A. Srikrishna et al. / Tetrahedron Letters 47 (2006) 1277–1281
1279
of aldehyde 13 with hydrazine hydrate, potassium
hydroxide and digol furnished arylcyclopenteneꢀ 6.
A hydroboration sequence was chosen for oxidation of
olefin 6. However, reaction of arylcyclopentene 6 with
freshly generated borane–THF, followed by oxidation
with hydrogen peroxide and sodium hydroxide fur-
nished predominantly neopentyl alcohol 14. On the
other hand, reaction of olefin 6 with borane–dimethyl
sulfide complex followed by oxidation gave a 3:1 mix-
ture of the regioisomers 14 and 15. Oxidation of alco-
hols 14 and 15 with pyridinium chlorochromate (PCC)
and silica gel furnished cyclopentanonesꢀ 16 and 17,
whose structures were established from their spectral
data. The preferred formation of the unwanted regio-
isomer in the hydroboration reaction is probably due
to complexation of the borane with the aromatic meth-
oxy group, cf. 18, and thereby delivering the borane to
the nearest carbon of the olefin in an intramolecular
manner.
In order to overcome the intramolecular delivery of
borane, the regioisomeric arylcyclopentene 19 was con-
sidered as an alternative precursor for lagopodin A 1a.
It was also readily identified that the two possible
regioisomeric cyclopentanones 17 and 20 that could
be generated from the arylcyclopentene would serve
as precursors for lagopodin A 1a and enokipodins A
and B 2a and 3a (Scheme 3). Accordingly, synthesis
of arylcyclopentene 19 was addressed via cyclopentene
carboxylate 21, which was prepared starting from aceto-
phenone 8 in six steps in 47% overall yield, employing
an Ireland ester Claisen rearrangement and RCM reac-
tion based sequence as described earlier.11 Thus, ace-
tophenone 8 was converted into ester 22 using iodine
and trimethyl orthoformate. Allylation of ester 22 with
LDA and allyl bromide furnished pentenoate 23, which
on hydrolysis with aqueous sodium hydroxide in meth-
anol followed by coupling of the resultant acid with
dimethylallyl alcohol employing DCC and 4-(N,N-di-
methylamino)pyridine (DMAP) generated ester 24. Gen-
eration of the TMS enol ether of ester 24 with LDA,
trimethylsilyl chloride and triethylamine in THF at
ꢀ70 ꢁC followed by refluxing the reaction mixture for
3 h resulted in the Ireland ester Claisen rearrange-
ment.12 Hydrolysis of the reaction mixture with dilute
hydrochloric acid followed by esterification with ethe-
real diazomethane furnished ester 25, which on RCM
reaction with 5 mol % of Grubbs’ first generation cata-
lyst [Cl2Ru(PCy3)2@CHPh] cleanly furnished cyclopen-
tene carboxylate 21. Reduction of the ester in 21 with
LAH followed by oxidation of the resultant alcohol
generated aldehyde 26, which on Wolff–Kishner reduc-
tion furnished arylcyclopenteneꢀ 19. Reaction of olefin
19 with freshly generated borane–THF followed by oxi-
dation with hydrogen peroxide and sodium hydroxide
furnished a 3:1 regioisomeric mixture of alcohols 15
and 27, which were separated by column chromatogra-
phy on silica gel.13 Oxidation of alcohols 15 and 27
with PCC and silica gel furnished cyclopentanones 17
and 20. Cyclopentanone 20 exhibited spectral data
identical to that of an authentic sample. Since, conver-
sion of cyclopentanone 20 to enokipodins A 3a and B
2a has already been described,7 the present synthesis of
20 constitutes a formal synthesis of enokipodins A and
B. Oxidation of cyclopentanone 17 with ceric ammo-
nium nitrate (CAN) furnished lagopodin A 1a, which
exhibited a 1H NMR spectrum identical to that
reported for the natural product.ꢀ On the other hand,
catalytic hydrogenation of arylcyclopentene 19 fur-
nished arylcyclopentane 28, the conversion of which
to cuparenediol 5 and cuparenequinone 4a is known.14
ꢀ Yields refer to isolated and chromatographically pure compounds.
All the compounds exhibited spectral data (IR, 1H and 13C NMR and
mass) consistent with their structures. Selected spectral data for 3,4,4-
trimethyl-3-(2,5-dimethoxy-4-methylphenyl)cyclopentene 6: IR
(neat): mmax/cmꢀ1 1502, 1211. 1H NMR (300 MHz, CDCl3+CCl4):
d 6.72 (1H, s), 6.61 (1H, s), 5.83 (1H, br d, J 6.0 Hz), 5.63 (1H, dt, J
6.0 and 2.5 Hz), 3.75 (3H, s), 3.74 (3H, s), 2.33 (1H, dt, J 15.9 and
2.5 Hz), 2.17 (3H, s), 2.13 (1H, ddd, J 15.9, 2.5 and 1.5 Hz), 1.37 (3H,
s), 1.24 (3H, s), 0.57 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): d
152.5 (C), 151.1 (C), 141.4 (CH), 132.1 (C), 126.0 (CH), 124.6 (C),
114.8 (CH), 112.1 (CH), 57.3 (C), 55.9 (CH3), 55.5 (CH3), 49.0 (CH2),
44.2 (C), 28.8 (CH3), 25.3 (CH3), 22.7 (CH3), 16.1 (CH3). Mass: m/z
260 (M+, 76%), 245 (16), 217 (15), 205 (25), 187 (100), 175 (13).
HRMS: m/z Calcd for C17H25O2 (M+1): 261.1854. Found: 261.1859.
2-(2,5-Dimethoxy-4-methylphenyl)-2,3,3-trimethylcyclopentanone
16: IR (neat): mmax/cmꢀ1 1738, 1506, 1209. 1H NMR (300 MHz,
CDCl3+CCl4): d 6.66 (1H, s), 6.61 (1H, s), 3.78 (3H, s), 3.60 (3H, s),
2.64 (1H, dt, J 18.0 and 9.0 Hz), 2.34 (1H, ddd, J 18.0, 7.8 and
4.5 Hz), 2.17 (3H, s), 1.90–1.65 (2H, m), 1.28 (3H, s), 1.04 (3H, s),
0.80 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): d 220.7 (C), 152.2
(C), 150.5 (C), 129.9 (C), 126.2 (C), 116.6 (CH), 111.4 (CH), 56.6 (C),
56.2 (CH3), 56.0 (CH3), 43.7 (C), 36.5 (CH2), 35.3 (CH2), 26.2 (CH3),
25.6 (CH3), 20.6 (CH3), 16.1 (CH3). HRMS: m/z Calcd for
C17H24O3Na (M+Na): 299.1623. Found: 299.1626. 3,3,4-Trimethyl-
4-(2,5-dimethoxy-4-methylphenyl)cyclopentene 19: IR (neat): mmax
/
cmꢀ1 1505, 1213. 1H NMR (300 MHz, CDCl3+CCl4): d 6.82 (1H, s),
6.63 (1H, s), 5.54–5.65 (1H, m), 5.36 (1H, dd, J 6.0 and 3.0 Hz), 3.77
(3H, s), 3.75 (3H, s), 3.29 (1H, br d, J 15.3 Hz), 2.27 (1H, dd, J 15.3
and 3.0 Hz), 2.18 (3H, s), 1.30 (3H, s), 1.29 (3H, s), 0.69 (3H, s). 13C
NMR (75 MHz, CDCl3+CCl4): d 152.2 (C), 151.3 (C), 142.7 (CH),
133.9 (C), 124.6 (C), 124.5 (CH), 114.6 (CH), 112.7 (CH), 56.1 (CH3),
55.2 (CH3), 52.6 (C), 49.6 (C), 46.5 (CH2), 25.4 (CH3), 25.1 (CH3),
23.7 (CH3), 16.0 (CH3). HRMS: m/z Calcd for C17H25O2 (M+1):
261.1854. Found: 261.1856. 4-(2,5-Dimethoxy-4-methylphenyl)-4,3,3-
trimethylcyclopentanone 17: IR (neat): mmax/cmꢀ1 1741, 1655, 1507,
1213. 1H NMR (300 MHz, CDCl3+CCl4): d 6.71 (1H, s), 6.66 (1H, s),
3.77 (3H, s), 3.67 (3H, s), 3.20 (1H, d, J 18.3 Hz), 2.34 (1H, d, J
18.3 Hz), 2.33 (1H, d, J 18.3 Hz), 2.18 (3H, s), 2.10 (1H, d, J 18.3 Hz),
1.50 (3H, s), 1.18 (3H, s), 0.82 (3H, s). 13C NMR (75 MHz,
CDCl3 + CCl4): d 217.4 (C), 151.7 (C), 151.4 (C), 131.2 (C), 126.0 (C),
115.7 (CH), 112.6 (CH), 56.0 (CH3), 55.5 (CH3), 53.3 (CH2), 52.4
(CH2), 48.4 (C), 43.0 (C), 26.1 (2C, CH3), 25.2 (CH3), 16.0 (CH3).
HRMS: m/z Calcd for C17H24O3Na (M+Na): 299.1623. Found:
299.1632. Lagopodin A 1a: IR (neat): mmax/cmꢀ1: 1744, 1654; 1H
NMR (300 MHz, CDCl3+CCl4): d 6.66 (1H, s), 6.56 (1H, q, J
1.5 Hz), 3.13 and 2.25 (2H, 2 · d, J 18.0 Hz), 2.33 and 2.25 (2H, 2 · d,
J 18.6 Hz), 2.04 (3H, d, J 1.5 Hz), 1.39 (3H, s), 1.22 (3H, s), 0.93 (3H,
s). 13C NMR (75 MHz, CDCl3+CCl4): d 215.6 (C), 188.1 (C), 188.0
(C), 151.6 (C), 144.4 (C), 135.4 (CH), 134.9 (CH), 52.6 (CH2), 50.8
(CH2), 48.4 (C), 42.0 (C), 27.0 (CH3), 25.2 (CH3), 23.8 (CH3), 14.8
(CH3). HRMS: m/z Calcd for C15H19O3 (M+1): 247.1334. Found:
247.1340.
In summary, we have accomplished the first total syn-
thesis of ( )-lagopodin A 1 and the formal total synthe-
ses of the antifungal sesquiterpenes ( )-enokipodins A
and B, starting from 2,5-dimethoxy-4-methylacetophe-
none in 12 steps, in a combined overall yield of ꢁ26%.