugated ester was reduced (DIBAL-H/CH2Cl2/
0 °C/0.5 h) to the corresponding allylic alcohol 7 (91%). Subse-
quently, allylic alcohol 7 was converted into chiral epoxy alcohol
10 under Sharpless4 conditions {(+)-DIPT/Ti(OiPr)4/TBHP/4 Å MS/
CH2Cl2/ꢀ20 °C/92%}. Furthermore, compound 10 on regioselective
ring-opening reaction with Gilman’s reagent5 (Me2CuLi/Ether/
ꢀ20 °C/1 h) led to the desired 1,3-diol precursor 6 (85%) as the ma-
jor isomer. The crude reaction mixture was treated with NaIO4 in
THF/H2O (4:1) in order to eliminate the minor 1,2-diol by an oxida-
tive cleavage. The thus obtained diol 6 constitutes one of the
important precursors in this synthesis.
Next, the primary alcohol of compound 6 (Scheme 3) was oxi-
dized under Swern oxidation conditions {(COCl)2/DMSO/Et3N/
CH2Cl2/ꢀ78 °C} to furnish the corresponding aldehyde which was
subjected to Grignard reaction with 4-bromo-1,2-(methylenedi-
oxy)benzene in THF under reflux conditions to afford compound
11 (71%) as a major isomer (dr = 89:11). The ratio was measured
by LCMS {column: XDB-C 18, 30% water in acetonitrile, flow rate:
1 mL/min, 254 nm, tr(major) = 2.814 min, tr(minor) = 2.339 min}.
The stereochemistry of the newly created stereogenic center was
assigned based on Rychnovsky’s analogy of the corresponding
⇑
Corresponding author. Fax: +91 4027160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.003

670
P. Radha Krishna et al. / Tetrahedron Letters 54 (2013) 669–671
OR
O
MeO
HO
OH
O
OH
O
MeO
HO
O
O
MeO
HO
O
O
OMe
2
4
Nicotlactone A1
3 R = H, Me, Et.
OMe
OH
Figure 1. Some lignan derivatives.
OH
O
O
O
OH
OH
Br
O
O
O
O
O
O
OH
PMBO
PMBO
6
+
O
5
Nicotlactone A 1
O
OH
HO
7
hydroxy acetone
Scheme 1. Retrosynthetic analysis.
O
O
O
b
PMBO
a
HO
c
HO
OC2H5
OC2H5
9
8
OH
O
e
d
PMBO
PMBO
OH
OH
OH
PMBO
7
6
10
Scheme 2. Reagents and conditions: (a) Ph3P@CHCO2Et, benzene, reflux, 8 h, 92%; (b) PMBO(C@NH)CCl3, PTSA, dry CH2Cl2, 0 °C to rt, 3 h, 90%; (c) DIBAL-H, dry CH2Cl2, 0 °C,
0.5 h, 91%; (d) (+)-DIPT, Ti(OiPr)4, TBHP, 4 Å MS, dry CH2Cl2, ꢀ20 °C, 5 h, 92%; (e) (i) Me2CuLi, dry ether, ꢀ20 °C, 1 h, (ii) NaIO4, THF/H2O (4:1) (over two steps 85%).
OH OH
OH OH
OPMB
OPMB
O
O
O
O
+
a
6
Br
(dr = 89:11)
12
11
O
O
b
O
O
O
O
OH
OPMB
O
O
O
O
c
13
5
d
f
OH
O
O
O
O
O
e
O
OH
O
O
Nicotlactone A1
14
O
Scheme 3. Reagents and conditions: (a) (i) (COCl)2, dry DMSO, Et3N, dry CH2Cl2, ꢀ78 °C; (ii) Mg, 4-bromo-1,2-(methylenedioxy)benzene, dry THF, reflux, 1 h, 0 °C, aldehyde,
1 h, 71% (major isomer, over two steps); (b) 2,2-DMP, PPTS, dry CH2Cl2, 0 °C to rt,12 h, 90%; (c) DDQ, CH2Cl2/H2O (19:1), 0 °C to rt, 0.5 h, 86%; (d) TEMPO/BAIB, CH2Cl2/H2O
(1:1), 0 °C to rt, 2 h; (e) 5 N HCl, THF, reflux; (f) same as d, then while acid workup with 2 N HCl, 75% (over three steps).

P. Radha Krishna et al. / Tetrahedron Letters 54 (2013) 669–671
671
acetonide 13.6 For instance, the 13C NMR of 13 revealed the carbon
atoms due to the acetonide methyls that appeared at d 19.7 and at
d 31.8 ppm characteristic of the acetonide of a syn-1,3-diol moiety.
Thus the relative stereochemistry of the newly created stereogenic
center was unequivocally assigned as syn to the existing one and
its absolute stereochemistry as ‘S’. Then the PMB group of com-
pound 13 was deprotected under standard DDQ oxidation condi-
tions (DDQ/CH2Cl2/H2O/0 °C to rt/0.5 h) to result in alcohol 5 (86%).
Finally, the primary alcohol was oxidized to its carboxylic acid
under TEMPO/BAIB conditions. Fortunately the acidic (2 N HCl)
work-up, normally adopted after the oxidation step, helped us real-
ize the target compound nicotlactone A 1 (75%) in one pot via
sequential reactions such as acetonide deprotection followed by
the intramolecular lactonization reactions. By this way the target
molecule was achieved in shorter steps than the envisaged step-
wise strategy. The data of the synthetic sample matched with the
reported values of the natural product.1,7
5. Komatsu, K.; Tanino, K.; Miyashita, M. Angew. Chem. 2004, 116, 4441–4445.
6. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945–948; (b)
Rychnovsky, S. D.; Yang, G. J. Org. Chem. 1993, 58, 3511–3515.
7. Spectral data of the compounds: Compound 8: Pale yellow liquid; 1H NMR
(300 MHz, CDCl3): d 5.93 (s, 1H), 4.20–4.06 (m, 4H), 2.08 (s, 3H), 1.99 (br s, 1H),
1.29 (t, 3H, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3): d 167.0, 157.4, 113.4, 66.7,
59.7, 15.4, 14.1; LCMS: 167 [M+Na]+. Anal. Calcd for C7H12O3: C, 58.32; H, 8.39;
O, 33.29. Found: C, 58.48; H, 8.25; O, 33.27. Compound 9: Colorless liquid; 1H
NMR (500 MHz, CDCl3): d 7.23 (d, 2H, J = 8.4 Hz), 6.84 (d, 2H, J = 8.4 Hz), 5.95 (s,
1H), 4.45 (s, 2H), 4.16 (q, 2H, J = 14.3, 6.9 Hz), 3.93 (s, 2H), 3.81 (s, 3H), 2.11 (s,
3H), 1.31(t, 3H, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3): d 166.6, 159.2, 154.5,
131.9, 129.8, 129.2, 115.2, 114.2, 113.8, 73.7, 72.1, 59.6, 55.2, 15.7, 14.2; HRMS
m/z: calcd for C15H20O4Na [M+Na]+: 287.1253; found: 287.1262. Compound 7:
Colorless liquid; 1H NMR (300 MHz, CDCl3): d 7.27 (d, 2H, J = 8.4 Hz), 6.88 (d, 2H,
J = 8.6 Hz), 5.68 (dt, 1H, J = 6.7, 1.1 Hz), 4.42 (s, 2H), 4.21 (d, 2H, J = 6.6 Hz), 3.90
(s, 2H), 3.81(s, 3H), 1.71 (s, 3H); 13C NMR (75 MHz, CDCl3): d 159.0, 135.3, 130.2,
129.2, 126.1(2), 113.6(2), 75.0, 71.5, 58.8, 55.1, 13.9; HRMS: m/z calcd for
C
13H18O3Na [M+Na]+: 245.1148; found: 245.1157. Compound 10: Colorless
liquid; ½a 2D5
ꢁ
5.9 (c 0.05, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.20 (d, 2H,
J = 8.4 Hz), 6.82 (d, 2H, J = 8.3 Hz), 4.45 (br s, 2H), 3.79 (br s, 4H), 3.72–3.61 (m,
1H), 3.39 (br s, 2H), 3.01 (t, 1H, J = 5.4 Hz), 1.33 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 159.2, 129.8, 129.3, 113.8(4), 73.8, 72.9, 60.9, 60.4, 60.0, 55.1, 25.7,
14.5; HRMS m/z: calcd for C13H18O4Na [M+Na]+: 261.1097; found: 261.1093.
In summary, the first total synthesis of nicotlactone A (24%
overall yield) was reported via acid catalyzed intramolecular lact-
onization of the corresponding hydroxyl protected acid wherein
multiple reactions occurred in one step. This strategy may be
adopted for the synthesis of similar ring-containing natural
products.
Compound 6: Pale yellow liquid; ½a D25
ꢁ
+12.5 (c 0.05, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.25 (d, 2H, J = 7.5 Hz), 6.89 (d, 2H, J = 8.6 Hz), 4.50 (q, 2H, J = 16.6,
11.5 Hz), 3.81 (br s, 3H), 3.74 (d, 1H, J = 9.6 Hz), 3.61–3.51 (m, 1H), 3.40 (d, 1H,
J = 9.0 Hz), 3.28 (d, 1H, J = 9.0 Hz), 2.97 (br s, 1H), 2.11–1.98 (m, 1H), 1.66 (br s,
1H), 1.14 (br s, 3H), 0.78 (d, 3H, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3): d 159.2,
129.8, 129.2, 113.7(2), 76.1, 75.9, 73.0, 65.5, 55.2, 40.0, 19.2, 12.6; HRMS m/z:
calcd for
C
14H22O4Na [M+Na]+: 277.1410; found: 277.1407. Compound 11:
Colored oil; ½a 2D5
ꢁ
ꢀ6.2 (c 0.05, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.24 (d, 2H,
J = 8.6 Hz), 6.88 (d, 3H, J = 7.9 Hz), 6.75 (dd, 2H, J = 9.8 Hz), 5.93 (s, 2H), 5.14 (br
s, 1H), 4.54 (d, 1H, J = 9.0 Hz), 4.45 (d, 1H, J = 11.3 Hz), 3.80 (br s, 3H), 3.41 (d, 1H,
J = 9.4 Hz), 3.25 (d, 1H, J = 9.4 Hz), 2.16–2.03 (m, 1H), 1.25 (s, 3H), 0.45 (d, 3H,
J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d 159.2, 147.6, 146.8, 137.6, 129.6, 129.3,
120.9, 113.7(3), 107.6, 107.4, 100.8, 77.6, 76.8, 76.1, 73.0, 60.3, 55.1, 44.4, 29.6,
Acknowledgments
Two of the authors (S.P. and C.S.) thank CSIR, New Delhi, for the
financial support in the form of a fellowship.
18.1, 13.3; HRMS m/z: calcd for
C
21H26O6Na [M+Na]+: 397.1621; found:
397.1637; LCMS {Column: XDB-C18, 30% water in acetonitrile, flow rate:
1 mL/min, 254 nm, tr(major) = 2.814 min, tr(minor) = 2.339 min}. Compound 13:
Supplementary data
Pale yellow oil; ½a D25
ꢁ
ꢀ16.5 (c 0.05, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.27 (d,
2H, J = 8.4 Hz), 6.93 (br s, 1H), 6.86 (d, 2H, J = 8.4 Hz), 6.81 (d, 1H, J = 8.1 Hz), 6.77
(d, 1H, J = 7.9 Hz), 5.93 (d, 2H, J = 3.0 Hz), 4.65 (d, 1H, J = 11.8 Hz), 4.54 (d, 1H,
J = 8.8 Hz), 4.47 (d, 1H, J = 7.5 Hz), 3.80 (br s, 3H), 3.35 (q, 2H, J = 12.6, 10.7 Hz),
2.16–1.99 (m, 1H), 1.55 (br s, 3H), 1.47 (br s, 3H), 1.29 (br s, 3H), 0.52 (d, 3H,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.003.
J = 6.9 Hz); 13C NMR (75 MHz, CDCl3):
d 159.0, 147.7, 147.2, 134.6, 130.7,
129.1(2), 121.2, 113.6(3), 107.6, 100.8, 98.5, 77.1, 74.2, 73.1, 55.1, 38.8, 31.8,
24.9, 19.7, 12.0; HRMS m/z: calcd for C24H30O6Na [M+Na]+: 437.1821; found:
References and notes
437.1816. Compound 5: Pale yellow oil; ½a D25
ꢁ
ꢀ14.5 (c 0.05, CHCl3); 1H NMR
(300 MHz, CDCl3): d 6.93 (d, 1H, J = 1.5 Hz), 6.83 (dd, 1H, J = 1.5 Hz), 6.78 (d, 1H,
J = 4 Hz), 5.96–5.93 (m, 2H), 4.53 (d, 1H, J = 10.5 Hz), 3.42–3.31 (m, 2H), 2.23–
1. Gao, X.; Li, X.; Yang, X.; Mu, H.; Chen, Y.; Yang, G.; Hu, Q. Heterocycles 2012, 85,
147–153.
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4997–4999.
2.13 (m, 1H), 1.57 (br s, 3H), 1.45 (s, 3H), 1.26 (s, 3H), 0.56 (d, 3H, J = 6.9 Hz); 13
C
NMR (75 MHz, CDCl3): d 146.7, 136.0, 120.5, 107.8, 100.8, 75.1, 71.8, 69.6, 48.5,
31.9, 29.6, 25.3, 22.6, 19.3, 14.0, 11.8; HRMS m/z: calcd for C16H22O5Na [M+Na]+:
317.1359; found: 317.1368. Nicotlactone A 1: Pale yellow crude oil; ½a D25
ꢁ
+23.3 (c
0.05, CHCl3); 1H NMR (500 MHz, CD3COCD3): d 6.97 (br s, 1H), 6.92 (d, 1H,
J = 8.1 Hz), 6.85 (d, 1H, J = 8.1 Hz), 6.02 (br s, 2H), 5.01 (d, 1H, J = 9.4 Hz), 4.86 (br
s, 1H), 2.19–2.12 (m, 1H), 1.43 (br s, 3H), 1.01 (d, 3H, J = 6.9 Hz); 13C NMR
(75 MHz, CD3COCD3): d 176.1, 147.5, 131.4, 120.5, 107.3, 113.3, 100.8, 83.9, 77.7,
73.4, 48.7, 20.0, 6.3; HRMS m/z: calcd for C13H14O5Na [M+Na]+: 273.0733;
found: 273.0746.
4. Sharpless, K. B.; Behrens, H. C.; Katsuki, T.; Lee, M. W. A.; Martin, S. V.; Takatani,
M.; Viti, M. S.; Walker, J. F.; Woodard, S. S. Pure Appl. Chem. 1983, 55, 589–604.