Hemisynthesis of oxetane-containing neoclerodane diterpenoids

Article abstract of DOI:10.1016/S0040-4020(00)00719-5

The hemisynthesis of the 4α,19-oxetane-containing neoclerodane diterpenoids 25 and 27, has been achieved from 19-acetylgnaphalin (4). Oxetane ring formation has been accomplished by intramolecular oxirane ring opening on the 4β,18-epoxy-neoclerodane 23, which yields derivative 25, and by electrophilic cyclization of the Δ⁴(¹⁸) homoallylic alcohol 26, which proceeds exclusively via the 4-exo mode, for obtaining the 18-iodo-4α,19-oxetane 27. The twisted boat conformation of ring A in derivative 27 favours an intramolecular unsaturated intermediate 21, access to Δ³-neoclerodane diterpenoids like 30 has been gained. The electrophilic cyclization of the Δ³ isomer 31 goes through a 5-endo mode exclusively, to form the 3α,19-epoxy-neoclerodane 33. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00719-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8007±8017
Hemisynthesis of Oxetane-Containing Neoclerodane Diterpenoids
*
Marõa C. de la Torre, Antonella Maggio and Benjamõn Rodrõguez
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Instituto de Quimica Organica, Consejo Superior de Investigaciones Cienti®cas (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
Dedicated to the memory of our colleague and friend Dr Peter Y. Malakov
Received 24 May 2000; revised 28 July 2000; accepted 10 August 2000
AbstractÐThe hemisynthesis of the 4a,19-oxetane-containing neoclerodane diterpenoids 25 and 27, has been achieved from 19-acetylg-
naphalin (4). Oxetane ring formation has been accomplished by intramolecular oxirane ring opening on the 4b,18-epoxy-neoclerodane 23,
which yields derivative 25, and by electrophilic cyclization of the D4(18) homoallylic alcohol 26, which proceeds exclusively via the 4-exo
mode, for obtaining the 18-iodo-4a,19-oxetane 27. The twisted boat conformation of ring A in derivative 27 favours an intramolecular
nucleophilic substitution reaction yielding compound 28, which possesses a very interesting tetracyclic moiety in its structure. From the D4(18)
unsaturated intermediate 21, access to D3-neoclerodane diterpenoids like 30 has been gained. The electrophilic cyclization of the D3 isomer
31 goes through a 5-endo mode exclusively, to form the 3a,19-epoxy-neoclerodane 33. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
This has precluded the study of their biological activities
and their chemical reactivity. Owing to the lack of ef®cient
routes for the preparation of this class of neoclerodanes, we
undertook the semisynthesis of 4a,19-oxetane containing
neoclerodanes, like teucroxide (1). 19-Acetylgnaphalin
a diterpenoid that can be isolated from
T. gnaphalodes in enough amount to be used in a multistep
synthesis and, seemed to be an appropriate starting material
Oxetanes are present in biologically important metabolites
like thromboxane A2,1 taxoids2 or the naturally occurring
antiviral nucleosides oxetanocins.3 Nevertheless, they are
scarcely found as part of the structure of natural products.
They have been identi®ed in the group of diterpenoids.4,5
The oxetane ring may feature at positions 4a,19,6±10
4b,6b,11,12 and 4b,10b.10 Teucroxide (1),7 chamaedroxide
(2)11 and teusandrin E (3)10 respectively, are representative
examples (Chart 1).
(4)23 is
The complex structures of neoclerodane diterpenoids have
made them attractive targets for total synthesis.13±16 More-
over, the dense array of functional groups present in these
compounds makes them interesting substrates to study the
chemistry of polyfunctionalized molecules. An additional
feature of neoclerodanes is that they behave as insect anti-
feedants17,18 and therefore may be employed as an alterna-
tive to the use of broad-spectrum chemical pesticides for
crop-protection.
We are currently involved in the study of the chemistry
of neoclerodane diterpenoids, focussing on the development
of semisynthetic routes for the ef®cient preparation of
neoclerodanes that are dif®cult to obtain from natural
sources.19±22 The oxetane-containing neoclerodanes
attracted our attention as they are minor terpenic con-
stituents of Teucrium plants isolated in minute amounts.
Keywords: hemisynthesis; diterpenoids; neoclerodanes; oxirane opening;
cyclofunctionalization; natural products.
* Corresponding author. Tel.: 134-91-562-29-00; fax: 134-91-564-48-
93; e-mail: iqot310@iqog.csic.es
Chart 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00719-5

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M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
Scheme 3. Key: (i) PhSeSePh, NaBH4; EtOH; room temperature 1.5 h.
epoxy alcohols,29 in a process that generally occurs with
complete anti stereoselectivity.30
Based on these premises, we designed the preparation of
4a,19-oxetane-containing neoclerodanes (5) (Scheme 2)
by intramolecular cyclization of the appropriate 4b,18-
epoxy-19-hydroxyneoclerodane 8, whose stereochemistry
at C-4 necessarily must be the opposite to that of the starting
material 19-acetylgnaphalin (4). Inversion of the con®gura-
tion at C-4 could be achieved by epoxidation of a D4(18)
exocyclic double bond14 on a substrate like 9 (Scheme 2),
which may, in turn, be obtained by deoxigenation of the
natural 4a,18-epoxide. Alternatively, we considered the
feasibility of getting the 4a,19-oxetane ring by cyclo-
functionalization of intermediate 10 (Scheme 2). As it is
known, the cyclofunctionalization of homoallylic alcohols
allows the preparation of the oxetane ring.31±38 It is inter-
esting to note, from a biogenetic point of view, that one
D4(18)-neoclerodane diterpenoid, related to intermediate 10,
has recently been isolated from T. polium.39 In this paper,
we report the successful implementation of the routes in
Scheme 2 to access 4a,19-oxetane-containing neoclero-
danes.
Scheme 1. Proposed biogenetic pathway for oxetane-containing neoclero-
danes.
for our study. Neoclerodanes like 4, having a 4a,18-spiro-
epoxide, are the most widespread and abundant in Teucrium
plants, and they have been proposed by us as the biogenetic
precursors24 of the less common diterpenoids, including the
4a,19-oxetane-containing neoclerodanes.
According to our biogenetic hypothesis9 (Scheme 1), the
4a,19-oxetane grouping (5) should arise from the 4a,18-
epoxide (6) by oxirane ring opening, leading to a carboca-
tion at C-4 (7) that may be trapped by the hydroxyl group at
C-19. A related process, namely the intramolecular opening
of epoxides, is involved in the biosynthesis of polyether
antibiotics that contain tetrahydrofuran, tetrahydropyran or
spiroketal rings.25 Furthermore, outside of the biological
system, intramolecular cyclization of epoxy alcohols is
one of the most important approaches to the synthesis of
cyclic ethers.26±28 Oxetanes may be obtained from 3,4-
Results and Discussion
Our synthesis began with the preparation of a derivative
having a D4(18) exocyclic double bond similar to 9 (Scheme
2), susceptible to epoxidation and electrophilic cyclization.
The 19-acetoxy-4a,18-epoxy-6-oxo-grouping in the neo-
clerodane framework is very reactive toward basic con-
ditions, yielding the corresponding 19-norderivatives.22,23
Thus, 19-acetylgnaphalin (4) was treated with NaBH4,
reducing the C-6 ketone grouping to an a-equatorial alcohol
and providing teujaponin B40 (11) in 91% yield.
With the purpose of getting the D4(18) double bond, teujapo-
nin B (11) was converted into the b-hydroxyselenide 12
(Scheme 3), by reaction with NaSePh.41 Epoxide ring open-
ing yielded 12 as the major reaction product (56%), together
with a small amount of the regioisomeric g-lactone 13 (6%).
The reaction conditions for the in situ generation of NaSePh,
from diphenyl diselenide and NaBH4, had to be carefully
tuned to avoid the translactonization from the C-12 to the
C-19 position. This isomerization was observed when a
slight excess of NaBH4 was employed. Accordingly,
NaBH4 had to be used in de®cit with respect to diphenyl
diselenide.
Scheme 2. Retrosynthesis of 4a,19-epoxy-neoclerodanes from 4.

M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
8009
Scheme 4. Key: (i) p-TsOH; toluene; 40 min. (ii) p-TsOH; toluene; room temperature; 24 h.
b-Hydroxyselenide 12 was treated with p-TsOH in order to
produce the D4(18) alkene 14 (Scheme 4) through trans
elimination of seleninic acid.42,43 A mixture of ole®ns 14
and 15 was obtained, after 24 h of reaction (26 and 21%
yields, respectively). Surprisingly, tetrahydrofuran deriva-
tive 16, which still retains the selenium moiety, was the
major reaction product (41% yield).44
was blocked. In fact acetate 20, obtained by treatment of 12
with acetic anhydride in pyridine, gave diacetylated ole®n
21 in almost quantitative yield by treatment with TsOH in
toluene (Scheme 5). Interestingly, acetylteujaponin B (22)48
failed to undergo successive epoxide opening when treated
with NaSePh.
As it is known that the b-alkylsubstituted furan ring in
neoclerodane diterpenoids is oxidized with m-CPBA,49
magnesium monoperoxyphthalate hexahydrate (MMPP)
was used to effect epoxidation of 21.50 Thus, treatment of
21 with 3 equiv. of MMPP in methanol for two days at room
temperature yielded 4b,18-epoxy neoclerodane 23 as the
major product (59% yield) together with acetylteujaponin
B 22 (30%, Scheme 6). Thus, inversion of the con®guration
Treatment of 12 with TsOH for shorter reaction times
(40 min) allowed the isolation of orthoester 17 in near
quantitative yield (Scheme 4). Orthoacetates related to 17
are known as natural45 and semisynthetic neoclero-
danes.24,46,47 Orthoester 17 was evidenced as a reaction
intermediate, since its further acid treatment under the
conditions above used to transform the b-hydroxyselenide
12 into 14, 15 and 16, leads to an identical reaction mixture.
Thus, formation of ole®ns 14 and 15, and tetrahydrofuran 16
may be rationalized as shown in Scheme 4. From ortho-
acetate 17, the ®rst product formed, two seleniranium
cations may be generated. Seleniranium cation 18, having
the acetate group at C-19, can evolve exclusively to ole®n
14. On the contrary, seleniranium cation 19, in which the
acetate group is located at the C-6a position, may lead to
ole®n 15 by seleninic acid elimination, or may be intra-
molecularly trapped by the hydroxyl group at C-19 yielding
the tetrahydrofuran derivative 16.
The above results show that the equatorial hydroxyl group at
the C-6 carbon is the responsible for the unexpected (and
unwelcome) result of the intended elimination reaction on
12. To increase ole®n production, the C-6a hydroxyl group
Scheme 5. Key: (i) Ac2O-pyridine; room temperature; 48 h. (ii) p-TsOH;
toluene; 508C; 1 h.

8010
M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
Table 1. Chemical shift of carbon C-2 compounds 22, 24, 25 and 27±29
Compound
22a
24
25
27
28
29
d C-2
24.9
19.5
16.0
18.0
16.9
16.6
a Taken from reference 24.
MeOH yielded lactone 24 (22% yield) and oxetane 25 (55%
yield) as the major reaction products.
Having successfully demonstrated the viability of the
epoxide ring opening approach for the preparation of the
4a,19-oxetane-containing neoclerodanes, we turned our
attention to the preparation of the oxetane moiety by elec-
trophilic cyclofunctionalization of a homoallylic alcohol
like 10 (Scheme 2), which in principle can be obtained
from intermediate 21. Thus, treatment of 21 with aqueous
NaOH in MeOH at 608C for 30 min yielded the desired
deacetyl derivative 26 as the sole reaction product (87%
yield). Translactonization from the C-12 to the more stable
C-19 position could be avoided by careful control of the
reaction time. The electrophilic cyclization of the homo-
allylic alcohol 26 with N-iodosuccinimide (NIS), in dry
MeCN at room temperature, consumed starting material in
a few minutes leading to the desired oxetane 27 in almost
quantitative yield (Scheme 7).
Scheme 6. Key: (i) MMPP; MeOH, room temperature, 48 h. (ii) aqNaOH
(2%), MeOH; 608C; 30 min.
From a structural point of view, it is interesting to note that
carbon C-2 undergoes a strong up®eld shift on changing
from a 4a,18- to a 4a,19-epoxy-neoclerodane (see Table
1). This shielding is compatible with a twisted boat confor-
mation for ring A in the decalin moiety, forced by the 4a,19-
oxetane ring. In this conformation the 4a-oxygen adopts
a pseudoaxial con®guration, and therefore it must be in a
g-gauche arrangement51 with respect to C-2, causing a
strong shielding on this carbon. The same effect is observed
in derivative 24, in which ring A should be a chair, placing
as well the 4b-hydroxyl group and carbon C-2 in a g-gauche
arrangement.
at C-4 had been successfully achieved in four steps from a
4a,18-epoxyneoclerodane in an overall yield of 25%.
Conditions for intramolecular epoxide ring opening were
next investigated. Treatment of 23 with aqueous NaOH in
As a consequence of the twisted boat conformation of ring
A, in 4a,19-epoxy-neoclerodane 27, the C-18b-iodomethyl-
ene grouping is pseudoequatorial and very easily undergoes
intramolecular nucleophilic substitution by attack of the
equatorial 6a hydroxyl group. Heating oxetane 27, at
608C in DMSO52,53 for 24 h leads to compound 28 in almost
quantitative yield (Scheme 7). Treatment of oxetane 27 with
acetic anhydride in pyridine at room temperature for 18 h
yielded the expected acetylated derivative 29 in 55% yield,
together with the substitution reaction product 28 in 27%
yield (Scheme 7). The isolation of derivatives 28 and 29
provides additional proof of the structure assigned to
oxetane 27, and that the oxetane ring formation via a
4-exo-trig cyclization of the homoallylic alcohol 26.54 In
fact, this is the expected result when the regiochemistry of
the cyclization is determined by electronic factors.55±60 In
order to check this point in the neoclerodane framework, we
prepared the homoallylic alcohol 31 (Scheme 8). Isomeri-
zation of the D4(18) exocyclic double bond to the endo
position was easily achieved by treatment of 21 with
p-TsOH, yielding derivative 30. It is interesting to note
that D3-neoclerodane diterpenoids are also natural products
isolated from Teucrium plants.5 Basic hydrolysis of the
Scheme 7. Key: (i) aqNaOH (2%), MeOH, 608C. (ii) NIS, CH3CN; room
temperature; 15 min. (iii) DMSO, 608C, 24 h. (iv) Ac2O-pyridine; room
temperature; 18 h.

M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
8011
Scheme 8. Key: (i) p-TsOH, Toluene, re¯ux, 4 h. (ii) aqNaOH (2%), MeOH; 608C; 30 min. (iii) NIS, CH3CN; room temperature; 5 min.
acetate groups of 30 yielded a mixture of inseparable regio-
isomeric lactones 31 and 32 in a 1:4 ratio. Submission of this
mixture to the reaction conditions used for the homoallylic
alcohol 26 yielded derivative 33 together with unreacted 32.
Teucjaponin B (11) from 19-acetylgnaphalin (4). To a
solution 4 (1.0 g, 2.49 mmol), in CH2Cl2:EtOH (100 mL,
10:1 v/v), at 08C, NaBH4 (400 mg, 10.6 mmol) was added.
The reaction mixture was allowed to warm to room
temperature and stirred for 30 min. Water (100 mL) was
added to the reaction mixture and stirred for 1 h. The
organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (100 mL£2). The combined organic
layers were washed with brine (100 mL£1) and dried. After
removal of the solvents under vacuum, 900 mg (89% yield)
of teucjaponin B (11)18 were obtained.
In conclusion, we have developed two ef®cient semi-
synthetic routes for the preparation of 4a,19-oxetane-
containing neoclerodane diterpenoids from 19-acetyl-
gnaphalin (4): the intramolecular epoxide ring opening of
the 4b,18-epoxyneoclerodane 23, and the electrophilic
cyclization of the homoallylic alcohol 26. Additionally,
access to D3- and D4(18)-neoclerodane diterpenoids has
been gained.
(12S)-19-Acetoxy-15,16-epoxy-4a,6a-dihydroxy-18-phenyl-
selenyl-neocleroda-13(16),14-dien-20,12-olide (12) and
(12S)-15,16-epoxy-4a,6a,12-trihydroxy-18-phenylselenyl-
neocleroda-13(16),14-dien-20,19-olide
(13).
NaBH4
Experimental Procedures
General
(61 mg, 1.61 mmol) were added in portions to a diphenyl-
diselenide solution (265 mg, 0.85 mmol) in ethanol
(150 mL) at room temperature under argon. When the
hydrogen evolution ceased, teucjaponin B (11, 490 mg,
1.21 mmol) was added to the reaction mixture and stirred
for 1.5 h. The reaction was quenched with water (100 mL)
and extracted with CH2Cl2 (100 mL£3). The residue
obtained after removal of the solvents, was chromato-
graphed using n-hexane:AcOEt (1:1) as eluent yielding
compounds 12 (380 mg, 56%) and 13 (40 mg, 6%).
All reagents were used as obtained from commercial
sources. Methylene chloride (CH2Cl2) and toluene (C6H5±
CH3) were distilled under positive pressure of argon from
CaH2. Other solvents were HPLC grade and were used with-
out puri®cation. Na2SO4 was used to remove water from the
organic layer in reaction workups. Silica gel 60 F254 plates
were used for TLC. Flash column chromatography was
performed using silica gel (Merck, no. 9385, 230±400
mesh), and mixtures of AcOEt:n-hexane or Cl3CH:MeOH
as eluents.
Compound 12: [Found: C, 59.62; H, 6.40. C28H34OSe
requires C, 59.89; H, 6.10%]; mp 90±958C (white amor-
phous solid); [a]2D5ˆ115.4 (cˆ0.467, CHCl3); IR (KBr)
nmax 3430 br, 3140, 3130, 3070, 3060, 1760, 1735, 1600,
1580, 1505, 1250, 870, 735, 690 cm21; dH (300 MHz,
CDCl3) 7.58 (2H, m, Ph), 7.40 (2H, m, H-16 and H-15),
7.25 (3H, m, Ph), 6.34 (1H, dd, Jˆ1.8, 0.9 Hz, H-14),
5.31 (1H, dd, Jˆ9.3, 8.0 Hz, H-12), 5.17 and 5.00 (each
1H, d, Jˆ 12.8 Hz, 2H-19), 4.08 (1H, dd, Jˆ11.7, 3.7 Hz,
H-6b), 3.58 and 3.50 (each 1H, d, Jˆ11.8 Hz, 2H-18), 2.34
(1H, dd, Jˆ14.0 and 8.0 Hz HB-11), 2.33 (1H, dd, Jˆ14.0,
9.3 Hz, HA-11), 2.02 (3H, s, OAc), 1.04 (3H, d, Jˆ6.6 Hz,
Me-17); dC (125.7 MHz, CDCl3) 176.2 (s, C-20), 170.1 (s,
OCOCH3), 144.1 (d, C-15), 139.5 (d, C-16), 133.5 (d, C-20
and C-60); 130.3 (s, C-10), 129.1 (d, C-30 and C-50), 127.3 (d,
C-40), 125.0 (s, C-13), 107.9 (d, C-14), 78.0 (s, C-4), 74.5 (d,
C-6), 71.4 (d, C-12), 63.4 (t, C-19), 51.7 (s, C-9), 50.7 (d,
C-10), 48.1 (s, C-5), 44.3 (t, C-11), 38.6 (d, C-8), 37.2 (t,
C-18), 35.2 (t, C-7), 32.5 (t, C-3), 23.0 (t, C-1), 22.4 (t, C-2),
21.4 (q, OCOCH3), 16.2 (q, C-17); m/z (EI) 562 [M]1 (17),
560 [M]1 (9), 391 (23), 373 (100), 313 (75), 172 (63), 157
(59), 105 (44), 95 (93), 91 (67), 78 (93%).
19-Acetylgnaphalin (4) was isolated from T. gnaphalodes L.
collected at `El Cerro de las Cabezas' in Villamiel (Toledo,
Spain).
Melting points were determined on a Ko¯er block. Optical
rotations were measured on a Perkin±Elmer 241 MC polari-
meter. IR spectra were obtained on a Perkin±Elmer 681
spectrophotometer. MS were recorded in the positive EI
mode on a Hewlett±Packard HP 5989A instrument
(70 eV). Elemental analyses were made with a Carlo Erba
1
EA 1108 apparatus. H NMR spectra were recorded on a
Varian Unity-500, a Varian INOVA-400, a Varian INOVA-
300 or a Bruker 200, at 500, 400, 300 or 200 MHz, respec-
tively. 13C NMR were recorded at 125.7, 100, 75 or
1
50 MHz. Chemical shifts for H NMR are reported with
respect to residual CHCl3 (d 7.25), and with respect to
CDCl3 (d 77.00) for 13C NMR spectra. 13C NMR assign-
ments were determined by gHSQC and gHMBC spectra.

8012
M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
Compound 13: mp 80±958C (white amorphous solid);
[a]2D5ˆ248.1 (cˆ0.783, CHCl3); IR (KBr) nmax 3400 br,
Compound 15: [Found: C, 68.34; H, 7.35. C22H28O6
requires C, 68.02; H, 7.27%]; mp 83±888C (white amor-
phous solid); [a]2D4ˆ157.7 (cˆ0.156, CHCl3); IR (KBr)
nmax 3580, 3480, 3140, 3080, 1760, 1735, 1640, 1500,
1240, 920, 870 cm21; dH (300 MHz, CDCl3) 7.41 (2H, m,
H-16 and H-15), 6.35 (1H, dd, Jˆ1.7, 0.9 Hz, H-14), 5.32
(1H, t, Jˆ8.7 Hz, H-12), 5.22 (1H, dd, Jˆ11.8, 3.3 Hz,
H-6b), 4.86 (1H, br s, HB-18), 4.63 (1H, d, Jˆ12.9 Hz,
HB-19), 4.53 (1H, br s, HA-18), 3.84 (1H, dd, Jˆ12.9,
6.5 Hz, HA-19, collapsed into a d, Jˆ12.9 Hz, after D2O
addition), 2.06 (3H, s, OAc), 0.99 (3H, d, Jˆ6.7 Hz,
Me-17); m/z (EI) 388 [M]1 (36), 298 (100), 253 (38), 204
(35), 171 (49), 159 (49), 131 (23), 96 (87%).
3160, 3080, 3060, 1710, 1580, 1505, 870, 740, 690 cm21
;
dH (300 MHz, CDCl3) 7.57 (2H, m, Ph), 7.38 (2H, m, H-16
and H-15), 7.26 (3H, m, Ph), 6.40 (1H, t, Jˆ1.3 Hz, H-14),
4.80 (1H, dd, Jˆ11.0, 1.8 Hz, H-12), 4.76 and 4.69 (each
1H, d, Jˆ13.4 Hz, H-19), 4.15 (1H, dd, Jˆ11.3, 4.8 Hz,
H-6b), 3.88 (1H, br s, OH-6a), 3.62 (1H, d, Jˆ12.2 Hz,
HB-18), 3.57 (1H, s, OH-4a), 3.49 (1H, dd, Jˆ12.2,
1.6 Hz, HA-18), 2.37 (1H, dd, Jˆ16.2, 1.8 Hz, HB-11),
2.04 (1H, dd, Jˆ16.1, 11.0 Hz, HA-11), 1.54 (1H, ddd,
Jˆ12.7, 11.3, 11.3, H-7a), 0.90 (3H, d, Jˆ6.7 Hz, Me-
17); dC (75.4 MHz, CDCl3) 172.6 (s, C-20), 143.6 (d,
C-15), 138.4 (d, C-16), 133.4 (d, C-20 and C-60), 130.1 (s,
C-13), 130.0 (s, C-10), 129.3 (d, C-30 and C-50), 127.5 (d,
C-40), 108.3 (d, C-14), 77.5 (s, C-4), 73.0 (d, C-6), 68.7 (t,
C-19), 63.5 (d, C-12), 49.8 (s, C-9), 43.7 (s, C-5), 41.8 (d,
C-10), 37.9 (t, C-7), 37.2 (t, C-18), 36.3 (t, C-11), 34.5 (d,
C-8), 33.4 (t, C-3), 25.1 (t, C-1), 21.7 (t, C-2), 16.5 (q, C-17);
m/z (EI) 520 [M]1 (3), 518 [M]1 (2), 362 (18), 331 (23), 313
(28), 301 (34), 172 (100), 158 (29), 95 (44), 78 (55%).
Compound 16: [Found: C, 62.03; H, 5.70. C28H36O6Se
requires C, 61.88; H, 5.93%]; mp 85±908C (white amor-
phous solid); [a]2D5ˆ180.1 (cˆ0.261, CHCl3); IR (KBr)
nmax 3140, 3070, 1765, 1740, 1600, 1580, 1505, 1240,
875, 740, 690 cm21; dH (400 MHz, CDCl3) 7.52 (2H, dd,
Jˆ6.9, 1.9 Hz, H-20 and H-60), 7.43 (2H, m, H-16 and H-
15), 7.35 (1H, td, Jˆ7.2, 1.9 Hz, H-40), 7.26 (2H, br t, Jˆ
7.2, 6.9 Hz, H-30 and H-50), 6.37 (1H, dd, Jˆ1.8, 0.9 Hz,
H-14), 5.34 (1H, dd, Jˆ8.9, 8.5 Hz, H-12), 4.90 (1H, dd,
Jˆ11.3, 3.5 Hz, H-6b), 4.39 (1H, d, Jˆ10.5 Hz, HB-19),
4.30 (1H, d, Jˆ7.1 Hz, HB-18), 4.04 (1H, d, Jˆ10.5 Hz,
HA-19), 3.42 (1H, d, Jˆ7.1 Hz, HA-18), 2.49 (1H, dd,
Jˆ14.2, 8.5 Hz, HB-11), 2.33 (1H, dd, Jˆ14.2, 8.9 Hz,
HA-11), 2.02 (1H, dd, Jˆ12.5, 2.7 Hz, H-10b), 1.92 (1H,
m, H-2a), 1.83 (1H, dt, Jˆ13.0, 3.5 Hz, H-7b), 1.71 (1H,
ddd, Jˆ12.9, 12.6, 2.8 Hz, H-3a), 0.97 (3H, d, Jˆ6.6 Hz,
Me-17); dC (100 MHz, CDCl3) 176.3 (s, C-20), 170.0 (s,
OCOCH3), 144.2 (d, C-15), 139.5 (d, C-16), 137.8 (d,
C-20 and C-60), 129.0 (d, C-30 and C-50), 128.9 (d, C-40),
125.3 (s, C-13), 125.1 (s, C-10), 108.0 (d, C-14), 80.3 (t,
C-18), 77.3 (d, C-6), 71,7 (d, C-12), 67.2 (t, C-19), 57.2
(s, C-4), 53.4 (s, C-5), 51.3 (s, C-9), 47.4 (d, C-10), 42.7
(t, C-11), 37.8 (d, C-8), 34.7 (t, C-3), 33.0 (t, C-7), 23.6 (t,
C-2), 23.0 (t, C-1), 21.9 (q, OCOCH3), 16.4 (q, C-17); m/z
(EI) 544 [M]1 (12), 542 [M]1 (7), 387 (100), 327 (46), 281
(52), 159 (12), 95 (27%).
(12S)-19-Acetoxy-15,16-epoxy-6a-hydroxy-neocleroda-
4(18),13(16),14-trien-20,12-olide (14), (12S)-6a-acetoxy-
15,16-epoxy-19-hydroxy-neocleroda-4(18),13(16),14-trien-
20,12-olide (15) and (12S)-6a-acetoxy-15,16;18,19-
diepoxy-4b-phenylseleny-neocleroda-13(16),14-dien-20,12-
olide (16). To a solution of 12 (120 mg, 0.21 mmol) in tolu-
ene (90 mL), p-TsOH (11 mg, 0.06 mmol) was added and
the solution stirred for 24 h at room temperature. Aqueous
NaHCO3 saturated solution (150 mL) was then added and
the reaction mixture extracted with AcOEt (100 mL£3).
Chromatography of the residue with n-hexane:AcOEt
(3:2) yielded in increasing order of chromatographic
polarity 16 (47 mg, 41%,), 15 (17 mg, 21%) and 14
(21 mg, 26%).
Compound 14: [Found: C, 67.89; H, 7.05. C22H28O6
requires C, 68.02; H, 7.27%]; mp 184±1868C (white
crystals from EtOAc:n-hexane); [a]2D4ˆ1101.8 (cˆ0.325,
CHCl3); IR (KBr) nmax 3600, 3130, 3100, 1760, 1730,
1640, 1595, 1500, 1250, 925, 870 cm21; dH (400 MHz,
CDCl3) 7.41 (2H, m, H-16 and H-15), 6.36 (1H, dd,
Jˆ1.7, 0.8 Hz, H-14), 5.31 (1H, t, Jˆ8.6 Hz, H-12), 5.16
(1H, br s, HB-18, pro Z hydrogen), 4.94 (1H, br s, HA-18, pro
E hydrogen), 4.92 (1H, d, Jˆ12.4 Hz, HB-19), 4.73, (1H, dd,
Jˆ12.4, 0.9 Hz, HA-19), 4.02 (1H, dt, Jˆ11.8, 3.8 Hz,
collapsed into dd with D2O, H-6b), 2.75 (1H, d, Jˆ
3.8 Hz, OH-6a), 2.31 (2H, d, Jˆ8.6 Hz, 2H-11), 2.22 (1H,
dt, Jˆ13.8, 11.8 H-7a), 2.00 (1H, m, H-2a), 1.99 (3H, s,
OAc), 1.82 (1H, dt, Jˆ13.8, 3.9 Hz, H-7b), 1.75 (1H, dtd,
Jˆ13.0, 12.7, 4.2 Hz, H-1a), 1.66 (1H, dqd, Jˆ11.8, 6.7,
3.9 Hz, H-8b), 1.58 (1H, dd, Jˆ12.7, 3.2 Hz, H-10b), 1.43
(1H, qt, Jˆ12.7, 5.6 (2) Hz, H-2b), 1.02 (3H, d, Jˆ6.7 Hz,
Me-17); dC (100 MHz, CDCl3) 176.6 (s, C-20), 170.2 (s,
OCOCH3), 150.4 (s, C-4), 144.1 (d, C-15), 139.5 (d,
C-16), 125.2 (s, C-13), 109.2 (t, C-18), 108.0 (d, C-14),
73.9 (d, C-6), 71.5 (d, C-12), 61.7 (t, C-19), 54.6 (d,
C-10), 51.6 (s, C-9), 50.0 (s, C-5), 43.5 (t, C-11), 38.3 (d,
C-8), 35.2 (t, C-7), 32.8 (t, C-3), 28.3 (t, C-2), 23.2 (t, C-1),
21.1 (q, OCOCH3), 16.6 (q, C-17); m/z (EI) 388 [M]1 (8),
331 (13), 328 (61), 310 (73), 265 (88), 216 (57), 171 (75),
159 (57), 95 (100), 91 (53%).
(12S)-15,16-Epoxy-18-phenylselenyl-neocleroda-13(16),14-
dien-20,12-olide 4a,6a,19-orthoacetate (17). To a solu-
tion of 12 (50 mg, 0.09 mmol) in toluene (30 mL), at
room temperature, p-TsOH (6 mg, 0.03 mmol) was added.
After 15 min, the mixture was diluted with EtOAc (25 mL)
and washed with aqueous NaHCO3 saturated solution
50 mL£3). The residue obtained after removal of the
solvents was chromatographed with n-hexane: AcOEt
(7:3) yielding 46 mg of pure 17 (94%): [Found: C, 61.73;
H, 5.40. C28H32O6Se requires C, 61.88; H 5.93%]; mp 90±
958C (white amorphous solid); [a]2D4ˆ22.1 (cˆ0.706,
CHCl3); IR (KBr) nmax 3140, 3130, 3070, 3050, 1755,
1600, 1580, 1505, 870, 745, 690 cm21; dH (300 MHz,
CDCl3) 7.62 (2H, m, Ph), 7.42 (2H, m, H-16 and H-15),
7.26 (3H, m, Ph), 6.35 (1H, dd, Jˆ1.7, 0.9 Hz, H-14),
5.30 (1H, dd, Jˆ9.3, 8.3 Hz, H-12), 5.29 (1H, d, Jˆ
10.5 Hz, HB-19), 4.30 (1H, ddd, Jˆ11.6, 4.0, 2.2 Hz,
H-6b), 4.20 (1H, dd, Jˆ10.5, 2.2 Hz, HA-19), 3.81 (1H,
dd, Jˆ11.8, 2.2 Hz, HB-18), 3.25 (1H, d, Jˆ11.8 Hz,
HA-18), 2.40 (1H, dd, Jˆ14.0, 9.3 Hz, HB-11), 2.32 (1H,
dd, Jˆ14.0, 8.3 Hz, HA-11), 2.14 (1H, tdd, Jˆ13.3, 4.3,
2.2 Hz, H-3a), 1.82 (1H, dt, Jˆ13.3, 4.0 Hz, H-3b), 1.08

M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
8013
(3H, d, Jˆ6.8 Hz, Me-17); dC (75.4 MHz, CDCl3) 176.3 (s,
C-20), 144.2 (d, C-15), 139.5 (d, C-16), 133.2 (d, C-20 and
C-60), 131.1 (s, C-10), 129.0 (d, C-30 and C-50), 127.0 (d,
C-40) 124.9 (s, C-13), 108.7 (s, CH3C(OR)3), 107.8 (d,
C-14), 77.6 (s, C-4), 72.7 (d, C-6), 71.5 (d, C-12), 60.3 (t,
C-19), 51.1 (s, C-9), 47.2 (d, C-10), 44.6 (t, C-11), 38.7 (s,
C-5), 37.9 (d, C-8), 34.1 (t, C-18), 32.9 (t, C-7), 30.0 (t,
C-3), 23.8 (q, CH3C(OR)3), 22.4 (t, C-1p), 22.2 (t, C-2p),
16.3 (q, C-17), assignments marked with an asterisk may
be interchanged; m/z (EI) 544 [M]1 (2), 542 [M]1 (1), 373
(100), 331 (25), 313 (23), 171 (4), 95 (9%).
CDCl3) 176.3 (s, C-20), 170.5 (s, OCOCH3), 170.4 (s,
OCOCH3), 150.7 (s, C-4), 144.1 (d, C-15), 139.5 (d,
C-16), 125.3 (s, C-13), 108.0 (d, C-14), 107.1 (t, C-18),
75.1 (d, C-6), 71.5 (d, C-12), 60.9 (t, C-19), 54.7 (d,
C-10), 51.4 (s, C-9), 48.7 (s, C-5), 43.3 (t, C-11), 38.0 (d,
C-8), 33.3 (t, C-3), 31.9 (t, C-7), 28.3 (t, C-2), 23.3 (t, C-1),
21.1 (q, 2£OCOCH3), 16.4 (q, C-17); m/z (EI) 430 [M]1 (1),
370 (12), 328 (53), 310 (99), 265 (80), 216 (72), 171 (73),
159 (47), 95 (100%).
(12S)-6a,19-Diacetoxy-4b,18;15,16-diepoxy-neocleroda-
13(16),14-dien-20,12-olide (23). To a solution of 21
(500 mg, 1.16 mmol) in methanol (100 mL), MMPP
(2.16 g, 3.49 mmol) was added at 08C. The mixture was
allowed to reach room temperature and stirred for 48 h.
The solvent was removed and aqueous NaHCO3 saturated
solution (100 mL) was added and extracted with EtOAc
(100 mL£3). Column chromatography of the residue with
n-hexane:EtOAc (7:3) yielded, in order of increasing
polarity, unreacted 21 (200 mg), 23 (157 mg, 59% based
on recovered 21) and 22 (80 mg, 30%).
(12S)-6a,19-Diacetoxy-15,16-epoxy-4a-hydroxy-18-phenyl-
selenyl-neocleroda-13(16),14-dien-20,12-olide (20). 12
(91 mg, 0.16 mmol) was treated with acetic anhydride:
pyridine (15 mL, 1:2 v/v) for 48 h. Solvents were removed
and the residue was ®ltered through silica with EtOAc. After
removal of the solvents 82 mg of 20 (85%) were obtained:
[Found: C, 59.95; H, 6.28. C30H36O8Se requires C, 59.70; H,
6.01%]; mp 85±908C (white amorphous solid); [a]2D5ˆ
140.8 (cˆ0.593, CHCl3); IR (KBr) nmax 3550, 3140,
3060, 1760, 1745, 1600, 1580, 1505, 1240, 875, 740,
690 cm21; dH (300 MHz, CDCl3) 7.59 (2H, m, Ph), 7.43
(2H, m, H-16 and H-15), 7.26 (3H, m, Ph), 6.36 (1H, dd,
Jˆ1.5, 1.0 Hz, H-14), 5.34 (1H, t, Jˆ8.5 Hz, H-12), 5.33
(1H, d, Jˆ12.9 Hz, HB-19), 5.21 (1H, dd, Jˆ11.5, 4.0 Hz,
H-6b), 4.92 (1H, d, Jˆ12.9 Hz, HA-19), 3.47 (1H, d,
Jˆ12.1 Hz, HB-18), 3.41 (1H, d, Jˆ12.1 Hz, HA-18), 2.91
(1H, s, OH-4a), 2.36 (2H, d, Jˆ8.5 Hz, 2H-11), 2.06 (3H, s,
OAc), 1.96 (3H, s, OAc), 1.30 (1H, m, H-2b), 1.02 (3H, d,
Jˆ6.5 Hz, Me-17); m/z (EI) 604 [M]1 (5), 602 [M]1 (2),
373 (100), 331 (39), 313 (37), 172 (16), 95 (24%).
Compound 23: [Found: C, 64.80; H, 6.50. C24H30O8
requires C, 64.56; H, 6.77%]; mp 194±1968C (white
crystals from EtOAc:n-hexane); [a]2D4ˆ189.2 (cˆ0.325,
CHCl3); IR (KBr) nmax 3150, 3130, 3120, 3080, 1755,
1730, 1500, 1260, 1240, 875 cm21; dH (500 MHz, CDCl3)
7.42 (1H, m, H-16), 7.41 (1H, t, Jˆ1.7 Hz, H-15), 6.36 (1H,
dd, Jˆ1.7, 1.0 Hz, H-14), 5.34 (1H, br t, Jˆ8.6 Hz, H-12),
5.25 (1H, d, Jˆ12.9 Hz, HB-19), 4,66 (1H, br dd, Jˆ11.7,
4.4 Hz, H-6b), 4.33 (1H, br d, Jˆ12.9 Hz, HA-19), 2.78 (1H,
d, Jˆ4.3 Hz, HB-18), 2.59 (1H, d, Jˆ4.3 Hz, HA-18), 2.41
(1H, dd, Jˆ14.2, 8.5 Hz, HB-11), 2.31 (1H, dd, Jˆ14.2,
8.8 Hz, HA-11), 2.14 (1H, td, Jˆ13.2, 4.2 Hz, H-3a), 2.13
(1H, dt, Jˆ13.2, 11.7 Hz, H-7a), 2.01 (3H, s OAc), 1.94
(3H, s, OAc), 1.94 (1H, dd, Jˆ12.7, 2.9 Hz, H-10b), 1.79
(1H, ddd, Jˆ13.2, 4.4, 3.9 Hz, H-7b), 1.66 (1H, ddq,
Jˆ11.7, 6.8, 3.9, H-8b), 1.12 (1H, ddd, Jˆ13.2, 3.9,
2.6 Hz, H-3b), 0.95 (3H, d, Jˆ6.8 Hz, Me-17); dC
(125.7 MHz, CDCl3) 176.5 (s, C-20), 170.0 (s, OCOCH3),
169.8 (s, OCOCH3), 144.1 (d, C-15), 139.5 (d, C-16), 125.2
(s, C-13), 108.0 (d, C-14), 71.8 (d, C-6), 71.7 (d, C-12), 61.6
(t, C-19), 60.8 (s, C-4), 55.3 (t, C-18), 50.9 (s, C-9), 50.0 (d,
C-10), 45.8 (s, C-5), 42.8 (t, C-11), 37.4 (d, C-8), 31.6 (t, C-
7), 30.9 (t, C-3), 23.1 (t, C-2), 22.5 (t, C-1), 21.4 (q,
OCOCH3), 21.0 (q, OCOCH3), 16.5 (q, C-17); m/z (EI)
446 [M]1 (2), 331 (100), 326 (19), 314 (18), 281 (14),
187 (10), 105 (10), 95 (25%).
(12S)-6a,19-Diacetoxy-15,16-epoxy-neocleroda-4(18),13(16),
14-trien-20,12-olide (21). A mixture of 20 (2 g, 3.31 mmol)
and p-TsOH (304 mg, 1.60 mmol) in toluene (50 mL) was
heated at 508C for 1 h. The reaction mixture was cooled
down to room temperature. Then, aqueous NaHCO3
saturated solution (125 mL) was added and the mixture
extracted with AcOEt (50 mL£3). Working in the usual
way a residue was obtained and, after column chroma-
tography with n-hexane:AcOEt (1:1), 1.3 g (91%) of pure
21 were obtained: [Found: C, 67.05; H, 7.30. C24H30O7
requires C, 66.96; H, 7.02%]; mp 184±1878C (white
crystals from EtOAc:n-hexane); [a]2D4ˆ184.6 (cˆ0.280,
CHCl3); IR (KBr) nmax 3150, 3140, 3120, 3080, 1765,
1740, 1730, 1645, 1610, 1505, 1250, 900, 875 cm21; dH
(400 MHz, CDCl3) 7.41 (1H, m, H-16), 7.40 (1H, t, Jˆ
1.9 Hz, H-15), 6.35 (1H, dd, Jˆ1.9, 1.0 Hz, H-14), 5.32
(1H, br t, Jˆ8.7 Hz, H-12), 5.23 (1H, d, Jˆ12.9 Hz,
HB-19), 5.11 (1H, ddd, Jˆ11.7, 4.1, 1.2 Hz, H-6b), 4.76
(1H, br s, HB-18, pro Z hydrogen), 4.49 (1H, br s, HA-18
pro E hydrogen), 4.29 (1H, dd, Jˆ12.9, 1.2 Hz, HA-19), 2.33
(1H, dd, Jˆ14.2, 8.5 Hz, HB-11), 2.28 (1H, dt, Jˆ13.3,
11.7 Hz, H-7a), 2.27 (1H, dd, Jˆ14.2, 8.9 Hz, HA-11),
2.26 (1H, ddd, Jˆ13.6, 12.7, 4.4 Hz, H-3b), 2.19 (1H,
ddd, Jˆ13.6, 5.5, 2.3 Hz, H-3b), 2.00 (1H, dtt, Jˆ12.7,
4.4, 2.3, H-2a), 1.97 (6H, s, 2£OAc), 1.87 (1H, dddd,
Jˆ12.7, 5.5, 3.7, 2.3 Hz, H-1b), 1.80 (1H, qd, Jˆ12.7,
4.4 Hz, H-1a), 1.78 (1H, ddd, Jˆ13.3, 4.1, 4.0 Hz, H-7b),
1.71 (1H, ddq, Jˆ11.7, 6.6, 4.0 Hz, H-8b), 1.63 (1H, dd,
Jˆ12.4, 3.7 Hz, H-10b), 1.44 (1H, qt, Jˆ12.7, 5,5 Hz,
H-2b), 0.99 (3H, d, Jˆ6.6 Hz, Me-17); dC (100 MHz,
(12S)-15,16-Epoxy-4b,6a,12-trihydroxy-18-methoxy-neo-
cleroda-13(16),14-dien-20,19-olide (24) and (12S)-4a,19;
15,16-diepoxy-6a,18-dihydroxy-neocleroda-13(16),15-
dien-20,12-olide (25). 160 mg (0.35 mmol) of 23 in MeOH
(100 mL), were treated with aqueous NaOH (30 mL, 2% w/
v) for 1 h at 608C. MeOH was removed and the residue was
extracted with CH2Cl2 (50 mL£3). After column chroma-
tography with n-hexane:EtOAc (1:4) compounds 24
(30 mg, 22%) and 25 (70 mg, 55%) were obtained.
Compound 24: [Found: C, 64.20; H, 7.50. C21H30O7
requires C, 63.94; H, 7.67%]; mp 227±2308C (white
crystals from EtOAc:n-hexane); [a]2D4ˆ217.1 (cˆ0.145,
CHCl3); IR (KBr) nmax 3500, 3400, 3160, 3130, 1715,

8014
M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
1600, 1505, 875 cm21; dH (400 MHz, CDCl3:MeOH-d4,
9:1) 7.26 (1H, m, H-16), 7.23 (1H, t, Jˆ1.8 Hz, H-15),
6.30 (1H, dd, Jˆ1.8, 0.9 Hz, H-14), 4.61 (1H, dd, Jˆ8.9,
3.4 Hz, H-12), 4.54 (1H, d, Jˆ12.0 Hz, HB-19), 4.17 (1H,
dd, Jˆ12.0, 1.5 Hz, HA-19), 3.94 (1H, ddd, Jˆ11.7, 5.5,
1.5 Hz, H-6b), 3.95 (1H, s, OH-4b), 3.94 (1H, s, OH-6a),
3.39 (1H, d, Jˆ10.1 Hz, HB-18), 3.25 (3H, s, OMe), 2.99
(1H, d, Jˆ10.1 Hz, HA-18), 2.25 (1H, dd, Jˆ15.8, 3.4 Hz,
HB-11), 2.11 (1H, dd, Jˆ12.6, 3.7 Hz, H-10b), 1.96 (1H, dd,
Jˆ15.8, 8.9 Hz, HA-11), 1.87 (1H, ddq, Jˆ11.7, 6.6, 4.1 Hz,
H-8b), 1.78 (1H, ddd, Jˆ13.2, 5.5, 4.1, Hz, H-7b), 1.59
(1H, tddd, Jˆ13.6, 12.9, 3.6, 3.2 Hz, H-2b), 1.19 (1H, dt,
Jˆ13.2, 11.7 Hz, H-7a), 0.91 (1H, tdd, Jˆ12.9, 12.6,
4.0 Hz, H-1a), 0.69 (3H, d, Jˆ6.6 Hz, Me-17); dC
(100 MHz CDCl3:MeOH-d4, 9:1) 173.8 (s, C-20), 143.1
(d, C-15), 138.3 (d, C-16), 130.1 (s, C-13), 108.3 (d,
C-14), 76.9 (t, C-18), 72.8 (s, C-4), 68.3 (d, C-6), 68.1 (t,
C-19), 62.2 (d, C-12), 58.9 (q, OMe), 49.7 (s, C-9), 44.6 (s,
C-5), 39.3 (d, C-10), 38.1 (t, C-7), 36.1 (t, C-11), 34.1 (d,
C-8), 33.5 (t, C-3), 24.3 (t, C-1), 19.5 (t, C-2), 16.3 (q,
C-17); m/z (EI) 394 [M]1 (100), 331 (28), 313 (37), 301
(67), 203 (38), 161 (29), 105 (33), 95 (60%).
Jˆ12.2, 4.6 Hz, collapsed to d after D2O addition, HA-19),
3.22 (1H, br d, Jˆ5.3, 4.6 Hz, OH-19), 2.31 (2H, d, Jˆ
8.7 Hz, 2H-11), 2.30 (1H, d, Jˆ3.7 Hz, OH-a), 1.02 (3H,
d, Jˆ6.9 Hz, Me-17); m/z (EI) 346 [M]1 (13), 298 (51), 253
(32), 204 (35), 171 (55), 159 (55), 131 (26), 105 (31), 96
(100), 95 (77%).
(12S)-4a,19;15,16-Diepoxy-6a-hydroxy-18-iodo-neo-
cleroda-13(16),14-dien-20,12-olide (27). N-Iodosuccini-
mide (195 mg, 0.87 mmol) was added to a solution of 26
(200 mg, 0.58 mmol) in dry acetonitrile (100 mL) under
argon, at room temperature. The reaction mixture was
stirred for 15 min, and then diluted with AcOEt (100 mL)
and washed with Na2S2O5 aqueous solution (100 mL£3).
The residue obtained after elimination of the solvents was
chromatographed with AcOEt as eluent yielding 260 mg of
pure 27 (95% yield): [Found: C, 50.65; H, 5.52. C20H25IO5
requires C, 50.86; H, 5.34%]; mp 135±1408C, decom. (pale
yellow crystals from EtOAc:n-hexane); [a]2D1ˆ130.6
(cˆ0.111, CHCl3); IR (KBr) nmax 3590, 3140, 3110, 1760,
1600, 1500, 870 cm21; dH (300 MHz, CDCl3) 7.42 (2H, m,
H-16 and H-15), 6.36 (1H, dd, Jˆ1.7, 0.8 Hz, H-14), 5.35
(1H, br t, Jˆ8.7 Hz, H-12), 4.65 (1H, d, Jˆ7.8 Hz, HB-19),
4.47 (1H, d, Jˆ7.8 Hz, HA-19), 4.12 (1H, dd, Jˆ11.4,
4.1 Hz, H-6b), 4.02 (1H, d, Jˆ9.5, Hz, HB-18), 3.62 (1H,
d, Jˆ9.5 Hz, HA-18), 2.41 (1H, dd, Jˆ14.0, 8.5 Hz, HB-11),
2.27 (1H, dd, Jˆ14.0, 8.9 Hz, HA-11), 2.14 (1H, dt, Jˆ12.9,
11.4 Hz, H-7a), 0.96 (3H, d, Jˆ6.6 Hz, Me-17); dC
(75 MHz, CDCl3) 177.6 (s, C-20), 144.1 (d, C-15), 139.5
(d, C-16), 124.7 (s, C-13), 107.9 (d, C-14), 86.9 (s, C-4),
72.1 (d, C-12), 69.9 (d, C-6), 67.8 (t, C-19), 51.9 (s, C-9),
48.8 (s, C-5), 43.9 (d, C-10), 40.7 (t, C-11), 37.4 (d, C-8),
35.9 (t, C-7), 33.9 (t, C-3), 22.3 (t, C-1), 18.0 (t, C-2), 16.7
(q, C-17), 11,1 (t, C-18); m/z (EI) 472 [M]1 (12), 378 (25),
360 (37), 314 (48), 299 (47), 281 (36), 220 (49), 161 (36),
105 (46), 96 (44), 95 (90), 94 (100%).
Compond 25: [Found: C, 65.90; H, 7.39. C20H26O6 requires
C, 66.28; H, 7.23%]; mp 188±1908C (white crystals from
EtOAc:n-hexane); [a]2D4ˆ114.9 (cˆ0.321, CHCl3); IR
(KBr) nmax 3440 br, 3340 br, 1750, 1600, 1510, 880 cm21
;
dH (300 MHz, CDCl3:MeOH-d4 9:1) 7.30 (1H, m, H-16),
7.28 (1H, t, Jˆ1.7 Hz, H-15), 6.23 (1H, dd, Jˆ1.7, 1.0 Hz,
H-14), 5.24 (1H, br t, Jˆ8.6 Hz, H-12), 4.53 (1H, d, Jˆ
7.2 Hz, HB-19), 4.49 (1H, d, Jˆ7.2 Hz, HA-19), 3.69 (1H,
dd, Jˆ11.6, 4.3 Hz, H-6b), 3.60 (1H, d, Jˆ13.0 Hz, HB-18),
3.42 (1H, d, Jˆ13.0 Hz, HA-18), 2.29 (1H, dd, Jˆ14.0,
8.5 Hz, HB-11), 2.13 (1H, dd, Jˆ14.0, 8.8 Hz, HA-11),
1.85 (1H, ddd, Jˆ13.4, 11.7, 11.6 Hz, H-7a), 1.36 (1H,
ddd, Jˆ14.5, 4.5, 4.1 Hz, H-3b), 0.80 (3H, q, Jˆ6.5 Hz,
Me-17); dC (75 MHz, CDCl3:MeOH-d4 9:1) 177.7 (s,
C-20), 143.9 (d, C-15), 139.3 (d, C-16), 124.7 (s, C-13),
107.7 (d, C-14), 90.3 (s, C-4), 72.1 (d, C-12), 69.2 (d,
C-6), 68.9 (t, C-19), 64.7 (t, C-18), 51.8 (s, C-9), 49.8 (s,
C-5), 42.6 (d, C-10), 40.7 (t, C-11), 37.2 (d, C-8), 34.8 (t,
C-7), 30.2 (t, C-3), 21.6 (t, C-1), 16.6 (q, C-17), 16.0 (t,
C-2); m/z (EI) 362 [M]1 (10), 331 (32), 313 (23), 250
(31), 179 (41), 161 (38), 105 (40), 95 (93), 94 (100%).
(12S)-4a,19;6a,18;15,16-Triepoxy-neocleroda-13(16),14-
dien-20,12-olide (28). The iodo derivative 27 (50 mg,
0.11 mmol) in DMSO (20 mL) was heated at 608C for
24 h. After elimination of the solvent compound 28
(35 mg, 95%) was obtained: [Found: C, 69.88; H, 7.30.
C20H24O5 requires C, 69.75; H, 7.02%]; mp 175±1778C
(white crystals from EtOAc:n-hexane); [a]1D9ˆ110.5
(cˆ0.133, CHCl3); IR (KBr) nmax 3150, 3140, 3130, 1760,
1600, 1505, 875 cm21; dH (400 MHz, CDCl3) 7.45 (1H, m,
H-16), 7.43 (1H, t, Jˆ1.9 Hz, H-15), 6.38 (1H, dd, Jˆ1.9,
1.0 Hz, H-14), 5.36 (1H, t, Jˆ8.8 Hz, H-12), 4.55 (1H, d,
Jˆ7.9 Hz, HB-19), 4.52 (1H, d, Jˆ7.9 Hz, HA-19), 4.25 (1H,
d, Jˆ10.2 Hz, HB-18), 3.40 (1H, d, Jˆ10.2 Hz, HA-18), 3.14
(1H, dd, Jˆ12.3, 3.4 Hz, H-6b), 2.36 (2H, d, Jˆ8.8 Hz,
2H-11), 2.32 (1H, m, W1/2 36 Hz, H-2b), 2.19 (1H, td,
Jˆ12.3, 11.4 Hz, H-7a), 2.10 (1H, m, W1/2 34 Hz, H-1a),
2.02 (1H, dt, Jˆ12.3, 3.4 Hz, H-7b), 1.95 (1H, dt, Jˆ14.5,
3.7 Hz, H-3b), 1.73 (1H, dd, Jˆ13.2, 6.4 Hz, H-10b), 1.65
(1H, ddq, Jˆ11.4, 6.7, 3.4 Hz, H-8b), 1.48 (1H, ddd,
Jˆ14.5, 13.0, 5.6 Hz, H-3a), 1.06 (3H, d, Jˆ6.7 Hz,
Me-17); dC (100 MHz, CDCl3) 176.4 (s, C-20), 144.2 (d,
C-15), 139.8 (d, C-16), 124.8 (s, C-13), 108.0 (d, C-14),
90.9 (s, C-4), 85.0 (d, C-6), 80.5 (t, C-18), 71.8 (d, C-12),
71.1 (t, C-19), 51.9 (s, C-9), 48.2 (s, C-5), 43.7 (d, C-10),
41.3 (t, C-11), 39.8 (d, C-8), 31.5 (t, C-7), 24.4 (t, C-3), 19.1
(t, C-1), 16.9 (t, C-2), 16.1 (q, C-17); m/z (EI) 344 [M]1 (1),
(12S)-15,16-Epoxy-6a,19-dihydroxy-neocleroda-4(18),
13(16),14-trien-20,12-olide (26). A mixture of 21 (300 mg,
0.70 mmol) in MeOH (30 mL) and aqueous NaOH
(100 mL, 2% w/v) were heated at 608C for 30 min. The
reaction mixture was cooled down to room temperature
and extracted with CH2Cl2 (100 mL£3). Column chroma-
tography of the residue obtained after removal of the
solvent, with n-hexane:EtOAc (7:3) yielded pure 26
(210 mg, 87%): [Found: C, 69.53; H, 7.80. C20H26O5
requires C, 69.34; H, 7.56%]; mp 206±2098C (white crys-
tals from EtOAc); [a]D24ˆ184.0 (cˆ0.338, CHCl3); IR
(KBr) nmax 3450, 3370, 3130, 3080, 1750, 1640, 1610,
1505, 910, 870 cm21; dH (300 MHz, CDCl3) 7.42 (2H, m,
H-16 and H-15), 6.36 (1H, dd, Jˆ1.8, 0.9 Hz, H-14), 5.32
(1H, t, Jˆ8.7 Hz, H-12), 5.26 (1H, br s, HB-18), 5.05 (1H, br
s, HA-18), 4.75 (1H, dd, Jˆ12.2, 5.3 Hz, collapsed to d after
D2O addition, HB-19), 4.08 (1H, ddd, Jˆ9.8, 3.7, 3.6 Hz,
collapsed to dd after D2O addition, H-6b), 3.91 (1H, dd,

M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
8015
314 (80), 286 (20), 269 (29), 220 (100), 187 (33), 161 (28),
147 (33), 105 (37), 96 (74), 95 (76), 94 (46%).
14-trien-20,12-olide (31) and (12S)-15,16-epoxy-6a,12-
dihydroxy-neocleroda-3,13(16),14-trien-20,19-olide (32).
A mixture of 30 (200 mg, 0.47 mmol) in MeOH (20 mL)
and aqueous NaOH solution (70 mL, 2% w/v) was heated at
608C for 45 min. The reaction mixture was cooled down to
room temperature and extracted with CH2Cl2 (100 mL£3).
After removal of the solvents an inseparable mixture of 31
and 32 (150 mg, 91%) in a 1:4 ratio (1H NMR spectrum)
was obtained.
(12S)-6a-Acetoxy-4a,19;15,16-diepoxy-18-iodo-neocleroda-
13(16),14-dien-20,12-olide (29) and 28. Treatment of 27
(100 mg, 0.21 mmol) with Ac2O:pyridine (1:1, 2 mL) at
room temperature for 48 h yielded a mixture of 29 and 28
(78 mg), which were separated by column chromatography.
Elution with n-hexane:EtOAc (4:1) and (1:4) yielded
successively 29 (58 mg, 55%) and 28 (20 mg, 27%).
(12S)-3a,19;15,16-Diepoxy-6a-hydroxy-4b-iodo-neo-
cleroda-13(16),14-dien-20,12-olide (33). To the mixture of
regioisomers 31132 (150 mg, 0.43 mmol) in dry aceto-
nitrile (80 mL), N-iodosuccinimide (148 mg, 0.66 mmol)
was added at room temperature, and the reaction mixture
was stirred for 5 min. The reaction mixture was diluted with
EtOAc (80 mL) and washed with Na2S2O5 saturated solu-
tion (80 mL£3). The residue obtained after removal of the
solvents was chromatographed with n-hexane:EtOAc (7:3)
as eluent, yielding 33 (10 mg) and unreacted 32 (110 mg).
Compound 29: [Found: C, 51.02; H, 5.40. C22H27IO6
requires C, 51.37; H, 5.29%]; mp 75±808C (white amor-
phous solid); [a]1D9ˆ159.8 (cˆ0.589, CHCl3); IR (NaCl)
nmax 3150, 3120, 1760, 1740, 1600, 1505, 1240, 875 cm21;
dH (400 MHz, CDCl3) 7.43 (1H, m, H-16), 7.42 (1H, t,
Jˆ1.8 Hz, H-15), 6.36 (1H, dd, Jˆ1.8, 0.9 Hz, H-14),
5.38 (1H, br t, Jˆ8.7, Hz, H-12), 5.19 (1H, dd, Jˆ11.6,
4.4 Hz, H-6b), 4.67 (2H, s, 2H-19), 3.58 and 3.24 (each
1H, d, Jˆ9.9 Hz, 2H-18), 2.44 (1H, dd, Jˆ14.0, 8.6 Hz,
HB-11), 2.28 (1H, dd, Jˆ14.0, 8.9 Hz, HA-11), 2.19 (3H,
s, OAc), 2.04 (1H, dt, Jˆ12.8, 11.6 Hz, H-7a), 1.85 (1H,
dt, Jˆ12.8, 4.4 Hz, H-7b), 0.93 (3H, d, Jˆ6.7 Hz, Me-17);
dC (100 MHz, CDCl3) 177.1 (s, C-20), 170.4 (s, OCOCH3),
144.2 (d, C-15), 139.5 (d, C-16), 124.9 (s, C-13), 108.0 (d,
C-14), 86.5 (s, C-4), 73.1 (d, C-6), 72.1 (d, C-12), 68.7 (t,
C-19), 51.9 (s, C-9), 47.2 (s, C-5), 43.7 (d, C-10), 41.1 (t,
C-11), 37.2 (d, C-8), 32.7 (t, C-3), 31.7 (t, C-7), 21.9 (q,
OCOCH3), 21.6 (t, C-1), 16.7 (q, C-17), 10.0 (t, C-18); m/z
(EI) 514 [M]1 (1), 454 (5), 409 (4), 342 (12), 309 (27), 281
(58), 215 (83), 173 (40), 119 (42), 105 (48), 95 (100), 94 (79%).
Compound 32: [Found: C, 69.10; H, 7.74. C20H26O5
requires C, 69.34; H, 7.56%]; mp 160±1628C (white crys-
tals from EtOAc:n-hexane); [a]2D0ˆ239.4 (cˆ0.226,
CHCl3); IR (KBr) nmax 3420, 2920, 1700, 1650, 1175,
1140, 1020, 870 cm21; dH (300 MHz, CDCl3) 7.40 (1H,
m, H-16), 7.39 (1H, t, Jˆ1.9 Hz, H-15), 6.42 (1H, dd,
Jˆ1.9, 1.0 Hz, H-14), 5.50 (1H, 1H, m, H-3), 4.85 (1H, d,
Jˆ12.0 Hz, HB-19), 4.81 (1H, dd, Jˆ9.5, 2.9 Hz, H-12),
4.25 (1H, d, Jˆ12.0 Hz, HA-19), 3.83 (1H, dd, Jˆ12.1,
6.6 Hz, H-6b), 2.42 (1H, dd, Jˆ15.9, 2.9 Hz, HB-11), 2.24
(1H, dd, Jˆ15.9, 9.5 Hz, HA-11), 1.81 (3H, d, Jˆ1.6 Hz,
Me-18), 0.89 (3H, d, Jˆ6.6 Hz, Me-17); m/z (EI) 346 [M]1
(27), 298 (7), 218 (31), 173 (70), 159 (51), 145 (39), 131
(52), 119 (41), 111 (75), 105 (88), 95 (100), 81 (57), 69 (53),
55 (39), 41 (63%).
(12S)-6a,19-Diacetoxy-15,16-epoxy-neocleroda-3,13(16),
14-trien-20,12-olide (30). A mixture of 21 (200 mg,
0.47 mmol) and p-TsOH (20 mg, 0.11 mmol) in toluene
(20 mL) was re¯uxed for 4 h. The reaction mixture was
diluted with EtOAc (25 mL) and washed with aqueous
NaHCO3 saturated solution (50 mL£3). The residue
obtained after solvent removal was chromatographed
using n-hexane:EtOAc (4:1) yielding 196 mg (98%) of
pure 30: [Found: C, 66.73; H, 7.35. C24H30O7 requires C,
66.96; H, 7.02%]; mp 146±1488C (white crystals from
EtOAc:n-hexane); [a]2D0ˆ118.7 (cˆ0.127, CHCl3); IR
(KBr) nmax 3090, 1745, 1730, 1720, 1695, 1340, 1210,
945, 850 cm21; dH (400 MHz, CDCl3) 7.41 (1H, m, H-16),
7.39 (1H, t, Jˆ1.9 Hz, H-15), 6.35 (1H, dd, Jˆ1.9,
0.9 Hz, H-14), 5.39 (1H, m, H-3), 5.38 (1H, br t, Jˆ
8.6 Hz, H-12), 4.94 (1H, d, Jˆ12.1 Hz, HB-19), 4.81 (1H,
d, Jˆ12.1 Hz, HA-19), 4.80 (1H, dd, Jˆ11.7, 4.1 Hz, H-6b),
2.37 (1H, dd, Jˆ14.1, 8.5 Hz, HB-11), 2.32 (1H, dd, Jˆ14.1,
8.8 Hz, HA-11), 2.03 (3H, s, OAc), 1.95 (3H, s, OAc), 1.63
(3H, d, Jˆ1.3 Hz, Me-18), 0.98 (3H, d, Jˆ6.6 Hz, Me-17);
dC (50 MHz, CDCl3) 176.7 (s, C-20), 170.4 (s, OCOCH3),
170.3 (s, OCOCH3), 144.1 (d, C-15), 139.5 (d, C-16), 136.8
(s, C-4), 125.3 (2C, s C-13 and d C-3), 108.0 (d, C-14), 76.0
(d, C-6), 71.9 (d, C-12), 62.4 (t, C-19), 51.5 (s, C-9), 51.0 (d,
C-10), 45.5 (s, C-5), 45.4 (t, C-11), 38.2 (d, C-8), 32.8 (t,
C-7), 25.2 (t, C-2), 22.0 (q, C-18), 21.7 (q, OCOCH3), 21.2
(q, OCOCH3), 19.9 (t, C-1), 16.3 (q, C-17);); m/z (EI) 430
[M]1 (absent), 370 (8), 310 (52), 265 (66), 216(63), 171
(49), 157 (41), 105 (41), 95 (73), 81 (38), 43 (100%).
Compound 33: [Found: C, 51.03; H, 5.50. C20H25IO5
requires C, 50.86; H, 5.34%]; mp 1708C, decomp. (spon-
taneous crystallyzation); [a]2D7ˆ124.1 (cˆ0.270, CHCl3);
IR (KBr) nmax 3560 (sharp), 1740, 1500, 1460, 950,
870 cm21; dH (500 MHz, CDCl3) 7.43 (2H, m, H-16 and
H-15), 6.37 (1H, dd, Jˆ1.4, 0.7 Hz, H-14), 5.41 (1H, t,
Jˆ8.8 Hz, H-12), 4.36 (1H, d, Jˆ8.8 Hz, HB-19), 4.17
(1H, dd, Jˆ 8.8, 1.2 Hz, HA-19), 3.99 (1H, d, Jˆ4.4 Hz,
H-3b), 3.93 (1H, dd, Jˆ12.1, 4.4 Hz, H-6b), 2.46 (1H, dd,
Jˆ14.2, 8.3 Hz, HB-11), 2.43 (3H, s, Me-18), 2.38 (1H, dd,
Jˆ14.2, 8.9 Hz, HA-11), 2.20 (1H, q, Jˆ12.5 Hz, H-7a),
2.09 (1H, dddd, Jˆ14.2, 6.7, 4.4, 1.1 Hz, H-2a), 1.64 (1H,
ddd, Jˆ12.5, 4.4, 3.4 Hz, H-7b), 1.00 (3H, d, Jˆ6.8 Hz,
Me-17); dC (125 MHz, CDCl3) 177.2 (s, C-20), 144.1 (d,
C-15), 139.4 (d, C-16), 125.2 (s, C-13), 108.0 (d, C-14),
83.3 (d, C-3), 72.0 (d, C-12), 69.0 (d, C-6), 65.9 (s, C-4),
60.3 (t, C-19), 53.4 (s, C-5), 52.8 (s, C-9), 52.5 (d, C-10),
43.4 (t, C-11), 38.1 (t, C-7), 37.5 (d, C-8), 36.2 (q, C-18),
31.1 (t, C-2), 20.7 (t, C-1), 16.7 (q, C-17);); m/z (EI) 472
[M]1 (2), 345 [M-I]1 (59), 299 (8), 253 (12), 159 (39), 145
(27), 121 (30), 105 (58), 95 (100), 81 (59%).
Acknowledgements
(12S)-15,16-Epoxy-6a,19-dihydroxy-neocleroda-3,13(16),
Â
This work was supported by the Spanish `Comision Inter-

8016
M. C. de la Torre et al. / Tetrahedron 56 (2000) 8007±8017
25. Robinson, J. A. Chemical and Biochemical Aspects of
Polyether-Ionophore Antibiotic Biosynthesis. In Progress in the
Chemistry of Organic Natural Products. Herz, W., Kirby, G. W.,
Steglich, W., Tamm, Ch., Eds.; Springer: New York, 1991,
pp 1±81.
Â
ministerial de Ciencia y Tecnologõa' (CICYT, Grant No.
AGF98-0805). A. M. thanks the Italian `Ministero dell'
Á
Universita e della Ricerca Scienti®ca e Tecnologica
(MURST)' for a predoctoral fellowship. We also thank to
Â
Prof. Mar Gomez Gallego (UCM) for a careful revision of
the manuscript, and to Prof. M. A. Sierra (UCM) for helpful
discussions.
È
26. Nicolaou, K. C.; Shi, G.; Ginzer, J. L.; Gartner, P.; Wallace,
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