Enantioselective synthesis of natural polyoxygenated cyclohexanes and cyclohexenes from [(p-tolylsulfinyl)methyl]-p-quinols

Article abstract of DOI:10.1002/chem.200601330

Exploitation of the β-hydroxysulfoxide fragment present in a number of enantiomerically pure (SR)and (SS)-[(p-tolylsulfinyl)methyl]-pquinols allowed chemo- and stereocontrolled conjugate additions of different organoaluminium reagents to the cyclohexadien

Full text of DOI:10.1002/chem.200601330

DOI: 10.1002/chem.200601330
Enantioselective Synthesis of Natural Polyoxygenated Cyclohexanes and
Cyclohexenes from [(p-Tolylsulfinyl)methyl]-p-quinols
M. Carmen CarreÇo,* Estíbaliz Merino, María Ribagorda, lvaro Somoza, and
Antonio Urbano[a]
Abstract: Exploitation of the b-hydrox-
ysulfoxide fragment present in
number of enantiomerically pure (SR)-
and (SS)-[(p-tolylsulfinyl)methyl]-p-
min, (ꢀ)-theobroxide and (+)-4-epiga-
bosine A (an epimer of the natural
product gabosine A)—has been ach-
ieved. The presence of the b-hydroxy
sulfone moiety makes the cyclic struc-
tures rigid, allowing a number of ste-
reoselective transformations such as
carbonyl reductions, enone epoxida-
tions or cis-dihydroxylations, en route
to the natural structures. The observed
selectivities were dependent on the
particular substitution in each sub-
strate, providing evidence of a strong
influence of remote groups on the pre-
ferred approach of the reactants to the
reactive conformations. An advanced
precursor of natural (+)-harveynone
was also synthesized, but the isolation
of the natural product was not possible
because of the instability of the corre-
sponding enone, containing a triple
bond, under the basic conditions neces-
sary to eliminate the b-hydroxy sul-
fone. This demonstrated that the limi-
tations of the use of the b-hydroxy sulf-
oxide as a chiral protecting carbonyl
group were dependent on the relative
stabilities of the final targets in the
presence of the required base.
a
quinols allowed chemo- and stereocon-
trolled conjugate additions of different
organoaluminium reagents to the cy-
clohexadienone moiety. The same frag-
ment was also shown to act as an effi-
cient chiral masking carbonyl group,
after oxidation to sulfone and retroad-
dition in basic medium, with elimina-
tion of methyl p-tolyl sulfone. Through
the use of both transformations as key
steps, enantiocontrolled syntheses of
different natural products—such as the
two enantiomers of dihydroepiepofor-
min, (ꢀ)-gabosine O, (+)-epiepofor-
Keywords: asymmetric synthesis ·
cyclohexanes
·
cyclohexenes
·
natural products · quinols
Introduction
common strategy allowing further stereoselective introduc-
tion of appropriate substitution en route to natural products.
This goal has been successfully achieved through the conver-
sion of the cyclohexanone carbonyl group into chiral
acetal[5] or hydrazone moieties.[6] Enantiopure a-acetoxysul-
fones, introduced by Trost[7] as chiral aldehyde equivalents,
have mainly been used in acyclic systems. Organocatalysis,[8]
as a strategy to transform ketones into intermediate enantio-
pure imines or enamines, is nowadays often successfully ap-
plied to achieve this goal. In spite of the important advances
already achieved, efficient asymmetric syntheses require
new chiral carbonyl equivalents to enable improved stereo-
selective transformations.
Stereoselective approaches to polyhydroxy-substituted cy-
clohexanes and cyclohexenes continue to attract considera-
ble attention, due to the widespread appearance of these
structural motifs in natural products such as cyclitols,[1] car-
basugars[1b,2] or alkaloids.[3] The cyclohexene oxide moiety[4]
is also a recurring structural feature found in a number of
natural derivatives. The stereocontrolled transformation of
cyclohexanones and cyclohexenones is a general means of
access to this important type of compounds, while conver-
sion of the ketone function into a chiral masked group is a
In connection with a project geared towards extending
the applications of sulfoxides in asymmetric synthesis,[9] we
have found that a b-hydroxy sulfoxide moiety placed at C4
in a system such as 4-[(p-tolylsulfinyl)methyl]cyclohexa-2,5-
dienone (1, R1 = H; Scheme 1), can be regarded as a chiral
ketone equivalent:[10] after stereoselective transformations
of the ring to afford intermediates such as 2 and 3, a carbon-
[a] Prof. Dr. M. C. CarreÇo, E. Merino, Dr. M. Ribagorda,
Dr. . Somoza, Dr. A. Urbano
Departamento de Química Orgµnica (C-I) Universidad Autónoma,
Cantoblanco
28049 Madrid (Spain)
Fax : (+34)914-973-966
E-mail: carmen.carrenno@uam.es
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FULL PAPER
yl group at C4 can be recovered through oxidation of the
sulfoxide to a sulfone and basic retroaddition with elimina-
tion of methyl p-tolyl sulfone, as shown in the transforma-
tion of 3 into 4. A systematic study on the behaviour of 1 as
an enantiopure conjugate acceptor[11] revealed that the
methylsulfinyl substituent permitted differentiation between
the two diastereotopic faces of the double bonds, directing
conjugate additions of organoaluminium reagents from the
face containing the OH group in a highly diastereoselective
way and with efficient desymmetrization of the cyclohexa-
dienone moiety (Scheme 1).
The interest in using p-quinols 1 as starting materials for
chiral targets is based on the combination of asymmetric Mi-
chael-type additions, affording 2, and subsequent stereose-
lective transformation processes on the resulting cyclohexe-
nones, completed with oxidation to the sulfones and elimi-
nation of MeSO2pTol to reestablish the C4 carbonyl group.
This approach has previously allowed us to synthesize differ-
ent chiral, nonracemic alkyl hydroxy cyclohexenones such as
phorenol (4).[10]
Scheme 1. Key steps in the synthesis of enantiopure cyclohexenones from
[p-(tolylsulfinyl)methyl]-p-quinols 1.
2- or 3-(p-tolylsulfinyl)-1,4-naphthoquinone resulted in the
totally enantio- and regioselective syntheses of the angucy-
clinone-type antibiotics rubiginone A2 and C2 and their 11-
methoxy regioisomers.[12]
We have also applied this methodology to the synthesis of
an enantiopure 3,6-dihydroxy-5-methyl-1-vinylcyclohexene
derivative, Diels–Alder reactions of which with 5-methoxy-
As a number of polyhydroxy-substituted cyclohexanes
and cyclohexenes, together with their epoxide analogues, are
found in many natural products and have also been pre-
pared for use as intermediates in total synthesis, we decided
to extend our methodology to the synthesis of different
polyoxygenated cyclohexane and cyclohexene derivatives.
Stereocontrolled transformation of the cyclic systems could
open easy access to a variety of natural structures. We first
focused on natural products containing cyclohexane struc-
tural elements, such as the two enantiomers of dihydroepie-
poformin (5)[13] and (ꢀ)-gabosine O (6) (Figure 1) and then
Abstract in Spanish: El fragmento de b-hidroxisulfóxido pre-
sente en varios (SR)- y (SS)-[(p-tolilsulfinil)metil]-p-quinoles
enantiomØricamente puros ha permitido la adición conjugada
quimio- y estereocontrolada de diferentes reactivos organo-
alumínicos sobre la unidad de ciclohexadienona. El mismo
fragmento ha demostrado actuar como un grupo carbonilo
quiral enmascarado muy eficiente, tras oxidación a sulfona y
eliminación en medio bµsico de metil p-tolil sulfona. Usando
ambas transformaciones como etapas clave, se ha logrado la
síntesis enantiocontrolada de diferentes productos naturales
como la dihidroepiepoformina, (ꢀ)-gabosina O, (+)-epiepo-
formina, (ꢀ)-theobroxido y (+)-4-epigabosina A, epímero
del producto natural gabosina A. La presencia del fragmento
de b-hidroxi sulfona confiere rigidez a las estructuras cíclicas
lo que permite llevar a cabo un gran nfflmero de transforma-
ciones estereoselectivas como reducciones de grupos carboni-
lo, epoxidaciones de enonas o dihidroxilaciones cis, en ruta
hacia los productos naturales. Las selectividades observadas
dependen de la sustitución particular de cada sustrato, evi-
denciµndose una fuerte influencia de grupos remotos en las
aproximaciones preferidas de los reactantes sobre las corres-
pondientes conformaciones mµs reactivas. TambiØn se ha
podido sintetizar un precursor avanzado de la (+)-harveyno-
na, pero el aislamiento de este producto natural no fue posi-
ble debido a la inestabilidad de la correspondiente enona,
portando un triple enlace, en las condiciones bµsicas necesa-
rias para eliminar el fragmento de b-hidroxi sulfona. Este re-
sultado pone en evidencia las limitaciones de usar el frag-
mento de b-hidroxi sulfóxido como un grupo protector quiral
de carbonilos que va a depender de la estabilidad relativa del
compuesto final en presencia de la base requerida.
Figure 1. Structures of natural polyoxygenated cyclohexane and cyclohex-
ene derivatives.
turned our attention to cyclohexene derivatives such as
(+)-epiepoformin (7),[13] (ꢀ)-theobroxide (8), (+)-4-epiga-
bosine A (9; an epimer of the natural product gabosine A)
and (+)-harveynone (10).
Dihydroepiepoformin (5) was isolated in 1995 by Kuo
et al.[14] by fermentation of Penicillium patulum and was
found to have antagonistic activity for interleukin-1, though
the authors did not report the specific rotation of the isolat-
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M. C. CarreÇo et al.
ed compound or its absolute configuration. In our previous
communication,[13] we described the independent syntheses
of both enantiomers of this natural product and determined
their absolute configurations.
The carbasugar (ꢀ)-gabosine O (6) was isolated from dif-
ferent Streptomyces strains[15,16] and showed weak DNA-
binding properties.[16] Its absolute configuration has recently
been assigned by Figueredo et al.,[17] through an enantiose-
lective total synthesis using an enzymatically resolved pro-
tected cyclohexenone as starting material.
tions on the resulting enantiopure cyclohexenone, and retro-
addition of methyl p-tolylsulfone, to reestablish the carbonyl
group at C4. We also report full details of the methodology
used for the preparation of all synthetic intermediates en
route to the two enantiomers of dihydroepiepoformin (5)
and to (+)-epiepoformin (7).[13] All this work has allowed us
to establish advantages and limitations of using the b-hy-
droxy sulfoxide moiety as a chiral masking carbonyl group
in a cyclic system.
(+)-Epiepoformin (7) was isolated in 1978 by Nagasawa[18]
from the culture filtrate of an unidentified fungus separated
from a diseased leaf, and showed marked inhibition activity
against the germination of lettuce seeds. The natural enan-
tiomer has been synthesized by several authors using differ-
ent strategies: Ogasawara et al.[19] based their approach on a
retro-Diels–Alder reaction to recover the cyclohexenone
fragment from a stereoselectively functionalized quinone
Diels–Alder adduct, previously asymmetrized by isomeriza-
tion with an enantiopure BINAP–RhI catalyst,[20] while the
formation of a bicyclic adduct in a cinchonine-catalysed re-
action between 3-hydroxy-2-pyrone and an acrylamide de-
rived from a chiral oxazolidinone was the key step in the ap-
proach of Okamura et al.[21] (ꢀ)-Quinic acid was the starting
material in the synthesis reported in 2000 by Maycock
et al.,[22], whereas a chiral building block obtained by enzy-
matic reduction was used by Kitahara et al.[23] to synthesize
(+)-7 in 2003.
(ꢀ)-Theobroxide (8), isolated from the culture filtrate of
the fungus Lasiodiplodia theobromae,[24] is a potato micro-
tuber inducing substance. Ogasawara[19] and Maycock[22] syn-
thesized both enantiomers of 8 and the natural one, respec-
tively, by applying the strategies described above, while Ari-
moto[25] recently published an enantioselective synthesis of
(ꢀ)-8 based on photooxygenation of 1-methyl-1,4-cyclohexa-
diene and enzymatic resolution of an immediate precursor.
(+)-4-Epigabosine A (9), the epimer of the natural prod-
uct (ꢀ)-gabosine A,[15] had not been synthesized to date.
All these compounds 7–9 share the feature of a methyl
substituent situated on the cyclohexene skeleton. Another
target in our work has been (+)-harveynone (10) (Figure 1),
containing an enyne substituent on the cyclohexene system.
This natural product was isolated from the tea gray fungus
Pestalotiopsis theae and is a phytotoxin.[26] Maycock[22] has
also synthesized (+)-10 from (ꢀ)-quinic acid. Other synthe-
ses of harveynone in enantiopure form have been reported
by Ogasawara,[27] Johnson[28] and Negishi[29], together with
one of the racemate by Taylor,[30] based on the use of a Pd-
catalysed cross-coupling reaction to introduce the acetylenic
substituent onto a functionalized a-iodocyclohexenone.
We now report new asymmetric total syntheses of (ꢀ)-ga-
bosine O (6), (ꢀ)-theobroxide (8) and (+)-4-epigabosine A
(9), as well as an enantioselective approach to an advanced
precursor of (+)-harveynone (10). All are based on the
combination of the stereoselective and chemoselective intro-
duction of a methyl or alkynyl group onto a p-quinol 1 from
an organoaluminium derivative, stereoselective transforma-
Results and Discussion
The enantiomerically pure 4-hydroxy-4-[(p-tolylsulfinyl)me-
thyl]cyclohexa-2,5-dienones
(SR)-13[31]
and
(SS)-13
(Scheme 2)[12] necessary to synthesize the two enantiomers
of dihydroepiepoformin (5) and (+)-gabosine O (6) were
obtained, as reported previously, by treatment of the lithium
anions derived from (SR)-[32] or (SS)-methyl p-tolyl sulfoxide
(12) with p-benzoquinone dimethyl monoketal (11),[33] fol-
lowed by hydrolysis of the intermediate acetal with oxalic
acid, in 76 and 78% overall yields, respectively.
The synthesis of the asymmetrically substituted 4-hy-
droxy-3-methyl-4-[(p-tolylsulfinyl)methyl]cyclohexa-2,5-di-
enone (4R,SR)-15[11b] was achieved from p-quinol (SR)-13 in
a two-pot, three-step sequence based on the 1,4-addition of
[34]
AlMe3 and trapping of the intermediate aluminium eno-
late with N-bromosuccinimide (NBS), followed by HBr
elimination upon heating of the resulting mixture of epimer-
ic bromides 14 with Li2CO3/LiBr (Scheme 2). The addition
of AlMe3 to (SR)-13 occurred exclusively at the pro-S conju-
gate position.
In a similar reaction sequence, starting from the p-quinol
(SR)-13, the 4-hydroxy-3-(3-methylbut-3-en-1-ynyl)-4-[(p-
tolylsulfinyl)methyl]cyclohexa-2,5-dienone isomer (4R,SR)-
17 could be synthesized as shown in Scheme 2. In this case,
the necessary dimethyl[3-methylbut-3-en-1-yl]aluminium re-
agent was generated from commercially available 3-methyl-
but-3-en-1-yne by sequential treatment with nBuLi at 08C
and with AlMe2Cl at room temperature. After dilution with
CH2Cl2, the p-quinol (SR)-13 was added to the resulting
mixture. The order of addition of the reagents was essential
to achieve successful selective 1,4-conjugate addition at the
pro-S position.[35] Once the reaction was complete, the inter-
mediate enolate was quenched with NBS at ꢀ788C. The re-
sulting mixture of C6 bromo epimers 16 was treated with
Li2CO3 and LiBr to afford a mixture of p-quinols (4R,SR)-
17 and (4S,SR)-18 that could be isolated pure, after flash
chromatography, in 64 and 10% yields, respectively. The
mixture of epimers must reflect the formation of a similar
mixture of diastereomers in the alkynyl aluminium reagent
addition step.
With the starting p-quinols to hand, we next focused on
the stereoselective transformations of the cyclohexadienone
rings, en route to the natural products. Taking into account
the known chemo- and diastereoselective addition of AlMe3
to the (SR)- and (SS)-p-quinols 13, which occur at the pro-
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Polyoxygenated Cyclohexanes and Cyclohexenes
FULL PAPER
Scheme 2. Synthesis of p-quinols (SR)- and (SS)-13, (4R,SR)-15 and
(4R,SR)-17.
Scheme 3. Synthesis of the advanced key intermediate (4R,6S)-24 from
p-quinol (SR)-13.
S[11] and the pro-R[12] conjugate positions, respectively, we
started the synthesis of the (6S)-6-methyl-substituted cyclo-
hexanone rings of natural products (ꢀ)-5 and (ꢀ)-6
(Figure 1) from p-quinol (SR)-13. Treatment of (SR)-13 with
4 equivalents of AlM3, thus resulted in the chemo- and dia-
stereoselective exclusive formation of (4S,5S,SR)-19[11b,34]
(Scheme 3), the product of addition at the pro-S conjugate
position of (SR)-13, in 76% yield.
In order to check the viability of transforming the b-hy-
droxy sulfoxide into a carbonyl group, we treated compound
19 with different bases. The retroaddition process to elimi-
nate methyl p-tolyl sulfoxide from 19 should be favoured,
since the 1,4-diketone that would be formed from the cyclo-
hexenone moiety is a tautomer of 2-methylhydroquinone
(Scheme 3). Nevertheless, in spite of the stability of this
product, no elimination occurred in the sulfoxide 19, even
when this compound was heated in DMF at 1208C in the
presence of Li2CO3. We thus decided to improve the leaving
group ability by transforming the sulfoxide 19 into the sul-
fone (4S,5S)-20 (meta-chloroperbenzoic acid (mCPBA),
98%). Upon treatment of 20 with different bases (Li2CO3,
LiHMDS, Cs2CO3) at different temperatures, we indeed ob-
served the quantitative elimination of methyl p-tolyl sulfone.
Although the hydroquinone was not isolated, the formation
of MeSO2pTol demonstrated the viability of the recovery of
the carbonyl moiety.
With a view towards functionalization of the cyclic
system, we tried to effect the stereoselective reduction of
the carbonyl group of 20 before the elimination step. The
preferred mode of attack of small hydrides on rigid cyclo-
hexanones is normally axial, and this preference is known to
be even higher in cyclohexenones.[36] In compound 20, a cy-
clohexenone with a fixed conformation positioning the
CH2SO2pTol and CH3 groups in pseudoequatorial orienta-
tions, the small hydride DIBALH reacted, as expected, to
give rise to the exclusive formation of carbinol (1S,4R,6S)-
21, resulting from axial attack, which could be isolated in
95% yield (Scheme 3). This excellent stereoselectivity could
also be due to the presence of the pseudoaxial OH at C4 in
compound 20, influencing the stereochemical course of hy-
dride approach by obstructing access from the same side
through electrostatic interactions[37] and thus enhancing the
axial attack preference. The bulky hydride L-Selectride,
which should normally promote equatorial attack, did not
invert the stereoselectivity of the process in this case, al-
though it was changed to a 40:60 mixture of carbinol epi-
mers (1S,4R,6S)-21 and (1S,4S,6S)-22. Although the minor
diastereomer 22 could be isolated by chromatography, the
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M. C. CarreÇo et al.
low (30%) yield prevented its use in the synthesis of other
natural targets. Again, the axial OH at C4 of 20, through re-
pulsive electrostatic interactions,[38] was hindering the other-
wise favoured equatorial attack by L-Selectride.
The retroaddition process to eliminate MeSO2pTol was
also tried on derivative 21, and although we observed the
formation of MeSO2pTol upon basic treatment we were
unable to isolate the resulting hydroxycyclohexenone. We
next protected the secondary OH in 21 (TBDMSOTf, 2,6-lu-
tidine, 93%), obtaining compound (1S,4R,6S)-23. The bulky
protecting group was chosen to facilitate the anti epoxida-
tion that would be necessary in the next steps to establish
the correct stereochemistry of the final target 5. After treat-
ment of 23 with Cs2CO3 in CH3CN at room temperature, we
were able to recover the cyclohexenone (4R,6S)-24 in 89%
yield.
The epoxidation of the TBDMS-protected carbinol 24
was carried out with different reagents under different con-
ditions (Scheme 4, Table 1) in a search for the best anti dia-
stereoselectiviy. As can be seen, use of H2O2 (30% aqueous
solution) as the oxidant and benzyltrimethylammonium hy-
droxide (Triton B, 40% in MeOH)[39] as the base in THF at
ꢀ788C resulted in a 55:45 mixture of the diastereoisomeric
epoxides syn-(2R,3S,4R,6S)-25 and anti-(2S,3R,4R,6S)-26
(entry 1). Methyl(trifluoromethyl)dioxirane,[40] generated in
situ from trifluoroacetone and Oxone and known to be
more reactive than dimethyldioxirane, behaved in a similar
way, giving rise to a 65:35 mixture of syn-25 and anti-26
(entry 2). Changing the oxidant to the bulkier tert-butyl hy-
droperoxide (TBHP) in the presence of Triton B[41] resulted
in a slight inversion of the syn-25/anti-26 ratio to 40:60
(entry 3). The effect of the temperature was shown to be im-
portant, as when the above reaction was carried out at 08C,
a slight but significant excess of the diastereomer syn-25 was
once again formed (60:40 mixture of syn-25 and anti-26,
entry 4). Use of the even bulkier triphenylmethyl (trityl) hy-
droperoxide (Ph3COOH) in the presence of Triton B[42] at
08C also gave rise to diastereomer syn-25 as the major com-
ponent (entry 5). The effect of the temperature was also
critical in this case and, after laborious experimentation, we
were able to establish that use of Ph3COOH and Triton B at
ꢀ788C and allowing the mixture to reach ꢀ308C until com-
pletion resulted in the quantitative formation of a 25:75
mixture of syn-25 and anti-26 (entry 6).
Although the diastereomers 25 and 26 could not be sepa-
rated at this stage, after removal of the OTBDMS groups
(TBAF, THF, 08C) from the 25:75 mixture the correspond-
ing alcohols, (2R,3R,4R,6S)-27 {[a]2D0 = ꢀ90 (c = 0.96 in
CHCl3)} and (2S,3S,4R,6S)-5 {[a]2D0 = ꢀ21 (c = 1.2 in ace-
tone) or [a]2D0 = ꢀ27 (c = 1.2 in CHCl3)}, were isolated by
chromatography in 16 and 41% yields, respectively
(Scheme 4). When a 60:40 mixture of derivatives 25 and 26
was deprotected, (ꢀ)-27 and (ꢀ)-5 were isolated in 59 and
38% yields, respectively. The spectral parameters of synthet-
ic (ꢀ)-5 (96% ee),[43] with the (2S,3S,4R,6S) absolute config-
uration, were identical to those reported for natural dihy-
droepiepoformin isolated by Kuo.[14]
Scheme 4. Epoxidation of cyclohexenone (4R,6S)-24 and completion of
the synthesis of (ꢀ)-27 and (ꢀ)-dihydroepiepoformin (5).
Table 1. Epoxidation of cyclohexenone (4R,6S)-24 under different exper-
imental conditions.
Entry Reagent
Solvent
T [8C]
syn-
anti-
25
26
1
2
H2O2,[a] Triton B[b]
Oxone, CF3COCH3,
THF
CH3CN/
H2O
THF
THF
ꢀ78
55
65
45
3
0
5
NaHCO3
[b]
3TBHP, Triton B
ꢀ78
0
0
40
60
60
60
40
40
75
4
5
6
TBHP, Triton B[b]
Ph3CO2H, Triton B[b]
Ph3CO2H, Triton B[b]
MeOH
MeOH
ꢀ78! 25
ꢀ30
[a] 30% Aqueous solution. [b] 40% Solution in MeOH.
The corresponding enantiomers (+)-27 and (+)-5 were
readily accessible from p-quinol (SS)-13 by a similar se-
quence of reactions, as summarized in Scheme 5. Initial ad-
dition of AlMe3 to (SS)-13 occurred stereo- and chemoselec-
tively at the pro-R conjugate position, in a 65% yield.
mCPBA oxidation of the sulfoxide to the sulfone (98%)
was followed by stereoselective DIBALH reduction (99%),
secondary OH protection and elimination of MeSO2pTol
(Cs2CO3, 87% for the two steps) to give the cyclohexenone
(4S,6R)-24,[12] while epoxidation under the conditions de-
scribed above (Ph3COOH, Triton B, ꢀ78 to ꢀ308C) afford-
ed a 25:75 mixture of (2S,3R,4S,6R)-25 and (2R,3S,4S,6R)-26
in almost quantitative yield (Scheme 5). After desilylation
(TBAF) and chromatographic separation, a 16% yield of
(2S,3S,4S,6R)-27 {[a]2D0 = +90 (c = 0.96 in CHCl3)} and a
61% yield of (+)-dihydroepiepoformin (2R,3R,4S,6R)-5
(96% ee)[43] {[a]2D0 = +22 (c = 0.1 in acetone) or [a]2D0
+3 4 (c = 0.1 in CHCl3)} were obtained.
=
The synthesis of the other natural target bearing a cyclo-
hexane structure—(ꢀ)-gabosine O (6)—only required the
diastereoselective cis-dihydroxylation of the double bond of
cyclohexenone (4R,6S)-24 and deprotection of the alcohol
(Scheme 6). When (4R,6S)-24 was treated with RuCl3/
NaIO4,[44] however, an inseparable 58:42 mixture of diaste-
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Polyoxygenated Cyclohexanes and Cyclohexenes
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dant, acetone, H2O], whereas low selectivity results when
hydrogen bonding is able to direct the reagent approach syn
to the OH (OsO4, CH2Cl2). The relative amount of OsO4
has also been shown to play an important role. In our case,
dihydroxylation of the free carbinol (4R,6S)-30, obtained
from 24 by TBAF treatment (80%), confirmed these obser-
vations, with the all-cis triol (2R,3R,4R,6R)-6—(ꢀ)-gabosi-
ne O, with the required stereochemistry—being obtained
from cyclohexenone 30 through the use of stoichiometric
amounts of OsO4 under the conditions indicated in
Scheme 6. It appears likely that the locked conformation of
30 shown in Scheme 6, with both the OH and methyl sub-
stituents in pseudoequatorial dispositions, should be the re-
active one. In this case, the efficiency of the hydrogen bond-
ing in directing the syn approach of the oxidant to give the
cis-dihydroxylation product was very high. Both the spectro-
scopic parameters and the sign of the specific rotation {[a]D20
=
ꢀ11.0 (c
= 0.15 in MeOH)} of the final product
(2R,3R,4R,6R)-6 were identical to those reported for the
natural[16] and synthetic[17] (ꢀ)-gabosine O, thus confirming
the absolute configurations of all stereogenic centres created
from the initial presence of the sulfoxide in the starting p-
quinol (SR)-13.
Scheme 5. Synthesis of (+)-27 and (+)-dihydroepiepoformin (5).
The synthesis of the natural product (+)-epiepoformin
(7), with a cyclohexene structure, was addressed by starting
from p-quinol (4R,SR)-15 (Scheme 7). Oxidation of 15
(mCPBA, 99%) to the corresponding sulfone, followed by
TBHP/Triton B epoxidation, which occurred stereoselec-
tively at the more electrophilic unsubstituted double bond,
afforded the epoxide (2S,3R,4S)-31 in 72% yield. The di-
recting effect of the free OH[47] at C4, as well as the prefer-
ence for approach of the oxidant from the less hindered face
of the double bond, anti to the CH2SO2pTol substituent,
must be the origin of the highly diastereoselective formation
of compound 31.
In contrast, the reduction of the carbonyl group in 31 was
less stereoselective. We tried different reducing agents, ach-
ieving the best results (in terms of yield of the desired dia-
stereomer 32) by treatment with DIBALH in THF at
ꢀ788C. Under these conditions, the quantitative formation
of a 77:23mixture of epimeric carbinols (1 S,2R,3R,4S)-32
and (1S,2R,3R,4R)-33 was observed, from which compound
32 could be separated diastereomerically pure by flash chro-
matography, in 67% yield. Several factors can influence the
stereoselectivity of the reduction of 31. The preference of
DIBALH for the axial approach to the cyclohexenone,[37]
would give a different epimer depending on the reactive
conformer. The most stable, and probably more reactive,
conformation of 31 would be A (inset in Scheme 7), in
which the severe interaction present in B between the Me
group at C3and the pseudoequatorial ( p-tolylsulfonyl)meth-
yl substituent at C4 is avoided. Axial attack of the small hy-
dride DIBALH on A would explain the predominant forma-
tion of the (4S)-epimer carbinol 32. Nevertheless, the elec-
trostatic effect of the C4 hydroxy substituent discussed
above must decrease this preference. The exclusive forma-
tion of epimer (1S,2R,3R,4R)-33 (83% isolated yield) on use
Scheme 6. Synthesis of (ꢀ)-gabosine O (6) from (4R,6S)-24.
reomeric diols (2R,3R,4S,6R)-28 and (2S,3R,4R,6S)-29 was
isolated after flash chromatography in a moderate 35%
yield, while OsO4 dihydroxylation of (4R,6S)-24 under dif-
ferent catalytic and stoichiometric conditions only yielded
decomposition, aromatic products or poor yields of mixtures
of diastereomers 28 and 29.
The p-facial diastereoselectivities of OsO4 dihydroxyla-
tions are normally governed by steric factors,[17,45] and the
bulky OTBDMS protecting group in 24 was slightly favour-
ing dihydroxylation anti to the vicinal OTBDMS substituent.
On the other hand, the diastereoselectivity of OsO4 dihy-
droxylation of free allylic cyclohexenols has been shown to
be dependent on the reactive conformation and the possibil-
ity of hydrogen bonding. According to Donohoe,[46] diaste-
reoselective attack anti to the OH group is normally ach-
ieved under standard conditions [OsO4 (cat), NMO as reoxi-
Chem. Eur. J. 2007, 13, 1064 – 1077
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1069

M. C. CarreÇo et al.
Figure 2. X-ray structure of 7.
treatment with NaBH4 in the presence of CeCl3 (Lucheꢁs re-
agent).[50] Under these conditions the reduction of the car-
bonyl group of 7 took place quantitatively giving rise, in a
highly diastereoselective manner, to the epoxy diol
(1S,2R,3S,4R)-(8) {[a]2D0 = ꢀ8.0 (c = 0.10 in EtOH)}, the
product of axial attack of the hydride on cyclohexenone 7
(Scheme 7).[51] The spectroscopic and optical properties of
synthetic (ꢀ)-8 matched those reported for natural (ꢀ)-theo-
broxide.[24]
Regioselective trans-diaxial opening of the epoxide
moiety in (+)-epiepoformin (7), with attack of an oxygenat-
ed nucleophile at C2, would give rise to the other target
(+)-4-epigabosine A (9) (Scheme 7). Acidic hydrolytic open-
ing (H2SO4, dioxane, H2O) of epoxide 7 proved to be unsuc-
Scheme 7. Syntheses of (+)-epiepoformin (7), (ꢀ)-theobroxide (8) and
(+)-4-epigabosine A (9).
cessful, while the use of the TiCAHTRE(UNG OiPr)4/propionic acid
of the bulky hydride L-Selectride, preferring the equatorial
approach, is in this case favoured by the repulsive effect of
the OH at C4 situated on the opposite face of the reactive
conformer A (Scheme 7).
system[47] also did not provide the expected triol. It appears
likely that the competitive complexation of the titanium
with the epoxide oxygen and the ketone or carbinol oxygens
before nucleophilic attack must be obstructing the reaction
on a defined species. Finally, heating of (+)-epiepoformin
(7) with an aqueous solution of NaOAc allowed the isola-
tion of a 45% yield of (4S,5R,6S)-(9) {[a]2D0 = +169 (c =
0.19 in MeOH)}, or 4-epigabosine A, after flash chromatog-
raphy. The regioselective opening of the epoxide at C2 by
NaOAc must be favoured by stereoelectronic factors when
the reacting conformer of cyclohexenone 7, shown in
Scheme 7, is axially attacked by the nucleophile. The stereo-
chemistry of compound 9 was established from the NMR
parameters, mainly the value of the coupling constant be-
tween H-2 and H-3(11.0 Hz), which is consistent with a
trans-diaxial disposition of the two hydrogens in the more
stable half-chair conformation, situating the three OH
groups in an equatorial disposition.
The synthesis of (+)-epiepoformin (7) was completed
after protection of the secondary OH of 32 as a TBDMS
ether (52%), elimination of MeSO2pTol (Cs2CO3, 99%), af-
fording (2R,3R,4S)-34, and desilylation (TBAF, 41%). The
overall yield of these three last steps was only 21%, but a
better yield was achieved by direct treatment of carbinol 32
with Cs2CO3, which afforded a 54% yield of (2R,3R,4S)-(7)
{[a]2D0 = +303 (c = 1.1 in EtOH)}. The optical and spectro-
scopic properties of synthetic (+)-7 matched those reported
for natural (+)-epiepoformin[18] and its enantiomeric purity
1
was shown to be 96% ee after H NMR analysis (500 MHz)
of the Mosherꢁs esters.[48] The relative configurations of all
stereogenic centres in 7 were confirmed by X-ray diffraction
(Figure 2).[49]
The transformation of (+)-epiepoformin (7) into the
other natural target, (ꢀ)-theobroxide (8), was achieved by
Having completed these syntheses, we next focused on
the natural cyclohexenone (+)-harveynone (10, Scheme 8).
1070
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Chem. Eur. J. 2007, 13, 1064 – 1077

Polyoxygenated Cyclohexanes and Cyclohexenes
FULL PAPER
When the starting p-quinol (4R,SR)-17 was subjected to
mCPBA oxidation, a mixture of sulfone 35 and sulfonyl ep-
oxide 36 (mixture of diastereomers) was formed, and this
was separated by flash chromatography to provide a 66%
yield of (4R)-35 and a 19% yield of 36. The TBHP/Triton B
treatment of pure 35 gave a clean reaction mixture in which
the exclusive product was the epoxide (2S,3R,4S)-37, result-
ing from reaction at the unsubstituted C5=C6 double bond
of 35. The observed high p-facial diastereoselectivity was
probably due to the presence of the allylic OH at C4, direct-
ing the epoxidation process from the same side. Although
the crude yield was almost quantitative, chromatographic
purification of 37 resulted in significant decomposition, so
we continued the synthesis without further purification. Re-
duction of the carbonyl group in 37 with DIBALH gave a
76:24 mixture of diastereomeric alcohols (1S,2R,3R,4S)-38
and (1S,2R,3R,4R)-39 (89% overall yield for the last two
steps). We also observed significant decomposition during
chromatographic separation of these products, it being possi-
ble to isolate pure 38 and 39 in only 15 and 10% yields, re-
spectively. When the reduction of 37 was performed with L-
Selectride, epimer 39 was the only detected product and
could be isolated in 52% yield. Again, however, chromato-
graphic purification resulted in only a 19% yield of pure 39.
The stereochemical outcomes of these reductions on cyclo-
hexenone 37 were very similar to that observed for deriva-
tive 31.
was never detected. Although MeSO2pTol was always pres-
ent in the final reaction mixtures, only products correspond-
ing to decomposition of the cyclohexenone moiety were ob-
served. Use of weaker bases such as NaHCO3 or iPr2NH left
the starting material unchanged. We next proceeded to pro-
tect the OH moieties in 38 and 39 (TBDMSOTf, 2,6-luti-
dine) as the corresponding OTBDMS derivatives, to give
(1S,2R,3S,4S)-40 (61%) and (1S,2R,3S,4R)-41 (53%), but,
again, treatment with different bases only afforded MeS-
O2pTol and decomposition products. Looking at the litera-
ture, we found that precedent instability of several epoxy-
quinols[28] similar to harveynone in basic media had been ob-
served. Our data clearly show that the presence of the al-
kynyl substituent in derivatives 38–41 could be responsible
for this instability, by increasing the acidity of the C4 allylic
hydrogen and resulting in the observed decomposition
under the basic conditions.
This failure illustrated that our approach, based on stereo-
selective organoaluminium additions to sulfinyl p-quinols in
combination with retroaddition of methyl p-tolylsulfone to
recover carbonyl groups, cannot be applied when the final
structure is sensitive to the basic medium necessary to effect
this transformation.
Conclusion
Unfortunately, all trials directed towards recovery of the
masked carbonyl groups at C1 in 38 and 39 with use of dif-
ferent bases [Cs2CO3, Ba(OH)2, tBuOK, NaH and nBuLi]
and temperatures were unsuccessful, and harveynone (10)
In summary, we report the total enantioselective syntheses
of the natural polyoxygenated cyclohexanes (ꢀ)-dihydro-
A
hydroxy-4-[(p-tolylsulfinyl)methyl]cyclohexa-2,5-dienone
(SR)-13, in seven steps and 24 and 28% overall yields, re-
spectively. The enantiomer of (ꢀ)-dihydroepiepoformin,
(+)-5, was in turn available from p-quinol (SS)-13 in 32%
overall yield. Two other natural targets, each containing a
methyl substituent in its cyclohexene structure, (+)-epiepo-
formin (7) and (ꢀ)-theobroxide (8), were obtained from the
4-hydroxy-3-methyl-4-[(p-tolylsulfinyl)methyl]cyclohexa-2,5-
dienone (4R,SR)-15, also by proceeding from p-quinol (SR)-
13, in six and seven steps from 13 and in 12 and 11% overall
yields, respectively. (+)-4-Epigabosine A (9), an epimer of
the natural product gabosine A, was obtained by controlled
opening of the epoxide fragment present in (+)-epiepofor-
min (7). The successful route presented employed the
chemo- and stereoselective addition of Me3Al to (SR)- or
(SS)-[(p-tolylsulfinyl)methyl]-p-quinol (13) and the elimina-
tion of the chiral sulfoxide as methyl p-tolylsulfone in the
advanced b-hydroxy sulfone intermediates as the key steps
for the synthesis of enantiopure cyclohexanes or cyclohex-
enes. Although the controlled chemo- and diastereoselective
addition of an enyne aluminium derivative to (SR)-13 was
also achieved, the presence of the alkynyl substituent on the
cyclohexene moiety prevented the isolation of the final cy-
clohexenone in the last steps, it not being possible to apply
our methodology to complete the enantioselective synthesis
of natural (+)-harveynone (10).
Scheme 8. Synthetic approaches to natural cyclohexenone (+)-harvey-
none (10).
Chem. Eur. J. 2007, 13, 1064 – 1077
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1071

M. C. CarreÇo et al.
1H), 5.46 (dq, J = 1.6, 1.2 Hz, 1H), 5.42 (dq, J = 1.6, 1.2 Hz, 1H), 4.92
Experimental Section
(s, 1H), 3.46 and 2.96 (AB system, J
= 13.3 Hz, 2H), 2.42 (s, 3H),
1.94 ppm (dd, J = 1.4, 1.0 Hz, 3H); 13C NMR: d = 184.2, 148.1, 142.7,
142.6, 139.9, 131.8, 130.3 (2C), 128.3, 125.7, 125.4, 123.9 (2C), 103.3, 83.9,
69.8, 66.4, 22.9, 21.4 ppm: MS (EI): m/z: calcd for C19H18O3S: 326.0977;
found: 326.0970 [M]+; MS (EI): m/z (%): 326 (1) [M]+, 187 (15), 170
(23), 142 (15), 139 (60), 137 (100), 115 (32), 91 (69), 65 (39).
Compound (4S,SR)-18: [a]D20 = +160 (c = 0.5 in acetone); 1H NMR: d
= 7.55 and 7.35 (AA’BB’ system, 4H), 7.13(d, J = 10.3Hz, 1H), 6.41
(d, J = 1.8 Hz, 1H), 6.19 (dd, J = 10.1, 1.8 Hz, 1H), 5.56 (dq, J = 1.8,
1.0 Hz, 1H), 5.47 (dq, J = 1.6, 1.2 Hz, 1H), 4.54 (brs, 1H), 3.06 (s, 2H),
2.42 (s, 3H), 2.00 ppm (dd, J = 1.6, 1.2 Hz, 3H); 13C NMR: d = 184.2,
148.6, 143.4, 142.3, 140.4, 131.6, 130.3 (2C), 127.6, 125.8, 124.0 (2C),
123.9, 104.4, 84.1, 70.5, 66.1, 22.7, 21.4 ppm; MS (EI): m/z: calcd for
C19H18O3S: 326.0977; found: 326.0975; MS (EI): m/z (%): 326(1) [M]+,
187 (14), 171 (30), 142 (11), 139 (56), 137 (100), 115 (29), 91 (66), 65 (37).
General: Melting points were obtained in open capillary tubes and are
uncorrected. 1H and 13C NMR spectra were recorded in CDCl3 at 300
and 75 MHz, respectively; diastereoisomeric ratios were established by
integration of well separated signals of both diastereomers in the crude
reaction mixtures. All reactions were monitored by thin-layer chromatog-
raphy performed on precoated silica gel 60 sheets, while flash column
chromatography was carried out on silica gel 60 (Merck, 230–400 mesh);
eluting solvents are indicated in the text. The apparatus for inert atmos-
phere experiments was flame-dried under a stream of dry argon. THF
and CH2Cl2 were dried over 4 Š molecular sieves, diisopropylamine was
distilled from KOH. All other reagent-quality solvents were used without
purification. For routine workup, hydrolysis was carried out with water,
extraction with CH2Cl2, and solvent drying with MgSO4. Full details for
the synthesis of (SS)-13, (4R,5R,SS)-19, (4R,5R)-20, (1R,4S,6R)-21,
(1R,4S,6R)-23, (4S,6R)-24 (see reference [,12b]) and 14 and (4R,SR)-15
(see ref. [,11b]) have been reported previously.
AHCTRE(GNU 4S,5S,SR)-4-Hydroxy-5-methyl-4-[(p-tolylsulfinyl)methyl]cyclohex-2-
enone (19): A solution of (SR)-13 (664 mg, 2.5 mmol) in CH2Cl2 (13mL)
was added under argon at ꢀ788C to a solution of Me3Al (2m in hexane,
5.0 mL, 10.0 mmol) in CH2Cl2 (13mL). After 4 h at the same tempera-
ture, the excess of Me3Al was destroyed with methanol, and the mixture
was poured into an Erlenmeyer containing EtOAc and a saturated solu-
tion of sodium potassium tartrate and stirred vigorously for 30 min. The
organic layer was washed with brine and dried over MgSO4. After
workup and flash chromatography (EtOAc/hexane 1:1), (4S,5S,SR)-19
was obtained as a white solid (500 mg, 76%). M.p. 119–1218C (EtOAc/
hexane); [a]2D0 = +236 (c = 1 in CHCl3); 1H NMR: d = 7.56 and 7.38
(AA’BB’ system, 4H), 7.25 (d, J = 10.2 Hz, 1H), 6.10 (dd, J = 10.2 Hz,
1H), 4.85 (s, 1H), 3.22 and 2.92 (AB system, J = 12.2 Hz, 2H), 2.62–2.22
(m, 3H), 2.44 (s, 3H), 1.10 ppm (d, J = 7.0 Hz, 3H); 13C NMR: d =
198.3, 149.7, 142.4, 139.7, 130.3 (2C), 129.0, 123.8 (2C), 71.6, 64.9, 41.7,
38.8, 21.3, 14.2 ppm; elemental analysis calcd (%) for C15H18O3S (278.4):
C 64.72, H 6.52, S 11.52; found: C 64.69, H 6.85, S 11.89.
(SR)-4-Hydroxy-4-[(p-tolylsulfinyl)methyl]cyclohexa-2,5-dienone (13): A
solution of n-butyllithium (2.4m in hexanes, 32 mL, 80.0 mmol) was
added under argon at ꢀ788C to a solution of freshly distilled diisopropyl-
amine (12.3mL, 88.0 mmol) in THF (150 mL). After the system had
been stirred for 30 min, a solution of (SR)-methyl-p-tolylsulfoxide[32]
(11.3g, 73.5 mmol) in THF (120 mL) was added at ꢀ788C. After 30 min,
a solution of 4,4-dimethoxycyclohexa-2,5-dienone[33c] (11.9 g, 77.0 mmol)
in THF (265 mL) was slowly added and the mixture was stirred for two
hours at ꢀ788C. The mixture was hydrolysed with a saturated aqueous
solution of ammonium chloride (40 mL) and the organic layer was ex-
tracted with EtOAc. After workup, the crude product was dissolved in
THF (40 mL) and a solution of oxalic acid (1.0 g, 11.1 mmol) in water
(20 mL) was added. After the system had been stirred for 2 h, hydrolysed
with a saturated solution of NaHCO3, extracted with EtOAc, and worked
up, the residue was recrystallized from EtOAc/hexane, giving compound
(SR)-13 as a white solid (15.4 g, 76%). M.p. 141–1438C; [a]2D0 = +144
(c = 1 in CHCl3); 1H NMR: d = 7.54 and 7.36 (AA’BB’ system, 4H),
7.25 (dd, J = 10.2, 3.2 Hz, 1H), 7.00 (dd, J = 10.2, 3.2 Hz, 1H), 6.29 (dd,
J = 10.2, 1.8 Hz, 1H), 6.18 (dd, J = 10.1, 1.9 Hz, 1H), 4.93(s, 1H), 3.16
and 2.85 (AB system, J = 13.3Hz, 2H), 2.43ppm (s, 3H); 13C NMR:
d = 184.9, 149.2, 149.1, 142.2, 139.6, 130.1 (2C), 128.1, 127.6, 123.9 (2C),
68.0, 67.1, 21.3ppm; elemental analysis calcd (%) for C 14H14O3S: C
64.10, H 5.38; found: C 63.63, H 5.10.
General procedure for mCPBA oxidations—Method A: A solution of
mCPBA (1.2 equiv) in CH2Cl2 (0.5m) was added at 08C to a solution of
the corresponding sulfoxide (1 equiv) in CH2Cl2 (0.5m). After stirring at
08C for 1–2 h, the mixture was hydrolysed with a saturated aqueous solu-
tion of Na2SO3 and extracted with CH2Cl2, and the organic layer was
washed with a saturated aqueous solution of NaHCO3. After workup, the
residue was purified by crystallization (EtOAc/hexane).
General procedure for reductions with DIBALH—Method B: A solution
of the appropriate carbonyl compound (1 equiv) in THF (0.3m) was
added dropwise under argon at ꢀ788C to a solution of DIBALH (1m in
hexane, 3equiv) in THF (0.2 m). After 30 min at the same temperature,
the excess of DIBALH was destroyed with methanol, and the mixture
was poured into an Erlenmeyer containing EtOAc and a saturated solu-
tion of sodium potassium tartrate and stirred vigorously for 30 min. The
organic layer was washed with brine and dried over MgSO4. After
workup, the residue was recrystallized or purified by flash chromatogra-
phy.
ACHTREUNG(4R,SR)-4-Hydroxy-3-(3-methylbut-3-en-1-ynyl)-4-[(p-tolylsulfinyl)me-
thyl]cyclohexa-2,5-dienone (17) and (4S,SR)-18: A solution of n-butyl-
lithium (2.4m in hexanes, 21.0 mL, 53.0 mmol) was added under argon at
08C to
a solution of commercially available 3-methylbut-3-en-1-yne
(5.8 mL, 53.0 mmol) in hexane (122 mL). After 30 min, a solution of
AlMe2Cl (1m in hexane, 53mL, 53.0 mmol) was added and the mixture
was stirred for 30 min at room temperature. The reaction mixture was di-
luted with CH2Cl2 (122 mL) and a solution of (SR)-13 (2.8 g, 11.0 mmol)
in CH2Cl2 (60 mL) was added. After the system had been stirred for 3h,
the mixture was cooled to ꢀ788C and a solution of freshly recrystallized
N-bromosuccinimide (5.6 g, 32.0 mmol) in THF (50 mL) was added.
After 1 h at ꢀ788C, the excess of aluminium reagent was destroyed with
MeOH, and the mixture was poured into an Erlenmeyer containing
EtOAc and a saturated solution of sodium potassium tartrate and stirred
vigorously for 1 h. The aqueous layer was extracted twice with EtOAc
and the combined organic layers were washed with a saturated solution
of Na2S2O8. After workup, an inseparable mixture of two bromo deriva-
tives 16 (5.0 g, 12.5 mmol) was obtained. This mixture was dissolved in
DMF (60 mL), and LiBr (3.3 g, 38.0 mmol) and Li2CO3 (2.9 g,
39.0 mmol) were added. After heating at 1008C for 1 h, the reaction mix-
ture was hydrolysed with H2O and extracted with EtOAc. After workup,
the residue was purified by column chromatography (EtOAc/hexane 1:1),
giving (4R,SR)-17 as a yellow solid (2.3g, 64%), together with the corre-
sponding 4-epimer (4S,SR)-18, also as a yellow oil (370 mg, 10%).
General procedure for reductions with L-Selectride—Method C: A solu-
tion of the appropriate carbonyl compound (1 equiv) in THF (0.3m) was
added at ꢀ788C to a solution of L-Selectride (1m in THF, 3equiv). After
stirring at the same temperature for 1–2 h, the mixture was sequentially
treated with H2O, MeOH, NaOH (5%), and H2O2. After several extrac-
tions with EtOAc and workup, the residue was purified by flash chroma-
tography.
General procedure for OH protection as OTBDMS—Method D: 2,6-Lu-
tidine (2.5 equiv) and TBDMSOTf (1.5 equiv) were sequentially added
under argon at 08C to a solution of the appropriate alcohol (1 equiv) in
CH2Cl2 (0.5m). After stirring for 4–5 h, the reaction mixture was treated
with HCl (5%). After workup, the residue was purified by flash chroma-
tography.
General procedure for MeSO2pTol elimination—Method E: Cs2CO3 (2–
3equiv) was added to a solution of the appropriate b-hydroxy sulfone
(1 equiv) in CH3CN (0.1m). After the time indicated in each case, the re-
action mixture was filtered through Celite and the solvent was evaporat-
ed to afford a residue, which was purified by flash chromatography.
Compound (4R,SR)-17: M.p. 126–1278C (EtOAc/hexane); [a]2D0 = +269
1
(c = 0.5 in acetone); H NMR: d = 7.51 and 7.31 (AA’BB’ system, 4H),
7.35 (d, J = 1.8 Hz, 1H), 6.41–6.36 (m, 1H), 6.34 (dd, J = 12.9, 1.8 Hz,
1072
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Chem. Eur. J. 2007, 13, 1064 – 1077

Polyoxygenated Cyclohexanes and Cyclohexenes
FULL PAPER
General procedure for cyclohexenone epoxidation—Method F:
Ph3COOH[42] (5 equiv) and a solution of Triton B in MeOH (40%,
3drops) were sequentially added at ꢀ788C to a solution of the appropri-
ate cyclohexenone (1 equiv) in THF (0.2m), and the reaction mixture was
allowed to warm to the desired temperature (Table 1). Once the starting
material had been consumed (TLC), the mixture was treated with a satu-
rated aqueous solution of Na2SO3 and extracted with diethyl ether. After
workup, the residue was purified by flash chromatography.
6H); 13C NMR: d = 201.1, 154.1, 128.3, 68.1, 41.9, 40.2, 25.7 (3C), 18.1,
15.0, ꢀ3.5, ꢀ3.7 ppm; MS (EI): m/z: calcd for C9H15O2Si: 183.0841;
found: 183.0844 [MꢀC4H9]+; MS (EI): m/z (%): 183(99) [ MꢀC4H9]+,
165 (7), 139 (13), 113 (11), 85.9 (40), 84 (62), 75 (100).
(2R,3S,4R,6S)-4-[(tert-Butyldimethylsilyl)oxy]-2,3-epoxy-6-methylcyclo-
hexanone (25) and (2S,3R,4R,6S)-26: A 25:75 mixture of compounds
(2R,3S,4R,6S)-25 and (2S,3R,4R,6S)-26 was obtained from (4R,6S)-24
(129 mg, 0.53mmol) by Method F ( ꢀ78 to ꢀ308C), after flash chroma-
tography (EtOAc/hexane 1:10), as a colourless oil in quantitative yield.
Compound (2R,3S,4R,6S)-25: 1H NMR: d = 4.45 (dd, J = 5.9, 2.8 Hz,
1H), 3.41 (ddd, J = 3.8, 3.2, 1.0 Hz, 1H), 3.23 (d, J = 3.6 Hz, 1H), 2.45
(ddq, J = 11.7, 7.1, 7.1 Hz, 1H), 1.77 (dd, J = 11.7, 2.4 Hz, 1H), 1.73
(ddd, J = 6.3, 3.4, 1.2 Hz, 1H), 1.09 (d, J = 7.1 Hz, 3H), 0.87 (s, 9H),
0.10 (s, 3H), 0.09 ppm (s, 3H).
General procedure for OTBDMS removal—Method G: A solution of
Bu4N+Fꢀ (1m in THF, 1.1 equiv) was added at 08C to a solution of the
appropriate OTBDMS derivative (1 equiv) in THF (0.3m). After the
system had been stirred for 30 min, a saturated aqueous solution of
NH4Cl was added and the mixture was extracted with CH2Cl2. After
workup, the residue was purified by flash chromatography.
Compound (2S,3R,4R,6S)-26: 1H NMR: d
= 4.34 (ddt, J = 7.7, 5.7,
ACHTREUNG(4S,5S)-4-Hydroxy-5-methyl-4-[(p-tolylsulfonyl)methyl]cyclohex-2-enone
(20): Compound (4S,5S)-20 was obtained from (4S,5S,SR)-19 (2.0 g,
6.9 mmol) by Method A, as a white solid (2.1 g, 98%). M.p. 144–1468C
(EtOAc/hexane); [a]2D0 = +21.2 (c = 1 in acetone); 1H NMR: d = 7.80
and 7.39 (AA’BB’ system, 4H), 7.06 (dd, J = 0.9, 10.2 Hz, 1H), 5.96 (d,
1.0 Hz, 1H), 3.45 (dt, J = 3.8, 1.4 Hz, 1H), 3.29 (dd, J = 3.8, 0.6 Hz,
1H), 2.66 (ddq, J = 11.1, 6.9, 5.5 Hz, 1H), 2.17 (dtd, J = 13.5, 5.5,
1.4 Hz, 1H), 1.56 (ddd, J = 13.5, 10.9, 7.9 Hz, 1H), 1.00 (d, J = 6.9 Hz,
3H), 0.88 (s, 9H), 0.11 (s, 3H), 0.08 ppm (s, 3H); 13C NMR (25:75 mix-
ture of 25 and 26): d = 208.2, 206.2, 65.8, 65.4, 63.2, 56.6, 55.4, 54.2, 41.0,
36.2, 34.6, 32.4, 25.6 (6C), 15.4 (2C), 15.0 (2C), ꢀ4.7, ꢀ4.8, ꢀ4.9,
ꢀ5.0 ppm; MS (EI): m/z: calcd for C9H15O3Si: 199.0790; found: 199.0783
[MꢀC4H9]+; MS (EI): m/z (%): 199 (36) [MꢀC4H9]+, 157 (41), 129 (20),
75 (100).
J
= 10.2 Hz, 1H), 4.08 (brs, 1H), 3.50 and 3.45 (AB system, J =
14.2 Hz, 2H), 2.62–2.37 (m, 3H), 2.47 (s, 3H), 1.09 ppm (d, J = 6.6 Hz,
3H); 13C NMR: d = 197.8, 148.9, 145.6, 137.4, 130.2 (2C), 129.1, 127.6
(2C), 71.7, 62.7, 42.0, 38.3, 21.7, 14.5 ppm; MS (FAB): m/z: calcd for
C15H19O4S: 295.1004; found: 295.1007 [M+H]+; MS (FAB): m/z (%): 295
(51) [M+H]+, 277 (77), 257 (66), 239 (54), 215 (60), 203 (76), 189 (94),
171 (100).
(2R,3R,4R,6S)-2,3-Epoxy-4-hydroxy-6-methylcyclohexanone (27) and
(2S,3S,4R,6S)-(5)
[(ꢀ)-dihydroepiepoformin]:
Compounds
ACHTREUNG(1S,4R,6S)-6-Methyl-1-[(p-tolylsulfonyl)methyl]cyclohex-2-ene-1,4-diol
(2R,3R,4R,6S)-27 and (2S,3S,4R,6S)-5 were obtained from a 25:75 mix-
ture of (2R,3S,4R,6S)-25 and (2S,3R,4R,6S)-26 (138 mg, 0.54 mmol) by
Method G, after flash chromatography (EtOAc/hexane 2:1), as colourless
oils in 16 and 41% yield, respectively.
(21): Compound (1S,4R,6S)-21 was obtained from (4S,5S)-20 (312 mg,
1.1 mmol) by Method B, as a white solid (298 mg, 95%). M.p. 118–1198C
1
(EtOAc/hexane); [a]2D0 = +56.0 (c = 1 in acetone); H NMR (CD3OD):
d = 7.76 and 7.40 (AA’BB’ system, 4H), 5.73(dd, J = 2.0, 10.2 Hz, 1H),
5.63(dt, J = 10.2, 1.6 Hz, 1H), 4.14 (m, 1H), 3.49 and 3.40 (AB system,
J = 14.5 Hz, 2H), 2.43(s, 3H), 2.13–2.00 (m, 1H), 1.70 (m, 1H), 1.48
(2R,3R,4R,6S)-27: [a]D20
=
ꢀ90 (c
=
0.96 in CHCl3); 1H NMR
(500 MHz): d = 4.58 (m, 1H), 3.56 (dt, J = 3.6, 0.8 Hz, 1H), 3.30 (d, J
= 3.5 Hz, 1H), 2.50 (ddq, J = 10.1, 8.5, 7.1 Hz, 1H), 1.87 (dd, J = 3.0,
0.8 Hz, 1H), 1.86 (dd, J = 10.2, 2.9 Hz, 1H), 1.84 (brs, 1H), 1.14 ppm (d,
(ddd, J
= 10.1, 12.3, 12.6 Hz, 1H), 0.94 ppm (d, J = 6.7 Hz, 3H);
13C NMR (CD3OD): d = 146.2, 139.4, 135.5, 132.2, 130.9 (2C), 129.1
(2C), 70.8, 68.1, 63.9, 36.8, 35.6, 21.5, 15.4 ppm; elemental analysis calcd
(%) for C15H20O4S (296.1): C 60.79, H 6.80, S 10.82; found: C 60.67, H
6.48, S 10.68.
J
= = 205.7, 64.9, 56.1, 54.2, 36.2, 32.2,
7.1 Hz, 3H); 13C NMR: d
15.4 ppm; MS (EI): m/z: calcd for C7H10O3: 142.0628; found: 142.0633
[M]+; MS (EI): m/z (%): 142 (1) [M]+, 125 (6), 88 (110), 86 (63), 85
(100).
ACHTREUNG(1S,4S,6S)-6-Methyl-1-[(p-tolylsulfonyl)methyl]cyclohex-2-ene-1,4-diol
(2S,3S,4R,6S)-5: [a]2D0 = ꢀ21 (c = 1.2 in acetone), [a]2D0 = ꢀ27 (c = 1.2
in CHCl3); 1H NMR (500 MHz): d = 4.45 (brdt, J = 8.7, 5.9 Hz, 1H),
3.57 (ddd, J = 3.7, 1.8, 0.9 Hz, 1H), 3.34 (dd, J = 3.8, 0.9 Hz, 1H), 2.75
(ddq, J = 11.8, 6.7, 5.1 Hz, 1H), 2.37 (dddd, J = 13.2, 6.0, 5.0, 1.8 Hz,
1H), 1.85 (d, J = 5.2 Hz, 1H), 1.63(ddd, J = 13.4, 12.0, 8.5 Hz, 1H),
1.04 ppm (d, J = 6.8 Hz, 3H); 13C NMR: d = 208.1, 65.1, 63.1, 55.3, 41.4,
34.4, 14.6 ppm; MS (EI): m/z: calcd for C7H10O3: 142.0628; found:
142.0628 [M]+; MS (EI): m/z (%): 142 (1) [M]+, 88 (10), 86 (66), 84
(100).
(22): Compound (1S,4S,6S)-22 was obtained from (4S,5S)-20 (80 mg,
0.28 mmol) by Method C, after chromatographic separation (CH2Cl2/ace-
tone 5:1) of the resulting 60:40 mixture of (1S,4R,6S)-21 and (1S,4S,6S)-
22, as a colourless oil (20 mg, 30%). [a]2D0 = ꢀ30.0 (c = 1 in acetone);
1H NMR: d = 7.79 and 7.77 (AA’BB’ system, 4H), 6.06 (d, J = 10.2 Hz,
1H), 5.89 (dd, J = 10.1, 4.7 Hz, 1H), 4.23–4.16 (m, 1H), 3.48 and 3.36
(AB system, J = 14.1 Hz, 2H), 3.41 (s, 1H), 2.44 (s, 3H), 2.38–2.20 (m,
1H), 1.91 (ddd, J = 14.1, 4.63, 3.7 Hz, 1H), 1.61 (dt, J = 14.1, 3.96 Hz,
1H), 1.00 ppm (d, J = 6.3Hz, 3H); 13C NMR: d = 145.0, 138.1, 132.2,
130.9, 130.0 (2C), 127.6 (2C), 71.1, 63.7, 63.5, 35.7, 33.8, 21.6, 14.3 ppm.
(2S,3R,4S,6R)-4-[(tert-Butyldimethylsilyl)oxy]-2,3-epoxy-6-methylcyclo-
hexanone (25) and (2R,3S,4S,6R)-26: A 25:75 mixture of compounds
(2S,3R,4S,6R)-25 and (2R,3S,4S,6R)-26 was obtained from (4S,6R)-24[12b]
by Method F (ꢀ78 to ꢀ308C), after flash chromatography (EtOAc/
hexane 1:10), as a colourless oil in quantitative yield. The spectroscopic
data were identical to those of their enantiomers (2R,3S,4R,6S)-25 and
(2S,3R,4R,6S)-26.
ACHTREUNG(1S,4R,6S)-4-[(tert-Butyldimethylsilyl)oxy]-6-methyl-1-[(p-tolylsulfonyl)-
methyl]cyclohex-2-en-1-ol (23): Compound (1S,4R,6S)-23 was obtained
from (1S,4R,6S)-21 (152 mg, 0.53mmol) by Method D, after flash chro-
matography (EtOAc/hexane 1:3), as a white solid (196 mg, 93%). M.p.
145–1478C (Et2O/hexane); [a]2D0 = +47.0 (c = 1 in acetone); 1H NMR:
d = 7.79 and 7.35 (AA’BB’ system, 4H), 5.94 (d, J = 10.2 Hz, 1H), 5.70
(dd, J = 3.2, 10.2 Hz, 1H), 4.21 (m, 1H), 3.60 (s, 1H), 3.53 and 3.31 (AB
system, J = 14.5 Hz, 2H), 2.44 (s, 3H), 2.32 (m, 1H), 1.89 (ddd, J = 5.4,
8.1, 13.5 Hz, 1H), 1.56 (ddd, J = 3.2, 5.3, 13.5 Hz, 1H), 1.00 (d, J =
7.0 Hz, 3H), 0.87 (s, 9H), 0.05 ppm (s, 6H); 13C NMR: d = 144.9, 138.3,
131.9, 130.8, 129.9 (2C), 127.6 (2C), 71.6, 64.1, 63.8, 36.5, 34.5, 25.9, 25.8
(3C), 21.6, 18.2, 14.3, ꢀ4.5 (2C) ppm.
(2S,3S,4S,6R)-2,3-Epoxy-4-hydroxy-6-methylcyclohexanone (27) and
(2R,3R,4S,6R)-5 [(+)-dihydroepiepoformin]: Compounds (2S,3S,4S,6R)-
27 and (2R,3R,4S,6R)-5 were obtained from
(2S,3R,4S,6R)-25 and (2R,3S,4S,6R)-26 by Method G, after flash chroma-
tography (EtOAc/hexane 2:1), as colourless oils in 16 and 61% yield, re-
spectively. The spectroscopic data were identical to those of their enan-
tiomers.
a 25:75 mixture of
ACHTREUNG(4R,6S)-4-[(tert-Butyldimethylsilyl)oxy]-6-methylcyclohex-2-enone (24):
(2S,3S,4S,6R)-27: [a]2D0 = +90 (c = 0.96 in CHCl3).
(2R,3R,4S,6R)-5: [a]2D0 = +22 (c = 0.1 in acetone), [a]2D0 = +3 4 (c = 0.1
Compound (4R,6S)-24 was obtained from (1S,4R,6S)-23 (80 mg,
0.19 mmol) by Method E (17 h), after flash chromatography (EtOAc/
hexane 3:1), as a colourless oil (42 mg, 89%). [a]2D0 = +67.0 (c = 0.4 in
acetone); 1H NMR: d = 6.77 (dt, J = 10.1, 2.0 Hz, 1H), 5.91 (dd, J =
2.4, 10.1 Hz, 1H), 4.59 (m, 1H), 2.38 (m, 1H), 2.21 (m, 1H), 1.77 (dt, J =
10.5, 12.5 Hz, 1H), 1.14 (d, J = 6.5 Hz, 3H), 0.91 (s, 9H), 0.12 ppm (s,
in CHCl3).
(2R,3R,4S,6R)-4-[(tert-Butyldimethylsilyl)oxy]-2,3-dihydroxy-6-methylcy-
clohexanone (28) and (2R,3R,4R,6S)-29: H2SO4 (1m, 21 mL, 0.002 mmol)
was added to a solution of NaIO4 (67 mg, 0.3mmol) in H 2O (400 mL).
Chem. Eur. J. 2007, 13, 1064 – 1077
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1073

M. C. CarreÇo et al.
After all solids had dissolved, the solution was cooled to 08C, an aqueous
solution of RuCl3 (0.1m, 10 mL, 0.002 mmol) was added, and the mixture
was stirred until the colour had turned bright yellow. EtOAc (1.2 mL)
was added, stirring was continued for 5 min, CH3CN (1.2 mL) was added,
and stirring was continued for a further 5 min. Compound (4R,6S)-24
(50 mg, 0.2 mmol) was added in one portion and the reaction mixture
was stirred for 10 min and then poured onto a mixture of saturated
NaHCO3 (5 mL) and saturated Na2S2O3 (5 mL) solutions. Phases were
separated, the aqueous layer was extracted with EtOAc (3”5 mL), and
after workup the residue was purified by flash chromatography (EtOAc/
hexane 1:2) to give an inseparable 58:42 mixture of (2R,3R,4S,6R)-28 and
(2R,3R,4R,6S)-29 as a colourless oil (20 mg, 35%). 1H NMR (mixture of
28 and 29): d = 4.74 (d, J = 2.3Hz, 1H), 4.29–4.26 (m, 1H), 4.23–4.17
(m, 4H), 3.74 (brs, 1H), 2.73 (dq, J = 2.3, 7.2 Hz, 1H), 2.66 (brs, 1H),
2.49–2.40 (m, 1H), 2.29 (ddd, J = 14.5, 6.6, 3.2 Hz, 1H), 1.98–1.93 (m,
1H), 1.76 (ddd, J = 14.5, 4.5, 2.4 Hz, 1H), 1.37 (d, J = 7.5 Hz, 3H), 1.09
(d, J = 6.6 Hz, 3H), ꢀ0.12 (s, 18H), ꢀ0.91 ppm (s, 12H); 13C NMR (mix-
ture of 28 and 29): d = 214.3, 209.9, 75.1, 72.0, 70.3, 69.1, 41.7, 38.5, 37.3,
34.9, 25.7, 19.7, 18.1, 17.9, 13.4, ꢀ4.7, ꢀ4.8, ꢀ4.9, ꢀ5.1 ppm.
calcd (%) for C15H16O5S: C 58.43, H 25.94, S 10.40; found: C 58.25, H
5.23, S 10.18.
(1S,2R,3R,4S)-2,3-Epoxy-6-methyl-1-[(p-tolylsulfonyl)methyl]cyclohex-5-
ene-1,4-diol (32): Compound (1S,2R,3R,4S)-32 was obtained from
(2S,3R,4S)-31 (50.0 mg, 0.16 mmol) by Method B, after chromatographic
separation (EtOAc/hexane 3:1) of a 77:23 mixture of 32 and 33, as a
white solid (33.4 mg, 67%). M.p. 140–1418C; [a]2D0 = ꢀ7 (c = 0.5 in ace-
tone); 1H NMR: d = 7.76 and 7.36 (AA’BB’ system, 4H), 5.64 (dq, J =
3.0, 1.4 Hz, 1H), 4.34 (ddd, J = 11.5, 5.1, 1.0 Hz, 1H), 3.66 (dd, J = 3.8,
2.0 Hz, 1H), 3.70 and 3.50 (AB system, J = 14.6 Hz, 2H), 3.55 (dd, J =
4.0, 1.0 Hz, 1H), 3.39 (d, J = 11.5 Hz, 1H), 2.79 (s, 1H), 2.45 (s, 3H),
1.65 ppm (d, J = 1.2 Hz, 3H); 13C NMR: d = 145.4, 137.1, 133.1, 130.0
(2C), 127.7 (2C), 125.6, 70.1, 63.0, 62.0, 58.5, 57.1, 21.6, 17.1 ppm; MS
(MALDI): m/z: calcd for C15H18O5S: 333.0767; found: 333.0775 [M+Na]+
.
(1S,2R,3R,4R)-2,3-Epoxy-5-methyl-1-[(p-tolylsulfonyl)methyl]cyclohex-
5-ene-1,4-diol (33): Compound (1S,2R,3R,4R)-33 was obtained from
(2S,3R,4S)-31 (50.0 mg, 0.16 mmol) by Method C, after flash chromatog-
raphy (EtOAc/hexane 3:1), as a white solid (41.6 mg, 83%). M.p. 145–
1468C; [a]2D0 = ꢀ60 (c = 0.5 in acetone); 1H NMR: d = 7.72 and 7.33
(AA’BB’ system, 4H), 5.29 (dd, J = 4.2 and 2.2 Hz, 1H), 4.50 (brs, 1H),
3.75 (d, J = 4.2 Hz, 1H), 3.71 (dd, J = 4.9, 2.4 Hz, 1H), 3.60 (brs, 1H),
3.50 and 3.44 (AB system, J = 14.6 Hz, 2H), 2.99 (d, J = 8.9 Hz, 1H),
2.43(s, 3H), 1.55 ppm (d, J = 1.6 Hz, 3H); 13C NMR: d = 145.1, 137.3,
132.8, 129.8 (2C), 127.7 (2C), 125.9, 70.2, 65.2, 61.1, 59.2, 57.2, 21.6,
16.9 ppm; MS (MALDI): m/z: calcd for C15H18O5S: 333.0767; found:
333.0771 [M+Na]+.
ACHTREUNG
a
(296 mg, 80%). [a]2D0 = +78 (c = 0.68 in acetone); 1H NMR: d = 6.89
(ddd, J = 10.2, 1.9, 1.9 Hz, 1H), 5.95 (dd, J = 10.2, 2.4 Hz, 1H), 4.67
(brs, 1H), 2.40–2.32 (m, 3H), 1.70 (ddd, J = 10.5, 13.1, 14.6 Hz, 1H),
1.15 ppm (d, J = 6.5 Hz, 3H); 13C NMR: d = 201.5, 153.4, 128.4, 67.2,
41.3, 40.0, 14.8 ppm; MS (EI): m/z: calcd for C7H10O2: 126.0681; found:
126.0684 [M]+; MS (EI): m/z (%): 126 (16) [M]+, 108 (19), 84 (100), 82
(35), 68 (12).
(1S,2R,3S,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2,3-epoxy-6-methyl-1-[(p-
tolylsulfonyl)methyl]cyclohex-5-en-1-ol: This compound was obtained
from (1S,2R,3R,4S)-32 (35.0 mg, 0.11 mmol) by Method D, after flash
chromatography (EtOAc/hexane 1:3), as a white solid (25 mg, 52%).
M.p. 110–1118C; [a]2D0 = +8 (c = 0.5 in acetone); 1H NMR: d = 7.82
and 7.35 (AA’BB’ system, 4H), 5.34 (dq, J = 7.3, 1.6 Hz, 1H), 4.41 (ddd,
J = 0.8, 2.2, 5.7 Hz, 1H), 3.96 (d, J = 1.6 Hz, 1H), 3.76 (brs, 1H), 3.55
and 3.45 (AB system, J = 14.6 Hz, 2H), 3.29 (dd, J = 4.2, 2.2 Hz, 1H),
2.45 (s, 3H), 1.69 (dd, J = 0.6, 2.2 Hz, 3H), 0.89 (s, 9H), 0.11 (s, 3H),
0.06 ppm (s, 3H); 13C NMR: d = 145.1, 137.8, 136.4, 129.9 (2C), 127.9
(2C), 123.0, 72.5, 64.0, 62.5, 55.8, 54.5, 25.7 (3C), 21.6, 18.0, 17.3, ꢀ4.5,
ꢀ4.9 ppm; MS (EI) m/z: calcd for C20H29O5SiS: 409.1505; found:
409.1501 [MꢀCH3]+; MS (EI) m/z (%): 409 (2) [MꢀCH3]+, 367 (100),
149 (40), 91 (30), 75 (50).
(2R,3R,4R,6S)-2,3,4-Trihydroxy-6-methylcyclohexanone (6) [(ꢀ)-gabosi-
ne O]: A solution of OsO4 in CH2Cl2 (420 mL, 0.16 mmol) was added at
ꢀ788C to a solution of (4R,6S)-30 (20.0 mg, 0.16 mmol) and TMEDA
(26 mL, 0.18 mmol) in CH2Cl2 (16 mL). After 1 h, the solution was con-
centrated under reduced pressure and the residue was dissolved in
MeOH (10 mL). HCl (35%, 5 drops) was added and the solution was
stirred for 3h. After workup and flash chromatography (EtOAc/EtOH
5:1), compound (2R,3R,4R,6S)-6 [(ꢀ)-gabosine O] was isolated pure as a
colourless oil (17.7 mg, 60%). [a]D20
=
ꢀ11 (c
= 0.15 in MeOH);
1H NMR (CD3OD): d = 4.27 (dd, J = 3.0, 1.3 Hz, 1H), 4.22 (dd, J =
5.0, 2.3Hz, 1H), 4.19 (ddd, J = 11.2, 4.6, 2.3Hz, 1H), 2.54 (tdq, J =
12.7, 1.5, 6.5 Hz, 1H), 2.03(ddd, J = 12.5, 6.0, 4.8 Hz, 1H), 1.84 (ddd, J
= 13.2, 12.2, 11.2 Hz, 1H), 1.05 ppm (d, J = 6.5 Hz, 3H); 13C NMR: d =
212.2, 78.1, 76.9, 69.4, 39.8, 37.9, 14.1 ppm; MS (EI): m/z: calcd for
C7H12O4: 160.0736; found: 160.0741 [M]+; MS (EI): m/z (%) 160 (5)
[M]+, 142 (5), 124 (12), 96 (17), 73(100), 57 (45).
AHCTRE(UGN 2R,3S,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2,3-epoxy-6-methylcyclohex-
5-enone (34): Compound (2R,3S,4S)-34 was obtained from (1S,2R,3S,4S)-
4-[(tert-butyldimethylsilyl)oxy]-2,3-epoxy-6-methyl-1-[(p-tolylsulfonyl)me-
thyl]cyclohex-5-en-1-ol (25.0 mg, 0.06 mmol) by Method E (24 h), after
flash chromatography (EtOAc/hexane 1:4), as a colourless oil (15 mg,
99%). [a]2D0 = +148 (c = 1.5 in acetone); 1H NMR: d = 6.28 (m, 1H),
4.63(dd, J = 2.2, 1.0 Hz, 1H), 3.63 (dd, J = 3.6, 1.2 Hz, 1H), 3.48 (d, J
= 3.6 Hz, 1H), 1.83 (d, J = 1.4 Hz, 3H), 0.92 (s, 9H), 0.17 (s, 3H),
0.14 ppm (s, 3H); 13C NMR: d = 194.0, 139.5, 133.3, 64.0, 58.4, 53.4, 26.2,
25.7 (3C), 15.9, ꢀ4.4, ꢀ4.6; MS (EI): m/z (%): 254 (3) [M]+, 253(11),
197 (3), 169 (5), 115 (10), 73 (100).
(4R)-4-Hydroxy-3-methyl-4-[(p-tolylsulfonyl)methyl]cyclohexa-2,5-dien-
one: This compound was obtained from (4R,SR)-15[11b] (503mg,
1.82 mmol) by Method A, as a white solid (528 mg, 99%). M.p. 122–
1238C (EtOAc/hexane); [a]2D0 = ꢀ70 (c = 0.5 in CHCl3), [a]2D0 = +16 (c
= 0.5 in acetone); 1H NMR: d = 7.68 and 7.31 (AA’BB’ system, 4H),
7.11 (d, J = 10.1 Hz, 1H), 6.01 (dd, J = 10.1, 2.0 Hz, 1H), 5.92 (dq, J =
1.4, 1.4 Hz, 1H), 4.4 (brs, 1H), 3.59 and 3.35 (AB system, J = 14.3Hz,
2H), 2.4 (s, 3H), 1.96 ppm (d, J = 1.6 Hz, 3H); 13C NMR: d = 185.3,
158.3, 148.6, 145.5, 136.4, 130.0 (2C), 127.8 (2C), 127.5, 127.3, 69.2, 63.01,
21.6, 18.1 ppm; MS (EI): m/z: calcd for C15H16O4S 292.0769; found:
292.0779 [M]+; MS (EI): m/z (%): 292 (3) [M]+, 170 (50), 155 (29), 137
(34), 123 (36), 105 (42), 91 (100), 65 (39).
AHCTRE(GNU 2R,3R,4S)-2,3-Epoxy-4-hydroxy-6-methylcyclohex-5-enone (7) [(+)-epi-
epoformin]: Compound (2R,3R,4S)-7 was obtained from (1S,2R,3R,4S)-
32 (173mg, 0.56 mmol) by Method E (30 min), after flash chromatogra-
phy (EtOAc/hexane 1:1), as a white solid (42 mg, 54%). M.p. 82–848C;
[a]2D0 = +303 (c = 1.1 in EtOH), 96% ee; 1H NMR (500 MHz): d =
6.47–6.44 (m, 1H), 4.66 (d, J = 4.4 Hz, 1H), 3.78 (ddd, J = 3.8, 2.5,
1.4 Hz, 1H), 3.51 (dd, J = 3.6, 1.3 Hz, 1H), 2.00 (brs, 1H), 1.85 ppm (d,
J = 1.6 Hz, 3H); 13C NMR (100 MHz): d = 194.1, 138.7, 134.7, 63.5,
57.6, 53.4, 15.9 ppm.
ACHTREUNG(2S,3R,4S)-2,3-Epoxy-4-hydroxy-5-methyl-4-[(p-tolylsulfonyl)methyl]cy-
clohex-5-enone (31): Compound (2S,3R,4S)-31 was obtained from (4R)-4-
hydroxy-3-methyl-4-[(p-tolylsulfonyl)methyl]cyclohexa-2,5-dienone
(50 mg, 0.17 mmol) by Method F (changing Ph3COOH for TBHP, 08C),
(+)-Epiepoformin (7) was also obtained from compound (2R,3S,4S)-34
(15.2 mg, 0.006 mmol) by Method G, after flash chromatography
(EtOAc/hexane 2:1), as a colourless oil (3.4 mg, 41%).
after flash chromatography (EtOAc/hexane 1:1), as
a white solid
(37.7 mg, 72%). M.p. 186–1878C; [a]2D0 = ꢀ209 (c = 0.5 in acetone);
1H NMR: d = 7.74 and 7.37 (AA’BB’ system, 4H), 5.72 (dq, J = 3.4,
1.4 Hz, 1H), 4.14 (d, J = 4.0 Hz, 1H), 3.55 (d, J = 4.0 Hz, 1H), 3.54
(brs, 1H), 3.52 (AB system, J = 14.6 Hz, 2H), 2.46 (s, 3H), 1.83ppm (d,
J = 1.4 Hz, 3H); 13C NMR: d = 192.1, 154.5, 145.7, 136.9, 130.1 (2C),
127.9 (2C), 124.5, 71.4, 61.5, 58.0, 55.0, 21.7, 18.2 ppm; elemental analysis
Synthesis of MTPA esters: Et3N (10 mL, 0.07 mmol) was added to a solu-
tion of alcohol (2R,3R,4S)-7 (5.0 mg, 0.04 mmol), DMAP (1 mg) and (R)-
or (S)-MTPA-Cl (14.4 mg, 0.04 mmol) in dry CH2Cl2 (2.2 mL). The mix-
ture was stirred for 1 h at room temperature and quenched with a satu-
1074
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1064 – 1077

Polyoxygenated Cyclohexanes and Cyclohexenes
FULL PAPER
rated solution of NH4Cl, and the organic layer was washed successively
with an aqueous solution of HCl (5%) and saturated NaHCO3. After
workup, the resulting mixture of diastereoisomeric esters was used direct-
(1S,2R,3R,4S)-2,3-Epoxy-6-(3-methylbut-3-en-1-ynyl)-1-[(p-tolylsulfo-
nyl)methyl]cyclohex-5-ene-1,4-diol (38): Compound (1S,2R,3R,4S)-38
was obtained from (2S,3R,4S)-37 (99.3mg, 0.29 mmol) by Method B, as a
76:24 mixture of epimers 38 and 39, in 89% overall yield from (4R)-35
(two steps). An analytical sample of pure 38 was obtained after flash
chromatography (EtOAc/hexane 1:1) as a yellow solid. M.p. 102–1038C;
1
ly for H NMR analysis in CDCl3.
(1S,2R,3S,4R)-2,3-Epoxy-5-methylcyclohex-5-ene-1,4-diol (8) [(ꢀ)-the-
obroxide]: CeCl3·7H2O (53mg, 0.14 mmol) was added to a solution of
(2R,3R,4S)-7 (10 mg, 0.07 mmol) in MeOH (0.8 mL) and the resulting
suspension was vigorously stirred for 1 h and then cooled to ꢀ788C. A
solution of NaBH4 (6 mg, 0.16 mmol) in MeOH (0.4 mL) was added and
the reaction mixture was stirred at ꢀ788C for 30 min. After quenching
with saturated aqueous NaHCO3 solution, workup and flash chromatog-
raphy (EtOAc), compound (1S,2R,3S,4R)-8 was obtained as a white solid
in quantitative yield. M.p. 62–648C; [a]2D0 = ꢀ8.0 (c = 0.10 in EtOH);
1H NMR: d = 5.52–5.49 (m, 1H), 4.45–4.43(m, 1H), 4.24 (brs, 1H),
3.36–3.34 (m, 1H), 3.30–3.37 (m, 1H), 1.82 ppm (s, 3H); 13C NMR: d =
135.2, 121.5, 66.2, 63.0, 53.0, 51.8, 21.2 ppm.
[a]2D0
=
ꢀ43( c
= = 7.72 and 7.35
1.07 in acetone); 1H NMR: d
(AA’BB’ system, 4H), 6.11 (dd, J = 5.1, 2.0 Hz, 1H), 5.25–5.23(m, 1H),
5.22–5.21 (m, 1H), 4.46 (dd, J = 11.3, 5.3 Hz, 1H), 3.89 and 3.63 (AB
system, J = 14.6 Hz, 2H), 3.70 (dd, J = 3.8, 0.8 Hz, 1H), 3.68 (dd, J =
1.8, 1.6 Hz, 1H), 2.43(s, 3H), 1.81 ppm (dd, J = 1.2 and 1.0 Hz, 3H);
13C NMR: d = 145.1, 136.9, 133.8, 129.8 (2C), 127.6 (2C), 125.9, 122.8,
122.3, 92.9, 84.1, 68.7, 62.6, 62.5, 57.0, 56.1, 22.9, 21.4 ppm; MS (EI): m/z:
calcd for C19H20O5S: 360.1026; found: 360.1018 [M]+; MS (EI): m/z (%):
360 (2) [M]+, 187 (100), 159 (32), 115 (15), 91 (77).
(1S,2R,3R,4R)-2,3-Epoxy-6-(3-methylbut-3-en-1-ynyl)-1-[(p-tolylsulfo-
nyl)methyl]cyclohex-5-ene-1,4-diol (39): Compound (1S,2R,3R,4R)-39
was obtained from (2S,3R,4S)-37 (8.8 mg, 0.026 mmol) by Method C, in
52% overall yield from (4R)-35 (two steps), and was used without further
purification in the next step. An analytical sample of pure 39 was ob-
tained after flash chromatography (EtOAc/hexane 2:1), as a yellow solid.
M.p. 42–438C; [a]2D0 = ꢀ29 (c = 0.58 in acetone); 1H NMR (500 MHz):
d = 7.71 and 7.29 (AA’BB’ system, 4H), 5.83(dd, J = 2.4, 2.0 Hz, 1H),
5.23(dq, J = 1.6, 1.2 Hz, 1H), 5.20 (dq, J = 2.0, 1.0 Hz, 1H), 4.60 (dd, J
= 2.8 Hz, 1H), 3.84 (d, J = 4.2 Hz, 1H), 3.76 (ddd, J = 5.1, 2.8, 2.4 Hz,
1H), 3.70 and 3.55 (AB system, J = 14.6 Hz, 2H), 2.42 (s, 3H), 1.79 ppm
(dd, J = 1.4, 1.2 Hz, 3H); 13C NMR (500 MHz): d = 144.9, 137.2, 135.3,
129.7 (2C), 127.9 (2C), 126.0, 123.0, 122.2, 92.5, 83.9, 68.9, 65.2, 61.7,
58.5, 56.9, 23.1, 21.6 ppm; MS (ES): m/z: calcd for C19H21O5S: 361.1104;
found: 361.1110 [M+H]+; MS (ES): m/z (%): 361 (48) [M+H]+, 187
(100), 159 (56), 139 (46).
ACHTREUNG(4S,5R,6S)-4,5,6-Trihydroxy-2-methylcyclohex-2-enone (9) [(+)-4-epiga-
bosine A]: A solution of (2R,3R,4S)-7 (10 mg, 0.07 mmol) in water, con-
taining sodium acetate (1.6 mg, 0.02 mmol), was heated at reflux for 2 d.
After evaporation of the solvent and flash chromatography (EtOAc/
EtOH 5:1), compound (4S,5R,6S)-9 was obtained as a colourless oil
(5.1 mg, 45%). [a]2D0 = +169 (c = 0.19 in MeOH); 1H NMR (CD3OD):
d = 6.64 (dq, J = 3.2, 1.6 Hz, 1H), 4.28 (dd, J = 8.1, 2.1 Hz, 1H), 3.96
(d, J = 11.0 Hz, 1H), 3.51 (dd, J = 10.8, 8.1 Hz, 1H), 1.80 ppm (d, J =
1.6 Hz, 1H); 13C NMR:
d = 200.1, 147.9, 134.7, 80.0, 78.0, 72.5,
15.2 ppm; MS (EI): m/z: calcd for C7H10O4: 158.0579 [M]+; found:
158.0585; MS (EI): m/z (%): 158 (1) [M]+, 140 (18), 98 (100), 70 (64).
(4R)-4-Hydroxy-3-(3-methylbut-3-en-1-ynyl)-4-[(p-tolylsulfonyl)methyl]-
cyclohexa-2,5-dienone (35): Compound (4R)-35 was obtained from
(4R,SR)-17 (913mg, 2.8 mmol) by Method A, after separation from epox-
ide 36 by flash chromatography (EtOAc/hexane 1:1), as a yellow solid, in
66% yield. M.p. 67–688C; [a]2D0 = +3 7 (c = 0.51 in acetone); 1H NMR:
d = 7.72 and 7.33 (AA’BB’ system, 4H), 7.18 (d, J = 9.9 Hz, 1H), 6.19
(t, J = 1.8 Hz, 1H), 6.16 (dd, J = 13.7, 2.0 Hz, 1H), 5.43–5.42 (m, 2H),
4.41 (brs, 1H), 3.80 and 3.63 (AB system, J = 14.3Hz, 2H), 2.44 (s, 3H),
1.92 ppm (t, J = 1.2 Hz, 3H); 13C NMR: d = 184.4, 147.4, 145.3, 142.0,
136.3, 131.6, 129.7 (2C), 127.9 (2C), 127.6 (2C), 125.4, 103.2, 83.4, 67.9,
63.5, 22.6, 21.5 ppm; MS (EI): m/z (%): calcd for C19H18O4S: 342.0926;
found: 342.0922 [M]+; MS (EI): m/z (%): 342 (5) [M]+, 220 (12), 187
(36), 173 (37), 155 (25), 139 (16), 115 (25), 91 (100), 65 (41).
(1S,2R,3S,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2,3-epoxy-6-(3-methylbut-
3-en-1-ynyl)-4-[(p-tolylsulfonyl)methyl]cyclohex-5-en-1-ol (40): Com-
pound (1S,2R,3S,4S)-40 was obtained from (1S,2R,3R,4S)-38 (30 mg,
0.09 mmol) by Method D, after flash chromatography (EtOAc/hexane
1:3), as a yellow solid (25 mg, 61%). M.p. 93–948C; [a]2D0 = ꢀ8 (c = 0.55
1
in acetone); H NMR: d = 7.85 and 7.32 (AA’BB’ system, 4H), 5.83(dd,
J = 5.4, 2.0 Hz, 1H), 5.26–5.24 (m, 2H), 4.50 (ddd, J = 5.4, 2.0, 0.8 Hz,
1H), 4.07 (dd, J = 4.0, 0.8 Hz, 1H), 3.72 and 3.55 (AB system, J =
14.8 Hz, 2H), 3.38 (ddd, J = 4.1, 2.2, 2.0 Hz, 1H), 3.25 (brs, 1H), 2.44 (s,
3H), 1.83 (dd, J = 1.5, 1.0 Hz, 3H), 0.90 (s, 9H), 0.14 (s, 3H), 0.11 ppm
(s, 3H); 13C NMR: d = 144.8, 137.8, 132.4, 129.6 (2C), 128.3 (2C), 126.0,
124.1, 123.1, 93.8, 83.8, 70.3, 63.4, 62.8, 55.3, 55.0, 25.7 (3C), 23.0, 21.6,
18.1, ꢀ4.6, ꢀ4.9 ppm; MS (EI): m/z: calcd for C25H34O5SiS: 474.1896;
found: 474.1876 [M]+; MS (EI): 474 (1) [M]+, 459 (2), 417 (100), 301
(19), 285 (11), 213(8), 187 (12), 149 (54), 91 (51), 73(73).
3-(3,4-Epoxy-3-methylbut-1-ynyl)-4-hydroxy-4-[(p-tolylsulfonyl)methyl]-
cyclohexa-2,5-dienone (36): Compound 36 was obtained, as a mixture of
diastereoisomers, from (4R,SR)-18 (913mg, 2.8 mmol) by Method A,
after separation from sulfone 35 by flash chromatography (EtOAc/
hexane 1:1), as a colourless oil (199 mg, 20%). [a]2D0 = +19 (c = 0.52 in
acetone); 1H NMR: d = 7.80 and 7.41 (AA’BB’ system, 4H), 7.28 (d, J
= 10.3Hz, 1H), 6.35 (dd, J = 4.5, 2.0 Hz, 1H), 6.25 (ddd, J = 10.3, 1.8,
0.6 Hz, 1H), 4.11 (brs, 1H), 3.80 and 3.49 (AB system, J = 14.1 Hz, 2H),
(1S,2R,3S,4R)-4-[(tert-Butyldimethylsilyl)oxy]-2,3-epoxy-6-(3-methylbut-
3-en-1-ynyl)-1-[(p-tolylsulfonyl)methyl]cyclohex-5-en-1-ol (41): Com-
pound (1S,2R,3S,4R)-41 was obtained from (1S,2R,3R,4R)-39 (60 mg,
0.17 mmol) by Method D, after flash chromatography (EtOAc/hexane
1:3), as a yellow solid (42 mg, 53%). M.p. 42–438C; [a]2D0 = ꢀ3 2 c( =
3.11 (d, J
= 5.5 Hz, 1H), 2.90 (d, J = 5.5 Hz, 1H), 2.51 (s, 3H),
1.64 ppm (s, 3H); 13C NMR: d = 183.8, 147.0, 145.7, 140.6, 136.6, 135.4,
133.2, 130.2 (2C), 128.0 (2C), 127.8, 101.2, 68.5, 63.7, 63.6, 55.7, 22.3,
21.7 ppm; MS (EI): m/z: calcd for C19H18O5S: 358.0875; found: 358.0872
[M]+; MS (EI): m/z (%): 358 (2) [M]+, 327 (11), 203 (15), 189 (29), 173
(58), 155 (46), 139 (26), 91 (100).
1
0.42 in acetone); H NMR: d = 7.75 and 7.33 (AA’BB’ system, 4H), 5.73
(dd, J = 2.4, 2.2 Hz, 1H), 5.23–5.20 (m, 2H), 4.74 (dd, J = 2.4, 2.0 Hz,
1H), 3.79 (d, J = 4.2 Hz, 1H), 3.68 and 3.56 (AB system, J = 14.6 Hz,
2H), 3.61 (ddd, J = 4.2, 2.4, 2.0 Hz, 1H), 2.44 (s, 3H), 1.81 (dd, J = 1.6,
1.0 Hz, 3H), 0.93 (s, 9H), 0.17 ppm (s, 6H); 13C NMR: d = 144.9, 137.3,
135.9, 129.7 (2C), 127.8 (2C), 126.1, 122.7, 121.7, 92.2, 83.8, 69.3, 66.4,
61.6, 57.0, 56.5, 25.7 (3C), 23.1, 21.6, 18.2, ꢀ4.6, ꢀ4.7 ppm; MS (EI): m/z
(%): calcd for C25H34O5SiS: 474.1896; found: 474.1881 [M]+; MS (EI):
m/z (%): 474 (1) [M]+, 465 (2), 447 (11), 417 (17), 365 (11), 324 (10), 301
(65), 261 (44), 243(38), 193(18), 149 (32), 91 (59), 73(100).
ACHTREUNG(2S,3R,4S)-2,3-Epoxy-5-(3-methylbut-3-en-1-ynyl)-4-[(p-tolylsulfonyl)me-
thyl]cyclohex-5-enone (37): Compound (2S,3R,4S)-37 was obtained from
(4R)-35 (10 mg, 0.03mmol) by Method F [TBHP (7 mL, 0.03mmol),
08C], as a yellow oil (8.8 mg, 84%). It was used without further purifica-
tion in the next step. [a]D20 = ꢀ143( c = 0.26 in acetone); 1H NMR
(500 MHz): d = 7.74 and 7.35 (AA’BB’ system, 4H), 5.98 (d, J = 2.0 Hz,
1H), 5.41 (dq, J = 1.7, 1.6 Hz, 1H), 5.38 (dq, J = 1.6, 1.1 Hz, 1H), 4.18
(d, J = 3.9 Hz, 1H), 3.70 (AB system, J = 14.8 Hz, 2H), 3.63 (ddd, J =
4.1, 2.0, 0.5 Hz, 1H), 2.45 (s, 3H), 2.17 (s, 1H), 1.87 ppm (dd, J = 1.6,
1.1 Hz, 3H); 13C NMR: d = 191.4, 145.5, 138.6, 136.8, 130.0 (2C), 129.5,
128.1 (2C), 125.8, 125.5, 102.8, 83.3, 70.2, 62.1, 57.8, 54.9, 22.7, 21.7 ppm;
MS (EI): m/z: calcd for C15H16O5S: 358.0875; found: 358.0866 [M]+; MS
(EI): m/z (%): 358 (17) [M]+, 203(9), 161 (46), 139 (19), 91 (100), 65
(43).
Acknowledgements
We thank the Dirección General de Investigación Científica y TØcnica
(Grant CTQ2005-02095/BQU) for financial support. M.R. and E.M.
Chem. Eur. J. 2007, 13, 1064 – 1077
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1075

M. C. CarreÇo et al.
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Chem. Eur. J. 2007, 13, 1064 – 1077

Polyoxygenated Cyclohexanes and Cyclohexenes
FULL PAPER
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Received: September 15, 2006
Published online: December 15, 2006
Chem. Eur. J. 2007, 13, 1064 – 1077
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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