Efficient construction of highly substituted and stereodefined cis-fused lactones

Article abstract of DOI:10.1002/ejoc.201000556

The methodology described in this paper involves the epoxidation of cyclic ene-acetals to spontaneously generate 6α-hydroxy-bis-acetals that could serve as precursors for a Cannizzaro-type rearrangement, yielding bis-angularly substituted cis-fused lactones. Both the oxidizing reagent, m-CPBA or NaBO ₃, and the substitution pattern can be important in determining the course of the epoxidation/ring-opening sequence, with NaBO₃ being the ideal electrophilic oxidant for the epoxidation/spontaneous ring-opening/ring-system interchange sequence.

Full text of DOI:10.1002/ejoc.201000556

FULL PAPER
DOI: 10.1002/ejoc.201000556
Efficient Construction of Highly Substituted and Stereodefined cis-Fused
Lactones
Zobida Elkhayat,[a] Imad Safir,[a] Zoila Gandara,[a] Pascal Retailleau,[a] and
Siméon Arseniyadis*[a]
Dedicated to Professor Henri Kagan on the occasion of his 80th birthday
Keywords: Epoxidation / Domino reactions / Lactones / Terpenoids / Fused-ring systems
The methodology described in this paper involves the epox- or NaBO3, and the substitution pattern can be important in
idation of cyclic ene-acetals to spontaneously generate 6α-
determining the course of the epoxidation/ring-opening se-
hydroxy-bis-acetals that could serve as precursors for a Can- quence, with NaBO3 being the ideal electrophilic oxidant for
nizzaro-type rearrangement, yielding bis-angularly substi-
tuted cis-fused lactones. Both the oxidizing reagent, m-CPBA
the epoxidation/spontaneous ring-opening/ring-system in-
terchange sequence.
palilactone (3b),[2e] and the norsesquiterpene spirolactone–
testosterone hybrid 6.[2b]
Introduction
Through our efforts towards the total synthesis of nor-
sesquiterpene spirolactones 3a and 3b, we investigated the
PhI(OAc)2-mediated oxidative cleavage of unsaturated diol
1a (obtained from (S)-(+)-Wieland–Miescher ketone),
which provided required tricyclic framework 2a (Scheme 1).
We then extended the synthetic usefulness of this domino[1]
approach to the synthesis of norsesquiterpene spirolactone–
testosterone hybrids of type 6 starting from steroidal unsat-
urated diol 4a as the domino precursor. This provided a
convenient route for the synthesis of 1-epi-pathylactone A
(3a, R = OH),[2a] thus invalidating the assigned C1 configu-
ration for pathylactone A,[2c,2d] the carbon skeleton of na-
Thus, a methodology has been developed within our
group that has proven valuable for the construction of
elaborated six-membered rings contained in natural as well
as unnatural products. A similar methodology could also
be employed for the preparation of advanced building
blocks for the agarofuran sesquiterpene skeleton (i.e., 7)[3–5]
as well as for hybrid molecules of type 8[6] starting from
the same tricyclic frameworks 2a and 5a, respectively
(Scheme 2).
Scheme 2.
The constant structural motif in the β-agarofuran series
is a trans-fused decalin, which incorporates two adjacent
quaternary centers at C5 and C10. The same ring system,
albeit with different locations of unsaturation and oxygen
functionality, is found in a large number of related mole-
cules. Inspired by the previous contributions reported by
Danishefsky,[7] Vankar,[8] and Goti[9] on the epoxidation of
View this journal online at
Scheme 1.
[a] Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS,
91198 Gif-sur-Yvette Cedex, France
E-mail: simeon.arseniyadis@icsn.cnrs-gif.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000556.
wileyonlinelibrary.com
Eur. J. Org. Chem. 2010, 4851–4860
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4851

Z. Elkhayat, I. Safir, Z. Gandara, P. Retailleau, S. Arseniyadis
FULL PAPER
glycals, we sought to exploit our domino approach along the Supporting Information). Fluoride-mediated deprotec-
with a facile preparation of bicyclic lactones that was devel- tion and subsequent Dess–Martin oxidation of 2a provided
oped in our laboratory[10] for the synthesis of various agaro- requisite C4 ketone 2b used for the synthesis of 2c–e. Treat-
furan precursors and hybrid molecules.
ment of 2b with methyllithium at low temperature afforded
Close precursors of β-agarofuran (7a), dihydro-β-agaro- the corresponding epimeric methyl carbinols 2d and 2e in
furan (7b), and its congeners celorbicol (7c), boariol (7d), 76% yield and a 2:1 diastereoselectivity. Diastereomerically
and 4β-hydroxycelorbicol (7e), as well as various derivatives pure 2e (m.p. 132–134 °C, heptane/Et2O) could be obtained
of β-agarofuran–testosterone hybrid 8 (Scheme 1) could be after purification of the crude reaction mixture by column
accessed by applying the proposed epoxidation/spontane- chromatography, and its C4 configuration was proved by
ous ring-opening/ring-system interchange sequence por- 1H NMR spectroscopy by using spatial proximity effect
trayed in Figure 1 to bicyclic and steroidal unsaturated diols measurements. The structure of crystalline carbinol 2d (m.p.
of types 1 and 4.
123–125 °C, heptane/Et2O), not surprisingly the major epi-
mer, was confirmed by a single-crystal X-ray diffraction
study, which showed that this compound arises from α-face
attack of the nucleophile at C4 (Figure 2).
Figure 1. Short and efficient reaction sequence from unsaturated
bicyclic diols (1/4) to cis-fused bicyclic lactones (11/16).
We report here an approach toward conveniently func-
tionalized cis-fused lactone building blocks of type 12/17
starting from type 2/5 domino products by a simple three-
step procedure in which sodium perborate[11] serves as an
ideal olefin oxidant and potassium carbonate as a Canniz-
zaro-type oxidoreduction promoter (Figure 1).
Scheme 3.
Results and Discussion
With the aim to investigate their reactivity pattern, a
series of tricyclic and pentacyclic ene-acetals of type 2 and
5 (half-cascade or interrupted domino products used in our
earlier studies) were prepared in quantity from the corre-
sponding domino precursors 1 and 4, respectively. Key
compounds 2a and 5a, obtained in one synthetic operation
upon treatment of 1a and 4a with PhI(OAc)2 (1.2 equiv.) in
acetonitrile, can be easily isolated, stored without any spe-
cial care, and further elaborated, thus allowing different
functional group interconversion in a stereodefined fashion.
We hypothesized that cyclic ene-acetals 2a and 5a might
Figure 2. ORTEP drawing of 2d (major carbinol, oxygen function-
alities in light gray).
Substrate 2c was obtained uneventfully from 2b by Wittig
behave as stereochemically biased building blocks provided olefination. Substrate 2f (Table 1) bearing an olefin and a
that their reactivity could be suitably controlled. To exam- protected alcohol was prepared from the known C1 ole-
ine this possibility, we investigated their epoxidation and fin[10b] through allylic oxidation at C2 and subsequent TBS
their trend to undergo a Cannizzaro-type oxidoreduction protection (see the Supporting Information). Cyclic ene-
upon orthogonal protection and subsequent mild base acetals 2a–h appear to possess the favorable attributes antic-
treatment. To that end, we chose m-CPBA and NaBO3 as ipated for highly regio- and stereoselective serial epoxid-
electrophilic oxidants and carried out initial experiments ation/ring opening and could thus be used as stereogenic
with m-CPBA.
scaffolds. Initial studies focused upon m-CPBA-treatment
Access to requisite substrates 2b–h with varying substitu- of half-cascade intermediates 2a–f as model compounds
tion and steric requirements was readily achieved from 2a (Table 1). This involved epoxidation at the sterically less
through trivial transformations (Schemes 3 and 5; see also screened face of the C6–C7 enol ether as well as the exocy-
4852
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4851–4860

Highly Substituted and Stereodefined cis-Fused Lactones
clic olefins at C1 and C4, and subsequent diaxial nucleo-
philic opening of the transient epoxide to form the corre-
sponding 6α-hydroxy-7β-aroyloxy bis-acetals 9a–f. Upon
treatment of 2a with m-CPBA (1.2 equiv.) in CH2Cl2 at
room temperature, corresponding bis-acetal 9a (m.p. 110–
112 °C, heptane/Et2O), whose structure was secured by X-
ray analysis (Figure 3), was isolated in 82% yield (96%
based on recovered starting material). The sense of selectiv-
ity favoring 9a is consistent with α-face attack (the more
exposed face of the π bond at C6–C7) for the peracid ad-
dition process setting the requisite stereochemistry at C6
(agarofuran numbering).[12]
Figure 3. ORTEP drawing of 9a (oxygen functionalities in light
gray).
Table 1. Reactions conducted with m-CPBA (2.0 mmol) and sub-
strate 2b–f (1.0 mmol) in CH2Cl2 (5 mL) at 25 °C.[a]
The results in Table 1 show that m-CPBA is highly ef-
ficient in controlling both the regio- and stereoselectivity
of oxyfunctionalization. No side products were observed;
instead, 7β-aroyloxy compounds were isolated (35–95%
yield) along with various amounts (10–20%) of unreacted
starting material. Templates bearing both an enol and an
alkene group such as 2c and 2f reacted cleanly with m-
CPBA, allowing stereoclean construction of highly func-
tionalized bicyclic bis-acetals 9c and 9f bearing four and six
contiguous stereogenic centers, respectively. In the one-step
transformations from 2d to 9d and from 2e to 9e, both C4
configurations required for boariol (7d) and 4β-hydroxy-
celorbicol (7e) were secured.
At the outset, we were concerned with the scope of the
sequential epoxidation/ring-opening process, whereas the
pending difficulty for the following Cannizzaro-type oxido-
reduction was not anticipated. Even though m-CPBA pro-
vided complete regioselectivity, difficulties were encoun-
tered during subsequent transformation; basic hydrolysis
(K2CO3, MeOH/H2O, 25 °C) did not give the desired lac-
tones even under forcing conditions (idem for the 6-MOM
protected bis-acetals). This disappointing result encouraged
us to explore more selective options for the planned three-
reaction process (serial epoxidation/nucleophilic ring open-
ing/mild basic treatment, Figure 1). Our second choice as
electrophilic oxidant, NaBO3 (SPB),[13] did the job per-
fectly, except as far as the regioselectivity was concerned.
Indeed, a C4 substitution (of any nature) was necessary to
ensure regioselectivity in the epoxide-opening step of the
process.[14] After examination of several options, the most
reliable and effective procedure was found to be the room-
temperature treatment in AcOH with the reagent (2 equiv.).
The optimized procedure involved addition of NaBO3 to a
solution of 2a in AcOH and stirring at room temperature
(TLC monitoring). This afforded desired acetoxy-bis-acetal
10a in satisfactory yields (68% along with 17% of recovered
starting material) and with an isomer profile identical to
[a] *9d was characterized as its corresponding C6 acetate. Ar stands
for m-ClC6H4.
Oxidation of substrates 2b–f with m-CPBA in CH2Cl2 that derived from m-CPBA. After purification by flash
gave hydroxyesters 9 as single products in each case through chromatography the structure of the crystalline 7β-acetoxy-
in situ nucleophilic epoxide opening, whereas no trace of 6α-hydroxy bis-acetal 10a (m.p. 97–98 °C, heptane/ether)
any intermediate epoxides was noted. NMR spectroscopic was first deduced by 2D NMR experiments, particularly
analysis did permit the assignment of both regio- and NOESY spectra, and was later confirmed by single-crystal
stereochemistry.
X-ray diffraction (Figure 4).
Eur. J. Org. Chem. 2010, 4851–4860
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4853

Z. Elkhayat, I. Safir, Z. Gandara, P. Retailleau, S. Arseniyadis
FULL PAPER
Baeyer–Villiger oxidation of 2g was detected.[13] MOM pro-
tection at C6 and subsequent basic treatment of 10h
(K2CO3, MeOH/H2O, 25 °C) ultimately allowed construc-
tion of the highly functionalized bicyclic lactone 12h.
Figure 4. ORTEP drawing of 10a (oxygen functionalities in light
gray).
Scheme 5.
The essence of our strategy toward the agarofuran back-
bone is depicted in Scheme 4.[15] Hence, conversion of 10a
into the corresponding MOM-protected 11a and subse-
quent mild base treatment (K2CO3, MeOH/H2O, 2 h,
25 °C) afforded targeted bicyclic lactone 12a in 98% yield.
A reasonable scheme to unveil the second quaternary center
at C5 and to set the correct C6 configuration of the agarof-
uran skeleton from 2a would involve intramolecular Can-
nizzaro-type oxidoreduction[16] of intermediate lactol i
through transient hemiacetal ii.
A key discovery in this first part was that conveniently
functionalized cyclic ene-acetals 2 undergo easy regio- and
stereoselective epoxidation/spontaneous ring-opening upon
treatment with NaBO3 in acetic acid, leading directly to 6α-
hydroxy-7β-acetoxy acetals 10 in good to high yields. Still,
the most interesting facet of this reaction is the ease of sub-
sequent mild base promoted ring-system interchange, lead-
ing to highly functionalized cis-fused lactone frameworks.
This approach provides easy access to the desired agaro-
furan building blocks, as starting unsaturated diols 1
(Scheme 1) are readily available from (S)-(+)-Wieland–
Miescher ketone.[2a]
Extension of the Method toward the Synthesis of
Agarofuran–Testosterone Hybrids
Given the success in forming cis-fused bicyclic lactones
from half-cascade intermediates 2, it seemed to us that this
approach could well prove to be adaptable to the synthesis
of hybrid molecules. Accordingly, a second set of experi-
ments was conducted in which the required half-cascade in-
termediates 5[10b] prepared from testosterone were subjected
to the epoxidation/ring-opening sequence.
Scheme 4. Ring-system interchange through mild base initiated in-
tramolecular hydride transfer.
To highlight the method, the above synthetic strategy was
Analogous results were obtained for the epoxidation of
applied to substrates 2g and 2h bearing a free carbonyl steroidal substrate 5, as both m-CPBA and NaBO3 were
group and an exocyclic olefin, respectively, both prepared successfully employed in the epoxidation/in situ opening
from known 2a by using standard literature procedures studies in CH2Cl2 and AcOH, respectively. The behavior
(Scheme 5 and Supporting Information). The importance of NaBO3, which displayed no substantial selectivity thus
of steric accessibility of the transient epoxide was confirmed leading to a mixture of regioisomeric products 13 and 15
by the regioselectivity observed for substrates 2g and 2h, under identical conditions, is again in sharp contrast with
which furnish solely acetoxy acetals 10g and 10h. Thus, un- that of m-CPBA. The stereostructures of the resulting prod-
der the standard epoxidation/ring-opening conditions ucts (easily separable by chromatography) were inferred
(NaBO3·4H2O, AcOH, 25 °C) the C4 substitution of the from their 1H NMR spectra, as the C6 and C7 proton reso-
substrates dictated the regiochemical outcome through nances of regioisomers 13 and 15 are considerably different
steric effects, whereas no trace of lactone formation by (Scheme 6).
4854
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4851–4860

Highly Substituted and Stereodefined cis-Fused Lactones
PhMe followed by MOMCl). Nucleophilic epoxidation un-
der Corey–Chaykovsky conditions (indirectly) or meth-
yllithium addition of 5c ensured access to C4 α-methyl
carbinol (5f and 14e), whereas electrophilic epoxidation of
5d provided access to the epimeric C4 oxygenated quater-
nary center via epoxide 14d. Unsurprisingly, alkylation (5c
to 5e) and epoxidations (5c to 5f, and 5d to 14d) did show
excellent levels of stereoselectivity. This allowed modular
construction of the C4 oxygenated quaternary center, thus
providing access to precursor molecules for either type 7d
or 7e agarofuran–testosterone hybrids (Scheme 2).
As with cyclic acetals 2, the intermediate epoxides were
not isolable under the reaction conditions (using either m-
CPBA or NaBO3) except in the case of substrate 5f, which
showed a slightly different reactivity pattern. Indeed, the m-
CPBA-mediated epoxidation of 5f is unusual in that for this
substrate the transient epoxide does not immediately un-
dergo ring opening. In this specific case, the reaction was
incomplete, as the intermediate epoxide was resistant to
esterification, thus allowing bis-epoxy cyclic acetal 18 to be
isolated and characterized. However, we observed that the
latter, originally obtained as a minor product, was gradually
converted into 14g upon prolonged reaction time.
Scheme 6.
The sense of stereoselectivity favoring 14 and 15 is con-
sistent with α-face attack of the peracid followed by trans-
diaxial epoxide opening. Obviously, nucleophilic attack of
m-CPBA at the C6 position of the transient epoxide is steri-
cally more obstructed than attack by acetic acid.
The substrates used in this part of the study were synthe-
sized in an efficient manner from known domino product
Interestingly, subjection of substrates 5d and 5e to m-
5a[2b] by the route illustrated in Scheme 7. Fluoride-pro- CPBA-mediated epoxidation proceeded uneventfully, lead-
moted desilylation and subsequent Dess–Martin oxidation ing exclusively to 14d and 14e in good isolated yields. Struc-
afforded cleanly desired ketone 5c, which served as a key tural assignment of 14d was determined by X-ray analysis
intermediate for the construction of the required templates. of chlorhydrine 14f (Figure 5b), which was accidentally ob-
Corey–Chaykovsky epoxidation[17] of 5c thus obtained af- tained upon attempted TBS protection of the hydroxy
forded 5f; Wittig olefination furnished 5d, whereas meth- group at C6 (Scheme 7).[18] MeLi addition to 5c provided
yllithium addition cleanly afforded methyl carbinol 5e as a 5e with complete facial selectivity; the incoming nucleophile
single isomer. Finally, 5b (Scheme 8) was obtained by was directed to approach from the α-face (rationalized with
transprotection achieved in two steps from 5a (BF3·Et2O in chelation and the unfavored β-face Bürgi–Dunitz trajectory,
Scheme 7. Towards the main representatives of agarofuran sesquiterpene–testosterone hybrids: varying the C4 configuration.
Eur. J. Org. Chem. 2010, 4851–4860
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4855

Z. Elkhayat, I. Safir, Z. Gandara, P. Retailleau, S. Arseniyadis
FULL PAPER
Figure 5. (a) Rationalization of facial selectivity upon nucleophilic attack on 5c (PM3 minimized structure). (b) ORTEP drawing of 14f
(oxygen functionalities in light gray).
Figure 5a). m-CPBA-mediated epoxidation then led to 14e, rofuran numbering) oxygenated compound 15b is formed
whose structure was confirmed by NMR spectroscopy and with complete selectivity (both regio- and stereo-), as the
by analogy with the compounds obtained from 2e and 2d starting ene-acetal is functionalized at C4. This significant
(Scheme 3).
orientation effect of the allylic OTBS substituent at C4 is
As discussed above, due to practical problems, NaBO3 not surprising considering the distance of this bulky group
was employed as a potential replacement for m-CPBA. In from the transient epoxide reaction center. Moreover, its
the reaction pathway depicted in Scheme 8, the C6,C7 (aga- influence on the conformation of the cyclohexane is an im-
portant determinant of acetoxy accessibility.[19]
Finally, having probed the susceptibility of a range of
cyclic ene-acetals toward the sodium perborate mediated
epoxidation, extension to a one-pot, three-component dom-
ino protocol was investigated. Hence, oxidative cleavage of
diol 5 with Pb(OAc)4 in CH2Cl2 (the solvent is compatible
with both reagents) triggered a hetero-[4π + 2π] cycload-
dition in which m-CPBA epoxidized the enol ether to afford
directly bis-acetal backbone I, though in very low yields
and as mixtures of aroylated and acetylated derivatives (the
acetyl group comes from the domino promoter). The latter,
added in a consecutive way (one-pot reaction) offered no
improvement and appeared to diminish the yield and purity
of the isolated product mixture (Scheme 9).
In summary, we have shown that variously functionalized
bicyclic or tetracyclic ene-acetals were amenable to this
epoxidation/spontaneous ring-opening reaction in which
Scheme 8. Synthesis of key intermediate 17 for agarofuran–testo-
sterone hybrids.
Scheme 9. Attempted “one-pot” oxidative cleavage/epoxidation/ring opening.
4856
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4851–4860

Highly Substituted and Stereodefined cis-Fused Lactones
2858, 1746, 1471, 1445, 1362, 1248, 1226, 1079, 1015, 1003, 913,
836, 778, 729, 672 cm–1. 1H NMR (500 MHz): δ = 0.10 (s, 3 H,
Me-Si), 0.12 (s, 3 H, Me-Si), 0.90 (s, 9 H, tBu), 1.42 (m, 1 H, H2),
1.50 (s, 3 H, Me14), 1.67 (ddd, J = 2.7, 3.0, 13.9 Hz, 1 H, H3),
1.90 (dt, J = 2.5, 13.8 Hz, 1 H, H3), 2.03 (dd, J = 2.9, 12.1 Hz, 1
H, H2), 2.10 (s, 3 H, MeC=O), 2.14 (m, 1 H, H9), 2.35 (dd, J =
6.2, 14.3 Hz, 1 H, H9), 2.46 (m, 1 H, OH), 3.69 [m, 4 H,
O(CH2)2O], 4.00 (dt, J = 1.3, 4.8 Hz, 1 H, H4), 4.31 (t, J = 2.2 Hz,
1 H, H6), 5.36 (d, J = 6.2 Hz, 1 H, H8), 6.03 (s, 1 H, H7) ppm.
13C NMR (125 MHz): δ = –5.2 (Me-Si), –4.8 (Me-Si), 17.6 (Me),
18.1 (Cq-tBu), 21.4 (C14), 23.1 (C2), 25.8 (3 C, tBu), 26.4 (C3),
39.1 (C9), 49.0 (C10), 50.7 (C1), 63.1 and 65.2 [O(CH2)2O], 66.5
(C6), 66.7 (C4), 88.1 (C5), 95.6 (C7), 100.1 (C8), 111.8 (C1), 169.1
ppm. MS (ESI+, MeOH): m/z (%) = 467.2 (100) [M + Na]+.
HRMS (ESI+, MeOH): calcd. C21H36O8NaSi 467.2077; found
467.2065. C21H36O8Si (444.22): calcd. C 56.73, H 8.16; found C
hydroxy and acyloxy (aroyloxy) substituents are regio- and
stereoselectively installed at C6 and C7, respectively, thus
yielding a variety of orthogonally protected α-hydroxy-bis-
acetals. The angular substituent at C10, in combination
with C4 substitution, enables a high measure of steric
manipulation in directing the attacking oxidant and the
sense of spontaneous epoxide ring opening.
Conclusions
Overall, a methodology has been developed that enables
the construction of useful stereodefined ring systems. The
ready availability of starting vicinal diols 1a and 4a, to-
gether with the effectiveness of the interrupted domino
transformations offering cleanly 2a and 5a, was vital to the 54.45, H 7.76. MOM protection at C6 was carried out on 10a
(2.5 g, 5.65 mmol) thus obtained in CH2Cl2 (20 mL) by adding
chloromethyl methyl ether (2.5 mL, 33.9 mmol) and diisopropyl-
ethylamine (6.3 mL, 36.1 mmol), and stirring for 1 h at 25 °C.
Usual workup and purification by flash chromatography (SiO2;
heptane/EtOAc, 7:3) afforded the corresponding MOM-protected
alcohol 11a (2.50 g, 93%). Yellow oil. [α]2D0 = +30.0 (c = 1.0,
development of the route presented in this work. Consider-
ing their special structural features, the investigated sub-
strates offer promising openings to explore their propensity
in regio- and stereoselective epoxidations (reagent and sub-
strate selectivity, respectively). The C10 methyl group along
with the system’s cavity dictates π-facial selectivity, whereas
C4 substitution, other than hydrogen, promotes regioselec-
tive ring opening when NaBO3 is used as the electrophilic
oxidant. In the course of the present study, we discovered
CHCl ), IR (film): ν = 2953, 1748, 1445, 1227, 1150, 1103, 1034,
˜
3
1050, 914, 828, 774 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.07
(s, 3 H, Me-Si), 0.12 (s, 3 H, Me-Si), 0.90 (s, 9 H, tBu), 1.46 (m, 1
H, H2), 1.49 (s, 3 H, Me14), 1.71 (m, 1 H, H3), 1.97 (m, 2 H, H3,
that the initially used m-CPBA is not compatible with the H2), 2.11 (s, 3 H, MeC=O), 2.13 (s, 1 H, H9), 2.43 (dd, J = 6.3,
14.3 Hz, 1 H, H9), 3.46 (s, 3 H, CH3-OCH2O), 3.84 (s, 1 H, H6),
3.94 [m, 4 H, O(CH2)2O], 4.48 (s, 1 H, H4), 4.89 and 4.92 (ABq, J
= 6.7 Hz, 2 H, OCH2OCH3), 5.38 (d, J = 6.1 Hz, 1 H, H8), 6.35
(s, 1 H, H7) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.2 (Me-Si),
–3.1 (Me-Si), 17.8 (Me14), 18.3 (Cq-tBu), 21.3 (CH3-OAc), 23.4
(C2), 25.5 (C3), 26.6 (3 C, tBu), 39.1 (C9), 49.5 (Cq10), 56.0 (CH3-
OCH2O), 63.1 and 65.1 [O(CH2)2O], 67.1 (C4), 74.8 (C6), 87.5
(Cq5), 93.6 (C7), 98.6 (OCH2-OCH3), 99.5 (C8), 111.7 (Cq9),
168.9 ppm. MS (ESI+, MeOH): m/z (%) = 511.2 (100) [M + Na]+.
HRMS (ESI+, MeOH): calcd. for C23H40O9NaSi 511.2339; found
511.2329. To a stirred solution of 11a (1.10 g, 2.25 mmol) in a mix-
ture of methanol (140 mL) and water (14 mL) was added potassium
carbonate (3.10 g, 22.5 mmol). The resulting mixture was stirred at
room temperature for 1 h. After removing solvents without heating,
dilution with EtOAc, usual workup, and chromatography on silica
gel (heptane/EtOAc, 4:1) bicyclic lactone 12a (0.98 g, 98%) was
obtained as a colorless oil. [α]2D0 = +34.3 (c = 1.0, CHCl3), IR (film):
mild base induced Cannizzaro oxidoreduction part of the
serial epoxidation/ring opening/intramolecular hydride
transfer and that only NaBO3 (SPB) is capable of achieving
the whole sequence. Reactivity can be increased by in-
clusion of olefinic functional groups, and the process is
compatible even with a free carbonyl group.
Experimental Section
General: "Usual workup" means washing of the organic layer with
brine, drying with anhydrous MgSO4, and concentrating in vacuo
under reduced pressure. Melting points were determined with a
Büchi B- 540 apparatus. IR spectra were recorded with a Perkin–
Elmer Spectrum BX instrument with an FTIR system. Optical Ro-
tations were measured with a JASCO- 810 polarimeter by using a
cell with a 1-dm-length path. NMR spectra were run in CDCl3
unless otherwise noted. Experimental evidence favoring the struc-
ν = 3469, 2952, 1775, 1462, 1231, 1104, 1042, 988, 834, 776, 730,
˜
1
670 cm–1. H NMR (500 MHz, CDCl3): δ = 0.07 (s, 3 H, Me-Si),
tures investigated came from a comprehensive range of 1H and 13
C
0.15 (s, 3 H, Me-Si), 0.91 (s, 9 H, tBu), 1.35 (s, 3 H, Me14), 1.62
(m, 2 H, 2 H2), 1.84 (m, 3 H, H8, 2 H3), 2.45 (m, 2 H, 2 H9), 3.44
(s, 3 H, CH3-OCH2O), 3.90 [m, 3 H, H6, O(CH2)2O], 4.02 [m, 5
H, 2H7, H4, O(CH2)2O], 4.59 and 4.74 (ABq, J = 6.7 Hz, 2 H,
OCH2OCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.1 (Me-
Si), –4.9 (Me-Si), 17.8 (Cq-tBu), 19.2 (C14), 25.6 (3 C, tBu), 26.2
(C8), 27.9 (C7), 39.9 (C1), 49.9 (Cq10), 55.8 (CH3-OCH2O), 62.4
(C7), 64.5 and 64.6 [O(CH2)2O], 73.3 (C4), 89.2 (C6), 92.7 (Cq5),
99.1 (OCH2-OCH3), 110.9 (Cq5), 175.7 ppm. MS (ESI+, MeOH):
m/z (%) = 469.2 (100) [M + Na]+. HRMS (ESI+, MeOH): calcd.
for C21H38O8NaSi 469.2234; found 469.2219.
NMR data (500/125 and 300/75 MHz respectively, 1D and 2D ex-
periments) and corroborated by spatial proximity (n.O.e). For all
compounds investigated, multiplicities of 13C resonances were as-
signed by the DEPT technique. 1H chemical shifts are expressed in
ppm downfield from TMS using the residual nondeuterated solvent
as internal standard (CDCl3, 1H: 7.26 ppm). 13C chemical shifts are
reported relative to CDCl3 triplet centered at 77.0 ppm.
Preparation of Bicyclic Lactone 12a by the Three-Reaction Se-
quence: NaBO3·4H2O-mediated epoxidation of substrate 2a
(170 mg, 0.46 mmol) was carried out in AcOH (10 mL) at room
temperature by using the general procedure (24 h, see the Support-
ing Information) to give, after SiO2 flash column chromatography
(heptane/EtOAc, 1:1), 6α-hydroxy-7β-acetoxy bis-acetal 10a
(138 mg, 68%) along with recovered starting material (28 mg,
17%). Data for 10a: White solid; m.p. 97–98 °C (heptane/Et2O).
Preparation of Steroidal Lactone 17 by the Three-Reaction Se-
quence: NaBO3·4H2O-mediated epoxidation of substrate 5b (90 mg,
0.25 mmol) was carried out proceeding as above (18 h) to give, after
SiO2 flash column chromatography (heptane/EtOAc, 1:1), 15b
(92.3 mg, 84%). Colorless oil. [α]2D0 = 39.1 (c = 1.1, CHCl3). IR
[α]2D0 = +9.3 (c = 1.0, CHCl ). IR (film): ν = 3447, 2954, 2935, 2889,
˜
3
Eur. J. Org. Chem. 2010, 4851–4860
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4857

Z. Elkhayat, I. Safir, Z. Gandara, P. Retailleau, S. Arseniyadis
FULL PAPER
(film): ν = 3431, 2950, 2926, 2853, 1747, 1470, 1460, 1388, 1361,
1330, 1247, 1221, 1164, 1152, 1098, 1071, 1046, 1018, 928, 834,
781, 732, 648 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.00 (s, 3 H, H, H16Ј), 2.50 and 2.28 (ABq, J = 17.6 Hz, 2 H, 2 H9), 3.23 (s, 3
Me-Si), 0.02 (s, 3 H, Me-Si), 0.74 (s, 3 H, Me18Ј), 0.82 (s, 9 H, H, CH3O-CH2O), 3.34 (s, 3 H, CH3O-CH2O), 3.40, (t, J = 8.5 Hz,
tBu), 0.89 (m, 1 H, H14Ј), 1.02 (m, 1 H, H12Ј), 1.13 (dt, J = 1.9, 1 H, H17Ј), 3.47, (dd, J = 4.0, 8.8 Hz, 1 H, OH), 3.72 (ddd, J =
H11Ј), 1.35 (m, 2 H, H16Ј, H3), 1.52 (m, 1 H, H11Ј), 1.60 (m, 2
H, H3, H15Ј), 1.62 (m, 1 H, H2), 1.70 (m, 1 H, H12Ј), 1.95 (m, 1
˜
5.7 Hz, 1 H, H1), 1.18 (s, 3 H, Me14), 1.20 (m, 2 H, H15Ј, H11Ј),
1.30 (m, 2 H, H16Ј, H3), 1.44 (td, J = 3.5, 12.3 Hz, 1 H, H15Ј),
4.2, 6.1, 12.0 Hz, 1 H, H7), 3.90, (dd, J = 1.8, 6.6 Hz, 1 H, H6),
3.98, (td, J = 2.5, 11.1 Hz, 1 H, H4), 4.19 (dd, J = 2.9, 6.0 Hz, 1
1.52 (m, 1 H, H3), 1.59 (td, J = 3.2, 13.9 Hz, 1 H, H2), 1.67 (dd, H, H6), 4.50 (ABq, J = 6.6 Hz, 2 H, OCH2-OCH3), 4.57 and 4.72
J = 2.3, 11.3 Hz, 1 H, H12Ј), 1.82 (td, J = 3.2, 12.3 Hz, 1 H, H16Ј), (ABq, J = 6.9 Hz, 2 H, OCH2-OCH3) ppm. 13C NMR (125 MHz,
1.98 (dd, J = 6.2, 14.1 Hz, 1 H, H9), 2.03 (s, 3 H, Me), 2.22 (d, J
= 14.1 Hz, 1 H, H9), 2.70 (d, J = 11.1 Hz, 1 H, OH), 3.27 (s, 3 H,
CDCl3): δ = –5.1 (Me-Si), –3.7 (Me-Si), 11.8 (C18Ј), 15.6 (C14),
18.1 (Cq-tBu), 22.1 (C11Ј), 23.1 (C15Ј), 25.9 (3 C, tBu), 28.0 (C12Ј),
CH3OCH2O), 3.45, (t, J = 8.2 Hz, 1 H, H17Ј), 3.80 (d, J = 11.1 Hz, 29.2 (C2), 31.8 (C3), 37.1 (C16Ј), 43.1 (C10), 43.4 (C13Ј), 44.7 (C9),
1 H, H6), 4.31 (t, J = 2.9 Hz, 1 H, H4), 4.58 (ABq, J = 8.0 Hz, 2 48.7 (C1), 50.2 (C14Ј), 55.1 (CH3-OCH2O), 56.1 (CH3-OCH2O),
H, OCH2-OCH3), 5.28 (d, J = 5.4 Hz, 1 H, H8), 5.95 (s, 1 H, H7)
62.7 (C4), 69.8 (C), 86.2 (C6), 86.9 (C17Ј), 91.1 (C5), 96.0 (OCH2-
OCH3), 98.2 (OCH2-OCH3), 176.2 (C8) ppm. MS (ESI+, MeOH):
ppm. 13C NMR (125 MHz, CDCl3): δ = –5.2 (Me-Si), –4.6 (Me-
Si), 11.6 (C18Ј), 15.1 (C14), 17.9 (Cq-tBu), 21.3 (C11Ј), 21.4 (C14), m/z (%) = 579.3 (100) [M + Na]+. HRMS (ESI+, MeOH): calcd.
23.1 (C15Ј), 25.8 (3 C, tBu), 28.1 (C2), 29.0 (C16Ј), 33.9 (C3), 37.4 for C29H52O8NaSi 579.3329; found 579.3316. C29H52O8Si (556.34):
(C12Ј), 42.8 (C10), 43.6 (C13Ј), 45.2 (C8Ј), 50.2 (C1), 51.8 (C14Ј),
55.0 (CH3O-CH2O), 66.6 (C6), 66.8 (C4), 86.4 (C5), 86.5 (C17Ј),
95.5 (C7), 95.9 (OCH2-OCH3), 99.3 (C8), 169.0 ppm. MS (ESI+,
MeOH): m/z (%) = 577.3 (100) [M + Na]+. HRMS (ESI+, MeOH):
calcd. for C29H50O8NaSi 577.3173; found 577.3176. C29H50O8Si
(554.32): calcd. C 62.78, H 9.08; found C 61.08, H 7.43. MOM
protection at C6 was carried out on 15b (210 mg, 0.37 mmol) as
described above. Purification by flash chromatography (SiO2; hep-
tane/EtOAc, 9:1) afforded the corresponding MOM-protected
alcohol 16 (189.3 mg, 86%). Colorless oil. [α]2D0 = +42.6 (c = 0.9,
calcd. C 62.56, H 9.41; found C 62.78, H 9.46.
Preparation of Epoxides 5f and 14d and Methyl Carbinol 5e through
Alteration of the Configuration at C4: To a solution of sodium hy-
dride (31.2 mg, 1.3 mmol) and trimethylsulfonuim iodide
(106.5 mg, 0.52 mmol) in DMSO (0.6 mL) was added dropwise a
solution of steroidal ketone 5c (100 mg, 0.26 mmol) in THF/
DMSO (1:1, 1.2 mL) at 25 °C. The reaction mixture was stirred at
the same temperature for 12 h. Then it was hydrolyzed with water
(3 mL) and extracted with EtOAc (4ϫ5 mL). The organic layer
was washed with water (5ϫ2 mL), dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by col-
umn chromatography (heptane/EtOAc, 4:1) to give 5f (82 mg,
CHCl ). IR (film): ν = 2953, 2929, 2857, 1753, 1471, 1460, 1388,
˜
3
1363, 1249, 1224, 1153, 1103, 1071, 1038, 973, 928, 836, 774, 732,
667 cm–1 1H NMR (500 MHz, CDCl3): δ = 0.00 (s, 3 H, Me-Si),
.
81%). Colorless oil. [α]2D0 = +35 (c = 1.5, CHCl ). IR (film): ν =
˜
3
0.06 (s, 3 H, Me-Si), 0.77 (s, 3 H, Me18Ј), 0.82 (m, 1 H, H14Ј),
0.87 (s, 9 H, tBu), 0.90 (m, 1 H, H12Ј), 1.07 (td, J = 3.8, 12.7 Hz,
1 H, H1), 1.20 (s, 3 H, Me14), 1.22 (m, 2 H, H15Ј, H11Ј), 1.34 (dd,
J = 3.2, 13.6 Hz, 1 H, H16Ј), 1.44 (td, J = 3.4, 13.0 Hz, 1 H, H7Ј),
1.50 (m, 1 H, H11Ј), 1.58 (m, 2 H, H3, H15Ј), 1.67 (m, 1 H, H2),
1.70 (td, J = 2.6, 11.1 Hz, 1 H, H12Ј), 1.85 (td, J = 3.3, 12.4 Hz, 1
H, H16Ј), 1.98 (dd, J = 6.1, 14.2 Hz, 1 H, H9), 2.05 (s, 3 H,
MeC=O), 2.25 (d, J = 14.2 Hz, 1 H, H9), 3.29 (s, 3 H, CH3O-
CH2O), 3.41 (s, 3 H, CH3O-CH2O), 3.47, (t, J = 8.2 Hz, 1 H,
H17Ј), 3.77 (s, 1 H, H6), 4.50 (dd, J = 2.4, 3.4 Hz, 1 H, H4), 4.57
(ABq, J = 6.7 Hz, 2 H, OCH2-OCH3), 4.78 and 4.87 (ABq, J =
6.8 Hz, 2 H, OCH2-OCH3), 5.33 (d, J = 6.1 Hz, 1 H, H8), 6.29 (s,
1 H, H7) ppm. 13C NMR (125 MHz, CDCl3): δ = –2.8 (Me-Si),
0.0 (Me-Si), 14.2 (C18Ј), 18.4 (C14), 20.2 (Cq-tBu), 23.9 (Me), 24.2
(C11Ј), 25.2 (C15Ј), 28.7 (3 C, tBu), 30.6 (C12Ј), 31.4 (C2), 35.4
(C3), 40.1 (C16Ј), 45.6 (C10), 46.4 (C13), 48.4 (C1), 52.8 (C9), 54.5
(C14Ј), 57.5 (CH3O-CH2O), 58.6 (CH3O-CH2O), 69.9 (C4), 77.9
(C6), 88.4 (C5), 88.9 (C17Ј), 96.0 (C7), 98.0, 101.2 (C8), 101.7,
171.5 ppm. MS (ESI+, MeOH): m/z (%) = 621.3 (100) [M + Na]+.
HRMS (ESI+, MeOH): calcd. for C31H54O8NaSi 621.3435; found
621.3447. C31H54O8Si (598.35): calcd. C 62.18, H 9.09; found C
62.22, H 9.25. To a stirred solution of 16 (188 mg, 0.31 mmol) in
a mixture of methanol (18 mL) and water (1.5 mL) was added po-
tassium carbonate (434.2 mg, 3.1 mmol). The resulting mixture was
stirred at room temperature for 2 h. After removing solvents with-
out heating, dilution with EtOAc, usual workup, and chromatog-
raphy on silica gel (heptane/EtOAc, 4:1) 17 (148.5 mg, 86%) was
2971, 2945, 2905, 2359, 1633, 1456, 1377, 1388, 1360, 1249, 1216,
1203, 1144, 1074, 1086, 1074, 902, 877, 823, 755 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.73 (s, 3 H, Me1Ј8), 0.96 (m, 1 H), 1.04
(dd, J = 4.7, 13.1 Hz, 1 H), 1.11 (s, 9 H, tBu), 1.14 (s, 3 H, Me14),
1.24 (m, 3 H), 1.39 (m, 1 H), 1.46 (m, 3 H), 1.66 (td, J = 4.0,
11.3 Hz, 1 H), 1.82 (m, 3 H), 1.90 (d, J = 14.2 Hz, 1 H, H9), 2.23
(dd, J = 5.6, 14.2 Hz, 1 H, H9), 2.46 (d, J = 4.6 Hz, 1 H, H15),
2.82 (d, J = 4.6 Hz, 1 H, H15Ј), 3.35 (t, J = 8.3 Hz, 1 H, H17Ј),
4.83 (d, J = 6.7 Hz, 1 H, H6), 5.60 (d, J = 5.6 Hz, 1 H, H8), 6.22
(d, J = 6.1 Hz, 1 H, H7) ppm. 13C NMR (125 MHz, CDCl3): δ =
11.6 (C18Ј), 13.8 (C14), 21.6 (C11Ј), 23.5 (C15Ј), 28.7 (3 C, tBu),
31.2 (C3), 33.3 (C8Ј), 34.3 (C16Ј), 37.2 (C12Ј), 42.7 (C13Ј), 47.5
(C9), 47.6 (C1), 48.2 (C15), 50.6 (C4), 55.4 (C13Ј), 55.9 (C10), 72.1
(Cq-tBu), 80.6 (C17Ј), 84.2 (C5), 100.1 (C8), 105.0 (C6), 140.7 (C7)
ppm. MS (ESI+, MeOH): m/z (%) = 390.3 (100) [M + Na]+.
HRMS (ESI+, MeOH): calcd. for C24H38O4Na 390.2692; found
390.2678. C24H36O4 (388.26): calcd. C 74.19, H 9.34; found C
72.75, H 9.48. A solution of potassium tert-butoxide (4.88 g,
43.5 mmol) in dry toluene (5 mL) was stirred under an atmosphere
of argon at room temperature and to this solution was added meth-
yltriphenylphosphonium bromide (15.56 g, 43.5 mmol). The re-
sulting bright yellow solution was stirred for 1 h and then cooled
to 0 °C before ketone 5c (2.7 g, 7.26 mmol) was added in dry tolu-
ene (5 mL). The ice bath was removed, and the solution was stirred
at room temperature while the reaction progress was monitored by
TLC. After 4 h stirring, the reaction mixture was diluted with hep-
tane and worked up as usual. Rapid filtration through silica gel
(heptane/EtOAc, 4:1) afforded 5d (2.11 g, 78%). Colorless oil.
obtained. Colorless oil. [α]2D0 = 49.7 (c = 1.1, CHCl ). IR (film): ν
˜
3
[α]2D0 = +50.4 (c = 0.95, CHCl ). IR (film): ν = 2971, 2928, 2871,
= 3734, 2951, 1789, 1699, 1658, 1558, 1506, 1472, 1250, 1205, 1149,
1066, 1044, 945, 917, 836, 777, 668 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 0.00 (s, 3 H, Me-Si), 0.06 (s, 3 H, Me-Si), 0.76 (s, 3
H, Me18Ј), 0.82 (m, 1 H, H14Ј), 0.88 (s, 9 H, tBu), 0.92 (m, 1 H,
H12Ј), 0.97 (m, 1 H, H1), 1.14 (s, 3 H, Me14), 1.20 (m, 2 H, H15Ј,
˜
3
1737, 1628, 1446, 1388, 1375, 1361, 1215, 1206, 1142, 1105, 1090,
1073, 1028, 1000, 912, 875, 825, 800, 749, 666 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.72 (s, 3 H, Me14), 0.90 (m, 1 H, H15Ј),
1.01 (s, 3 H, Me14), 1.13 (s, 9 H, tBu), 1.26 (m, 3 H, H11Ј, H14Ј,
4858
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4851–4860

Highly Substituted and Stereodefined cis-Fused Lactones
H15Ј), 1.38 (m, 3 H, H12Ј, H1, H16Ј), 1.45 (m, 1 H, H16Ј), 1.64 CCDC-772959 (for 2d), -772958 (for 9a), -772956 (for 10a), and
(ddd, J = 2.8, 7.1, 9.1 Hz, 1 H, H11Ј), 1.76 (td, J = 2.9, 12.5 Hz, 1
H, H12Ј), 1.87 (m, 1 H, H8Ј), 1.95 (dd, J = 9.8, 12.9 Hz, 1 H, H1Ј),
-772957 (for 14f) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
2.07 (dd, J = 2.9, 11.4 Hz, 1 H, H3), 2.25 (m, 1 H, H3), 2.26 (td, Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
J = 5.8, 13.9 Hz, 1 H), 3.38, (t, J = 8.2 Hz, 1 H, H17Ј), 5.08 (s, 2 data_request/cif.
H, 2 H15), 5.26 (d, J = 6.3 Hz, 1 H, H6), 5.64 (d, J = 5.6 Hz, 1 H,
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the reactions described herein
and characterization data for all new compounds.
H8), 6.30 (d, J = 6.3 Hz, 1 H, H7) ppm. 13C NMR (125 MHz,
CDCl3): δ = 11.7 (C18Ј), 13.3 (C14), 21.6 5 (C11Ј), 23.6 (C15Ј),
28.7 (3 C, tBu), 31.2 (C3), 36.7 (C16Ј), 37.2 (C12Ј), 37.5 (C8Ј), 42.7
(C10), 47.5 (C1), 47.9 (C9), 50.7 (C14Ј), 56.9 (C13Ј), 72.2 (Cq-tBu),
80.1 (C17Ј), 84.1 (C5), 100.2 (C8), 107.0 (C6), 113.9 (C15), 139.8
(C7), 144.5 (C4) ppm. MS (ESI+, MeOH): m/z (%) = 395.2 (100)
Acknowledgments
[M + Na]+. HRMS (ESI+, MeOH): calcd. for C24H36O3Na
395.2562; found 395.2555. C23H34O3 (372.27): calcd. C 77.38, H
9.74; found C 76.83, H 9.56. m-CPBA-mediated epoxidation of
substrate 5d (210 mg, 0.56 mmol) was carried out by using the ge-
neral procedure (3 h, see the Supporting Information) to give, after
Financial support from the Centre National de la Recherche Sci-
entifique (CNRS) and fellowship awards from the Institut de Chi-
mie des Substances Naturelles (ICSN) are gratefully acknowledged.
SiO2 flash column chromatography (heptane/EtOAc, 4:1), 14d
(204 mg, 65%). Colorless oil. [α]2D0 = +24.0 (c = 0.88, CHCl3). IR
[1] a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 32, 115–136;
(film): ν = 3374, 3018, 2972, 2358, 1731, 1576, 1426, 1362, 1251,
˜
Angew. Chem. Int. Ed. Engl. 1993, 32, 131–163; b) L. F. Tietze,
Chem. Rev. 1996, 96, 115–136; c) L. F. Tietze, A. Modi, Med.
Res. Rev. 2000, 20, 304–322; d) L. F. Tietze, F. Haunert in Stim-
ulating Concepts in Chemistry (Eds.; M. Shibasaki, J. F. Stod-
dart, F. Vogtle), Wiley-VCH, Weinheim, 2000, pp. 39–64; e)
L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006.
1
1215, 1057, 916, 743, 667 cm–1. H NMR (500 MHz, CDCl3): δ =
0.75 (s, 3 H, Me18Ј), 0.88 (m, 3 H), 1.12 (s, 9 H, tBu), 1.25 (m, 2
H), 1.31 (s, 3 H, Me-14), 1.46 (m, 3 H), 1.51 (m, 2 H), 1.82 (td, J
= 3.8, 12.6 Hz, 1 H, H16), 2.06 (m, 1 H), 2.18 (dd, J = 6.3, 14.6 Hz,
1 H, H1), 2.55 (d, J = 14.6 Hz, 1 H, H1), 2.79 (d, J = 3.2 Hz, 1 H,
H15), 3.24 (t, J = 3.2 Hz, 1 H, H15), 3.38 (d, J = 8.1 Hz, 1 H,
H17Ј), 4.02 (s, 1 H, H6), 5.44 (s, 1 H, OH), 5.64 (d, J = 6.3 Hz, 1
H, H8), 6.13 (s, 1 H, H7), 7.42 (t, J = 7.5 Hz, 1 H), 7.57 (td, J =
1.4, 8.3 Hz, 1 H), 7.89 (td, J = 1.7, 7.8 Hz, 1 H), 7.90 (d, J =
1.7 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 11.7 (C18Ј),
14.6 (C14), 21.6 (C11Ј), 23.4 (C15Ј), 28.7 (3 C, tBu), 31.2 (C3), 35.6
(C16Ј), 36.0 (C8Ј), 37.1 (C12Ј), 42.6 (C13Ј), 45.0 (C9), 49.1 (C10),
50.2 (C1), 50.7 (C15), 52.4 (C14Ј), 62.3 (C4), 68.7 (C6), 72.3 (Cq-
tBu), 80.3 (C17Ј), 84.6 (C5), 96.4 (C8), 100.6 (C7), 127.7, 129.7,
130.0, 133.2, 133.5, 134.8, 163.5 ppm. MS (ESI+, MeOH): m/z (%)
= 583.2 (100) [M + Na]+. HRMS (ESI+, MeOH): calcd. for
C31H41ClO7Na 583.2439; found 583.2438. C31H41ClO7 (560.25):
calcd. C 66.36, H 7.37; found C 68.29, H 8.17. To a solution of
ketone 5c (606 mg, 1.62 mmol) in THF (7 mL) was added meth-
yllithium (1.6  in ether, 16.2 mmol) at –78 °C, and the mixture
was stirred for 45 min under an atmosphere of argon. The reaction
mixture was poured into saturated aqueous solution of NH4Cl at
0 °C, then extracted with EtOAc, washed with saturated aqueous
solution of NaHCO3, worked up as usual, and chromatographed
on SiO2 (heptane/EtOAc, 1:1) to give carbinol 5e (512 mg, 81%) as
a single diastereomer. Colorless oil. [α]2D0 = +14.6 (c = 0.6, CHCl3).
[2] a) A. Chanu, I. Safir, R. Basak, A. Chiaroni, S. Arseniyadis,
Org. Lett. 2007, 9, 1351–1354; b) A. Chanu, I. Safir, R. Basak,
A. Chiaroni, S. Arseniyadis, Eur. J. Org. Chem. 2007, 4305–
4312; c) J. Y. Su, Y.-L. Zhong, L.-M. Zeng, J. Nat. Prod. 1993,
56, 288–291; d) F. Coehlo, G. Diaz, Tetrahedron 2002, 58,
1647–1656; e) J. R. Vyvyan, C. A. Rubens, J. A. Halfen, Tetra-
hedron Lett. 2002, 43, 221–224.
[3] a) A. C. Spivey, M. Weston, S. Woodhead, Chem. Soc. Rev.
2002, 31, 43–59; b) J.-M. Gao, W.-J. Wu, J.-W. Zhang, Y. Koni-
shi, Nat. Prod. Rep. 2007, 24, 1153–1189.
[4] D. Torres-Romero, F. Muñoz-Martínez, I. A. Jiménez, S. Cas-
tanys, F. Gamarro, I. L. Bazzocchi, Org. Biomol. Chem. 2009,
7, 5166–5172 and references cited therein.
[5] a) J. A. Marshall, M. T. Pike, J. Org. Chem. 1968, 33, 435–437;
b) J. D. White, H. Shin, T.-S. Kim, N. S. Cutshall, J. Am. Chem.
Soc. 1997, 119, 2404–2419; c) Y. Q. Tu, L. D. Sun, Tetrahedron
Lett. 1998, 39, 7935–7938; d) A. C. Spivey, S. J. Woodhead, M.
Weston, B. I. Andrews, Angew. Chem. Int. Ed. 2001, 40, 769–
771; e) G. Zhou, X. Gao, W. Z. Li, Y. Li, Tetrahedron Lett.
2001, 42, 3101–3103; f) F.-D. Boyer, C. L. Descoins, C. Desco-
ins, T. Prange, P.-H. Ducrot, Tetrahedron Lett. 2002, 43, 8277–
8279; g) W. J. Xia, D. R. Li, L. Shi, Y. Q. Tu, Tetrahedron Lett.
2002, 43, 627–630; h) G. Mehta, R. M. Kumaran, Tetrahedron
Lett. 2003, 44, 7055–7059; i) F.-D. Boyer, T. Prangé, P.-H. Duc-
rot, Tetrahedron: Asymmetry 2003, 14, 1153–1159; j) C. A. Lee,
P. E. Floreancig, Tetrahedron Lett. 2004, 45, 7193–7196.
[6] a) G. Mehta, V. Singh, Chem. Soc. Rev. 2002, 31, 324–334; b)
L. F. Tietze, H. P. Bell, S. Chandrasekhar, Angew. Chem. Int.
Ed. 2003, 42, 3996–4028.
[7] There is ample literature evidence wherein a glycal could be
converted into its 1,2-oxirane derivative, see: a) R. L. Halcomb,
S. J. Danishefsky, J. Am. Chem. Soc. 1989, 111, 6661–6666; b)
U. Iserloh, V. Dudkin, Z.-G. Wang, S. J. Danishefsky, Tetrahe-
dron Lett. 2002, 43, 7027–7030.
[8] S. Rani, Y. D. Vankar, Tetrahedron Lett. 2003, 44, 907–909.
[9] G. Soldaini, F. Cardona, A. Goti, Tetrahedron Lett. 2003, 44,
5589–5592.
IR (film): ν = 3508, 2969, 2928, 2868, 2359, 2250, 1632, 1447, 1367,
˜
1370, 1361, 1251, 1202, 1193, 1084, 1099, 995, 928, 906, 884, 729,
1
647 cm–1. H NMR (500 MHz, CDCl3): δ = 0.73 (s, 3 H, Me18Ј),
0.94 (m, 2 H), 1.02 (dd, J = 4.4, 10.6 Hz, 1 H), 1.06 (dd, J = 4.4,
10.9 Hz, 1 H), 1.11 (s, 9 H, tBu), 1.15 (s, 3 H, Me14), 1.25 (s, 3 H,
Me15), 1.37 (m, 3 H), 1.48 (dd, J = 3.4, 13.0 Hz, 1 H), 1.57 (m, 2
H), 1.76 (td, J = 3.2, 12.5 Hz, 1 H), 1.86 (m, 2 H, H3, H9), 2.18
(dd, J = 6.0, 14.0 Hz, 1 H, H9), 3.35 (t, J = 8.3 Hz, 1 H, H17Ј),
5.27 (d, J = 6.1 Hz, 1 H, H6), 5.48 (d, J = 5.6 Hz, 1 H, H8), 6.29
(d, J = 6.1 Hz, 1 H, H7) ppm. 13C NMR (125 MHz, CDCl3): δ =
11.7 (C18Ј), 15.4 (C14), 21.3 (C11Ј), 23.7 (C15Ј), 26.7 (C14Ј), 28.7
(3 C, tBu), 31.2 (C3), 31.3 (C8Ј), 37.3 (C16Ј), 40.7 (C12Ј), 42.7
(C13Ј), 47.5 (C1), 48.1 (C9), 50.2 (C14Ј), 54.5 (C10), 71.1 (Cq-tBu),
72.0 (C4), 80.8 (C17Ј), 85.2 (C5), 98.9 (C8), 107.2 (C6), 140.2 (C7)
ppm. MS (ESI+, MeOH): m/z (%) = 390.3 (100) [M + Na]+.
HRMS (ESI+, MeOH): calcd. for C24H38O4Na 390.2692; found
390.2678.
[10] a) S. Arseniyadis, J. Quilez del Moral, R. Brondi Alves, P. Pot-
ier, L. Toupet, Tetrahedron: Asymmetry 1998, 9, 2871–2878; b)
J. I. Candela Lena, E. Sánchez Fernández, A. Ramani, N. Birli-
rakis, A. F. Barrero, S. Arseniyadis, Eur. J. Org. Chem. 2005,
683–700.
Eur. J. Org. Chem. 2010, 4851–4860
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4859

Z. Elkhayat, I. Safir, Z. Gandara, P. Retailleau, S. Arseniyadis
FULL PAPER
[11] The versatility of sodium perborate (SPB), which is considered
as a dry carrier of the hazardous hydrogen peroxide, in func-
tional group oxidations has been highlighted in the literature;
a) A. McKillop, W. R. Sanderson, Tetrahedron 1995, 51, 6145–
6166; b) A. McKillop, W. R. Sanderson, J. Chem. Soc. Perkin
Trans. 1 2000, 471–476; c) J. Muzart, Synthesis 1995, 1325–
1347.
[15] The site-selective disproportionation of the Cannizzaro oxido-
reduction is consistent with direct hydride shift on lactol–alde-
hyde ii. Conversion of 10a into MOM-protected 11a preceded
basic treatment because a free hydroxy group at C6 was suscep-
tible to react with the resulting lactone carbonyl.
[16]
C. G. Swain, A. L. Powell, W. A. Sheppard, C. H. Morgan, J.
Am. Chem. Soc. 1979, 101, 3576–3583.
[12] The numbering system for agarofurans as in ref.[3a] will be used
throughout the paper for all compounds, including hybrids.
[13] SPB was also used as a Baeyer–Villiger oxidation reagent: M.
Espiritu, P. N. Handley, R. Neumann, Adv. Synth. Catal. 2003,
345, 325–327 and references cited therein.
[17]
a) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87,
1353–1364; b) M. Yus, T. Soler, F. Foubelo, Tetrahedron: Asym-
metry 2001, 12, 801–810.
[18] Carrying out TBS protection at 60 °C for 4 h forced the strain
releasing nucleophilic opening of the epoxide ring.
[19] It seems reasonable that proximal ring substituents in domino
substrate 5 might control approach of the reagent (the angular
methyl group at C10) as well as create repulsive nonbonding
interactions (the C4 substituents) within the intermediates and
encourage conditions for stereoselective epoxide formation and
regioselective opening.
[14] No substituent other than hydrogen at C4 leads to a mixture:
Received: April 21, 2010
Published Online: July 15, 2010
4860
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4851–4860