Copper(I)-mediated 1,2-metallate rearrangements of 1-metallated glycals

Article abstract of DOI:10.1055/s-0031-1289721

1,2-Metallate rearrangements involving reaction of 1-metallated glycals with organolithium reagents under copper(I) mediation give alkenylpolyol chains in 45-91% yield (19 examples). The reaction was applied to a formal synthesis of KRN7000 as well as a synthesis of a ^5,6-ceramide derivative. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289721

946
PAPER
Copper(I)-Mediated 1,2-Metallate Rearrangements of 1-Metallated Glycals
1, 2-Metallate
R
ear
r
rangeme
z
nts ysztof Jarowicki, Philip Kocieński,* Zofia Komsta, Anna Wojtasiewicz
Institute of Process Research & Development, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
E-mail: p.j.kocienski@leeds.ac.uk
Received 2 December 2011; revised 18 January 2012
side 7. The first route is based on a nickel(0)-catalysed
Abstract: 1,2-Metallate rearrangements involving reaction of 1-
metallated glycals with organolithium reagents under copper(I) me-
diation give alkenylpolyol chains in 45–91% yield (19 examples).
The reaction was applied to a formal synthesis of KRN7000 as well
as a synthesis of a D5,6-ceramide derivative.
coupling reaction to substitute the sulfone 8 by
Bu3SnMgBr·LiBr.14 This route conserves the virtues of
stability and crystallinity typical of the unsaturated sul-
fones and the reaction is easily scalable. The prime detrac-
tion to route 1 is the volume of tin waste: 2 equivalents of
the Bu3SnMgBr·LiBr are required for complete reaction
and the Bu3SnMgBr·LiBr is generated from Bu3SnLi
which in turn is generated from the reaction of BuLi with
Bu3SnSnBu3. Hence there are 3 atoms of tin waste for
each coupling reaction. The second route is based on a
sulfoxide–lithium exchange of the sulfoxide 10 to gener-
ate a 1-lithiated glycal intermediate 11 which is then
quenched by the addition of 1.3 equivalents of Bu3SnCl.
It benefits from the cheaper source of tin and only 0.3
equivalent of tin waste is generated at best.
Key words: 1,2-metallate rearrangement, retro-[1,4]-Brook rear-
rangement, 1-metallated glycals, cuprates, organolithiums,
KRN7000
We have previously described a one-pot connective syn-
thesis of trisubstituted alkenes involving the reaction of a-
metallated cyclic enol ethers with organocuprates1 which
was inspired by an earlier report by Sato and co-workers.2
The key step in the sequence exemplified in Scheme 1 is
a 1,2-metallate rearrangement3,4 of the putative higher or-
der cuprate 3. The sequence has practical value – it can be
performed on a 45 mmol scale5 – and it has broad scope:
five-,6–8 six-,9 and seven-membered-ring a-metallated
enol ethers10,11 participate. A noteworthy feature of the
1,2-metallate rearrangement depicted in Scheme 1 is the
connection of two organometallic reagents – a-lithiated
dihydrofuran 1 and n-BuLi – under copper(I) mediation to
generate the alkenylmetal species 4 which is capable of
further elaboration. Formally, the 1,2-metallate rearrange-
ment is equivalent to the stereospecific insertion of a vi-
nylidenecarbene derived by a-elimination of 1 into a C–
Cu bond. Early attempts to implement this chemistry in
the glycal series were thwarted by the low reactivity of the
1-lithiated glycal substrates compared with their lithiated
dihydropyran counterparts; however, in 2002 we were
able to achieve the first copper(I)-mediated 1,2-metallate
rearrangement of a glycal derivative 5 in the context of a
synthesis of D-erythro-sphingosine.12 We now show that
the reaction is applicable to 1-lithiated glycals derived
from the common monosaccharides as a general proce-
dure for appending carbon chains to carbohydrates.
Bu
1. Bu2CuLi (1.1 equiv)
Et2O, –80 to 0 °C, 3.5 h
Li
O
2. allyl bromide (3.3 equiv)
–80 °C to r.t., overnight
84% (45 mmol scale)
OH
2
1
Bu2CuLi
allyl bromide
(retention)
2–
–
Bu
O
Bu
Bu
1,2-metallate
2Li+
+
Cu
rearrangement
Bu
Cu
O
(inversion)
3
4
Li
C13H27Li
O
OH OH SiMe2t-Bu
C13H27
CuBr•SMe2
OTBS
Et2O–Me2S
–35 °C to r.t.
68%
OTBS
OTBS
5
6
Scheme 1
Synthesis of 1-Lithiated Glycals
The 1-lithiated glycals at the heart of our investigation
were prepared by transmetallation of the corresponding 1-
tributylstannyl glycals with n-BuLi as first described by
Beau and co-workers.13 Two routes were used for the syn-
thesis of the requisite stannanes as illustrated in Scheme 2
by the synthesis of 1-tributylstannyl glucal derivative 9.
Both routes start from the same 1-thio-b-D-glucopyrano-
Optimisation Studies Using 1-Tributylstannyl Glucal
9
Our investigation of the 1,2-metallate rearrangement of
carbohydrate derivatives began with the effects of solvent,
temperature, stoichiometry, and copper(I) source on the
reaction of 1-tributylstannyl glucal derivative 9 with n-
BuLi. After extensive experiments, we ascertained that
optimal conditions (procedure 1) entailed the addition of
a solution of 1-tributylstannyl glucal 9 (1.0 equiv) in Et2O
to a mixture of CuCN (1.2 equiv) and n-BuLi (5.4 equiv)
SYNTHESIS 2012, 44, 946–952
x
x
.x
x
.2
0
1
2
Advanced online publication: 24.02.2012
DOI: 10.1055/s-0031-1289721; Art ID: N112711SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,2-Metallate Rearrangements
947
Ph
O
O–
effected in 80% yield using freshly recrystallised
CuBr·SMe2 (1.2 equiv) in a mixture of Et2O and Me2S in
place of CuCN (procedure 2).
S
Li
O
route 2
t-BuLi (1.2 equiv)
O
A mechanism for the formation of alkenylsilane 12a is
given in Scheme 4. Under the reaction conditions, the
stannane 9 transmetallates in situ to the corresponding
lithiated glycal 11 which then adds to BuCu(CN)Li to
give the higher order cuprate 15. A 1,2-metallate rear-
rangement of the putative higher order cuprate 15 is then
followed by transmetallation of the alkenyl cuprate 16 to
the alkenyllithium 17 whereupon a retro-[1,4]-Brook rear-
rangement via the pentacoordinate siliconate 18 gives the
alkenylsilane 19, the final intermediate in the sequence.
Similar retro-[1,4]-Brook rearrangements of alkenyllithi-
ums have been observed previously.12,15–20 A potentially
significant consequence of the transmetallation of alkenyl
cuprate 16, is the liberation of BuCu(CN)Li suggesting
that the 1,2-metallate rearrangement could be catalytic in
Cu(I). Thus, when 0.2 equivalent of CuCN was used to-
gether with 5.4 equivalents of BuLi, 12a was formed in
71% yield.
OTBS
OTBS
Et2O, –78 °C
O
O
O
Ph
Ph
11
10
1. MCPBA (1.1 equiv)
CH2Cl2, –78 °C (93%)
2. LDA (2.5 equiv)
Bu3SnCl (1.3 equiv)
–78 °C to r.t.
RLi
66% from 10
THF, –78 °C (82%)
SnBu3
SPh
OTBS
OTBS
O
O
OTBS
O
O
O
O
Ph
Ph
7
9
5 steps from D-glucose
1. MCPBA (2.5 equiv)
CH2Cl2, r.t. (83%)
2. MeLi (1.5 equiv)
THF, –78 °C (88%)
Li
SnBu3
SO2Ph
route 1
O
O
O
Bu3SnMgBr•LiBr (2 equiv)
Ni(0) (0.1 equiv), Ph3P (0.2 equiv)
n-BuLi
OTBS
OTBS
OTBS
THF–Et2O, –78 °C to r.t.
91%
O
O
O
O
O
O
Ph
Ph
Ph
11
9
8
BuCu(CN)Li
Scheme 2
2–
2Li+
NC
Bu
Bu
Cu
SnBu3
1,2-metallate
rearrangement
OLi
Cu(CN)Li
O
OH OH
n-BuLi (5.4 equiv)
CuCN (1.2 equiv)
SiMe2t-Bu
Bu
O
OTBS
OTBS
OTBS
O
O
O
O
Et2O, –35 °C to r.t., 16 h
91% (1.0 mmol scale)
O
O
O
O
Ph
Ph
Ph
Ph
16
15
9
12a
– BuLi + BuLi
TBAF•3H2O
DMF, 120 °C, 10 min
91%
+ BuCu(CN)Li – BuCu(CN)Li
Bu
Li+
SiMe2t-Bu
Bu
OH OTBS
OH OH
OLi
Li
OLi
retro-[1,4]-Brook
rearrangement
Bu
Bu
O
O–SiMe2t-Bu
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
14
13
17
18
Scheme 3
Bu
in Et2O at –35 °C (Scheme 3). The mixture was then al-
lowed to warm gradually to room temperature overnight
whereupon a standard aqueous workup gave the crystal-
line Z-alkenylsilane 12a in 91% yield. None of the expect-
ed E-alkene 13 was observed. The Z-stereochemistry of
the alkenylsilane 12a was established by C-desilylation
using TBAF in DMF at 120 °C to give the E-alkene 14 in
91% yield. The conversion of 9 into 12a could also be
OLi
SiMe2t-Bu
OLi
OH OH SiMe2t-Bu
H2O
Bu
O
O
O
O
Ph
Ph
12a
19
Scheme 4
© Thieme Stuttgart · New York
Synthesis 2012, 44, 946–952

948
K. Jarowicki et al.
PAPER
OTBS
The solvent plays a crucial role in the course of the reac-
tion. When the 1,2-metallate rearrangement was per-
formed in THF (Scheme 5), only 16% of 12a was isolated
along with octan-1-ol (23%); the major product was the
glucal 20 (38%) derived from protonation of 11 or 15.
When the identical reaction was performed in t-BuOMe,
22% of 12a was obtained along with 2% rearrangement
product 13 and an unstable conjugated triene 21 (17%)
that incorporated two molecules of the glycal (one of them
minus the benzylidene acetal) and one butyl group.
O
Ph
O
Bu
O
Bu
=
Cu
OLi
Cu(CN)Li
OLi
O
CN
2LI+
11
OTBS
O
O
TBS
O
O
Ph
Ph
22
16
1,2-metallate
rearrangement
Ph
Ph
O
O
O
O
O
n-BuLi (5.4 equiv)
TBSO
LiO
CuCN (1.2 equiv)
OTBS
TBSO
12a octan-1-ol
+
16%
23%
H2O
THF
–35 °C to r.t.
O
O
O
O
OH
– CuCN
– PhCHO
Bu
Cu(CN)Li
Ph
20
38%
Bu
O
O
OH
9
Ph
21
Ph
23
O
O
Scheme 6
TBSO
n-BuLi (5.4 equiv)
CuCN (1.2 equiv)
12a + 13
O
+
OH
t-BuOMe
–35 °C to r.t.
22%
2%
Scope of the 1,2-Metallate Rearrangement of
1-Lithiated Glycal Derivatives
Bu
All of the foregoing optimisation experiments were con-
ducted solely with 1-tributylstannyl glucal derivative 9
and n-BuLi. We next explored the reactions of 9 with var-
ious organolithiums using both CuCN (procedure 1) and
CuBr (procedure 2) mediation. The temperature, time, and
stoichiometry were identical in both procedures but the
solvents were Et2O in the case of CuCN and Et2O–Me2S
in the case of CuBr.21 The results are summarised in the
table provided in Scheme 7. All eight of the organolithi-
ums examined gave the corresponding alkenylsilanes
12a–h in 45–91% yield. Entries 1–6, using n-BuLi, MeLi,
and PhLi, reveal that the yields were 7–11% higher with
CuCN compared with CuBr.22 When t-BuLi was em-
ployed as the nucleophilic partner the alkenylsilane 12d
resulting from 1,4-O → C silicon migration was obtained
in 45% yield, but it was accompanied by 25% of a second
1,2-metallate rearrangement product, the E-alkene 25,
suggesting steric impedance of the retro-[1,4]-Brook rear-
rangement. In one case (entry 3) a conjugated triene 24
was observed resulting from a double 1,2-metallate rear-
rangement akin to that described in Scheme 6.
OH
21
17%
Scheme 5
A possible mechanism for the formation of 21 is depicted
in Scheme 6. We suggest that the initial alkenyl cyanocu-
prate 16 derived from 1,2-metallate rearrangement of the
higher order cyanocuprate 15 adds the lithiated glucal 11
to give the higher order cyanocuprate 22 which then un-
dergoes a second 1,2-metallate rearrangement with elimi-
nation of t-BuMe2SiOLi to give allylcuprate 23. Finally,
1,4-elimination of CuCN and concomitant cleavage of the
benzylidene acetal gave the triene 21 as a single stereoiso-
mer after aqueous workup together with benzaldehyde
(see below).
To complement the solvent studies described above, a
number of experiments were performed to ascertain the
optimum stoichiometry of the reaction. The 1,2-metallate
rearrangement shown in Scheme 3 employed 5.4 equiva-
lents of n-BuLi. One equivalent is consumed in the trans-
metallation of the stannane 9 to the corresponding lithium
reagent 11 and 1.2 equivalents are consumed in the forma-
tion of the BuCu(CN)Li leaving a further 3.2 equivalents
of excess n-BuLi. When the same reaction was performed
with 4.4 equivalents of BuLi, the yield of 12a decreased
to 79% but when 3.4 equivalents of n-BuLi was used,
none of the alkenylsilane 12a was formed and instead the
protonated glycal 20 (41%) was isolated along with an 8%
yield of the rearrangement product 13 and 1-phenylpen-
tan-1-ol (9%), a product that is presumably generated
from the addition of n-BuLi to benzaldehyde resulting
from destruction of the benzylidene acetal moiety.
The examples depicted in Scheme 8 show that a variety of
TBS-protected 1-tributylstannyl glycals derived from the
common monosaccharides undergo a Cu(I)-mediated 1,2-
metallate rearrangement together with a regioselective
retro-[1,4]-Brook rearrangement to afford alkenylsilanes
in modest to good yield (48–79%). For purposes of com-
parison, n-BuLi was used as the nucleophilic partner in all
cases. The 1-tributylstannyl glycals were prepared from
the following precursors as described previously:23 27 and
29 from D-galactose, 31 from L-rhamnose, 33 from D-xy-
lose, 35 from D-arabinose, and 37 from D-ribose.
Synthesis 2012, 44, 946–952
© Thieme Stuttgart · New York

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1,2-Metallate Rearrangements
949
SnBu3
SnBu3
O
O
OH OH
n-BuLi (4.4 equiv)
CuCN (1.2 equiv)
SiMe2t-Bu
Bu
OH OH SiMe2t-Bu
RLi (5.4 equiv)
CuX (1.2 equiv)
OTBS
OTBS
R
O
O
O
O
O
O
solvent
–35 °C to r.t., 16 h
O
O
Et2O, –35 °C to r.t., 16 h
54% (0.91 mmol scale)
Ph
Ph
O
Ph
Ph
27
28
9
12a–h
SnBu3
Product(s) and yields
Entry
R
CuX
OH OH
SiMe2t-Bu
Bu
CuCNa
CuBr•SMe2
CuCNa
CuBr•SMe2
CuCNa
CuBr•SMe2
CuBr•SMe2
CuCNa
CuCNa
CuCNa
CuCNa
1
2
3
4
5
6
7
8
n-Bu
n-Bu
Me
Me
Ph
Ph
t-Bu
trans-hex-1-enyl
cis-hex-1-enyl
Bu3Sn
12a (91%)
12a (80%)
12b (60%) + 24 (13%)
12b (53%)
12c (90%)
n-BuLi (5.4 equiv)
b
b
CuBr•SMe2 (1.2 equiv)
OTBS
Et2O, –35 °C to r.t., 16 h
48% (1.0 mmol scale)
O
O
O
O
b
12c (83%)
29
30
b
12d (45%) + 25 (25%)
12e (55%) + 26 (15%)
12f (57%)
12g (65%)
12h (49%)
SnBu3
9
n-BuLi (5.4 equiv)
CuBr•SMe2 (1.2 equiv)
O
OH OH
SiMe2t-Bu
Bu
10
11
Me3SiCH2
OTBS
OTBS
OTBS
Et2O, –35 °C to r.t., 16 h
79% (1.0 mmol scale)
OTBS
31
OTBS
32
a Procedure 1 using Et2O as solvent.
b Procedure 2 using Et2O–Me2S (3:5) as solvent.
SnBu3
O
OH OH
OTBS
SiMe2t-Bu
Bu
Ph
OH OTBS
n-BuLi (5.4 equiv)
CuBr•SMe2 (1.2 equiv)
O
O
Et2O, –35 °C to r.t., 16 h
67% (1.0 mmol scale)
TBSO
OTBS
O
O
33
34
36
SnBu3
O
Ph
OH
25
n-BuLi (5.4 equiv)
CuBr•SMe2 (1.2 equiv)
O
OH OH
OTBS
SiMe2t-Bu
Bu
OH
OH
Et2O, –35 °C to r.t., 16 h
63% (1.0 mmol scale)
24
OTBS
35
26
SnBu3
Scheme 7 Reaction of 1-tributylstannyl glucal 9 with various orga-
nolithiums under Cu(I) mediation
O
n-BuLi (5.4 equiv)
CuCN (1.2 equiv)
OTBS OH
OH
SiMe2t-Bu
Bu
OTBS
OTBS
The 1,2-metallate rearrangement of the furanoid glycal 37
afforded a low yield (18%) of the expected product 38
together with significant quantities of a by-product which
was identified as the b,g-unsaturated ketone 42
(Scheme 9) by NMR spectroscopy of an impure sample
isolated by column chromatography. We surmise that the
furanoid glycal 37 undergoes both transmetallation and
elimination of TBSOLi by the excess n-BuLi to the lithi-
ated furan 39 which can then participate in a 1,2-metallate
rearrangement via intermediates 40 and 41 to give the ob-
served ketone after protonation and tautomerisation. Evi-
dence for this process derives from reaction of the furan
43 with n-BuLi and CuCN according to procedure 1 to
give the ketone 42 in 32% yield. The easy aromatisation
of furanoid glycals has been observed previously.23,24
Et2O, –35 °C to r.t., 16 h
18% (1.0 mmol scale)
37
38
Scheme 8
2–
2Li+
NC
Bu
SnBu3
O
Li
Cu
n-BuLi
O
BuCu(CN)Li
O
– SnBu4
– LiOTBS
OTBS
OTBS
37
OTBS
39
OTBS
40
SnBu3
Li(CN)Cu
LiO
Bu
Bu
n-BuLi (5.4 equiv)
CuCN (1.2 equiv)
O
O
In all the foregoing examples, the glycal substrates bore a
TBS ether protecting group at C3 that underwent a tandem
1,2-metallate rearrangement followed by a regiospecific
O → C silyl migration (retro-[1,4]-Brook rearrangement)
to give a trisubstituted alkenylsilane. Whether the O → C
silyl migration is a boon or nuisance will depend on cir-
cumstances. In those cases where it is a nuisance, the TBS
group in the alkenylsilane can be excised by treatment
with TBAF in DMF at elevated temperature. However, in
H2O
Et2O, –35 °C to r.t.
32%
OTBS
43
OTBS
OTBS
42
41
Scheme 9
order to avoid the vexation of an additional step, we ex-
amined 1-tributylstannyl glycal substrates either with no
protecting group or a non-transferrable protecting group
© Thieme Stuttgart · New York
Synthesis 2012, 44, 946–952

950
K. Jarowicki et al.
PAPER
at C3. The results are shown in Scheme 10. In all four lation of the C2-OH followed by hydrogenation on Pd/C
cases, the 1,2-metallate rearrangement proceeded normal- gave mesylate 54 – an advanced intermediate in
ly to give 56–86% yields of trans-alkenes directly. The Schmidt’s total synthesis of KRN7000.33 The synthesis of
high yield of alkene 45 from the furanoid glycal 44 is intermediate 54 was thus accomplished in 12 steps and in
markworthy because it shows that deprotonation of the 16% overall yield from commercially available D-galac-
C3-OH group effectively blocked the easy aromatisation tose pentaacetate. The synthesis of 1-tributylstannyl ga-
reaction observed with substrate 37.
lactal 51 is presented in the Supporting Information.
The diol 52 was also incorporated into a synthesis of the
D5,6-ceramide derivative 59 of D5,6-KRN7000 in which the
alkene function introduced during the 1,2-metallate rear-
rangement is retained.34 An attempt to introduce an azide
moiety via displacement of the mesylate 53 with sodium
azide in DMF or DMSO or with tetramethylguanidinium
azide in DMF or MeCN over several days failed. Howev-
er, by first selectively protecting the C4-OH group in diol
52 as its TBS ether, the remaining C2-OH was then con-
verted into its triflate derivative that underwent substitu-
tion by NaN3 in DMF to give 57 in 82% yield over two
steps. The azide was reduced with zinc in the presence of
NH4Cl. The resulting amine was fairly unstable; there-
fore, it was directly coupled with hexacosanoic acid with-
out purification, to give amide 58 in about 51% yield over
SnBu3
n-BuLi (6.4 equiv)
OTBS OH
OH
CuCN (1.2 equiv)
O
Bu
Et2O, –35 °C to r.t., 16 h
69% (1.0 mmol scale)
OH
OTBS
44
SnBu3
45
OH OH
O
n-BuLi (6.4 equiv)
CuCN (1.2 equiv)
Bu
OH
O
O
Et2O, –35 °C to r.t., 16 h
86% (0.26 mmol scale)
O
O
Ph
14
Ph
46
SnBu3
n-BuLi (4.4 equiv)
CuCN (1.2 equiv)
OH OBn
1
two steps. H NMR and 13C NMR spectroscopy of the
O
amide purified by column chromatography revealed that
the product was only 90% pure and the unknown impurity
could not be removed by column chromatography or by
recrystallisation from various solvents. Therefore, the
contaminated material was treated with TBAF to remove
the TBS group and then with TsOH in methanol to cleave
the benzylidene acetal. The desired D5,6-ceramide 59
(≥95% pure according to 1H NMR spectroscopic analysis)
was obtained as a white amorphous solid (mp 93–95 °C
from MeOH) in a lamentable 9% yield from azide 57 (4
steps) after column chromatography.
Bu
Bu
Et2O, –35 °C to r.t., 3.5 h
66% (1.0 mmol scale)
OBn
OBn
OBn OBn
48
OBn OBn
47
SnBu3
n-BuLi (4.4 equiv)
CuCN (1.2 equiv)
OH OBn
O
Et2O, –35 °C to r.t., 2.5 h
56% (0.29 mmol scale)
OBn OBn
50
OBn OBn
49
Scheme 10
In conclusion, we have shown that 1-metallated glycals
derived from the common monosaccharides D-glucose, D-
galactose, L-rhamnose, D-xylose, D-arabinose, and D-ri-
bose react with a variety of organolithium reagents under
Cu(I) mediation to give alkenylpolyol chains in 45–91%
yield (19 examples). The reaction can be divided into 2
classes depending on the structure of the 1-metallated gly-
cal. In class 1 reactions, 1-metallated glycals bearing ei-
ther no protecting group at C3 or a non-transferrable
protecting group undergo 1,2-metallate rearrangements to
alkenylcuprate intermediates that hydrolyse to give trans-
alkenes. In class 2 reactions, 1-metallated glycals bearing
a TBS ether at C3 undergo a tandem 1,2-metallate rear-
rangement followed by a regiospecific retro-[1,4]-Brook
rearrangement to give Z-alkenylsilanes after aqueous
workup. Crucial to the success of both class 1 and class 2
reactions is the use of an excess of the nucleophilic orga-
nolithium partner.35 Application of the 1,2-metallate rear-
rangement to the total syntheses of sphingolipids D-
erythro-ceramide,12 Sch II, and phalluside-136 as well as
the syntheses of KRN7000 and the D5,6-ceramide reported
herein attest to its practical value.
Formal Synthesis of KRN7000 and Synthesis of
D5,6-Ceramide 59
KRN7000 (55, Scheme 11) is a synthetic a-galactosyl ce-
ramide analogue of the agelasphins isolated from the
Okinawan sponge Agelas mauritianus in 1993.25,26 It is a
potent immunostimulant that displays remarkable activity
in animal models against a diverse range of diseases in-
cluding various cancers, malaria, hepatitis B, juvenile di-
abetes, and autoimmune encephalomyelitis.27–29 The first
synthesis of KRN7000 was reported by Koezuka and co-
workers of the Kirin Brewery Company in 199530 and
since then intense effort has been invested in the synthesis
of KRN7000 itself as well as a myriad of analogues.31,32
We now describe an application of our 1,2-metallate rear-
rangement methodology to a formal synthesis KRN7000
as well as a synthesis of the D5,6-ceramide derivative 59 of
D5,6-KRN7000.
1-Tributylstannyl galactal 51 bearing a free hydroxy
group at C3, was treated with n-dodecyllithium (6.4
equiv) and CuCN (1.2 equiv) in Et2O according to proce-
dure 1 to afford the 1,2-metallate rearrangement product
52 in 89% yield (Scheme 11). Subsequent selective mesy-
Synthesis 2012, 44, 946–952
© Thieme Stuttgart · New York

PAPER
1,2-Metallate Rearrangements
951
SnBu3
OH OH
OH OTBS
N3
OTBS
O
3
e, f
d
a
2
4
C12H25
C12H25
C12H25
OH
82%
86%
89%
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
51
52
56
57
mp 102–104 °C
oil
oil
g, h
b
75%
O
O
C25H51
OMs OH
O
OMs OH
O
NH OTBS
c
C12H25
C14H29
80%
O
O
C12H25
O
Ph
Ph
53
54
mp 64–66 °C
mp 93–96 °C
Ph
58
ref. 33
i, j 28% from 58
OH
O
C25H51
O
C25H51
O
HO
HO
NH OH
NH OH
HO
O
HO
C14H29
C12H25
OH
OH
59
55 (KRN7000)
mp 93–95 °C
Scheme 11 Reagents and conditions: (a) n-C12H25Li (6.4 equiv), CuCN (1.2 equiv), Et2O, –35 to 10 °C, 3 h, 89%; (b) MsCl (1.1 equiv), Py–
CH2Cl2, –15 °C, 5 h, 75%; (c) H2 (1 bar), 10% Pd/C, MeOH–CH2Cl2, r.t., 16 h, 80%; (d) TBSCl (1.4 equiv), DBU (1.6 equiv), THF, r.t., 3 h,
86%; (e) Tf2O (1.4 equiv), Py (2.0 equiv), CH2Cl2, –15 °C, 20 min; (f) NaN3 (5.0 equiv), DMF, r.t., 80 min, 82% from 56; (g) Zn (10.4 equiv),
NH4Cl (10.4 equiv), THF–H2O, r.t., 3 h; (h) n-C25H51CO2H (2.3 equiv), HOBT (3.2 equiv), EDC·HCl (3.2 equiv), DMAP (3.2 equiv), CH2Cl2,
r.t., 16 h; (i) TBAF·3H2O (1.2 equiv), THF, r.t., 3 h; (j) p-TsOH·H2O (6.5 equiv), CH2Cl2–MeOH, r.t., 1 h, 9% from 57.
(2R,4S,5R)-4-[(R,Z)-1-Hydroxy-3-(tert-butyldimethylsilyl)hept-
For general information and materials, see the Supporting Informa-
tion.
2-enyl]-2-phenyl-1,3-dioxan-5-ol (12a)
White solid; mp 121.0–122.0 °C (hexane); [a]D –45 (c 1.00,
25
CHCl3).
CuCN Mediation; Procedure 1
To a stirred suspension of CuCN (Fluka, 0.107 g, 1.2 mmol) in Et2O
(8.0 mL) cooled to –78 °C was added dropwise n-BuLi (1.56 M in
hexanes, 3.4 mL, 5.4 mmol). The mixture was allowed to warm to
0 °C, stirred for 6 min, and then cooled to –35 °C. A solution of stan-
nane 9 (0.64 g, 1.0 mmol) in Et2O (3.0 mL) was added by cannula
with an additional amount of Et2O (2.0 mL) being used for washing.
The reaction was allowed to warm gradually to r.t. over 16 h and
then quenched with sat. aq NH4Cl (20 mL). The organic layer was
separated from the blue aqueous layer which was then extracted
with Et2O (3 × 20 mL). The combined organic layers were dried
(Na2SO4) and the solvent evaporated. The residue was purified by
column chromatography (SiO2, hexanes–Et2O) to give the title
compound 12a (0.37 g, 0.91 mmol, 91%).
IR (diamond compression system): 3372 (br s), 2955 (s), 2928 (s),
2856 (s), 1461 (m), 1389 (m), 1077 (s), 1014 (s), 822 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 7.51–7.47 (2 H, m, ArH), 7.41–
7.36 (3 H, m, ArH), 6.30 (1 H, dt, J = 10.1, 1.1 Hz, C5H), 5.52 (1
H, s, CHPh), 4.56 (1 H, ddd, J = 10.0, 5.6, 4.1 Hz, C4H), 4.30 (1 H,
dd, J = 10.8, 5.4 Hz, C1HAHB), 4.04–3.96 (1 H, m, C2H), 3.62 (1 H,
t, J = 10.6 Hz, C1HAHB), 3.59 (1 H, dd, J = 9.2, 4.1 Hz, C3H), 2.55
(1 H, d, J = 3.6 Hz, HOC2), 2.35 (1 H, d, J = 5.8 Hz, HOC4), 2.17–
2.06 (2 H, m, C7H2), 1.43–1.27 (4 H, m, C8H2 + C9H2), 0.94 [9 H,
s, (CH3)3C], 0.91 (3 H, t, J = 7.1 Hz, C10H3), 0.21 (3 H, s, CH3Si),
0.20 (3 H, s, CH3Si).
13C NMR (75 MHz, CDCl3): d = 144.8 (C6), 140.5 (C5H), 137.9
(CAr), 129.4 (CArH), 128.6 (2CArH), 126.5 (2CArH), 101.3 (CHPh),
84.3 (C3H), 71.1 (C1H2), 70.3 (C4H), 62.4 (C2H), 38.3 (C7H2),
33.1 (C8H2), 27.4 [CH3)3C], 23.1 (C9H2), 17.9 [C(CH3)3], 14.4
(C10H3), –2.3 (CH3Si), –3.4 (CH3Si).
CuBr Mediation; Procedure 2
To a stirred suspension of freshly recrystallised CuBr·SMe2 (0.247
g, 1.2 mmol) in Et2O (3.0 mL) and Me2S (5.0 mL) cooled to –78 °C
was added dropwise n-BuLi (1.8 M in hexanes, 3.0 mL, 5.4 mmol).
The mixture was allowed to warm to 0 °C and stirred for 6 min. The
yellow solution was then cooled to –35 °C and a solution of a 1-
tributylstannyl glucal 9 (1.0 mmol) in Et2O (3.0 mL) was added by
cannula with an additional amount of Et2O (2.0 mL) being used for
washing. The reaction was allowed to warm gradually to r.t. during
16 h and then quenched with sat. aq NH4Cl (20 mL). Aqueous ex-
tractive workup as described in procedure 1 gave diol 12a (0.325 g,
0.80 mmol, 80%).
Anal. Calcd for C23H38O4Si: C, 67.94; H, 9.42. Found: C, 68.20; H,
9.45.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 946–952

952
K. Jarowicki et al.
PAPER
(21) In all of our earlier studies we routinely used Me2S as a
Primary Data for this article are available online at http://
www.thieme-connect.com/ejournals/toc/synthesis and can be cited
using the following DOI: 10.4125/pd0025th.
cosolvent on the assumption that it stabilised the higher
order cuprate intermediates. However, we later discovered
that Me2S is deleterious to the CuCN-mediated reactions in
some cases. In the case of CuBr-mediated reactions, the
presence of Me2S as a co-solvent generally had a neutral or
beneficial effect.
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Synthesis 2012, 44, 946–952
© Thieme Stuttgart · New York