Tandem addition-cyclization mediated by sulfanyl radicals: a versatile strategy for iridoids synthesis

Article abstract of DOI:10.1016/j.tet.2008.03.058

Sulfanyl radicals trigger a tandem addition-cyclization protocol in linalool or citronelene derivatives for the efficient construction of the iridane monoterpene skeleton. Best results in yields and diastereoselectivity were obtained when phenylethylsulfanyl was used as radical initiator. We have proved the utility of this protocol with the enantiospecific synthesis of natural iridane dehydroiridomyrmecin starting from a (-)-linalyl acetate ester derivative in five steps with a 28% overall yield.

Full text of DOI:10.1016/j.tet.2008.03.058

Tetrahedron 64 (2008) 5111–5118
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem addition–cyclization mediated by sulfanyl radicals:
a versatile strategy for iridoids synthesis
´
´
´
´
Elena M. Sanchez, Jesus F. Arteaga, Victor Domingo, Jose F. Quılez del Moral,
*
M. Mar Herrador, Alejandro F. Barrero
Department of Organic Chemistry, Institute of Biotechnology, University of Granada, Avda de Fuentenueva s/n, 18071 Granada, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Sulfanyl radicals trigger a tandem addition–cyclization protocol in linalool or citronelene derivatives for
the efficient construction of the iridane monoterpene skeleton. Best results in yields and diaster-
eoselectivity were obtained when phenylethylsulfanyl was used as radical initiator. We have proved the
utility of this protocol with the enantiospecific synthesis of natural iridane dehydroiridomyrmecin
starting from a (ꢀ)-linalyl acetate ester derivative in five steps with a 28% overall yield.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 14 February 2008
Received in revised form 14 March 2008
Accepted 17 March 2008
Available online 21 March 2008
Keywords:
Sulfanyl radical
Radical cyclizations
Iridanes
Enantioselective synthesis
1. Introduction
of the olefin. The thus-generated radical centered at C-2 (A) should
originate the cyclopentane ring present in the iridane backbone via
Iridanes are an interesting group of natural monoterpenes, due
mainly to their structural varietydover 100 naturally occurring
compounds belonging to this family have been reporteddand wide
range of biological properties including antibiotic, anti-tumour,
antioxidant, antibacterial and antiviral activities.1 The interest of
these molecules is shown in the number of imaginative routes
delineated for their synthesis,2 although the first example of radi-
cal-induced cyclization leading to this skeleton was reported very
recently.3 Of the different types of sulfur-centered radicals used in
organic synthesis,4 the sulfanyl radical (RSꢁ) is one of the most at-
tractive5 and its ability to add to a multiple bond intramolecularly
deserving special attraction.6 This strategy has been successfully
employed in the synthesis of alkaloids and other bioactive het-
erocycles.7–13
Considering all the above and the different selectivity of the
addition of sulfanyl radicals to double bonds reported elsewhere,
we surmised that tandem processes of sulfanyl radical addition–
cyclization of dienes possessing the basic structure of 3,7-dime-
thylocta-1,6-diene could be a suitable approach to the synthesis of
natural iridoids. According to this proposal, the key addition step
should be both chemoselective towards the monosubstituted
double bond and also regioselective to the less substituted extreme
a 5-exo-trig process. The capture by the cyclic radical B of a hydro-
gen radical from a thiol molecule would lead to completion of the
process (Scheme 1).
R1
R1
R2
R2
R3
RS
R4
SR
R4
H
R3
RS
1) Addition
R2
3) Termination
R2
R1
R1
SR
R4
SR
R4
2) 5-exo-trig
cyclization
HSR
R3
R3
B
A
Scheme 1. Tandem addition–cyclization reaction triggered by sulfanyl radicals:
formation of the iridane ring.
In this paper, we describe the results obtained in the construc-
tion of five-membered rings possessing the carbon framework of
the iridane skeleton via radical cyclization promoted by the regio-
selective addition of sulfanyl radicals to suitable polyprenes related
to linalool. We previously published a short summary of this
* Corresponding author. Tel./fax: þ34 958243318.
E-mail address: afbarre@ugr.es (A.F. Barrero).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.058

´
E.M. Sanchez et al. / Tetrahedron 64 (2008) 5111–5118
5112
methodology.14 Herein the enantiospecific synthesis of the natural
iridoid dehydroiridomyrmecin and other achievements will be
described in detail.
OAc
OH
OH
silicagel
CC
SPh K2CO3
98%
SPh
SPh
H
H
2. Results and discussion
2
3
3a
Scheme 2. Synthesis of 3.
We started our study by making commercial linalyl acetate react
with the radical generated by treating PhSH (1 equiv) with AIBN
(1 equiv) in refluxing benzene. Under these conditions the products
obtained resulting from the expected addition–cyclization, 2, rep-
resented only 29%, while 40% of starting material was recovered
(Table 1, entry 1). From the mixture of diastereomers 2, the major
component 3a could be isolated as the corresponding alcohol
(Scheme 2). Different experimental conditions failed to sub-
stantially improve the yield of 2, and only a 35% of the desired
cyclized adduct was obtained when the equivalents of thiophenol
were doubled relative to those of the starting material (Table 1,
entry 2). Gratifyingly, when 2 equiv of 2-phenylethylthiol and 4-
nitrophenylthiol were also made to react with linalyl acetate, the
hoped-for conversion took place with 87 and 16% yields, re-
spectively (Table 1, entries 3 and 4). To account for this result, it is
postulated that the higher instability of the alkylsulfanyl radical
would favourably shift the equilibrium in the initial addition step,15
making the process more efficient and, therefore, more attractive
from a synthetic perspective. Due to the nucleophilic nature of
the initially originated carbon-centered radical, the conjugation of
the radical-accepting olefin with an ester enabled us to improve the
efficiency of the process (Table 1, entries 5–7), except when the
reaction was triggered with 4-nitrophenylsulfanyl radical.
Our efforts then focused on analyzing the diastereoselectivity of
the process. Thus, the addition–cyclization reaction of sulfanyl
radical with the unsaturated ester 6 could be studied with detail, as
three (7a, 7c and 7d) out of the four diastereomers originated (7a–d)
could be isolated via semi preparative HPLCdthe ratio of the four
stereoisomers obtained was 47:25:22:6.16 The relative configura-
tions of these molecules were assigned after analysis of the corre-
sponding NOEDIFFexperiencesandcoupling constantvalues (Fig.1).
The stereoselectivity observed could be interpreted in terms of
the conformational preferences of the intermediate carbon-cen-
tered radical according to the Beckwith–Houk model, suggesting
that the stereochemistry of 5-hexenyl ring closures is consistent
with the involvement of both cyclohexane chair-like and boat-like
transition structures.17 Thus, the major isomer, 7a, is formed via
AcO
H
AcO
AcO
H
SPh
AcO
H
H
SPh
SPh
SPh
H
H
H
H
H
H
H
CO2Me
MeO2C
H
H
MeO2C
MeO2C
7a
7b
7c
7d
Figure 1. Selected NOEs observed for compounds 7a, 7c and 7d.
demanding substituent at C-1 (CH3 group)18 adopts a pseudo-
equatorial position. This transition state leads to a cyclopentane
ring closure where the acetoxy, phenylthiomethyl and isopropyl
groups are disposed cis (Fig. 2). A second chair-like transition
structure (B) with the methyl group at C-1 being pseudo-axially
disposed may well account for the stereochemistry of diastereomer
7d. In this case, the phenylthiomethyl group is disposed anti to the
acetoxy and syn to the chain at C-3. Finally, the formation of
diastereomers 7c and 7b can be rationalized by considering the in-
volvement of boat-like transition structures C and D. It is interesting
to note the complete diastereoselectivity in the formation of the
stereocenter at C-8, regardless of the relative configuration at C-3. To
account for this result, the carbon-centered radicals originated after
the cyclization step are proposed to adopt the conformations shown
in Figure 3, where the methoxy carbonyl and phenylthiomethyl
groups are disposed anti, thus minimizing stereoelectronic re-
pulsions. In these preferred conformations, the approaching of
phenylthiol to transfer the hydrogen radical occurs in the less hin-
dered face to afford compounds 7a–d. This selectivity in the proton
abstraction has been previously observed by other authors.19
Once proved the success in the construction of the five-mem-
bered ring, it was then analyzed the influence of both, the sub-
stituent at C-3 and the electronic density in the double bond
acceptor of the carbon-centered radical upon the process to gain
a deeper understanding of this transformation. Thus, when methyl
(2E,6R)-2,6-dimethyl-6-pivaloyloxy-2,7-octadienoate (11) and
a
chair-like transition state (A) where the most sterically
Table 1
Addition–cyclization reaction mediated by sulfanyl radicals
R1 R2
R2
R1
SR´
SR´
R4
R4
R3
R3
Entry
Compound
R1
R2
R3
R4
R0
Product
Yield (%)
Diastereomeric ratio (a/b/c/d)
1
2
3
4
5
6
7
8
1
1
1
1
6
6
6
6
11
13
15
17
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CO2Et
CO2Et
CH3
CH3
CH3
CH3
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
Ph
Ph
2
2
4
5
7
8
9
10
12
14
16
18
29a
35
87
16
90
93
16
95
87
85
80
96
Not determined
40:23:20:17
46:26:17:11
Not determined
47:25:22:6
PhCH2CH2
4-NO2C6H4
Ph
PhCH2CH2
4-NO2C6H4
t-Bub
Ph
Ph
Ph
Ph
50:25:16:9
Not determined
48:23:20:19
46:20:17:17
54:20:19:7
36:28:18:18
58:21:14:7
9
OCOC(CH3)3
CH3
OAc
10
11
12
CH3
H
CH3
CO2Et
a
A 40% of 1 was recovered.
Four equivalents of t-BuSH were required.
b

´
E.M. Sanchez et al. / Tetrahedron 64 (2008) 5111–5118
5113
SPh
CO2Me
AcO
SPh
SPh
OAc
OAc
OAc
PhSH
PhSH
1
2
SPh
1
2
CO2Me
CO2Me
H
3
3
H
A
MeO2C
7a (47%)
H
AcO
AcO
AcO 1
AcO
2
SPh
SPh
SPh
SPh
3
CO2Me
CO2Me
H
H
B
MeO2C
MeO2C
7d (6%)
SPh
AcO
SPh
OAc
OAc
OAc
SPh
1
SPh
2
PhSH
PhSH
3
H
H
MeO2C
7c (22%)
CO2Me
CO2Me
CO2Me
CO2Me
C
AcO
AcO
CO2Me
SPh
CO2Me
SPh
AcO
AcO
SPh
H
SPh
H
D
MeO2C
7b (25%)
Figure 2. Mechanistic proposal for the cyclization of 6.
AcO
AcO
PhS-H
1) LDA, TMSCl,
PhSeCl
SPh
SPh
SPh
SPh
96%
3
2
4
3
H2C
CHCH2SPh
8
8
2) H2O2
CO2Et
CO2Et
H
H
8
H
H
EtO2C
MeO2C
MeO2C
CH3
EtO2C
17
MeO2C
97%
H
H
7a
7b
18
AcO
AcO
SPh
MeO2C
CH3
SPh
SPh
8
3
SPh
CO2Et
3
SOPh
CO2Et
8
8
+
+
TFAA
CHCH2SPh
H2C
H
H
2
4
H
H
CO2Et
MeO2C
MeO2C
7c
EtO2C
PhS-H
EtO2C
EtO2C
7d
19
24 (21%)
21 (41%)
Figure 3.
115 °C
Py
CHO
CO2Et
methyl (2E,6R)-2,6-dimethylocta-2,7-dienoate (13) were made to
react with phenylsulfanyl radical, good yields of 12 and 14, re-
spectively, were obtained (entries 9 and 10). On the other hand, it
was noted that an increase in the electronic deficiency of the olefin
acceptor of the carbon-centered radical not only speeded up the
process (entries 11 and 12) but also, in the case of diester 17, led to
an increase in the diastereoselectivity of the addition–cyclization,
producing a 58:21:14:7 ratio of 18 (entry 12).
O
+
O
CO2Et
EtO2C
CO2Et
22 (6%)
EtO2C
20
23 (15%)
Scheme 3. Synthesis of compounds 19–24.
Given the high efficiency found in the preparation of 18, dif-
ferent chemical transformations of this diastereomeric mixture
were studied with the aim of not only fitting the functionality of
these intermediates to those of natural iridoids but also of making
the mixture of diastereomers to converge into a single isomer, thus
producing a valuable synthetic intermediate in the preparation of
these compounds. In this context, the a-selenylation of 18 followed
by treatment with H2O2 led to sulfoxide 19 where the disappear-
ance of the stereocenters at C-3 and C-8 involved a first simplifi-
cation (Scheme 3).
Heating of 19 in refluxing pyridine led to the elimination of the
corresponding sulfinic acid affording mixtures of conjugated dienes
with ratios varying with reaction times. Diene 20 was obtained as
major reaction product (50% yield) when reflux was maintained for
9 h. When diester 19 was treated with Tf2O, vinylsulfide 21 was
obtained in a 41% yield, together with only 6% of the expected al-
dehyde, 15% of lactone 23 and 21% of 24 as a result of the reduction
of the sulfoxide moiety. Thus, although sulfoxide 19 did not prog-
ress efficiently towards the Pummerer rearranged derivative, once
aldehyde 22 is formed, it evolves to g-lactone 23 via its enolic form.
Vinylsulfide 21 did not evolve to the expected aldehyde when
allowed to react with concentrated HCl.20 This transformation was
achieved upon treatment with HgCl2,20 leading to 28% of aldehyde
22 together with 26% of 23 (yields based on recovered starting
material).
Continuing with the reactivity studies of these sulfur de-
rivatives, sulfoxide 19 was chemoselectively oxidized with MCPBA
at 0 ꢂC to the corresponding sulfone 25 almost quantitatively. The
presence of the sulfone then enabled deconjugation of the double
bond on 25 when this compound was heated in refluxing pyridine.
Allylic sulfone 26 was thus obtained as a single enantiomer in four
steps starting from readily available acyclic ester 17 with a 69% yield
(Scheme 4).

´
5114
E.M. Sanchez et al. / Tetrahedron 64 (2008) 5111–5118
OAc
SOPh
CO2Et
19
TsOH
85%
MCPBA
80%
SOPh
CO2Me
SPh
CO2Me
SPh
CO2Me
COOEt
H
H
EtO2C
EtOOC
17
29
27
7
SO2Ph
CO2Et
SO2Ph
CO2Et
Py, Δ
MCPBA
98%
TFAA
OCOCF3
CO2Me
O
1N NaOH
52%
19
69%
H
O
H
EtO2C
EtO2C
(from 29, based on
recovered 30)
30
31
25
Scheme 4. Synthesis of enantiopure 26 from 17.
26
Scheme 6. Enantioselective synthesis of (ꢀ)-dehydroiridomyrmecin 31.
With these results in mind we felt that this protocol could be
used to efficiently synthesize natural iridoids. To test the feasibility
of this methodology natural dehydroiridomyrmecin 31, isolated
from Actinidia polygama Miq, was selected.21 The enantioselective
synthesis of this natural product 31 was designed to start with
commercially available (ꢀ)-linalool. The key step of this strategy
rests on the phenylsulfanyl radical-mediated 5-exo-trig cyclization
of 6 to obtain, after regioselective deacetylation, the key in-
termediate 27, which already possesses the stereochemistry and
carbon framework of the natural product (Scheme 5).
3. Conclusion
In conclusion, we describe a tandem addition–cyclization pro-
tocol triggered either by phenyl- or phenylethylsulfanyl radical, for
the construction of the iridane skeleton, when applied to acyclic
derivatives of linalool or citronellene. The reactivity of the cycliza-
tion products was studied and it was found that the sulfide moiety
could be transformed into other functional groups suitable for the
synthesis of natural products. Although the utility of this route has
been already proved with the enantioselective synthesis of the
natural iridoid dehydroiridomyrmecin, we believe that the versa-
tility and modulability of this protocol is promising enough to war-
rant new achievements in the preparation of other natural iridoids.
OAc
O
SPh
4. Experimental section
CO2Me
CO2Me
O
H
H
4.1. General procedure for radical cyclization
31
27
6
Scheme 5. Retrosynthesis of (ꢀ)-dehydroiridomyrmecin.
A solution of the corresponding thiol (11.4 mmol, 2.0 equiv) and
AIBN (939 mg, 5.72 mmol, 1.0 equiv) in benzene (114 mL) was
added dropwise (8 mL/h) under an argon atmosphere to a boiling
solution of the corresponding acyclic diene (5.72 mmol, 1.0 equiv)
in benzene (57 mL) (TLC monitoring). The solvent was evaporated
under reduced pressure. Purification of the residue by column
chromatography afforded the corresponding cyclic compounds.
As we mentioned earlier (Table 1, entry 5), exposure of ester 6
to phenylsulfanyl radical afforded cyclopentane 7 in high yield.
When compound 7 was allowed to react with 2,4,6-collidine at
reflux for 40 h, only a 30% of the hoped-for elimination product
was obtained together with a 51% of unaltered starting material.
Gratifyingly, it was found that 7 could be deacetylated to efficiently
lead to olefin 27 after being treated with TsOH in refluxing ben-
zene (Scheme 6). According to the results shown in Table 1, 27 was
constituted by a couple of enantiomers in an approximate ratio of
3:1 (see Fig. 2), the major enantiomer being as shown in Scheme 6.
Moving forward with the synthetic planning, phenylsulfide 27 was
chemoselectively oxidized with MCPBA at a low temperature22
to produce phenylsulfoxide 29. When this compound was exposed
to Pummerer experimental conditions,23 trifluoroacetate 30
was obtained as result of the nucleophilic displacement of
PhSOCOCF3.24 Chemoselective saponification of the trifluoro-
acetate ester in 30 with 1 N NaOH at rt afforded natural dehy-
droiridomyrmecin (31) with a 46% yield together with a 11% of
starting trifluoroacetate 30 (Scheme 6). Since no enantiomeric
separation was performed, (ꢀ)-dehydroiridomyrmecin was syn-
thesized in a 50% ee. In this sense, the sign of the optical rotation
[a]D of synthetic (ꢀ)-dehydroiridomyrmecin (ꢀ46.2 (c 1.0, CHCl3))
matched that of the natural compound (ꢀ106.5 (c 0.9, CHCl3)).
Finally, the spectroscopic data of 31 fully agree with those reported
for natural dehydroiridomyrmecin. The enantioselective synthesis
of (ꢀ)-dehydroiridomyrmecin starting from the (ꢀ)-linalyl acetate
ester derivative 6 was thus completed in five steps with a 28%
overall yield. Furthermore, the stereocontrolled synthesis of
lactone 31 from (ꢀ)-linalool proved the absolute configuration of
dehydroiridomyrmecin, as originally suggested by Sakai and
co-workers.21
4.1.1. 1-Acetoxy-7-phenylthioiridane (2)
Accordingtothegeneralproceduredescribedabove, theresulting
crude was purified by column chromatography (hexane/t-BuOMe,
25:1) on silica gel to afford 35% of 2 as a diastereomeric mixture.
4.1.2. (1R,2S,3R)-1-Hydroxy-7-phenylthioiridane (3a)
To a solution of 2 (100 mg, 0.32 mmol) in MeOH (5 mL), K2CO3
(133 mg, 0.96 mmol) was added at rt and stirred for 48 h (TLC mon-
itoring). The solvent was removed under reduced pressure and the
residue obtained was dissolved in H2O and extracted with t-BuOMe.
The combined organic layer was washed with brine, dried over an-
hydrous Na2SO4 and concentrated under reduced pressure. The
resulting crude was purified by column chromatography (hexane/t-
BuOMe, 20:1) to afford 40 mg of 3a. IR (film) nmax 3443, 3058, 2957,
1731, 1584,1479, 1374, 1151, 1025, 737, 690 cmꢀ1; 1H NMR (400 MHz,
CDCl3) d 0.80 (3H, d, J¼5.6 Hz), 0.90 (3H, d, J¼5.6 Hz), 1.40 (3H, br s),
1.42–1.50 (1H, m),1.51–1.75 (4H, m),1.80–1.92 (1H, m),1.93–2.10 (1H,
m), 2.48 (1H, s), 2.90–3.10 (2H, m), 7.15–7.22 (1H, m), 7.28 (2H, br t,
J¼7.4 Hz), 7.37 (2H, br d, J¼7.4 Hz); 13C NMR (100 MHz, CDCl3) d 21.6,
22.1, 27.1, 29.0, 31.2, 32.1, 39.8, 49.7, 51.1, 80.8,126.5,129.0,130.1136.6;
HRFABMS calcd for C16H24OSNa [MþNa]þ 287.1445, found 287.1442.
4.1.3. Methyl 1-acetoxy-7-phenylthioiridan-9-oate (7)
According to the general procedure, the resulting crude was
purified by column chromatography (hexane/t-BuOMe, 20:1) on

´
E.M. Sanchez et al. / Tetrahedron 64 (2008) 5111–5118
5115
silica gel to afford 90% of 7 as a diastereomeric mixture at
a 47:25:22:6 ratio. The mixture was subjected to HPLC (mobile
phase: 0–5 min, hexane/t-BuOMe, 97:3; 5–15 min, hexane/t-
BuOMe, 96:4; 15–50 min, hexane/t-BuOMe, 9:1) to give pure 7a, 7c
and 7d.
hexane/t-BuOMe, 96:4; 15–50 min, hexane/t-BuOMe, 9:1) to give
pure 14a and 14c.
4.1.5.1. Methyl (1R,2S,3S,8R)-7-phenylthioiridan-9-oate (14a). tR¼
17.3 min; [a]D þ4.9 (c 0.8, CH2Cl2); IR (film) n
2950, 2869, 1735,
max
1583, 1480, 1437, 1167, 739, 691 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
4.1.3.1. Methyl
(7a). tR¼34.5 min; [a]D þ17.0 (c 0.7, CH2Cl2); IR (film) nmax 2949,
1736, 1437, 1368, 1248, 1169, 1135, 1086, 740, 692 cmꢀ1 1H NMR
(1R,2S,3R,8S)-1-acetoxy-7-phenylthioiridan-9-oate
d 1.04 (3H, d, J¼7.0 Hz), 1.07–1.26 (1H, m), 1.15 (3H, d, J¼6.8 Hz), 1.33–
1.50 (1H, m), 1.55–1.74 (1H, m), 1.75–1.85 (1H, m), 1.90–2.05 (1H, m),
2.10–2.30 (2H, m), 2.48 (1H, dq, J¼6.8, 10.6 Hz), 2.60 (1H, t, J¼11.9 Hz),
3.02 (1H, dd, J¼4.1, 11.9 Hz), 3.70 (3H, s), 7.17–7.25 (1H, m), 7.27–7.40
(4H, m); 13C NMR (75 MHz, CDCl3) d 16.8, 22.8, 28.6, 31.8, 34.9, 37.7,
40.4, 45.8, 46.4, 51.6, 126.1, 129.0 (2C), 129.6 (2C), 137.0, 177.1;
HRFABMS calcd for C17H24O2SNa [MþNa]þ 315.1395, found 315.1397.
;
(300 MHz, CDCl3) d 1.10 (3H, d, J¼6.7 Hz), 1.40–1.68 (2H, m), 1.50
(3H, s), 1.90–2.30 (4H, m), 1.94 (3H, s), 2.54 (1H, dq, J¼6.7, 9.9 Hz),
2.76 (1H, dd, J¼5.6, 13.0 Hz), 3.05 (1H, dd, J¼5.6, 13.0 Hz), 3.60 (3H,
s), 7.09–7.16 (1H, m), 7.19–7.33 (4H, m); 13C NMR (75 MHz, CDCl3)
d 17.6, 22.3, 25.7, 25.9, 30.3, 35.7, 41.1, 43.9, 50.8, 51.6, 88.4, 126.2,
129.0, 129.6, 137.5, 170.2, 176.6; HRFABMS calcd for C19H26O4SNa
[MþNa]þ 373.1449, found 373.1447.
4.1.5.2. Methyl (1R,2S,3R,8S)-7-phenylthioiridan-9-oate (14c). tR¼
16.5 min; IR (film) nmax 2949, 2869, 1734, 1583, 1480, 1438, 1259,
1162, 739, 690 cmꢀ1 1H NMR (300 MHz, CDCl3) d 0.93 (3H, d,
;
4.1.3.2. Methyl (1R,2S,3S,8R)-1-acetoxy-7-phenylthioiridan-9-oate
J¼6.7 Hz), 1.05 (3H, d, J¼7.0 Hz), 1.05–1.22 (1H, m), 1.35–1.55 (2H,
m), 1.57–1.72 (2H, m), 1.80 (1H, q, J¼6.8 Hz), 1.92 (1H, t, J¼7.5 Hz),
2.46 (1H, t, J¼6.9 Hz), 2.93 (1H, dd, J¼6.0, 12.5 Hz), 3.00 (1H, dd,
J¼6.0, 12.5 Hz), 3.56 (3H, s), 7.05–7.12 (1H, m), 7.15–7.30 (4H, m);
13C NMR (75 MHz, CDCl3) d 16.0, 20.4, 28.2, 33.2, 38.6, 39.8, 43.1,
48.2, 49.2, 51.4, 125.8, 128.9 (2C), 129.1 (2C), 137.5, 176.3; HRFABMS
calcd for C17H24O2SNa [MþNa]þ 315.1395, found 315.1396.
(7c). tR¼28.3 min; [a]D ꢀ52.9 (c 1.0, CH2Cl2); IR (film) n
3057,
max
2972, 2948, 2878, 1733, 1582, 1480, 1438, 1368, 1254, 1168, 1088,
1022, 940, 741, 691 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 1.20 (3H, d,
J¼7.1 Hz),1.50–1.60 (1H, m),1.62 (3H, s),1.70–1.86 (2H, m), 1.96 (1H,
dt, J¼6.3, 9.1 Hz), 2.03 (3H, s), 2.12–2.23 (1H, m), 2.38–2.48 (1H, m),
2.80 (1H, dq, J¼7.1, 5.1 Hz), 3.05 (1H, dd, J¼6.3,13.1 Hz), 3.30 (1H, dd,
J¼6.3, 13.1 Hz), 3.61 (3H, s), 7.20 (1H, t, J¼7.2 Hz), 7.28–7.41 (4H, m);
13C NMR (75 MHz, CDCl3) d 16.3, 22.3, 23.6, 25.1, 33.8, 36.3, 42.0, 47.1,
51.4, 52.2, 90.3, 126.0, 129.0, 129.2, 137.2, 170.2, 175.7; HRFABMS
calcd for C19H26O4SNa [MþNa]þ 373.14495, found 373.1449.
4.1.6. Diethyl 1-acetoxy-7-phenylthioiridan-9,10-dioate (16)
According to the general procedure described for radical cycli-
zation, the resulting crude was purified by column chromatography
(hexane/t-BuOMe, 8:1) on silica gel to afford 80% of 16 as a di-
astereomeric mixture at a 36:28:18:18 ratio. The mixture was
subjected to HPLC (mobile phase: 0–5 min, hexane/t-BuOMe, 97:3;
5–15 min, hexane/t-BuOMe, 96:4; 15–50 min, hexane/t-BuOMe,
9:1) to give pure 16a and 16d.
4.1.3.3. Methyl (1R,2R,3S,8R)-1-acetoxy-7-phenylthioiridan-9-oate
(7d). tR¼37.2 min; [a]D ꢀ0.8 (c 0.75, CH2Cl2); IR (film) nmax 2938,
1731, 1436, 1368, 1255, 1195, 1167, 1053 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) d 1.08 (3H, d, J¼6.7 Hz), 1.37–1.50 (1H, m), 1.67 (3H, s), 1.68–
1.87 (2H, m),1.98 (3H, s), 2.23 (1H, ddd, J¼9.2, 6.3,15.4 Hz), 2.36–2.46
(1H, m), 2.54 (1H, dq, J¼6.7,10.9 Hz), 2.67–2.77 (2H, m), 2.85 (1H, dd,
4.1.6.1. Diethyl (1R,2S,3R)-1-acetoxy-7-phenylthioiridan-9,10-dioate
(16a). tR¼51.3 min; IR (film) nmax 2958, 2924, 2853,1736,1729,1583,
1481, 1463, 1443, 1367, 1248, 1188, 1155, 1082, 1026, 967, 859,
740 cmꢀ1; 1H NMR (500 MHz, CDCl3) d 1.23 (3H, t, J¼7.1 Hz),1.26 (3H,
t, J¼7.1 Hz), 1.60 (3H, s), 1.70–1.80 (1H, m), 1.92–2.00 (2H, m), 2.00
(3H, s), 2.23 (1H, ddd, J¼4.8,10.2,14.8 Hz), 2.37 (1H, q, J¼7.1 Hz), 2.81
(1H, dd, J¼7.2, 13.1 Hz), 2.90–2.98 (1H, m), 3.17 (1H, dd, J¼5.5,
13.1 Hz), 3.60 (1H, d, J¼11.0 Hz), 4.16 (2H, q, J¼7.1 Hz), 4.18 (2H, q,
J¼7.1 Hz), 7.16–7.20 (1H, m), 7.25–7.34 (4H, m); 13C NMR (125 MHz,
CDCl3) d 14.2, 14.3, 22.4, 25.4, 26.0, 30.2, 35.9, 39.7, 51.2, 53.9, 61.7,
61.8, 88.8, 126.3, 129.1 (2C), 129.4 (2C), 138.9, 168.8, 169.1, 170.2;
HRFABMScalcdforC22H30O6SNa[MþNa]þ 445.1660, found445.1661.
J¼3.7,12.2 Hz), 3.65 (3H, s), 7.15–7.22 (1H, m), 7.25–7.32 (4H, m); 13
C
NMR (100 MHz, CDCl3) d 17.2, 20.8, 22.8, 26.5, 30.9, 36.2, 41.0, 45.2,
48.0, 51.7, 92.7,126.5,129.1,129.9,137.0,170.7,176.8; HRFABMS calcd
for C19H26O4SNa [MþNa]þ 373.1449, found 373.1451.
4.1.4. Methyl 7-phenylthio-1-pivaloyloxiiridan-9-oate (12)
According to the general procedure described for radical cycli-
zation, the resulting crude was purified by column chromatography
(hexane/t-BuOMe, 25:1) on silica gel to afford 87% of 12 as a di-
astereomeric mixture at a 46:20:17:17 ratio. The mixture was
subjected to HPLC (mobile phase: 0–5 min, hexane/t-BuOMe, 97:3;
5–15 min, hexane/t-BuOMe, 96:4; 15–50 min, hexane/t-BuOMe,
9:1) to give pure 12a.
4.1.6.2. Diethyl (1R,2R,3S)-1-acetoxy-7-phenylthioiridan-9,10-dioate
(16d). tR¼63.7 min; IR (film) nmax 3058, 2978, 2935, 2874, 1729,
1584, 1480, 1439, 1368, 1258, 1231, 1176, 1152, 1066, 1025, 937, 861,
803 cmꢀ1; 1HNMR (400 MHz, CDCl3)d 1.13(3H, t, J¼7.2 Hz),1.20 (3H,
t, J¼7.1 Hz), 1.40–1.58 (2H, m), 1.59 (3H, s), 1.73–1.86 (2H, m), 1.93
(3H, s), 2.16–2.30 (1H, m), 2.74–2.90 (2H, m), 2.95–3.06 (1H, m), 3.56
(1H, d, J¼11.6 Hz), 4.08 (2H, q, J¼7.2 Hz), 4.13 (2H, q, J¼7.2 Hz), 7.10–
7.16 (1H, m), 7.18–7.29 (4H, m); 13C NMR (100 MHz, CDCl3) d 14.2,
14.3, 20.8, 22.8, 26.3, 31.4, 36.2, 40.6, 48.6, 53.9, 61.7 (2C), 92.4,126.5,
129.2 (2C), 129.6 (2C), 136.9, 168.7, 169.3, 170.7; HRFABMS calcd for
4.1.4.1. Methyl (1R,2S,3R,8S)-7-phenylthio-1-pivaloyloxiiridan-9-oate
(12a). tR¼27.8 min; [a]D þ6.0 (c 0.97, CH2Cl2); IR (film) nmax 2972,
1726, 1480, 1288, 1164, 1132, 739 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d 1.10 (9H, s), 1.15 (3H, d, J¼6.7 Hz), 1.37–1.66 (2H, m), 1.49 (3H, s),
2.00 (2H, t, J¼8.0 Hz), 2.10–2.24 (1H, m), 2.27 (1H, q, J¼5.8 Hz), 2.55
(1H, dq, J¼6.7, 10.5 Hz), 2.76 (1H, dd, J¼6.0, 12.9 Hz), 3.07 (1H, dd,
J¼5.1, 12.9 Hz), 3.60 (3H, s), 7.08–7.15 (1H, m), 7.18–7.32 (4H, m); 13
C
NMR (75 MHz, CDCl3) d 17.7, 26.0, 26.3, 27.2 (3çC), 29.8, 32.5, 36.0,
41.2, 44.1, 51.0, 51.6, 87.9, 126.1, 129.0 (2C), 129.4 (2C), 138.8, 176.7;
HRFABMS calcd for C22H32O4SNa [MþNa]þ 415.1914, found 415.1915.
C
22H30O6SNa [MþNa]þ 445.1660, found 445.1661.
4.2. Synthesis of cyclopentane derivative 26 from acyclic
diene 17
4.1.5. Methyl 7-phenylthioiridan-9-oate (14)
According to the general procedure for radical cyclization, the
resulting crude was purified by column chromatography (hexane/
t-BuOMe, 20:1) on silica gel to afford 85% of 14 as a diastereo-
meric mixture at a 54:20:19:7 ratio. The mixture was subjected to
HPLC (mobile phase: 0–5 min, hexane/t-BuOMe, 97:3; 5–15 min,
4.2.1. Diethyl 7-phenylsulfinyl-3(8)-iriden-9,10-dioate (20)
To a solution of diisopropylamine (4.9 mL, 35.0 mmol,10.0 equiv)
and n-BuLi (2 M in pentane, 8.7 mL, 17.5 mmol, 5.0 equiv) in anhy-
drous THF (24 mL) underan argon atmosphere and cooled at ꢀ78 ꢂC,

´
E.M. Sanchez et al. / Tetrahedron 64 (2008) 5111–5118
5116
diethyl 7-phenylthioiridan-9,10-dioate (18) (1273 mg, 3.50 mmol,
1.0 equiv) in 10 mL of THF was added and stirred for 15 min. Then
TMSCl (2.70 mL, 23.0 mmol, 6.6 equiv) was added and the reaction
mixture was stirred for 15 min more. Finally PhSeCl (4420 mg,
23.0 mmol, 6.6 equiv) in 10 mL of THF was added and the reaction
mixture was stirred for 5 min (TLC monitoring), diluted with t-
BuOMe and quenched with NH4Cl solution. The aqueous phase was
extracted with t-BuOMe. The organic layer was washed with brine,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The resulting crude was dissolved in 100 mL of CH2Cl2 and
oxidized with H2O2 (30%) (1.1 mL, 11.0 equiv) at rt. The reaction
mixture was stirred for 1 h 45 min (TLC monitoring), washed with
brine, dried over anhydrous Na2SO4 and concentrated under re-
duced pressure. The resulting crude was purified by column chro-
matography (hexane/t-BuOMe, 1:1) to afford 1200 mg (97%) of the
corresponding sulfoxide 19 as colourless oil. A solution of sulfoxide
19 (118 mg, 0.31 mmol) in pyridine (1.0 mL) under an argon atmo-
sphere was heated at 115 ꢂC for 9 h (TLC monitoring). The reaction
mixture was diluted with t-BuOMe and washed with 1 N HCl and
NaHCO3 solution. The organic layer was washed with brine, dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The resulting crude was purified by column chromatography (hex-
ane/t-BuOMe, 8:1) to afford 58 mg (74%) of a mixture of dienes, from
which 20 was the major component. The mixture was subjected to
HPLC (mobile phase: 0–5 min, hexane/t-BuOMe, 97:3; 5–15 min,
hexane/t-BuOMe, 96:4; 15–50 min, hexane/t-BuOMe, 9:1) to give
CO(CD3)2) d 1.08 (3H, d, J¼6.9 Hz), 1.21–1.29 (1H, m), 1.24 (3H, t,
J¼7.1 Hz), 1.25 (3H, t, J¼7.1 Hz), 1.50 (1H, octuplet, J¼4.2 Hz), 2.06–
2.13 (1H, m), 2.66 (1H, ddd, J¼4.5, 8.3, 18.7 Hz), 2.78–2.87 (1H, m),
3.02–3.12 (1H, m), 4.20 (2H, q, J¼7.1 Hz), 4.21 (2H, q, J¼7.1 Hz),
10.05 (1H, s); 13C NMR (125 MHz, CO(CD3)2) d 13.6 (2C), 18.8, 30.5,
34.2, 38.6, 51.2, 61.7, 61.8, 146.0, 152.1, 166.6, 166.7, 188.3; HRFABMS
calcd for C14H20O5Na [MþNa]þ 291.1209, found 29.1212.
4.2.5. Ethyl (7R)-3,5,6,7-tetrahydro-7-methyl-3-
oxocyclopenta[c]pyran-4-carboxylate (23)
Mp (hexane) 105–108 ꢂC; [a]D þ37.0 (c 1.0, CH2Cl2); IR (film)
nmax 3075, 2985, 2924, 2877, 1740, 1686, 1549, 1465, 1391, 1314,
1279, 1224, 1200, 1146, 1042, 901, 854 cmꢀ1 1H NMR (500 MHz,
;
CDCl3) d 1.24 (3H, d, J¼6.7 Hz), 1.37 (3H, t, J¼7.1 Hz), 1.55–1.64 (1H,
m), 2.22–2.32 (1H, m), 2.87–2.96 (1H, m), 3.02 (1H, br sextuplet,
J¼7.0 Hz), 3.15 (1H, ddd, J¼3.7, 8.2, 18.8 Hz), 4.35 (2H, q, J¼7.1 Hz),
7.33 (1H, br s); 13C NMR (125 MHz, CDCl3) d 14.5, 19.2, 32.8, 34.6,
35.0, 61.6, 113.2, 129.2, 146.8, 159.0, 164.3, 169.5; HRFABMS calcd for
C
12H14O4Na [MþNa]þ 245.0789, found 245.0791.
4.2.6. Diethyl (1R,2S)-7-phenylthio-3(8)-iriden-9,10-dioate (24)
IR (film) n 3058, 2957, 2929, 2870, 1721, 1638, 1582, 1479,
max
1439, 1367, 1239, 1176, 1092, 1057, 1033, 741 cmꢀ1
;
1H NMR
(500 MHz, CDCl3) d 0.93 (3H, d, J¼7.1 Hz), 1.22 (3H, t, J¼7.1 Hz), 1.28
(3H, t, J¼7.1 Hz), 1.36–1.44 (1H, m), 1.92–2.02 (1H, m), 2.38–2.48
(1H, m), 2.64–2.88 (3H, m), 2.92–2.98 (1H, m), 3.25 (1H, dd, J¼3.7,
12.7 Hz), 4.14 (2H, q, J¼7.1 Hz), 4.18–4.26 (2H, dq, J¼2.5, 7.1 Hz), 7.17
(1H, tt, J¼1.2, 7.2 Hz), 7.25–7.30 (2H, m), 7.35–7.39 (2H, m); 13C NMR
(125 MHz, CDCl3) d 14.2, 14.3, 20.4, 30.4, 31.7, 37.1, 37.2, 51.7, 61.1,
61.2, 123.0, 126.4, 129.0 (2C), 130.0 (2C), 136.1, 165.3, 165.4, 168.6;
20: tR¼13.1 min; IR (film) n
2961, 2932, 2871, 1721, 1632, 1610,
1462, 1447, 1413, 1367, 1289, 1263, 1238, 1218, 1172, 1127, 1096, 1037,
max
907, 865, 803 cmꢀ1 1H NMR (500 MHz, (CD3)2CO) d 0.98 (3H, d,
;
J¼6.6 Hz), 1.08–1.16 (7H, m,), 1.84–1.93(1H, m,), 2.37–2.45 (1H, m),
2.62 (1H, dt, J¼8.8,19.5 Hz), 2.94 (1H, ddd, J¼3.2, 8.5,19.5 Hz), 4.03–
4.11 (4H, m), 5.10 (1H, d, J¼2.3 Hz), 5.37 (1H, d, J¼2.5 Hz); 13C NMR
(125 MHz, (CD3)2CO) d 18.6, 18.9, 22.8, 36.9, 37.0, 44.9, 65.8, 66.2,
117.6 (2C), 158.1, 161.9, 169.2, 171.8; HRFABMS calcd for C14H20O4Na
[MþNa]þ 275.1660, found 275.1661.
HRFABMS calcd for
385.1443.
C
20H26O4SNa [MþNa]þ 385.1441, found
4.2.7. Treatment of thioenolether 21 with HgCl2/CdCO3
To a mixture of 21 and 24 at a 2.5:1 ratio (130 mg, 0.36 mmol)
dissolved in acetone (18 mL), CdCO3 (213 mg, 1.22 mmol) and HgCl2
(1.5 g, 5.56 mmol) were added at rt. The mixture was refluxed for
48 h (TLC monitoring), the inorganic salts were filtered off and the
residue obtained was diluted with water, extracted with t-BuOMe,
washed with brine, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The resulting crude was purified by col-
umn chromatography (hexane/t-BuOMe, 15:1–1:1) to afford 10 mg
(14%) of 22 and 15 mg (26%) of 23 as white solids. A 68% yield of 21
was recovered.
4.2.2. Treatment of sulfoxide 19 with trifluoroacetic anhydride
Trifluoroacetic anhydride (0.27 mL, 1.98 mmol, 4.0 equiv) was
added to a stirred solution of sulfoxide 19 (187 mg, 0.49 mmol,
1.0 equiv) in anhydrous CH2Cl2 (20 mL) at 0 ꢂC. The reaction mix-
ture was stirred for 2 h 30 min (TLC monitoring) and washed with
NH4Cl solution and brine. The aqueous phase was extracted with
CH2Cl2 three times. The combined organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
resulting crude was purified by column chromatography (hexane/t-
BuOMe, 15:1–1:1) to afford 37 mg of sulfide 24 (21%), 73 mg of
thioenolether 21 (41%), together with 8 mg (6%) of aldehyde 22 and
16 mg (15%) of 23 as a white solid. A 4% yield of starting material 19
was recovered.
4.2.8. Diethyl (1R)-7-phenylsulfonyl-3(8)-iriden-9,10-dioate (25)
To a solution of 7-phenylsulfinyl-3(8)-iriden-9,10-dioate (19)
(450 mg, 1.19 mmol, 1.0 equiv) in 20 mL of CH2Cl2, MCPBA (316 mg,
1.28 mmol, 1.08 equiv) was added at 0 ꢂC. The reaction mixture was
stirred for 10 min at 0 ꢂC and for 50 min at rt (TLC monitoring),
washed sequentially with aqueous NaHCO3, brine, dried over an-
hydrous Na2SO4 and concentrated under reduced pressure. The
resulting crude was purified by column chromatography (hexane/t-
BuOMe, 1:1) to afford 460 mg (98%) of the corresponding sulfone
25 as a mixture of epimers at C-2 in a 3:1 ratio. Data for compound
4.2.3. Diethyl (1R)-7-phenylthio-2(7)E,3(8)-iridadien-9,10-dioate
(21)
IR (film) nmax 3059, 2959, 2935, 2904, 2869, 1714, 1610, 1555,
1479, 1442, 1366, 1264, 1229, 1187, 1103, 1036, 843, 806, 744,
691 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 1.05 (3H, d, J¼7.1 Hz), 1.11
(3H, t, J¼7.2 Hz), 1.20 (3H, t, J¼7.1 Hz), 1.50–1.56 (1H, m), 1.82–1.92
(1H, m), 2.84–3.00 (2H, m), 3.05 (1H, ddd, J¼2.6, 9.2, 19.1 Hz), 4.02–
4.10 (2H, m), 4.13 (2H, q, J¼7.1 Hz), 6.91 (1H, br s), 7.18–7.32 (5H, m);
13C NMR (125 MHz, CDCl3) d 14.0, 14.4, 18.5, 30.9, 32.4, 38.7, 60.9,
61.5, 117.9, 127.7, 129.1, 129.5 (2C), 130.0 (2C), 135.2, 143.0, 156.9,
164.7, 167.9; HRFABMS calcd for C20H24O4SNa [MþNa]þ 383.1293,
found 383.1291.
25: IR (film) n
2963, 1720, 1638, 1561, 1499, 1447, 1367, 1304,
max
1230, 1179, 1150, 1058, 1030, 740, 690 cmꢀ1. Isomer 2S: 1H NMR
(500 MHz, CDCl3) d 0.93 (3H, d, J¼7.0 Hz), 1.26 (6H, q, J¼7.0 Hz), 1.52
(1H, m), 1.98 (1H, m), 2.64 (1H, br dd, J¼9.0, 19.8 Hz), 2.69–2.83 (2H,
m), 3.06 (1H, dd, J¼11.5, 13.8 Hz), 3.20 (1H, br d, J¼11.5 Hz), 3.40
(1H, dd, J¼2.2, 13.8 Hz), 4.11–4.23 (4H, m), 7.56 (2H, t, J¼7.6 Hz),
7.64 (1H, t, J¼7.6 Hz), 7.93 (2H, d, J¼7.6 Hz); 13C NMR (125 MHz,
CDCl3) d 14.2, 14.3, 19.9, 29.8, 30.7, 36.6, 47.3, 58.2, 61.2, 61.5, 123.9,
128.3 (2C), 129.4 (2C), 133.8, 140.2, 164.8, 165.1, 166.8. Isomer 2R:
(only distinctive signals) 1H NMR (500 MHz, CDCl3) d 1.11 (3H, d,
J¼7.0 Hz),1.30 (6H, m),1.45 (1H, m),1.82 (1H, m), 2.61–2.79 (2H, m),
4.2.4. Diethyl (1R,2S)-7-oxo-3(8)-iriden-9,10-dioate (22)
IR (film) n
3056, 2958, 2926, 2854, 1736, 1669, 1628, 1448,
max
1369, 1302, 1234, 1149, 1095, 1032, 741 cmꢀ1 1H NMR (500 MHz,
;

´
E.M. Sanchez et al. / Tetrahedron 64 (2008) 5111–5118
5117
3.17 (1H, dd, J¼3.0, 14.4 Hz), 3.27 (1H, dd, J¼8.6, 14.4 Hz), 3.75 (1H,
br t, J¼8.0 Hz), 4.11–4.31 (4H, m); (only distinctive signals) 13C NMR
(125 MHz, CDCl3) d 14.2, 15.6, 31.2, 31.9, 36.9, 42.9, 55.7, 61.2, 61.7,
123.2, 128.2 (2C), 129.4 (2C), 133.7, 140.9, 164.9, 165.5, 167.3.
2.65 (1H, dq, J¼3.9, 7.0 Hz), 2.76 (2H, dq, J¼3.7, 6.7 Hz), 2.91 (1H, m),
3.45–3.65 (2H, m), 3.55 (3H, s), 3.56 (3H, s), 3.67–3.80 (2H, m),
7.40–7.65 (10H, m); 13C NMR (100 MHz, CDCl3) d 13.9, 14.0, 14.5,
14.6, 24.6, 25.1, 36.7, 36.9, 40.9, 41.2, 51.0 (2C), 51.5, 51.6, 56.5, 57.0,
124.1 (2C), 124.3 (2C), 125.0, 125.3, 125.5, 128.9 (2C), 129.1 (2C),
131.0, 131.1, 143.8, 143.9, 144.2, 175.5, 175.8; HRFABMS calcd for
4.2.9. Diethyl (1R)-7-phenylsulfonyl-2-iriden-9,10-dioate (26)
Sulfone 25 (70 mg, 0.17 mmol) was dissolved in 0.9 mL of pyri-
dine under an argon atmosphere and heated at 113 ꢂC for 9 h
30 min. The reaction mixture was diluted with t-BuOMe (50 mL),
washed with 1 N HCl, brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The resulting crude was
purified by column chromatography (hexane/t-BuOMe, 10:1) to
C
17H22O3S [MþH]þ 307.1367, found 307.1365.
4.3.3. (ꢀ)-Dehydroiridomyrmecin (31)
Trifluoroacetic anhydride (1.02 mL, 7.32 mmol) was added to
a stirred solution of sulfoxide 29 (560 mg, 1.83 mmol) in CH2Cl2
(73 mL) at 0 ꢂC. The mixture was stirred for 30 min at 0 ꢂC and then
1 N aq NaOH (18.3 mL) and THF (60 mL) were added and stirring
was continued for 4 h at rt (TLC monitoring). The reaction mixture
was extracted with diethyl ether and the combined organic layer was
washed with aqueous NH4Cl and brine. Evaporation of the solvent
followed by column chromatography (petroleum ether 30–40 ꢂC/
diethyl ether, 5:1) furnished 60 mg of trifluoroacetate 30 and 140 mg
of dehydroiridomyrmecin 31 (46%). Data for compound 30: IR (film)
afford 48 mg of 26 (69%). Data for compound 26: IR (film) n
max
2950, 1740, 1654, 1445, 1367, 1306, 1150, 1028, 787 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 0.87 (3H, t, J¼7.2 Hz), 1.26 (6H, m), 1.32 (1H, m),
2.32 (1H, m), 2.41 (1H, m), 2.60 (1H, m), 3.81 (1H, d, J¼13.6 Hz), 3.99
(1H, d, J¼13.6 Hz), 4.18 (4H, br q, J¼7.2 Hz), 4.38 (1H, s), 7.54 (1H, br
t, J¼7.6 Hz), 7.63 (1H, br t, J¼7.6 Hz), 7.88 (1H, br d, J¼7.6 Hz); 13C
NMR (125 MHz, CDCl3) d 14.2, 14.3, 18.5, 31.4, 32.6, 42.0, 52.3, 54.4,
61.7, 61.9, 128.8 (2C), 129.4 (2C), 133.9, 140.0, 138.4, 139.2, 167.1,
167.6.
nmax 2952, 1783, 1734, 1457, 1348, 1220, 1164 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 1.12 (3H, d, J¼7.0 Hz), 1.74 (3H, s), 1.74–1.82 (1H,
m), 1.97–2.05 (1H, m), 2.15–2.35 (2H, m), 2.75 (1H, dq, J¼3.9, 7.0 Hz),
3.03 (1H, br s), 3.56 (3H, s), 4.88 (1H, d, J¼12.2 Hz), 4.97 (1H, d,
J¼12.2 Hz); 13C NMR (100 MHz, CDCl3) d 14.3, 14.4, 24.6, 37.3, 41.2,
50.1, 51.5, 63.4, 124.6,128.4,144.9,175.6. (ꢀ)-Dehydroiridomyrmecin
(31):[a]D ꢀ46(c1.0, CHCl3);IR(film)nmax 2948,1733,1437,1376,1206,
4.3. Synthesis of (L)-dehydroiridomyrmecin (31)
4.3.1. Methyl 7-phenylthio-1-iriden-9-oate (27)
p-TsOH (5 mg) was added to a stirred solution of 7 (91 mg,
0.26 mmol) in benzene (4 mL) and heated at reflux for 10 min (TLC
monitoring). The reaction mixture was diluted with t-BuOMe and
washed with aqueous NaHCO3 solution. The organic layer was
washed with brine, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The resulting crude was purified by col-
umn chromatography (hexane/t-BuOMe, 6:1) to afford 64 mg of 27.
IR (film) nmax 2946, 2844, 1731, 1583, 1479, 1437, 1378, 1197, 1170,
1088, 1024, 741, 691 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 1.17 (3H, d,
J¼7.1 Hz), 1.50 (3H, br s), 1.69–1.81 (1H, m), 1.90–2.04 (1H, m), 2.13–
2.25 (2H, m), 2.82 (1H, dq, J¼4.0, 7.0 Hz), 3.15–3.23 (1H, m), 3.51
(1H, br d, J¼12.9 Hz), 3.62 (3H, s), 3.89 (1H, br d, J¼12.9 Hz), 7.18–
7.40 (5H, m); 13C NMR (75 MHz, CDCl3) d 14.1, 15.0, 24.4, 31.8, 36.9,
41.0, 50.0, 51.6, 126.5, 128.3 (2C), 130.9 (3C), 136.7, 138.9, 175.9;
1156 cmꢀ1
;
1H NMR (400 MHz, (CD3)2CO) d 1.01 (3H, d, J¼7.2 Hz),
1.40–1.51 (1H, m), 1.70 (3H, s), 1.85–1.97 (1H, m), 2.20–2.30 (1H, m),
2.35–2.45 (1H, m), 2.90 (1H, quint, J¼7.2 Hz), 3.15–3.25 (1H, m), 4.77
(1H, d, J¼13.1 Hz), 4.87 (1H, d, J¼13.1, Hz); 13C NMR (100 MHz,
(CD3)2CO) d 11.6, 13.6, 27.1, 38.3, 40.3, 46.9, 65.8, 130.0, 137.0, 174.9;
HRCIMS calcd for C10H15O2 [MþH]þ 167.1072, found 167.1070.
Acknowledgements
This research was supported by the Spanish Ministry of Science
and Technology under projects BQU 2002-03211 and CTQ2006-
15575-C02-01. Thanks are due to Dr. M.J. de la Torre for revising our
English text.
HRFABMS calcd for
313.1239.
C
17H22O2SNa [MþNa]þ 313.1238, found
Supplementary data
4.3.2. Methyl 7-phenylsulfinyl-1-iriden-9-oate (29)
Detailed description of the preparation of the acyclic precursors
6, 11, 13, 15 and 17 as well as their spectral data is included.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.03.058.
To a stirred solution of 27 (220 mg, 0.75 mmol) in CH2Cl2 (8 mL)
under an argon atmosphere, MCPBA (186 mg, 0.75 mmol) in CH2Cl2
(6 mL) at ꢀ78 ꢂC was added. The reaction mixture was stirred at
this temperature for 5 min (TLC monitoring), diluted with CH2Cl2
(25 mL), washed with NaHCO3 and brine. The organic layer was
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The resulting crude was purified by column chromatog-
raphy (hexane/t-BuOMe, 1:1) to afford 25 mg of methyl 7-phenyl-
sulfonyl-1-iriden-9-oate 28 (5%), together with 184 mg of methyl
7-phenylsulfinyl-1-iriden-9-oate 29 (80%) as a diastereomeric
References and notes
1. (a) Meinwald, J.; Jones, T. H.; Eisner, T.; Hicks, K. Proc. Natl. Acad. Sci. U.S.A., Early
Ed. 1977, 74, 2189–2193; (b) Boros, C. A.; Stermitz, F. R. J. Nat. Prod. 1990, 53,
1055–1147; (c) Boros, C. A.; Stermitz, F. R. J. Nat. Prod. 1991, 54, 1173–1246; (d)
Nangia, A.; Prasuna, G.; Rao, B. Tetrahedron 1997, 53, 14507–14545; (e) Dinda,
B.; Debnath, S.; Harigaya, Y. Chem. Pharm. Bull. 2007, 55, 159–222.
2. (a) Franzyk, H. Synthetic Aspects of Iridoid Chemistry. In Progress in the Chem-
istry of Organic Natural Products; Kinghorn, A. D., Falk, H., Kirby, G. W., Herz, W.,
Eds.; Springer: Wien, New York, NY, 2000; Vol. 79, pp 1–114; (b) Piccinini, P.;
Vidari, G.; Zanoni, G. J. Am. Chem. Soc. 2004, 126, 5088–5089; (c) Tanaka, H.;
Kamikubo, T.; Yoshida, N.; Sakagami, H.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2001,
3, 679–681; (d) Korte, F.; Falbe, J.; Zschocke, A. Tetrahedron 1959, 6, 201–216; (e)
Chauhan, K. R.; Zhang, Q.-H.; Aldrich, J. R. Tetrahedron Lett. 2004, 45, 3339–3340.
3. Scho¨llhorn, B.; Mulzer, J. Eur. J. Org. Chem. 2006, 901–908.
4. (a) Chatgilialoglu, C.; Asmus, K. D. Sulfur-centered Reactive Intermediates in
Chemistry and Biology; Plenum: New York, NY, 1990; (b) Wardman, P. S-Centered
Radicals; Alfassi, Z. B., Ed.; Wiley: New York, NY, 1999; Chapter 10; (c) Abe-
dinzadeh, Z. Can. J. Physiol. Pharmacol. 2001, 79, 166–170; (d) Giles, G. I.; Jacob,
C. Biol. Chem. 2002, 383, 375–388.
5. For revisions of sulfanyl radicals, see: (a) Griesbaum, K. Angew. Chem., Int. Ed. Engl.
1970, 9, 273–287; (b) Miyata, O.; Naito, T. C. R. Acad. Sci. , Ser. IIc: Chim. 2001, 4,
401–421.
mixture at a 1:1 ratio. Data for compound 28: IR (film) n
2925,
max
1730, 1447, 1306, 1150, 1085, 747, 689 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) d 1.10 (3H, d, J¼7.0 Hz), 1.18 (3H, s), 1.60–1.70 (1H, m), 1.90–
2.03 (1H, m), 2.11 (2H, m), 2.85 (1H, dq, J¼3.8, 7.0 Hz), 3.10–3.20
(1H, m), 3.55 (3H, s), 3.92 (1H, d, J¼14.4 Hz), 4.05 (1H, d, J¼14.4 Hz),
7.47–7.53 (2H, m), 7.58–7.63 (1H, m), 7.79–7.84 (2H, m); 13C NMR
(100 MHz, CDCl3) d 14.1, 14.6, 24.4, 36.7, 40.5, 50.8, 51.5, 54.8, 123.7,
128.3 (2C), 129.1 (2C), 133.7, 138.9, 145.3, 175.6; HRFABMS calcd for
C
17H22O4SNa [MþNa]þ 345.1136, found 345.1134. Data for com-
pound 29: IR (film) n
2935, 1727, 1443, 1378, 1259, 1198, 1086,
max
1043, 751, 692 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.00 (3H, d,
;
J¼7.0 Hz), 1.10 (3H, d, J¼7.0 Hz), 1.16 (3H, s), 1.50 (3H, s), 1.55–1.75
(2H, m), 1.80–1.95 (2H, m), 2.05–2.19 (2H, m), 2.17 (2H, t, J¼7.3 Hz),

´
E.M. Sanchez et al. / Tetrahedron 64 (2008) 5111–5118
5118
6. (a) Bertrand, P.; Ferreri, C. Sulfur-Centered Radicals. In Radicals in Organic
Vofsi, D. J. Chem. Soc. 1964, 4962–4971; (d) Sinnreich, J.; Asscher, M. J Chem. Soc.,
Perkin Trans. 1 1971, 1543–1545.
Synthesis; Renaud, P., Sibi, P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 485–
504; (b) Zard, S. Z. Radical Reactions in Organic Synthesis; Compton, R. G., Davies,
S. G., Evans, J., Eds.; Oxford University Press: 2003; (c) Miyata, O.; Ozawa, Y.;
Ninomiya, I.; Naito, T. Tetrahedron 2000, 56, 6199–6207.
7. Naito, T.; Honda, Y.; Bhavakul, V.; Yamaguchi, S.; Fujiwara, A.; Miyata, O.;
Ninomiya, I. Chem. Pharm. Bull. 1997, 45, 1932–1939.
16. The ratio of stereoisomers obtained was determined by HPLC.
17. (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373–376; (b)
Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925–3941; (c) Spell-
meyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959–974; (d) Beckwith, A. L. J.;
Zimmermann, J. J. Org. Chem. 1991, 56, 5791–5796.
8. Miyata, O.; Nishiguchi, A.; Inomiya, I.; Aoe, K.; Okamura, K.; Naito, T. J. Org.
Chem. 2000, 65, 6922–6931.
9. Miyata, O.; Muroya, K.; Koide, J.; Naito, T. Synlett 1998, 271–272.
10. Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953, 73, 1026–1029.
11. Feldman, K. S.; Romanelli, A. L.; Ruckle, R. E., Jr.; Miller, R. F. J. Am. Chem. Soc.
1988, 110, 3300–3302.
18. The conformational or steric energy the methyl group is 1.74 kcal/mol, whereas
that of the acetate is 0.79 kcal/mol. Eliel, E. L.; Wilen, S. H.; Mander, L. N.
Stereochemistry of Organic Compounds; John Wiley and Sons: New York, NY,
1994.
19. Giese, B. Stereoselectivity of Radical Reactions. In Radicals in Organic Syn-
thesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1,
pp 380–399.
20. Rosenkranz, G.; Kaufmann, S. T.; Romo, J. J. Am. Chem. Soc. 1949, 71, 3689–3694.
21. Sakai, T.; Nakajima, K.; Sakan, T. Bull. Chem. Soc. Jpn. 1980, 53, 3683–3686.
22. Boulin, B.; Arreguy-San Miguel, B.; Delmond, B. Tetrahedron 2000, 56, 3927–
3932.
12. (a) Feldman, K. S.; Burns, C. B. J. Org. Chem. 1991, 56, 4601–4602; (b) Feldman,
K. S.; Ruckle, R. E.; Romanelli, A. L. Tetrahedron Lett. 1989, 30, 5845–5848.
´
13. Pedrosa, R.; Andres, C.; Duque-Soladana, J. P.; Maestro, A.; Nieto, J. Tetrahedron:
Asymmetry 2003, 14, 2985–2990.
14. Barrero, A. F.; Arseniyadis, S.; Herrador, M. M.; Quı´lez del Moral, J. F.; Arteaga, J.;
´
Sanchez, E. M. Synlett 2005, 591–594.
23. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157–405.
24. Hagiwara, H.; Kobayashi, T.; Suzuki, T.; Ando, M. Tetrahedron 2001, 57,
5039–5043.
15. (a) Montevecchi, P. C.; Navacchia, M. L. J. Org. Chem. 1997, 62, 5600–5607; (b)
Walling, C.; Helmreich, W. J. Am. Chem. Soc. 1959, 81, 1144–1148; (c) Asscher, M.;