A stereoselective synthesis of verbalactone-determination of absolute stereochemistry

Article abstract of DOI:10.1016/j.tetlet.2004.08.052

A total synthesis of verbalactone has been achieved starting from l-malic acid. A total synthesis of verbalactone has been achieved starting from l-malic acid. The two appropriately protected acid and alcohol segments were prepared from l-malic acid and l

Full text of DOI:10.1016/j.tetlet.2004.08.052

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7483–7485
A stereoselective synthesis of verbalactone—determination
of absolute stereochemistryI
G. V. M. Sharma* and Ch. Govardhan Reddy
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 May 2004; revised 22 July 2004; accepted 6 August 2004
Available online 27 August 2004
Abstract—A total synthesis of verbalactone has been achieved starting from L-malic acid. The two appropriately protected acid and
alcohol segments were prepared from L-malic acid and lactonized under Yamaguchi conditions.
Ó 2004 Elsevier Ltd. All rights reserved.
Verbalactone (1), a novel macrocyclic dimer lactone,
was isolated from the roots of Verbascum undulatum
and exhibited interesting antibacterial activity.1 It was
the first example where a 1,7-dioxacyclododecane moi-
ety was reported as the ring system of a natural product.
The structure and the absolute stereochemistry of 1 as
4R,6R,10R,12R was determined by spectral methods
(1D and 2D NMR, MS) and chemical correlation. Verba-
lactone (1) is thus a dimeric lactone with C2-symmetry
and has a NMR profile similar to the monomer lactone
of (3R,5R)-dihydroxydecanoic acid.2 In continuation of
our interest on the synthesis of natural lactones,3 we
herein report a stereoselective synthesis of verbalactone
(1).
The retrosynthetic plan for 1 (Scheme 1) indicated that
the seco acid 2 could be a late stage intermediate. Acid
2, in turn, could be prepared by coupling 3 and 4 via
an esterification, while 3 and 4 could be prepared from
L-malic acid. Thus, the basic strategy for the synthesis
of the key fragment 3 was to utilize the lone stereocenter
in malic acid as C-5 and to introduce the C-3 hydroxyl
of the target molecule by an asymmetric Sharpless
epoxidation.
COOH
O
BnO
H
H
H
HO
H
O
HO
H
H
O
O
H
OBn
H
OH
O
O
1
2
OH
OBn
OBn O
PMBO
+
COOH
HOOC
SO2Tol
O
3
4
OH
COOH
L-malic acid
Scheme 1. Retrosynthetic analysis of verbalactone 1.
Keywords: Verbalactone; Sharpless epoxidation; Macrolactonization; Absolute stereochemistry.
q IICT Communication No: 040512.
*
Corresponding author. Fax: +91 40 27160387; e-mail: esmvee@iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.052

7484
G. V. M. Sharma, Ch. Govardhan Reddy / Tetrahedron Letters 45 (2004) 7483–7485
Accordingly, the known alcohol 54 (Scheme 2), derived
from L-malic acid, was silylated (TBDPSCl, imidazole,
CH2Cl2) to give 6 (89%), which on hydrolysis (60% aq
AcOH) gave the diol 7 (82%). Selective tosylation of 7
with p-TsCl and Et3N in CH2Cl2 furnished 8 (78%),
which was reacted with 2equiv of K2CO3 in MeOH to
give the epoxide 9 (76%). Selective opening of 9 with
CuI and n-BuLi5 furnished 10 in 78% yield (Scheme
2), which on protection with PMBBr gave 11 in 85%
yield. Desilylation of 11 with TBAF gave alcohol 12
(81%), which on oxidation under Swern conditions
and homologation of 13 with (methoxycarbonylmethyl-
ene)triphenyl phosphorane in benzene at reflux afforded
ester 14 in 85% yield. Reduction of 14 using DIBAL-H
furnished the alcohol 15 (79%), which on Sharpless
asymmetric epoxidation6 with cumene hydroperoxide,
(ꢀ)-DIPT and Ti(Oi-Pr)4 exclusively gave the epoxide
16 in 83% yield. Regioselective reductive opening of 16
with NaAlH2(OCH2CH2OMe)2 gave the 1,3-diol 17
7
in 80% yield. Silylation (TBDMSCl, imidazole, CH2Cl2)
of 17 and subsequent benzylation of the secondary alco-
hol in 18 using NaH and BnBr gave 19 (78%). Deprotec-
tion of the TBDMS ether in 19 with TBAF and
subsequent oxidation of 20 under Swern conditions fur-
nished the corresponding aldehyde 21 (94%), which on
8
further oxidation using NaClO2 and 30% H2O2 in
t-BuOH/H2O (2:1) gave 3 in 83% yield.
Having completed a synthesis of the key fragment 3, it
was subjected to esterification with p-toluenesulfonyl-
ethanol via the mixed anhydride prepared on reaction
of 3 with 2,4,6-trichlorobenzoyl chloride (Et3N, THF)
in the presence of DMAP to afford ester 22 (68%). Since
the cleavage of p-toluenesulfonylethyl groups with
DBN3,9 is very facile and highly selective and does not
effect other ester groups, it was thus chosen for the
OH
O
O
d
b
R'O
a
O
OR
O
OTPS
OH
7 R = TPS; R' = H (82%)
8 R = TPS; R' = Ts (78%)
c
6 (89%)
OR
5
O
e
OPMB
g
i
R
OTPS
OTPS
9 (76%)
10 R = H (78%)
f
12 R = CH2OH (81%)
13 R = CHO (88%)
h
11 R = PMB (85%)
PMBO
OPMB
H
O
H
k
R
l
OH
14 R = COOMe (85%)
15 R = CH2OH (79%)
j
16 (83%)
PMBO
OR'
OBn
o
PMBO
g
R
OR
17 R = R' = H (80%)
18 R = TBS; R' = H (84%)
19 R = TBS; R' = Bn (78%)
20 R = CH2OH (89%)
21R = CHO (94%)
m
h
n
PMBO
OBn
OBn
PMBO
O
p
q
COOH
4 (73%)
SO2Tol
O
22 (68%)
3 (83%)
Scheme 2. Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, rt, 5h; (b) 60% aq AcOH, rt, 12h; (c) p-TsCl, Et3N, CH2Cl2, 0°C, 10h; (d)
K2CO3, MeOH, rt, 2h; (e) Cul, n-BuLi, dry ether, 0°C, 2h; (f) PMBBr, NaH, THF, 0°C—rt, 5h; (g) TBAF, CH2Cl2, rt, 10h; (h) (COCl)2 DMSO,
Et3N, CH2Cl2, ꢀ78°C, 3h; (i) Ph3P@CHCOOMe, benzene, reflux, 2h; (j) DIBAL-H, CH2Cl2, rt, 3h; (k) (ꢀ)-DIPT, Ti(Oi-Pr)4 cumene
˚
hydroperoxide, 4A—MS, CH2Cl2, ꢀ20°C, 3h; (1) NaAlH2 (OCH2CH2OMe)2, THF, 0°C, 5h; (m) TBDMSCl, imidazole, CH2Cl2 rt, 6h; (n) BnBr,
NaH, THF, 0°C—rt, 4h; (o) NaClO2, 30% H2O2, t-BuOH/H2O (2:1), 0°C—rt, 10h; (p) 2,4,6-trichlorobenzoyl chloride, Et3N, THF,
HOCH2CH2SO2Ar, DMAP, toluene, rt, 16h; (q) DDQ, CH2Cl2/H2O (19:1), 0°C—rt, 5h.
O
SO2To l
OBn
PMBO
O
a
H
H
BnO
H
c
O
OR
COOH
OBn
H
O
3
23 R = PMB (66%)
24 R = H (69%)
b
O
COOH
e
d
H
H
BnO
H
BnO
H
H
H
O
OBn
OH
OBn
O
1 (76%)
O
H
H
O
O
2 (68%)
25 (61%)
Scheme 3. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 4, DMAP, toluene, rt, 20h; (b) DDQ, CH2Cl2/H2O (19:1), rt,
3h; (c) DBN, benzene, rt, 12h; (d) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, 90°C, 24h; (e) TiCl4, CH2Cl2, 0°C, 1h.

G. V. M. Sharma, Ch. Govardhan Reddy / Tetrahedron Letters 45 (2004) 7483–7485
7485
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. Tetrahe-
dron Lett. 1982, 23, 4305–4308.
3. (a) Sharma, G. V. M.; Chandramouli, Ch. Tetrahedron
Lett. 2002, 43, 9159–9161; (b) Sharma, G. V. M.;
Chandramouli, Ch. Tetrahedron Lett. 2003, 44, 8161–
8163.
4. Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can. J.
Chem. 1984, 62, 2146.
5. Diter Acker, R. Tetrahedron Lett. 1978, 19, 2399–
2402.
6. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5976.
7. (a) Minami, N.; Ko, S.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 1109; (b) Ma, P.; Martin, V. S.; Masamune, S.;
Sharpless, K. B.; Viti, S. M. J. Org. Chem. 1982, 47,
1378.
protection of acid 3, in the present synthesis. Oxidative
deprotection of the PMB group in 22 using DDQ in
aq CH2Cl2 gave the hydroxy ester 4 in 73% yield, ready
for coupling with segment 3.
Esterification of acid 3 with alcohol 4 under Yamaguchi
conditions gave 23 (66%), which on PMB deprotection
furnished 24 in 69% yield (Scheme 3). Selective cleavage
of the p-toluenesulfonylethyl group in 24 was effected
with DBN in C6H6 to give seco acid 2 (68%), which on
lactonization under Yamaguchi conditions10 (2,4,6-trich-
lorobenzoyl chloride, Et3N, THF, DMAP, toluene) af-
forded 25 in 61% yield. Finally, deprotection of the
benzyl groups in 24 was effected with TiCl4 (1equiv) in
CH2Cl2 at 0°C to give synthetic 1 as a colorless oil in
25
D
1
76% yield, ½aꢁ þ 8:2 (c 0.3, CHCl3). The H and 13C
NMR data and optical rotation value of synthetic 111
were in good accordance with those of the natural
product.1
8. Dalcanala, E.; Montanari, F. J. Org. Chem. 1986, 51, 567–
569.
9. Colvin, E. W.; Purcell, T. A.; Raphael, R. A. J. Chem.
Soc., Perkin Trans. 1 1976, 1718.
In conclusion, a synthesis of verbalactone (1) by a com-
bination of chiral pool and asymmetric approaches has
been achieved.
10. Inanga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
25
11. Spectral data of verbalactone (1): Colorless oil, ½aꢁD +8.2
25
(c 0.3, CHCl3); lit.1 ½aꢁD þ 7:3 (c 0.9, CHCl3); IR (neat):
3518, 1710, 1265, 1170cmꢀ1. 1H NMR (CDCl3, 400MHz):
d 0.85 (t, 6H, J = 7.0Hz, H-17, 22), 1.22–1.31 (m, 12H, H-
14, 15, 16,19, 20, 21), 1.49–1.55 (m, 4H, H-13, 18), 1.96
(td, 2H, J = 15.2, 4.2Hz, H-5a, 11a), 2.05 (ddd, 2H,
J = 15.2, 10.2, 3.1Hz, H-5b, 11b), 2.68 (d, 4H, J = 3.6Hz,
H-3, 9), 3.73 (br s, 2H, 3-OH, 10-OH), 4.06 (ddd, 2H,
J = 4.2, 3.6, 3.1Hz, H-4, 10), 4.94 (ddd, 2H, J = 10.2, 4.7,
4.6Hz, H-6, 12); 13C NMR (CDCl3, 300MHz): d 13.91,
22.45, 25.52, 31.42, 31.78, 38.24, 39.29, 64.97, 72.57,
172.91; FAB MS (m/z, %): 373 (M++1, 32), 187 (94), 151
(26), 127 (100), 93 (34), 55 (44).
Acknowledgements
Ch.G.R. is thankful to UGC, New Delhi for financial
assistance.
References and notes
1. (a) Magiatis, P.; Spanakis, D.; Mitaku, S.; Tsitsa, E.;
Mentis, A.; Harvala, C. J. Nat. Prod. 2001, 64, 1093–1094.