First total synthesis of verbalactone, a macrocyclic dilactone isolated from Verbascum undulatum

Article abstract of DOI:10.1016/j.tetlet.2004.05.149

Verbalactone, a new macrocyclic dilactone was synthesized efficiently in a steroselective manner involving a Barbier-Grignard reaction, a Sharpless asymmetric dihydroxylation, monotosylation, epoxidation, ring opening of the epoxide, hydrolysis and lacton

Full text of DOI:10.1016/j.tetlet.2004.05.149

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5577–5579
First total synthesis of verbalactone, a macrocyclic dilactone
isolated from Verbascum undulatum
Siddhartha Gogoi, Nabin C. Barua* and Biswajit Kalita
Natural Products Chemistry Division, Regional Research Laboratory (CSIR), Jorhat-785 006, Assam, India
Received 12 February2004; revised 11 May2004; accepted 28 May2004
Abstract—Verbalactone, a new macrocyclic dilactone was synthesized efficiently in a steroselective manner involving a Barbier–
Grignard reaction, a Sharpless asymmetric dihydroxylation, monotosylation, epoxidation, ring opening of the epoxide, hydrolysis
and lactonization. A d-lactone, (+)-(3R,5R)-3-hydroxy-5-decanolide was also formed along with the dimeric lactone.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Verbalactone1 1 is a macrocyclic dilactone isolated from
the roots of Verbascum undulatum Lam., a biennial plant
of the genus Verbascum that belongs to the family
Scrophulariaceae. This molecule showed activityagainst
three Gram-positive bacteria with optimum activity
MIC ¼ 62.5 lg/mL and five Gram-negative bacteria with
optimum activityMIC ¼ 125 lg/mL1;2 and was found to
exhibit interesting antibacterial properties. This macro-
cyclic lactone is a symmetrical dimer of the lactone 2
(a d-lactone), (+)-(3R,5R)-3-hydroxy-5-decanolide3 and
which is a potent inhibitor of the enzyme HMG-CoA
reductase. The NMR profile of 1 is verysimilar to the
monomeric lactone of (3R,5R)-dihydroxydecanoic acid.
The structure and the absolute stereochemistryof this
lactone, 4R,6R,10R,12R,4,10-dihydroxy-2,8-dioxo-6,12-
dipentyl-1,7-dioxacyclododecane, were determined by
spectroscopic methods and chemical correlation. It
is the first example of a 1,7-dioxacyclododecane unit
being present in the ring system of a natural product
(Scheme 1).
Due to its interesting antibacterial activityand our
4
interest in the chemistryof macrolide antibiotics, we
were attracted towards its total synthesis. Herein we
wish to report the first asymmetric total synthesis of this
lactone.
The retrosynthesis envisaged for the synthesis of verb-
alactone is shown in Scheme 2. The dimeric lactone can
be disconnected as shown in the Scheme. The resulting
3,5-dihydroxy acid 3 could be synthesized from the
cyanide 4, which in turn can be obtained from a pre-
cursor such as 5 through a regioselective ring opening
À
strategywith CN as the nucleophile.5 The epoxide 5
15
13
OH
R
17
11
8
O
OH
R
3
R
O
6
1 O
4
1
R
2
O
O
O
22
3
18
HO
Verbalactone 1
2
Scheme 1.
Keywords: Macrocyclic dilactone; Verbalactone; Barbier–Grignard reaction; Sharpless asymmetric dihydroxylation; Tosylation; HMG-CoA re-
ductase; Kinetic resolution; Lactonization.
* Corresponding author. Tel.: +91-376-2370121; fax: +91-376-2370011; e-mail: ncbarua2000@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.149

5578
S. Gogoi et al. / Tetrahedron Letters 45 (2004) 5577–5579
15
13
1
17
OH
11
8
O
O
CN
O
6
O
4
OH
OH OH OH
OH
2
O
22
3
18
4
HO
3
Regiocontrolled opening
ADH
H
O
O
OAc
OH
Lipase catalysed
transesterification
5
Scheme 2.
with the desired stereochemistrycan be generated via a
three-step protocol involving asymmetric dihydroxyl-
ation,6 monotosylation7 of the primaryalcohol and
subsequent epoxide8 formation under the influence of
a suitable base. We envisioned that the desired ‘R’ ste-
8 in a diastereoisomeric ratio of 85:1512 (from 1H
NMR). The required isomer R-(+)-8 was separated from
the diastereoisomeric mixture bypreparative TLC in
88% yield and with 95% ee (determined by NMR spec-
troscopyusing the chiral shift reagent Eu(hfc) )13 and
3
reochemistryof the free alcohol group could be gener-
9
was monotosylated using TsCl and pyridine in CH2Cl2
at room temperature whereby hydroxy tosylate R-(+)-9
was obtained in 75% yield. Tosylate R-(+)-9 was con-
verted into the epoxide R-(+)-5 in 72% yield by treat-
ment with 2 M NaOH in a 1:1 water–ether mixture at rt.
Treatment of R-(+)-5 with NaCN and MgSO4 in re-
fluxing drymethanol gave cyanoalcohol R-(+)-4 in 74%
yield. It was observed that during this step the acetate
group in R-(+)-4 was hydrolyzed under the reaction
conditions. Completion of the synthesis required
hydrolysis14 of the cyanoalcohol R-(+)-4, which was
carried out using a 25% methanolic solution of NaOH
followed byacidic work-up (pH 5) with hdyrochloric
acid to give 3 in 77% yield. The pH during hydrolysis
had to be carefullycontrolled as formation of the
monomeric lactone 2 (62% yield, 94% ee) was observed
at pH 2, as confirmed byIR, NMR and mass spectro-
ated bylipase-catazlyed transesterification
of the
corresponding homoallylic precursor formed by a Bar-
bier–Grignard reaction.10 The synthetic approach to
verbalactone is outlined in Scheme 3.
Treatment of the allyl zinc reagent prepared in situ from
allyl bromide and zinc in THF and aq NH4Cl with
hexanal afforded the homoallylic alcohol ( )-6 in 90%
yield. The homoallylic acetate R-(+)-7 possessing the
same absolute configuration at C-12 as found in verb-
alactone 1 was prepared bytransesterification of ( )- 6
with Amano lipase from Pseudomonas fluorescens, giv-
ing R-(+)-7 in 47% yield and with an enantiomeric ex-
cess11(ee) of 94% as determined bychiral HPLC analyses
of the 3,5-dinitrobenzoate derivative. Next asymmetric
dihydroxylation of R-(+)-7 was effected using the ligand
(DHQD)2PHAL to give a diastereoisomeric mixture of
3
scopydata, which were identical with those reported.
ii
i
CHO
90%
47%
OH
OR
(+)-6
R-(+)-7, R=Ac
iii
88%
vi
viii
vii
OR
R-(+)-5
R-(+)-4
1
(58%) + 2 (30%)
R-(+)-3
77%
74%
OH
OAc
R-(+)-8,R=H
v
72%
iv
75%
R-(+)-9,R=Ts
Scheme 3. Reagents and conditions: (i) allyl bromide, Zn, THF, aq NH4Cl, rt, 1 h (90%); (ii) Amano Lipase from Pseudomonas fluorescens, hexane,
rt, 26 h (47%); (iii) K3Fe(CN)6, K2CO3, (DHQD)2PHAL, OsO4, t-BuOH–water (1:1), 0 ꢁC, 24 h (88%); (iv) TsCl/Py, CH2Cl2, rt, 27 h (75%);
(v) NaOH (2 M soln in water), Et2O, 15 h, rt. (72%); (vi) MgSO4Æ7H2O, NaCN, dryMeOH, reflux, 6 h (74%); (vii) aqueous NaOH (25%), MeOH,
reflux, 1 M aq HCl (pH 5) (77%); (viii) (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, 1.5 h; (b) DMAP (20 equiv), toluene, reflux, 4 h (58%).

S. Gogoi et al. / Tetrahedron Letters 45 (2004) 5577–5579
5579
10. (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Rodri-
guez, R. A. J. Org. Chem. 2001, 66, 5208–5216; (b) Lu, W.;
Chan, T. H. J. Org. Chem. 2000, 65, 8589–8594; (c)
Wilson, S. R.; Guazzaroni, M. E. J. Org. Chem. 1989, 54,
3087–3091.
11. The enantiomeric excess (ee) of R-(+)-7 was determined by
chiral HPLC analyses using a Daicel CHIRALCEL OD
column (250 mm · 4.6 mm, eluent: hexane–iPrOH) after
conversion to the corresponding 3,5-dinitrobenzoate.
Conversion of R-(+)-7 to the corresponding 3,5-dini-
trobenzoate was carried out bysaponification followed by
esterification.
In the next and final step, lactonization of 2 moles of 3
to give the dimeric lactone 1 was successfullyachieved
byYamaguchi’s method in 58% yield and with >95%
ee, the spectroscopic data16 of which were identical with
those of the natural product. In this step, a small
amount of the monomeric lactone 2 (30%) was formed.
No lactone formation took place at 3-OH perhaps due
to ring strain effects or steric effects.
15
In conclusion, we have completed the first total synthesis
of the macrocyclic dimeric lactone, verbalactone in a
regioselective manner in 5.2% overall yield from hex-
anal. The desired stereochemistrywas generated by
kinetic resolution of a homoallylic alcohol and a
Sharpless asymmetric dihydroxylation reaction.
12. During the Sharpless asymmetric dihydroxylation step,
diastereoisomers were formed.
+
R-(+)-7
OR
OR
OH
OAc
R-(+)-8
OH
OAc
R-(+)-10
Acknowledgements
Diastereoisomers
The diastereoisomeric ratio was determined as 85:15 by 1H
NMR (500 MHz) spectroscopic analyses of the crude
product mixture.
The authors gratefullyacknowledge the Director, Re-
gional Research Laboratory(CSIR), Jorhat, Assam,
India for providing facilities for this work. S.G. thanks
the CSIR, New Delhi for the award of a Junior Re-
search Fellowship.
13. The ee’s of R-(+)-8, 2 and 1 were determined by 1H NMR
spectroscopyin the presence of the chiral shift reagent
Eu(hfc)3.
14. (a) Aristoff, P. A.; Johnson, P. D.; Harrison, A. W. J. Am.
Chem. Soc. 1985, 107, 7967–7974; (b) Fernandes, R. A.;
Kumer, P. Tetrahedron: Asymmetry 1999, 10, 4349–
4356.
References and notes
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mann, P. Tetrahedron 1991, 47, 3335–3346.
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Barua, N. C. Ind. J. Chem. 1998, 37B, 325–328; (b) Kalita,
D.; Khan, A. T.; Saikia, A. K.; Barua, N. C. Synthesis
1998, 975–976; (c) Kalita, D.; Khan, A. T.; Barua, N. C.;
Bez, G. Tetrahedron 1999, 55, 5177–5184.
5. (a) Smith, J. G. Synthesis 1984, 629–656; (b) Kamal, A.;
Khanna, G. B. R.; Ramu, R. Tetrahedron: Asymmetry
2002, 13, 2039–2051; (c) Kalita, B.; Barua, N. C.;
Bezbarua, M.; Bez, G. Synlett 2001, 1411–1414; (d)
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1990, 31, 6209–6212; (e) Sassaman, M. B.; Prakash, G. K.
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Chem. 1992, 57, 2768–2771; (b) Pandey, R. K.; Fernandes,
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1990, 55, 1957–1959; (b) Fleming, P. R.; Sharpless, K. B.
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Katsuki, T. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993; (b)
Mulzer, J.; Mareski, P. A.; Buschmann, J.; Luger, P.
Synthesis 1992, 215–228.
25
D
16. Spectroscopic data: data for compound 1: ½aŠ +6.2 (c 0.9,
25
D
CHCl3) [lit.1 ½aŠ þ7:3 (c 0.9, CHCl3)]; 1H NMR dH
(500 MHz, CDCl3): 4.90–4.95 (2H, ddd, J ¼ 9:9, 4.7,
4.5 Hz, H-6, 12), 4.05–4.08 (2H, ddd, J ¼ 4:5, 3.8, 3.2 Hz,
H-4, 10), 3.51–3.65 (2H, br, 3-OH, 10-OH), 2.41–2.86 (4H,
d, J ¼ 3:5 Hz, H-3, 9), 2.03–2.10 (2H, ddd, J ¼ 14:5, 9.5,
3.1 Hz, H-5b, 11b), 1.96 (2H, td, J ¼ 15, 4.5 Hz, H-5a,
11a), 1.49–1.57 (4H, m, H-13, 18), 1.22–1.29 (12H, m, H-
14, 15, 16, 19, 20, 21), 0.85–0.87 (6H, t, J ¼ 7:5 Hz, H-17,
22); 13C NMR dC (125 MHz, CDCl3): 172.9 (C-2, 8), 72.5
(C-6, 12), 64.5 (C-4, 10), 39.4 (C-3, 9), 36.9 (C-5, 11), 31.5
(C-13, 18), 31.3 (C-15, 20), 24.4 (C-14, 19), 22.4 (C-16, 21),
13.9 (C-17, 22); IR mmax: 3520, 1712, 1269, 1172 cmÀ1
;
25
D
1
MS(ESI): m=z 395.2 ([M +Na]þ). Data for 2: ½aŠ +18 (c
20
D
0.9, CHCl3) [lit.3 ½aŠ þ36:9 (c 0.92, CH2Cl2)]; H NMR
dH (500 MHz, CDCl3): 4.62–4.68 (1H, dddd, J ¼ 10:5, 7.5,
4.8, 4.2 Hz, 5-Hax), 4.30–4.38 (1H, dddd J ¼ 5, 4.1, 3.9,
3.6 Hz, 3-Heq), 2.69–2.73 (1H, dd, J ¼ 17, 5.5 Hz, 2-Hax),
2.57–2.62 (1H, ddd, J ¼ 17, 4.2, 3 Hz, 2-Heq), 2.07–2.12
(1H, br, 3-OHax), 1.94–1.96 (1H, dddd, J ¼ 13:5, 4.5, 3.5,
2.2 Hz, 4-Heq), 1.73–1.74 (1H, ddd, J ¼ 13:5, 10.3, 4.2 Hz,
4-Hax), 1.56–1.76 (2H, m, H-6), 1.34–1.55 (2H, m, H-7),
1.31–1.34 (2H, m, H-8), 1.29–1.30 (2H, m, H-9), 0.86–0.89
(3H, t, J ¼ 7:2 Hz, H-10); 13C NMR dC (125 MHz,
CDCl3): 170.4 (C-1), 76.1 (C-5), 62.7 (C-3), 38.7 (C-2),
36 (C-4), 35.5 (C-6), 31.6 (C-8), 24.4 (C-7), 22.6 (C-9), 13.9
(C-10); IR mmax: 3200–3600 (OH), 1739 (lactone).
8. Cho, B. T.; Yang, W. K.; Choi, O. K. J. Chem. Soc.,
Perkin Trans. 1 2001, 1204–1211.
9. (a) Sing, S.; Kumar, S.; Chimni, S. S. Synlett 2002, 8,
1277–1280; (b) Mandai, T.; Oshitari, T.; Susowake, M.
Synlett 2002, 1665–1668.