Progress toward the total synthesis of mirabalin isomers

Article abstract of DOI:10.24820/ark.5550190.p010.874

Key fragments of the cytotoxic marine macrolide mirabalin have been synthesized, by using a flexible strategy based on asymmetric reductions to control the hydroxy- and carbamate-bearing stereocenters. In particular, ruthenium or rhodium-mediated asymmetric hydrogenation and transfer hydrogenation were used in combination with a dynamic kinetic resolution to control two contiguous stereocenters in a single step.

Full text of DOI:10.24820/ark.5550190.p010.874

The Free Internet Journal
for Organic Chemistry
Review
Archive for
Arkivoc 2019, part iv, 0-0
Organic Chemistry
to be inserted by editorial office
Progress toward the total synthesis of mirabalin isomers
a
a
a
a
b
Pierre-Georges Echeverria, Amandine Pons, Sébastien Prévost, Charlène Férard, Johan Cornil, Amandine
b
b
a
a
Guérinot, Janine Cossy,* Phannarath Phansavath* and Virginie Ratovelomanana-Vidal*
a
PSL University, Chimie ParisTech, CNRS, Institute of Chemistry for Life and Health Sciences (i-CLeHS)
5005 Paris, France
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI)-UMR 8231,
ESPCI Paris/CNRS/PSL Research University, 10 rue Vauquelin 75231 Cedex 05 Paris, France
Email: janine.cossy@espci.fr, phannarath.phansavath@chimieparistech.psl.eu,
virginie.vidal@chimieparistech.psl.eu
7
b
Dedicated to Prof. Stephen Hanessian for his outstanding contributions to the field of organic chemistry
Received 01-07-2019
Accepted 02-24-2019
Published on line 02-28-2019
Abstract
Key fragments of the cytotoxic marine macrolide mirabalin have been synthesized, by using a flexible strategy
based on asymmetric reductions to control the hydroxy- and carbamate-bearing stereocenters. In particular,
ruthenium or rhodium-mediated asymmetric hydrogenation and transfer hydrogenation were used in
combination with a dynamic kinetic resolution to control two contiguous stereocenters in a single step.
Keywords: Marine macrolides, asymmetric hydrogenation, asymmetric transfer hydrogenation,
enantioselectivity, diastereoselectivity
DOI: https://doi.org/10.24820/ark.5550190.p010.874
Page 1
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
Introduction
1
,2
Lithistid demosponges are an assemblage of sponges predominantly found in deeper waters. They are
regarded as an excellent source of structurally diverse and bioactive secondary metabolites.3 In particular,
numerous novel macrolides have been isolated from the Theonellidae family exhibiting excellent biological
activities.6 Among them, mirabalin, a macrocycle, has been extracted from Siliquariaspongia mirabilis, a
-5
-7
8
,9
lithistid demosponge collected from the archipelago of Chuuk, Micronesia (Figure 1). This macrocycle
exhibits potent cytotoxicity toward human colon tumor cell line HCT-116 with an IC50 of 0.27 µM. Morever, it
has been found that the macrocycle ring is crucial to mirabalin antitumor activity. Indeed, no inhibition of the
tumor cells growth was observed when treated with the linear polyketide side-chain. From a structural point
of view, mirabalin exhibits a 35-membered macrocyclic lactam-lactone possessing a fully conjugated pentaene
system along with a tetrasubstituted tetrahydropyran ring. In addition, a linear polyketide side-chain is linked
to the macrocyclic ring with an amide linkage. An investigation combining advanced NMR and MS techniques
allowed the partial elucidation of the structure of mirabalin. Undeniably, because of the large number of
stereocenters and the low amount of material available, the absolute configurations of 12 out of the 25
stereocenters could not be assigned. Nevertheless, the geometry for each of the double bonds was
established unambiguously (Figure 1).
OH
OH
H
N
*
*
*
*
OH
O
O
HO
*
OH
O
HN
*
*
*
*
H
O
H
OH OH
OH
OH
OH
O
MeO
MeO
H
*
N *
O
O
HO
*
COOH
Mirabalin, 1
Figure 1. Picture of Siliquariaspongia mirabilis and the structure of mirabalin (1)9.
As part of our ongoing studies on the total synthesis of natural products,10-17 and intrigued by the
structural intricacy of this macrolide, we embarked on a study aiming at developing a flexible, convergent and
modular route to one isomer of mirabalin where the configurations of the twelve unknown stereocenters
were arbitrarily fixed (Scheme 1). Recently, we reported a synthetic strategy toward the C44−C65 polyketide
side chain18 and toward the C14−C29 fragment of mirabalin, as well as a straightforward method to
19
2
0
construct the pentaene moiety C4-C14. Scheme 1 shows the mirabalin global retrosynthetic plan with late
stage esterification, peptide coupling and C=C bond formation to access the macrocycle by macro-
lactamization, suggesting A and B as suitable key intermediates for the sake of convergence.
Page 2
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
OH
OH
H
4
8
NHP
O
O
N
54
6
5
64
60
3
50
67
66
34
S
7
1
N
N
OH
O
O
46
OH
O
42
69
30
73
N
HO 72
N
OP OP OP
4
4
Ph
peptide
coupling
9
Julia-Kocienski
HN
A
29
3
8
66
20
22
34
67
25
4
2
H
NHP
17
O
H
OH OH
OH
OH
OH
esterification
O
36
MeO
35
1
OH
H
1
PO
2
4
N
MeO
O
2
OP
B
O
14
O
35
HO
COOH
:
unknown stereocenters,
arbitrarily assigned
36
macrolactamization
(
P = protecting group)
Mirabalin (1)
Scheme 1. Global retrosynthetic plan for mirabalin (1)
Herein, we report a flexible synthesis of fragments A and B but also details about the synthesis of isomers
of the C44−C65 side chain of mirabalin.
Results and Discussion
Synthesis of fragment A
Our retrosynthetic analysis was based on known methods for the introduction of the phenyltetrazolyl sulfone
moiety by a hydroboration/Mitsunobu/oxidation sequence applied to alkene 2. We therefore envisaged that
the aldehyde 3 represented a useful intermediate in the synthesis of the unsaturated compound 2, and
2
1-23
aldehyde 3 could be obtained from α-amino β-ketoester 4 after asymmetric hydrogenation
via a dynamic
kinetic resolution,2 Claisen condensation and asymmetric hydrogenation (Scheme 3).
4-26
27-29
asymmetric
hydrogenation
hydroboration / Mitsunobu
TBS
vinylation
O
TBS
O
34
O
O
N
O
O
O
34
O
N
BocN
BocN
BocN 42
42
N
66
34 O
H
4
2
S
N
42
34
67
66
66
67
66
O
NH .HCl
2
67
2
67
Ph
OTBS
OTBS
OTBS
A'
2
3
4
asymmetric
hydrogenation
via dynamic kinetic
resolution
Scheme 2. Retrosynthetic analysis of fragment A (compound A')
Page 3
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
Our synthesis began with the preparation of the hydrochloride ammonium salt 4 in two steps from methyl
acetoacetate 5 after nitrosation followed by hydrogenolysis of the oxime 6 under acidic conditions. To control
the anti configuration at C66 and C42, a ruthenium-catalyzed asymmetric hydrogenation through dynamic
kinetic resolution of the racemic α-amino β-keto ester hydrochloride 4 was envisaged. Using this method, the
corresponding anti-aminoalcohol was successfully prepared with 90% diastereomeric excess and 91%
o
enantiomeric excess. The reaction was performed in CH
mol% of the in situ prepared [Ru((R)-Synphos)]Br
2
Cl
2
3
/MeOH (10:1) at 50 C under 13 bar of H
2
using 2
0
2
] catalyst (Scheme 3). Protection of the amino group as a
carbamate and conversion of the hydroxy function into a TBS ether delivered compound 8. The ensuing fully
protected amino hydroxy ester 8 was then submitted to a Claisen condensation with tert-butyl acetate under
basic conditions to deliver β-keto ester 9 in 87% yield (Scheme 3).
1
. H (13 bar)
2
NaNO2
AcOH/H O
[Ru((R)-Synphos)Br2] (2 mol %)
O
O
O
O
O
O
H , Pd/C, HCl
2
CH Cl /MeOH (10:1), 50 °C
2
2 2
OMe
OH
OMe
OMe
0
°C then rt
1%
MeOH, rt
77%
2. NaHCO , Boc O, MeOH, rt
3
2
N
NH .HCl
2
5
70%
5
6
4
TBSCl, imidazole
DMF, rt
TBSO
O
TBSO
O
O
HO
O
LDA, t-BuOAc, THF, -45 °C
7%
42
66
34
OtBu
OMe
Boc
(dr = 95:5, er = 95.5:4.5)
OMe
8
95%
HN
HN
HN
Boc
Boc
7
8
9
Scheme 3. Preparation of -keto ester 9
We then turned our attention to the asymmetric hydrogenation of ketone 9 (Scheme 4). Different
conditions varying catalyst loading and hydrogen pressure were screened using the binuclear complex
30
o
[
{RuCl((S)-Synphos)}
2
(μ-Cl)
3
][Me
2
NH ] in EtOH at 50 C. No influence of the catalyst loading was observed on
2
the stereochemical outcome of the reaction. However, changing the hydrogen pressure from 70 to 100 bar
afforded a better result in terms of diastereoselectivity (dr switching from 74:26 to >99:1). With these
optimized conditions in hand, the synthesis was pursued with the protection of aminoalcohol 10 to the
oxazolidine 11. It was found that the starting material 10 was not fully converted during the reaction and the
acidic conditions led to the cleavage of the TBS group on both compounds 10 and 11. The yield was modest
and variable despite several experimentations. Nevertheless, compound 11 was converted to aldehyde 3 with
Dibal-H in 77% yield. Addition of vinylmagnesium bromide to aldehyde 3 at low temperature provided the
desired allylic alcohol 12 in 77% yield with a diastereoselectivity of 62:38. The two stereoisomers were
separated by flash column chromatography and the synthesis of compound A' was carried out with the major
diastereomer, the absolute configuration of which was determined by Mosher analysis (Scheme 4).31
Page 4
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
N
H
H
Ph Cl
Cl Ph2
2
Cl
Cl
H (100 bar)
Ru] (1 mol %)
2
O
TBSO
O
O
TBSO
OH
O
P
P
O
[
Ru
Ru
P
O
OtBu
OtBu
O
P
Cl
EtOH, 50 °C
O
Ph
Ph
O
2
2
NHBoc
NHBoc
70%
O
O
9
10 (dr > 99:1)
-
+
[
Ru] = [{RuCl((S)-Synphos)} (m-Cl) ] [Me NH ]
2
3
2
2
OH
O
O
O
O
O
MgBr
CSA, DMP
Dibal-H
BocN
BocN
BocN
10
OtBu
H
CH Cl , reflux
CH2Cl2, -85 °C
THF, -78 °C
2
2
27%
OTBS
77%
OTBS
77%
OTBS
12 (dr = 62:38)
11
3
Scheme 4. Preparation of alcohol 12
After protection of alcohol 12 (TBSCl, imid, DMF, rt), hydroboration/oxidation of the obtained compound 2
furnished the desired product 13 in 75% yield. Formation of thioether 14 was accomplished using a Mitsunobu
reaction3 applied to alcohol 13 (1-phenyl-1H-tetrazole-5-thiol, DIAD, PPh
, THF, rt) and the thioether 14 was
2,33
3
converted to the corresponding sulfone in 68% yield by oxidation with m-CPBA (Scheme 5). Thus, compound
A' was obtained in 14 steps in 1.1% overall yield from methyl acetoacetate 5 and three contiguous
stereocenters were controlled using asymmetric hydrogenation. To appreciate the feasibility of our envisaged
34
retrosynthetic plan, we performed a Julia-Kocienski olefination between compound A' and the aldehyde
3
5
generated from alcohol 15 (corresponding to the C25-C28 fragment of the macrocycle, Scheme 1). Pleasingly,
the desired E-alkene was obtained in 76% yield with tight control of the double bond geometry (E/Z > 95:5)
(Scheme 5).
Page 5
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
BH .Me S
NaOH/H2O2
3
2
O
OH
O
OTBS
O
OTBS
TBSCl, imidazole
DMF, rt
BocN
BocN
BocN
OH
THF, rt
75%
79%
OTBS
OTBS
OTBS
OTBS
1
2
2
13
m-CPBA, NaHCO3
CH Cl , rt
O
N
N
O
OTBS
N
N
PPh , DIAD, PTSH
BocN
3
N
BocN
2
2
N
S
N
S
N
THF, rt
68%
Ph
O
O
Ph
80%
OTBS
OTBS
A'
14
KHMDS, THF
78 °C
OTBS
OTBS
TPAP, NMO, MS 4Å
CH Cl , rt
-
HO
I
O
I
2
2
76%
quant.
15
O
OTBS
OTBS
BocN
I
OTBS
16 (E:Z > 95:5)
Scheme 5. Synthesis of compound A' and subsequent Julia-Kocienski olefination
Synthesis of fragment B
The retrosynthetic analysis for the construction of the second major building block B is summarized in Scheme
6
for compound B'. Our strategy focused on the flexibility in term of stereochemistry. For this purpose,
3
6-40
asymmetric hydrogenation and transfer hydrogenation
were chosen as complementary methods to access
all four stereoisomers of compound B'.
asymmetric reduction
via dynamic kinetic resolution
aldolization/
oxidation
TBSO
PMBO
O
O
O
O
O
PMBO
OH
NHBoc
OMe
NHBoc
PMBO
18
OMe
NHBoc
19
H
B'
17
Scheme 6. Retrosynthetic analysis of fragment B (compound B').
Page 6
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
The synthesis of the α-carbamate β-ketoester 17 proceeded as shown in Scheme 7. After PMB-
monoprotection of ethane-1,2-diol 20 and Dess-Martin oxidation of the obtained 21, aldehyde 18 was isolated
in 61% yield. The other partner 19 was prepared by simple N-Boc protection of glycine methyl ester
hydrochloride 22 in 97% yield. Thereafter, reaction of the zinc derivative of 19 with aldehyde 18 furnished the
corresponding α-carbamate β-hydroxy ester whose oxidation afforded the desired β-keto ester 17. It is
noteworthy that, after thorough investigation, only the use of Dess-Martin periodinane in the absence of
NaHCO allowed the oxidation, albeit in low yield; other attempts using IBX, Parikh-Doering, Ley-Griffith,
3
Swern, Fétizon or pyridinium dichromate reagents led only to degradation products. With the desired keto
ester 17 in hand, we focused on the asymmetric reduction of 17 via dynamic kinetic resolution.
After careful optimization of the reaction parameters, compound syn-23 was obtained in 73% yield with
good diastereomeric ratio (dr = 86:14) and enantioselectivity (er = 90:10) by using 0.5 mol% of the complex
3
0
[
5
RuBr
2
((S)-Synphos)] prepared in situ from [Ru(COD)(2-methylallyl) ], under 50 bar of hydrogen pressure at
2
o
0 C in dichloromethane. Subsequent TBS protection of the hydroxyl gave syn-24 and the desired compound
syn-B' was finally obtained by hydrolysis of the methyl ester to the corresponding carboxylic acid (Scheme 7).
Dess-Martin
periodinane
O
PMBCl, NaH, nBu NI
4
HO
PMBO
PMBO
OH
OH
CH Cl , rt
H
THF, reflux
88%
2
2
20
21
61%
18
O
O
Boc O, Et N, CH Cl , rt
1. LDA, ZnCl , THF, -78 °C, 18
2
2
3
2
2
OMe
NH .HCl
OMe
2
. DMP, CH Cl , rt
97%
2
2
2
NHBoc
17%
22
19
OH
O
O
O
H (50 bar), [RuBr (S)-Synphos] (0.5 mol %)
2
2
PMBO
PMBO
OMe
NHBoc
syn-23 (dr = 86:14, er = 90:10)
OMe
CH Cl , 50 °C, 4 d
2
2
NHBoc
73%
17
TBSCl
imidazole
TBSO
PMBO
O
TBSO
PMBO
O
KOH
OMe
NHBoc
syn-24
OH
NHBoc
syn-B'
DMF, rt
MeOH/H O, 40 °C
2
87%
43%
Scheme 7. Synthesis of compound syn-B' through asymmetric hydrogenation.
To obtain the anti-isomer of fragment B, we turned our attention to the use of asymmetric transfer
hydrogenation of 17 in combination with dynamic kinetic resolution. Preliminary screening employing
41
42
43,44
different catalysts Cat I, Cat II, and Cat III
with HCOOH/Et N (5:2) as the hydrogen donor demonstrated
3
that faster reaction times as well as better diastereoselectivities in favor of compound anti-23 (dr = 78:22)
were obtained with catalyst Cat III. Moreover, the catalytic charge could be decreased from 2 mol% to 0.1
Page 7
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
mol% without any loss of stereoselectivity and compound 23 was isolated with a comparable 70% yield. It is
noteworthy that at this point of the synthesis inseparable mixtures of syn- and anti-isomers were obtained. To
complete the synthesis of fragment B, the newly formed hydroxy-ester 23 was protected by using TBSCl and
imidazole in 51% yield before hydrolysis of the ester with TMSOK yielded the fully protected compound anti-
B'. Gratifyingly, flash chromatography allowed separation of the syn- and anti-isomers (Scheme 8).
O
O
OH O
Cat (2 mol %)
HCOOH/Et N (5:2) (2 equiv)
PMBO
Cat =
PMBO
OMe
NHBoc
OMe
NHBoc
anti-23
3
CH Cl , T (°C), t (h)
2
2
1
7
Ru
Rh
Cl
NH
Ru
Cl
Cl
NTs
Ph
NTs
Ph
MeO
TsN
H N
2
N
Ph
H
Ph
Cat III
rt, 45 min
Ph
Ph
Cat II
Cat I
rt, 25 h then 40 °C, 24 h
rt, 1 h
71% (dr = 62:38, er = 96:4) 69% (dr = 58:42, er = 88:12) 74% (dr = 78:22, er = 97:3)
TBSO
PMBO
O
TBSO
PMBO
O
TBSCl, imidazole
DMF, rt
TMSOK
anti-23
OMe
NHBoc
anti-24
OH
NHBoc
anti-B'
THF, rt
66%
51%
Scheme 8. Synthesis of compound anti-B' through asymmetric transfer hydrogenation.
Thus, compound anti-B' was synthesized in 7 steps starting from ethylene glycol 20 in 2.2% overall yield.
This strategy inherently makes the synthesis flexible because all the four stereoisomers of fragment B can be
synthesized by simply changing the configuration of the chiral ligand and by moving from asymmetric
hydrogenation to asymmetric transfer hydrogenation.
Synthesis of stereoisomers of the C44−C65 side chain
As outlined above, flexibility of our synthetic plan was essential as the configurations of several stereogenic
centers remain unknown. We decided to prepare other isomers of the north fragment of the targeted
molecule (C44-C65 fragment, the two relevant stereocenters are highlighted with a star on Scheme 9). As
such, it was shown previously that the C44-C65 part of the molecule could easily be synthesized after
1
8
assembly of fragments C1, C2 and C3 (Scheme 9). Herein, we focused our attention to the modifications of
the two C46 and C49 stereocenters of fragment C3. The stereogenic center at C46 would be easily modulated
by simply changing the configuration of the upstream Roche ester, while modification of the configuration at
the C49 stereocenter would be achieved by switching the ligand configuration during the asymmetric
hydrogenation, thus allowing access to new isomers of the side chain.
Page 8
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
peptide
coupling
Nozaki-Hiyama-Kishi
TBS
OTBS
OTBS
50
O
O
H
56
N
*
46
44 OMe
65
57
*49
51
TBSO
O
O
TBSO
C1
C2
C3
Scheme 9. Retrosynthetic analysis of mirabalin side chain C44-C65
The synthesis began with the benzyl protection of (R)-Roche ester 25 followed by reduction of the
4
5
resulting ester 26 to 27 using LiAlH
2
4
. Garegg iodination (I
2
, PPh
3
, imid, CH
2
Cl
2
, rt) of the latter afforded iodide
4
6
8, which was used for the alkylation of methyl acetoacetate to provide the key β-keto ester 29 (Scheme 10).
With convenient amounts of compound 29 in hand, ruthenium-catalyzed asymmetric hydrogenation of the
ketone was tackled. This transformation was accomplished using the in situ generated chiral complexes either
[
RuBr
2
((S)-Synphos)] or [RuBr
2
((R)-Synphos)]. The stereochemical outcome of the reaction was controlled by
choosing the appropriate configuration of the Synphos ligand and the reaction afforded (S,S)-30 and (R,S)-30 in
8
7% and 93% yields, respectively, as single diastereomers. The protection of these alcohols (TBSOTf, 2,6-
o
lutidine, CH
2
Cl
2
, 0 C) yielded (S,S)-31 and (R,S)-31 which were subjected to debenzylation conditions (H
2
,
Pd/C) to give (S,S)-32 and (R,S)-32, and subsequent Dess-Martin oxidation afforded aldehydes (S,S)-33 and
R,S)-33 required for the Nozaki-Hiyama-Kishi47,48 coupling with (E)-iodoalkene 34. This reaction was
18
(
performed in DMSO using CrCl
2
(14 equiv) in the presence of a catalytic amount of NiCl (dppe) (6 mol%).
2
Under these conditions, alcohols 35 and 36 were obtained in 25% and 34% yields, respectively (quantitative
yields based on the recovered starting material) as a mixture of diastereomers (dr = 75:25 for 35, dr = 71:29
for 36) which were separated by flash chromatography on silica gel.
Page 9
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
OH
O
OBn O
OBn OH
OBn I
BnOC(NH)CCl , TfOH
LiAlH4
I2, PPh3, imidazole
CH Cl , rt
3
OMe
OMe
Et O, 0 °C
2
CH Cl , rt
2
2
2
2
7
4%
95%
81%
2
5
26
27
28
H (11 bar)
CH COCH CO Me
2
R1 R2
O
3
2
2
O
O
NaH, n-BuLi
[RuBr ((S)-Synphos)]
2
BnO
OMe
BnO
OMe
THF, 0 °C then rt
or [RuBr2((R)-Synphos)]
1 mol %)
(
5
6%
1
2
2
9
(S,S)-30, R = H, R = OH (87%)
MeOH, 50 °C
1
2
or (R,S)-30, R = OH, R = H (93%)
1
2
1
2 O
O
R R
R R
TBSOTf, 2,6-lutidine
H (1 atm), Pd/C
2
BnO
OMe
HO
OMe
CH Cl , 0 °C
THF, rt
2
2
1
2
1
2
(
S,S)-31, R = H, R = OTBS (96%)
(S,S)-32, R = H, R = OTBS (93%)
1
2
1
2
(
R,S)-31, R = OTBS, R = H (82%)
(R,S)-32, R = OTBS, R = H (95%)
1
2
O
R R
Dess-Martin periodinane
CH Cl , rt
O
OMe
2
2
1
2
OTBS
H
(
(
S,S)-33, R = H, R = OTBS (67%)
1
2
N
I
R,S)-33, R = OTBS, R = H (64%)
TBSO
O
O
TBSO
3
4
3
4, CrCl , NiCl (dppe)
34, CrCl , NiCl (dppe)
DMSO, rt
2
2
2
2
25%
34%
DMSO, rt
OTBS
OH
OTBS
OH
H
H
N
N
TBSO
O
O
TBSO
O
O
OTBS
OTBS
TBSO
TBSO
MeO
O
MeO
O
3
5 (75:25)
36 (71:29)
Scheme 10. Synthesis of stereoisomers 35 and 36 of the C44-C65 side chain of mirabalin.
In summary, the facile synthesis of two new isomers 35 and 36 of the C44-C65 part of mirabalin
demonstrated the high flexibility of the synthetic plan offered by using asymmetric reduction and one can
envisage to access other stereoisomers using this versatile reduction.
Page 10
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
Conclusions
In conclusion, the synthesis of several key fragments of mirabalin 1 was achieved using flexible and robust
methods based on asymmetric hydrogenation and transfer hydrogenation. The C30–C67 fragment (compound
A') as well as two isomers of the C1–C36 subunits (compounds syn-B' and anti-B') have been prepared.
Moreover the synthesis of two isomers of the C44-C65 part of mirabalin has been achieved. Most importantly,
the flexibility of this approach provides a platform for modification of several unknown stereocenters. The
assembly of the different fragments is currently being pursued in our laboratory.
Experimental Section
General. All air and/or water sensitive reactions were carried out under an argon atmosphere.
Tetrahydrofuran and diethyl ether were distilled from sodium-benzophenone. Dichloromethane was distilled
from calcium hydride. Reactions were monitored by thin layer chromatography carried out on precoated silica
gel plates (E. Merck ref. 5554 60 F254) and revealed with either an ultra-violet lamp (= 254 nm), a potassium
permanganate solution (3 g KMnO
4
, 20 g K
2
CO
3
, 0.25 mL AcOH, 300 mL H O), a ninhydrin solution (1 g
2
ninhydrin, 100 mL EtOH/H
2
SO
4
: 95/5) or a Kagi-Mosher solution (8 mL p-anisaldehyde, 16 mL H
2
13
SO , 800 mL
4
1
AcOH). The nuclear magnetic resonance spectra were recorded on a Bruker AC 300 ( H: 300 MHz, C: 75 MHz)
1
13
or an Avance 400 ( H: 400 MHz, C: 100 MHz) instrument. Data are reported as follows: chemical shifts (δ),
multiplicity (recorded as s singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sxt, sextet; sep, septet; m,
multiplet; dd, doublet of doublets; dt, doublet of triplets; td, triplet of doublets; br, broad), integration and
coupling constants. Melting points (mp) were determined on a Bꢀchi apparatus and are uncorrected. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter. High resolution mass spectrometric (HRMS)
analyses were measured on LTQ-Orbitrap (Thermo Fisher Scientific) at Pierre et Marie Curie University.
Enantiomeric excesses were determined by HPLC using a chiral stationary phase column (Chiralpak IA) and
eluting with a hexane/isopropanol mixture as indicated.
Methyl (Z)-2-(hydroxyimino)-3-oxobutanoate (6). A solution of methyl acetoacetate 5 (15 g, 129 mmol, 1
o
equiv) in acetic acid (100 mL) was cooled to 0 C and a suspension of NaNO
2
(22.3 g, 323 mmol, 2.5 equiv) in
o
water (75 mL) was added dropwise, the temperature of the reaction mixture being kept below 5 C. After
evolution of the brown fumes, the stirring was maintained 1.5 h at 0 C and then at rt until completion of the
o
reaction, monitored by TLC (1 h). The reaction mixture was then diluted and extracted with Et
2
O. The
combined organic layers were washed with saturated aqueous NaHCO , dried over MgSO , concentrated
3
4
under reduced pressure and the crude mixture was purified by silica gel column chromatography
o
(
(
cyclohexane/EtOAc: 6/4) to give the desired product 6 (9.54 g, 51%) as a white solid. mp 39 C; R
f
-
1 1
cyclohexane/EtOAc: 8/2) 0.17; IR (film): 3353, 1742, 1681, 1415, 1317, 1244, 1070, 1000 cm ; H NMR (300
1
3
MHz, CDCl
3
)  9.33 (s, 1H), 3.91 (s, 3H), 2.41 (s, 3H). C NMR (75 MHz, CDCl )  193.9, 162.1, 151.0, 52.8, 25.3.
3
Methyl 2-amino-3-oxobutanoate hydrochloride (4). To a solution of oxime 6 (7.34 g, 51 mmol, 1 equiv) in
MeOH (126 mL) was added Pd/C 10% (1.79 g, 1.68 mmol, 0.033 equiv). 2N HCl in Et O (84.2 mL, 168.3 mmol,
.3 equiv) was added dropwise to the resulting mixture and the argon atmosphere was replaced with
hydrogen (balloon). The reaction mixture was stirred at rt under atmospheric pressure of hydrogen for 24 h
reaction monitored by TLC). The suspension was then filtered on a celite pad and washed with MeOH. The
filtrate was concentrated under reduced pressure and the yellow solid was washed with EtOAc to give the title
2
3
(
Page 11
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
o
compound 4 as a white solid (6.57 g, 77%). mp 148 C; IR (film): 3419, 2986, 1745, 1727, 1469, 1279, 1241,
-
1 1
1
164, 1131, 1089, 878 cm ; H NMR (300 MHz, DMSO-d
6
)  9.08 (s, 3H), 5.26 (s, 1H), 3.79 (s, 3H), 2.38 (s, 3H);
1
3
C NMR (75 MHz, DMSO-d
6
)  196.7, 164.2, 61.2, 53.6, 28.2.
Methyl (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate (7). (R)-Synphos (377 mg, 0.59 mmol,
3
0
.022 equiv) and [Ru(COD)(η -2-methylallyl)
2
] (171 mg, 0.54 mmol, 0.02 equiv) were placed in a reaction tube
and the vessel was purged with argon. Anhydrous acetone (20 mL) previously degassed by three vacuum-
argon cycles was added at rt. To this suspension was added dropwise methanolic HBr (6.6 mL, 0.044 equiv of a
0
.18N solution prepared by adding 48% aqueous HBr in degassed methanol) and the suspension was stirred at
room temperature for 30 min. The suspension immediately turned yellow, then an orange precipitate
appeared and the solvent was thoroughly evaporated under vacuum to give the catalyst as an orange-brown
solid [RuBr
2
((R)-Synphos)], which was used directly. The β-keto ester hydrochloride 4 (4.5 g, 26.9 mmol, 1
Cl (20 mL) and degassed alcoholic
equiv) was then added followed by previously degassed anhydrous CH
2
2
solvent MeOH (2 mL). The reaction vessel was degassed by three vacuum-argon cycles and then placed under
argon in a 250 mL stainless steel autoclave. The argon atmosphere was replaced with hydrogen by three cycles
o
of pressurizing and the pressure adjusted to 13 bar. The autoclave was heated at 50 C and stirring was
maintained for 23 h. After cooling, the reaction mixture was concentrated under reduced pressure to afford
the crude β-hydroxy ester. It was then dissolved in degassed MeOH (50 mL) and NaHCO
3
(9.02 g, 107.4 mmol,
4
equiv) and di-tert-butyl dicarbonate (5.86 g, 26.9 mmol, 1 equiv) was added. The mixture was stirred under
ultrasonic irradiation during 4 h. The solvent was removed under reduced pressure and the crude mixture was
purified by silica gel column chromatography (petroleum ether/EtOAc: 6/4) to give the desired product 7 (4.37
2
D
0
1
g, 70%) as a white solid. R
f
(cyclohexane/EtOAc: 6/4) 0.28; [] −19.0 (c 0.63, CHCl
3
); H NMR (300 MHz,
CDCl )  5.46 (s, 1H), 4.36 (s, 1H), 4.17 − 4.05 (m, 1H), 3.76 (s, 3H), 2.55 (s, 1H), 1.43 (s, 9H), 1.20 (d, J 6.3 Hz,
3
1
3
3
H); C NMR (75 MHz, CDCl
diastereoselectivities were determined by HPLC after the asymmetric hydrogenation step on the
corresponding benzamide derivative. HPLC : Chiralpak AS-H, hexane/iPrOH 94/6, 1 mL/min, λ = 215 nm; t
syn] = 33.8 min, t [anti] = 37.3 min, t [syn] = 41.4 min, t [anti] = 50.4 min.
3
)  171.0, 156.1, 80.5, 68.9, 59.0, 52.4, 28.2, 18.8. Enantio- and
R
[
R
R
R
Methyl (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]butanoate (8). To a solution
of 7 (7.23 g, 31 mmol, 1 equiv) in dry DMF (28 mL) were added successively imidazole (0.876 g, 12.87 mmol, 3
equiv) and TBSCl (1.62 g, 10.73 mmol, 2.5 equiv) at rt. The mixture was stirred for 23 h at rt, then brine and
Et
brine, dried over MgSO
petroleum ether/EtOAc: 96/4) to give 8 (10.23 g, 95%) as a colorless oil. R
2
O were added. The aqueous phase was extracted with Et
, filtered and concentrated. The residue was purified by flash chromatography (SiO
(cyclohexane/EtOAc: 95/5) 0.26;
2
O. The combined organic layers were washed with
4
2
,
f
20
-
1 1
[
] −27.6 (c 0.78, CHCl ); IR (film): 2955, 2935, 2858, 1721, 1498, 1365, 1253, 1168, 834, 778 cm ; H NMR
3
D
(
9
5
300 MHz, CDCl
3
)  5.26 (d, J 8.6 Hz, 1H), 4.23 (dd, J 8.2, 3.4 Hz, 1H), 4.12 − 4.02 (m, 1H), 3.74 (s, 3H), 1.44 (s,
1
3
H), 1.23 (d, J 6.4 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 6H); C NMR (75 MHz, CDCl
1.9, 28.3, 25.6, 20.4, 17.9, –4.6, –5.1.
3
)  170.7, 155.1, 79.7, 69.9, 59.6,
tert-Butyl (4R,5R)-4-[(tert-butoxycarbonyl)amino]-5-[(tert-butyldimethylsilyl)oxy]-3-oxohexanoate (9)
To a solution of diisopropylamine (14.1 mL, 100.4 mmol, 3.6 equiv) in dry THF (175 mL) was added n-
o
o
butyllithium (49 mL, 97.7 mmol, 2M, 3.5 equiv) at 0 C and the mixture was stirred at 0 C for 45 min. The
o
solution was then cooled to −45 C and tert-butyl acetate (15 mL, 111.6 mmol, 4 equiv) was added. The
resulting mixture was stirred for 1.5 h at −45 C before a solution of 8 (9.7 g, 27.9 mmol, 1 equiv) in 50 mL of
dry THF was added via cannula (rinsed with 25 mL). The reaction mixture was stirred at −45 C for 22 h. The
solution was then warmed to 0 C before the reaction was quenched with 200 mL of saturated NH
o
o
o
4
Cl. The
aqueous phase was extracted with EtOAc and the combined organic layers were washed with saturated
Page 12
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
NaHCO
3
and brine. The organic phase was dried over MgSO
4
, filtered and concentrated under reduced
pressure to afford the crude mixture which was purified by flash column chromatography (SiO
2
, petroleum
ether/EtOAc: 92/8) to yield the desired compoud 9 (10.5 g, 87%) as a colorless oil. R (cyclohexane/EtOAc: 9/1)
f
2
D
0
-
1 1
0
(
.49; [] −13.2 (c 2.05, CHCl
3
); IR (film) : 2979, 2931, 2859, 1714, 1500, 1367, 1253, 1161, 833 cm ; H NMR
)  5.22 (d, J 8.4 Hz, 1H), 4.29 (dd, J 7.1, 6.4 Hz, 1H), 4.02 (quint, J 6.2 Hz, 1H), 3.59 (d, J 16.0
Hz, 1H), 3.45 (d, J 16.1 Hz, 1H), 1.46 (s, 9H), 1.43 (s, 9H), 1.23 (d, J 6.3 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s,
300 MHz, CDCl
3
1
3
3
−
H); C NMR (75 MHz, CDCl
4.7, −5.0; HRMS (ESI): calculated for C21
3
)  201.5, 165.9, 155.2, 82.0, 79.9, 70.2, 64.3, 50.4, 28.3, 27.9, 25.7, 20.7, 17.9,
NSiNa: 454.2595, found : 454.2592.
H O
41 6
tert-Butyl (3R,4S,5R)-4-[(tert-butoxycarbonyl)amino]-5-[(tert-butyldimethylsilyl)oxy]-3-hydroxyhexanoate (10)
A degassed solution of 9 (100 mg, 0.23 mmol, 1 equiv) in EtOH (3.8 mL) was prepared in a reaction tube and
the vessel was purged with argon. Solid catalyst [{RuCl((S)-Synphos)}
.01 equiv) was then added and the reaction vessel was degassed by three vacuum-argon cycles and then
2
(μ-Cl)
3
][Me
2
NH ] (3.9 mg, 0.0023 mmol,
2
0
placed under argon in a 250 mL stainless steel autoclave. The argon atmosphere was replaced with hydrogen
o
by three cycles of pressurizing and the pressure adjusted to 100 bar. The autoclave was heated at 50 C and
stirring was maintained for 6 h. After cooling, the reaction mixture was concentrated under reduced pressure
to afford the crude product which was purified by flash chromatography (SiO
2
, petroleum ether/iPr
2
O: 8/2) to
20
afford the desired compound 10 (70 mg, 70%) as a colorless oil. R
f
(cyclohexane/EtOAc: 9/1) 0.41; [] −25.0
)  5.22 (d, J 9.2 Hz, 1H), 4.61 (dd, J 4.8, 8.5 Hz, 1H), 4.13 (m, 1H), 3.57
D
1
(
(
(
c 0.88, CHCl
3
); H NMR (300 MHz, CDCl
3
bs, 1H), 3.31 (dd, J 3.5, 9.3 Hz, 1H), 2.40 (dd, J 8.5, 16.0 Hz, 1H), 2.33 (dd, J 4.9, 16.1 Hz, 1H), 1.46 (s, 9H), 1.44
1
3
s, 9H), 1.27 (d, J 6.4 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.08 (s, 3H); C NMR (75 MHz, CDCl
3
)  171.1, 155.7,
8
C
0.9, 79.3, 71.8, 66.0, 56.9, 40.0, 28.4, 28.1, 25.7, 20.7, 17.8, −4.7, −5.1; HRMS (ESI): calculated for
+
21
H
43
6
O NSiNa [M + Na] : 456.2757, found : 456.2752.
tert-Butyl (4S,5R)-5-[2-(tert-butoxy)-2-oxoethyl]-4-(R)-1-{[(tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyl-
oxazolidine-3-carboxylate (11). To a solution of ester 10 (2.6 g, 6 mmol, 1 equiv) in dry CH Cl (100 mL) was
2
2
added distilled dimethoxypropane (3.9 mL, 32 mmol, 5.3 equiv) and ()-camphorsulfonic acid (0.265 g, 1.14
mmol, 0.19 equiv) at rt. The mixture was stirred at reflux for 1 h. The solution was then cooled to rt and
saturated NaHCO
were washed with saturated NaHCO
pressure. The crude product was purified by flash chromatography (SiO
to 6/4) to afford the desired compound 11 (0.757 g, 27%) as a white solid. R
3
was added. The aqueous phase was extracted with CH
and brine, dried over MgSO , filtered and concentrated under reduced
, petroleum ether/EtOAc: 93/7 to 8/2
(cyclohexane/EtOAc: 8/2,
) δ 5.00 − 4.77 (m, 1H), 4.60 (s, 1H), 3.72 (s,
H), 2.77 − 2.05 (m, 2H), 1.59 (bs, 6H), 1.38 (s, 9H), 1.35 (s, 9H), 1.06 (d, J 6.4 Hz, 3H), 0.94 (s, 9H), 0.09 (s, 3H),
2
Cl
2
and the combined organic layers
3
4
2
f
20
1
ninhydrin) 0.68; [] −21.5 (c 0.79, CHCl
); H NMR (300 MHz, C
6 6
D
3
D
1
0
2
4
1
3
.03 (s, 3H); C NMR (75 MHz, C
6
D
6
) δ 169.2, 152.3, 79.9, 79.4 (2C), 72.2, 67.5, 66.5, 42.7, 28.5, 28.2, 28.0,
+
7.3, 26.2, 21.2, 18.3, −4.4, −4.5; HRMS (ESI): calculated for C24
H
47
6
O NSiNa [M + Na] : 496.3070, found :
96.3065.
tert-Butyl (4S,5R)-4-{(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyl-5-(2-oxoethyl)oxazolidine-3-car-
boxylate (3). Diisobutylaluminum hydride (1 M solution in toluene, 2.3 mL, 2.3 mmol, 1.5 equiv) was added to
o
o
a cooled (–85 C) solution of the ester 11 (733 mg, 1.5 mmol, 1 equiv) in CH
2
Cl (19 mL). After 1.5 h at –85 C,
2
o
Rochelle salt was added at –85 C and the resulting mixture was warmed to rt and stirred overnight. The
biphasic solution was extracted with CH
and brine, dried over MgSO and concentrated under reduced pressure. The residue was purified by flash
column chromatography (pentane/EtOAc: 9/1) to afford compound 3 (1.23 g, 77%) as a colorless oil. R
2
2
Cl . The combined organic extracts were washed with Rochelle salt
4
f
2
D
0
(
cyclohexane/EtOAc: 8/2, ninhydrin) 0.41; [] −35.4 (c 0.79, CHCl
3
); IR (film): 3439, 2978, 2937, 2856, 1697,
) δ 9.44 (dd, J 2.9, 1.5 Hz, 1H), 4.76 (ddd, J
-
1 1
1
463, 1376, 1257, 1079, 838, 777, 741 cm ; H NMR (300 MHz, C
6
D
6
Page 13
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
8
.4, 5.6, 4.3 Hz, 1H), 4.70 (bs, 1H), 3.50 (bs, 1H), 2.27 (ddd, J 16.0, 8.4, 2.9 Hz, 1H), 2.13 (ddd, J 16.0, 4.3, 1.5
1
3
Hz, 1H), 1.58 (bs, 6H), 1.41 (s, 9H), 0.96 (s, 9H), 0.95 (bs, 3H), 0.10 (s, 3H), 0.05 (s, 3H); C NMR (75 MHz, C
6
D )
6
δ 198.5, 152.2, 94.5, 79.5, 69.8, 67.6, 65.4, 49.6, 28.3, 27.2, 27.1, 26.0, 20.9, 18.1, −4.3, −4.7; HRMS (ESI):
+
calculated for C20
H
39
O
5
NSiNa [M + Na] : 424.2495, found : 424.2490.
tert-Butyl (4S,5R)-4-{(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-5-((R)-2-hydroxybut-3-en-1-yl)-2,2-dimethyl-
oxazolidine-3-carboxylate (12). A 0.7 M solution of vinyl magnesium bromide in THF (4.8 mL, 3.33 mmol, 3
o
equiv) was added to a solution of aldehyde 3 (447 mg, 1.11 mmol, 1 equiv) in dry THF (1.9 mL) at –78 C. The
o
o
mixture was stirred at –78 C for 4 h. Saturated NH
The aqueous phase was extracted with EtOAc and the combined organic layers were washed with saturated
NH Cl, dried over MgSO , filtered and concentrated under vacuum. Purification of the crude material by flash
chromatography (SiO , pentane/iPr O: 8/2 to pentane/EtOAc: 8/2) afforded 12 (major diastereomer, 231 mg,
8%) as well as the minor diastereoisomer (137 mg, 29%) as colorless oils. R (cyclohexane/EtOAc: 8/2,
); H NMR (major) (300 MHz, CDCl ) δ
.82 (ddd, 1H, J 17.2, 10.4, 5.6 Hz), 5.35 (dd, 1H, J 17.2, 1.7 Hz), 5.06 − 4.99 (m, 1H), 4.72 (s l, 1H), 4.56 (ddd,
H, J 9.9, 5.5, 3.3 Hz), 4.38 (m, 1H), 3.60 (bs, 1H), 2.69 (s, 1H), 2.02 − 1.48 (m, 8H), 1.41 (s, 9H), 1.01 (d, 3H, J
4
Cl was added at –78 C and the solution was warmed to rt.
4
4
2
2
4
f
2
D
0
1
ninhydrin) 0.46 (minor), 0.37 (major); [] (major): −35.8 (c 0.74, CHCl
3
3
5
1
5
7
C
1
3
.2 Hz), 0.96 (s, 9H), 0.11 (s, 3H), 0.06 (s, 3H); C NMR (major) (75 MHz, C
4.1, 71.4, 68.3, 65.4, 43.9, 28.3, 27.4, 27.1, 26.0, 21.0, 18.1, −4.3, −4.7; HRMS (ESI): calculated for
6
6
D ) δ 150.2, 141.2, 114.1, 94.4, 79.4,
+
22
H
43
O
5
NSiNa [M + Na] : 452.2808, found : 452.2803.
tert-Butyl (4S,5R)-5-((R)-2-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4-((R)-1-((tert-butyldimethylsilyl)oxy)
ethyl)-2,2-dimethyloxazolidine-3-carboxylate (2). To a solution of 12 (146 mg, 0.34 mmol, 1 equiv) in dry DMF
(
1 mL) were added successively TBSCl (75 mg, 0.5 mmol, 1.5 equiv) and imidazole (46 mg, 0.68 mmol, 2 equiv)
o
at 0 C. The mixture was stirred for 19 h at rt, then brine and EtOAc were added. The aqueous phase was
extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO
concentrated. The residue was purified by flash chromatography (SiO , petroleum ether/iPr O: 95/5) to give 2
(cyclohexane/EtOAc: 85/15, ninhydrin) 0.79; [] −11.7 (c 0.74, CHCl
); IR
) δ 5.95
ddd, J 17.2, 10.3, 6.8 Hz, 1H), 5.29 (d, J 17.1 Hz, 1H), 5.05 (d, J 10.3 Hz, 1H), 4.90 − 4.21 (m, 3H), 3.63 (bs, 1H),
.17 − 1.54 (m, 8H), 1.43 (s, 9H), 1.01 (bs, 12H), 0.96 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.06 (s, 3H);
4
, filtered and
2
2
20
(
(
(
146 mg, 79%) as a colorless oil. R
film): 2957, 2930, 2858, 1695, 1471, 1464, 1364, 1256, 1082, 836, 776 cm ; H NMR (300 MHz, C
f
3
D
-
1 1
D
6 6
2
1
3
C NMR (75 MHz, C
6
D
6
) δ 152.2, 141.2, 114.8, 93.8, 79.2, 72.1, 71.2, 68.1, 65.4, 45.4, 28.3, 27.4, 27.1, 26.1,
+
2
6.0, 21.1, 18.3, 18.1, −4.2, −4.6 (2C), −4.7; HRMS (ESI): calculated for C28
H
57
O
5
NSi
2
Na [M + Na] : 566.3673,
found : 566.3668.
tert-Butyl (4S,5R)-5-{(S)-2-[(tert-butyldimethylsilyl)oxy]-4-hydroxybutyl}-4-{(R)-1-[(tert-butyldimethylsilyl)-
oxy]ethyl}-2,2-dimethyloxazolidine-3-carboxylate (13). To a solution of 2 (137 mg, 0.25 mmol, 1 equiv) in dry
o
THF (1.4 mL) was added BH
0
3
3
.Me
2
S (2M in THF, 0.25 mL, 0.75 mmol, 3 equiv) at 0 C. The mixture was stirred at
o
C for 1 h then allowed to rise to rt. NaOH 3M (1.25 mL, 3.75 mmol, 15 equiv) and 35% H
2
O
2
in H
2
O (0.32 mL,
Cl
. The combined organic layers were washed with
, filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography (SiO , petroleum ether/EtOAc: 9/1 to 8/2) to give 13 (105 mg, 75%) as a pale
yellow oil. R (cyclohexane/EtOAc: 8/2, ninhydrin) 0.41; H NMR (400 MHz, C
o
.75 mmol, 15 equiv) were added at 0 C and the resulting solution was stirred at rt for 1 h. Saturated NH
Cl
4
was added and the aqueous phase was extracted with CH
saturated NH Cl, dried over MgSO
2
2
4
4
2
1
o
f
6
D , 50 C) δ 4.74 − 4.60 (m, 1H),
6
4
2
9
.52 (ddd, J 9.8, 5.7, 3.0 Hz, 1H), 4.27 (m, 1H), 3.82 − 3.63 (m, 2H), 3.58 (dd, J 5.7, 3.1 Hz, 1H), 2.04 − 1.85 (m,
H), 1.82 − 1.67 (m, 2H), 1.62 (bs, 3H), 1.44 (s, 9H), 1.43 (bs, 3H), 1.11 (d, J 6.5 Hz, 3H), 0.97 (s, 9H), 0.97 (s,
1
3
o
H), 0.13 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.09 (s, 3H); C NMR (100 MHz, C
6
D
6
, 50 C) δ 152.6, 94.7, 79.6,
Page 14
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
7
2.3, 69.2, 69.0, 66.6, 59.8, 44.9, 38.9, 28.6, 27.7, 27.3, 26.3, 26.2, 21.4, 18.3, 18.3, −3.9, −4.1, −4.4, −4.5;
+
HRMS (ESI): calculated for C28
H
59
O
6
NSi Na [M + Na] : 584.3779, found : 584.3773.
2
tert-Butyl (4S,5R)-5-{(R)-2-[(tert-butyldimethylsilyl)oxy]-4-{[(1-phenyl-1H-tetrazol-5-yl)thio]butyl}-4-{[(R)-1-
tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyloxazolidine-3-carboxylate (14). To a solution of 13 (107 mg,
.19 mmol, 1 equiv) in dry THF (1.6 mL) were successively added triphenylphosphine (60 mg, 0.23 mmol, 1.2
equiv), 1-phenyl-1H-tetrazole-5-thiol (41 mg, 0.23 mmol, 1.2 equiv) and DIAD (0.12 mL, 0.23 mmol, 1.2 equiv)
dropwise at rt. The mixture was stirred at rt for 22.5 h. Saturated NaHCO was added and the aqueous phase
was extracted with EtOAc. The combined organic phases were washed with saturated NaHCO , dried over
MgSO , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography
SiO , petroleum ether/iPr O: 9/1 to petroleum ether/EtOAc: 9/1) to give 14 (109 mg, 80%) as a pale yellow
oil. R (cyclohexane/EtOAc: 8/2, ninhydrin, UV) 0.63; H NMR (400 MHz, CDCl
(
0
3
3
4
(
2
2
1
o
f
3
, 50 C) δ 7.62 − 7.48 (m, 5H),
4
2
9
1
.46 (bs, 1H), 4.33 (ddd, J 10.0, 5.7, 2.9 Hz, 1H), 4.15 − 4.06 (m, 1H), 3.58 − 3.40 (m, 3H), 2.24 − 2.13 (m, 1H),
.06 − 1.86 (m, 2H), 1.84 − 1.74 (m, 1H), 1.56 (s, 3H), 1.49 (s, 9H), 1.46 (s, 3H), 1.11 (d, J 6.5 Hz, 3H), 0.91 (s,
1
3
o
H), 0.89 (s, 9H), 0.09 (s, 6H), 0.07 (s, 3H), 0.04 (s, 3H); C NMR (100 MHz, CDCl , 50 C) δ 154.6, 152.7, 134.4,
3
30.1, 129.9, 124.2, 94.6, 80.1, 71.7, 69.0, 68.7, 66.3, 44.2, 35.8, 29.9, 28.7, 27.4, 27.2, 26.2, 26.1, 21.4, 18.2
+
(2C), −4.0, −4.1, −4.3 (2C); HRMS (ESI): calculated for C35
H
63
5
O N
5
Si
2
SNa [M + Na] : 744.3986, found : 744.3981.
tert-Butyl (4S,5R)-5-{(R)-2[(tert-butyldimethylsilyl)oxy]-4-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]butyl}-4-{(R)-
1
0
0
-[(tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyloxazolidine-3-carboxylate (A'). To a solution of 14 (95 mg,
.13 mmol, 1 equiv) in dry CH
2
Cl
2
(2 mL) were added NaHCO
3
(33 mg, 0.39 mmol, 3 equiv) and m-CPBA (67 mg,
o
o
.39 mmol, 3 equiv) at 0 C. The mixture was stirred for 14 h at rt. Saturated Na
2
S
2
O
3
was added at 0 C and
the mixture was diluted with CH
CH Cl . The combined organic phases were dried over MgSO
pressure. The residue was purified by flash chromatography (SiO
mg, 68%) as a pale yellow oil. R (cyclohexane/EtOAc: 8/2, ninhydrin, UV) 0.58; H NMR (300 MHz, CDCl
.74-7.65 (m, 2H), 7.65 − 7.55 (m, 3H), 4.54 (bs, 1H), 4.41 − 4.24 (m, 1H), 4.18 − 4.05 (m, 1H), 3.94 − 3.74 (m,
H), 3.43 (bs, 1H), 2.36 − 2.21 (m, 1H), 2.19 − 2.05 (m, 1H), 1.80 − 1.60 (m, 2H), 1.55 (bs, 3H), 1.47 (s, 9H), 1.44
2
Cl
2
. The white solid was filtered and the aqueous layer was extracted with
, filtered and concentrated under reduced
, pentane / iPr O: 9/1 to 8/2) to give A' (67
2
2
4
2
2
1
f
3
) δ
7
2
1
3
(
bs, 3H), 1.08 (d, J 6.6 Hz, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.01 (s, 3H); C
NMR (75 MHz, CDCl ) δ 153.7, 152.7, 133.3, 131.6, 129.9, 125.2, 94.4, 80.2, 70.3, 68.1, 67.7, 64.7, 52.8, 43.4,
0.3, 28.6, 27.0 (2C), 26.1, 26.0, 21.2, 18.1, 18.1, −4.1, −4.3, −4.6 (2C); HRMS (ESI): calculated for
3
3
C
+
35
H
63
O
7
N
5
Si SNa [M + Na] : 776.3884, found : 776.3879.
2
(
2S,3S)(E)-2-[(tert-Butyldimethylsilyl)oxy]-5-iodo-3-methylhex-4-en-1-ol (15). To a solution of (2S,3S,E)-2-
19
((tert-butyldimethylsilyl)oxy)-5-iodo-3-methylhex-4-en-1-ol (150 mg, 0.31 mmol, 1 equiv) in EtOH (70 mL)
was added PPTS (7.8 mg, 0.03 mmol, 0.1 equiv) at rt. After 24 h at rt, the mixture was concentrated under
reduced pressure. Purification by flash chromatography on silica gel (petroleum ether/Et O = 100:0 to 80:20)
afforded the alcohol 15 as a pale yellow oil (55 mg, 47%) and bis-protected alcohol was recovered (57 mg,
2
2
D
0
3
8%). [] –35.5 (c 0.64, CHCl
3
); IR (neat): 3416, 1636, 1471, 1462, 1378, 1361, 1525, 1150, 1098, 1046, 1006
) δ 6.01 (dq, J 10.2, 1.5 Hz, 1H), 3.61 – 3.48 (m, 3H), 2.69 (m, 1H), 2.38 (d, J 1.5
-
1 1
cm ; H NMR (400 MHz, CDCl
Hz, 3H), 1.71 (brt, J 6.0 Hz, 1H), 0.97 (d, J 6.9 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); C NMR (100 MHz,
CDCl ) δ 143.5, 94.5, 75.8, 64.3, 38.3, 27.9, 25.9, 18.0 (3C), 16.5, –4.4, –4.5; MS (EI) m/z: 339 (4), 313 (9, [M-
tBu] ), 255 (20), 195 (37), 186 (5), 185 (11), 181 (10), 175 (11), 119 (5), 117 (14), 115 (12), 111 (7), 105 (30),
03 (23), 94 (9), 93 (9), 77 (11), 75 (98), 73 (100).
3
1
3
3
+
1
tert-Butyl (4S,5R)-5-{(2S,4E,6R,7S,8E)-2,6-bis[(tert-butyldimethylsilyl)oxy]-9-iodo-7-methyldeca-4,8-dien-1-
yl}-4-{(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyloxazolidine-3-carboxylate (16). To a solution of
1
5 (40 mg, 0.11 mmol, 1 equiv) in dry CH
2
2
Cl were added at rt MS 4Å (30 mg), TPAP (3 mg, 0.01 mmol, 0.08
Page 15
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
equiv) and NMO (15 mg, 0.13 mmol, 1.2 equiv). The mixture was stirred for 2 h at rt and filtered over a pad of
celite (CH Cl ). The crude aldehyde was used directly into the next step. To a solution of A (55 mg, 0.07 mmol,
equiv) in dry THF (1.5 mL) was added dropwise KHMDS (0.15 mL, 0.07 mmol, 0.5 M in toluene, 1.05 equiv) at
2
2
1
o
o
–
78 C. The brown solution was stirred for 30 min at –78 C before adding dropwise a solution of the crude
o
aldehyde (40 mg, 0.11 mmol, 1.5 equiv) in THF (0.5 mL). The mixture was stirred 2 h at –78 C then 1 h at rt.
An aqueous solution of NH
twice with EtOAc. The combined organic layers were washed with water, dried over Na
under reduced pressure. Purification by flash chromatography on silica gel (SiO , pentane/Et
afforded 16 as a colorless oil (50 mg, 76%, E/Z > 95:5, mixture of rotamers). [] −33.0 (c 0.78, CHCl
4
Cl was added and the phases were separated. The aqueous layer was extracted
SO and concentrated
O: 100/0 to 95/5)
); IR
) δ 6.18 (dq, J 10.0, 1.5
Hz, 1H), 5.84 (m, 1H), 5.54 (ddt, J 15.9, 6.5, 1.1 Hz), 4.70 (bs, 1H), 4.56 (ddd, J 9.3, 5.9, 3.6 Hz, 1H), 4.18 (m,
2
4
2
2
2
D
0
3
-
1 1
(neat): 1692, 1462, 1387, 1365, 1253, 1178, 1079, 1025 cm ; H NMR (400 MHz, C
D
6 6
1
3
0
1
H), 3.90 (t, J 6.5 Hz, 1H), 3.64 (dd, J 5.9, 2.7 Hz, 1H), 2.54 (m, 1H), 2.45 (m, 1H), 2.37 (m, 1H), 2.27 (d, J 1.5 Hz,
H), 2.01 – 1.86 (m, 2H), 1.73 (s, 3H), 1.64 (s, 3H), 1.45 (s, 9H), 1.15 (d, J 6.6 Hz, 3H), 1.01 (s, 9H), 1.00 (s, 18H),
1
3
.90 (d, J 6.9 Hz, 3H), 0.16 – 0.14 (m, 9H), 0.12 – 0.09 (m, 9H); C NMR (100 MHz, C
28.3, 94.5, 93.7, 79.4, 77.2, 72.1, 70.3, 68.8, 66.4, 43.8, 43.1, 39.4, 28.5 (3C), 27.9 (2C), 27.5, 26.23 (3C), 26.16
6
D ) δ 152.4, 144.4, 134.3,
6
(
C
3C), 26.12 (3C), 21.4, 18.30, 18.25, 18.23, 16.0, –3.9, –4.0, –4.26, –4.29, –4.5 (2C); HRMS (ESI): calculated for
+
41
H82INO
6
Si
3
Na [M + Na] : 918.4387, found : 918.4382.
2
-[(4-Methoxybenzyl)oxy]ethan-1-ol (21). To a slurry of NaH (60% dispersion in oil, 7.0 g, 110 mmol, 1 equiv)
in dry THF (300 mL) were added dropwise ethylene glycol 20 (28.8 mL, 510 mmol, 3 equiv),
tetrabutylammonium iodide (7.1 g, 17 mmol, 0.1 equiv) and para-methoxylbenzyl chloride (23.2 mL, 9.8
o
mmol, 1 equiv) at 0 C. The mixture was stirred for 4 h under reflux and a saturated aqueous ammonium
chloride solution was added. The aqueous layer was extracted with EtOAc and the combined organic layers
were washed with brine, dried, filtered and concentrated. Flash chromatography (SiO
2
, petroleum
ether/EtOAc: 55/45) gave the alcohol 21 as a yellow oil (27.45 g, 88%). R
f
(cyclohexane/EtOAc:6/4, KMnO , UV)
4
1
0
3
7
2
.29; H NMR (300 MHz, CDCl
.66 (m, 2H), 3.56 (t, J 4.9 Hz, 2H), 2.57 (t, J 6.1 Hz, 1H); C NMR (75 MHz, CDCl ) δ 159.2, 129.9, 129.3, 113.7,
2.8, 71.0, 61.7, 55.1.
3
) δ 7.28 (d, J 8.6 Hz, 2H), 6.89 (d, J 8.6 Hz, 2H), 4.49 (s, 2H), 3.81 (s, 3H), 3.78 –
13
3
-[(4-Methoxybenzyl)oxy}acetaldehyde (18). Dess-Martin periodinane (2.54 g, 6 mmol, 1.1 equiv) was added
o
to a solution of alcohol 21 (1 g, 5.5 mmol, 1 equiv) in dry CH
reaction was quenched with saturated NaHCO
were obtained. The layers were separated and the aqueous layer was extracted with EtOAc. The combined
organic layers were dried over MgSO and the solvent was removed under reduced pressure to a crude
mixture which was purified by flash chromatography (SiO
as a yellow oil (0.605 g, 61%). R
2
Cl
2
(30 mL) at 0 C. After stirring 3 h at rt, the
3
and the mixture was stirred vigorously until two clear layers
4
2
, petroleum ether/EtOAc: 6/4) to give the alcohol 18
1
f
(cyclohexane/EtOAc:4/6, KMnO
4
, UV) 0.59; H NMR (300 MHz, CDCl
3
) δ 9.69
1
3
(s, 1H), 7.28 (d, J 8.7 Hz, 2H), 6.89 (d, J 8.7 Hz, 2H), 4.55 (s, 2H), 4.06 (d, J 0.7 Hz, 2H), 3.80 (s, 3H); C NMR (75
MHz, CDCl ) δ 200.6, 159.6, 129.7, 128.8, 113.9, 74.9, 73.2, 55.2.
3
Methyl (tert-butoxycarbonyl)glycinate (19). Glycine methyl ester hydrochloride 22 (7.28 g, 58 mmol, 1 equiv)
o
was suspended in CH
stirred for 30 min at 0 C and Boc
2
Cl
2
(200 mL) and Et
3
N (9 mL, 64 mmol, 1.1 equiv) was added at 0 C. The mixture was
o
2
O (13.95 g, 64 mmol, 1.1 equiv) was added at rt. The reaction was stirred for
Cl and the organic phase was
and 100 mL of brine. The organic layer was
, filtered, and the solvent was removed under reduced pressure. Flash chromatography of
the crude mixture (SiO , petroleum ether/EtOAc: 7/3) gave the desired compound 19 as a colorless oil (10.59
2
6 h at rt and H
washed with 100 mL of HCl (1 N), 100 mL of saturated Na
dried over MgSO
2
O (150 mL) was added. The mixture was extracted with CH
2
2
2
CO
3
4
2
Page 16
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
1
g, 97%). R
2
f
(cyclohexane/EtOAc:1/1, KMnO
4
) 0.63; H NMR (300 MHz, CDCl
3
)  5.00 (bs, 1H), 3.92 (d, J 5.5 Hz,
1
3
H), 3.75 (s, 3H), 1.45 (s, 9H); C NMR (75 MHz, CDCl ) δ 170.8, 155.7, 80.0, 52.2, 42.2, 28.3.
3
Methyl 2-[(tert-butoxycarbonyl)amino]-4-[(4-methoxybenzyl)oxy]-3-oxobutanoate (17). To a solution of
o
diisopropylamine (11.6 mL, 82.5 mmol, 3.3 equiv) in THF (90 mL), was added dropwise at –78 C, a 2.3 M
o
solution of nBuLi in THF (33 mL, 75 mmol, 3 equiv). The solution was stirred for 30 min at –78 C then
transferred via cannula to a solution of 19 (4.7 g, 25 mmol, 1 equiv) and ZnCl
dry THF (55 mL). The mixture was stirred 45 min at –78 C and a solution of 18 (5.82 g, 32.3 mmol, 1.3 equiv) in
dry THF (35 mL) was added via cannula. The resulting solution was stirred for 30 min at –78 C before it was
2
(4.09 g, 30 mmol, 1.2 equiv) in
o
o
hydrolyzed with saturated NH
MgSO , the solvent was evaporated in vacuo, and the crude product was purified by flash chromatography
SiO , petroleum ether/EtOAc: 6/4). The corresponding alcohol was obtained as a colorless oil (6.94 g, 75%).
4
Cl and extracted with EtOAc. The combined organic layers were dried over
4
(
2
Dess-Martin periodinane (14.1 g, 27.2 mmol, 1.8 equiv) was added to a solution of this alcohol (6.70 g, 18.1
o
mmol, 1 equiv) in dry CH
saturated NaHCO
separated and the aqueous layer was extracted with CH
MgSO and the solvent was removed under reduced pressure. The crude mixture was purified by flash
chromatography (SiO
2
Cl
2
(160 mL) at 0 C. After stirring 3.5 h at rt, the reaction was quenched with
3
and the mixture was stirred vigorously until two clear layers were obtained. The layers were
Cl . The combined organic layers were dried over
2
2
4
2
, cyclohexane/EtOAc: 8/2) to give the ketone 17 as a colorless oil (1.54 g, 23%). R
f
1
(
cyclohexane/EtOAc: 1/1, KMnO
4
, UV) 0.65; H NMR (300 MHz, CDCl
3
) δ 7.19 (d, J 8.7 Hz, 2H), 6.80 (d, J 8.7 Hz,
2
H), 5.65 (d, J 7.4 Hz, 1H), 5.10 (d, J 7.6 Hz, 1H), 4.44 (s, 2H), 4.35 (d, J 17.0 Hz, 1H), 4.20 (d, J 17.0 Hz, 1H), 3.71
1
3
(s, 3H), 3.65 (s, 3H), 1.35 (s, 9H); C NMR (75 MHz, CDCl
3
) δ 199.7, 166.6, 159.4, 154.7, 129.6, 128.7, 113.7,
8
0.5, 72.9 (2C), 60.0, 55.1, 53.0, 28.0.
Methyl (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxy-4-[(4-methoxybenzyl)oxy]butanoate (syn-23). (S)-
3
Synphos (2.9 mg, 4.5 mol, 0.011 equiv) and [Ru(COD)(η -2-methylallyl)
2
] (1.3 mg, 4.1 mol, 0.01 equiv) were
placed in a reaction tube and the vessel was purged with argon. Anhydrous acetone (1.5 mL) previously
degassed by three vacuum-argon cycles was added at rt. To this suspension was added dropwise methanolic
HBr (47 L, 0.009 equiv of a 0.19N solution prepared by adding 48% aqueous HBr in degassed methanol) and
the suspension was stirred at room temperature for 30 min. The suspension immediately turned yellow, then
an orange precipitate appeared and the solvent was thoroughly evaporated under vacuum to give the catalyst
as an orange-brown solid [RuBr
chloride 17 (150 mg, 0.41 mmol, 1 equiv) in degassed anhydrous CH
2
((S)-Synphos)], which was used directly. A solution of β-ketoester hydro-
Cl (1.5 mL) was then added. The reaction
2
2
vessel was degassed by three vacuum-argon cycles and then placed under argon in a 250 mL stainless steel
autoclave. The argon atmosphere was replaced with hydrogen by three cycles of pressurizing and the pressure
o
adjusted to 120 bar. The autoclave was heated at 50 C and stirring was maintained for 96 h. After cooling, the
reaction mixture was concentrated under reduced pressure to afford the crude β-hydroxy ester which was
purified by flash chromatography (SiO
oil. R (cyclohexane/AcOEt: 1/1, KMnO
H), 5.40 (d, 1H, J 9.0 Hz), 4.45 (s, 2H, H
.51 (dd, 1H, J 8.9, 5.4 Hz), 3.43 (m, 1H), 2.98 (br s, 1H), 1.43 (s, 9H); C NMR (75 MHz, CDCl
55.8, 129.6, 129.4, 113.8, 80.3, 73.1, 70.7, 70.3, 55.2, 52.5, 52.3, 28.2; HPLC : Chiralpak IA, hexane/iPrOH
5/5, 1 mL/min, λ = 215 nm; t [syn] = 37.71 min, t [syn] = 42.65 min, t [anti] = 50.56 min, t [anti] = 61.98
2
, cyclohexane/EtOAc: 6/4) to give syn-23 (110 mg, 73%) as a colorless
1
f
4
, UV) 0.47; H NMR (300 MHz, CDCl
3
) δ 7.27-7.18 (m, 2H), 6.90-6.82 (m,
2
3
1
9
6
), 4.39 (dd, 1H, J 16.1, 6.2 Hz), 4.23 (br s, 1H), 3.78 (s, 3H), 3.72 (s, 3H),
1
3
3
) δ 171.4, 159.3,
R
R
R
R
min.
Methyl (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]-4-[(4-methoxybenzyl)oxy]-
butanoate (syn-24). To a solution of syn-23 (97 mg, 0.26 mmol, 1 equiv) in dry DMF (0.5 mL) were added
successively imidazole (54 mg, 0.79 mmol, 3 equiv) and TBSCl (99 mg, 0.66 mmol, 2.5 equiv) at rt. The mixture
Page 17
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
was stirred for 18 h at rt, then saturated aqueous NaCl and iPr
2
O were added. The aqueous phase was
extracted with iPr
concentrated. The residue was purified by flash chromatography (SiO
syn-24 (111 mg, 87%) as a colorless oil. R
CDCl
2
O. The combined organic layers were washed with brine, dried over MgSO , filtered and
4
2
, petroleum ether/EtOAc: 9/1) to give
(cyclohexane/AcOEt: 7/3, ninhydrin, UV) 0.67; H NMR (300 MHz,
1
f
3
) δ 7.26 (d, 2H, J 8.5 Hz), 6.91-6.83 (m, 2H), 5.13 (d, 1H, J 9.9 Hz), 4.55 (dd, 1H, J 10.0, 1.4 Hz), 4.43 (s, 2H),
.41-4.32 (m, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 3.43 (dd, 1H, J 9.7, 6.4 Hz), 3.35 (dd, 1H, J 9.3, 5.8 Hz), 1.47 (s, 9H),
4
0
7
1
3
.82 (s, 9H), 0.01 (s, 3H), -0.03 (s, 3H); C NMR (75 MHz, CDCl
3
) δ 171.8, 159.2, 156.0, 130.0, 129.4, 113.7,
9.8, 73.1, 71.5, 70.7, 55.7, 55.2, 52.2, 28.3, 25.6, 17.9, –4.5, –5.4.
(2R,3R)-2-[(tert-Butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]-4-[(4-methoxybenzyl)oxy]butanoic
acid (syn-B'). To a solution of syn-24 (48 mg, 0.099 mmol, 1 equiv) in water/MeOH (0.2 mL:1.4 mL) was added
at rt an aqueous solution of potassium hydroxide (400 L, 0.20 mmol, 2 équiv, 0.5 M). The mixture was stirred
o
at 40 C for 4 h, then quenched with a 1M HCl solution. The aqueous layer was extracted with EtOAc. The
combined organic layers were dried over MgSO
Purification by flash chromatography (SiO , CH Cl /MeOH: 8/2) afforded syn-B' as a colorless oil (20 mg, 43%).
(cyclohexane/AcOEt: 8/2, ninhydrin, UV) 0.15; [] : –7.3 (c 0.78, CHCl
4
, filtered and concentrated under reduced pressure.
2
2
2
20
1
R
f
3
); H NMR (300 MHz, MeOD) δ 7.30-
D
7
.22 (m, 2H), 6.92-6.85 (m, 2H), 4.44 (br s, 2H), 4.39 (br s, 2H), 3.78 (s, 3H), 3.43-3.34 (m, 2H), 1.47 (s, 9H), 0.85
1
3
(s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); C NMR (75 MHz, MeOD) δ 174.4, 160.8, 157.9, 131.3, 130.6, 114.7, 80.9,
7
4.0, 72.9, 71.6, 56.8, 55.6, 28.7, 26.3, 18.9, –4.3, –5.0.
Methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxy-4-[(4-methoxybenzyl)oxy]butanoate (anti-23). A
reaction vessel fitted with a rubber septum equipped with a balloon of argon was charged with the ester 17
(
124 mg, 0.34 mmol, 1 equiv) and CH
teth-TsDPEN)] (0.1 mol%) in CH Cl was added and the resulting mixture was subjected to three vacuum/argon
cycles before the azeotropic mixture HCOOH/NEt (5/2) (0.17 mL, 0.68 mmol, 2 equiv) was added dropwise.
The reaction mixture was stirred at rt for 4 h (monitored by TLC). Saturated NaHCO was added and the
aqueous layer was extracted with CH Cl . The combined organic phases were dried over MgSO , filtered and
2
Cl
2
(2.5 mL). 126 μL of a 0.0027 M solution of Cat III [RhCl(Cp*)((R,R)-
2
2
3
3
2
2
4
the solvent was removed under reduced pressure. The conversion and the diastereoisomeric ratio were
1
determined by H NMR analysis of the crude product. The crude product was purified by flash
chromatography (SiO
2
, pentane/EtOAc: 7/3) to afford compound anti-23 (88 mg, 70%). R
f
(cyclohexane/AcOEt:
1
6
1
/4, KMnO
4
, UV) 0.33; H NMR (300 MHz, CDCl
3
) δ 7.26 – 7.21 (m, 2H), 6.87 (d, J 8.6 Hz, 2H), 5.58 (d, J 7.1 Hz,
H), 4.45 (s, 2H), 4.42 – 4.15 (m, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 3.55 – 3.41 (m, 2H), 2.87 (d, J 4.0 Hz, 1H), 1.43
1
3
(
s, 9H); C NMR (75 MHz, CDCl
2.5, 28.2; HPLC : Chiralpak IA, hexane/iPrOH 95/5, 1 mL/min, λ = 215 nm; t
min, t [anti-(R,S)] = 50.56 min, t [anti-(S,R)] = 61.98 min (major).
3
) δ 171.4, 159.3, 155.9, 129.6, 129.5, 113.8, 80.0, 73.1 (2C), 70.7, 70.3, 55.2,
5
R
[syn] = 37.71 min, t [syn] = 42.65
R
R
R
Methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]-4-[(4-methoxybenzyl)oxy]-
butanoate (anti-24). To a solution of anti-23 (173 mg, 0.47 mmol, 1 equiv) in dry DMF (1 mL) were added
successively imidazole (64 mg, 0.94 mmol, 2 equiv) and TBSCl (107 mg, 0.71 mmol, 1.5 equiv) at rt. The
mixture was stirred for 33 h at rt, then brine and iPr
iPr O. The combined organic layers were washed with brine, dried over MgSO
residue was purified by flash chromatography (SiO
2
O were added. The aqueous phase was extracted with
2
4
, filtered and concentrated. The
2
, petroleum ether/EtOAc: 9/1) to give anti-24 (115 mg,
1
5
8
3
1
1%) as a colorless oil. R
f
(cyclohexane/EtOAc:8/2, ninhydrin, UV) 0.45; H NMR (300 MHz, CDCl
3
) δ 7.26 (d, J
.2 Hz, 2H), 6.87 (d, J 8.2 Hz, 1H), 5.13 (d, J 10.0 Hz, 1H), 4.56 – 4.35 (m, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.72 (s,
H), 3.46 – 3.33 (m, 2H), 1.47 (s, 9H), 0.85 (s, 9H), 0.01 (s, 3H), –0.03 (s, 3H); C NMR (75 MHz, CDCl
59.2, 156.0, 130.0, 129.4, 113.8, 79.8, 73.1, 71.6, 70.7, 55.7, 55.2, 52.2, 29.7, 28.3, 25.7, –4.5, –5.4.
1
3
3
) δ 171.8,
Page 18
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
(2S,3R)-2-[(tert-Butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]-4-[(4-methoxybenzyl)oxy]butanoic
acid (anti-B'). To a solution of anti-24 (93 mg, 0.19 mmol, 1 equiv) in THF (3 mL) was added at rt a 2 M solution
of TMSOK (0.76 mL, 1.52 mmol, 8 equiv) in THF. After 1.5 h, the reaction medium was quenched with a 10%
aqueous solution of citric acid (5 mL). The phases were separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine, dried over MgSO
reduced pressure. Purification by flash chromatography (SiO , CH Cl /MeOH: 9/1) afforded anti-B' as a pale
yellow oil (59 mg, 66%). R (CH Cl /MeOH:9/1, ninhydrin, UV) 0.26; H NMR (300 MHz, MeOD)  7.30 – 7.22
m, 2H), 6.92 – 6.85 (m, 2H), 4.44 (bs, 2H), 4.39 (bs, 2H), 3.78 (s, 3H), 3.43 – 3.34 (m, 2H), 1.47 (s, 9H), 0.85 (s,
4
and concentrated under
2
2
2
1
f
2
2
(
9
7
1
3
H), 0.04 (s, 3H), 0.03 (s, 3H); C NMR (75 MHz, MeOD)  174.4, 160.8, 157.9, 131.3, 130.6, 114.7, 80.9, 74.0,
2.9, 71.6, 56.8, 55.6, 28.7, 26.3, 18.9, –4.3, –5.0.
Methyl (R)-3-(benzyloxy)-2-methylpropanoate (26). To a solution of (R)-Roche ester 25 (200 mg, 1.69 mmol, 1
o
equiv) in CH
solution of CF
2
Cl
2
(3 mL) was added at 0 C benzyl trichloroacetimidate (640 mg, 2.54 mmol, 1.5 equiv). A
o
3
SO
3
H in CH
2
Cl
2
(0.85 M, 100 µL, 0.09 mmol, 0.05 equiv) was added at 0 C and the mixture was
stirred at room temperature for 44 h. After filtration, the filtrate was concentrated under reduced pressure
and saturated aqueous NaHCO (15 mL) was added. The aqueous layer was extracted with EtOAc, the
combined organic layers were washed with brine, dried over MgSO and concentrated under reduced
pressure. The crude mixture was purified by flash column chromatography (SiO , petroleum ether/Et O: 95/5)
to afford the desired product 26 (262 mg, 74%) as a yellow oil. R (cyclohexane/EtOAc: 9/1, UV, KMnO ) 0.30;
] –8.0 (c 1.60, CHCl ); H NMR (CDCl , 300 MHz) δ = 7.38 – 7.24 (m, 5H), 4.53 (s, 2H), 3.70 (s, 3H), 3.66 (dd,
3
4
2
2
f
4
2
D
0
1
[
3
3
1
3
J 9.2, 7.3 Hz, 1H), 3.50 (dd, J 9.1, 5.9 Hz, 1H), 2.86 – 2.72 (m, 1H), 1.18 (d, J 7.1 Hz, 3H); C NMR (CDCl
MHz) δ 175.4, 138.3, 128.5, 127.7 (2C), 73.2, 72.1, 51.8, 40.3, 14.1.
3
, 75
(
S)-3-(Benzyloxy)-2-methylpropan-1-ol (27). To a suspension of LiAlH
4
(287 mg, 7.56 mmol, 1.5 equiv) in Et O
2
o
(7.5 mL) was added dropwise a solution of 26 (1.05 g, 5.04 mmol, 1 equiv) in Et
2
O (7.5 mL) at 0 C. The mixture
o
was stirred for 1.5 h and 600 mg of SiO
5% NaOH (3 mL) and water again (1 mL). MgSO
removed under reduced pressure to afford the desired product 27 (866 mg, 95%) as a colorless oil. R
2
were added at 0 C, followed by water (1 mL), an aqueous solution of
1
4
was added, the mixture was filtered and the solvent was
f
2
D
0
1
(cyclohexane/EtOAc: 8/2, KMnO
4
) 0.19; [] –22.2 (c 0.45, CHCl
3
); H NMR (CDCl
3
, 300 MHz) δ 7.39 – 7.24 (m,
5
H), 4.52 (s, 2H), 3.68 – 3.52 (m, 3H), 3.43 (dd, J 9.0, 8.1 Hz, 1H), 2.52 (s, 1H), 2.15 – 2.02 (m, 1H), 0.89 (d, J 7.0
1
3
Hz, 3H); C NMR (CDCl
3
, 75 MHz) δ 138.2, 128.6, 127.9, 127.7, 75.6, 73.5, 68.0, 35.7, 13.6.
R)-[(3-Iodo-2-methylpropoxy)methyl]benzene (28). To a solution of PPh (1.40 g, 5.33 mmol, 1.2 equiv) in
(15 mL) cooled to 0 C were successively added imidazole (453 mg, 6.66 mmol, 1.5 equiv) and I (1.52 g,
Cl (2.5 mL) was added and the
mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and
saturated aqueous Na was added. The aqueous layer was extracted with Et O and the combined organic
layers were washed with water and brine, dried over MgSO and concentrated under reduced pressure.
Pentane was added, the suspension was filtered and the solvent was removed under reduced pressure. The
crude mixture was purified by flash column chromatography (SiO , petroleum ether/toluene: 83/7) to afford
(cyclohexane/EtOAc: 98/2, phosphomolybdic acid) 0.23;
(
CH
5
3
o
2
Cl
2
2
.99 mmol, 1.35 equiv). A solution of 27 (800 mg, 4.44 mmol, 1 equiv) in CH
2
2
2
S O
2 3
2
4
2
the desired product 28 (1.04 g, 81%) as a yellow oil. R
f
1
H NMR (CDCl , 300 MHz) δ 7.40 – 7.24 (m, 5H), 4.53 (s, 2H), 3.40 (dd, J 9.3, 5.2 Hz, 1H), 3.35 – 3.26 (m, 3H),
3
1
3
1
1
.87 – 1.70 (m, 1H), 1.00 (d, J 6.7 Hz, 3H); C NMR (CDCl , 75 MHz) δ 138.5, 128.5, 127.8 (2C), 74.3, 73.3, 35.3,
3
7.8, 14.1.
Methyl (S)-7-(benzyloxy)-6-methyl-3-oxoheptanoate (29). To a suspension of NaH (60% dispersion in mineral
oil) (91 mg, 2.27 mmol, 1.5 equiv) in THF (3 mL) was added dropwise methyl acetoacetate (0.16 mL, 1.52
o
o
mmol, 1 equiv) at 0 C. The mixture was stirred at 0 C for 10 min and a 2.28 M solution of nBuLi (0.73 mL, 1.67
Page 19
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
o
mmol, 1.1 equiv) was added dropwise. The mixture was stirred at 0 C for 10 min and a solution of 28 (484 mg,
1
2
.67 mmol, 1.1 equiv) in THF (2.5 mL) was added dropwise. The mixture was stirred at room temperature for
3 h. A 10% aqueous solution of HCl (8 mL) and AcOEt (8 mL) were added and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO
concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (SiO
petroleum ether/EtOAc: 98/2 then 85/15) to afford the desired product 29 (238 mg, 56%) as a yellow oil. R
4
and
2
,
f
20
1
(cyclohexane/EtOAc: 8/2, KMnO
4
) 0.40; [] –5.8 (c 0.60, CHCl
3
); H NMR (CDCl
3
, 300 MHz) δ 7.38 – 7.25 (m,
D
5
1
7
H), 4.48 (s, 2H), 3.73 (s, 3H), 3.43 (s, 2H), 3.29 (d, J 5.9 Hz, 2H), 2.68 – 2.47 (m, 2H), 1.85 – 1.68 (m, 2H), 1.57 –
1
3
.40 (m, 1H), 0.92 (d, J 6.7 Hz, 3H); C NMR (CDCl
3
, 75 MHz) δ 202.9, 167.8, 138.7, 128.5, 127.7, 127.7, 75.6,
3.2, 52.5, 49.1, 40.9, 33.0, 27.5, 17.1.
3
Methyl (3R,6S)-7-(benzyloxy)-3-hydroxy-6-methylheptanoate (R,S)-(30). Ru(COD)[η -(CH
2
)
2
CHCH
3
2
] (4.1 mg,
0
.0129 mmol, 0.02 equiv.) and (R)-SYNPHOS (9.1 mg, 0.0142 mmol, 0.022 equiv.) were placed in a Schlenk
tube, which was purged with argon. Anhydrous acetone (0.7 mL), previously degassed by three vacuum-argon
cycles, and a 0.165 M solution of methanolic hydrobromic acid (0.17 mL, 0.0285 mmol, 0.044 equiv.) were
successively added. The suspension was stirred at room temperature for 30 min. The solvent was evaporated
under vacuum to provide the catalyst as an orange solid. A solution of 29 (180 mg, 0.647 mmol, 1 equiv) in
o
previously degassed MeOH (1 mL) was added and the mixture was stirred under 11 bar of H
2
at 50 C for 22 h.
The solvent was evaporated under reduced pressure and the crude mixture was purified by flash column
chromatography (petroleum ether/AcOEt: 8/2) to afford the desired product (R,S)-30 (168 mg, 93%) as a
2
D
0
1
yellow oil. R
f
(cyclohexane/EtOAc: 7/3, KMnO
4
) 0.28; [] –14.8 (c 0.50, CHCl
3
); H NMR (C
6
6
D , 300 MHz) δ
7
1
1
1
.34 – 7.28 (m, 2H), 7.23 – 7.06 (m, 3H), 4.33 (s, 2H), 3.91 – 3.80 (m, 1H), 3.28 (s, 3H), 3.17 (dd, J 8.9, 5.8 Hz,
H), 3.10 (dd, J 8.9, 6.2 Hz, 1H), 2.78 (d, J 3.7 Hz, 1H), 2.22 (dd, J 16.2, 8.0 Hz, 1H), 2.15 (dd, J 16.2, 4.2 Hz, 1H),
1
3
.79 – 1.54 (m, 2H),1.43 – 1.22 (m, 2H), 1.16 – 1.01 (m, 1H), 0.91 (d, J 6.6 Hz, 3H); C NMR (C
6
6
D , 75 MHz) δ
73.2, 139.5, 128.6, 127.8, 127.6, 75.8, 73.2, 68.4, 51.1, 41.5, 34.4, 33.9, 29.9, 17.5.
Methyl (3S,6S)-7-(benzyloxy)-3-hydroxy-6-methylheptanoate (S,S)-(30). (S,S)-30 was obtained in 87% yield
2
D
0
using (S)-SYNPHOS and the same protocol as for (R,S)-30. R
f
(cyclohexane/EtOAc: 7/3, KMnO
) 0.33; [] +6.8
4
1
(c 0.40, CHCl
3
); H NMR (C
6
D , 300 MHz) δ 7.34 – 7.28 (m, 2H), 7.23 – 7.06 (m, 3H), 4.33 (s, 2H), 3.92 – 3.79 (m,
6
1
1
7
H), 3.27 (s, 3H), 3.17 (dd, J 8.9, 6.0 Hz, 1H), 3.11 (dd, J 8.9, 6.3 Hz, 1H), 2.75 (s, 1H), 2.22 (dd, J 16.2, 8.3 Hz,
1
3
H), 2.14 (dd, J 16.2, 4.0 Hz, 1H), 1.78-1.61 (m, 1H), 1.52 – 1.08 (m, 4H), 0.90 (d, J 6.7 Hz, 3H); C NMR (C
5 MHz) δ 173.1, 139.5, 128.4, 127.8, 127.7, 75.9, 73.2, 68.3, 51.1, 41.6, 33.8, 33.8, 29.8, 17.4.
6
6
D ,
Methyl (3R,6S)-7-(benzyloxy)-3-[(tert-butyldimethylsilyl)oxy]-6-methylheptanoate (R,S)-(31). To a solution of
o
(
(
R,S)-30 (137 mg, 0.49 mmol, 1 equiv) in CH
2
Cl
2
(3 mL) cooled to 0 C were successively added 2,6-lutidine
o
0.45 mL, 1.96 mmol, 4 equiv) and TBSOTf (0.40 mL, 3.42 mmol, 7 equiv). The mixture was stirred at 0 C for 3
o
h and quenched by saturated aqueous NH
4
Cl at 0 C. The aqueous layer was extracted with CH
2
Cl
and concentrated under reduced
pressure. The crude mixture was purified by silica gel column chromatography (pentane/AcOEt: 97/3) to
afford the desired product (R,S)-31 (159 mg, 82%) as a yellow oil. R (cyclohexane/AcOEt: 7/3, KMnO ) 0.75;
] : –15.8 (c 0.45, CHCl ). H NMR (C D , 300 MHz) δ 7.34 – 7.28 (m, 2H), 7.24 – 7.06 (m, 3H), 4.33 (s, 2H),
2
, the
combined organic layers were washed with brine, dried over MgSO
4
f
4
2
D
0
1
[
3
6 6
4
1
.26 – 4.16 (m, 1H), 3.37 (s, 3H), 3.17 (dd, J 8.9, 6.0 Hz, 1H), 3.12 (dd, J 8.9, 6.2 Hz, 1H), 2.45 (dd, J 14.7, 7.7 Hz,
H), 2.29 (dd, J 14.7, 4.8 Hz, 1H), 1.78 – 1.62 (m, 1H), 1.62-1.40 (m, 3H), 1.22-1.04 (m, 1H), 0.98 (s, 9H), 0.92 (d,
1
3
J 6.7 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H); C NMR (C
0.1, 51.0, 42.5, 35.3, 34.0, 29.2, 26.1, 18.3, 17.4, –4.3, –4.6.
Methyl (3S,6S)-7-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6-methylheptanoate (S,S)-(31). Compound
S,S)-31 was obtained in 96% yield following the same protocol as for compound (S,R)-31. R
6
6
D , 75 MHz) δ 171.7, 139.5, 128.6, 128.4, 127.7, 75.8, 73.2,
7
(
f
Page 20
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
2
D
0
1
(cyclohexane/AcOEt: 7/3, KMnO
4
) 0.68; [] : +11.5 (c 0.75, CHCl
3
); H NMR (C
6
D
6
, 300 MHz) δ 7.34 – 7.28 (m,
2
8
H), 7.24 – 7.06 (m, 3H), 4.33 (s, 2H), 4.25 – 4.15 (m, 1H), 3.37 (s, 3H), 3.18 (dd, J 8.9, 6.0 Hz, 1H), 3.12 (dd, J
.9, 6.2 Hz, 1H), 2.45 (dd, J 14.7, 7.7 Hz, 1H), 2.29 (dd, J 14.7, 4.8 Hz, 1H), 1.78 – 1.62 (m, 1H, H ), 1.59 – 1.40
, 75
MHz) δ 171.7, 139.5, 128.6, 127.7, 127.6, 75.8, 73.2, 70.1, 51.0, 42.6, 35.3, 34.0, 29.2, 26.1, 18.3, 17.3, –4.3, –
.6.
7
1
3
(m, 3H), 1.22 – 1.04 (m, 1H), 0.98 (s, 9H), 0.92 (d, J 6.7 Hz, 3H), 0.11 (s, 3H), 0.11 (s, 3H); C NMR (C
D
6 6
4
Methyl (3R,6S)-3,7-dihydroxy-6-methylheptanoate (R,S)-(32). To a solution of (R,S)-31 (138 mg, 0.35 mmol, 1
equiv) in THF (1.8 mL) was added palladium on carbon 10% (56 mg, 0.05 mmol, 0.15 equiv). The medium was
purged with argon and three vaccum–H
2 h under 1 atm of H , filtered on celite and concentrated under reduced pressure. The crude mixture was
purified on silica gel column chromatography (petroleum ether/MTBE: 6/4) to afford the desired product (R,S)-
2
cycles were made. The mixture was stirred at room temperature for
2
2
2
0
1
3
2 (102 mg, 95%) as a colorless oil. R
NMR (C , 300 MHz) δ 4.24 – 4.14 (m, 1H), 3.38 (s, 3H), 3.21 (dd, J 10.4, 5.7 Hz, 1H), 3.15 (dd, J 10.4, 5.9 Hz,
H), 2.44 (dd, J 14.7, 7.6 Hz, 1H), 2.29 (dd, J 14.7, 4.8 Hz, 1H), 1.59 – 1.26 (m, 4H), 1.12 – 1.00 (m, 1H), 0.98 (s,
f
(cyclohexane/AcOEt: 7/3, KMnO
4
) 0.38; [] : –17.8 (c 0.75, CHCl
); H
3
D
D
6 6
1
9
3
1
3
H), 0.82 (d, J 6.6 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H); C NMR (C
6.0, 35.2, 28.6, 26.1, 18.3, 16.8, –4.3, –4.6.
6
D , 75 MHz) δ 171.8, 70.0, 67.8, 51.1, 42.4,
6
Methyl (3S,6S)-3,7-dihydroxy-6-methylheptanoate (S,S)-(32). Compound (S,S)-32 was obtained in 93% yield
2
D
0
following the same procedure than for compound (S,R)-32. R
f
(cyclohexane/AcOEt: 7/3, KMnO :
) 0.43; []
4
1
+
3
–
7
13.7 (c 0.80, CHCl
3
); H NMR (C
6
D , 300 MHz) δ 4.23 – 4.13 (m, 1H), 3.37 (s, 3H), 3.23 (dd, J 10.3, 5.5 Hz, 1H),
.16 (dd, J 10.3, 6.0 Hz, 1H), 2.45 (dd, J 14.7, 7.8 Hz, 1H), 2.28 (dd, J 14.7, 5.0 Hz, 1H), 1.58 – 1.24 (m, 4H), 1.13
6
1
3
1.00 (m, 1H), 0.98 (s, 9H), 0.82 (d, J 6.6 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H); C NMR (C
0.1, 67.8, 51.1, 42.5, 36.1, 35.2, 28.6, 26.1, 18.3, 16.8, –4.4, –4.6.
6
D , 75 MHz) δ 171.8,
6
Methyl (3R,6S)-3-hydroxy-6-methyl-7-oxoheptanoate (R,S)-(33). To a solution of (R,S)-32 (82 mg, 0.27 mmol,
equiv) in CH Cl (1 mL) was added DMP (171 mg, 0.40 mmol, 1.5 equiv) and the mixture was stirred at room
temperature for 3 h. After dilution with Et O, the organic layer was successively washed with saturated
aqueous Na and a saturated solution of NaHCO . The aqueous layer was extracted with AcOEt, the
combined organic layers were washed with brine, dried over MgSO and concentrated under reduced
pressure. The crude mixture was purified by silica gel column chromatography (petroleum ether/iPr O: 8/2) to
(cyclohexane/AcOEt: 6/4, KMnO ) 0.68;
1
2
2
2
2
S
2
O
3
3
4
2
afford the desired product (R,S)-33 (52 mg, 64%) as a colorless oil. R
f
4
1
H NMR (C
6
D
6
, 300 MHz) δ 9.26 (d, J 1.6 Hz, 1H), 4.17 – 4.06 (m, 1H), 3.37 (s, 3H), 2.38 (dd, J 14.8, 7.4 Hz, 1H),
2
1
5
.19 (dd, J 14.8, 5.0 Hz, 1H), 1.78 (sxtd, J 6.9, 1.5 Hz, 1H), 1.56-1.44 (m, 1H), 1.39 – 1.25 (m, 2H), 1.19 – 1.05 (m,
1
3
H), 0.95 (s, 9H), 0.75 (d, J 7.1 Hz, 3H), 0.09 (s, 3H), 0.06 (s, 3H); C NMR (C
1.1, 46.1, 42.3, 34.9, 26.0, 25.8, 18.2, 13.3, –4.4, –4.6.
6
6
D , 75 MHz) δ 203.0, 171.5, 69.5,
Methyl (3S,6S)-3-hydroxy-6-methyl-7-oxoheptanoate (S,S)-(33). Compound (S,S)-33 was obtained in 67%
yield following the same procedure than for compound (S,R)-33. R (cyclohexane/AcOEt: 6/4, KMnO ) 0.62;
] : +12.0 (c 0.40, CHCl ); H NMR (C D , 300 MHz) δ 9.27 (d, J 1.6 Hz, 1H), 4.16 – 4.06 (m, 1H), 3.37 (s, 3H),
f
4
2
D
0
1
[
3
6 6
2
–
7
.39 (dd, J 14.8, 7.4 Hz, 1H), 2.19 (dd, J 14.8, 5.1 Hz, 1H), 1.79 (sxtd, J 6.5, 1.4 Hz, 1H), 1.56 – 1.41 (m, 1H), 1.40
1
3
1.24 (m, 2H), 1.20 – 1.06 (m, 1H), 0.95 (s, 9H), 0.74 (d, J 7.0 Hz, 3H), 0.09 (s, 3H), 0.06 (s, 3H); C NMR (C
5 MHz) δ 203.0, 171.5, 69.5, 51.1, 46.1, 42.4, 34.8, 26.0, 25.9, 18.2, 13.2, –4.4, –4.6.
6
6
D ,
Methyl
dimethylsilyl)oxy]-4,4,6,8-tetramethyl-5-oxonon-2-enamido}-7-hydroxy-6,8,10,14-tetramethylpentadec-8-
enoate (35). To a solution of 34 (145 mg, 0.16 mmol, 1.4 equiv) and (S,S)-33 (36 mg, 0.12 mmol, 1 equiv) in
freshly distilled DMSO (4.1 mL) were successively added CrCl (230 mg, 1.87 mmol, 16 equiv) and NiCl (dppe)
3.8 mg, 0.007 mmol, 0.06 equiv). Three vacuum/argon cycles were performed and the mixture was stirred at
(3S,6S,10R,11R,12R,13R)(E)-3,11,13-tris[(tert-butyldimethylsilyl)oxy]-12-{(6S,7S)(E)-7-[(tert-butyl-
2
2
(
Page 21
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
o
room temperature for 21 h. A mixture of sodium serinate/AcOEt 1/1 (20 mL) was added at 0 C and the
medium was stirred at room temperature for 1 h. After filtration, the aqueous layer was extracted with AcOEt,
the combined organic layers were washed with water and brine, dried over MgSO
reduced pressure. The crude mixture was purified by silica gel column chromatography (pentane/iPr
/3 and 5/5) to afford the minor diastereomer (8 mg) and the major diastereomer (24 mg) as yellow oils (total
4
and concentrated under
2
O: 8/2 to
7
yield: 25%).
Major diastereomer: R
1
f
(cyclohexane/iPr
2
O:5/5, Kagi-Mosher) 0.38; H NMR (C
6
6
D , 300 MHz) δ 7.30 (d, J 15.5
Hz, 1H), 6.03 (d, J 9.8 Hz, 1H), 5.97 (d, J 15.5 Hz, 1H), 5.63 (d, J 9.2 Hz, 1H), 4.52 – 4.43 (m, 1H), 4.32 – 4.22 (m,
1
–
1
1
6
3
8
2
–
H), 4.11 (dd, J 3.6, 0.9 Hz, 1H), 3.95 – 3.85 (m, 1H), 3.70 – 3.64 (m, 2H), 3.39 (s, 3H), 3.24 – 3.12 (m, 1H), 2.85
2.71 (m, 1H), 2.50 (dd, J 14.7, 7.7 Hz, 1H), 2.37 (dd, J 14.7, 4.6 Hz, 1H), 2.11 – 1.98 (m, 1H), 1.89 – 1.77 (m,
H), 1.77 – 1.68 (m, 1H), 1.68 – 1.59 (m, 6H), 1.46 (m, 2H), 1.25 (s, 3H), 1.24 (s, 3H), 1.18 (dd, J 6.8, 5.4 Hz, 6H),
.11 (d, J 7.1 Hz, 3H), 1.04 (s, 9H), 1.02 (s, 9H), 1.01 (s, 9H), 0.98 (s, 9H), 0.97 – 0.94 (m, 3H), 0.94 – 0.90 (m,
H), 0.89 (d, J 5.6 Hz, 3H), 0.25 (s, 3H), 0.19 (s, 3H), 0.16 (s, 3H), 0.16 (s, 3H), 0.15 (s, 3H), 0.14 (s, 3H), 0.12 (s,
1
3
H), 0.10 (s, 3H); C NMR (major isomer) (100 MHz, C
6
6
D ) δ 211.9, 171.7, 165.5, 149.2, 139.1, 128.3, 123.1,
3.7, 79.5, 78.9, 76.1, 70.4, 54.6, 51.3, 51.0, 45.1, 42.7, 40.0, 36.2, 35.2, 31.6, 31.4, 30.2, 28.8, 26.7, 26.4, 26.3,
6.1, 23.9, 23.0, 20.0, 19.9, 18.9, 18.8, 18.3, 18.0, 16.7, 16.6, 16.6, 16.3, 11.1, –2.6, –2.8, –3.4 (2C), –3.7, –4.2,
+
+
4.6 (2C). MS (ESI: NH
3
) m/z 1093 [M+Na] , 1088 [M+NH ] .
4
Methyl (3R,6S,10R,11R,12R,13R)(E)-3,11,13-tris[(tert-butyldimethylsilyl)oxy]-12-{(6S,7S)(E)-7-[(tert-butyl-
dimethylsilyl)oxy]-4,4,6,8-tetramethyl-5-oxonon-2-enamido}-7-hydroxy-6,8,10,14-tetramethylpentadec-8-
enoate (36). Compound 36 was obtained in 34% yield as a colorless oil from 34 (112 mg, 0.125 mmol, 1.2
1
equiv) and (R,S)-33 (32 mg, 0.104 mmol, 1 equiv) following the same procedure than for compound 35. H
NMR (major isomer) (400 MHz, C
6
D
6
) δ 7.36 (d, J 15.5 Hz, 1H), 6.09 (d, J 9.7 Hz, 1H), 5.97 (d, J 15.5 Hz, 1H),
5
.42 (d, J 10.2 Hz, 1H), 4.23 (d, J 2.1 Hz, 2H), 4.15 (t, J 9.6 Hz, 1H), 3.92 (dd, J 9.2, 1.7 Hz, 1H), 3.62 (dd, J 9.6, 1.5
Hz, 1H), 3.55 (d, J 9.3 Hz, 1H), 3.36 (s, 3H), 3.21 (dd, J 9.2, 6.8 Hz, 1H), 2.78 – 2.73 (m, 1H), 2.46 (dd, J 14.8, 7.7
Hz, 1H), 2.26 (dd, J 14.8, 4.7 Hz, 1H), 2.03 – 2.00 (m, 2H), 1.83 (d, J 1.2 Hz, 3H), 1.77 – 1.72 (m, 1H), 1.36 (s, 3H),
1
.27 (s, 3H), 1.18 – 1.14 (m, 11H), 1.10 (d, J 7.1 Hz, 3H), 1.02 (s, 18H), 0.995 (s, 9H), 0.991 (s, 9H), 1.02 – 0.90
1
3
(
(
5
2
m, 12H), 0.18 (s, 3H), 0.17 (s, 3H), 0.15 (s, 6H), 0.15 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H); C NMR
major isomer) (100 MHz, C ) δ 211.9, 171.7, 165.5, 149.2, 139.1, 128.7, 123.1, 83.9, 79.5, 78.9, 76.1, 70.3,
4.6, 51.3, 51.0, 45.1, 42.7, 40.0, 36.5, 35.4, 32.4, 31.6, 31.4, 30.2, 30.0, 29.8, 28.7, 26.7, 26.4, 26.3, 26.1, 23.9,
3.1, 23.0, 19.9, 18.9, 18.8, 18.0, 16.3, 14.4, 11.1, –2.6, –2.8, –2.8, –3.5, –3.7, –4.2, –4.5, –4.6; MS (ESI, NH ) :
D
6 6
3
+
+
+
m/z 1071 [M+H] , 1093 [M+Na] , 1088 [M+NH ] .
4
Acknowledgements
We thank the Agence Nationale de la Recherche for financial support (ANR STIMAS, 2011–2014, J.C. and P.-
G.E.).
References
1
2
. Bewley, C. A.; Faulkner, D. J. Angew. Chem Int. Ed. 1998, 37, 2162.
https://doi.org/10.1002/(SICI)1521-3773(19980904)37:16<2162::AID-ANIE2162>3.0.CO;2-2
. Winder, P. L.; Pomponi, S. A.; Wright, A. E. Mar. Drugs 2011, 9, 2643.
Page 22
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
https://doi.org/10.3390/md9122643
3
4
5
6
7
8
. Molinski, T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes, J. P. Nature Rev. Drug Discovery 2009, 8, 69.
https://doi.org/10.1038/nrd2487
. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, T. Nat. Prod. Rep. 2010, 27, 165.
https://doi.org/10.1039/b906091j
. Vinothkumar, S.; Parameswaran, P. S. Biotechnol. Adv. 2013, 31, 1826.
https://doi.org/10.1016/j.biotechadv.2013.02.006
. Matsunaga, S.; Fusetani, N.; Kato, Y.; Hirota, H. J. Am. Chem. Soc. 1991, 113, 9690.
https://doi.org/10.1021/ja00025a054
. Youssef, D.T.; Mooberry, S.L. J. Nat. Prod. 2006, 69, 154.
https://doi.org/10.1021/np050404a
. Plaza, A.; Baker, H. L.; Bewley, C. A. J. Nat. Prod. 2008, 71, 473-477. Correction: Plaza, A.; Baker, H. L.;
Bewley, C. A. J. Nat. Prod. 2009, 72, 324.
https://doi.org/10.1021/np800736v
9
1
. Marine sponge picture is by courtesy and copyright of Patrick Colin and Lori Bell, Coral Reef Research
Foundation, Republic of Palau.
0. Prévost, S.; Gauthier, S.; Cano de Andrade, M. C.; Mordant, C.; Touati, A. R.; Lesot, P.; Savignac, P.; Ayad,
T.; Phansavath, P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Tetrahedron: Asymmetry 2010, 21, 1436.
https://doi.org/10.1016/j.tetasy.2010.05.017
1
1
1. Prévost, S.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2011, 353, 3213.
https://doi.org/10.1002/adsc.201100579
2. Perez, M.; Echeverria, P.-G.; Martinez-Arripe, E.; Ez Zoubir, M.; Touati, R.; Zhang, Z.; Genet, J.; Phansavath,
P.; Ayad, T.; Ratovelomanana-Vidal, V. Eur. J. Org. Chem. 2015, 5949.
https://doi.org/10.1002/ejoc.201500661
1
3. Perez, M.; Ayad, T.; Maillos, P.; Poughon, V.; Fahy, J.; Ratovelomanana-Vidal, V. ACS Med. Chem. Lett.
2
016, 7, 403.
https://doi.org/10.1021/acsmedchemlett.5b00441
1
1
1
1
1
4. Cossy, J.; Willis, C.; Bellosta, V.; Saint-Jalmes, L. Synthesis 2002, 7, 951.
https://doi.org/10.1055/s-2002-28505
5. Cossy, J.; Dumas, C.; Gomez Pardo, D. Synlett 1997, 8, 905.
https://doi.org/10.1055/s-1997-5789
6. Bensoussan, C.; Rival, N.; Hanquet, G.; Colobert, F.; Reymond, S.; Cossy, J. Tetrahedron 2013, 69, 7759.
https://doi.org/10.1016/j.tet.2013.05.067
7. Guérinot, A.; Lepesqueux, G.; Sablé, S.; Reymond, S.; Cossy, J. J. Org. Chem. 2010, 75, 5151.
https://doi.org/10.1021/jo100871m
8. Echeverria, P.-G.; Prévost, S.; Cornil, J.; Férard, C.; Reymond, S.; Guérinot, A.; Cossy, J.; Ratovelomanana-
Vidal, V.; Phansavath, P. Org. Lett. 2014, 16, 2390.
https://doi.org/10.1021/ol500720j
1
2
9. Cornil, J.; Echeverria, P.-G.; Reymond, S.; Phansavath, P.; Ratovelomanana-Vidal, V.; Guérinot, A.; Cossy, J.
Org. Lett. 2016, 18, 4534.
https://doi.org/10.1021/acs.orglett.6b02162
0. Cornil, J.; Echeverria, P.-G.; Phansavath, P.; Ratovelomanana-Vidal, V.; Guérinot, A.; Cossy, J. Org. Lett.
2
015, 17, 948.
https://doi.org/10.1021/acs.orglett.5b00042
Page 23
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
2
1. Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew. Chem. Int. Ed. 2004, 43, 882.
https://doi.org/10.1002/anie.200353072
2
2
2
2. Mordant, C.; Dꢀnkelmann, P.; Ratovelomanana-Vidal, V.; Genꢁt, J.-P. Chem. Commun. 2004, 1296.
3. Mordant, C.; Dꢀnkelmann, P.; Ratovelomanana-Vidal, V.; Genꢁt, J.-P. Eur. J. Org. Chem. 2004, 3017.
4. Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36.
https://doi.org/10.1246/bcsj.68.36
2
2
2
2
2
5. Pellissier, H. Tetrahedron 2003, 59, 8291.
https://doi.org/10.1016/S0040-4020(03)01022-6
6. Echeverria, P.-G.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Synthesis 2016, 48, 2523.
https://doi.org/10.1055/s-0035-1561648
7. Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008.
https://doi.org/10.1002/1521-3773(20020617)41:12<2008::AID-ANIE2008>3.0.CO;2-4
8. Yoshimura, M.; Tanaka, S.; Kitamura, M. Tetrahedron Lett. 2014, 55, 3635.
https://doi.org/10.1016/j.tetlet.2014.04.129
9. Xie, J.-H.; Bao, D.-H.; Zhou, Q.-L. Synthesis 2015, 47, 460.
https://doi.org/10.1055/s-0034-1378939
3
3
0. Jeulin, S.; Champion, N.; Dellis, P.; Ratovelomanana-Vidal, V.; Genêt, J.-P. Synthesis 2005, 3666.
1. Seco, J. M.; Quiñoá, E.; Riguera, R. Chem. Rev. 2012, 112, 4603.
https://doi.org/10.1021/cr2003344
3
3
2. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
https://doi.org/10.1246/bcsj.40.2380
3. Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109,
2
551.
https://doi.org/10.1021/cr800278z
3
4. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
https://doi.org/10.1039/b208078h
3
3
5. See the experimental section.
6. Ikariya, T.; Blacker, J. Acc. Chem. Res., 2007, 40, 1300.
https://doi.org/10.1021/ar700134q
3
3
3
4
4
4
4
7. Wang, D.; Astruc, D. Chem. Rev., 2015, 115, 6621.
https://doi.org/10.1021/acs.chemrev.5b00203
8. Foubelo, F.; Najera, C.; Yus, M. Tetrahedron: Asymmetry 2015, 26, 769.
https://doi.org/10.1016/j.tetasy.2015.06.016
9. Zheng, L.-S.; Férard, C.; Phansavath, P.; Ratovelomanana-Vidal, V. Chem. Commun. 2018, 54, 283.
https://doi.org/10.1039/C7CC08231B
0. Zheng, L.-S.; Phansavath, P.; Ratovelomanana-Vidal, V. Org. Lett. 2018, 20, 5107.
https://doi.org/10.1021/acs.orglett.8b01943
1. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738.
https://doi.org/10.1021/ja971570a
2. Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005, 127, 7318.
https://doi.org/10.1021/ja051486s
3. Echeverria, P.-G.; Férard, C.; Phansavath, P.; Ratovelomanana-Vidal, V. Catal. Commun. 2015, 62, 95.
https://doi.org/10.1016/j.catcom.2015.01.012
Page 24
©ARKAT USA, Inc

Arkivoc 2018, iv, 0-0
Echeverria, P.-G. et al.
4
4. Zheng, L.-S.; Llopis, Q.; Echeverria, P.-G.; Férard, C.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal,
V. J. Org. Chem. 2017, 82, 5607.
https://doi.org/10.1021/acs.joc.7b00436
4
4
4
4
5. Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979, 978.
https://doi.org/10.1039/c39790000978
6. Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702.
https://doi.org/10.1021/ja00725a088
7. Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.
https://doi.org/10.1021/ja00279a068
8. Harnying, W.; Kaiser, A.; Klein, A.; Berkessel, A. Chem. Eur. J. 2011, 17, 4765.
https://doi.org/10.1002/chem.201003366
Page 25
©ARKAT USA, Inc