Stereodivergent synthesis of the C1-C9 tetrahydropyran subunit of zincophorin and isomers thereof

Article abstract of DOI:10.1055/s-0031-1289661

Zincophorin C1-C9 fragment and seven tetrahydropyran analogues were prepared diastereoselectively by sequential iodoetherification and radical hydrogen-transfer reactions. Stereoselective formation of 3,7-trans or 3,7-cis rings was rationalized through minimization of allylic-1,3 strain in chair-like transition states. Subsequent hydrogen-transfer provided 7,8-anti or 7,8-syn isomers under acyclic stereocontrol or endocyclic control respectively. The latter approach relies on the formation of a [4.4.0] bicyclic complexes resulting from the chelation of the oxygen of the tetrahydropyran ring and the ester by a bidentate Lewis acid. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1289661

474
PAPER
Stereodivergent Synthesis of the C1–C9 Tetrahydropyran Subunit of
Zincophorin and Isomers Thereof
S
ynthesis of th
r
e
C
1–C
a
o
n
f
Z
incophori
ç
a
nd Isom
o
e
rs
T
hereof is Godin,a,b Ioannis Katsoulis,a Émilie Fiola-Masson,a Sabrina Dhambri,a Philippe Mochirian,a,b
Yvan Guindon*a,b,c
a
Institut de recherches cliniques de Montréal (IRCM), Bioorganic Chemistry Laboratory, 110 avenue des Pins Ouest, Montréal, QC,
H2W 1R7, Canada
Fax +1(514)9875789; E-mail: yvan.guindon@ircm.qc.ca
Department of Chemistry, Université de Montréal, C.P. 6128, succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, QC, H3A 2K6, Canada
b
c
Received 13 October 2011
one side and a complex network of steric interactions be-
tween the polypropionate substituents side chain on the
other.1a,b Is chelation to a cation the real mechanism of ac-
tion? Are these induced conformations (pre- or post-com-
Abstract: Zincophorin C1–C9 fragment and seven tetrahydropyran
analogues were prepared diastereoselectively by sequential iodo-
etherification and radical hydrogen-transfer reactions. Stereoselec-
tive formation of 3,7-trans or 3,7-cis rings was rationalized through
minimization of allylic-1,3 strain in chair-like transition states. Sub- plexation) optimal for their biological activity? We hope
sequent hydrogen-transfer provided 7,8-anti or 7,8-syn isomers un-
to answer these questions by synthesizing zincophorin (1)
der acyclic stereocontrol or endocyclic control respectively. The
and related analogues in the context of our QSAR study.
latter approach relies on the formation of a [4.4.0] bicyclic com-
The development of a strategy to generate efficiently and
plexes resulting from the chelation of the oxygen of the tetrahydro-
selectively a library of C1–C9 subunits of 1 was therefore
pyran ring and the ester by a bidentate Lewis acid.
considered. Keeping the configuration at C2 constant,6 16
Key words: ionophore, iodoetherification, radical reduction, Lewis
isomers of the C1–C9 fragment are possible. We report
acid, substituted tetrahydropyrans
herein the synthesis of eight of them, as illustrated in
Figure 2.
The need to identify novel lead molecules and mecha-
Me
O
OH OH OH
OH
nisms of action to control infections or resistant cancers is
still acutely present. Several complex natural products of
the polyketide family, such as zincophorin (1)1 and salino-
mycin (2),2 are highly interesting in this regard (Figure 1).
Zincophorin (1) is an antibiotic, while salinomycin (2) has
been recently shown to kill selectively cancer stem cells in
vitro and in vivo.3 Significant differences of gene expres-
sion were noted when cancerous cells were treated with
this molecule as compared to other antiproliferative
agents (e.g., paclitaxel). The complexity of these mole-
cules, however, limits their drug potential. Little is known
about the structural features of these polyketides respon-
sible for their biological activities, a crucial information
that could lead to the development of simplified analogues
with improved biological and pharmacological properties.
To identify these pharmacophores, a QSAR study4 will be
conducted where stereogenic centers will be removed or
their relative stereochemistry altered.
3
7
22
11
13
19
1
HO
O
16
H
H
Me
Me Me Me
Me Me Me
zincophorin (1)
OH
Me
H
Me
Me
O
Me
O
O
OH
O
Me
O
HO
O
O
H
H
H
Me Me
OH
salinomycin (2)
Figure 1 Structure of zincophorin (1) and salinomycin (2)
Me
Me
BnO
BnO
3
7
3
7
CO2Et
CO2Et
2
8
2
8
O
O
H
H
H
H
Me
Me
Me
Me
3a: 3,7-trans; 7,8-anti
3b: 3,7-trans; 7,8-syn
4a: 3,7-cis; 7,8-anti
4b: 3,7-cis; 7,8-syn
5a: 3,7-cis; 7,8-anti
5b: 3,7-cis; 7,8-syn
6a: 3,7-trans; 7,8-anti
6b: 3,7-trans; 7,8-syn
Numerous compounds of the polyketide family are
ionophores2 owing to their ability to bind inorganic cat-
ions and form lipophilic complexes that facilitate ion
transport across cell membrane. Zincophorin (1), for in-
stance, forms preferentially complexes with zinc cation,
the carboxyl functionality at C1 and the secondary alco-
hols at C11 and C13 acting as ligands.5 These functional-
ities are oriented in space by the tetrahydropyran ring on
Figure 2 Structure of tetrahydropyran isomers 3a–6b6
Inspired by a methodology previously developed by our
group to access tetrahydrofuran,7 we envisioned that the
targeted substituted tetrahydropyran (Figure 2) could be
generated by an intramolecular iodoetherification coupled
to a radical reduction (Scheme 1). An electron-poor
trisubstituted olefin, adjacent to a stereogenic center, will
SYNTHESIS 2012, 44, 474–488
x
x
.x
x
.2
0
1
2
Advanced online publication: 16.01.2012
DOI: 10.1055/s-0031-1289661; Art ID: M97511SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of the C1–C9 Subunit of Zincophorin and Isomers Thereof
475
Me
CO2R1
Me
Me
8
OR2
OR2
OR2
∗
6
7
•
I2
H
7
CO2R1
I
CO2R1
∗
O
O
OH
H
H
H
H
Me
Me
Me
Me
Me
Me
Scheme 1 Methodology to access trisubstituted tetrahydropyrans
be used to control the relative C6–C7 stereochemistry in stituents in these complexes may raise their energy of for-
the iodoetherification step.
mation and influence the diastereoselectivity of the
reduction, a hypothesis tested herein.
Hydrogen-transfer reaction of the resulting tertiary io-
dides will then be performed in order to control the stereo- We embarked on the synthesis of zincophorin C1–C9
chemistry at C8. We and others8–10 have discovered that fragments as exemplified by the retrosynthesis of tetrahy-
acyclic carbon-centered radicals could react stereoselec- dropyran 3b (Scheme 3). As previously discussed, a radi-
tively in hydrogen-transfer reactions. Our group has dem- cal reduction under endocyclic control (Scheme 2, TS II)
onstrated the efficiency of the reduction of a carbon- would generate the latter from tertiary iodide 7. Construc-
centered free radical flanked on one side by an ester and tion of the tetrahydropyran ring will be achieved using a
on the other, by a stereogenic center bearing an oxygen in kinetically-controlled iodoetherification reaction on
order to access the anti-isomer (acyclic stereocon- trisubstituted a,b-unsaturated olefin 8, leading to a C6–C7
trol).7b,c,11 Such stereocontrol, obtained in other series of trans relationship.
molecules, was rationalized from the minimizations of al-
lylic-1,3 strain and intramolecular dipole–dipole effect to
Me
CO2Et
8
Me
BnO
RO
favor transition state I (Scheme 2).12
6
6
7
CO2Et
2
8
O
O
H
H
H
H
I
Me
Me
Me
Me
R1
OR2
3b
7
Bu3SnH
O
OR
CO2Me
CO2Me
CO2Me
Me
CO2Me
H
R1
R1
R1
R2O
Et3B, air
H
Me
anti
H
SnBu3
Me
Me
10
RO
RO
O
OR
I
3
Me
CO2Et
2
R1
+
6
OH
OR2
OR2
Me
L.A.
L.A.
O
RO
O
O
P
Bu3SnH
Me
Me
Me
Me
OMe
OMe
CO2Me
R2O
R1
H
OMe
Et3B, air
8
9
Me
anti
I
H
H
SnBu3
I'
Me
11
Scheme 3 Retrosynthetic analysis of tetrahydropyran ring 3b
SnBu3
L.A.
L.A.
Bu3SnH
OR2
H
Me
O
R2
OMe
O
The hydroxy group at C3 of 8 would in turn originate from
a stereocontrolled reduction of a,b-unsaturated ketone 9
using the Corey–Bakshi–Shibata (CBS) oxazaboroli-
dine.15 These enones would be obtained from a Horner–
Wadsworth–Emmons (HWE) coupling between aldehyde
10 and b-ketophosphonate 11, both derived from (R)-
Roche ester.
Et3B, air
Me
syn
R1
II
Scheme 2 Transition states for radical reduction on substituted
tetrahydropyrans
As importantly, we demonstrated that adding a bidentate
Lewis acid to the reaction mixture leads to the opposite
syn-isomer (i.e., endocyclic control) through a bicyclic
transition state II (Scheme 2).13 These bidentate complex-
es have to display a slow equilibration rate to avoid an ero-
sion of diastereoselectivity resulting from competitive
pathways (i.e., monodentate activation of the ester as in I¢
or uncomplexed substrate as in I). Indeed, no kinetic pref-
erences favoring either the bidentate or the monodentate
complexes in hydrogen-transfer reactions have been ob-
served in previous studies,14 thus the need to pre-organize
stable bidentate complexes in order to achieve syn-diaste-
reoselectivity. In the present study, we planned to form
[4.4.0] bicyclic bidentate complexes from functionalized
tetrahydropyrans. Steric effects induced by the ring sub-
The stereodivergent synthesis of all diastereoisomers at
C3 and C6 illustrated in Figure 2 began with the prepara-
tion of the b-ketophosphonate 13 from the benzylated (R)-
Roche ester 12 (Scheme 4). Compound 13 was reacted
with the OTBS protected aldehyde 14a and 14b deriva-
tives of the (R)- and (S)-Roche esters (using hydrated
LiOH as a base)16 to give the a,b-unsaturated ketones 15
(2,6-anti) and 16 (2,6-syn), respectively, in good yields.
Enones 15 and 16 were then reduced diastereoselectively
with chiral oxazaborolidine reagents to give the 2,3-anti
(17 and 19) and 2,3-syn (18 and 20) allylic alcohols with
good to excellent diastereoselectivities. Only few exam-
ples of such reductions have been reported in the litera-
ture.17 The four allylic alcohols 17–20 were then reduced
© Thieme Stuttgart · New York
Synthesis 2012, 44, 474–488

476
F. Godin et al.
PAPER
OTBS
OTBS
BnO
O
OHC
OHC
BnO
O
OTBS
BnO
O
OTBS
R
Me
14b
Me
14a
Me
13 R = CH2PO(OMe)2
Me
Me
Me
Me
Me
a
78%
b
80%
b
75%
16
15
12 R = OMe
6
BnO
i, g
BnO
OH
OTBS BnO
e, f
OTBS
OTBS BnO
g, h
OTBS
BnO
O
OTBS
3
Me
CO2Et
CHO
2
2
6
2
6
2
6
2
6
c or d
3
3
3
OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
c
d
c
d
2,3-anti; 2,6-anti 17 (>20:1, 86%) 2,3-anti; 2,6-anti 21 (80%)
2,3-anti; 2,6-anti 25 (83%)
2,3-anti; 2,6-anti 29 (50%)
2,6-anti 15
2,6-syn 16
2,3-syn; 2,6-anti
2,3-anti; 2,6-syn
2,3-syn; 2,6-syn
2,3-syn; 2,6-anti
2,3-anti; 2,6-syn
2,3-syn; 2,6-syn
2,3-syn; 2,6-anti
2,3-anti; 2,6-syn
2,3-syn; 2,6-syn
2,3-syn; 2,6-anti
2,3-anti; 2,6-syn
2,3-syn; 2,6-syn
18 (6.5:1, 69%)
19 (8:1, 86%)
20 (8:1, 52%)
22 (64%)
23 (81%)
24 (97%)
26 (53%)
27 (75%)
28 (65%)
30 (44%)
31 (63%)
32 (42%)
Scheme 4 Synthesis of trisubstituted olefins 29–32. Reagents and conditions: (a) MePO(OMe)2, n-BuLi, THF, –78 °C; (b) LiOH·H2O, THF,
r.t.; (c) (S)-2-Me-CBS-oxazaborolidine, THF·BH3, THF, –40 °C; (d) (R)-2-Me-CBS-oxazaborolidine, THF·BH3, THF, –40 °C; (e) H2, Pd/C,
pyridine, MeOH, r.t.; (f) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (g) HF·pyridine, THF, 0 °C; (h) DMP, NaHCO3, CH2Cl2, r.t.; (i) Ph3P(Me)CO2Et,
toluene, reflux.
by hydrogenation using Pd/C in the presence of pyridine18 whereas 3,7-cis products were obtained from 30 and 31
and a TBS protecting group was installed on the second- (Scheme 5, equations 2 and 3) in good to excellent yields.
ary alcohol to give products 21–24. The primary silyloxy
Iodocyclization reaction, which involves activation of a
groups were then selectively cleaved with HF·pyridine
double bond by iodine followed by an intramolecular nu-
and the corresponding alcohols oxidized to aldehydes 25–
cleophilic attack, have been extensively studied in the
28 using Dess–Martin periodinane. Olefination of each al-
context of the synthesis of various heterocycles including
dehyde provided trisubstituted a,b-unsaturated esters in
good yields. Removal of the TBS protecting groups from
the secondary alcohols completed the synthetic sequence
to access precursors 29–32 for the subsequent key iodo-
etherification reaction.
carbamates,19a,20 carbonates,21 lactones,22 and cyclic
ethers (furans and pyrans).7a,23 Under kinetic control, the
outcome of these reactions has been rationalized by mech-
anisms taking into account steric and stereoelectronic
effects23,24 (e.g., endo-alkoxy effect) generated in the cy-
Iodoetherification of substituted olefins 29–32 was then
studied under reaction conditions reported to provide ki-
netic products (I2, AgOTf, and NaHCO3 in THF at
r.t.).7a,b,19 As shown in Scheme 5, all substrates reacted
diastereoselectively to give 6,7-trans relative stereochem-
istry. The 3,7-trans products were generated from the cy-
clization of 29 and 32 (Scheme 5, equations 1 and 4),
Me
CO2Et
Me
CO2Et
I2, AgOTf
NaHCO3
BnO
BnO
a)
3
7
O
THF, r.t.
(70%)
OH
H
H
I
Me
Me
Me
Me
29
33a
H
HO
H
H
H
Me
6
HO
6
R
Me
EtO2C
Me
Me
Me
Me
R
EtO2C
Me
I2
I2
I2, AgOTf
NaHCO3
BnO
BnO
6
7
3
CO2Et
(1)
A
B
33a
(3,7-trans)
33b
(3,7-cis)
O
OH
(70%)
>20:1
H
H
I
CO2Et
Me
Me
Me
Me
H
29
33a
Me
EtO2C
H
I2
Me
H
R
HO
EtO2C
I2, AgOTf
NaHCO3
6
BnO
BnO
BnO
BnO
BnO
BnO
6
R
HO
6
3
7
I2
Me
Me
CO2Et
CO2Et
CO2Et
(2)
(3)
(4)
O
OH
(90%)
>20:1
H
Me
Me
D
H
H
I
CO2Et
Me
Me
Me
Me
Me
Me
Me
Me
C
30
34a
Me
b)
Me
Me
CO2Et
Me
CO2Et
I2, AgOTf
NaHCO3
I2, AgOTf
NaHCO3
BnO
BnO
6
3
7
3
7
Me
O
THF, r.t.
(90%)
O
OH
30
OH
(59%)
>20:1
H
H
H
H
I
Me
Me
Me
I
CO2Et
Me
Me
34a
31
35a
Me
R
Me
I2, AgOTf
NaHCO3
6
HO
3
7
Me
EtO2C
O
OH
(64%)
>20:1
Me
H
I2
H
H
H
I
CO2Et
Me
A'
32
36a
Scheme 6 Possible transition states for iodoetherification of 29 and
30
Scheme 5 Iodoetherification of substrates 29–32
Synthesis 2012, 44, 474–488
© Thieme Stuttgart · New York

PAPER
Synthesis of the C1–C9 Subunit of Zincophorin and Isomers Thereof
477
clic transition states by substituents proximal to the olefin. the iodoetherification following a competitive scenario.
The reacting intermediate has been suggested to be either Interestingly, both 29 and 30 were consumed equally, sug-
an iodonium ion or a p-complex, between the double bond gesting similar reaction rates. This lack of apparent reac-
and the iodine. Plausible six-membered-ring chair-like tion rate difference could point to an early transition state.
transition states leading to isomers of 33a are depicted in The forming bond being longer in such instance, steric ef-
Scheme 6 (part a).
fects induced by the axial substituent are expected to de-
crease, a hypothesis that would need to be verified by
theoretical calculations.
The presence of a terminal trisubstituted olefin induces
strong steric interactions (allylic-1,3 strain; depicted in
red in Scheme 6, part a) with the substituent at C6 in B and Hydrogen-transfer reactions were then performed on rad-
D, which should therefore be prohibitively high in ener- ical precursors 33a–36a (Table 1). Under an acyclic stereo-
gy.25 Conversely, transition state C should be disfavored control, a 7,8-anti relative stereochemistry was observed
because of interactions between the methyl group of the at –78 °C using Bu3SnH and Et3B as radical chain initiator
olefin and the ring. Minimization of both allylic 1,3-strain (condition A: entries 1, 3, 5, and 7). In the presence of
and steric effects leads therefore to transition state A. In- MgBr2·OEt2, a bidentate Lewis acid (condition B), an in-
verting the configuration at C3 led to the 3,7-cis product version of configuration at C8 was observed as expected
34a obtained from 30 (TS A¢, Scheme 6, part b). The re- (see Scheme 2, TS II). An excellent ratio for 7,8-syn prod-
sulting transition state A¢ differ from A by having the R ucts was noted (entries 2, 4, and 6). The structural assign-
substituent in an equatorial position. It is tempting to sug- ment for ester 3b, which displays the same configuration
gest that transition state A is higher in energy than A¢, as zincophorin tetrahydropyran fragment, was confirmed
which would lead to a faster cyclization rate of 30 as com- by reduction to the corresponding known alcohol.1c Re-
pared to 29. In order to test this hypothesis, we combined duced stereoselectivity was, however, noted when the rad-
together an equal amount of 29 and 30. Half of the neces- ical precursor 36a was reacted in the presence of
sary amount of I2 and AgOTf were then added to initiate MgBr2·OEt2 (entry 8), and a lower yield in the case of 33a
Table 1 Radical Reduction of Substrates 33a–36a
Entry
Substrate
Conditionsa
Products
7,8-anti:7,8-syn
Me
Ratiob
Yield (%)c
Me
BnO
BnO
3,7-trans (33a)
3,7-cis (34a)
7
3
7
A or B
3
8
CO2Et
8
CO2Et
+
O
O
H
H
H
H
Me
Me
Me
Me
7,8-anti
3,7-trans 3a
3,7-cis
7,8-syn
3,7-trans 3b
3,7-cis 4b
4a
1
2
3
4
3,7-trans (33a)
3,7-trans (33a)
3,7-cis (34a)
3,7-cis (34a)
A
B
A
B
3a/3b
>20:1
1:>20
>20:1
1:>20
62
40
96
79
3a/3b
4a/4b
4a/4b
Me
Me
BnO
BnO
3,7-cis (35a)
7
7
3
3
A or B
8
CO2Et
8
CO2Et
+
O
O
H
H
H
H
3,7-trans (36a)
Me
5a
Me
5b
Me
Me
7,8-anti
3,7-cis
3,7-trans 6a
7,8-syn
3,7-cis
3,7-trans 6b
5
6
7
8
3,7-cis (35a)
3,7-cis (35a)
3,7-trans (36a)
3,7-trans (36a)
A
B
A
B
5a/5b
>20:1
1:>20
>20:1
1:6.4
76
71
82
79
5a/5b
6a/6b
6a/6b
a Conditions A: Substrate in toluene (0.1 M) at –78 °C was treated with Bu3SnH (1.5 equiv) followed by Et3B (0.2 equiv) and air. Conditions
B: Substrate in CH2Cl2 (0.1 M) was pretreated with MgBr2·OEt2 (3 equiv) for 1 h at 0 °C. Mixture cooled to –78 °C before successive addition
of Bu3SnH (1.5 equiv), Et3B (0.2 equiv), and air.
b Product ratios determined by 1H NMR analysis of the crude reaction mixture.
c Yields of isolated products.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 474–488

478
F. Godin et al.
PAPER
Deprotection of TBS Group with HF·Pyridine; General Proce-
dure (A1)
(entry 2). As discussed before, a pre-organization of bicy-
clic bidentate intermediates, prior to the homolytic cleav-
age of the carbon–iodine bond, is important to avoid
competitive anti-selective monodentate activation path-
ways (Scheme 2).14 The trans-decalin-like bidentate com-
plex originating from complexation of 33a (or 36a) with
MgBr2·OEt2 exhibits indeed an axial substituent (i.e., R)
at C3 as seen in Scheme 7. It is likely that their energy of
formation would be increased because of these additional
steric interactions.26
To a cold (0 °C) solution of TBS protected alcohol (1 equiv) in an-
hyd THF (0.1 M) was added dropwise a solution of HF·pyridine (1
mL per mmol of substrate), followed by stirring at 0 °C and moni-
toring of the reaction mixture by TLC until complete consumption
of starting material. The reaction mixture was then treated slowly
with sat. aq NaHCO3 (5 mL per mmol of substrate) followed by sep-
aration of the organic phase at r.t. The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL per mmol of substrate) and the combined or-
ganic fractions were dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel (hexanes–EtOAc, 80:20) to give the desired alcohol prod-
uct.
Me
Me
H
H
O
O
I
I
O
O
Mg
Mg
Me
Me
Me
33a
35a
34a
36a
EtO
EtO
Radical Reduction – Acyclic Stereocontrol; General Procedure
(A2)
H
R
3
3
H
H
lower yield
R
H
To a cold (–78 °C) solution of iodide (1 equiv) in anhyd toluene (0.1
M) was added successively Bu3SnH (1.5 equiv), a 1 M solution of
Et3B in CH2Cl2 (0.2 equiv), and air (syringe). Supplementary addi-
tions of Et3B solution (0.2 equiv) and air were realized each 30 min,
until reaction was judged complete by TLC (eluent: hexanes–
EtOAc, 90:10; 3–4 h). The reaction mixture was treated with 1,3-
dinitrobenzene (0.2 equiv) and stirred for 15 min at –78 °C. Once at
r.t., the mixture was concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (hexanes–EtOAc,
90:10) to give the reduced product.
H
H
OEt
O
I
OEt
Me
H
I
H
R
3
3
Mg
Me
Mg
Me
O
O
O
R
H
H
lower dr
26
Scheme 7 Bidentate complexes of 33a–36a with MgBr2·OEt2
This analysis points to the importance of considering the
structure of bidentate complexes to predict the stereo-
chemical outcome in reactions involving chelated inter-
mediates such as the ones depicted herein. The presence
of an axial substituent in a [4.4.0] bicyclic complex could
be at the origin of reduced ratio or yield.
Radical Reduction – Endocyclic Control; General Procedure
(A3)
To a cold (0 °C) solution of iodide (1 equiv) in anhyd CH2Cl2 (0.1
M) was added MgBr2·OEt2 (3 equiv). The reaction mixture was
stirred at 0 °C for 1 h and then cooled to –78 °C before successive
additions of Bu3SnH (1.5 equiv), a 1 M solution of Et3B in CH2Cl2
(0.2 equiv), and air (syringe). Supplementary additions of Et3B so-
lution (0.2 equiv) and air were realized each 30 min until reaction
was judged completed by TLC (eluent: hexanes–EtOAc, 90:10; 3–
4 h). The reaction mixture was treated with 1,3-dinitrobenzene (0.2
equiv), stirred for 15 min at –78 °C before treating with sat. aq
NH4Cl (5 mL per mmol of substrate). The organic phase was sepa-
In conclusion, iodine-mediated cyclization of g-methyl
a,b-unsaturated esters proceeds with excellent diastereo-
control to yield exclusively 6,7-trans products bearing a
tertiary iodide. These intermediates then undergo diaste-
reoselective radical reductions, either under acyclic ste-
reocontrol or endocyclic control, to generate respectively
the 7,8-anti or 7,8-syn isomers. Results obtained using rated at r.t. and the aqueous layer was extracted with CH2Cl2 (3 × 5
mL per mmol of substrate). The combined organic fractions were
this methodology improve the understanding of radical
dried (MgSO4), filtered, and concentrated in vacuo. The crude prod-
processes involving bidentate Lewis acids complexed to
uct was purified by flash chromatography on silica gel (hexanes–
EtOAc, 90:10) to give the reduced product.
trisubstituted tetrahydropyrans. Moreover, the efficacy of
these radical reductions to access selectively both config-
urations a to the tetrahydropyran ring was demonstrated
in the preparation of zincophorin C1–C9 fragment and
Dimethyl (–)-(R)-4-(Benzyloxy)-3-methyl-2-oxobutylphospho-
nate (13)
isomers thereof from which analogues will be derived in To a cold (–78 °C) solution of dimethyl methylphosphonate (15.3
mL, 143 mmol, 4 equiv) in anhyd THF (0.5 M, 310 mL) was added
the context of a QSAR study.
dropwise a 2.5 M solution of n-BuLi in hexanes (3.5 equiv, 125
mmol, 50 mL). The mixture was stirred for 1 h at –78 °C before
slow addition of a solution of benzyl ester 1212c (7.43 g, 35.7 mmol)
All reactions requiring anhydrous conditions were conducted under
a positive argon atmosphere in oven-dried glassware using standard
syringe techniques (exception should be noted that free-radical
based reactions were conducted under N2). All solvents were puri-
fied by standard methods. Flash chromatography was performed on
silica gel (0.040–0.063 mm) using compressed air pressure. Analyt-
ical TLC was carried out on precoated (0.25 mm) aluminum-backed
silica gel plates. 1H (400 or 500 MHz) and 13C spectra (100 or 125
MHz) were referenced to residual solvents peak and ratios of prod-
ucts were measured from crude 1H spectra. IR spectra were record-
ed on a FTIR spectrophotometer on a NaCl support. Mass spectra
were recorded through electrospray ionization (ESI) on an instru-
ment operating at 70 eV.
in THF (1 M, 36 mL), followed by stirring for 15 min at –78 °C. The
reaction mixture was then treated with sat. aq NH4Cl (175 mL) fol-
lowed by separation of the organic phase at room temperature. The
aqueous layer was extracted with CH2Cl2 (3 × 100 mL) and the
combined organic fractions were dried (MgSO4), filtered, and con-
centrated in vacuo. The crude product was purified by flash chroma-
tography on silica gel (EtOAc); colorless oil; yield: 8.36 g (78%);
Rf = 0.33 (EtOAc–MeOH, 95:5); [a]D25 –48.9 (c 1.7, CDCl3).
IR (neat): 3468, 2957, 2858, 1713, 1455, 1367, 1253, 1186, 1031,
877, 842, 743, 700 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36–7.24 (m, 5 H), 4.48 (d,
J = 12.5 Hz, 1 H), 4.46 (d, J = 12.9 Hz, 1 H), 3.75 (dd, J = 7.6, 11.2
Hz, 6 H), 3.61–3.51 (m, 2 H), 3.30 (dd, J = 14.1, 22.5 Hz, 1 H),
3.18–3.09 (m, 2 H), 1.10 (d, J = 7.0 Hz, 3 H).
Synthesis 2012, 44, 474–488
© Thieme Stuttgart · New York

PAPER
Synthesis of the C1–C9 Subunit of Zincophorin and Isomers Thereof
479
13C NMR (100 MHz, CDCl3): d = 203.9 (J = 6.3 Hz), 137.3, 127.8,
127.1, 127.0, 72.6, 71.6, 52.3 (J = 1.7 Hz), 52.2 (J = 6.7 Hz), 46.5,
40.8, 39.5, 12.4.
13C NMR (125 MHz, CDCl3): d = 202.5, 150.2, 138.4, 128.9, 128.5,
127.72, 127.70, 73.4, 72.3, 67.1, 44.1, 39.6, 26.0, 18.4, 15.8, 14.3,
–5.24, –5.25.
MS (ESI): m/z (%) = 193.1 (46), 301.1 (M + H+, 100), 400.2 (17),
601.2 (18).
MS (ESI): m/z (%) = 137.1 (8), 217.2 (7), 269.2 (10), 377.3 (M +
H+, 100).
HRMS (ESI): m/z calcd for C14H22O15P [M + H+]: 301.1199; found:
HRMS (ESI): m/z calcd for C22H37O3Si [M + H+]: 377.2506; found:
301.1202 (0.8 ppm).
377.2518 (3.0 ppm).
(–)-(2R,6S,E)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-2,6-
dimethylhept-4-en-3-one (15)
(–)-(2R,3S,6S,E)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
2,6-dimethylhept-4-en-3-ol (17)
To a cold (0 °C) solution of 13 (2.02 g, 6.7 mmol, 1.05 equiv) in an-
hyd THF (0.15 M, 45 mL) was added LiOH·H2O (0.28 g, 6.7 mmol,
1.05 equiv). The mixture was stirred for 10 min at 0 °C before slow
addition of aldehyde 14a19b (1.29 g, 6.4 mmol) in THF (1 M, 6.4
mL), followed by stirring for 18 h allowing warming to r.t. The re-
action mixture was then treated with sat. aq NH4Cl (30 mL) fol-
lowed by separation of the organic phase at r.t. The aqueous layer
was extracted with EtOAc (3 × 20 mL) and the combined organic
fractions were dried (MgSO4), filtered, and concentrated in vacuo.
Crude product was purified by flash chromatography on silica gel
(hexanes–EtOAc, 90:10) to give the desired 2,6-anti-enone 15; col-
orless oil; yield: 1.81 g (75%); Rf = 0.51 (hexanes–EtOAc, 80:20);
[a]D25 –17.0 (c 1.0, CDCl3).
To a cold (–40 °C) solution of 15 (1.19 g, 3.15 mmol) in anhyd THF
(0.1 M, 31 mL) was added dropwise a 1 M solution of (S)-2-Me-
CBS oxazaborolidine in toluene (3.30 mL, 3.30 mmol, 1.05 equiv),
followed by stirring for 1 h at –40 °C. The reaction mixture was
then treated with a 1 M solution of THF·BH3 in THF (7.9 mL, 7.9
mmol, 2.5 equiv), followed by stirring for 1 h at –40 °C or until
enone was completely consumed as verified by TLC (eluent: hex-
anes–EtOAc, 80:20). The reaction mixture was then treated with
sat. aq NH4Cl (15 mL) followed by separation of the organic phase
at r.t. The aqueous layer was extracted with EtOAc (3 × 10 mL) and
combined organic fractions were dried (MgSO4), filtered, and con-
1
centrated in vacuo. H NMR analysis indicated a >20:1 ratio of
product 2,3-anti (17): 2,3-syn (18). The crude product was purified
by flash chromatography on silica gel (hexanes–EtOAc, 85:15);
colorless oil; yield: 1.02 g (86%); Rf = 0.38 (hexanes–EtOAc,
80:20); [a]D25 –22.9 (c 1.3, CDCl3).
IR (neat): 2956, 2931, 2857, 1695, 1669, 1627, 1457, 1363, 1255,
1201, 1099, 839, 777, 738, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.35–7.25 (m, 5 H), 6.86 (dd,
J = 7.1, 15.9 Hz, 1 H), 6.19 (dd, J = 1.3, 15.9 Hz, 1 H), 4.52 (d,
J = 12.1 Hz, 1 H), 4.47 (d, J = 12.1 Hz, 1 H), 3.70 (dd, J = 7.1, 9.2
Hz, 1 H), 3.54 (dd, J = 6.4, 9.8 Hz, 1 H), 3.52 (dd, J = 6.4, 9.8 Hz,
1 H), 3.45 (dd, J = 6.1, 9.2 Hz, 1 H), 3.14 (hept, J = 7.0 Hz, 1 H),
2.50 (hept, J = 6.7 Hz, 1 H), 1.11 (d, J = 7.1 Hz, 3 H), 1.05 (d,
J = 6.8 Hz, 3 H), 0.88 (s, 9 H), 0.033 (s, 3 H), 0.031 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 202.2, 149.9, 138.1, 128.6, 128.2,
127.5, 126.8, 73.2, 72.1, 66.9, 44.0, 39.3, 25.8, 18.2, 15.5, 14.1,
–3.6, –5.5.
IR (neat): 3446, 2957, 2930, 2887, 2857, 1459, 1387, 1363, 1254,
1092, 1025, 1009, 973, 838, 777, 739, 697, 667 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 5.57 (dd,
J = 7.2, 15.5 Hz, 1 H), 5.46 (ddd, J = 0.8, 7.2, 15.5 Hz, 1 H), 4.55
(d, J = 12.1 Hz, 1 H), 4.53 (d, J = 12.1 Hz, 1 H), 3.96 (dt, J = 3.1,
7.3 Hz, 1 H), 3.60 (dd, J = 4.4, 9.2 Hz, 1 H), 3.49 (dd, J = 6.2, 9.8
Hz, 1 H), 3.47 (dd, J = 7.5, 9.2 Hz, 1 H), 3.39 (dd, J = 7.0, 9.8 Hz,
1 H), 3.25 (d, J = 3.1 Hz, 1 H), 2.33 (hept, J = 6.7 Hz, 1 H), 1.89 (dh,
J = 4.4, 7.1 Hz, 1 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.87
(d, J = 7.0 Hz, 3 H), 0.034 (s, 3 H), 0.031 (s, 3 H).
MS (ESI): m/z (%) = 137.1 (12), 245.2 (6), 269.2 (11), 287.2 (7),
13C NMR (100 MHz, CDCl3): d = 137.8, 135.4, 131.0, 128.4, 127.7,
127.6, 77.6, 74.8, 73.4, 68.0, 39.1, 38.7, 25.9, 18.3 16.6, 13.8,
–5.33, –5.36.
377.3 (M + H+, 100), 401.3 (21).
HRMS (ESI): m/z calcd for C22H37O3Si [M + H+]: 377.2506; found:
377.2519 (3.2 ppm).
MS (ESI): m/z (%) = 211.1 (17), 229.2 (100), 361.3 (M – H2O + H+,
71), 757.5 (22).
(+)-(2R,6R,E)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-2,6-
dimethylhept-4-en-3-one (16)
HRMS (ESI): m/z calcd for C22H37O2Si [M – H2O + H+]: 361.2557;
To a cold (0 °C) solution of 13 (5.2 g, 17.3 mmol, 1.05 equiv) in an-
hyd THF (0.15 M, 116 mL) was added LiOH·H2O (0.73 g, 17.4
mmol, 1.05 equiv). The mixture was stirred for 10 min at 0 °C be-
fore slow addition of aldehyde 14b27 (3.34 g, 16.5 mmol) in THF (1
M, 16.5 mL), followed by stirring for 18 h allowing warming to r.t.
The reaction mixture was then treated with sat. aq NH4Cl (75 mL)
followed by separation of the organic phase at r.t. The aqueous layer
was extracted with EtOAc (3 × 60 mL) and the combined organic
fractions were dried (MgSO4), filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography on silica
gel (hexanes–EtOAc, 90:10) to give the desired 2,6-syn-enone 16;
colorless oil; yield: 4.97 g (80%); Rf = 0.38 (hexanes–EtOAc,
90:10); [a]D25 +29.2 (c 0.12, CDCl3).
found: 361.2565 (2.1 ppm).
(–)-(2R,3R,6S,E)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
2,6-dimethylhept-4-en-3-ol (18)
Product 18 was prepared from 15 (1.32 g, 3.50 mmol) following the
procedure used to prepare 17 using a 1 M solution of (R)-2-Me-CBS
oxazaborolidine in toluene. 1H NMR analysis indicated a 1:6.5 ratio
of product 2,3-anti (17):2,3-syn (18). The crude product, obtained
as a separable mixture of diastereoisomers, was purified by flash
chromatography on silica gel (hexanes–EtOAc, 85:15); colorless
25
oil; yield: 915 mg (69%); Rf = 0.42 (hexanes–EtOAc, 80:20); [a]D
–8.5 (c 1.0, CDCl3).
IR (neat): 3441, 2957, 2930, 2886, 2857, 1459, 1387, 1362, 1253,
1090, 1025, 1009, 972, 838, 777, 735, 697, 667 cm–1.
IR (neat): 2956, 2930, 2857, 1695, 1671, 1628, 1457, 1363, 1254,
1098, 838, 776, 697 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.26 (m, 5 H), 5.61 (ddd,
J = 0.9, 6.9, 15.6 Hz, 1 H), 5.50 (ddd, J = 0.9, 6.2, 15.6 Hz, 1 H),
4.53 (d, J = 12.3 Hz, 1 H), 4.51 (d, J = 12.4 Hz, 1 H), 4.18 (dd,
J = 5.7, 9.1 Hz, 1 H), 3.54–3.48 (m, 2 H), 3.47 (dd, J = 4.9, 9.1 Hz,
1 H), 3.38 (dd, J = 7.2, 9.7 Hz, 1 H), 2.76 (d, J = 5.6 Hz, 1 H), 2.34
(hept, J = 6.7 Hz, 1 H), 2.09–2.00 (m, 1 H), 0.99 (d, J = 6.7 Hz, 3
H), 0.89 (d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
1H NMR (500 MHz, CDCl3): d = 7.36–7.25 (m, 5 H), 6.85 (dd,
J = 15.9, 7.2 Hz, 1 H), 6.19 (dd, J = 15.9, 0.9 Hz, 1 H), 4.51 (d,
J = 12.1 Hz, 1 H), 4.47 (d, J = 12.1 Hz, 1 H), 3.70 (dd, J = 9.1, 7.3
Hz, 1 H), 3.53 (dd, J = 6.3, 4.3 Hz, 2 H), 3.45 (dd, J = 9.1, 6.1 Hz,
1 H), 3.15 (hept, J = 7.0 Hz, 1 H), 2.50 (hept, J = 6.5 Hz, 1 H), 1.11
(d, J = 7.0 Hz, 3 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s,
6 H).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 474–488

480
F. Godin et al.
PAPER
(–)-(2R,3S,6S)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
13C NMR (100 MHz, CDCl3): d = 138.0, 134.5, 129.7, 128.4, 127.7,
127.6, 75.3, 73.8, 73.4, 68.0, 39.1, 38.6, 25.9, 18.3, 16.6, 11.9,
–5.32, –5.33.
MS (ESI): m/z (%) = 211.1 (16), 229.2 (100), 361.3 (M – H2O + H+,
67), 757.5 (13).
HRMS (ESI): m/z calcd for C22H37O2Si [M – H2O + H+]: 361.2557;
found: 361.2563 (1.6 ppm).
2,6-dimethylheptan-3-ol (S1); Typical Procedure
To a solution of allylic alcohol 17 (1.40 g, 3.7 mmol) in MeOH (0.1
M, 37 mL) at r.t. was added pyridine (0.30 mL, 1 equiv), followed
by 10 wt% Pd/C (0.98 g, 0.92 mmol, 0.25 equiv). Inert gas atmo-
sphere was purged by 3 cycles of vacuum/H2 gas before stirring the
reaction mixture for 2 h or until reaction was judged complete by
TLC (eluent: hexanes–EtOAc, 85:15). The mixture was then fil-
tered onto a pad of Celite and washed with hexanes (3 × 15 mL).
The filtrate was concentrated in vacuo and purified by flash chro-
matography on silica gel (hexanes–EtOAc, 85:15); colorless oil;
(–)-(2R,3S,6R,E)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
2,6-dimethylhept-4-en-3-ol (19)
25
Product 19 was prepared from 16 (2.19 g, 5.80 mmol) following the
procedure used to prepare 17 using a 1 M solution of (S)-2-Me-CBS
oxazaborolidine in toluene. 1H NMR analysis indicated an 8:1 ratio
of product 2,3-anti (19):2,3-syn (20). The crude product, obtained
as a separable mixture of diastereoisomers, was purified by flash
chromatography on silica gel (hexanes–EtOAc, 85:15); colorless
yield: 1.15 g (82%); Rf = 0.25 (hexanes–EtOAc, 85:15); [a]D
–16.5 (c 1.5, CDCl3).
IR (neat): 3434, 2955, 2931, 2857, 1459, 1363, 1253, 1094, 837,
776, 737, 697 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.24 (m, 5 H), 4.53 (d,
J = 12.2 Hz, 1 H), 4.51 (d, J = 12.2 Hz, 1 H), 3.61 (dd, J = 4.2, 9.2
Hz, 1 H), 3.54–3.43 (m, 3 H), 3.37 (dd, J = 6.8, 9.5 Hz, 1 H), 3.27
(d, J = 3.7 Hz, 1 H), 1.89–1.80 (m, 1 H), 1.62–1.53 (m, 1 H), 1.53–
1.41 (m, 3 H), 1.32–1.22 (m, 1 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.90–
0.86 (m, 3 H), 0.89 (s, 9 H), 0.03 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 137.8, 128.4, 127.7, 127.6, 76.2,
75.0, 73.5, 68.5, 38.3, 35.8, 32.3, 28.9, 26.0, 18.4, 16.7, 14.0, –5.34,
–5.35.
25
oil; yield: 1.89 g (86%); Rf = 0.27 (hexanes–EtOAc, 85:15); [a]D
–0.1 (c 3.6, CDCl3).
IR (neat): 3424, 2956, 2930, 2856, 1455, 1362, 1254, 1089, 837,
776, 738, 699 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.25 (m, 5 H), 5.61 (dd,
J = 15.5, 6.9 Hz, 1 H), 5.47 (ddd, J = 15.6, 7.2, 1.0 Hz, 1 H), 4.53
(d, J = 12.5 Hz, 1 H), 4.51 (d, J = 12.7 Hz, 1 H), 3.97 (dt, J = 3.1,
7.3 Hz, 1 H), 3.59 (dd, J = 9.2, 4.4 Hz, 1 H), 3.52 (dd, J = 9.7, 5.9
Hz, 1 H), 3.47 (dd, J = 9.2, 7.4 Hz, 1 H), 3.39 (dd, J = 9.7, 7.2 Hz,
1 H), 3.17 (d, J = 3.2 Hz, 1 H), 2.34 (hept, J = 6.8 Hz, 1 H), 1.89 (dh,
J = 4.5, 7.2 Hz, 1 H), 1.00 (d, J = 6.7 Hz, 3 H), 0.89 (s, 9 H), 0.87
(d, J = 7.0 Hz, 3 H), 0.03 (s, 6 H).
MS (ESI): m/z (%) = 381.3 (M + H+, 100)
HRMS (ESI): m/z calcd for C22H41O3Si [M + H+]: 381.2819; found:
381.2830 (2.8 ppm).
13C NMR (125 MHz, CDCl3): d = 135.4, 131.0, 128.6, 127.9, 127.8,
77.7, 75.0, 73.6, 68.1, 39.1, 38.9, 26.1, 16.7, 13.9, –5.2.
(+)-(2R,3R,6S)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptan-3-ol (S2)
Product S2 was prepared from 18 (1.17 g, 3.1 mmol) following the
MS (ESI): m/z (%) = 167.1 (83), 229.2 (100), 287.2 (6), 361.3 (M –
typical procedure used to prepare S1; colorless oil; yield: 1.02 g
H2O + H+, 75), 377.3 (18), 413.2 (8), 757.5 (29).
25
(87%); Rf = 0.26 (hexanes–EtOAc, 90:10); [a]D +182.9 (c 0.24,
HRMS (ESI): m/z calcd for C22H37O2Si [M – H2O + H+]: 361.2557;
found: 361.2567 (2.6 ppm).
CDCl3).
IR (neat): 3463, 2954, 2931, 2857, 1458, 1363, 1253, 1094, 838,
776, 737, 697, 667 cm–1.
(+)-(2R,3R,6R,E)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
2,6-dimethylhept-4-en-3-ol (20)
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.53 (d,
J = 12.1 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 3.74 (t, J = 5.8 Hz, 1
H), 3.53 (d, J = 5.4 Hz, 2 H), 3.47 (dd, J = 9.8, 5.6 Hz, 1 H), 3.37
(dd, J = 9.8, 6.4 Hz, 1 H), 2.55 (br s, 1 H), 1.93–1.85 (m, 1 H), 1.66–
1.51 (m, 2 H), 1.51–1.40 (m, 2 H), 1.12–1.02 (m, 1 H), 0.94 (d,
J = 7.1 Hz, 3 H), 0.90 (s, 9 H), 0.89 (d, J = 7.0 Hz, 3 H), 0.04 (s, 6
H).
Product 20 was prepared from 16 (1.17 g, 3.1 mmol) following the
procedure used to prepare 17 using a 1 M solution of (R)-2-Me-CBS
oxazaborolidine in toluene. 1H NMR analysis indicated a 1:8 ratio
of product 2,3-anti (19):2,3-syn (20). The crude product, obtained
as a separable mixture of diastereoisomers, was purified by flash
chromatography on silica gel (hexanes–EtOAc, 85:15); colorless
25
oil; yield: 0.91 g (52%); Rf = 0.47 (hexanes–EtOAc, 85:15); [a]D
+1.7 (c 4.4, CDCl3).
13C NMR (125 MHz, CDCl3): d = 138.2, 128.6, 127.8, 127.7, 75.0,
74.5, 73.5, 68.4, 37.8, 36.0, 31.5, 29.9, 26.1, 18.5, 16.9, 10.7, –5.2.
IR (neat): 3450, 2956, 2930, 2857, 1458, 1363, 1090, 972, 838, 776,
736, 697, 667 cm–1.
MS (ESI): m/z (%) = 381.3 (M + H+, 100), 403.3 (M + Na+, 81),
440.4 (6), 783.5 (10).
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 5.59 (dd,
J = 15.6, 7.1 Hz, 1 H), 5.50 (dd, J = 15.6, 6.1 Hz, 1 H), 4.51 (d,
J = 12.2 Hz, 1 H), 4.49 (d, J = 12.2 Hz, 1 H), 4.18 (dd, J = 8.9, 5.5
Hz, 1 H), 3.54–3.49 (m, 2 H), 3.47 (dd, J = 9.2, 5.3 Hz, 1 H), 3.39
(dd, J = 9.7, 7.1 Hz, 1 H), 2.80 (d, J = 5.5 Hz, 1 H), 2.33 (hept,
J = 6.7 Hz, 1 H), 2.10–2.00 (m, 1 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.89
(s, 9 H), 0.89 (d, J = 7.0 Hz, 3 H), 0.04 (s, 3 H), 0.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 138.1, 134.8, 129.9, 128.6, 127.9,
127.8, 75.5, 74.0, 73.6, 68.2, 39.4, 38.8, 26.1, 18.5, 16.8, 12.1, –5.1,
–5.2.
HRMS (ESI): m/z calcd for C22H41O3Si [M + H+]: 381.2819; found:
381.2818 (–0.4 ppm); m/z calcd for C22H40O3Si + Na [M + Na+]:
403.2639; found: 403.2640 (0.2 ppm).
(+)-(2R,3S,6R)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptan-3-ol (S3)
Product S3 was prepared from 19 (0.98 g, 2.6 mmol) following the
typical procedure used to prepare S1; colorless oil; yield: 0.91 g
25
(92%); Rf = 0.18 (hexanes–EtOAc, 90:10); [a]D +24.9 (c 0.55,
CDCl3).
MS (ESI): m/z (%) = 211.1 (14), 229.2 (100), 361.3 (M – H2O + H+,
69), 377.3 (10), 757.5 (7).
IR (neat): 3435, 2954, 2930, 2857, 1742, 1456, 1363, 1253, 1093,
838, 776, 738, 698 cm–1.
HRMS (ESI): m/z calcd for C22H37O2Si [M – H2O + H+]: 361.2557;
found: 361.2561 (1.1 ppm).
1H NMR (500 MHz, CDCl3): d = 7.38–7.27 (m, 5 H), 4.53 (d,
J = 12.2 Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 3.61 (dd, J = 9.2, 4.3
Hz, 1 H), 3.54–3.44 (m, 3 H), 3.36 (dd, J = 9.8, 6.4 Hz, 1 H), 3.26
(d, J = 3.9 Hz, 1 H), 1.85 (dh, J = 7.0, 4.4 Hz, 1 H), 1.62–1.53 (m,
Synthesis 2012, 44, 474–488
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Synthesis of the C1–C9 Subunit of Zincophorin and Isomers Thereof
481
3 H), 1.38 (ddd, J = 13.6, 10.8, 2.1 Hz, 1 H), 1.19–1.08 (m, 1 H),
0.92 (d, J = 7.0 Hz, 3 H), 0.89 (s, 9 H), 0.89 (d, J = 6.2 Hz, 3 H),
0.03 (s, 6 H).
(–)-(5R,8S)-5-[(R)-1-(Benzyloxy)propan-2-yl]-
2,2,3,3,8,11,11,12,12-nonamethyl-4,10-dioxa-3,11-disila-
tridecane (22)
Product 22 was prepared from S2 (1.14 g, 3.0 mmol) following the
13C NMR (100 MHz, CDCl3): d = 137.9, 128.6, 127.9, 127.8, 76.6,
typical procedure used to prepare 21; colorless oil; yield: 1.08 g
75.2, 73.6, 68.4, 38.2, 36.1, 32.4, 28.9, 26.1, 18.5, 17.1, 14.2, –5.2.
25
(73%); Rf = 0.70 (hexanes–EtOAc, 90:10); [a]D –0.2 (c 5.6,
MS (ESI): m/z (%) = 167.1 (6), 381.3 (M + H+, 100).
HRMS (ESI): m/z calcd for C22H41O3Si [M + H+]: 381.2819; found:
CDCl3).
IR (neat): 3031, 2955, 2931, 2887, 2857, 1469, 1387, 1362, 1253,
1097, 1050, 837, 774 cm–1.
381.2825 (1.5 ppm).
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.52 (d,
J = 12.0 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 3.75 (dt, J = 2.9, 6.4
Hz, 1 H), 3.48 (dd, J = 8.9, 6.6 Hz, 1 H), 3.43 (dd, J = 9.8, 5.8 Hz,
1 H), 3.37 (dd, J = 9.7, 6.4 Hz, 1 H), 3.27 (dd, J = 8.8, 7.0 Hz, 1 H),
1.91 (dh, J = 3.0, 6.8 Hz, 1 H), 1.58–1.49 (m, 2 H), 1.46–1.32 (m, 2
H), 1.02–0.95 (m, 1 H), 0.93–0.90 (m, 3 H), 0.91 (s, 9 H), 0.90–0.87
(m, 3 H), 0.89 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 6 H), 0.03 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 138.9, 128.4, 127.7, 127.5, 73.4,
73.1, 72.8, 68.4, 37.7, 36.1, 32.0, 29.3, 26.13, 26.10, 18.5, 18.3,
16.9, 11.1, –3.9, –4.6, –5.19, –5.20.
(+)-(2R,3R,6R)-1-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptan-3-ol (S4)
Product S4 was prepared from 20 (0.84 g, 2.2 mmol) following the
typical procedure used to prepare S1; colorless oil; yield: 835 mg
25
(99%); Rf = 0.23 (hexanes–EtOAc, 85:15); [a]D +6.7 (c 1.1,
CDCl3).
IR (neat): 3454, 2954, 2931, 2857, 1460, 1363, 1253, 1094, 838,
776, 737, 698, 667 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.26 (m, 5 H), 4.53 (d,
J = 12.1 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 3.76–3.70 (m, 1 H),
3.53 (d, J = 5.4 Hz, 2 H), 3.45 (dd, J = 9.7, 5.9 Hz, 1 H), 3.39 (dd,
J = 9.7, 6.4 Hz, 1 H), 1.89 (ddd, J = 12.4, 5.5, 2.1 Hz, 1 H), 1.64–
1.54 (m, 2 H), 1.54–1.46 (m, 1 H), 1.44–1.33 (m, 2 H), 1.30–1.19
(m, 1 H), 0.93 (d, J = 7.1 Hz, 3 H), 0.89 (s, 9 H), 0.88 (d, J = 6.9 Hz,
3 H), 0.03 (s, 6 H).
MS (ESI): m/z (%) = 363.3 (10), 381.3 (5), 495.4 (M + H+, 100),
512.4 (17), 517.3 (M + Na+, 13).
HRMS (ESI): m/z calcd for C28H55O3Si2 [M + H+]: 495.3684;
found: 495.3674 (–2.0 ppm); m/z calcd for C28H54O3Si2 + Na [M +
Na+]: 517.3504; found: 517.3496 (–1.5 ppm).
13C NMR (100 MHz, CDCl3): d = 136.5, 128.6, 127.82, 127.75,
75.0, 74.4, 73.6, 68.5, 38.1, 36.0, 31.7, 30.0, 26.1, 18.6, 17.0, 10.9,
–5.2.
MS (ESI): m/z (%) = 381.3 (M + H+, 100).
HRMS (ESI): m/z calcd for C22H41O3Si [M + H+]: 381.2819; found:
(+)-(5S,8R)-5-[(R)-1-(Benzyloxy)propan-2-yl]-
2,2,3,3,8,11,11,12,12-nonamethyl-4,10-dioxa-3,11-disila-
tridecane (23)
Product 23 was prepared from S3 (0.83 g, 2.2 mmol) following the
typical procedure used to prepare 21; colorless oil; yield: 0.95 g
25
(88%); Rf = 0.47 (hexanes–EtOAc, 95:5); [a]D +5.7 (c 1.0,
381.2829 (2.5 ppm).
CDCl3).
IR (neat):2955, 2930, 2857, 1463, 1253, 1093, 836, 774 cm–1.
(+)-(5S,8S)-5-[(R)-1-(Benzyloxy)propan-2-yl]-
2,2,3,3,8,11,11,12,12-nonamethyl-4,10-dioxa-3,11-disila-
tridecane (21); Typical Procedure
1H NMR (500 MHz, CDCl3): d = 7.38–7.25 (m, 5 H), 4.52 (d,
J = 12.1 Hz, 1 H), 4.47 (d, J = 12.1 Hz, 1 H), 3.67 (dd, J = 10.3, 5.2
Hz, 1 H), 3.50 (dd, J = 9.2, 5.6 Hz, 1 H), 3.44 (dd, J = 9.7, 5.5 Hz,
1 H), 3.37 (ddd, J = 9.8, 6.2, 3.3 Hz, 1 H), 3.30 (dd, J = 9.1, 7.1 Hz,
1 H), 1.95 (hept, J = 6.7 Hz, 1 H), 1.57–1.33 (m, 4 H), 1.12–1.00 (m,
1 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.87 (d,
J = 6.6 Hz, 3 H), 0.05 (s, 3 H), 0.044 (s, 6 H), 0.038 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 139.0, 128.4, 127.6, 127.5, 74.0,
73.1, 72.9, 68.4, 38.6, 36.3, 30.8, 28.7, 26.13, 26.10, 18.5, 18.3,
17.1, 13.5, –4.1, –4.5, –5.19, –5.20.
MS (ESI): m/z (%) = 167.1 (14), 363.3 (15), 495.4 (M + H+, 100),
496.4 (27).
HRMS (ESI): m/z calcd for C28H55O3Si2 [M + H+]: 495.3684;
found: 495.3687 (0.6 ppm).
To a cold (0 °C) solution of alcohol S1 (564 mg, 1.5 mmol) in anhyd
CH2Cl2 (0.1 M, 15 mL) was added successively 2,6-lutidine (0.35
mL, 3.0 mmol, 2.05 equiv) and TBSOTf (0.51 mL, 2.2 mmol, 1.5
equiv). The reaction mixture was stirred for 1.5 h at 0 °C or until al-
cohol was completely consumed as verified by TLC. The reaction
mixture was then treated with sat. aq NaHCO3 (10 mL) followed by
separation of the organic phase at r.t. The aqueous layer was extract-
ed with CH2Cl2 (3 × 10 mL) and the combined organic fractions
were dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (hex-
anes–EtOAc, 95:5); colorless oil; yield: 0.72 g (98%); Rf = 0.49
(hexanes–EtOAc, 95:5); [a]D25 +1.1 (c 1.8, CDCl3).
IR (neat): 2955, 2930, 2857, 1463, 1254, 1095, 836, 774 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.35–7.29 (m, 5 H), 4.52 (d,
J = 12.1 Hz, 1 H), 4.48 (d, J = 12.1 Hz, 1 H), 3.66 (dd, J = 10.2, 5.2
Hz, 1 H), 3.47 (dd, J = 5.7, 9.1 Hz, 1 H), 3.43 (dd, J = 5.9, 9.7 Hz,
1 H), 3.35 (dd, J = 6.6, 9.7 Hz, 1 H), 3.28 (dd, J = 7.2, 9.0 Hz, 1 H),
1.96 (hept, J = 6.4 Hz, 1 H), 1.55–1.49 (m, 1 H), 1.49–1.36 (m, 2
H), 1.36–1.23 (m, 1 H), 1.16–1.06 (m, 1 H), 0.92 (d, J = 6.9 Hz, 3
H), 0.89 (s, 9 H), 0.87 (s, 9 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.03 (s, 9
H), 0.02 (s, 3 H).
(+)-(5R,8R)-5-[(R)-1-(Benzyloxy)propan-2-yl]-
2,2,3,3,8,11,11,12,12-nonamethyl-4,10-dioxa-3,11-disila-
tridecane (24)
Product 24 was prepared from S4 (1.11 g, 2.9 mmol) following the
typical procedure used to prepare 21; colorless oil; yield: 1.41 g
25
(98%); Rf = 0.48 (hexanes–EtOAc, 95:5); [a]D +1.5 (c 1.1,
CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 138.9, 128.3, 127.5, 127.4, 73.8,
73.0, 72.8, 68.6, 38.7, 36.1, 30.4, 28.6, 25.98, 25.95, 18.4, 18.1,
16.6, 13.1, –4.3, –4.6, –5.3.
MS (ESI): m/z (%) = 363.3 (15), 495.4 (M + H+, 100).
HRMS (ESI): m/z calcd for C28H55O3Si2 [M + H+]: 495.3684;
IR (neat): 2955, 2930, 2887, 2857, 1362, 1253, 1097, 1049, 836,
774 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36–7.27 (m, 5 H), 4.52 (d,
J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 3.72 (dt, J = 2.9, 6.3
Hz, 1 H), 3.48 (dd, J = 8.8, 6.6 Hz, 1 H), 3.43 (dd, J = 9.7, 5.8 Hz,
1 H), 3.36 (dd, J = 9.7, 6.4 Hz, 1 H), 3.26 (dd, J = 8.6, 7.3 Hz, 1 H),
1.89 (dh, J = 6.8, 2.9 Hz, 1 H), 1.58–1.47 (m, 1 H), 1.47–1.39 (m, 2
H), 1.37–1.28 (m, 1 H), 1.11–0.98 (m, 1 H), 0.89 (s, 9 H), 0.88 (d,
found: 495.3691 (1.4 ppm).
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Synthesis 2012, 44, 474–488

482
F. Godin et al.
PAPER
J = 6.9 Hz, 3 H), 0.87 (s, 9 H), 0.86 (d, J = 6.8 Hz, 3 H), 0.03 (s, 9
H), 0.02 (s, 3 H).
IR (neat): 3368, 2954, 2930, 2857, 1459, 1363, 1253, 1075, 1043,
836, 774, 735, 697 cm–1.
13C NMR (125 MHz, CDCl3): d = 138.9, 128.4, 127.7, 127.5, 73.3,
73.10, 73.05, 68.3, 37.9, 36.2, 32.0, 29.4, 26.1, 18.5, 18.3, 17.0,
11.3, –3.9, –4.5, –5.2.
MS (ESI): m/z (%) = 363.3 (16), 495.4 (M + H+, 100), 496.4 (29).
HRMS (ESI): m/z calcd for C28H55O3Si2 [M + H+]: 495.3684;
1H NMR (500 MHz, CDCl3): d = 7.38–7.26 (m, 5 H), 4.51 (d,
J = 12.1 Hz, 1 H), 4.45 (d, J = 12.1 Hz, 1 H), 3.67 (dd, J = 10.1, 5.3
Hz, 1 H), 3.53–3.45 (m, 2 H), 3.40 (dd, J = 10.4, 6.6 Hz, 1 H), 3.28
(dd, J = 9.2, 6.8 Hz, 1 H), 1.98 (hept, J = 6.6 Hz, 1 H), 1.61–1.52
(m, 1 H), 1.50–1.41 (m, 2 H), 1.41–1.30 (m, 1 H), 1.18–1.08 (m, 1
H), 0.92 (d, J = 6.1 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3 H), 0.88 (s, 9 H),
0.04 (s, 3 H), 0.03 (s, 3 H). One signal missing (OH) presumably
due to proton exchange in CDCl3.
13C NMR (125 MHz, CDCl3): d = 138.9, 128.4, 127.7, 127.6, 73.9,
73.1, 72.7, 68.3, 38.5, 36.1, 30.4, 28.5, 26.1, 18.3, 16.9, 13.5, –4.1,
–4.5.
MS (ESI): m/z (%) = 167.1 (60), 249.2 (73), 381.3 (M + H+, 100),
547.4 (25).
found: 495.3689 (0.9 ppm).
(–)-(2S,5S,6R)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptan-1-ol (S5)
Primary alcohol S5 was obtained from bis-TBS product 21 (503 mg,
1.0 mmol) following general procedure A1; colorless oil; yield:
0.33 g (85%); Rf = 0.29 (hexanes–EtOAc, 80:20); [a]D25 –3.0 (c 1.3,
CDCl3).
IR (neat): 3372, 2954, 2929, 2857, 1460, 1363, 1253, 1074, 1044,
943, 836, 774, 735, 697, 669 cm–1.
HRMS (ESI): m/z calcd for C22H41O3Si [M + H+]: 381.2819; found:
381.2824 (1.1 ppm).
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.51 (d,
J = 12.1 Hz, 1 H), 4.45 (d, J = 12.1 Hz, 1 H), 3.68 (dd, J = 10.5, 5.0
Hz, 1 H), 3.52–3.44 (m, 2 H), 3.44–3.38 (m, 1 H), 3.27 (dd, J = 6.7,
9.1 Hz, 1 H), 1.98 (hept, J = 6.1 Hz, 1 H), 1.53–1.33 (m, 3 H), 1.31–
1.24 (m, 1 H), 1.22–1.10 (m, 1 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.90
(d, J = 6.7 Hz, 3 H), 0.87 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 138.8, 128.3, 127.5, 127.4, 73.7,
73.0, 72.7, 68.3, 38.5, 36.0, 30.4, 28.4, 25.9, 18.1, 16.6, 13.2, –4.3,
–4.6.
(–)-(2R,5R,6R)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptan-1-ol (S8)
Primary alcohol S8 was obtained from bis-TBS product 24 (387 mg,
0.78 mmol) following general procedure A1. Colorless oil; yield:
25
213 mg (72%); Rf = 0.32 (hexanes–EtOAc, 80:20); [a]D –1.6 (c
0.9, CH2Cl2).
IR (neat): 3369, 2954, 2928, 2856, 1459, 1377, 1252, 1100, 1044,
835, 773, 735, 697 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36–7.27 (m, 5 H), 4.52 (d,
J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 3.73 (dt, J = 3.1, 6.3
Hz, 1 H), 3.53–3.48 (m, 1 H), 3.47 (dd, J = 8.8, 6.6 Hz, 1 H), 3.44–
3.37 (m, 1 H), 3.26 (dd, J = 8.8, 6.9 Hz, 1 H), 1.89 (dh, J = 3.1, 6.8
Hz, 1 H), 1.62–1.52 (m, 1 H), 1.48–1.41 (m, 2 H), 1.39–1.30 (m, 1
H), 1.28 (t, J = 5.7 Hz, 1 H), 1.16–1.08 (m, 1 H), 0.91 (d, J = 6.7 Hz,
3 H), 0.88 (d, J = 6.1 Hz, 3 H), 0.87 (s, 9 H), 0.04 (s, 3 H), 0.02 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 138.8, 128.4, 127.7, 127.6, 77.3,
73.2, 72.9, 68.3, 37.9, 36.1, 31.8, 29.2, 26.1, 18.3, 16.8, 11.4, –3.9,
–4.5.
MS (ESI): m/z (%) = 141.1 (20), 249.2 (69), 381.3 (M + H+, 100).
HRMS (ESI): m/z calcd for C22H41O3Si [M + H+]: 381.2819; found:
MS (ESI): m/z (%) = 141.1 (12), 233.2 (10), 249.2 (90), 381.3 (M +
H+, 100).
HRMS (ESI): m/z calcd for C22H41O3Si [M + H+]: 381.2819; found:
381.2824 (1.2 ppm).
(–)-(2S,5R,6R)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptan-1-ol (S6)
Primary alcohol S6 was obtained from bis-TBS product 22 (1.08 g,
2.2 mmol) following general procedure A1; colorless oil; yield:
0.44 g (53%); Rf = 0.09 (hexanes–EtOAc, 90:10); [a]D25 –3.2 (c 1.1,
CDCl3).
IR (neat): 3359, 2954, 2930, 2857, 1460, 1362, 1252, 1102, 1047,
836, 774 cm–1.
381.2823 (1.0 ppm).
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.51 (d,
J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 3.75 (dt, J = 3.0, 6.8
Hz, 1 H), 3.51–3.44 (m, 1 H), 3.46 (dd, J = 8.8, 6.9 Hz, 1 H), 3.40
(t, J = 8.2 Hz, 1 H), 3.26 (dd, J = 8.8, 6.8 Hz, 1 H), 1.89 (dh, J = 3.1,
6.8 Hz, 1 H), 1.60–1.50 (m, 2 H), 1.45–1.32 (m, 2 H), 1.29–1.22 (m,
1 H), 1.07–0.97 (m, 1 H), 0.91 (d, J = 6.7 Hz, 3 H), 0.87 (s, 9 H),
0.87 (d, J = 6.6 Hz, 3 H), 0.04 (s, 3 H), 0.02 (s, 3 H). One signal was
missing (OH) presumably due to proton exchange in CDCl3.
(+)-(2S,5S,6R)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptanal (25); Typical Procedure
To a solution of alcohol S5 (377 mg, 0.99 mmol) in anhyd CH2Cl2
(0.1 M, 10 mL) was added successively NaHCO3 (0.83 g, 9.9 mmol,
10 equiv) and Dess–Martin periodinane (0.63 g, 1.5 mmol, 1.5
equiv). The mixture was stirred for 30 min at r.t. and then concen-
trated. The product was digested from white solid residue in hex-
anes (3 × 10 mL) and filtered onto a pad of Celite. The filtrate was
concentrated in vacuo and purified by flash chromatography on sil-
ica gel (hexanes–EtOAc, 85:15); colorless oil; yield: 366 mg (98%);
Rf = 0.58 (hexanes–EtOAc, 80:20); [a]D25 +5.8 (c 1.3, CDCl3).
13C NMR (125 MHz, CDCl3): d = 138.9, 128.5, 127.8, 127.6, 73.3,
73.2, 72.7, 68.5, 44.9, 37.6, 36.1, 32.0, 29.2, 26.1, 18.3, 16.7, 11.1,
–3.9, –4.5.
MS (ESI): m/z (%) = 249.2 (35), 338.3 (5), 381.3 (M + H+, 100),
403.3 (M + Na+, 70).
IR (neat):2956, 2856, 1727, 1459, 1254, 1074, 836 cm–1.
HRMS (ESI): m/z calcd for C22H41O3Si [M + H+]: 381.2819; found:
381.2814 (–1.3 ppm); m/z calcd for C22H40O3Si + Na [M + Na+]:
403.2639; found: 403.2637 (–0.6 ppm).
1H NMR (400 MHz, CDCl3): d = 9.58 (d, J = 2.0 Hz, 1 H), 7.38–
7.26 (m, 5 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.44 (d, J = 12.1 Hz, 1 H),
3.74–3.68 (m, 1 H), 3.43 (dd, J = 9.2, 6.2 Hz, 1 H), 3.28 (dd, J = 9.2,
6.5 Hz, 1 H), 2.33–2.23 (m, 1 H), 1.98 (hept, J = 6.5 Hz, 1 H), 1.78–
1.63 (m, 1 H), 1.52–1.34 (m, 3 H), 1.07 (d, J = 7.0 Hz, 3 H), 0.90
(d, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 205.3, 138.8, 128.4, 127.63,
127.59, 73.1, 72.7, 46.5, 38.7, 30.0, 26.2, 26.0, 18.2, 13.4, 12.9,
–4.2, –4.4.
(+)-(2R,5S,6R)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptan-1-ol (S7)
Primary alcohol S7 was obtained from bis-TBS product 23 (837 mg,
1.7 mmol) following general procedure A1; colorless oil; yield: 519
25
mg (81%); Rf = 0.24 (hexanes–EtOAc, 85:15); [a]D +7.3 (c 1.0,
CDCl3).
Synthesis 2012, 44, 474–488
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Synthesis of the C1–C9 Subunit of Zincophorin and Isomers Thereof
483
MS (ESI): m/z (%) = 401.2 (M + Na+, 100).
HRMS (ESI): m/z calcd for C22H38O3Si + Na [M + Na+]: 401.2482;
J = 3.2, 6.8 Hz, 1 H), 1.69–1.59 (m, 1 H), 1.53–1.35 (m, 3 H), 1.08
(d, J = 7.0 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s,
3 H), 0.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.1, 138.7, 128.4, 127.7, 127.6,
73.2, 72.9, 72.5, 46.5, 38.1, 31.8, 26.9, 26.0, 18.3, 13.6, 11.5, –4.0,
–4.5.
found: 401.2474.
(+)-(2S,5R,6R)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptanal (26)
Aldehyde 26 was obtained from alcohol S6 (398 mg, 1.0 mmol) fol-
lowing the typical procedure used to prepare 25; colorless oil; yield:
387 mg (98%); Rf = 0.41 (hexanes–EtOAc, 90:10); [a]D +5.2 (c
1.5, CH2Cl2).
MS (ESI): m/z (%) = 155.1 (25), 233.2 (37), 247.2 (100), 263.2
(35), 351.3 (15), 379.3 (M + H+, 44), 395.3 (75).
25
HRMS (ESI): m/z calcd for C22H39O3Si [M + H+]: 379.2663; found:
379.2671 (2.1 ppm).
IR (neat): 2956, 2930, 2856, 1726, 1461, 1361, 1252, 1100, 1049
cm–1.
Ethyl (+)-(4S,7S,8R,E)-9-(Benzyloxy)-7-(tert-butyldimethyl-
silyloxy)-2,4,8-trimethylnon-2-enoate (S9); Typical Procedure
To a solution of aldehyde 25 (280 mg, 0.74 mmol) in toluene (0.1
M, 7.4 mL) at r.t. was added (carbethoxyethylidene)triphenylphos-
phorane (0.40 g, 1.1 mmol, 1.5 equiv), followed by stirring and
warming to reflux for 18 h. The mixture was then cooled and con-
centrated. The product was digested from dark yellow residue in
hexanes and filtered onto a pad of Celite. The filtrate was concen-
trated in vacuo and purified by flash chromatography on silica gel
(hexanes–EtOAc, 95:5); pale yellow oil; yield: 244 mg (72%); Rf =
0.70 (hexanes–EtOAc, 90:10); [a]D25 +10.9 (c 1.1, CDCl3).
1H NMR (500 MHz, CDCl3): d = 9.58 (d, J = 1.9 Hz, 1 H), 7.37–
7.26 (m, 5 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H),
3.76 (dt, J = 3.3, 6.3 Hz, 1 H), 3.46 (dd, J = 8.9, 6.7 Hz, 1 H), 3.26
(dd, J = 8.9, 6.7 Hz, 1 H), 2.29 (dh, J = 1.8, 6.9 Hz, 1 H), 1.93–1.84
(m, 1 H), 1.79–1.68 (m, 1 H), 1.51 (ddd, J = 17.9, 11.5, 5.6 Hz, 1
H), 1.40 (ddd, J = 13.1, 11.1, 5.5 Hz, 1 H), 1.34–1.23 (m, 1 H), 1.09
(d, J = 7.0 Hz, 3 H), 0.88 (d, J = 7.5 Hz, 3 H), 0.87 (s, 9 H), 0.04 (s,
3 H), 0.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.1, 138.8, 128.5, 127.7, 127.6,
73.2, 73.0, 72.5, 46.5, 38.0, 31.8, 26.8, 26.1, 18.3, 13.5, 11.5, –4.0,
–4.5.
IR (neat): 2957, 2932, 2857, 1711, 1649, 1458, 1366, 1255, 1198,
1097, 941, 836, 774, 719, 698 cm–1.
MS (ESI): m/z (%) = 247.2 (25), 379.3 (M + H+, 12), 401.2 (M + H+,
81), 433.3 (100).
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 6.55 (dd,
J = 1.4, 10.1 Hz, 1 H), 4.52 (d, J = 12.1 Hz, 1 H), 4.47 (d, J = 12.1
Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 3.67 (dd, J = 5.4, 9.7 Hz, 1 H),
3.48 (dd, J = 5.6, 9.1 Hz, 1 H), 3.30 (dd, J = 6.8, 9.1 Hz, 1 H), 2.49–
2.40 (m, 1 H), 2.00–1.91 (m, 1 H), 1.85 (d, J = 1.4 Hz, 3 H), 1.52–
1.33 (m, 4 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.02 (d, J = 6.7 Hz, 3 H),
0.93 (d, J = 7.0 Hz, 3 H), 0.90 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 168.3, 147.8, 138.7, 128.2, 127.4,
127.3, 126.4, 73.3, 72.9, 72.6, 60.3, 45.0, 38.4, 33.5, 31.8, 30.8,
25.9, 20.0, 18.1, 14.3, 13.2, 12.5, –4.3, –4.7.
HRMS (ESI): m/z calcd for C22H39O3Si [M + H+]: 379.2663; found:
379.2662 (–0.2 ppm); m/z calcd for C22H38O3Si + Na [M + Na+]:
401.2482; found: 401.2483 (0.1 ppm).
(2R,5S,6R)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-2,6-
dimethylheptanal (27)
Aldehyde 27 was obtained from alcohol S7 (434 mg, 1.1 mmol) fol-
lowing the typical procedure used to prepare 25; colorless oil; yield:
402 mg (93%); Rf = 0.48 (hexanes–EtOAc, 90:10).
IR (neat): 2956, 2931, 2857, 1726, 1459, 1363, 1254, 1074, 836,
774, 736, 698 cm–1.
MS (ESI): m/z (%) = 223.2 (8), 331.2 (29), 463.3 (M + H+, 100).
HRMS (ESI): m/z calcd for C27H47O4Si [M + H+]: 463.3238; found:
1H NMR (500 MHz, CDCl3): d = 9.58 (d, J = 1.9 Hz, 1 H), 7.37–
7.26 (m, 5 H), 4.51 (d, J = 12.1 Hz, 1 H), 4.44 (d, J = 12.1 Hz, 1 H),
3.71 (q, J = 5.1 Hz, 1 H), 3.44 (dd, J = 9.2, 6.1 Hz, 1 H), 3.29 (dd,
J = 9.1, 6.6 Hz, 1 H), 2.29 (dh, J = 1.7, 6.7 Hz, 1 H), 1.98 (hept,
J = 6.5 Hz, 1 H), 1.83–1.73 (m, 1 H), 1.45–1.34 (m, 3 H), 1.07 (d,
J = 7.1 Hz, 3 H), 0.90 (d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H), 0.042 (s, 3
H), 0.037 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.3, 138.8, 128.5, 127.63,
127.59, 73.2, 73.1, 72.7, 46.6, 38.7, 30.2, 26.2, 26.0, 18.2, 13.6,
13.0, –4.2, –4.4.
463.3225 (–2.9 ppm).
Ethyl (–)-(4S,7R,8R,E)-9-(Benzyloxy)-7-(tert-butyldimethyl-
silyloxy)-2,4,8-trimethylnon-2-enoate (S10)
Product S10 was prepared from 26 (393 mg, 1.0 mmol) following
the typical procedure used to prepare S9; pale yellow oil; yield: 290
mg (60%); Rf = 0.53 (hexanes–EtOAc, 95:5); [a]D –1.4 (c 0.3,
CDCl3).
25
IR (neat): 2956, 2930, 2856, 1712, 1457, 1364, 1253, 1100, 1044,
836, 774, 749, 697 cm–1.
MS (ESI): m/z (%) = 155.1 (19), 233.2 (25), 247.2 (55), 263.2 (44),
1H NMR (500 MHz, CDCl3): d = 7.36–7.25 (m, 5 H), 6.51 (dd,
J = 10.1, 1.2 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.44 (d, J = 12.0
Hz, 1 H), 4.18 (dq, J = 1.8, 7.1 Hz, 2 H), 3.75–3.69 (m, 1 H), 3.44
(dd, J = 8.8, 6.8 Hz, 1 H), 3.24 (dd, J = 8.8, 6.8 Hz, 1 H), 2.47–2.38
(m, 1 H), 1.88–1.81 (m, 1 H), 1.82 (d, J = 1.2 Hz, 3 H), 1.47–1.37
(m, 1 H), 1.36–1.24 (m, 3 H), 1.29 (t, J = 7.1 Hz, 3 H), 0.99 (d,
J = 6.7 Hz, 3 H), 0.86 (s, 9 H), 0.85 (d, J = 7.1 Hz, 3 H), 0.01 (s, 3
H), 0.00 (s, 3 H).
379.3 (M + H+, 43), 395.3 (100).
HRMS (ESI): m/z calcd for C22H39O3Si [M + H+]: 379.2663; found:
379.2672 (2.3 ppm).
(2R,5R,6R)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-2,6-
dimethylheptanal (28)
Aldehyde 28 was obtained from alcohol S8 (293 mg, 0.77 mmol)
following the typical procedure used to prepare 25; colorless oil;
yield: 262 mg (90%); Rf = 0.41 (hexanes–EtOAc, 90:10).
13C NMR (125 MHz, CDCl3): d = 168.5, 147.8, 138.9, 128.5, 127.7,
127.6, 126.7, 73.2, 73.2, 72.5, 60.5, 44.9, 37.9, 33.4, 32.9, 32.3,
26.1, 20.1, 18.3, 14.5, 12.7, 11.2, –4.0, –4.5.
IR (neat): 2956, 2931, 2857, 1727, 1459, 1363, 1253, 1100, 1048,
836, 774, 736, 697 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.60 (d, J = 1.8 Hz, 1 H), 7.38–
7.26 (m, 5 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H),
3.76 (dt, J = 3.4, 6.1 Hz, 1 H), 3.47 (dd, J = 8.8, 6.7 Hz, 1 H), 3.26
(dd, J = 8.8, 6.7 Hz, 1 H), 2.30 (dh, J = 1.5, 6.9 Hz, 1 H), 1.90 (dh,
MS (ESI): m/z (%) = 463.3 (M + H+, 100), 480.3 (61), 485.3 (M +
Na+, 51).
HRMS (ESI): m/z calcd for C27H47O4Si [M + H+]: 463.3238; found:
463.3234 (–0.8 ppm); m/z calcd for C27H46O4Si + Na [M + Na+]:
485.3058; found: 485.3051 (–1.4 ppm).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 474–488

484
F. Godin et al.
PAPER
Ethyl (–)-(4R,7S,8R,E)-9-(Benzyloxy)-7-(tert-butyldimethyl-
silyloxy)-2,4,8-trimethylnon-2-enoate (S11)
13C NMR (100 MHz, CDCl3): d = 168.5, 147.9, 137.6, 128.5, 127.8,
127.6, 126.4, 76.4, 75.2, 73.5, 60.4, 38.2, 33.5, 32.8, 32.6, 20.0,
14.3, 14.0, 12.6.
Product S11 was prepared from 27 (387 mg, 1.0 mmol) following
the typical procedure used to prepare S9. Pale yellow oil; yield: 369
MS (ESI): m/z (%) = 223.2 (6), 285.2 (8), 331.2 (13), 349.2 (M +
25
mg (78%); Rf = 0.30 (hexanes–EtOAc, 95:5); [a]D –6.2 (c 1.0,
H+, 100).
CH2Cl2).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2366 (–2.1 ppm).
IR (neat): 2957, 2931, 2857, 1711, 1457, 1366, 1254, 1198, 1098,
836, 774 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 6.52 (dd,
J = 10.0, 1.2 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 4.44 (d, J = 12.1
Hz, 1 H), 4.18 (dq, J = 1.1, 7.1 Hz, 2 H), 3.65 (q, J = 5.0 Hz, 1 H),
3.45 (dd, J = 9.2, 5.8 Hz, 1 H), 3.27 (dd, J = 9.1, 6.8 Hz, 1 H), 2.47–
2.36 (m, 1 H), 1.94 (hept, J = 6.1 Hz, 1 H), 1.82 (s, 3 H), 1.45–1.32
(m, 4 H), 1.29 (t, J = 7.1 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 0.89 (d,
J = 7.0 Hz, 3 H), 0.87 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.5, 148.0, 138.9, 128.4, 127.6,
127.5, 126.6, 73.5, 73.1, 72.7, 60.5, 38.6, 33.5, 32.2, 30.9, 26.0,
20.2, 18.2, 14.4, 13.3, 12.7, –4.2, –4.5.
Ethyl (+)-(4S,7R,8R,E)-9-(Benzyloxy)-7-hydroxy-2,4,8-trimeth-
ylnon-2-enoate (30)
Primary alcohol 30 was obtained from TBS-protected alcohol S10
(394 mg, 0.85 mmol) following general procedure A1; colorless oil;
25
yield: 219 mg (74%); Rf = 0.41 (hexanes–EtOAc, 70:30); [a]D
+180 (c 0.7, CDCl3).
IR (neat): 3505, 2960, 2932, 2868, 1707, 1649, 1454, 1367, 1257,
1194, 1099, 747, 699 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.27 (m, 5 H), 6.54 (dd,
J = 10.1, 1.2 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.49 (d, J = 12.0
Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 3.72 (dt, J = 4.3, 7.9 Hz, 1 H),
3.54–3.48 (m, 2 H), 2.54 (d, J = 4.6 Hz, 1 H), 2.57–2.45 (m, 1 H),
1.90–1.84 (m, 1 H), 1.83 (d, J = 1.3 Hz, 3 H), 1.55–1.46 (m, 1 H),
1.46–1.37 (m, 2 H), 1.37–1.31 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H),
1.01 (d, J = 6.7 Hz, 3 H), 0.91 (d, J = 7.1 Hz, 3 H).
MS (ESI): m/z (%) = 145.1 (5), 191.1 (12), 223.2 (9), 331.2 (32),
463.3 (M + H+, 3).
HRMS (ESI): m/z calcd for C27H47O4Si [M + H+]: 463.3238; found:
463.3243 (1.0 ppm).
Ethyl (–)-(4R,7R,8R,E)-9-(Benzyloxy)-7-(tert-butyldimethyl-
silyloxy)-2,4,8-trimethylnon-2-enoate (S12)
Product S12 was prepared from 28 (268 mg, 0.71 mmol) following
13C NMR (125 MHz, CDCl3): d = 168.6, 147.8, 138.1, 128.6, 127.9,
127.7, 126.7, 74.9, 74.2, 73.6, 60.6, 38.0, 33.5, 33.3, 31.8, 20.3,
14.5, 12.7, 10.9.
the typical procedure used to prepare S9; pale yellow oil; yield: 177
mg (54%); Rf = 0.34 (hexanes–EtOAc, 95:5); [a]D –15.5 (c 1.2,
CH2Cl2).
MS (ESI): m/z (%) = 223.2 (5), 331.2 (11), 349.2 (M + H+, 100),
25
371.2 (M + Na+, 82), 408.3 (5), 719.4 (7).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2369 (–1.3 ppm); m/z calcd for C21H32O4 + Na [M + Na+]:
371.2193; found: 371.2190 (–0.7 ppm).
IR (neat): 2956, 2931, 2857, 1711, 1458, 1365, 1255, 1198, 1099,
1046, 836, 774, 749 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.27 (m, 5 H), 6.52 (dd,
J = 10.1, 1.1 Hz, 1 H), 4.51 (d, J = 11.9 Hz, 1 H), 4.45 (d, J = 11.9
Hz, 1 H), 4.19 (dq, J = 1.0, 7.0 Hz, 2 H), 3.73 (dt, J = 3.3, 6.2 Hz, 1
H), 3.45 (dd, J = 8.8, 6.9 Hz, 1 H), 3.25 (dd, J = 8.8, 6.7 Hz, 1 H),
2.49–2.37 (m, 1 H), 1.86 (dh, J = 3.1, 6.8 Hz, 1 H), 1.82 (d, J = 1.1
Hz, 3 H), 1.44–1.33 (m, 3 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.28–1.21
(m, 1 H), 0.98 (d, J = 6.7 Hz, 3 H), 0.87 (s, 9 H), 0.85 (d, J = 7.0 Hz,
3 H), 0.02 (s, 3 H), 0.01 (s, 3 H).
Ethyl (–)-(4R,7S,8R,E)-9-(Benzyloxy)-7-hydroxy-2,4,8-trimeth-
ylnon-2-enoate (31)
Primary alcohol 31 was obtained TBS-protected alcohol S11 (677
mg, 1.5 mmol) following general procedure A1; colorless oil; yield:
413 mg (81%); Rf = 0.25 (hexanes–EtOAc, 80:20); [a]D25 –33.4 (c
1.0, CH2Cl2).
IR (neat): 3493, 2960, 2931, 2868, 1707, 1648, 1454, 1367, 1258,
1098, 749, 699 cm–1.
13C NMR (100 MHz, CDCl3): d = 168.5, 147.8, 138.8, 128.4, 127.7,
127.6, 126.7, 73.1, 72.3, 60.5, 37.7, 33.4, 33.0, 32.4, 26.1, 20.3,
18.3, 14.4, 12.7, 11.2, –4.0, –4.6.
1H NMR (500 MHz, CDCl3): d = 7.38–7.27 (m, 5 H), 6.54 (dd,
J = 10.1, 1.1 Hz, 1 H), 4.53 (d, J = 13.3 Hz, 1 H), 4.49 (d, J = 12.1
Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 3.60 (dd, J = 9.2, 4.0 Hz, 1 H),
3.55–3.45 (m, 1 H), 3.45 (dd, J = 9.0, 7.9 Hz, 1 H), 3.40 (d, J = 3.6
Hz, 1 H), 2.56–2.44 (m, 1 H), 1.88–1.78 (m, 1 H), 1.83 (d, J = 1.0
Hz, 3 H), 1.54–1.41 (m, 3 H), 1.39–1.31 (m, 1 H), 1.29 (t, J = 7.1
Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 7.0 Hz, 3 H).
MS (ESI): m/z (%) = 191.1 (5), 223.2 (12), 233.2 (9), 331.2 (35),
463.3 (M + H+, 100).
HRMS (ESI): m/z calcd for C27H47O4Si [M + H+]: 463.3238; found:
463.3240 (0.4 ppm).
Ethyl (–)-(4S,7S,8R,E)-9-(Benzyloxy)-7-hydroxy-2,4,8-trimeth-
ylnon-2-enoate (29)
13C NMR (125 MHz, CDCl3): d = 168.6, 147.9, 137.9, 128.6, 128.0,
127.8, 126.7, 76.2, 75.4, 73.7, 60.5, 38.4, 33.4, 32.9, 32.5, 20.4,
14.5, 14.2, 12.8.
Primary alcohol 29 was obtained from TBS-protected alcohol S9
(483 mg, 1.0 mmol) following general procedure A1; colorless oil;
MS (ESI): m/z (%) = 195.1 (7), 303.2 (11), 331.2 (16), 349.2 (M +
25
yield: 254 mg (70%); Rf = 0.21 (hexanes–EtOAc, 80:20); [a]D
–6.1 (c 0.8, CDCl3).
H+, 100).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2382 (2.4 ppm).
IR (neat): 3501, 3030, 2960, 2930, 2868, 1708, 1649, 1454, 1367,
1259, 1193, 1098, 1029, 991, 749, 699 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 6.54 (dd,
J = 1.2, 10.1 Hz, 1 H), 4.54 (d, J = 12.1 Hz, 1 H), 4.52 (d, J = 12.1
Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 3.60 (dd, J = 4.0, 9.2 Hz, 1 H),
3.53–3.44 (m, 1 H), 3.45 (dd, J = 7.6, 9.2 Hz, 1 H), 3.38 (d, J = 3.7
Hz, 1 H), 2.54–2.42 (m, 1 H), 1.89–1.77 (m, 1 H), 1.83 (d, J = 1.2
Hz, 3 H), 1.70–1.60 (m, 1 H), 1.53–1.40 (m, 1 H), 1.40–1.31 (m, 2
H), 1.29 (t, J = 7.1 Hz, 3 H), 1.01 (d, J = 6.7 Hz, 3 H), 0.89 (d,
J = 7.0 Hz, 3 H).
Ethyl (–)-(4R,7R,8R,E)-9-(Benzyloxy)-7-hydroxy-2,4,8-tri-
methylnon-2-enoate (32)
Primary alcohol 32 was obtained from TBS-protected alcohol S12
(139 mg, 0.30 mmol) following general procedure A1; colorless oil;
yield: 80.5 mg (77%); Rf = 0.24 (hexanes–EtOAc, 80:20); [a]D
–10.6 (c 1.5, CH2Cl2).
25
Synthesis 2012, 44, 474–488
© Thieme Stuttgart · New York

PAPER
Synthesis of the C1–C9 Subunit of Zincophorin and Isomers Thereof
485
IR (neat): 3488, 2959, 2928, 2855, 1706, 1639, 1453, 1365, 1255,
1189, 1097, 747, 697 cm–1.
Hz, 1 H), 4.07 (dq, J = 10.8, 7.1 Hz, 1 H), 3.43–3.36 (m, 1 H), 3.388
(d, J = 9.1 Hz, 1 H), 3.392 (dd, J = 9.2, 5.8 Hz, 1 H), 3.26 (dd,
J = 9.1, 6.3 Hz, 1 H), 2.05 (s, 3 H), 1.80–1.70 (m, 2 H), 1.69–1.59
(m, 1 H), 1.55–1.49 (m, 1 H), 1.46–1.34 (m, 2 H), 1.27 (t, J = 7.1
Hz, 3 H), 1.14 (d, J = 6.7 Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 172.3, 138.8, 128.5, 127.63,
127.60, 86.3, 79.1, 73.2, 73.1, 61.9, 44.9, 38.9, 35.2, 33.7, 29.2,
27.0, 20.1, 13.9, 12.5.
MS (ESI): m/z (%) = 369.2 (4), 475.1 (M + H+, 14), 497.1 (M + Na+,
100), 498.1 (19).
HRMS (ESI): m/z calcd for C21H32IO4 [M + H+]: 475.1340; found:
475.1341 (0.3 ppm); m/z calcd for C21H31IO4 + Na [M + Na+]:
497.1159; found: 497.1155 (–0.8 ppm).
1H NMR (500 MHz, CDCl3): d = 7.37–7.27 (m, 5 H), 6.53 (dd,
J = 10.1, 1.1 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H), 4.49 (d, J = 12.0
Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 3.71 (ddd, J = 8.4, 6.5, 4.1 Hz,
1 H), 3.54–3.48 (m, 2 H), 2.58 (d, J = 4.5 Hz, 1 H), 2.54–2.43 (m, 1
H), 1.90–1.81 (m, 1 H), 1.83 (d, J = 1.1 Hz, 3 H), 1.68–1.60 (m, 1
H), 1.45–1.35 (m, 1 H), 1.34–1.24 (m, 2 H), 1.29 (t, J = 7.1 Hz, 3
H), 1.01 (d, J = 6.7 Hz, 3 H), 0.91 (d, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 168.6, 147.9, 138.1, 128.6, 127.9,
127.8, 126.7, 74.9, 74.5, 73.6, 60.6, 38.0, 33.8, 33.6, 32.1, 20.3,
14.5, 12.8, 10.8.
MS (ESI): m/z (%) = 223.2 (12), 285.2 (7), 331.2 (18), 349.2 (M +
H+, 100), 363.3 (5).
Ethyl (–)-(R)-2-{(2R,3R,6S)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl)-2-iodopropanoate (35a)
Product 35a was prepared from alcohol 31 (126 mg, 0.36 mmol)
following the typical procedure used to prepare 33a. 1H NMR anal-
ysis indicated a >20:1 ratio of product 3,7-trans:3,7-cis. The crude
product was purified by flash chromatography on silica gel (hex-
anes–EtOAc, 90:10); pale yellow oil; yield: 101 mg (59%); Rf =
0.38 (hexanes–EtOAc, 90:10); [a]D25 –3.5 (c 0.7, CDCl3).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2385 (3.2 ppm).
Ethyl (+)-(S)-2-{(2S,3S,6S)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl}-2-iodopropanoate (33a);
Typical Procedure
To a solution of alcohol 29 (174 mg, 0.50 mmol) in anhyd THF (0.1
M, 5 mL) at r.t. was added successively NaHCO3 (0.17 g, 2.0 mmol,
4 equiv), I2 (0.76 g, 3.0 mmol, 6 equiv), and AgOTf (0.26 g, 1.0
mmol, 2 equiv) in a flask protected from light. Stirring is main-
tained for 1.5 h or until reaction was judged complete by TLC (elu-
ent: hexanes–EtOAc, 90:10). The reaction mixture was diluted with
EtOAc (10 mL), treated with brine (5 mL) and sat. aq Na2S2O3 (5
mL), followed by separation of the organic phase at r.t. The aqueous
layer was extracted with EtOAc (3 × 10 mL) and the combined or-
ganic fractions were dried (MgSO4), filtered, and concentrated in
IR (neat): 2929, 2849, 1732, 1453, 1378, 1249, 1189, 1074, 1025,
736, 697 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36–7.29 (m, 5 H), 4.48 (d,
J = 12.4 Hz, 1 H), 4.45 (d, J = 12.2 Hz, 1 H), 4.24–4.16 (m, 1 H),
4.12–4.02 (m, 1 H), 3.50 (dd, J = 9.1, 4.9 Hz, 1 H), 3.37 (d, J = 9.3
Hz, 1 H), 3.28–3.20 (m, 1 H), 3.22 (dd, J = 8.8, 7.6 Hz, 1 H), 2.04
(s, 3 H), 1.88–1.74 (m, 2 H), 1.70–1.58 (m, 1 H), 1.40–1.29 (m, 3
H), 1.26 (t, J = 7.1 Hz, 3 H), 1.14 (d, J = 6.8 Hz, 3 H), 0.90 (d,
J = 6.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 172.3, 138.9, 128.5, 127.6, 127.5,
86.4, 80.1, 73.2, 72.5, 61.9, 44.9, 39.0, 35.2, 33.7, 28.9, 27.0, 20.1,
13.9, 13.7.
1
vacuo. H NMR analysis indicated a >20: 1 ratio of product 3,7-
trans:3,7-cis. The crude product was purified by flash chromatogra-
phy on silica gel (hexanes–EtOAc, 90:10) yielding an inseparable
~5:1 mixture of iodides; pale yellow oil; yield: 0.33 g (70%); Rf =
0.23 (hexanes–EtOAc, 90:10); [a]D25 +30.7 (c 1.2, CDCl3).
MS (ESI): m/z (%) = 475.1 (M + H+, 100), 476.1 (22), 489.2 (10).
HRMS (ESI): m/z calcd for C21H32IO4 [M + H+]: 475.1340; found:
IR (neat): 3030, 2960, 2933, 2860, 1730, 1453, 1377, 1248, 1098,
1052, 737, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36–7.24 (m, 5 H), 4.52 (d,
J = 12.0 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 1 H), 4.27–4.03 (m, 2 H),
3.68 (d, J = 6.4 Hz, 1 H), 3.66 (ddd, J = 9.2, 6.7, 5.3 Hz, 1 H), 3.57
(dd, J = 3.6, 8.9 Hz, 1 H), 3.26 (dd, J = 7.4, 8.9 Hz, 1 H), 2.10 (s, 3
H), 1.75–1.41 (m, 6 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.11 (d, J = 6.9 Hz,
3 H), 0.92 (d, J = 6.8 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 172.0, 138.8, 128.2, 127.5, 127.3,
80.2, 75.0, 73.1, 72.4, 61.9, 47.4, 35.7, 31.6, 28.5, 27.3, 23.9, 20.5,
13.9, 13.7.
475.1351 (2.3 ppm).
Ethyl (–)-(R)-2-{(2R,3R,6R)-6-[(R)-1-(Benzyloxy)propan-2-yl)-
3-methyltetrahydro-2H-pyran-2-yl)-2-iodopropanoate (36a)
Product 36a was prepared from alcohol 32 (72 mg, 0.21 mmol) fol-
lowing the typical procedure used to prepare 33a. 1H NMR analysis
indicated a >20:1 ratio of product 3,7-trans:3,7-cis. The crude prod-
uct was purified by flash chromatography on silica gel (hexanes–
EtOAc, 90:10) yielding an inseparable ~4:1 mixture of iodides; pale
yellow oil; yield: 63 mg (64%); Rf = 0.42 (hexanes–EtOAc, 90:10);
[a]D25 –4.2 (c 0.6, CDCl3).
MS (ESI): m/z (%) = 347.2 (14), 475.1 (M + H+, 100), 492.2 (22).
HRMS (ESI): m/z calcd for C21H32IO4 [M + H+]: 475.1340; found:
475.1342 (0.4 ppm).
IR (neat): 2953, 2922, 2855, 1718, 1453, 1359, 1246, 1092, 1049,
1013, 721, 697 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.51 (d,
J = 11.9 Hz, 1 H), 4.42 (d, J = 11.9 Hz, 1 H), 4.29–4.20 (m, 1 H),
4.20–4.13 (m, 1 H), 3.77 (d, J = 5.6 Hz, 1 H), 3.72 (dt, J = 4.2, 7.4
Hz, 1 H), 3.36 (dd, J = 9.1, 5.7 Hz, 1 H), 3.27 (dd, J = 9.1, 5.8 Hz,
1 H), 2.17 (s, 3 H), 1.99–1.90 (m, 1 H), 1.87–1.66 (m, 2 H), 1.65–
1.57 (m, 1 H), 1.55–1.45 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.13 (d,
J = 6.9 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.3, 138.7, 128.5, 127.7, 127.6,
80.8, 75.3, 73.3, 73.1, 62.1, 47.6, 36.5, 30.9, 28.8, 27.7, 24.2, 20.9,
14.0, 13.5.
Ethyl (+)-(S)-2-{(2S,3S,6R)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl}-2-iodopropanoate (34a)
Product 34a was prepared from alcohol 30 (229 mg, 0.66 mmol)
following the typical procedure used to prepare 33a. 1H NMR anal-
ysis indicated a >20:1 ratio of product 3,7-trans:3,7-cis. The crude
product was purified by flash chromatography on silica gel (hex-
anes–EtOAc, 90:10) yielding an inseparable ~12:1 mixture of io-
dides; pale yellow oil; yield: 281 mg (90%); Rf = 0.59 (hexanes–
EtOAc, 85:15); [a]D25 +6.5 (c 1.7, CDCl3).
IR (neat): 2977, 2930, 2853, 1733, 1454, 1380, 1249, 1082, 1025,
737, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.48 (d,
J = 12.1 Hz, 1 H), 4.45 (d, J = 12.1 Hz, 1 H), 4.23 (dq, J = 10.9, 7.1
MS (ESI): m/z (%) = 347.2 (7), 475.1 (M + H+, 100), 476.1 (23),
489.2 (5).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 474–488

486
F. Godin et al.
PAPER
HRMS (ESI): m/z calcd for C21H32IO4 [M + H+]: 475.1340; found:
475.1344 (1.0 ppm).
1H NMR (500 MHz, CDCl3): d = 7.35–7.24 (m, 5 H), 4.50 (d,
J = 12.1 Hz, 1 H), 4.47 (d, J = 12.3 Hz, 1 H), 4.16–4.06 (m, 2 H),
3.54 (dd, J = 9.0, 4.8 Hz, 1 H), 3.40 (dd, J = 9.1, 6.7 Hz, 1 H), 3.19
(ddd, J = 10.9, 7.1, 1.9 Hz, 1 H), 3.07 (dd, J = 9.9, 2.7 Hz, 1 H), 2.72
(dq, J = 2.6, 6.9 Hz, 1 H), 1.91–1.81 (m, 1 H), 1.78 (ddd, J = 13.0,
6.8, 3.4 Hz, 1 H), 1.65–1.49 (m, 1 H), 1.31–1.20 (m, 3 H), 1.24 (t,
J = 7.1 Hz, 3 H), 1.18 (d, J = 7.1 Hz, 3 H), 0.93 (d, J = 6.9 Hz, 3 H),
0.83 (d, J = 6.6 Hz, 3 H).
Ethyl (+)-(S)-2-{(2S,3S,6S)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl}propanoate (3a)
Product 3a was obtained from iodide product 33a (39 mg, 0.08
mmol) following general procedure A2. 1H NMR analysis of crude
product indicated a >20:1 ratio of product 7,8-anti (3a):7,8-syn
(3b); colorless oil; yield: 17.8 mg (62%); Rf = 0.29 (hexanes–
EtOAc, 90:10); [a]D25 +43.9 (c 1.5, CDCl3).
13C NMR (125 MHz, CDCl3): d = 173.9, 139.1, 128.4, 127.6, 127.5,
85.5, 79.3, 73.1, 72.6, 60.1, 42.2, 39.0, 33.4, 33.0, 28.7, 17.6, 14.5,
13.74, 13.69.
IR (neat): 3030, 2969, 2933, 2860, 1735, 1552, 1455, 1376, 1338,
1267, 1251, 1208, 1172, 1110, 1047, 1028, 737, 698 cm–1.
MS (ESI): m/z (%) = 349.2 (M + H+, 20), 371.2 (M + Na+, 100),
1H NMR (500 MHz, CDCl3): d = 7.35–7.23 (m, 5 H), 4.52 (d,
J = 12.4 Hz, 1 H), 4.50 (d, J = 12.7 Hz, 1 H), 4.14–4.02 (m, 2 H),
3.64 (dd, J = 4.3, 9.1 Hz, 1 H), 3.56 (dd, J = 8.3, 3.6 Hz, 1 H), 3.54
(dt, J = 3.6, 7.4 Hz, 1 H), 3.17 (t, J = 8.8 Hz, 1 H), 2.96 (dq, J = 6.9,
8.4 Hz, 1 H), 2.03–1.94 (m, 1 H), 1.79–1.63 (m, 2 H), 1.62–1.52 (m,
1 H), 1.50–1.42 (m, 1 H), 1.42–1.34 (m, 1 H), 1.22 (t, J = 7.1 Hz, 3
H), 1.09 (d, J = 6.9 Hz, 3 H), 1.05 (d, J = 6.9 Hz, 3 H), 0.92 (d,
J = 6.8 Hz, 3 H).
372.2 (20).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2365 (–2.3 ppm); m/z calcd for C21H32O4 + Na [M + Na+]:
371.2193; found: 371.2180 (–3.5 ppm).
Ethyl (–)-(R)-2-{(2R,3R,6R)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl)propanoate (6a)
Product 6a was obtained from iodide product 36a (32 mg, 0.07
mmol) following general procedure A2. 1H NMR analysis of crude
product indicated a >20:1 ratio of product 7,8-anti (6a):7,8-syn
(6b); colorless oil; yield: 19 mg (82%); Rf = 0.25 (hexanes–EtOAc,
95:5); [a]D25 –10.6 (c 0.3, CDCl3).
13C NMR (125 MHz, CDCl3): d = 174.7, 138.9, 128.3, 127.5, 127.3,
79.8, 73.0, 72.8, 72.7, 60.2, 40.9, 36.7, 28.3, 25.4, 23.5, 18.4, 14.4,
14.2, 13.8.
MS (ESI): m/z (%) = 349.2 (M + H+, 100).
IR (neat): 2970, 2931, 2859, 1735, 1455, 1378, 1266, 1250, 1206,
1174 cm–1.
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2363 (–2.9 ppm).
1H NMR (500 MHz, CDCl3): d = 7.36–7.27 (m, 5 H), 4.51 (d,
J = 12.1 Hz, 1 H), 4.44 (d, J = 12.1 Hz, 1 H), 4.17–4.04 (m, 2 H),
3.61 (ddd, J = 9.3, 6.5, 3.0 Hz, 1 H), 3.54 (dd, J = 9.1, 2.8 Hz, 1 H),
3.41 (dd, J = 9.1, 4.6 Hz, 1 H), 3.28 (dd, J = 9.1, 7.1 Hz, 1 H), 3.02
(dq, J = 9.0, 6.9 Hz, 1 H), 1.91–1.82 (m, 1 H), 1.79–1.72 (m, 1 H),
1.72–1.66 (m, 1 H), 1.65–1.56 (m, 1 H), 1.44–1.35 (m, 2 H), 1.24 (t,
J = 7.2 Hz, 3 H), 1.11 (d, J = 6.9 Hz, 3 H), 1.08 (d, J = 6.9 Hz, 3 H),
0.99 (d, J = 6.8 Hz, 3 H).
Ethyl (–)-(S)-2-{(2S,3S,6R)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl}propanoate (4a)
Product 4a was obtained from iodide product 34a (23 mg, 0.05
mmol) following general procedure A2. 1H NMR analysis of crude
product indicated a >20:1 ratio of product 7,8-anti (4a):7,8-syn
(4b); colorless oil; yield: 16 mg (96%); Rf = 0.16 (hexanes–EtOAc,
95:5); [a]D25 –5.0 (c 0.2, CDCl3).
IR (neat): 2973, 2933, 2852, 1736, 1456, 1376, 1248, 1182, 1091,
1059, 736, 698 cm–1.
13C NMR (125 MHz, CDCl3): d = 175.0, 138.9, 128.4, 127.7, 127.6,
80.1, 73.3, 73.2, 72.7, 60.3, 41.1, 37.6, 27.9, 25.4, 23.7, 18.6, 14.7,
14.4, 13.3.
MS (ESI): m/z (%) = 349.2 (M + H+, 35), 371.2 (M + Na+, 100),
372.2 (24).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2380 (1.8 ppm); m/z calcd for C21H32O4 + Na [M + Na+]:
371.2193; found: 371.2199 (1.6 ppm).
1H NMR (500 MHz, CDCl3): d = 7.37–7.27 (m, 5 H), 4.51 (d,
J = 12.1 Hz, 1 H), 4.48 (d, J = 12.1 Hz, 1 H), 4.18–4.06 (m, 2 H),
3.50 (dd, J = 8.9, 6.9 Hz, 1 H), 3.35 (ddd, J = 13.3, 4.7, 3.6 Hz, 1
H), 3.32 (dd, J = 9.0, 6.1 Hz, 1 H), 3.06 (dd, J = 9.9, 2.5 Hz, 1 H),
2.72 (dq, J = 2.5, 7.0 Hz, 1 H), 1.84–1.73 (m, 2 H), 1.64–1.55 (m, 2
H), 1.47–1.40 (m, 1 H), 1.40–1.32 (m, 1 H), 1.25 (t, J = 7.1 Hz, 3
H), 1.18 (d, J = 7.1 Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.84 (d,
J = 6.6 Hz, 3 H).
Ethyl (+)-(R)-2-{(2S,3S,6S)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl}propanoate (3b)
13C NMR (125 MHz, CDCl3): d = 173.9, 139.0, 128.5, 127.7, 127.6,
85.5, 78.1, 73.23, 73.19, 60.1, 42.2, 38.8, 33.4, 33.1, 29.0, 17.6,
14.5, 13.9, 12.1.
Product 3b was obtained from iodide product 33a (52 mg, 0.11
mmol) following general procedure A3. 1H NMR analysis of crude
product indicated a >20:1 ratio of product 7,8-syn (3b):7,8-anti
(3a); colorless oil; yield: 15.1 mg (40%); Rf = 0.35 (hexanes–
EtOAc, 90:10); [a]D25 +16.7 (c 1.5, CDCl3).
MS (ESI): m/z (%) = 349.2 (M + H+, 100), 350.2 (22), 366.3 (8),
371.2 (M + Na+, 93), 372.2 (20).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2372 (–0.5 ppm); m/z calcd for C21H32O4 + Na [M + Na+]:
371.2193; found: 371.2192 (–0.3 ppm).
IR (neat): 3030, 2957, 2930, 2860, 1731, 1553, 1456, 1375, 1249,
1181, 1150, 1100, 1073, 1046, 735, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.35–7.24 (m, 5 H), 4.51 (d,
J = 12.3 Hz, 1 H), 4.49 (d, J = 12.8 Hz, 1 H), 4.20–4.03 (m, 2 H),
3.65 (dd, J = 5.2, 7.4 Hz, 1 H), 3.55 (dd, J = 3.9, 8.9 Hz, 1 H), 3.45
(ddd, J = 4.1, 7.4, 8.5 Hz, 1 H), 3.36 (dd, J = 6.9, 8.9 Hz, 1 H), 2.89
(hept, J = 7.0 Hz, 1 H), 2.10–2.00 (m, 1 H), 1.78–1.70 (m, 1 H),
1.65–1.46 (m, 3 H), 1.43–1.34 (m, 1 H), 1.25 (t, J = 7.1 Hz, 3 H),
1.15 (d, J = 7.0 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8
Hz, 3 H).
Ethyl (+)-(R)-2-{(2R,3R,6S)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl}propanoate (5a)
Product 5a was obtained from iodide product 35a (21 mg, 0.04
mmol) following general procedure A2. 1H NMR analysis of crude
product indicated a >20:1 ratio of product 7,8-anti (5a):7,8-syn
(5b); colorless oil; yield: 12 mg (76%); Rf = 0.38 (hexanes–EtOAc,
95:5); [a]D25 +2.1 (c 1.1, CDCl3).
IR (neat): 2958, 2926, 2852, 1734, 1456, 1376, 1248, 1200, 1181,
1085, 910, 736, 650 cm–1.
13C NMR (125 MHz, CDCl3): d = 175.3, 138.8, 128.3, 127.5, 127.3,
78.2, 73.1, 72.4, 72.3, 60.3, 40.6, 35.8, 30.4, 25.9, 24.1, 18.1, 14.2,
13.9, 11.9.
Synthesis 2012, 44, 474–488
© Thieme Stuttgart · New York

PAPER
Synthesis of the C1–C9 Subunit of Zincophorin and Isomers Thereof
487
MS (ESI): m/z (%) = 303.2 (5), 349.2 (M + H+, 100).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
1H NMR (500 MHz, CDCl3): d = 7.39–7.27 (m, 5 H), 4.50 (d,
J = 11.9 Hz, 1 H), 4.44 (d, J = 11.9 Hz, 1 H), 4.20–4.04 (m, 2 H),
3.61 (dd, J = 7.8, 4.6 Hz, 1 H), 3.52 (dt, J = 2.9, 7.6 Hz, 1 H), 3.44
(dd, J = 9.0, 6.1 Hz, 1 H), 3.30 (dd, J = 9.1, 5.7 Hz, 1 H), 2.94 (hept,
J = 7.3 Hz, 1 H), 1.97 (dt, J = 12.5, 6.3 Hz, 1 H), 1.76 (dt, J = 11.6,
6.4 Hz, 1 H), 1.67 (dd, J = 17.8, 9.6 Hz, 1 H), 1.59–1.49 (m, 1 H),
1.45–1.36 (m, 2 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.16 (d, J = 6.9 Hz, 3
H), 1.01 (d, J = 6.9 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H).
349.2364 (–2.6 ppm).
Ethyl (+)-(R)-2-{(2S,3S,6R)-6-[(R)-1-(Benzyloxy)propan-2-yl)-
3-methyltetrahydro-2H-pyran-2-yl)propanoate (4b)
Product 4b was obtained from iodide product 34a (23 mg, 0.05
mmol) following general procedure A3. 1H NMR analysis of crude
product indicated a >20:1 ratio of product 7,8-syn (4b):7,8-anti
(4a); colorless oil; yield: 13 mg (79%); Rf = 0.26 (hexanes–EtOAc,
95:5); [a]D25 +27 (c 0.3, CDCl3).
13C NMR (125 MHz, CDCl3): d = 175.5, 138.7, 128.5, 127.7, 127.6,
78.5, 73.3, 73.1, 72.0, 60.5, 40.7, 36.4, 30.3, 26.1, 24.4, 18.3, 14.3,
13.0, 12.4.
IR (neat):2927, 2853, 1739, 1455, 1200, 1090, 1025, 736, 698 cm–1.
MS (ESI): m/z (%) = 338.3 (12), 349.2 (M + H+, 19), 371.2 (M +
Na+, 100).
1H NMR (500 MHz, CDCl3): d = 7.37–7.27 (m, 5 H), 4.48 (d,
J = 12.1 Hz, 1 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.14–4.04 (m, 2 H),
3.44 (dd, J = 9.9, 3.2 Hz, 1 H), 3.41 (dd, J = 9.1, 6.1 Hz, 1 H), 3.32–
3.29 (m, 1 H), 3.28 (dd, J = 9.0, 6.4 Hz, 1 H), 2.64 (dq, J = 3.2, 7.1
Hz, 1 H), 1.83–1.71 (m, 2 H), 1.51–1.31 (m, 4 H), 1.23 (t, J = 7.2
Hz, 3 H), 1.10 (d, J = 7.1 Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.81
(d, J = 6.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 175.2, 138.9, 128.5, 127.7, 127.5,
83.6, 78.4, 73.3, 73.2, 60.4, 41.7, 38.8, 33.1, 32.2, 29.3, 17.2, 14.5,
12.4, 9.0.
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2373 (–0.1 ppm); m/z calcd for C21H32O4 +Na [M + Na+]:
371.2193; found: 371.2191 (–0.4 ppm).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ ejournals/toc/synthesis.
Acknowledgment
MS (ESI): m/z (%) = 227.0 (12), 349.2 (M + H+, 30), 371.2 (M +
The authors wish to express their gratitude to the Natural Sciences
and Engineering Research Council of Canada (NSERC) and to the
Fonds Québécois de la Recherche sur la Nature et les Technologies
(FQRNT) for their financial support. Fellowship support from
NSERC PGS D and FQRNT B2 (F.G.) is also gratefully acknow-
ledged.
Na+, 100), 372.2 (23).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2381 (2.2 ppm); calcd for C21H32O4 + Na [M + Na+]: 371.2193;
found: 371.2201 (2.1 ppm).
Ethyl (–)-(S)-2-{(2R,3R,6S)-6-[(R)-1-(Benzyloxy)propan-2-yl]-
3-methyltetrahydro-2H-pyran-2-yl)propanoate (5b)
Product 5b was obtained from iodide product 35a (21 mg, 0.04
mmol) following general procedure A3. 1H NMR analysis of crude
product indicated a >20:1 ratio of product 7,8-syn (5b):7,8-anti
(5a); colorless oil; yield: 11 mg (71%); Rf = 0.36 (hexanes–EtOAc,
90:10); [a]D25 –71 (c 0.2, CDCl3).
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J. Antibiot. 1984, 37, 1501. (b) Gräfe, U.; Schade, W.; Roth,
M.; Radics, L.; Incze, M.; Ujszaszy, K. J. Antibiot. 1984, 37,
836.
IR (neat): 2958, 1919, 2850, 1739, 1455, 1378, 1249, 1200, 1089,
1073, 1027 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.47 (d,
J = 12.8 Hz, 1 H), 4.44 (d, J = 12.3 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 2
H), 3.55 (dd, J = 9.1, 4.7 Hz, 1 H), 3.42 (dd, J = 9.9, 3.3 Hz, 1 H),
3.26 (dd, J = 9.1, 7.3 Hz, 1 H), 3.17–3.10 (m, 1 H), 2.63 (dq, J = 3.3,
7.0 Hz, 1 H), 1.85–1.76 (m, 1 H), 1.64–1.56 (m, 2 H), 1.33–1.16 (m,
3 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.10 (d, J = 7.1 Hz, 3 H), 0.91 (d,
J = 6.9 Hz, 3 H), 0.81 (d, J = 6.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 175.2, 139.1, 128.4, 127.6, 127.5,
83.7, 79.5, 73.1, 72.7, 60.4, 41.7, 39.0, 33.1, 32.2, 29.2, 17.2, 14.5,
13.9, 9.1.
(6) Numbering of atoms throughout article was attributed
MS (ESI): m/z (%) = 171.1 (5), 349.2 (M + H+, 12), 371.2 (M + Na+,
according to that of zincophorin 1.
(7) (a) Labelle, M.; Guindon, Y. J. Am. Chem. Soc. 1989, 111,
2204. (b) Guindon, Y.; Yoakim, C.; Gorys, V.; Ogilvie, W.
W.; Delorme, D.; Renaud, J.; Robinson, G.; Lavallée, J. F.;
Slassi, A.; Jung, G.; Rancourt, J.; Durkin, K.; Liotta, D.
J. Org. Chem. 1994, 59, 1166. (c) Guindon, Y.; Slassi, A.;
Rancourt, J.; Bantle, G.; Bencheqroun, M.; Murtagh, L.;
Ghiro, E.; Jung, G. J. Org. Chem. 1995, 60, 288.
(8) Selected examples involving chiral auxiliaries: (a) Curran,
D. P.; Shen, W.; Zhang, J. C.; Heffner, T. A. J. Am. Chem.
Soc. 1990, 112, 6738. (b) Porter, N. A.; Rosenstein, I. J.;
Breyer, R. A.; Bruhnke, J. D.; Wu, W. X.; Mcphail, A. T.
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D. P.; Geib, S. V.; Rebek, J.; Ballester, P. J. Am. Chem. Soc.
1992, 114, 7007. (d) Sibi, M. P.; Ji, J. G. Angew. Chem., Int.
Ed. Engl. 1996, 35, 190. (e) Sibi, M. P.; Ji, J. G. J. Org.
Chem. 1996, 61, 6090.
100), 397.2 (18).
HRMS (ESI): m/z calcd for C21H33O4 [M + H+]: 349.2373; found:
349.2370 (–1.1 ppm); m/z calcd for C21H32O4 + Na [M + Na+]:
371.2193; found: 371.2191 (–0.5 ppm).
Ethyl (–)-(S)-2-{(2R,3R,6R)-6-[(R)-1-(Benzyloxy)propan-2-yl)-
3-methyltetrahydro-2H-pyran-2-yl)propanoate (6b)
Product 6b was obtained from iodide product 36a (35 mg, 0.07
mmol) following general procedure A3. 1H NMR analysis of crude
product indicated a 6.4:1 ratio of product 7,8-syn (6b):7,8-anti (6a),
which could be separated by flash chromatography on silica gel
(hexanes–EtOAc, 95:5); colorless oil; yield: 23 mg (79%); Rf = 0.31
(hexanes–EtOAc, 95:5); [a]D25 –5.3 (c 0.3, CDCl3).
IR (neat): 2959, 2924, 2853, 1732, 1455, 1376, 1260, 1179, 1093,
1028 cm–1.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 474–488

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F. Godin et al.
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