Optimisation of enantioselectivity for the chiral base-mediated rearrangement of bis-protected meso-4,5-dihydroxycyclohexene oxides: Asymmetric synthesis of 4-deoxyconduritols and conduritol F

Article abstract of DOI:10.1016/S0040-4020(02)00370-8

A strategy based on diastereoselective epoxidation of a cyclohexene followed by chiral lithium amide-mediated epoxide rearrangement has been used to synthesise an allylic alcohol building block of >95% ee. The key step is the enantioselective rearrangement of a bis-protected meso-4,5-dihydroxycyclohexene oxide. A range of protecting groups and chiral base structures were surveyed in order to find the optimum protocol for high enantioselectivity. Using a tert-butyldimethylsilyloxy protecting group and a norephedrine-derived chiral base, a 93% yield of an allylic alcohol of >95% ee was achieved. To demonstrate the synthetic utility, this allylic alcohol was subsequently transformed into 4-deoxyconduritols and (+)-conduritol F.

Full text of DOI:10.1016/S0040-4020(02)00370-8

TETRAHEDRON
Pergamon
Tetrahedron 58 42002) 4643±4654
Optimisation of enantioselectivity for the chiral base-mediated
rearrangement of bis-protected meso-4,5-dihydroxycyclohexene
oxides: asymmetric synthesis of 4-deoxyconduritols
and conduritol F
Simon E. de Sousa, Peter O'Brienp and Christopher D. Pilgram
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 1 March 2002; accepted 21 March 2002
AbstractÐA strategy based on diastereoselective epoxidation of a cyclohexene followed by chiral lithium amide-mediated epoxide
rearrangement has been used to synthesise an allylic alcohol building block of .95% ee. The key step is the enantioselective rearrangement
of a bis-protected meso-4,5-dihydroxycyclohexene oxide. A range of protecting groups and chiral base structures were surveyed in order to
®nd the optimum protocol for high enantioselectivity. Using a tert-butyldimethylsilyloxy protecting group and a norephedrine-derived chiral
base, a 93% yield of an allylic alcohol of .95% ee was achieved. To demonstrate the synthetic utility, this allylic alcohol was subsequently
transformed into 4-deoxyconduritols and 41)-conduritol F. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Whitesell and Felman's seminal contribution in 19801
described the chiral base-mediated rearrangement of cyclo-
hexene oxide to cyclohex-2-en-1-ol 436% optical purity), a
reaction that had previously been known in the racemic
sense for some time.5 Over the last 20years, the use of chiral
bases in epoxide rearrangements has been studied exten-
sively from a methodology 4Asami,6 Murphy,7 Hodgson,8
Singh,9 Andersson,10 Ahlberg11 and ourselves12), synthetic
4Asami,13 Mori,14 Leonard,15 Hodgson,16 Singh,17 Koskinen18
and ourselves19), mechanistic 4Morgan,20 Hodgson21 and
Collum22) and theoretical perspective 4Ahlberg11,23). In
addition, Asami,6d,e Alexakis,24 Andersson10 and Ahlberg11a,c
have had much success in the development of epoxide rear-
rangement reactions using sub-stoichiometric amounts of
The ®rst example of the use of a chiral lithium amide base as
a reagent for asymmetric synthesis was described in 1980by
Whitesell and Felman.1 Since then, research into chiral base
chemistry has grown dramatically and chiral bases can now
be regarded as genuinely useful reagents for organic syn-
thesis. There are three main classes of desymmetrisation
reactions2 mediated by chiral lithium amide bases: 4i) rear-
rangement of epoxides to allylic alcohols; 4ii) deprotonation
of cyclic ketones and related substrates and 4iii) aromatic
and benzylic functionalisation of tricarbonyl 4h6-arene)
chromium complexes; these areas have been compre-
hensively reviewed.3,4
Scheme 1.
Keywords: epoxides; rearrangement; allylic alcohols; diamines.
Corresponding author. Tel.: 144-1904-432535; fax: 144-1904-432516; e-mail: paob1@york.ac.uk
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020402)00370-8

4644
S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
Table 1. Synthesis of meso-cyclohexene oxides
Entry
R
Alkene
Epoxidation method
trans/cisa
Epoxide
Yield 4%)b
c
1
2
3
4
5
6
7
8
TES
TES
TES
TBS
TBS
TBS
7
7
7
9
9
9
11
13
m-CPBA, CH2Cl2
m-CPBA, cyclohexaned
39: 61
85: 15
98: 2
56: 44
93: 7
98: 2
trans-8
trans-8
trans-8
trans-10
trans-10
trans-10
trans-12
trans-14
38
n.d.
74
51
81
n.d.
92
77
Dioxiranee
m-CPBA, CH2Cl2
c
m-CPBA, cyclohexaned
Dioxiranee
m-CPBA, CH2Cl2
m-CPBA, CH2Cl2
c
TBDPS
±C4Me)2±
98: 2
90: 10
c
a
Ratio determined by 1H NMR spectroscopy on the crude product mixture.
Isolated yield after chromatography.
m-CPBA, NaHCO3, CH2Cl2, rt, 16±46 h.
m-CPBA, NaHCO3, cyclohexane, rt, 16±20h.
Oxonew, tri¯uoroacetone, Na2´EDTA, MeCN±water, NaHCO3, 08C, 2±3 h.
b
c
d
e
chiral bases. Speci®cally, Andersson10 and Ahlberg11b,c have
shown that cyclohexene oxide can be rearranged to 4R)- or
4S)-cyclohex-2-en-1-ol of $96% ee using 5±10mol% of
chiral lithium amide base in the presence of approximately
2 equiv. of achiral 4bulk) base.
studies on the preparation and chiral base-mediated rear-
rangement of bis-protected meso-4,5-dihydroxycyclo-
hexene oxides trans-2. Furthermore, to showcase the
methodology, allylic alcohol 3 4RˆTBS, $89% ee) is
used in the ®rst asymmetric synthesis of 4-deoxyconduritols
5 and 6 and a new synthesis of the tetraacetate of naturally
ocurring 41)-conduritol F is also presented.
Our own interest in epoxide rearrangements using chiral
bases has focused on methodology and synthetic appli-
cations. In particular, over the last few years, we have
been developing a general strategy for the diastereo- and
enantiocontrolled synthesis of polyhydroxylated cyclo-
hexanes.12a,19c,e The essence of the approach is captured in
Scheme 1. The key step is the chiral base-mediated rear-
rangement of bis-protected meso-4,5-dihydroxycyclo-
hexene oxides 4such as trans- and cis-2) to the
corresponding allylic alcohols 43 and 4, respectively).
Allylic alcohols 3 and 4 can then be used to synthesise
4-deoxyconduritols 4such as 5 and 6), conduritols and
related cyclitols25 as such compounds possess a range of
useful biological activity.26
2. Results and discussion
2.1. Epoxide synthesis
The ®rst step to be investigated in the approach outlined in
Scheme 1 was the epoxidation of diprotected cis-4,5-di-
hydroxycyclohexenes 1 to give trans- and cis-2. Previously,
we have communicated27,28 some of the details on our study
of the diastereoselectivity of epoxidation of alkenes 1. In the
present work, we were particularly interested in synthe-
sising epoxides trans-2 equipped with different protecting
groups with a view to discovering which protecting group
would give the highest enantioselectivity upon chiral base
rearrangement 4vide infra). Thus, four alkenes 47, 9, 11, and
13) were prepared from the known12a,29,30 1,2-diol precursor
using standard conditions 4see Section 4). The results of
their epoxidation are summarised in Table 1.
Ideally, we wanted to discover a high yielding, diastereo-
selective way of synthesising each of epoxides trans- and
cis-2 as this would enable us to study the enantioselectivity
of the epoxide rearrangements on single epoxide diastereo-
mers. Previously, we have noted that for the bis tert-butyl-
dimethylsilyl protected epoxides trans- and cis-2 4RˆTBS),
the cis epoxide rearranged to the corresponding allylic
alcohol with higher enantioselectivity than its trans counter-
part.12a However, despite considerable efforts, we have been
unable to develop a high yielding diastereoselective entry
into bis protected epoxides cis-2. Fortunately, this was
unimportant as we have now developed 4i) a good method
for generating epoxides trans-2 stereoselectively; 4ii) a
highly enantioselective chiral base-mediated rearrangement
of epoxides trans-2 to allylic alcohols 3 4using a new chiral
lithium amide base, developed independently by Ahlberg et
al.11 and ourselves12b) and 4iii) a simple oxidation±reduction
sequence for converting allylic alcohol 3 into the diastereo-
meric allylic alcohol 4.19e
Our standard method for epoxidation involves treatment of
the alkenes with m-CPBA in sodium hydrogencarbonate-
buffered dichloromethane 4room temperature, 16±46 h).
The relative stereochemistry of the epoxides reported in
Table 1 was elucidated using a combination of X-ray
crystallography 4of epoxide trans-12) and chemical corre-
lation. Use of the standard m-CPBA/dichloromethane
conditions with alkenes 11 and 13 gave high stereoselec-
tivity in favour of the trans epoxides and hence good to
excellent isolated yields of epoxides trans-12 and trans-14
4Table 1, entries 7 and 8). In contrast, with sterically less
demanding silyl protecting groups 4RˆTES or TBS), the
m-CPBA/dichloromethane conditions were considerably
less trans-stereoselective and furnished much lower
4#51%) yields of epoxides trans-8 and trans-10 4Table 1,
In this paper, we describe in full all of the optimisation

S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
Table 2. Enantioselective rearrangement of meso-cyclohexene oxides
4645
Entry
R
Epoxide
Diamine
Alcohol
Yield 4%)a
ee 4%)b
1
2
3
4
5
6
7
8
TES
TBS
TBS
TBS
TBDPS
TBDPS
trans-8
4R)-15
4R)-15
41R,2S)-16
41R,2S)-16
4R)-15
41R,2S)-16
4R)-15
41R,2S)-16
41S,4R,5S)-17
41S,4R,5S)-18
41S,4R,5S)-18
41S,4R,5S)-18
41S,4R,5S)-19
41S,4R,5S)-19
41S,4R,5S)-20
41S,4R,5S)-20
91
71
94
93c
76
85
39
56
70
76
94
trans-10
trans-10
trans-10
trans-12
trans-12
trans-14
trans-14
.95c
68
84
48
26
±C4Me)2±
±C4Me)2±
a
Isolated yield after chromatography.
Enantiomeric excess determined by formation of Mosher's esters.
b
c
Reaction carried out with 3.8 g of epoxide trans-10 410.5 mmol) added slowly to the chiral base solution which was kept between 0 and 2108C during the
addition 4see Section 4).
entries 1 and 4). We have suggested that a hydrogen bond-
ing cis-directing effect with sterically less demanding silyl
protecting groups 4eg RˆTES and TBS) disrupts the usual
sterically controlled trans-stereoselective epoxidations in
these systems.27
derived diamine 41R,2S)-16, independently developed by
Ahlberg et al.11 and ourselves,12b in order to screen the effect
of the hydroxyl protecting group on enantioselectivity.
Diamines 4R)-1532a and 41R,2S)-1612c were easily prepared
using our aziridinium ion-based methods for diamine
synthesis.32
Interestingly, it appears that the proposed hydrogen bonding
interaction can be minimised by carrying out the epoxi-
dations in cyclohexane, a result which has some related
literature precedent in ®ve-ring systems but has not been
fully explained.6b Thus, epoxidation of alkenes 7 and 9
with m-CPBA in cyclohexane gave signi®cantly improved
trans stereoselectivity 4Table 1, entries 2 and 5) when
compared to the dichloromethane results 4Table 1, entries
1 and 4). Finally, the most stereoselective way of synthe-
sising epoxides trans-8 and trans-10 4Table 1, entries 3 and
6) involved the use of Yang's dioxirane31 4generated in
situ from tri¯uoroacetone and Oxonew). However, we
encountered dif®culties when attempting to scale up the
dioxirane epoxidations above 100 mg of epoxide and so
this method was less useful.
The preferred conditions for epoxide rearrangement in our
group involve adding a THF solution of the epoxide to
2 equiv. of the chiral lithium amide base 4generated from
the diamine and butyllithium in THF at 08C). Then, the
reaction mixture is allowed to warm slowly from 08C to
room temperature over 4 h followed by stirring at room
temperature for a further 16 h. The rearrangements are
typically quenched with aqueous ammonium chloride and
subjected to a standard acidic work-up 4see Section 4 for full
details). Using these conditions, epoxides trans-8, trans-10,
trans-12 and trans-14 were rearranged using the chiral bases
derived from diamines 4R)-15 and 41R,2S)-16 and the results
are presented in Table 2. The enantiomeric excess33 and the
absolute stereochemistry34 of the allylic alcohols were
determined by formation of diastereomeric Mosher's
esters.12a
From a synthetic viewpoint, our optimised methods for the
preparation of the required trans epoxides are summarised
as follows. The dioxirane method31 gave a 74% isolated
yield of epoxide trans-8 4Table 1, entry 3); the m-CPBA/
cyclohexane method gave an 81% isolated yield of epoxide
trans-10 4Table 1, entry 5) and the m-CPBA/dichloro-
methane method gave a 92% isolated yield of epoxide
trans-12 4Table 1, entry 7) and a 77% isolated yield of
epoxide trans-14 4Table 1, entry 8). For the large-scale
synthesis of trans epoxides, the m-CPBA reactions were
the most useful.
A comparison of the results obtained with Singh's diamine
4R)-15 for the four protecting groups 4Table 2, entries 1, 2, 5
and 7) indicates that the tert-butyldimethylsilyl protecting
group is optimal in terms of enantioselectivity: epoxide
trans-10 gave allylic alcohol 41S,4R,5S)-18 with 76% ee
4Table 2, entry 2). Epoxide trans-14, with the isopropyl-
idene acetal protecting group, was rearranged with the
lowest 448%) enantioselectivity 4Table 2, entry 7).
Presumably the reacting conformation of the epoxide in
trans-14 is somewhat distorted when compared to the
conformations of the other epoxides 4trans-8, trans-10 and
trans-12) which lack a ring-fused protecting group and
this results in the lower observed enantioselectivity with
epoxide trans-14.
2.2. Optimisation of enantioselectivity for epoxide
rearrangement using chiral lithium amide bases
With four trans epoxides in hand, we were ready to study
their chiral base-mediated rearrangement and the effect on
the enantioselectivity of 4i) the hydroxyl protecting group
and 4ii) the chiral base structure was assessed. Thus, we
selected Singh's9a diamine 4R)-15 and the norephedrine-
For the silyl protected epoxides trans-10 and trans-12,
improved enantioselectivity was obtained using the
norephedrine-derived base 41R,2S)-16 compared with

4646
S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
Table 3. Enantioselective rearrangement of epoxide trans-10 with different chiral bases
Entry
1
Amine/diamine
Alcohol
Yield 4%)a
ee 4%)b
.95
41S,4R,5S)-18
93
2
3
41R,4S,5R)-18c
41R,4S,5R)-18
9095
97
86
4
41R,4S,5R)-18
41R,4S,5R)-18
41S,4R,5S)-18
41S,4R,5S)-18
41S,4R,5S)-18
41R,4S,5R)-18
41R,4S,5R)-18
41S,4R,5S)-18
41S,4R,5S)-18
98
84
84
84
5
53
6
93
7
9080
71
8
76
35
20
18
12
9
95
10
11
65
62
12
81
a
Isolated yield after chromatography.
Enantiomeric excess determined by formation of Mosher's esters.
Reaction carried out using 0.2 equiv. of diamine 21 and 1.8 equiv. of diisopropylamine in the presence of DBU.10
b
c
Singh's base 4R)-15 4Table 2, compare entries 2 and 3 or
entries 5 and 6). In contrast, rearrangement of the isopropyl-
idene acetal-protected epoxide trans-14 with diamine
41R,2S)-16 proceeded with a poor 26% enantioselectivity
4Table 2, entry 8). It is clear from Table 2 that the highest
enantioselectivity for rearrangement is achieved using a
tert-butyldimethylsilyl protecting group and the nore-
phedrine-dervied diamine 41R,2S)-16: our optimised con-
ditions for the rearrangement are presented in Table 2,
entry 4. On a 10.5 mmol scale of epoxide trans-10, slow
addition of this epoxide 4as a THF solution) to the chiral
lithium amide solution was required in order to maintain an
internal reaction temperature of between 0and 2108C and
in this way, a 93% isolated yield of allylic alcohol
41S,4R,5S)-18 of .95% ee was obtained. This reaction
was simple to carry out, reliable and reproducible allowing
multi-gram quantities of allylic alcohol 41S,4R,5S)-18 to be
synthesised. It is important to emphasise that the preparation
of diamine 41R,2S)-16 is very simple 4two steps with no
intermediate puri®cation)12c and the diamine can be easily
recovered 4$70% yield) using a simple acid-base extraction
during the work-up 4see Section 4).

S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
4647
For the rearrangement of epoxide trans-10, it is possible to
improve on the enantioselectivity observed with Singh's
diamine 4R)-15 476% ee; Table 3, entry 8) by varying the
chiral base structure. For example, replacement of the
pyrrolidinyl group in 4R)-15 by an iso-indolinyl group, a
dimethylamino group or a diethylamino group 4Table 3,
entries 5±7) all gave improved enantioselectivity 4up to
84% ee). However, even better results were obtained
using pyrrolidinyl-substituted diamines with increased
steric bulk as in the norephedrine-derived chiral diamines
41R,2S)-16 and 41S,2S)-22 4Table 3, entries 1 and 3). Of
these, diamine 41R,2S)-16 is preferred.
The use of a N-methyl substituent on the secondary nitrogen
is essential for high enantioselectivity 4Table 3, entries 11
and 12) as Singh has previously noted for the rearrangement
of cyclohexene oxide itself.9a Our results also con®rm that
Whitesell's1 base 4S,S)-28, the base of choice for ketone
deprotonations,3 is not appropriate for epoxide rearrange-
ment reactions 4Table 3, entry 10). We note in passing
that Asami's base 4S)-23 also performs well in the rear-
rangement of epoxide trans-10 4Table 3, entry 4). Probably
the most useful chiral base system available to synthetic
chemists at the present time is Andersson's diamine 21
used in sub-stoichiometric amounts together with excess
LDA and DBU.10 We can con®rm that this base system is
also very successful for the rearrangement of epoxide
trans-10Ðin our hands, a 90% isolated yield of allylic
alcohol 41R,4S,5R)-18 of 95% ee was obtained using
diamine 21 4Table 3, entry 2).
Scheme 2.
Using the tert-butyldimethylsilyl protected epoxide trans-
10 as a model substrate, a detailed and systematic study on
the effect of chiral lithium amide base structure on enantio-
selectivity has also been carried out. The full results 4in
descending order of enantioselectivity) are presented in
Table 3. Most of the diamines studied were structurally
related to Singh's9a diamine 4R)-15 but we also decided
to include Andersson's10 diamine 21, Asami's6a,b diamine
4S)-23 and Whitesell's1 amine 4S,S)-28. Diamines 4S)-23
and 4S,S)-28 are commercially available and we have
previously described the preparation of diamines
41S,2S)-22,12c 4S)-24, 4S)-27, 4R)-29 and 4R)-30.32b
In summary, this is the ®rst systematic study of an epoxide
rearrangement that directly compares the enantioselectivity
of most of the widely-used chiral lithium amide bases
on one substrate at the same time. Our results demonstrate
that diamine 41R,2S)-16 provides high enantioselectivity
4.95%) for the rearrangement of epoxide trans-10. Given
that Ahlberg and co-workers11b,c have recently described its
successful use in sub-stoichiometric amounts for epoxide
rearrangement, this easily synthesised diamine could have
great potential in the future. However, at present, the use of
sub-stoichiometric amounts of Andersson's diamine 21
represents the most versatile reagent system for epoxide
rearrangements and epoxide trans-10 was not an exception.
The known35 diamines 4R)-25 and 4R)-26 were prepared
using a new synthesis as delineated in Scheme 2. Thus,
4R)-styrene oxide was reacted with either diethylamine or
dimethylamine in the presence of lithium perchlorate
according to Chini's procedure36 to give a mixture of regio-
isomeric amino alcohols 43137 and 3237 or 3338 and 3439).
After chromatography, each mixture was separately treated
with mesyl chloride and then methylamine 4our usual
diamine forming conditions32) to give either diamine
4R)-25 485% yield over two steps) or 4R)-26 431% yield
over two steps).
2.3. Asymmetric synthesis of 4-deoxyconduritols and
conduritol F
The epoxidation and chiral base-mediated rearrangement
Scheme 3.

4648
S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
Scheme 4.
studies had shown that multi-gram quantities of highly
enantioenriched allylic alcohol 41S,4R,5S)-18 could be
prepared. Next, we wanted to convert this compound into
its diastereomer 41R,4R,5S)-36 and utilise both compounds
in some synthetic studies. Although a Mitsunobu approach
was brie¯y considered, it was found that a simple oxidation-
reduction approach was most ef®cacious 4Scheme 3).
Finally, the general strategy described in this paper has been
used in a concise asymmetric synthesis of the tetraacetate of
41)-conduritol F.25a,b In order to synthesise the naturally
occurring enantiomer, enone 44S,5R)-35 was required.
Enone 44S,5R)-35 489% ee43) was prepared by rearrange-
ment of epoxide trans-10 with the chiral lithium amide
base derived from diamine 41S,2R)-16 and subsequent
PCC oxidation. The synthesis of the tetraacetate of
41)-conduritol F is shown in Scheme 4.
Allylic alcohol 41S,4R,5S)-18 4.95% ee) was oxidised
using PCC in dichloromethane to give enone 44R,5S)-35
4.95% ee) in 90% yield. Then, reduction under Luche
conditions40 generated a 90% yield of allylic alcohol
41R,4R,5S)-36 4.95% ee) as a single, different 4by 1H
NMR spectroscopy) diastereoisomer. The reduction is
completely diastereoselective and presumably results
from axial attack on a preferred conformation of enone
44R,5S)-35 4with one silyloxy group in a pseudo-axial
position and the other silyloxy group in an equatorial
position), as depicted in Fig. 1 4RˆH).
For the a-hydroxylation of enone 44S,5R)-35, the use of lead
tetraacetate44 4in re¯uxing toluene) and Davis' oxaziridine45
4on a preformed sodium enolate) were explored. We were
never able to obtain more than a 57% yield of acetoxy enone
39 using lead tetraacetate and thus preferred the oxaziridine
methodology. Deprotonation of enone 44S,5R)-35 with
sodium hexamethyldisilazide at low temperature and
enolate trapping with Davis' oxaziridine 37 produced a
91% yield of a single diastereoisomer 4by 1H NMR spectro-
scopy) of hydroxy ketone 38. Interestingly, no b-elimi-
nation of the silyloxy group was observed. The relative
stereochemistry of 38 was established by completing the
synthesis of the tetraacetate of 41)-conduritol F 4vide
1
infra) and comparing the H and 13C NMR spectroscpic
data with that of all of the conduritol tetraacetates.
The sense of diastereoselectivity in the formation of 38
presumably arises by attack trans to the bulky silyloxy
groups on the almost planar six-membered ring enolate.
Figure 1.
As a trivial illustration of the utility of allylic alcohols
41S,4R,5S)-18 and 41R,4R,5S)-36 in synthesis, they were
converted into 4-deoxyconduritols 5 and 6, respectively.
This was accomplished in quantitative yield by treatment
of each of 41S,4R,5S)-18 and 41R,4R,5S)-36 with TBAF
followed by standard acetylation 4Scheme 3). This is
the ®rst asymmetric synthesis of 4-deoxyconduritols 5
{[a]Dˆ2236.1 4c 3.5 in CHCl3)} and 6 {[a]Dˆ254.04 c
3.5 in CHCl3)}; the spectroscopic data of 5 and 6 were
consistent with literature data on the racemates.41,42
Next, we wanted to reduce the ketone in hydroxy ketone 38
and for high diastereoselectivity, it was necessary to protect
the hydroxyl group 4vide infra). Acetylation of hydroxy
ketone 38 4to give 39) and then Luche reduction40 afforded
allylic alcohol 40 as the only diastereomeric product in 96%
yield. Axial attack of hydride on a preferred conformation of
the enone 4see Fig. 1; RˆOAc) accounts for the stereo-
selectivity in a similar fashion to the reduction of enone
44R,5S)-35 described previously 4see Scheme 3). Finally,
Scheme 5.

S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
4649
TBAF deprotection and a ®nal acetylation 487% for the two
steps) yielded 41)-conduritol F tetraacetate 489% ee). The
was titrated against diphenylacetic acid before use.
m-CPBA 4approx. 70% pure) was used as supplied by
Aldrich Chemical Company Ltd.
synthetic material exhibited [a]Dˆ146.9 4c 1.0in CHCl )
3
4lit.,46 [a]Dˆ145.6 4c 1.1 in CHCl3)) and was identical
spectroscopically to the tetraacetate of 41)-conduritol
F.25a,b,40
Proton 4270MHz) and carbon 467.9 MHz) NMR spectra
were recorded on a 270MHz spectrometer using an internal
deuterium lock. All samples were recorded as solutions in
deuteriated chloroform and chemical shifts are quoted in
parts per million down®eld of tetramethylsilane. Coupling
constant 4J) values are given in Hz. Carbon NMR spectra
were recorded with broad band proton decoupling.
We brie¯y attempted to divert the synthesis from hydroxy
ketone 38 to conduritol E 4Scheme 5). Direct Luche reduc-
tion40 of hydroxy ketone 38 gave a 59:41 mixture of
diastereomeric 1,2-diols 41 and 4247 4corresponding to
conduritol F and E stereochemistry, respectively). In this
case we suggest that the preferred attack shown in Fig. 1
4RˆOAc) is disrupted by complexation of the reagent to the
hydroxyl group 4RˆOH) such that chelation-controlled
reduction is competitive leading to a stereorandom reaction.
The diastereoselectivity could be further improved in favour
of conduritol E stereochemistry by carrying out a reported
chelation-controlled cis-selective reduction using lithium
aluminium hydride-aluminium trichloride 44i) 4 equiv.
AlCl3, Et2O, rt, 5 min; 4ii) 2 equiv. LiAlH4, Et2O, rt,
1 min; 4iii) water).48 In this way, an 80:20 mixture of
1,2-diols 41 and 4247 were obtained. However, we could
not ®nd conditions for complete diastereoselectivity in the
synthetic route to conduritol E.
Melting points were measured on a digital melting point
apparatus. Infra red spectra were recorded on an FT IR
spectrometer as solutions in chloroform. Chemical ioni-
sation and high resolution mass spectra were recorded on
an Autospec spectrometer. Optical rotations were recorded
on a polarimeter 4using the sodium D line; 589 nm) at 208C
and [a]D values are given in units of 1021 deg cm2 g21
.
The synthesis of diamines 41R,2S)-16,12c 41S,2S)-22,12c
4S)-24,32b 4R)-15,32a 4S)-27,32b 4R)-2932b and 4R)-3032b has
been reported previously. Diamine 21 was a gift from
Professor P. G. Andersson and diamines 4S)-23 and
4S,S)-28 are commercially available from Aldrich Chemical
Company Ltd. Diprotected alkenes 912a and 1330 were
prepared using literature procedures.
3. Conclusion
4.1.1. .4Rp,5Sp)-4,5-Dihydroxycyclohexene. Cyclohexa-
1,4-diene 425.0 g, 0.301 mol) was added to a stirred solution
of KIO3 416.1 g, 75.2 mmol) and I2 438.2 g, 0.150 mol) in
AcOH 4500 mL) at rt under N2. The resulting mixture was
stirred at 608C for 4 h. After cooling, KOAc 429.5 g,
0.301 mol) was added and the mixture heated at re¯ux for
4 h. After cooling, water 410mL) was added and the solvent
was evaporated under reduced pressure over a period of 3 h.
Et2O 4200 mL) was added and the organic layer was washed
with saturated Na2SO34aq) until the brown colour was
removed, dried 4MgSO4) and evaporated under reduced
pressure to give a crude mixture of mono and diacetate.
To this crude mixture was added Amberlite IRA4OH)
resin 4150g), MeOH 4300mL) and THF 4150mL) and the
resulting suspension was stirred at rt for 16 h. The mixture
was ®ltered through Celite and the resin washed well with
hot MeOH 490mL). The ®ltrate was evaporated under
reduced pressure and puri®cation by recrystallisation from
CHCl3±petrol gave known12a,29,30 44Rp,5Sp)-4,5-dihydroxy-
cyclohexene 425.4 g, 74%) as white crystals, mp 78±808C
4lit.,29 798C), data identical to those reported previously.29,30
In summary, several features of our optimised route to key
intermediates 4eg allylic alcohol 41S,4R,5S)-18 and enone
44R,5S)-35) for polyhydroxylated cyclohexane synthesis are
described. The ®rst step is the highly diastereoselective
epoxidation of alkene 9 in cyclohexane which generates
an 81% isolated yield of epoxide trans-10. Then, after a
survey a wide range of chiral bases for the enantioselective
rearrangement of epoxide trans-10, the second crucial step
in the strategy, it was found that diamines 41S,2R)-16 or
21 were optimal. For example, rearrangement of epoxide
trans-10 using 2 equiv. of diamine 41S,2R)-16 gave a 93%
yield of allylic alcohol 41S,4R,5S)-18 of .95% ee. We
believe that since allylic alcohol 41S,4R,5S)-18, enone
44R,5S)-35 and their enantiomers can be readily synthesised
in multi-gram quantities, they should be considered as
useful building blocks for the synthesis of polyhydroxylated
cyclohexane-based natural and unnatural products.49
4. Experimental
4.1. General
4.1.2. .4Rp,5Sp)-4,5-Bis.triethylsilyloxy)cyclohexene 7.
Triethylsilyl chloride 43.23 mL, 19.1 mmol) was added
dropwise to a stirred solution of imidazole 43.4 g, 48.4
mmol) and 44Rp,5Sp)-4,5-dihydroxycyclohexene 41.1 g,
9.6 mmol) in DMF 422 mL) at rt under N2. After stirring
for 22 h, water 410mL) was added and the two layers sepa-
rated. The aqueous layer was extracted with CH2Cl2
42£20mL) and the combined organic extracts were washed
with brine 43£20mL), dried 4Na 2SO4) and evaporated under
reduced pressure to give the crude product. Puri®cation by
chromatography 450:1 petrol±Et2O) gave alkene 7 43.08 g,
93%) as a colourless oil, RF 430:1 petrol±Et2O) 0.7; IR
Water is distilled water. THF was dried over sodium-benzo-
phenone and distilled before use. CH2Cl2 was dried over
calcium hydride and distilled before use. Petrol refers to
the fraction of petroleum ether boiling in the range
40±608C and was redistilled before use. All non-aqueous
reactions were carried out under oxygen-free nitrogen using
oven-dried glassware. Flash column chromatography was
carried out using ICN Biomedicals GmbH 33±63 silica
Ê
460A ) or Fisher Matrex silica 60. Thin layer chroma-
tography was carried out on commercially available
Merck F254 aluminium-backed silica plates. n-Butyllithium
1
4®lm) 2954, 1076, 1007, 737 cm21; H NMR 4270MHz,

4650
S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
CDCl3): d 5.62±5.61 4m, 2H), 3.96±3.92 4m, 2H), 2.37±
2.27 4m, 4H), 1.09±1.00 4m, 18H), 0.75±0.57 4m, 12H); 13C
NMR 467.9 MHz, CDCl3): d 124.5, 70.7, 32.9, 7.2, 5.2; MS
4CI, NH3) m/z 343 4M1H)1, 313, 234, 132; HRMS 4CI,
NH3) m/z calcd for C18H38O2Si2 4M1H)1 343.2489, found
343.2490.
2H), 3.16±3.15 4m, 2H), 2.12±1.97 4m, 4H), 0.94 4t, 18H,
Jˆ8.5 Hz), 0.63±0.54 4m, 12H); 13C NMR 467.9 MHz,
CDCl3): d 68.5, 52.2, 31.2, 6.8, 4.8; MS 4CI, NH3) m/z
359 4M1H)1, 329; HRMS 4CI, NH3) m/z calcd for
C18H38O3Si2 4M1H)1 359.2438, found 359.2439.
4.2.2. .1Sp,2Rp,4Rp,5Sp)-4,5-Bis.tert-butyldimethylsilyl-
oxy)cyclohexene oxide trans-10 .Table 1, entry 5).
Using the general method for m-CPBA epoxidation,
NaHCO3 4490mg, 5.8 mmol), m-CPBA 41.0g, 4.0mmol)
and di-TBS protected alkene 9 41.0g, 2.9 mmol) in cyclo-
hexane 440mL) gave, after 18 h, a crude product which
contained a 93:7 mixture of epoxides trans- and cis-10.
Puri®cation by chromatography 420:1 petrol±Et2O) gave
known12a epoxide trans-10 4806 mg, 81%) as a colourless
oil, data identical to those reported previously.12a
4.1.3. .4Rp,5Sp)-4,5-Bis.tert-butyldiphenylsilyloxy)cyclo-
hexene 11. tert-Butyldiphenylsilyl chloride 41.08 mL,
4.2 mmol) was added dropwise to a stirred solution of
imidazole 4600 mg, 8.8 mmol) and 44Rp,5Sp)-4,5-dihydroxy-
cyclohexene 4200 mg, 1.8 mmol) in CH2Cl2 422 mL) at rt
under N2. After stirring for 20h, water 45 mL) was added
and the two layers separated. The aqueous layer was
extracted with CH2Cl2 42£10mL) and the combined
organic extracts were washed with brine 43£10mL), dried
4Na2SO4) and evaporated under reduced pressure to give
the crude product. Puri®cation by chromatography 410:1
petrol±Et2O) gave alkene 11 4993 mg, 94%) as a white
solid, mp 92±968C; RF 410:1 petrol±Et2O) 0.7; IR 4Nujol)
4.2.3. .1Sp,2Rp,4Rp,5Sp)-4,5-Bis.tert-butyldiphenylsilyl-
oxy)cyclohexene oxide trans-12 .Table 1, entry 7).
Using the general method for m-CPBA epoxidation,
NaHCO3 4172 mg, 2.1 mmol), m-CPBA 4518 mg, 2.1
mmol) and di-TBDPS protected alkene 11 4688 mg,
1.2 mmol) in CH2Cl2 430mL) gave, after 20h, a crude
product which contained a 98:2 mixture of epoxides trans-
and cis-12. Puri®cation by chromatography 410:1 petrol±
Et2O) gave epoxide trans-12 4649 mg, 92%) as a waxy
white solid, mp 68±708C; RF 410:1 petrol±Et2O) 0.4; IR
1
1105 cm21; H NMR 4270MHz, CDCl 3): d 7.70±7.66 4m,
8H), 7.43±7.21 4m, 12H), 5.59 4s, 2H), 3.92 4t, 2H, Jˆ5 Hz),
2.32±2.24 4m, 2H), 1.89±1.81 4m, 2H), 1.08 4s, 18H); 13C
NMR 467.9 MHz, CDCl3): d 136.0, 135.9, 134.9, 134.1,
129.4, 127.5, 127.4, 124.2, 71.7, 32.2, 27.0, 19.3 4some
signals not resolved); MS 4CI, NH3) m/z 608 4M1NH4)1,
374, 157; HRMS 4CI, NH3) m/z calcd for C38H46O2Si2
4M1NH4)1 608.3380, found 608.3380.
1
4®lm) 2927, 1276 cm21; H NMR 4270MHz, CDCl 3): d
7.67±7.62 4m, 8H), 7.43±7.21 4m, 12H), 3.78±3.76 4m,
2H), 3.00 4br s, 2H), 2.12±1.97 4m, 2H), 1.76±1.71 4m,
2H), 1.08 4s, 18H); 13C NMR 467.9 MHz, CDCl3): d
136.0, 135.9, 135.8, 134.4, 133.7, 129.6, 129.5, 127.5,
69.9, 51.8, 30.7, 27.0, 19.3; MS 4CI, NH3) m/z 624
4M1NH4)1, 607, 529, 351; HRMS 4CI, NH3) m/z calcd
for C38H46O3Si2 4M1NH4)1 624.3329, found 624.3330.
4.2. General method for m-CPBA epoxidation
Solid NaHCO3 43.8 mmol) and m-CPBA 4approx. 70% pure
material, 2.9 mmol) were added in portions to a stirred solu-
tion of the alkene 40.6 mmol) in solvent 45 mL) at rt under
N2. After 16±20h at rt, 20% Na SO34aq) 45 mL) was added
2
and the two layers separated. The aqueous layer was
extracted with CH2Cl2 42£20mL) and the combined
organic extracts were washed with 20% Na2SO34aq)
420mL), 5% NaHCO 34aq) 420mL), water 420mL), dried
4Na2SO4) and evaporated under reduced pressure to give
4.2.4. .1Sp,2Rp,4Rp,5Sp)-4,5-Bis.isopropylidenedioxy)cy-
clohexene oxide trans-14 .Table 1, entry 8). Using the
general method for m-CPBA epoxidation, NaHCO3
4500 mg, 6.0 mmol), m-CPBA 41.48 g, 6.0mmol) and
acetal protected alkene 13 4500 mg, 3.2 mmol) in CH2Cl2
410mL) gave, after 46 h, a crude product which contained a
90:10 mixture of epoxides trans- and cis-14. Puri®cation by
chromatography 4EtOAc) gave epoxide trans-1450 4418 mg,
77%) as a colourless oil, RF 4EtOAc) 0.6; IR 4®lm) 3033,
1
the crude product. Analysis of the crude product by H
NMR spectroscopy revealed the ratio of diastereoisomers
4see Table 1) and the crude product was then puri®ed by
chromatography.
1
2937, 1519, 1425, 1382, 1060, 979, 929 cm21; H NMR
4.2.1.
.1Sp,2Rp,4Rp,5Sp)-4,5-Bis.triethylsilyloxy)cyclo-
4270MHz, CDCl 3): d 4.27±4.19 4m, 2H), 3.20±3.19 4m,
2H), 2.42±2.34 4m, 2H), 2.12±2.04 4m, 2H), 1.45 4s, 3H),
1.29 4s, 3H); 13C NMR 467.9 MHz, CDCl3): 107.4, 71.2,
50.1, 28.0, 27.5, 24.6; MS 4CI, NH3) m/z 171 4M1H)1,
155; HRMS 4CI, NH3) m/z calcd for C9H14O3 4M1H)1
171.1021, found 171.1019. Diagnostic signals for epoxide
cis-14: 1H NMR 4270MHz, CDCl 3): d 1.52 4s, 3H), 1.26 4s,
3H).
hexene oxide trans-8 .Table 1, entry 3). 1,1,1-Tri¯uor-
acetone 40.57 mL, 6.38 mmol) was added via a pre-cooled
syringe to a stirred solution of di-TES protected alkene 7
4200 mg, 0.58 mmol) and Na2EDTA 42.5 mL of
a
4£1024 M aqueous solution, 0.001 mmol) in MeCN
44 mL) at 08C. Then, a mixture of Oxonew 41.78 g,
6.38 mmol) and solid NaHCO3 4378 mg, 4.5 mmol) was
added in portions over 1 h. After stirring at 08C for a further
1 h, the reaction mixture was poured into water 420mL) and
extracted with CH2Cl2 43£20mL). The combined organic
extracts were dried 4MgSO4) and evaporated under reduced
pressure to give the crude product which contained a 98:2
4.3. General method for epoxide rearrangement .Tables
2 and 3)
1
mixture of epoxides trans- and cis-8 4by H NMR spectro-
n-Butyllithium 41.2±1.6 M solution in hexane, 1.12 mmol)
was added dropwise to a stirred solution of diamine 4or
amine) 41.12 mmol) in THF 42 mL) at 08C under N2. After
30min at 0 8C, a solution of the epoxide 40.56 mmol) in THF
43 mL) was added dropwise via a cannula and the mixture
scopy). Puri®cation by chromatography 420:1 petrol±Et2O)
gave epoxide trans-8 4155 mg, 74%) as a colourless oil, RF
420:1 petrol±Et2O) 0.35; IR 4®lm) 2954, 1462, 1103, 1003,
1
741 cm21; H NMR 4270MHz, CDCl 3): d 3.69±3.65 4m,

S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
4651
was warmed to rt over 4 h. After 16 h at rt, saturated
NH4Cl4aq) 45 mL) was added followed by Et2O 420mL)
and the two layers separated. The aqueous layer was
extracted with Et2O 42£20mL) and the combined organic
extracts were washed with 2% HCl4aq) 43£20mL), saturated
NaHCO34aq) 43£20mL) and brine 415 mL), dried 4Na 2SO4)
and evaporated under reduced pressure to give the crude
product.
134.0, 133.8, 130.9, 130.0, 129.7, 129.55, 129.5, 127.6,
127.5, 127.4, 69.9, 69.1, 65.8, 35.9, 27.1, 27.0, 19.35,
19.25 4some signals not resolved); MS 4CI, NH3) m/z 624
4M1NH4)1, 351; HRMS 4CI, NH3) m/z calcd for
C38H46O3Si2 4M1NH4)1 624.3329, found 624.3334; Anal.
calcd for C38H46O3Si2: C, 75.20; H, 7.64. Found: C, 75.01;
H, 7.91.
4.3.4. .1S,4R,5S)-4,5-Bis.isopropylidenedioxy)cyclohex-
2-enol .1S,4R,5S)-19 .Table 2, entry 7). Using the general
method for epoxide rearrangement 4note: the wash with 2%
HCl4aq) during the work-up was omitted), n-butyllithium
41.1 mL of a 1.6 M solution in hexane, 1.8 mmol), diamine
4R)-15 4360mg, 1.8 mmol) and epoxide trans-14 4150mg,
0.9 mmol) in THF 45 mL) gave the crude product. Puri®-
cation by chromatography 4EtOAc) gave allylic alcohol
41S,4R,5S)-2051 458 mg, 39%, 48% ee by Mosher's ester
formation) as a colourless oil, [a]Dˆ225.3 4c 0.4 in
4.3.1. .1S,4R,5S)-4,5-Bis.triethylsilyloxy)cyclohex-2-enol
.1S,4R,5S)-17 .Table 2, entry 1). Using the general method
for epoxide rearrangement, n-butyllithium 40.76 mL of a
1.6 M solution in hexane, 1.12 mmol), diamine 4R)-15
4228 mg, 1.12 mmol) and epoxide trans-8 4200 mg,
0.56 mmol) in THF 45 mL) gave the crude product. Puri®-
cation by chromatography 47:3 Et2O±petrol) gave allylic
alcohol 41S,4R,5S)-17 4182 mg, 91%, 70% ee by Mosher's
ester formation) as a colourless oil, [a]Dˆ288.3 4c 1.0in
CHCl3); RF 43:1 petrol±Et2O) 0.3; IR 4®lm) 3375, 2954,
1
CHCl3); RF 4EtOAc) 0.4; IR 4®lm) 3440, 2970 cm21; H
1
1122, 1032, 741 cm21; H NMR 4CDCl3): d 5.76 4dd, 1H,
NMR 4270MHz, CDCl 3): d 5.91 4td, 1H, Jˆ0.5, 10 Hz),
5.73±5.67 4m, 1H), 4.51±4.38 4m, 3H), 2.52±2.43 4m, 1H),
2.14 4br s, 1H), 1.72±1.63 4m, 1H), 1.37 4s, 3H), 1.36 4s,
3H); 13C NMR 467.9 MHz, CDCl3): 133.9, 126.9, 108.5,
72.6, 71.3, 63.0, 35.1, 27.6, 26.3; MS 4CI, NH3) m/z 171
4M1H)1, 155; HRMS 4CI, NH3) m/z calcd for C9H14O3
4M1H)1 171.1021, found 171.1025.
Jˆ3, 10.5), 5.67±5.62 4m, 1H), 4.46±4.41 4m, 1H), 4.13±4.04
4m, 2H), 2.28±2.26 4m, 1H), 1.90 4br s, 1H), 1.56 4ddd, 1H,
Jˆ2, 6, 13 Hz), 0.98±0.92 4m, 18H), 0.69±0.57 4m, 12H).
4.3.2.
.1S,4R,5S)-4,5-Bis.tert-butyldimethylsilyloxy)-
cyclohex-2-enol .1S,4R,5S)-18 .Table 2, entry 4 and
Table 3, entry 1). Using the general method for epoxide
rearrangement, a solution of epoxide trans-10 43.78 g,
10.5 mmol) in THF 415 mL) was added dropwise via a
cannula over 20min to a solution of n-butyllithium
413.4 mL of a 1.6 M solution in hexane, 21.0mmol) and
diamine 41R,2S)-16 44.6 g, 21.0mmol) in THF 415 mL) at
2108C 4to ensure that the internal reaction temperature did
not exceed 08C at any time during the addition). After
stirring for the usual length of time and standard work-up,
puri®cation by chromatography 47:3 Et2O±petrol) gave
allylic alcohol 41S,4R,5S)-18 43.5 g, 93%, .95% ee by
Mosher's ester formation) as a white solid, [a]Dˆ2100.8
4.3.5. .R)-N-Methyl-1-phenyl-2-.1-N,N0-diethyl)ethan-
amine .R)-25. LiClO4 4931 mg, 8.8 mmol) was added to a
stirred solution of 4R)-styrene oxide 41.0mL, 8.8 mmol) in
MeCN 42 mL) at rt under N2. After 10min at rt, diethyl-
amine 40.9 mL, 8.8 mmol) was added dropwise and the
solution stirred for a further 30min. Then, Et 2O 410mL)
and water 410mL) were added, the layers separated and the
aqueous layer was extracted with Et2O 43£20mL). The
combined organic extracts were dried 4Na2SO4) and evapo-
rated under reduced pressure to give the crude product.
Puri®cation by chromatography 45:2 CH2Cl2±MeOH)
gave a 74:26 mixture 4by 1H NMR spectroscopy) of
amino alcohols 31 and 32 41.43 g, 85%) as a yellow oil,
RF 410:1 CH2Cl2±MeOH) 0.1. Diagnostic signal for
4c 1.0in CHCl ) 4lit.,12a [a]Dˆ287.1 4c 0.6 in CHCl3) for
3
allylic alcohol 41S,4R,5S)-18 of 76% ee), data identical to
those reported previously.12a The aqueous layer was basi®ed
with K2CO3 and extracted with Et2O 42£30mL). The
combined organic extracts were dried 4Na2SO4), evaporated
under reduced pressure and puri®ed by Kugelrohr distil-
lation to give the known diamine 41R,2S)-16 43.25 g, 70%
recovery) as a colourless oil.
1
known37 amino alcohol 31: H NMR 4270MHz, CDCl 3):
d 4.71 4dd, 1H, Jˆ3.5, 10.5 Hz); diagnostic signals for
1
known37 amino alcohol 32: H NMR 4270MHz, CDCl 3):
d 4.03±3.94 4m, 2H), 3.69±3.64 4m, 1H).
MsCl 40.53 mL, 6.8 mmol) was added dropwise to a stirred
solution of a 74:26 mixture of amino alcohols 31 and 32
4750mg, 3.9 mmol) and Et 3N 41.8 mL, 12.9 mmol) in Et2O
415 mL) at 08C under N2. A white precipitate formed. After
30min at 0 8C, Et3N 41.2 mL, 8.7 mmol) was added and the
mixture was allowed to warm to rt. Then, MeNH24aq) 440%;
4.8 mL, 65.5 mmol) was added and the two-phase mixture
was stirred vigorously for 16 h at rt. The layers were sepa-
rated and the aqueous layer was extracted with Et2O
42£20mL). The combined organic extracts were washed
with 5% NaHCO34aq) 430mL) and water 430mL), dried
4Na2SO4) and evaporated under reduced pressure to give
the crude product. Puri®cation by Kugelrohr distillation
gave known35 diamine 4R)-25 4806 mg, 100%) as a colour-
less oil, [a]Dˆ2156.2 4c 0.9 in CHCl3) 4lit.,35 [a]Dˆ
2135.4 4c 1.9 in CHCl3)), data identical to those reported
previously.35
4.3.3. .1S,4R,5S)-4,5-Bis.tert-butyldiphenylsilyloxy)cyclo-
hex-2-enol .1S,4R,5S)-19 .Table 2, entry 6). Using the
general method for epoxide rearrangement, n-butyllithium
40.45 mL of a 1.5 M solution in hexane, 0.66 mmol),
diamine 41R,2S)-16 4144 mg, 0.66 mmol) and epoxide
trans-12 4200 mg, 0.33 mmol) in THF 45 mL) gave the
crude product. Puri®cation by chromatography 47:3 Et2O±
petrol) gave allylic alcohol 41S,4R,5S)-19 4169 mg, 85%,
84% ee by Mosher's ester formation) as a white solid,
[a]Dˆ272.2 4c 1.0in CHCl 3); mp 52±588C; RF 43:1
petrol±Et2O) 0.3; IR 4Nujol) 3379 cm21
;
1H NMR
4CDCl3): d 7.73±7.64 4m, 8H), 7.44±7.22 4m, 10H), 5.54
4dd, 1H, Jˆ3.5, 10), 5.39 4dd, 1H, Jˆ3.5, 10Hz), 4.23±4.21
4m, 2H), 4.15±4.11 4m, 1H), 2.27 4ddd, 1H, Jˆ5, 10,
12 Hz), 1.43±1.12 4m, 2H), 1.08 4s, 9H), 1.06 4s, 9H); 13C
NMR 4CDCl3): d 136.1, 136.05, 135.95, 134.6, 124.3,

4652
S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
4.3.6. .R)-N-Methyl-1-phenyl-2-.1-N,N0-dimethyl)ethan-
amine .R)-26. LiClO4 4931 mg, 8.8 mmol) was added to a
stirred solution of 4R)-styrene oxide 41.0mL, 8.8 mmol) in
MeCN 42 mL) at rt under N2. After 10min at rt, dimethyl-
amine 44.4 mL of a 2 M solution in THF, 8.8 mmol) was
added dropwise and the solution stirred for a further 30min.
Then, Et2O 410mL) and water 410mL) were added, the
layers separated and the aqueous layer was extracted with
Et2O 43£20mL). The combined organic extracts were dried
4Na2SO4) and evaporated under reduced pressure to give the
crude product. Puri®cation by chromatography 410:1
CH2Cl2±MeOH) gave a 76:24 mixture 4by 1H NMR
spectroscopy) of amino alcohols 33 and 34 4650mg, 41%)
as a yellow oil, RF 410:1 CH2Cl2±MeOH) 0.3. Diagnostic
41S,4S,5R)-36 of 92% ee), data identical to those reported
previously.12a
4.3.9.
.1S,4R,5S)-4,5-Bis.acetyloxy)cyclohex-2-en-1yl
acetate 5. A solution of allylic alcohol 41S,4R,5S)-18
4100 mg, 0.28 mmol, .95% ee) in TBAF 42 mL of a 1 M
solution in THF) was stirred at rt under N2 for 25 h. The
solvent was evaporated and the residue dissolved in pyridine
42 mL) and Ac2O 41 mL) at rt under nitrogen. After stirring
at rt for 72 h, 2 M HCl4aq) 410mL) and Et 2O 420mL) were
added, the layers separated and the aqueous layer was
extracted with Et2O 43£20mL). The combined organic
extracts were washed with 2 M HCl4aq) 42£10mL), satu-
rated NaHCO34aq) 43£10mL) and water 420mL), dried
4MgSO4) and evaporated under reduced pressure to give
the crude product. Puri®cation by chromatography 41:1
petrol±Et2O) gave triacetate 5 473 mg, 100%, .95% ee)
as a pale yellow oil, [a]Dˆ2236.1 4c 3.5 in CHCl3), data
identical to those reported previously for the racemate.41
1
signal for known38 amino alcohol 33: H NMR 4270MHz,
CDCl3): d 4.65 4dd, 1H, Jˆ3.5, 10.5 Hz); diagnostic signal
for known39 amino alcohol 34: 1H NMR 4270MHz, CDCl 3):
d 3.89 4dd, 1H, Jˆ8.5, 10.5 Hz).
MsCl 40.35 mL, 4.5 mmol) was added dropwise to a stirred
solution of a 76:24 mixture of amino alcohols 33 and 34
4500 mg, 3.0 mmol) and Et3N 41.4 mL, 10.0 mmol) in Et2O
410mL) at 0 8C under N2. A white precipitate formed. After
30min at 0 8C, Et3N 40.8 mL, 5.7 mmol) was added and the
mixture was allowed to warm to rt. Then, MeNH24aq) 440%;
3.2 mL, 43.7 mmol) was added and the two-phase mixture
was stirred vigorously for 16 h at rt. The layers were sepa-
rated and the aqueous layer was extracted with Et2O
42£20mL). The combined organic extracts were washed
with 5% NaHCO34aq) 430mL) and water 430mL), dried
4Na2SO4) and evaporated under reduced pressure to give
the crude product. Puri®cation by Kugelrohr distillation
gave known35 diamine 4R)-26 4403 mg, 75%) as a colourless
oil, [a]Dˆ290.0 4c 0.9 in EtOH) 4lit.,35 [a]Dˆ193.8 4c 2.0
in EtOH) for diamine 4S)-26), data identical to those
reported previously.35
4.3.10. .1R,4R,5S)-4,5-Bis.acetyloxy)cyclohex-2-en-1-yl
acetate 6. A solution of allylic alcohol 41R,4R,5S)-36
4100 mg, 0.28 mmol, .95% ee) in TBAF 42 mL of a 1 M
solution in THF) was stirred at rt under N2 for 25 h. The
solvent was evaporated and the residue dissolved in pyridine
42 mL) and Ac2O 41 mL) at rt under nitrogen. After stirring
at rt for 72 h, 2 M HCl4aq) 410mL) and Et 2O 420mL) were
added, the layers separated and the aqueous layer was
extracted with Et2O 43£20mL). The combined organic
extracts were washed with 2 M HCl4aq) 42£10mL), satu-
rated NaHCO34aq) 43£10mL) and water 420mL), dried
4MgSO4) and evaporated under reduced pressure to give
the crude product. Puri®cation by chromatography 41:1
petrol±Et2O) gave triacetate 6 473 mg, 100%, .95% ee)
as a pale yellow oil, [a]Dˆ254.04 c 3.5 in CHCl3), data
identical to those reported previously for the racemate.42
4.3.7. .4R,5S)-4,5-Bis.tert-butyldimethylsilyloxy)cyclo-
hex-2-enone .4R,5S)-35. PCC 41.8 g, 8.37 mmol) was
added to a stirred solution of allylic alcohol 41S,4R,5S)-18
42.0g, 5.58 mmol, .95% ee) in CH2Cl2 450mL) at rt under
N2. After 18 h at rt, the solvent was evaporated under
reduced pressure and the residue puri®ed by chroma-
tography 43:1 petrol±Et2O) to give known12a enone
44R,5S)-35 41.8 g, 90%, .95% ee) as a white solid,
[a]Dˆ 2108.1 4c 0.6 in CHCl3) 4lit.,12a [a]Dˆ1109.8 4c
0.65 in CHCl3) for 44S,5R)-35 of 92% ee), data identical
to those reported previously.12a
4.3.11. .4S,5R,6S)-4,5-Bis.tert-butyldimethylsilyloxy)-6-
hydroxycyclohex-2-enone 38.
A solution of enone
44S,5R)-36 4100 mg, 0.28 mmol, 89% ee) in THF 43 mL)
was added dropwise to a stirred solution of NaHMDS
40.42 mL of a 1 M solution in THF, 0.42 mmol) in THF
42 mL) at 2788C under N2. After 30min at 2788C, a solu-
tion of oxaziridine 37 4110mg, 0.42 mmol) in THF 45 mL)
was added dropwise via a cannula. After a further 20min at
2788C, saturated NH4Cl4aq) 42 mL) and Et2O 42 mL) were
added. After warming to rt, the two layers were separated
and the aqueous layer was extracted with Et2O 43£20mL).
The combined organic extracts were washed with water
420mL), dried 4Na 2SO4) and evaporated under reduced
pressure to give the crude product. Puri®cation by chroma-
tography 44:1 petrol±Et2O) gave hydroxy enone 38 495 mg,
91%) as a white solid, [a]Dˆ2118.9 4c 0.2 in CHCl3); mp
78±808C; RF 44:1 petrol±EtOAc) 0.2; IR 4CHCl3) 3498,
4.3.8. .1R,4R,5S)-4,5-Bis.tert-butyldimethylsilyloxy)cyclo-
hex-2-enol .1R,4R,5S)-36. CeCl3´7H2O 41.88 g, 5.05
mmol) was added to a stirred solution of enone 44R,5S)-35
41.8 g, 5.05 mmol) in MeOH 450 mL) at rt under N2. After
cooling to 08C, NaBH4 4380mg, 10.1 mmol) was added in
portions over 10min and the mixture was stirred for a
further 10min. Then, Et 2O 420mL) and water 420mL)
were added, the layers separated and the aqueous layer
was extracted with Et2O 42£20mL). The combined organic
extracts were washed with brine 420mL) and water
420mL), dried 4Na 2SO4) and evaporated under reduced
pressure to give known12a allylic alcohol 41R,4R,5S)-36
41.7 g, 90%, .95% ee) as a white solid, [a]Dˆ235.4 4c
1.00 in CHCl3) 4lit.,12a [a]Dˆ120.6 4c 0.6 in CHCl3) for
1
1685, 1095, 839 cm21; H NMR 4CDCl3): d 6.92 4dd, 1H,
Jˆ6, 10Hz), 6.09 4d, 1H, Jˆ10Hz), 4.56 4d, 1H, Jˆ10Hz),
4.35 4dd, 1H, Jˆ3.5, 6 Hz), 3.75 4dd, 1H, Jˆ3.5, 10Hz),
3.19 4br s, 1H), 0.92 4s, 9H), 0.88 4s, 9H), 0.15 4s, 3H), 0.14
4s, 3H), 0.10 4s, 3H), 0.07 4s, 3H); 13C NMR 4CDCl3): d
199.7, 147.8, 127.6, 74.8, 74.3, 68.5, 25.9, 25.7, 18.3,
18.0, 24.3, 24.4, 24.6, 24.7; MS 4CI, NH3) m/z 390
4M1NH4)1, 373, 241; HRMS 4CI, NH3) m/z calcd for
C18H36O4Si2 4M1NH4)1 390.2496, found 390.2495.

S.E.de Sousa et al./ Tetrahedron 58 &2002) 4643±4654
4653
4.3.12. .4S,5R,6S)-6-Acetoxy-4,5-bis.tert-butyldimethyl-
Acknowledgements
silyloxy)cyclohex-2-enone 39. A solution of hydroxy
enone 38 450mg, 0.13 mmol) in pyridine 42 mL) and
Ac2O 42 mL) was stirred at rt under N2 for 16 h. Then,
saturated NaHCO34aq) 410mL) and Et 2O 410mL) were
added, the layers separated and the aqueous layer was
extracted with Et2O 43£10mL). The combined organic
extracts were washed with saturated NaHCO34aq) 420mL),
dried 4Na2SO4) and evaporated under reduced pressure to
give acetoxy enone 39 455 mg, 100%) as a pale yellow solid,
mp 88±948C; RF 44:1 petrol±Et2O) 0.4; IR 4CH2Cl2) 1692,
We thank the EPSRC for a grant 4to S. E. d S.) and a project
studentship 4to C. D. P.; reference GR/L 58439), Daniel
Roder 4for carrying out the dioxirane reaction presented in
Table 1, entry 3) and Professor P. G. Andersson 4for the kind
gift of a sample of diamine 21). Additional support from
P®zer and the Astra-Zeneca Strategic Research Fund is also
gratefully acknowledged.
1
1597, 1422 cm21; H NMR 4CDCl3): d 6.904dd, 1H, Jˆ6,
References
10Hz), 6.06 4d, 1H, Jˆ10Hz), 5.75±5.65 4m, 1H), 4.37 4dd,
1H, Jˆ3, 5.5 Hz), 4.04 4dd, 1H, Jˆ3, 10Hz), 2.18 4s, 3H),
0.93±0.85 4m, 18H), 0.15±0.09 4m, 12H); 13C NMR
4CDCl3): d 193.8, 170.0, 146.7, 129.0, 75.4, 71.8, 68.5,
25.7, 20.9, 18.1, 24.1, 24.6, 24.8 4some signals not
resolved); MS 4CI, NH3) m/z 432 4M1NH4)1, 415, 357,
355, 283, 225; HRMS 4CI, NH3) m/z calcd for
C20H38O5Si2 4M1NH4)1 432.2602, found 432.2604.
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2
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È
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