Total synthesis of verbalactone: an efficient, carbohydrate-based approach

Article abstract of DOI:10.1016/j.tetlet.2009.02.062

A carbohydrate-based strategy for the total synthesis of verbalactone has been described. (3R,5R)-3,5-dihydroxydecanoic acid was dimerised under Yamaguchi conditions to provide verbalactone in an overall yield of 17% starting from 3-deoxy-1,2:5,6-di-O-iso

Full text of DOI:10.1016/j.tetlet.2009.02.062

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Tetrahedron Letters 50 (2009) 2048–2049
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Tetrahedron Letters
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Total synthesis of verbalactone: an efficient, carbohydrate-based approach
*
*
Ganesh B. Salunke, I. Shivakumar , Mukund K. Gurjar
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A carbohydrate-based strategy for the total synthesis of verbalactone has been described. (3R,5R)-3,5-
Received 15 December 2008
Revised 4 February 2009
Accepted 10 February 2009
Available online 13 February 2009
dihydroxydecanoic acid was dimerised under Yamaguchi conditions to provide verbalactone in an overall
yield of 17% starting from 3-deoxy-1,2:5,6-di-O-isopropylidine-
a-
D
-glucofuranose.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Verbalactone
D-Glucose
Chiral pool approach
Yamaguchi’s macrolactonization
OH
OH
Verbalactone (1) is a novel macrocyclic dimer lactone with C2-
symmetry and it exhibits interesting antibacterial activity. Verb-
alactone was isolated1 by Mitaku et al from the roots of Verbascum
undulatum. The structure and the absolute stereochemistry of 1
were determined as 4R, 6R, 10R, 12R by spectral methods (1D
and 2D NMR, MS) and chemical correlation spectroscopy. The mol-
ecule has a NMR profile very similar to (+)-(3R,5R)-dihydroxy-5-
decanolide (2).2
verbalactone
COOH
OH
1
3
O
O
O
O
D
-Glucose
O
O
O
O
H
OH
4
O
5
H
O
HO
H
H
OH
O
O
Retrosynthetic analysis for Verbalactone
OH
2
1
The retrosynthetic analysis delineated above indicated that verb-
alactone (1) can easily be synthesized exploiting Yamaguchi’s lact-
onization on the key monomer seco acid, (3R,5R)-3,5-dihydroxy
The unique dimeric lactone, verbalactone (1), has attracted several
organic chemists3–5 to develop its total synthesis. Interesting struc-
tural complexity and our continued interest in the area of synthesis
of bioactive natural products containing 1,3 polyol systems using
carbohydrate-based strategies6 prompted us to undertake the syn-
thesis of 1. Herein, we report a simple and efficient total synthesis
of verbalactone adopting the chiral pool approach.
decanoic acid 3, which can in turn be derived from
intermediates 5 and 4 (Scheme 1).
D-glucose via
The synthesis of seco acid 3 started with the preparation of 3-
deoxy-1,2;5,6-di-O-isopropylidene- -glucofuranose 5 from
a
-D
D-
glucose.7 Selective deprotection of the 5,6-O-isopropylidene
group of compound 5 with 0.8% H2SO4 in MeOH at ambient tem-
perature afforded the C5–C6 diol in 94% yield. Oxidative cleavage
by using sodium metaperiodate followed by subsequent Wittig
olefination with butyltriphenyl phosphorane provided alkene 6
in the ratio 3:7 (E/Z). Hydrogenation of alkene 6 using Raney-
Ni in ethanol and then hydrolysis of the 1,2-O-isopropylidine
* Corresponding authors. Tel.: +91 20 2590 2575; fax: +91 20 2590 2629.
E-mail address: i.shivakumar@ncl.res.in (I. Shivakumar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.062

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G. B. Salunke et al. / Tetrahedron Letters 50 (2009) 2048–2049
2049
O
O
O
O
a
c
b
O
OH
D-Glucose
O
O
O
4
OH
6
5
O
d
OH
OH
O
O
e
f
O
O
COOH
OH
7
9
8
g
O
OH
OH
h
H
HO
H
H
OH
O
O
COOH
H
O
3
1
Scheme 1. Reagents and conditions: (a) Ref. 7; (b) (i) 0.8% aq H2SO4, MeOH, rt, 16 h, 95%; (ii) NaIO4 on silica gel, CH2Cl2, 96%; (iii) C4H9P+Ph3Brꢁ, n-BuLi, THF, 0 °C, 81%; (c) (i)
Raney-Ni, ethanol, 98%; (ii) 4% aq H2SO4, THF, 60 °C, 3 h, 94%; (d) CH3P+Ph3Iꢁ, n-BuLi, THF, 0 °C ? rt, 80%; (e) (i) CSA (cat), 2,2-dimethoxypropane, CH2Cl2, 0 °C, 15 min, 98%;
(ii) BH3-DMS, THF, 0 °C, 4 h, 76%; (f) (i) Dess–Martin periodinane, CH2Cl2, 0 °C ? rt, 1 h, 92%; (ii) NaClO2, NaH2PO4.2H2O, 30% H2O2, tBuOH:H2O (3:1), 0 °C ? rt, 3 h, 95%; (g)
CSA (5 mol %), MeOH, rt, 30 min, 80%; (h) (i) 2,4,6-trichlorobenzoylchloride, Et3N, THF, rt, 3 h; (ii) DMAP (30 equiv), toluene, reflux, 4 h, 60% (over two steps).
group with 4% aq sulfuric acid in THF at 60 °C afforded the dia-
stereomeric lactol 4.
Acknowledgment
One-carbon Wittig homologation of lactol 4 at 0 °C with in
situ-generated methylenetriphenyl phosphorane yielded syn-1,3-
diol 7, thus providing the desired ten-carbon chain of the verb-
alactone monomer. In the 1H NMR of diol 78, the C4 methylene
protons resonated separately as two distinguishable doublets of
triplets indicating a 1,3-syn-relationship. This was further sub-
stantiated in the 13C NMR studies of its isopropylidene derivative
where the isopropylidene methyl carbons showed two separate
signals at 30.2 and 19.8 ppm. The syn-1,3-diol 7 was transformed
quantitatively into its isopropylidene derivative with 2,2-dime-
thoxypropane in the presence of catalytic camphor sulfonic acid
(CSA). Selective hydroboration9 of this acetonide derivative of 7
with BH3-DMS reagent at 0 °C afforded primary alcohol 8 in
76% yield (9% of its regioisomer). The alcohol 8 on treatment
with Dess–Martin periodinane gave the corresponding aldehyde,
which on further oxidation10 with sodium chlorite in the pres-
ence of 30% H2O2 and sodium dihydrogen phosphate dihydrate
gave acid 9. The spectral and analytical data11 of 9 were in full
agreement with the reported5 compound. The unmasking of the
1,3-isopropylidine group was achieved by treating 9 with cat.
CSA in anhydrous methanol and by carefully controlling the pH
(=6) during work-up3,5 to provide the (3R,5R)-3,5-dihydroxydeca-
noic acid 3.
GBS thanks CSIR, New Delhi, for financial assistance in the form
of a research fellowship.
References and notes
1. Magiatis, P.; Spanakis, D.; Mitaku, S.; Tsitsa, E.; Mentis, A.; Harvala, C. J. Nat.
Prod. 2001, 64, 1093–1094.
2. (a) Takano, S.; Seton, M.; Ogasawara, K. Tetrahedron: Asymmetry 1992, 3, 533–
534; (b) Bennett, F.; Knight, D.; Fenton, G. J. Chem. Soc., Perkin Trans. 1 1991,
1543–1547; (c) Bennett, F.; Knight, D.; Fenton, G. Heterocycles 1989, 29, 639–
642; (d) Yang, Y. L.; Falck, J. R. Tetrahedron Lett. 1982, 23, 4305–4308.
3. Gogoi, S.; Barua, N. C.; Kalita, B. Tetrahedron Lett. 2004, 45, 5577–5579.
4. Sharma, G. V. M.; Reddy, Ch. G. Tetrahedron Lett. 2004, 45, 7483–7485.
5. Allais, F.; Louvel, M. C.; Cossy, J. Synlett 2007, 451–452.
6. (a) Gurjar, M. K.; Karmakar, S.; Mohapatra, D. K. Tetrahedron Lett. 2004, 45,
4525–4526; (b) Gurjar, M. K.; Srinivas, B.; Puranik, V. G.; Ramana, C. V. J. Org.
Chem. 2005, 70, 8216–8219.
7. Barton, D. H. R.; McCombie, W. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–
1585.
8. Spectral data for compound 7: ½a D25
ꢀ
ꢁ2.8 (c 1, CHCl3); 1H NMR d: (400 MHz,
CDCl3): 5.92–5.84 (m, 1H), 5.25 (dt, J = 17.1, 1.3 Hz, 1H), 5.10 (dt, J = 10.5,
1.3 Hz, 1H), 4.42–4.34 (m, 1H), 3.93–3.84 (m, 1H), 3.15 (br s, 1H), 3.03 (br s,
1H), 1.67 (dt, J = 14.6, 2.8 Hz, 1H), 1.58 (dt, J = 14.6, 9.7 Hz, 1H), 1.51–1.39 (m,
2H), 1.25–1.35 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR d: (100 MHz, CDCl3):
140.7 (d), 114.3 (t), 73.7 (d), 72.5 (d), 42.8 (t), 38.0 (t), 31.8 (t), 25.0 (t), 22.5 (t),
14.0 (q); IR (CHCl3):
m
= 3368, 3012, 2932, 2860, 1647, 1424, 1216 cmꢁ1; MS
(ESI): m/z 195.1 ([M + Na]+).
9. Evans, D. A.; Andrew, M. R.; Huff, B. E.; George, S. S. J. Am. Chem. Soc. 1995, 117,
3448–3467.
10. Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567–569.
Finally, the synthesis of verbalactone was successfully com-
pleted using Yamaguchi’s macrolactonization12 to obtain 1 in 60%
11. Spectral data for compound 9: ½a D25
ꢀ
+12.4 (c 0.5, CHCl3); 1H NMR d: (400 MHz,
yield from 3 as a colorless oil ½a D25
ꢀ
9.1 (c 0.9, CHCl3) along with
CDCl3): 4.33–4.25 (m, 1H), 3.88–3.79 (m, 1H), 2.57 (dd, J = 15.8, 7.0, 1H), 2.46
(dd, J = 15.8, 5.5, 1H), 1.55–1.24 (m, 10H), 1.45 (s, 3H), 1.39 (s, 3H), 0.88 (t,
J = 6.8 Hz, 3H); 13C NMR d: (100 MHz, CDCl3): 176.0 (s), 99.0 (s), 68.8 (d), 65.8
(d), 41.2 (t), 36.3 (t), 36.2 (t), 31.7 (t), 30.0 (q), 24.5 (t), 22.6 (t), 19.7 (q), 14.0
monomer lactone 2 (22%). The 1H and 13C NMR spectra as well as
other analytical data of synthetic 1 were identical with those of
the natural product.1
(q); IR (CHCl3):
m
= 3019, 2931, 1713, 1382, 1216 cmꢁ1; MS (ESI): m/z 267.5 ([M
+Na]+).
In conclusion, an expeditious and economic total synthesis of
verbalactone has been achieved in 17% overall yield by adopting
the chiral pool approach.
12. (a) Yamaguchi, M.; Inanaga, J.; Hirata, K.; Sacki, H.; Katsuki, T. Bull. Chem. Soc.
Jpn. 1979, 52, 1989; (b) Mulzer, J.; Mareski, P. A.; Buschmann, J.; Luger, P.
Synthesis 1992, 215.