Total synthesis of symbioramide: A flexible approach for the efficient preparation of structural isomers

Article abstract of DOI:10.1002/adsc.201100579

A concise, enantioselective total synthesis of symbioramide, starting from simple achiral compounds and racemic α-amino-β-keto ester derivatives is reported. This highly flexible strategy allowed the efficient preparation of seven structural isomers of the natural product as well. The synthesis relies on a convergent route that involves the efficient stereoselective reduction of a α-keto-β-yne ester, and the dynamic kinetic resolution of an α-amino-β-keto ester through ruthenium-mediated asymmetric hydrogenation. Copyright

Full text of DOI:10.1002/adsc.201100579

FULL PAPERS
DOI: 10.1002/adsc.201100579
Total Synthesis of Symbioramide: a Flexible Approach for the
Efficient Preparation of Structural Isomers
Sꢀbastien Prꢀvost,a,b Tahar Ayad,a,b Phannarath Phansavath,a,b,*
and Virginie Ratovelomanana-Vidala,b,*
a
ENSCP Chimie ParisTech, Laboratoire Charles Friedel (LCF), 75005 Paris, France
CNRS, UMR 7223, 75005 Paris, France
b
Fax : (+33)-1-4407-1062; e-mail: phannarath-phansavath@chimie-paristech.fr or virginie-vidal@chimie-paristech.fr
Received: July 21, 2011; Published online: November 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100579.
Abstract: A concise, enantioselective total synthesis lective reduction of a a-keto-b-yne ester, and the dy-
of symbioramide, starting from simple achiral com- namic kinetic resolution of an a-amino-b-keto ester
pounds and racemic a-amino-b-keto ester derivatives through ruthenium-mediated asymmetric hydrogena-
is reported. This highly flexible strategy allowed the tion.
efficient preparation of seven structural isomers of
the natural product as well. The synthesis relies on a Keywords: asymmetric catalysis; dynamic kinetic res-
convergent route that involves the efficient stereose- olution; hydrogenation; ruthenium; total synthesis
Introduction
the absolute stereochemistry at the C-2’ position to be
R. A synthesis of symbioramide based on Sharpless
Symbioramide (1) is a naturally occuring bioactive ce- asymmetric epoxidation for the preparation of the
ramide that has been isolated by Kobayashi et al.[1] (2R,3E)-2-hydroxy-3-octadecenoic acid fragment was
from the laboratory-cultured dinoflagellate Symbiodi- later reported by Mori et al.,[3] who also relied on l-
nium sp., obtained from the inside of gill cells of the serine to attain the d-erythro-dihydrosphingosine part
Okinawan bivalve Fragum sp. This sphingosine deriv- by using a known route. Azuma, Ogino et al.[4] de-
ative was the first example of a sarcoplasmic reticu- scribed the total syntheses of symbioramide and de-
lum Ca2+-ATPase activator from a marine source. In rivatives starting from l-serine for the preparation of
addition, symbioramide has been found to exhibit an- both the fatty acid fragment and the dihydrosphingo-
tileukemic activity against L1210 murine leukemia sine subunit. However, a major drawback of this ap-
cells in vitro with an IC50 value of 9.5 mgmLÀ1. The proach lies in the construction of the (E)-olefin of the
structure of symbioramide was initially proposed acid part, which was obtained through photoisomeri-
as (2S,3R,3’E)-N-(2’-hydroxy-3’-octadecenoyl)dihydro- zation of the (Z)-isomer using diphenyl disulfide, as a
ACHTUNGTRENNUNGsphingosine, composed of d-erythro-dihydrosphingo- 76:24 mixture of E:Z olefins which had to be separat-
sine as the amino part and (2R,3E)-2-hydroxy-3-octa- ed by column chromatography followed by recrystalli-
decenoic acid as the acid part, with unknown absolute zation. A chemo-enzymatic total synthesis of symbior-
configuration at C-2’.
amide was later reported by the group of Sugai in
Due to its significant biological properties as well 2005.[5] This approach relied on a lipase-catalyzed
as its interesting structural features, several syntheses coupling between (Æ)-dihydrosphingosine and an (R)-
of symbioramide have been reported. The first total b,g-unsaturated a-hydroxy ester, both of which were
synthesis of 1, reported by Nakagawa, Hino et al.[2] derived from a common intermediate, methyl (Æ)-
relied on the use of l-ascorbic acid and l-serine as trans-2,3-epoxyoctadecanoate. Although concise, this
chiral synthons for the preparation of, respectively, route suffers from the inherent drawback associated
the unusual fatty acid subunit and the d-erythro-dihy- with enzymatic methods, which give at the most 50%
drosphingosine part. Moreover, the synthesis of both yield of the desired enantiomerically enriched com-
enantiomers of methyl (E)-2-hydroxy-3-octodecen- pound. Moreover, the direct enzyme-mediated cou-
ACHTUNGTRENNUNGoate allowed the authors to unambiguously establish pling reaction proceeded in a non-enantioselective
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manner, delivering both symbioramide and the un- (Z) and (E)-alkenes 2. On the other hand, ruthenium-
natural diastereomer, which were separated on mediated asymmetric hydrogenation of 5 or of the
column chromatography. More recently, Posner et al. parent compound, an a-amido-b-keto ester, would
achieved a formal synthesis of symbioramide by using readily afford respectively the anti[7,11] or syn[12] iso-
an elegant asymmetric organocatalytic approach to a- mers of 3. Coupling of these various isomers of subu-
hydroxy (E)-b,g-unsaturated esters.[6]
nits 2 and 3 would then produce all sixteen stereoiso-
In order to complement the reported total synthe- mers of symbioramide.
ses of 1 which generally involved enzymatic routes or
Following this strategy, we report herein the concise
chiral pool-based approaches, we were interested in stereodivergent synthesis of eight stereoisomers of
designing an efficient catalytic approach to the natu- symbioramide, including the natural compound, start-
ral product.
ing from prochiral 4 and racemic 5.
Thus, as an extension of our work on dynamic ki-
netic resolution (DKR) of a-amino-b-keto ester hy-
drochlorides through ruthenium-catalyzed asymmetric Results and Discussion
hydrogenation,[7] and in connection with our ongoing
projects involving the synthesis of biologically rele- The synthesis of methyl oxooctadecanoate 4 relied in-
vant natural products via transition metal-promoted itially on conversion of monomethyl oxalyl chloride 6
reactions,[8] we report herein an application of this into Weinreb amide 7,[13] followed by addition of
methodology to the total synthesis of symbioramide.
hexadec-1-yne which furnished the target com-
From a retrosynthetic point of view, symbioramide pound[14] in 30% overall yield (Scheme 2). However,
can be disconnected at the amide bond into (2R,3E)- the parent compound ethyl oxooctadecanoate 9 was
2-hydroxy-3-octadecenoic acid 2 and d-erythro-dihy- more efficiently prepared in 70% yield by reaction of
drosphingosine 3 (Scheme 1).
n-hexadecylmagnesium bromide with diethyl oxalate
Subunit 2 would result from stereoselective reduc- 8.[15]
tion of the ketone function of an a-keto-b,g-unsatu-
To the best of our knowledge, the stereoselective
rated ester 4 through asymmetric transfer hydrogena- reduction of a-keto-b,g-acetylenic esters has not been
tion, followed by stereoselective reduction of the reported so far. However, since transition metal-cata-
alkyne into the corresponding (E)-alkene. On the lyzed asymmetric transfer hydrogenation (ATH)[16] of
other hand, d-erythro-dihydrosphingosine 3 would be either a,b-acetylenic ketones or a-keto esters is an ef-
obtained via ruthenium-catalyzed asymmetric hydro- ficient method for the preparation of, respectively,
genation[9] of the racemic a-amino-b-keto ester hydro- enantiomerically enriched propargylic alcohols or a-
chloride 5 through DKR.[10]
hydroxy esters, we logically decided to investigate the
Interestingly, this approach opens an easy access to ATH of a-keto-b,g-acetylenic esters 4 and 9 in order
all sixteen diastereomers of symbioramide. Indeed, on to synthesize the corresponding a-hydroxy-b,g-acety-
the one hand, enantioselective reduction of ketone 4 lenic esters. Nevertheless, since our preliminary ef-
would deliver both enantiomers of the corresponding forts to optimize this reaction with either the Noyori
alcohol, whereas stereoselective reduction of the catalyst
[(S,S)-RuCl
G
G
or
alkyne function would furnish both the corresponding other ruthenium, iridium and rhodium complexes
were unsuccessful,[18] we chose to use stoichiometric
methods for the preparation of the desired enantio-
Scheme 2. Preparation of a-keto-b,g-acetylenic esters 4 and
9.
Scheme 1. Retrosynthetic analysis of symbioramide 1.
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Total Synthesis of Symbioramide: a Flexible Approach for the Efficient Preparation of Structural Isomers
merically enriched alcohols. Thus, methyl oxooctade- the corresponding (E)-allylic alcohol was first at-
canoate 4 was treated with the Corey–Bakshi–Shibata tempted using Red-Al. With this reagent, however,
oxazaborolidine[19] in the presence of BH3·Me2S. The only reduction of the ester function occurred, and no
reaction afforded 10 in a good 76% yield but with a trace of alkene was observed. A hydrosilylation/pro-
moderate 34% ee. The stereoselective reduction of 4 todesilylation sequence using (EtO)3SiH and the
and of the parent compound, ethyl oxooctadecanoate [RuACTHNUTRGNEUNG
(NCMe)3Cp*]PF6 complex[22] was next applied.
9, was nevertheless successfully accomplished by Unfortunately, despite considerable experimentation,
using (S)-alpine borane[20] which furnished, respective- the desired (E)-allylic alcohol could not be obtained
ly, the enantiomerically enriched alcohols 10 and 11 in acceptable yields by using this approach. On the
in good yields (71–83%) and excellent enantioselec- other hand, the required (E)-alkene 18 was synthe-
tivities (96–97% ee)[21] after careful optimization of sized from 11 using a five-step sequence as depicted
the reaction conditions (Scheme 3).
below (Scheme 4).
Subsequent hydrogenation of 11 using Lindlar cata-
Treatment of 11 with LiAlH4 in refluxing THF al-
lyst, followed by hydrolysis of the ester function then lowed the formation of diol 14 in 60% yield. After a
delivered the expected (Z)-allylic alcohol 13 in 81% protection/deprotection sequence of the diol moiety,
yield.
the primary alcohol of 17 was finally oxidized with
For the synthesis of the related (E)-isomer 18 the Jones reagent to the corresponding carboxylic
(Scheme 4), conversion of propargylic alcohol 11 into acid 18, ready for the peptide coupling reaction with
the d-erythro-dihydrosphingosine part.
Having secured the preparation of the hydroxyocta-
decanoic fragments, we then turned to the synthesis
of the dihydrosphingosine counterparts starting from
racemic a-amino-b-keto ester derivatives. The hydro-
genation reaction of compound 5[10c] was first attempt-
ed using an iridium complex bearing as a ligand the
atropisomeric diphosphine SYNPHOS[23] developed
in our group (Scheme 5).
Thus the reaction was carried out with 1 mol% of
the [{Ir((S)-SYNPHOS)H}2ACTHNUTRGNEUNG
(m-Cl)3]Cl complex,[24]
under 75 bar of hydrogen in a CH2Cl2/MeOH mixture
at 508C for 48 h. Under these conditions, however, a
low conversion of 20% was observed. Ruthenium-
mediated asymmetric hydrogenation of 5 was then at-
tempted using 2 mol% of {RuCl[(S)-SYNPHOS]-
AHCTUNGTRENNUNG
(p-cymene)}Cl[25] complex in CH2Cl2/MeOH at 508C
Scheme 3. Preparation of the (Z)-fatty acid subunit 13.
under 12 bar of hydrogen. Nevertheless, after 24 h of
reaction, no trace of the expected alcohol was ob-
served. The reduction was also carried out using the
convenient procedure developed in our laboratories
for the in situ preparation of chiral ruthenium-diphos-
phine complexes starting directly from RuCl3.[26] How-
ever, hydrogenation of 5 using 2 mol% of RuCl3 asso-
ciated to (R)-SYNPHOS as a ligand showed no con-
version at all. Finally, the asymmetric hydrogenation
of a-amino-b-keto ester hydrochloride 5 was per-
formed using ruthenium(II) complexes prepared in
situ from [Ru(1,5-cyclooctadiene)(2-methylallyl)2].[27]
The reaction was conducted in CH2Cl2/MeOH at
508C under 12 bar of hydrogen in the presence of
2 mol% of either {Ru[(R)-SYNPHOS]Br2} or
{Ru[(S)-SYNPHOS]Br2} complex,[7a,b] and afforded
respectively the anti amino alcohols 19 and (ent)-19 in
high enantio- and diastereoselectivities after treat-
ment of the hydrogenated products with triethylamine
in Et2O/MeOH. These compounds were reduced to
the corresponding diols using LiAlH4 and protected
as their acetonides 20 and (ent)-20 by treatment with
Scheme 4. Preparation of the (E)-fatty acid subunit 18.
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Scheme 6. Synthesis of symbioramide structural isomers 28
and 29.
and 27 were thus obtained in 60–65% yield, allowing
after acetonide removal, the enantioselective synthe-
sis of two other symbioramide isomers 28 and 29.
Preparation of the syn-1,2-amino alcohol isomers of
symbioramide relied on the ruthenium-catalyzed
asymmetric hydrogenation of a-amido-b-keto ester
30.[7a,b] The reaction was conducted in CH2Cl2 at 808C
under 60 bar of hydrogen in the presence of 2 mol%
of either {Ru[(R)-SYNPHOS]Br2} or {Ru[(S)-SYN-
PHOS]Br2} complexes, and afforded respectively the
syn-amino alcohols 31 and (ent)-31 in high enantio-
and diastereoselectivities up to 98% ee and 98% de
(Scheme 7). Treatment of these compounds with
excess LiAlH4 in refluxing THF provided the corre-
sponding benzylaminodiols and subsequent debenzy-
lation (H2, Pd/C) followed by protection of the 1,3-
diol moiety delivered acetonides 33 and (ent)-33 in
good 57–67% overall yields. Coupling of these com-
pounds with (E)-carboxylic acid 18 and subsequent
Scheme 5. Total synthesis of symbioramide (1) and of its
structural isomer 25.
dimethoxypropane/PPTS in refluxing chloroform. acetonide removal then yielded 36 and 37.
Coupling of these compounds with (E)-carboxylic Finally, deprotection of the remaining hydroxy
acid 18 proceeded cleanly using HATU/DIPEA in di- function with TBAF delivered two novel structural
chloromethane and the expected peptides 21 and 22 isomers 38 and 39 of symbioramide.
were obtained in 64–74% yields. Subsequent global
The related (Z)-isomers 42 and 43 were prepared
deprotection of the hydroxy functions with successive- as well from compounds 33 and (ent)-33 according to
ly PTSA and TBAF then delivered symbioramide 1 the two-step sequence employed for the synthesis of
and its structural isomer 25, respectively. The spectral 28 and 29 (Scheme 8).
data of synthetic symbioramide were found to be in
Thus, coupling of 33 and (ent)-33 with the fatty acid
agreement with those reported for the natural product subunit 13 in the presence of HATU/DIPEA provid-
{[a]2D0: +4.7 (c 0.29, CHCl3), lit.:[1a] [a]D22: +5.8 (c 1, ed 40 and 41, which were subsequently subjected to
CHCl3)}.
PTSA in CH2Cl2/MeOH to afford structural isomers
In order to synthesize the related (Z)-isomers 28 42 and 43 of symbioramide in good overall yields.
and 29 of symbioramide, compounds 20 and (ent)-20
were subjected to peptide coupling reaction with
(2R,3Z)-2-hydroxy-3-octadecenoic acid 13 under the
conditions mentioned above (Scheme 6). Peptides 26
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Total Synthesis of Symbioramide: a Flexible Approach for the Efficient Preparation of Structural Isomers
Conclusions
In summary, a short and efficient synthesis of sym-
bioramide 1 was achieved starting from readily acces-
sible racemic a-amino-b-keto ester 5 and a-keto-b,g-
unsaturated ester 4. Application of the ruthenium-cat-
alyzed asymmetric hydrogenation reaction to racemic
a-amino-b-keto ester derivatives 5 and 30 allowed the
preparation of the corresponding anti- and syn-amino
alcohols in high enantio- and diastereoselectivities
through a dynamic kinetic resolution process. Further-
more, an efficient preparation of both (E)- and (Z)-
isomers of the a-hydroxy b,g-unsaturated fatty acid
part has been achieved by stereoselective reduction of
the ketone and alkyne functions of a-keto-b,g-unsatu-
rated ester 9. This flexible strategy allowed the short
synthesis of seven structural isomers of symbioramide,
namely compounds 25, 28/29, 38/39, and 42/43 which
were efficiently obtained in high enantio- and diaste-
reoselectivities.
Experimental Section
General Remarks
All air- and/or water-sensitive reactions were carried out
under an argon atmosphere. Tetrahydrofuran and diethyl
ether were distilled from sodium-benzophenone. Dichloro-
methane was distilled from calcium hydride. Reactions were
monitored by thin layer chromatography carried out on pre-
coated silica gel plates (E. Merck ref. 5554 60 F254) and re-
vealed with either a ultra-violet lamp (l=254 nm) or a po-
tassium permanganate solution. The nuclear magnetic reso-
nance spectra were recorded on a Bruker AC 300 or Avance
Scheme 7. Synthesis of symbioramide structural isomers 38
and 39.
1
400 instrument at 300 or 400 MHz, respectively, for H and
75 or 100 MHz, respectively, for 13C. The chemical shifts are
expressed in parts per million (ppm) referenced to residual
chloroform (7.26 ppm for 1H and 77.1 ppm for 13C). Data
are reported as follows: chemical shifts (d), multiplicity (re-
corded as s, singlet; d, doublet; t, triplet; q, quadruplet;
sept, septuplet; m, multiplet; and br, broad), integration and
coupling constants. Melting points (mp) were determined on
a Bꢂchi apparatus and are uncorrected. Optical rotations
were measured on a Perkin–Elmer 241 polarimeter. High
resolution mass spectrometric (HR-MS) analyses were mea-
sured on LTQ-Orbitrap (Thermo Fisher Scientific) at Pierre
et Marie Curie University.
General Procedure for the Dynamic Kinetic
Resolution of a-Amino-b-keto Ester Derivatives
through Asymmetric Hydrogenation
(R)- or (S)-SYNPHOS (28.1 mg, 0.044 mmol) and [Ru(1,5-
cyclooctadiene)ACTHNURGTENNUG CAHTUNGTREN(NNGU CH2)2CHCH3)2] (12.8 mg, 0.04 mmol)
(h3-
were placed in a round-bottom tube, degassed by three
vacuum/argon cycles at room temperature, and dissolved in
degassed acetone (1 mL). To this suspension was added
dropwise at room temperature, methanolic hydrobromic
acid (0.088 mmol, 564 mL of a 0.156N solution) and the mix-
Scheme 8. Synthesis of symbioramide structural isomers 42
and 43.
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ture was stirred at room temperature for 30 min. The sus-
pension immediately turned yellow, and then an orange pre-
cipitate appeared. The solvent was thoroughly evaporated
under vacuum to afford the ruthenium complex as an
orange-brown solid. A solution of a-amino-b-keto ester
(2 mmol) in either CH2Cl2/MeOH (4 mL) or CH2Cl2 (4 mL)
was added to the ruthenium complex and the resulting mix-
ture was placed under the desired hydrogen pressure and
temperature for either 24 h or 96 h. After removal of the
solvent, the crude product was either directly used for the
next step used or purified by flash chromatography on silica
gel.
s, 20H), 0.87 (t, 3H, J=6.7 Hz); 13C NMR (CDCl3,
75 MHz): d=169.9, 159.5, 102.8, 79.9, 63.3, 32.1, 29.8, 29.7,
29.5, 29.1, 29.0, 27.5, 22.8, 19.6, 14.2, 14.1; HR-MS (ESI):
m/z=345.2401, calcd. for C20H34O3Na [M+Na]+: 345.2400.
(2R)-Methyl 2-Hydroxyoctadec-3-ynoate [(R)-10] and
(2S) Methyl 2-Hydroxyoctadec-3-ynoate [(S)-10]
A solution of (S)-alpine borane (0.5M in THF, 1.0 mL,
0.51 mmol) was introduced in a round-bottom flask and the
solvent was removed under vacuum. A solution of 4 (75 mg,
0.24 mmol) in CH2Cl2 (0.4 mL) was then added dropwise at
08C, the solvent was removed under vacuum and the reac-
tion mixture was stirred for 16 h at 208C. Et2O (0.5 mL) and
silica (100 mg) were added, the mixture was stirred for 1 h
at room temperature and filtered. The solvent was removed
under vacuum and the residue was purified by two succes-
sive flash chromatographies (cyclohexane/CH2Cl2/AcOEt:
75/20/5) then (cyclohexane/AcOEt: 95/5) to afford (R)-10 as
a white solid; yield: 53 mg (71%); mp 378C; [a]2D0: À42.6 (c
1.02, CHCl3).
Monomethyloxalic Acid N-Methoxy-N-methylamide
(7)[13]
To a solution of N,O-dimethylhydroxylamine hydrochloride
(5.29 g, 54.2 mmol) and monomethyl oxalyl chloride
(5.0 mL, 54.2 mmol) in CH2Cl2 (350 mL) was added triethyl-
amine (15.2 mL, 108.5 mmol) at 08C. The mixture was
stirred for 2 h at 08C, and concentrated after addition of
MeOH (7 mL). THF (150 mL) was then added, the mixture
was filtered, washed with THF and concentrated under
vacuum. Purification of the residue by distillation (kugel-
rohr, bp 114–1208C/2–3 torr), afforded 7 as a colorless oil;
Compound (S)-10
Obtained from 4 (100 mg, 0.32 mmol) and (R)-alpine borane
(1.36 mL, 0.68 mmol) following the procedure described for
(R)-10. Purification of the residue by flash chromatography
(cyclohexane/CH2Cl2/AcOEt: 75/20/5) then (cyclohexane/
AcOEt: 95/5) afforded (S)-10 as a white solid; yield: 77 mg
(77%); [a]2D0: +40.5 (c 1.00, CHCl3). 1H NMR (CDCl3,
300 MHz): d=4.84 (dt, 1H, J=7.4 and 2.2 Hz), 3.86 (s, 3H),
2.93 (d, 1H, J=7.4 Hz), 2.21 (td, 2H, J=7.1and 2.2 Hz),
1.56–1.44 (m, 2H), 1.25 (br s, 22H), 0.88 (t, 3H, J=7.2 Hz);
13C NMR (CDCl3, 75 MHz): d=171.4, 87.2, 75.4, 61.7, 53.5,
32.1, 29.8, 29.6, 29.5, 29.2, 29.0, 28.4, 27.0, 22.8, 18.8, 14.3;
CSP-SFC (Chiralpak AD-H, 94:6 CO2:methanol, 100 bar,
5.0 mLminÀ1, l=215 nm): tR 2.00 min, (R)-10; tR 2.12 min,
(S)-10.
1
yield: 7.50 g (94%). H NMR (CDCl3, 300 MHz): d=3.84 (s,
3H), 3.72 (s, 3H), 3.19 (s, 3H); 13C NMR (CDCl3, 75 MHz):
d=162.8, 161.8, 62.3, 52.6, 31.4.
Methyl 2-Oxooctadec-3-ynoate (4)
To a solution of 1-hexadecyne (2.37 mL, 8.5 mmol) in THF
(15 mL) was added n-BuLi (2.1M in hexane, 3.95 mL,
8.3 mmol) at À308C. The mixture was stirred for 2 h at
room temperature and was added dropwise to a solution of
7 (1.0 g, 6.80 mmol) in THF (10 mL) at À788C. The temper-
ature was slowly raised to room temperature and the mix-
ture was stirred for 15 h. The solution was filtered on a silica
pad and the solvent was removed under vacuum. Purifica-
tion of the residue by flash chromatography (pentane/diiso-
propyl ether: 96/4 to 9/1) afforded 4 as a pale yellow oil;
(2R)-Ethyl 2-Hydroxyoctadec-3-ynoate [(R)-11] and
(2S)-Ethyl 2-Hydroxyoctadec-3-ynoate [(S)-11]
1
yield: 662 mg (32%). H NMR (CDCl3, 300 MHz): d=3.91
(s, 3H), 2.47 (t, 2H, J=7.1 Hz), 1.68–1.55 (m, 2H), 1.48–
1.36 (m, 2H), 1.24 (br s, 20H), 0.88 (t, 3H, J=6.7 Hz);
13C NMR (CDCl3, 75 MHz): d=169.3, 159.8, 103.0, 79.8,
53.6, 32.0, 29.8, 29.7, 29.5, 29.1, 29.0, 27.5, 22.8, 19.6, 14.2.
A solution of (S)-alpine borane (0.5M in THF, 6.51 mL,
3.25 mmol) was introduced in a round-bottom flask and the
solvent was removed under vacuum. A solution of 5
(500 mg, 1.55 mmol) in CH2Cl2 (2 mL) was then added drop-
wise at 08C. The solvent was removed under vacuum and
the reaction mixture was stirred for 16 h at 208C. Et2O
(3.5 mL) and silica (650 mg) were added, the mixture was
stirred for 1 h at room temperature and filtered. The solvent
was removed undervacuum and the residue was purified by
two successive flash chromatographies (cyclohexane/CH2Cl2/
AcOEt: 70/24/6) and (cyclohexane/AcOEt: 95/5) to afford
(R)-11 as a white solid; yield: 420 mg (83%); mp 408C;
[a]2D0: À27.3 (c 0.74, CHCl3).
Ethyl 2-Oxooctadec-3-ynoate (9)
To a solution of 1-hexadecyne (4.6 mL, 16.5 mmol) in Et2O
(50 mL) was added ethyl magnesium bromide (0.78M in
Et2O, 23.2 mL, 18.1 mmol). The mixture was stirred for 6 h
under reflux, then added dropwise to a solution of diethyl
oxalate (2.5 mL, 18.1 mmol) in Et2O (20 mL) at À308C. The
mixture was stirred for 1.5 h at this temperature and saturat-
ed NH4Cl was added. The aqueous layer was extracted with
(i-Pr)2O, the combined organic layers were washed with
brine, dried over MgSO4 and concentrated under vacuum.
Purification of the residue by flash chromatography (cyclo-
hexane/diisopropyl ether: 95/5) afforded 9 as a pale yellow
oil; yield: 3.72 g (70%). 1H NMR (CDCl3, 300 MHz): d=
4.35 (q, 2H, J=7.1 Hz), 2.47 (t, 2H, J=7.1 Hz), 1.70–1.55
(m, 2H), 1.49–1.34 (m, 2H), 1.38 (t, 3H, J=7.1 Hz), 1.25 (br
Compound (S)-11
Obtained from 5 (500 mg, 1.55 mmol) and (R)-alpine borane
(6.51 mL, 3.26 mmol) following the procedure described for
(R)-11. Purification of the residue by flash chromatography
(cyclohexane/CH2Cl2/AcOEt: 70/24/6) then (cyclohexane/
AcOEt: 95/5) afforded (S)-11 as a white solid; yield: 389 mg
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Total Synthesis of Symbioramide: a Flexible Approach for the Efficient Preparation of Structural Isomers
(77%); [a]2D0: 26.1 (c 1.02, CHCl3). 1H NMR (CDCl3,
300 MHz): d=4.80 (dt, 1H, J=7.3 and 2.1 Hz), 4.30 (q, 2H,
J=7.1 Hz), 3.00 (d, 1H, J=7.3 Hz), 2.20 (td, 2H, J=7.1 and
2.2 Hz), 1.56–1.43 (m, 2H), 1.33 (t, 3H, J=7.1 Hz), 1.25 (br
s, 22H), 0.87 (t, 3H, J=6.7 Hz); 13C NMR (CDCl3,
75 MHz): d=171.0, 86.9, 75.7, 62.7, 61.7, 32.1, 29.8, 29.6,
29.5, 29.2, 28.9, 28.4, 22.8, 18.8, 14.3, 14.2; CSP-SFC (Chiral-
pak AD-H, 94:6 CO2:methanol, 100 bar, 5.0 mLminÀ1, l=
215 nm): tR 1.75 min, (R)-11; tR 2.03 min, (S)-11; HR-MS
(ESI): m/z=347.2554, calcd. for C20H36O3Na [M+Na]+:
347.2557.
flash chromatography (CH2Cl2/AcOEt: 8/2) afforded 14 as a
white solid; yield: 245 mg (60%); [a]2D0: À11.0 (c 0.83,
CHCl3), lit.:[2b] [a]15: À8.97 (c 0.858, CHCl3). 1H NMR
(CDCl3, 300 MHz):D d=5.75 (dtd, 1H, J=15.3, 6.7 and
1.0 Hz), 5.45 (ddt, 1H, J=15.5, 6.6 and 1.4 Hz), 4.23–4.12
(m, 1H), 3.60 (dd, 1H, J=11.2 and 2.9 Hz), 3.45 (dd, 1H,
J=11.2 and 7.8 Hz), 2.90 (br s, 2H), 2.02 (q like, 2H, J=
6.8 Hz), 1.40–1.28 (m, 2H), 1.24 (br s, 22H), 0.87 (t, 3H, J=
6.7 Hz); 13C NMR (CDCl3, 75 MHz): d=134.5, 128.3, 73.4,
66.8, 32.5, 32.1, 29.8, 29.6, 29.5, 29.4, 29.2, 22.8, 14.2.
AHCTUNGTREG(NNUN 2R,3E)-1-tert-Butyldimethylsilyloxy-3-octadecen-2-ol
(15)
G
To a solution of 11 (409 mg, 1.26 mmol) in AcOEt (10 mL)
were added Lindlar catalyst (134 mg, 0.063 mmol) and quin-
oline (48 mL, 0,40 mmol). The argon atmosphere was re-
placed with hydrogen and the reaction mixture was stirred
at room temperature under hydrogen (balloon) for 2.5 h.
The suspension was then filtered on a celite pad, the filtrate
was concentrated under vacuum and the residue was puri-
fied by flash chromatography (cyclohexane/AcOEt: 9/1) to
afford 12 as a white solid; yield: 355 mg (86%); mp 248C;
To a solution of 14 (85 mg, 0.29 mmol) in CH2Cl2 (1 mL)
were added tert-butyldimethylsilyl chloride (68 mg,
0.46 mmol), dimethylaminopyridine (3 mg, 0.029 mmol) and
diisopropylethylamine (84 mL, 0.48 mmol). The mixture was
stirred for 15 h at room temperature, then water was added,
and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were dried over MgSO4, and concen-
trated under vacuum. Purification of the residue by flash
chromatography (cyclohexane/diisopropyl ether: 93/7) af-
forded 15 as a colorless oil; yield: 100 mg (89%); [a]2D0:
À13.6 (c 0.98, CHCl3), lit.:[3] [a]D23: À11.4 (c 1.33, CHCl3).
1H NMR (CDCl3, 300 MHz): d=5.75 (dtd, 1H, J=15.5, 6.8
and 0.9 Hz), 5.38 (ddt, 1H, J=15.4, 6.7 and 1.4 Hz), 4.16–
4.05 (m, 1H), 3.61 (dd, 1H, J=10.0 and 3.6 Hz), 3.41 (dd,
1H, J=9.9 and 8.1 Hz), 2.56 (d, 1H, J=6.9 Hz), 2.02 (q like,
2H, J=6.9 Hz), 1.40–1.28 (m, 2H), 1.25 (br s, 22H), 0.90 (s,
9H), 0.87 (t, 3H, J=6.7 Hz), 0.07 (s, 6H); 13C NMR
(CDCl3, 75 MHz): d=134.2, 128.1, 73.0, 67.5, 32.5, 32.1,
29.8, 29.6, 29.5, 29.3, 29.2, 27.1, 26.0, 22.8, 18.4, 14.2, À5.2.
1
[a]2D0: À140.0 (c 0.93, CHCl3). H NMR (CDCl3, 300 MHz):
d=5.69 (dtd, 1H, J=10.8, 7.5 and 1.2 Hz), 5.38–5.27 (m,
1H), 4.94–4.86 (m, 1H), 4.23 (dq, 2H, J=7.1 and 1.2 Hz),
2.96 (d, 1H, J=5.6 Hz), 2.24–2.12 (m, 2H), 1.47–1.34 (m,
2H), 1.28 (t, 3H, J=7.1 Hz), 1.25 (br s, 22H), 0.87 (t, 3H,
J=6.7 Hz); 13C NMR (CDCl3, 75 MHz): d=174.3, 136.3,
126.2, 67.4, 62.1, 32.1, 29.8, 29.7, 29.5, 29.4, 28.1, 22.8, 14.3;
HR-MS (ESI): m/z=349.2711, calcd. for C20H38O3Na [M+
Na]+: 349.2713.
ACHTUNGTRENNUNG(2R,3Z)-2-Hydroxyoctadec-3-enoic Acid (13)
AHCTUNGTREG(NNNU 2R,3E)-1-tert-Butyldimethylsilyloxy-2-tert-butyl-
diphenylsilyloxy-3-octadecene (16)
To a solution of 12 (308 mg, 0.94 mmol) in THF (8 mL) was
added lithium hydroxide (434 mg, 10.3 mmol) in water/
MeOH (5 mL/2.5 mL) at 08C. The mixture was stirred for
2 h at room temperature and aqueous HCl (1M) was added
at 08C. The aqueous layer was extracted with AcOEt and
the combined organic layers were washed with brine, dried
over MgSO4 and concentrated under vacuum to afford 13 as
a white solid; yield: 265 mg (94%); mp 608C; [a]2D0: À106.4
To a solution of 15 (430 mg, 1.08 mmol) in DMF (4.5 mL)
were added imidazole (360 mg, 5.28 mmol) and tert-butyldi-
phenylsilyl chloride (813 mL, 3.13 mmol). The mixture was
stirred at room temperature for 3 h. Brine was added, the
aqueous layer was extracted with AcOEt, the combined or-
ganic layers were dried over MgSO4, concentrated under
vacuum and the residue was purified by flash chromatogra-
phy (cyclohexane/diisopropyl ether: 99/1) to afford 16 as a
colorless oil; yield: 621 mg (90%); [a]2D0: À14.1 (c 0.96,
1
(c 1.08, CHCl3). H NMR (CDCl3, 300 MHz): d=5.77 (dt,
1H, J=10.6 and 7.5 Hz), 5.44–5.32 (m, 1H), 5.02 (d, 1H, J=
8.7 Hz), 2.27–2.12 (m, 2H), 1.50–1.35 (m, 2H), 1.25 (br s,
22H), 0.88 (t, 3H, J=6.7 Hz); 13C NMR (CDCl3, 75 MHz):
d=178.7, 137.5, 125.1, 67.2, 32.1, 29.8, 29.7, 29.6, 29.5, 29.4,
28.2, 22.8, 14.3; HR-MS (ESI): m/z=321.2401, calcd. for
C18H34O3Na [M+Na]+: 321.2400.
1
CHCl3), lit.:[3] [a]D23: À13.3 (c 1.66, CHCl3). H NMR (CDCl3,
300 MHz): d=7.69 (tt, 4H, J=7.9 and 1.9 Hz), 7.46–7.30
(m, 6H), 5.45–5.30 (m, 2H), 4.13 (q like, 1H, J=5.7 Hz),
3.57 (dd, 1H, J=9.9 and 5.8 Hz), 3.43 (dd, 1H, J=9.9 and
6.5, Hz), 1.98–1.81 (m, 2H), 1.27 (br s, 24H), 1.07 (s, 9H),
0.89 (t, 3H, J=6.6 Hz), 0.84 (s, 9H), À0.04 (s, 3H), À0.07 (s,
3H); 13C NMR (CDCl3, 75 MHz): d=136.2, 136.1, 134.6,
134.5, 132.8, 130.4, 129.6, 129.5, 127.5, 127.4, 75.2, 67.9, 32.4,
32.1, 29.9, 29.8, 29.7, 29.5, 29.3, 29.2, 27.2, 26.1, 22.9, 19.5,
18.5, 14.3, À5.2.
ACHTUNGTRENNUNG(2R,3E)-Octadec-3-ene-1,2-diol (14)
To a suspension of LiAlH4 (328 mg, 8.64 mmol) in THF
(27 mL) was added dropwise a solution of 11 (467 mg,
1.44 mmol) in THF (5 mL) at 08C. The mixture was stirred
at room temperature for 1 h and then heated to reflux for
4 h. At 08C, a Rochelle salt solution and Et2O were added,
and the mixture was stirred for 1 h at room temperature.
The aqueous layer was extracted with Et2O and the com-
bined organic layers were washed with water and brine,
dried over MgSO4, and concentrated under vacuum (heating
bath temperature: 258C). Purification of the residue by
AHCTUNGTREG(NNUN 2R,3E)-2-tert-Butyldiphenylsilyloxy-3-octadecen-1-ol
(17)
A solution of 16 (615 mg, 0.97 mmol) in AcOH/THF/H2O:3/
1/1 (15 mL) was stirred at 708C for 24 h. AcOEt and satu-
rated NaHCO3 were then added. The aqueous layer was ex-
Adv. Synth. Catal. 2011, 353, 3213 – 3226
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Sꢀbastien Prꢀvost et al.
FULL PAPERS
tracted with AcOEt and the combined organic layers were
washed with water and brine, dried over MgSO4, and con-
centrated under vacuum. Purification of the residue was pu-
rified by flash chromatography (cyclohexane/diisopropyl
ether: 95/5) afforded 17 as a colorless oil; yield: 306 mg
(61%); [a]2D0: À40.0 (c 0.98, CHCl3), lit.:[3] [a]2D3: À38.1 (c
1.16, CHCl3). 1H NMR (CDCl3, 300 MHz): d=7.68 (ddd,
4H, J=7.9, 3.0 and 1.6 Hz), 7.47–7.32 (m, 6H), 5.38 (dd like,
2H, J=5.4 and 2.4 Hz), 4.26–4.16 (m, 1H), 3.57–3.39 (m,
2H), 1.96–1.78 (m, 3H), 1.27 (br s, 24H), 1.08 (s, 9H), 0.89
(t, 3H, J=6.6 Hz); 13C NMR (CDCl3, 75 MHz): d=136.1,
135.9, 134.4, 134.1, 133.9, 129.9, 129.8, 129.0, 127.8, 127.6,
75.4, 67.2, 32.3, 32.1, 29.8, 29.7, 29.6, 29.5, 29.3, 29.0, 27.2,
27.1, 22.8, 19.5, 14.3.
Compound (ent)-19
Obtained from 5 (1.0 g, 2.75 mmol) according to the general
procedure with [Ru((S)-SYNPHOS)Br2]. Purification of the
residue by flash chromatography (CH2Cl2/MeOH: 95/5) af-
forded (ent)-19 as a pale pink solid; yield: 535 mg (59%);
[a]2D0: +30.5 (c 0.85, CHCl3). 1H NMR (CDCl3, 300 MHz):
d=3.81–3.74 (m, 1H), 3.73 (s, 3H), 3.56 (d, 1H, J=4.5 Hz),
2.52 (br s, 3H), 1.55–1.36 (m, 2H), 1.24 (br s, 26H), 0.86 (t,
3H, J=6.7 Hz); 13C NMR (CDCl3, 75 MHz): d=174.5, 72.5,
58.7, 52.2, 32.5, 32.0, 29.8, 29.7, 29.5, 25.9, 22.8, 14.2.
The diastereo- and enantiomeric excesses were deter-
mined by HPLC after conversion of the crude hydrogenated
products into the corresponding methyl (2R,3R)-2-benzoyla-
mino-3-hydroxyoctadecanoate 19’ and methyl (2S,3S)-2-ben-
zoylamino-3-hydroxyoctadecanoate (ent)-19’, respectively.
HPLC (Chiralpak AS-H, 98:2 hexane:2-propanol,
1.0 mLminÀ1, l=254 nm): tR 26.37 min, 19’, tR 32.31 min,
(ent)-19’.
ACHTUNGTRENNUNG(2R,3E)-2-tert-Butyldiphenylsilyloxy-3-octadecenoic
Acid (18)
Jonesꢃs reagent (8N, 614 mL) was added slowly to a stirred
solution of 17 (306 mg, 0.59 mmol) in acetone (3.4 mL) at
08C. The mixture was stirred at 08C for 4 h and poured
onto ice/water. The aqueous layer was extracted with
AcOEt and the combined organic layers were washed with
brine, dried over MgSO4, concentrated under vacuum. Pu-
rification of the residue by flash chromatography (cyclohex-
ane/diisopropyl ether: 8/2) afforded 18 as a colorless oil;
yield: 255 mg (81%); [a]2D0: À33.0 (c 1.03, CHCl3), lit.:[3]
[a]2D3: À34.1 (c 1.16, CHCl3). 1H NMR (CDCl3, 300 MHz):
d=7.60–7.51 (m, 4H), 7.41–7.25 (m, 6H), 5.53 (dt, 1H, J=
15.4 and 6.7 Hz), 5.35 (dd, 1H, J=15.4 and 6.6 Hz), 4.55 (d,
1H, J=6.4 Hz), 1.91 (q like, 2H, J=6.4 Hz), 1.26 (br s,
24H), 1.12 (s, 9H), 0.88 (t, 3H, J=6.7 Hz); 13C NMR
(CDCl3, 75 MHz): d=175.1, 135.9, 134.9, 132.7, 132.4, 130.3,
130.2, 128.0, 127.9, 127.8, 74.1, 32.2, 32.1, 29.8, 29.7, 29.6,
29.5, 29.3, 28.8, 27.0, 26.7, 22.8, 19.4, 14.3.
AHCTUNGTREG(NNUN 2S,3R)-1,3-O-Isopropylidene-[2-amino-1,3-dihy-
droxyoctadecane] (20) and (2R,3S)-1,3-O-Isopro-
pylidene-[2-amino-1,3-dihydroxyoctadecane] [(ent)-
20]
To a suspension of LiAlH4 (87 mg, 2.30 mmol) in THF
(4 mL) was added dropwise a solution of 19 (505 mg,
1.53 mmol) in THF (4 mL) at 08C. The mixture was stirred
for 2 h at room temperature, then cooled to 08C, and silica
(90 mg), water (90 mL), a 10% aqueous solution of sodium
hydroxide (90 mL) and again water (270 mL) were added.
The resulting mixture was stirred at 08C for 30 min and fil-
tered. The filtrate was concentrated under vacuum and the
crude amino-diol was dissolved in CHCl3 (14 mL). Dime-
thoxypropane (2.8 mL, 22.3 mmol) and PPTS (384 mg,
1.53 mmol) were added and the reaction mixture was stirred
for 2 h under reflux. CHCl3 and saturated NaHCO3 were
added. The aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over
MgSO4 and concentrated under vacuum. Purification of the
residue by flash chromatography (CH2Cl2/MeOH: 96/4) af-
forded 20 as a white solid; yield: 325 mg (62%); mp 328C,
lit.:[4] mp 36–378C, lit.:[3] mp 61–628C; [a]2D0: +29.2 (c 1.3,
CHCl3), lit.:[2b] [a]D22: +29.5 (c 1.178, CHCl3), lit.:[4] [a]2D5:
+31.7 (c 1.03, CHCl3), lit.:[3] [a]D21: +32.4 (c 1.08, CHCl3).
ACHTUNGTRENNUNG(2R,3R)-Methyl 2-Amino-3-hydroxyoctadecanoate
(19) and (2S,3S)-Methyl 2-Amino-3-hydroxyocta-
decanoate [(ent)-19]
To the complex [Ru((R)-SYNPHOS)Br2] (0.14 mmol,
0.02 equiv., prepared according to the general procedure)
was added 5 (2.5 g, 6.87 mmol) followed by degassed anhy-
drous CH2Cl2 (18 mL) and MeOH (2 mL). The round-
bottom flask was degassed by three vacuum-argon cycles
and then placed under argon in a stainless steel autoclave.
The argon atmosphere was replaced with hydrogen by three
cycles of pressurizing and the pressure adjusted to 12 bar.
The autoclave was heated at 508C and stirring was main-
tained for 24 h. After cooling, the reaction mixture was con-
centrated under reduced pressure to afford the crude a-
amino-b-hydroxy ester hydrochloride.
Compound (ent)-20
Obtained from (ent)-19 (300 mg, 0.91 mmol). Purification of
the residue by flash chromatography (CH2Cl2/MeOH: 96/4)
afforded (ent)-20 as a white solid; yield: 159 mg (51%);
[a]2D0: À32.0 (c 0.84, CHCl3). 1H NMR (CDCl3, 300 MHz):
d=3.80 (dd, 1H, J=11.3 and 5.3 Hz), 3.44 (dd, 1H, J=11.3
and 9.9 Hz), 3.43–3.33 (m, 1H), 2.62 (td, 1H, J=9.7 and
5.3 Hz), 1.78–1.64 (m, 2H), 1.42 (s, 3H), 1.37 (s, 3H), 1.24
(br s, 26H), 1.06 (br s, 2H), 0.86 (t, 3H, J=6.7 Hz);
13C NMR (CDCl3, 75 MHz): d=98.5, 75.8, 66.4, 49.9, 32.4,
32.1, 29.8, 29.5, 29.2, 25.2, 22.8, 19.4, 14.3.
To a solution of the above crude product in Et2O/MeOH
(80 mL/8 mL)
was
added
triethylamine
(6.76 mL,
48.1 mmol). The mixture was stirred at room temperature
for 2 h, filtered and the filtrate was concentrated under
vacuum. Purification of the residue by flash chromatography
(CH2Cl2/MeOH: 95/5) afforded 19 as a pale pink solid;
yield: 1.50 g (66%); mp 568C; [a]2D0: À31.3 (c 0.46, CHCl3).
3220
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Total Synthesis of Symbioramide: a Flexible Approach for the Efficient Preparation of Structural Isomers
9H), 0.88 (t, 6H, J=6.7 Hz); 13C NMR (CDCl3, 75 MHz):
d=172.6, 136.0, 135.8, 134.7, 133.1, 132.8, 130.3, 130.2, 128.0,
127.8, 127.3, 75.6, 73.9, 62.7, 53.7, 34.6, 32.2, 32.1, 30.3, 29.8,
29.5, 29.3, 29.0, 27.1, 26.1, 22.8, 19.3, 14.3.
(2S,3R,2’R,3’E)-2-N-(2’-tert-Butyldiphenylsilyloxy-3’-
octadecenoyl)-1,3-O-isopropylidene-[2-aminoocta-
decane-1,3-diol] (21)
To a solution of 20 (31 mg, 0.09 mmol) and 18 (59 mg,
0.11 mmol) in CH2Cl2 (1.5 mL) were added HATU (41 mg,
0.11 mmol) and diisopropylamine (47 mL, 0.27 mmol) at
08C. The mixture was stirred for 2 h at 08C and filtered on
a silica pad. The filtrate was concentrated under vacuum
and the residue was purified by flash chromatography (cy-
clohexane/diisopropyl ether: 8/2) to afford 21 as a colorless
oil; yield: 50 mg (64%). 1H NMR (CDCl3, 300 MHz): d=
7.65–7.57 (m, 4H), 7.49–7.32 (m, 6H), 6.54 (d, 1H, J=
9.0 Hz), 5.66 (dtd, 1H, J=15.3, 6.7 and 1.1 Hz), 5.45 (dd,
1H, J=15.4 and 6.0 Hz), 4.58 (dd, 1H, J=6.0 and 0.9 Hz),
3.82–3.67 (m, 2H), 3.55–3.42 (m, 1H), 3.26 (dd, 1H, J=13.0
and 9.9 Hz), 1.95 (q like, 2H, J=6.2 Hz), 1.58–1.40 (m, 2H),
1.39 (s, 3H), 1.38 (s, 3H), 1.26 (br s, 50H), 1.14 (s, 9H), 0.88
(t, 6H, J=6.7 Hz); 13C NMR (CDCl3, 75 MHz): d=171.9,
135.9, 135.7, 134.5, 132.8, 132.5, 130.4, 130.3, 128.1, 127.9,
127.2, 98.9, 75.5, 72.7, 62.9, 47.9, 32.9, 32.2, 29.9, 29.7, 29.5,
29.3, 29.1, 28.2, 27.1, 25.3, 22.8, 20.1, 19.4, 14.3.
(2R,3S,2’R,3’E)-2-N-(2’-tert-Butyldiphenylsilyloxy-3’-
octadecenoyl)-[2-aminooctadecane-1,3-diol] (24)
Obtained from 22 (58 mg, 0.067 mmol) following the proce-
dure described for compound 23. Purification of the residue
by flash chromatography (cyclohexane/AcOEt: 9/1 to 8/2)
afforded 24 as a white solid; yield: 36 mg (65%). [a]2D0: À8.7
1
(c 1.00, CHCl3). H NMR (CDCl3, 300 MHz): d=7.63 (ddd,
4H, J=16.1, 7.9 and 1.4 Hz), 7.56 (d, 1H, J=7.7 Hz), 7.48–
7.31 (m, 6H), 5.63 (dtd, 1H, J=15.3, 6.8 and 0.8 Hz), 5.47
(dd, 1H, J=15.4 and 6.2 Hz), 4.63 (d, 1H, J=5.8 Hz), 4.04–
3.91 (m, 1H), 3.74–3.62 (m, 2H), 3.62–3.51 (m, 1H), 2.78 (br
s, 1H), 2.25 (br s, 1H), 2.00–1.87 (m, 2H), 1.54–1.40 (m,
2H), 1.26 (br s, 50H), 1.14 (s, 9H), 0.88 (t, 6H, J=6.7 Hz);
13C NMR (CDCl3, 75 MHz): d=172.6, 136.0, 135.8, 134.8,
133.1, 132.8, 130.3, 130.2, 128.0, 127.7, 127.3, 75.7, 74.1, 62.4,
53.9, 34.5, 32.2, 32.1, 29.9, 29.5, 29.3, 29.0, 27.1, 26.1, 22.8,
19.3, 14.3.
(2R,3S,2’R,3’E)-2-N-(2’-tert-Butyldiphenylsilyloxy-3’-
octadecenoyl)-1,3-O-isopropylidene-[2-aminoocta-
decane-1,3-diol] (22)
(2S,3R,2’R,3’E)-2-N-(2’-hydroxy-3’-octadecenoyl)-[2-
aminooctadecane-1,3-diol]: Symbioramide (1)
Obtained from (ent)-20 (32 mg, 0.09 mmol) and 18 (60 mg,
0.11 mmol) following the procedure described for compound
21. Purification of the residue by flash chromatography (cy-
clohexane/diisopropyl ether: 88/12) afforded 22 as a color-
less oil; yield: 60 mg (74%). 1H NMR (CDCl3, 300 MHz):
d=7.61 (ddd, 4H, J=7.9, 5.3 and 1.5 Hz), 7.47–7.32 (m,
6H), 6.71 (d, 1H, J=9.0 Hz), 5.54 (dt, 1H, J=15.4 and
6.7 Hz), 5.40 (dd, 1H, J=15.4 and 6.4 Hz), 4.56 (d, 1H, J=
6.3 Hz), 3.91 (dd, 1H, J=11.3 and 5.2 Hz), 3.85–3.73 (m,
1H), 3.52 (dd, 1H, J=11.3 and 7.3 Hz), 3.50–3.40 (m, 1H),
1.90 (q like, 2H, J=6.3 Hz), 1.49–1.29 (m, 2H), 1.43 (s, 3H),
1.42 (s, 3H), 1.27 (br s, 50H), 1.13 (s, 9H), 0.89 (t, 6H, J=
6.7 Hz); 13C NMR (CDCl3, 75 MHz): d=172.1, 135.9, 135.7,
134.9, 132.8, 132.6, 130.3, 130.2, 128.1, 127.8, 127.1, 99.2,
75.8, 72.5, 63.2, 48.6, 33.1, 32.2, 32.1, 29.8, 29.6, 29.5, 29.3,
28.9, 27.7, 27.1, 26.7, 25.4, 22.8, 20.6, 19.5, 14.3.
To a solution of 23 (29 mg, 0.035 mmol) in THF (2.2 mL)
was added tetrabutylamonium fluoride (1M in THF, 51 mL,
0.051 mmol). The mixture was stirred for 1 h at room tem-
perature, then poured onto water. The aqueous layer was
extracted with CHCl3. The combined organic layers were
washed with brine, dried over MgSO4 and concentrated
under vacuum. Purification of the residue by flash chroma-
tography (CHCl3/MeOH: 96/4) afforded 1 as a white solid;
yield: 17 mg (83%); mp 1048C; [a]2D0: +4.7 (c 0.29, CHCl3),
lit.:[1] [a]D20: +5.8 (c 1, CHCl3), lit.:[2b] [a]2D0: +2.65 (c 0.378,
CHCl3), lit.:[3] [a]D20: +1.19 (c 0.5, CHCl3), lit.:[4] [a]2D0: +3.6
1
(c 0.31, CHCl3). H NMR (CDCl3, 400 MHz, 508C): d=6.92
(d, 1H, J=7.2 Hz), 5.90 (dtd, 1H, J=15.3, 7.2 and 0.6 Hz),
5.59 (ddt, 1H, J=15.4, 6.9 and 1.3 Hz), 4.53 (d, 1H, J=
6.9 Hz), 4.00 (dd, 1H, J=11.2 and 3.4 Hz), 3.87–3.74 (m,
3H), 3.02 (br s, 1H), 2.51 (br s, 1H), 2.41 (br s, 1H), 2.10 (q
like, 2H, J=6.9 Hz), 1.59–1.48 (m, 2H), 1.47–1.37 (m, 2H),
1.29 (br s, 48H), 0.90 (t, 6H, J=6.8 Hz); 13C NMR (CDCl3,
100 MHz, 508C): d=173.0, 136.3, 128.0, 74.1, 73.4, 62.5,
54.8, 34.8, 32.4, 32.1, 29.9, 29.8, 29.5, 29.4, 26.1, 22.8, 14.1.
(2S,3R,2’R,3’E)-2-N-(2’-tert-Butyldiphenylsilyloxy-3’-
octadecenoyl)-[2-aminooctadecane-1,3-diol] (23)
To a solution of 21 (48 mg, 0.056 mmol) in CH2Cl2/MeOH
(0.5 mL/0.5 mL) was added PTSA (1.7 mg, 0.008 mmol).
The mixture was stirred for 2.5 h at room temperature and
saturated NaHCO3 was added. The aqueous layer was ex-
tracted with AcOEt. The combined organic layers were
dried over MgSO4 and concentrated under vacuum. Purifica-
tion of the residue by flash chromatography (cyclohexane/
AcOEt: 8/2) afforded 23 as a white solid; yield: 30 mg
(66%); [a]2D0: +0.8 (c 1.00, CHCl3), lit.:[4] [a]2D0: +2.02 (c
0.945, CHCl3). 1H NMR (CDCl3, 300 MHz): d=7.63 (ddd,
4H, J=14.8, 7.9 and 1.4 Hz), 7.55 (d, 1H, J=7.6 Hz), 7.48–
7.30 (m, 6H), 5.64 (dtd, 1H, J=15.3, 6.7 and 0.8 Hz), 5.47
(dd, 1H, J=15.4 and 6.1 Hz), 4.62 (d, 1H, J=5.8 Hz), 3.89
(dd, 1H, J=11.2 and 2.1 Hz), 3.77–3.65 (m, 2H), 3.57 (d
like, 1H, J=11.0 Hz), 2.56 (br s, 1H), 2.28 (br s, 1H), 2.01–
1.87 (m, 2H), 1.79–1.58 (m, 2H), 1.25 (br s, 50H), 1.14 (s,
(2R,3S,2’R,3’E)-2-N-(2’-Hydroxy-3’-octadecenoyl)-[2-
aminooctadecane-1,3-diol] (25)
Obtained from 24 (34 mg, 0.041 mmol) following the proce-
dure described for compound 1. Purification of the residue
by flash chromatography (CHCl3/MeOH: 95/5) afforded 25
as a white solid; yield: 18 mg (75%); [a]2D0: +76.1 (c 0.30,
1
CHCl3). H NMR (CDCl3, 400 MHz, 508C): d=6.87 (d, 1H,
J=7.0 Hz), 5.90 (dtd, 1H, J=15.4, 6.9 and 1.0 Hz), 5.58
(ddt, 1H, J=15.3, 7.0 and 1.4 Hz), 4.52 (d, 1H, J=7.0 Hz),
4.00 (dd, 1H, J=11.3 and 3.4 Hz), 3.87–3.71 (m, 3H), 2.96
(br s, 1H), 2.44 (br s, 1H), 2.38 (br s, 1H), 2.10 (q like, 2H,
J=6.9 Hz), 1.61–1.48 (m, 2H), 1.48–1.34 (m, 2H), 1.29 (br s,
48H), 0.90 (t, 6H, J=6.9 Hz); 13C NMR (CDCl3, 100 MHz,
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Sꢀbastien Prꢀvost et al.
FULL PAPERS
508C): d=173.0, 136.4, 128.1, 74.1, 73.4, 62.5, 54.8, 34.7,
32.4, 32.1, 29.9, 29.8, 29.5, 29.4, 29.2, 26.1, 22.8, 14.1.
(2R,3S,2’R,3’Z)-2-N-(2’-Hydroxy-3’-octadecenoyl)-[2-ami-
nooctadecane-1,3-diol] (29): Obtained from 27 (55 mg,
0.088 mmol) following the procedure described for com-
pound 28. Purification of the residue by flash chromatogra-
phy (CHCl3/MeOH: 95/5) afforded 29 as a white solid;
(2S,3R,2’R,3’Z)-2-N-(2’-Hydroxy-3’-octadecenoyl)-1,3-
O-isopropylidene-[2-amino-octadecane-1,3-diol] (26)
1
yield: 43 mg (83%); [a]20: À73.4 (c 0.32, CHCl3). H NMR
(CDCl3, 400 MHz, 508CD): d=6.91 (d, 1H, J=7.2 Hz), 5.77
(dt, 1H, J=10.6 and 7.4 Hz), 5.46 (dd, 1H, J=10.6 and
9.0 Hz), 4.87 (d, 1H, J=8.7 Hz), 3.99 (dd, 1H, J=11.7 and
3.5 Hz), 3.87–3.70 (m, 3H), 3.06 (br s, 1H), 2.58 (br s, 1H),
2.52 (br s, 1H), 2.30–2.16 (m, 2H), 1.61–1.50 (m, 2H), 1.50–
1.40 (m, 2H), 1.29 (br s, 48H), 0.90 (t, 6H, J=6.8 Hz);
13C NMR (CDCl3, 100 MHz, 508C): d=173.2, 137.0, 127.5,
74.0, 68.7, 62.4, 54.9, 34.7, 32.1, 29.8, 29.5, 28.2, 26.1, 22.8,
14.3; HR-MS (ESI): m/z=604.5270, calcd. for C36H71NO4Na
[M+Na]+: 604.5275.
To a solution of 20 (50 mg, 0.15 mmol) and 13 (52 mg,
0.18 mmol) in CH2Cl2 (2.5 mL) were added HATU (67 mg,
0.18 mmol) and diisopropylamine (76 mL, 0.44 mmol) at
08C. The mixture was stirred for 2 h at 08C and filtered on
a silica pad. The filtrate was concentrated under vacuum
and the residue was purified by flash chromatography (cy-
clohexane/AcOEt: 83/17) to afford 26 as a white solid;
yield: 55 mg (60%); mp 608C; [a]2D0: À53.9 (c 0.78, CHCl3).
1H NMR (CDCl3, 300 MHz): d=6.19 (d, 1H, J=9.0 Hz),
5.78 (dt, 1H, J=10.2 and 7.9 Hz), 5.39 (dd, 1H, J=10.7 and
9.1 Hz), 4.83 (d, 1H, J=8.9 Hz), 3.97–3.76 (m, 2H), 3.63–
3.48 (m, 2H), 2.98 (br s, 1H), 2.27–2.12 (m, 2H), 1.58–1.36
(m, 4H), 1.42 (s, 3H), 1.38 (s, 3H), 1.25 (br s, 48H), 0.87 (t,
6H, J=6.7 Hz); 13C NMR (CDCl3, 75 MHz): d=172.4,
137.4, 126.9, 99.2, 72.4, 68.3, 63.1, 48.9, 32.9, 32.1, 29.8, 29.7,
29.5, 28.1, 28.0, 25.3, 22.8, 20.4, 14.3; HR-MS (ESI): m/z=
644.5589, calcd. for C39H75ONNa [M+Na]+: 644.5588.
AHCTUNGTREGUN(NN 2S,3R)-Methyl 2-Benzoylamino-3-hydroxyocta-
decanoate (31) and (2R,3S) Methyl 2-Benzoyl-
amino-3-hydroxyoctadecanoate [(ent)-31]
To the complex [Ru((R)-SYNPHOS)Br2] (0.009 mmol,
0.02 equiv., prepared according to the general procedure)
was added 30 (200 mg, 0.46 mmol) followed by degassed an-
hydrous CH2Cl2 (3 mL). The round-bottom flask was de-
gassed by three vacuum-argon cycles and then placed under
argon in a stainless steel autoclave. The argon atmosphere
was replaced with hydrogen by three cycles of pressurizing
and the pressure adjusted to 60 bar. The autoclave was
heated at 808C and stirring was maintained for 4 days. After
cooling, the reaction mixture was concentrated under re-
duced pressure and the residue was purified by flash chro-
matography (cyclohexane/AcOEt: 8/2) afforded 31 as a
white solid; yield: 176 mg (88%); mp 728C, lit.:[7b] mp 728C;
[a]2D0: +6.0 (c 1.0, CHCl3), lit.:[7b] [a]D21: +6.0 (c 1.0, CHCl3).
(2R,3S,2’R,3’Z)-2-N-(2’-Hydroxy-3’-octadecenoyl)-1,3-
O-isopropylidene-[2-aminooctadecane-1,3-diol] (27)
Obtained from (ent)-20 (50 mg, 0.15 mmol) and 13 (52 mg,
0.18 mmol) following the procedure described for compound
26. Purification of the residue by flash chromatography (cy-
clohexane/AcOEt: 8/2) afforded 27 as a white solid; yield:
1
59 mg (65%); [a]2D0: À68.5 (c 1.02, CHCl3). H NMR (CDCl3,
300 MHz): d=6.17 (d, 1H, J=8.9 Hz), 5.77 (dtd, 1H, J=
10.7, 7.5 and 0.8 Hz), 5.45–5.33 (m, 1H), 4.82 (dd, 1H, J=
9.0 and 2.3 Hz), 3.95–3.77 (m, 2H), 3.62–3.46 (m, 2H), 3.01
(d, 1H, J=3.3 Hz), 2.28–2.12 (m, 2H), 1.57–1.35 (m, 4H),
1.42 (s, 3H), 1.38 (s, 3H), 1.25 (br s, 50H), 0.87 (t, 6H, J=
6.7 Hz); 13C NMR (CDCl3, 75 MHz): d=172.4, 137.3, 127.0,
99.2, 72.2, 68.2, 63.1, 48.9, 32.9, 32.1, 29.8, 29.7, 29.5, 28.1,
27.9, 25.2, 22.8, 20.4, 14.3.
Compound (ent)-31
Obtained from 30 (400 mg, 0.93 mmol) with [Ru((S)-SYN-
PHOS)Br2] following the procedure described for com-
pound 31. Purification of the residue by flash chromatogra-
phy (cyclohexane/AcOEt: 8/2) afforded (ent)-31 as a white
solid; yield: 331 mg, (82%); [a]2D0: À7.0 (c 1.0, CHCl3), lit.:[7b]
(2S,3R,2’R,3’Z)-2-N-(2’-hydroxy-3’-octadecenoyl)-[2-
aminooctadecane-1,3-diol] (28)
1
[a]2D1: À7.0 (c 1.0, CHCl3). H NMR (CDCl3, 300 MHz): d=
7.89–7.80 (m, 2H), 7.56–7.39 (m, 3H), 6.94 (br d, J=
8.8 Hz), 4.88 (dd, 1H, J=8.9 and 1.8 Hz), 4.29–4.18 (m,
1H), 3.79 (s, 3H), 1.60–1.42 (m, 2H), 1.25 (br s, 26H), 0.87
(t, 3H, J=6.6 Hz).13C NMR (CDCl3, 75 MHz): d=172.1,
167.9, 133.9, 132.0, 128.8, 128.4, 72.3, 56.5, 52.8, 34.0, 32.1,
29.8, 29.7, 29.5, 25.8, 22.8, 14.3; HPLC (Chiralpak AS-H,
98:2 hexane:2–propanol, 1.0 mLminÀ1, l=254 nm): tR
24.13 min, (ent)-31, tR 29.59 min, 31.
To a solution of 26 (48 mg, 0.077 mmol) in CH2Cl2/MeOH
(0.5 mL/0.5 mL) was added PTSA (2.0 mg, 0.011 mmol).
The mixture was stirred for 1.5 h at room temperature and
saturated NaHCO3 was added. The aqueous layer was ex-
tracted with CHCl3. The combined organic layers were dried
over MgSO4 and concentrated under vacuum. Purification
of the residue by flash chromatography (CHCl3/MeOH: 95/
5) afforded 28 as a white solid; yield: 29 mg (64%); [a]2D0:
À48.7 (c 0.34, CHCl3), lit.:[3] [a]D20: À49.9 (c 0.5, CHCl3).
1H NMR (CDCl3, 400 MHz, 508C): d=6.92 (d, 1H, J=
7.1 Hz), 5.78 (dt, 1H, J=11.4 and 7.5 Hz), 5.46 (dd, 1H, J=
10.6 and 8.9 Hz), 4.88 (d, 1H, J=8.8 Hz), 3.99 (dd, 1H, J=
11.2 and 3.5 Hz), 3.87–3.72 (m, 3H), 3.01 (br s, 1H), 2.52 (br
s, 1H), 2.42 (br s, 1H), 2.28–2.18 (m, 2H), 1.60–1.49 (m,
2H), 1.49–1.40 (m, 2H), 1.29 (s, 48H), 0.90 (t, 6H, J=
6.8 Hz); 13C NMR (CDCl3, 100 MHz, 508C): d=173.1,
137.1, 127.4, 74.1, 68.7, 62.4, 54.8, 34.8, 32.1, 29.9, 29.8, 29.5,
28.2, 26.1, 22.8, 14.3.
AHCTUNGTREG(NNUN 2S,3R)-2-Benzoylamino-3-hydroxyoctadecan-1-ol
(32) and (2R,3S)-2-Benzoylamino-3-hydroxyocta-
decan-1-ol [(ent)-32]
To suspension of LiAlH4 (136 mg, 3.58 mmol) in THF
(2.5 mL) was added dropwise a solution of 31 (485 mg,
1.12 mmol) in THF (5 mL) at 08C. The mixture was stirred
for 4 h under reflux, then EtOAc (5 mL) and water (5 mL)
were added at room temperature. The mixture was filtered
on a celite pad and the aqueous layer was extracted with
3222
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Adv. Synth. Catal. 2011, 353, 3213 – 3226

Total Synthesis of Symbioramide: a Flexible Approach for the Efficient Preparation of Structural Isomers
CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated under vacuum. Purification of the
residue by flash chromatography (CH2Cl2/MeOH: 95/5) af-
forded 32 as a white solid; yield: 344 mg (79%); mp 468C;
[a]2D0: À5.6 (c 0.96, CHCl3).
21. Purification of the residue by flash chromatography (cy-
clohexane/diisopropyl ether: 8/2) afforded 34 as a colorless
oil; yield: 70 mg (75%). 1H NMR (CDCl3, 300 MHz): d=
7.69 (d, 1H, J=12.9 Hz), 7.66 (ddd, 4H, J=8.0, 4.9 and
1.5 Hz), 7.46–7.31 (m, 6H), 5.47–5.31 (m, 2H), 4.60 (d, 1H,
J=5.6 Hz), 4.10 (dd, 1H, J=11.9 and 1.6 Hz), 4.00–3.91 (m,
1H), 3.85 (dd, 1H, J=9.8 and 1.5 Hz), 3.72 (dd, 1H, J=11.9
and 1.6 Hz), 1.91–1.76 (m, 2H), 1.48 (s, 3H), 1.40 (s, 3H),
1.26 (br s, 52H), 1.14 (s, 9H), 0.88 (t, 6H, J=6.7 Hz);
13C NMR (CDCl3, 75 MHz): d=172.1, 136.1, 135.9, 135.5,
133.1, 132.8, 130.1, 130.0, 127.9, 127.7, 127.3, 99.2, 75.9, 71.5,
65.7, 45.4, 32.2, 32.1, 30.3, 29.8, 29.7, 29.5, 29.3, 28.7, 27.2,
27.0, 25.0, 22.8, 19.4, 18.7, 14.3.
Compound (ent)-32
Obtained from (ent)-31 (570 mg, 1.31 mmol) following the
procedure described for compound 32. Purification of the
residue by flash chromatography (cyclohexane/AcOEt: 8/2)
afforded (ent)-32 as a white solid; yield: 349 mg (68%);
1
[a]2D0: +6.4 (c 1.3, CHCl3). H NMR (CDCl3, 300 MHz): d=
7.38–7.22 (m, 5H), 3.92 (d, 1H, J=13.0 Hz), 3.79 (d, 1H,
J=13.0 Hz), 3.77 (dd, 1H, J=11.2 and 3.9 Hz), 3.59 (dd,
1H, J=11.3 and 3.8 Hz), 3.66–3.56 (m, 1H), 2.90 (br s, 3H),
2.54 (dd, 1H, J=9.2 and 3.8 Hz), 1.58–1.36 (m, 2H), 1.26
(br s, 24H), 0.87 (t, 3H, J=6.7 Hz); 13C NMR (CDCl3,
75 MHz): d=139.7, 128.7, 128.4, 127.5, 72.0, 61.8, 61.4, 52.1,
34.6, 32.1, 29.8, 29.5, 25.9, 22.8, 14.3.
(2S,3S,2’R,3’E)-2-N-(2’-tert-Butyldiphenylsilyloxy-3’-
octadecenoyl)-1,3-O-isopropylidene-[2-aminoocta-
decan-1,3-diol] (35)
Obtained from (ent)-33 (26 mg, 0.08 mmol) and 18 (50 mg,
0.09 mmol) following the procedure described for compound
21. Purification of the residue by flash chromatography (cy-
clohexane/diisopropyl ether: 8/2 to 7/3) afforded 35 as a col-
ACHTUNGTRENNUNG(2R,3R)-1,3-O-Isopropylidene-[2-amino-1,3-dihy-
1
droxyoctadecane] (33) and (2S,3S)-1,3-O-Isopro-
pylidene-[2-amino-1,3-dihydroxyoctadecane] [(ent)-
33]
orless oil; yield: 44 mg (68%). H NMR (CDCl3, 300 MHz):
d=7.66 (ddd, 4H, J=7.9, 2.9 and 1.5 Hz), 7.58 (d, 1H, J=
9.9 Hz), 7.46–7.31 (m, 6H), 5.60 (dtd, 1H, J=15.4, 6.6 and
0.8 Hz), 5.44 (dd, 1H, J=15.4 and 6.1 Hz), 4.58 (d, 1H, J=
5.7 Hz), 4.06 (dd, 1H, J=11.9 and 1.7 Hz), 3.99–3.91 (m,
1H), 3.79 (dd, 1H, J=9.9 and 1.5 Hz), 3.60 (dd, 1H, J=12.0
and 1.5 Hz), 1.96–1.80 (m, 2H), 1.78–1.56 (m, 2H), 1.47 (s,
3H), 1.35 (s, 3H), 1.26 (br s, 50H), 1.15 (s, 9H), 0.88 (t, 6H,
J=6.7 Hz); 13C NMR (CDCl3, 75 MHz): d=171.9, 136.0,
135.9, 134.3, 133.0, 132.7, 130.2, 130.0, 127.9, 127.7, 127.7,
99.1, 75.5, 71.3, 65.0, 44.9, 32.2, 32.1, 32.0, 30.3, 30.0, 29.6,
29.5, 29.4, 29.0, 27.2, 27.0, 24.8, 22.8, 19.4, 18.8, 14.3.
To a solution of 32 (200 mg, 0.51 mmol) in EtOH (5 mL)
was added Pd/C (10%, 54 mg, 0.051 mmol). The argon at-
mosphere was replaced with hydrogen and the reaction mix-
ture was stirred at room temperature under hydrogen (bal-
loon) for 20 h. The suspension was then filtered on a celite
pad and washed with CH2Cl2. The filtrate was concentrated
under vacuum and the residue was dissolved in CHCl3
(4 mL). Dimethoxypropane (0.94 mL, 7.65 mmol) and PPTS
(128 mg, 0.51 mmol) were added and the reaction mixture
was stirred for 2 h under reflux. CHCl3 and saturated
NaHCO3 were added. The aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with
brine, dried over MgSO4 and concentrated under vacuum.
Purification of the residue by flash chromatography
(CH2Cl2/MeOH: 96/4) afforded 33 as a white solid; yield:
100 mg (57%); mp 338C. [a]2D0: +6.9 (c 0.71, CHCl3).
(2R,3R,2’R,3’E)-2-N-(2’-tert-Butyldiphenylsilyloxy-3’-
octadecenoyl)-[2-aminooctadecane-1,3-diol] (36)
Obtained from 34 (67 mg, 0.078 mmol) following the proce-
dure described for compound 23. Purification of the residue
by flash chromatography (cyclohexane/AcOEt: 8/2) afford-
ed 36 as a white solid; yield: 40 mg (63%); [a]2D0: À10.7 (c
1
1.00, CHCl3). H NMR (CDCl3, 300 MHz): d=7.68–7.58 (m,
Compound (ent)-33
4H), 7.48 (d, 1H, J=7.7 Hz), 7.46–7.30 (m, 6H), 5.53 (dt,
1H, J=15.3 and 6.2 Hz), 5.42 (dd, 1H, J=15.4 and 6.3 Hz),
4.61 (d, 1H, J=6.2 Hz), 3.91 (br s, 1H), 3.87–3.74 (m, 3H),
2.73 (br s, 1H), 2.41 (d, 1H, J=6.7 Hz), 1.93–1.82 (m, 2H),
1.26 (br s, 52H), 1.12 (s, 9H), 0.88 (t, 6H, J=6.7 Hz);
13C NMR (CDCl3, 75 MHz): d=173.2, 136.1, 135.9, 135.2,
132.9, 130.2, 130.1, 128.0, 127.7, 127.4, 75.8, 73.1, 65.3, 53.4,
34.6, 32.2, 32.1, 29.9, 29.5, 29.3, 28.9, 27.1, 25.8, 22.8, 19.4,
14.3.
Obtained from (ent)-32 (170 mg, 0.43 mmol) following the
procedure described for compound 33. Purification of the
residue by flash chromatography (CH2Cl2/MeOH: 96/4) af-
forded (ent)-33 as a white solid; yield: 99 mg (67%); [a]2D0:
1
À9.7 (c 0.67, CHCl3). H NMR (CDCl3, 300 MHz): d=4.08
(dd, 1H, J=11.7 and 2.1 Hz), 3.86–3.79 (m, 1H), 3.71 (dd,
1H, J=11.7 and 1.8 Hz), 2.47 (q, 1H, J=1.8 Hz), 1.69 (br s,
2H), 1.55–1.44 (m, 2H), 1.43 (s, 3H), 1.39 (s, 3H), 1.24 (br s,
26H), 0.86 (t, 3H, J=6.7 Hz); 13C NMR (CDCl3, 75 MHz):
d=98.8, 72.1, 67.5, 47.8, 32.0, 29.9, 29.8, 29.7, 29.5, 25.2,
22.8, 18.8, 14.3.
(2S,3S,2’R,3’E)-2-N-(2’-tert-Butyldiphenylsilyloxy-3’-octa-
decenoyl)-[2-aminooctadecane-1,3-diol] (37)
Obtained from 35 (40 mg, 0.046 mmol) following the pro-
cedure described for compound 23. Purification of the resi-
due by flash chromatography (cyclohexane/AcOEt: 8/2) af-
forded 37 as a white solid; yield: 31 mg (82%); mp 498C;
(2R,3R,2’R,3’E)-2-N-(2’-tert-Butyldiphenylsilyloxy-3’-
octadecenoyl)-1,3-O-isopropylidene-[2-aminoocta-
decane-1,3-diol] (34)
1
[a]2D0: À4.1 (c 1.00, CHCl3). H NMR (CDCl3, 300 MHz): d=
7.63 (ddd, 4H, J=14.6, 8.0 and 1.5 Hz), 7.48–7.31 (m, 7H),
5.67 (dtd, 1H, J=15.3, 6.8 and 1.0 Hz), 5.49 (dd, 1H, J=
15.4 and 6.0 Hz), 4.63 (d, 1H, J=5.3 Hz), 3.98–3.88 (m,
Obtained from 33 (37 mg, 0.11 mmol) and 18 (70 mg,
0.13 mmol) following the procedure described for compound
Adv. Synth. Catal. 2011, 353, 3213 – 3226
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3223

Sꢀbastien Prꢀvost et al.
FULL PAPERS
1H), 3.81–3.57 (m, 3H), 2.65 (br s, 1H), 2.17 (br s, 1H),
2.00–1.87 (m, 2H), 1.76–1.58 (m, 2H), 1.25 (br s, 50H), 1.13
(s, 9H), 0.88 (t, 6H, J=6.7 Hz); 13C NMR (CDCl3,
75 MHz): d=172.9, 136.0, 135.8, 134.4, 133.1, 132.8, 130.3,
130.2, 128.0, 127.8, 127.5, 75.6, 73.1, 65.6, 52.9, 34.4, 32.3,
32.1, 30.3, 29.9, 29.8, 29.5, 29.3, 29.1, 27.1, 25.7, 22.8, 19.3,
14.3.
(2S,3S,2’R,3’Z)-2-N-(2’-Hydroxy-3’-octadecenoyl)-1,3-
O-isopropylidene-[2-aminooctadecane-1,3-diol] (41)
Obtained from (ent)-33 (40 mg, 0.12 mmol) and 13 (42 mg,
0.10 mmol) following the procedure described for compound
21. Purification of the residue by flash chromatography (cy-
clohexane/AcOEt: 8/2) afforded 41 as a white solid; yield:
1
42 mg (58%); [a]2D0: À40.8 (c 1.03, CHCl3). H NMR (CDCl3,
300 MHz): d=6.84 (d, 1H, J=9.6 Hz), 5.80 (dt, 1H, J=10.8
and 7.5 Hz), 5.46 (dd, 1H, J=10.7 and 9.1 Hz), 4.89 (dd,
1H, J=9.0 and 1.9 Hz), 4.06 (dd, 1H, J=12.0 and 1.7 Hz),
3.99–3.88 (m, 1H), 3.82 (dd, 1H, J=9.6 and 1.6 Hz), 3.70
(dd, 1H, J=12.0 and 1.7 Hz), 3.23 (d, 1H, J=3.0 Hz), 2.22
(q, 2H, J=7.2 Hz), 1.50–1.35 (m, 4H), 1.46 (s, 3H), 1.37 (s,
3H), 1.25 (br s, 48H), 0.87 (t, 6H, J=6.7 Hz); 13C NMR
(CDCl3, 75 MHz): d=172.4, 136.9, 127.4, 99.2, 71.2, 68.0,
65.0, 46.0, 32.1, 29.8, 29.6, 29.5, 28.1, 24.9, 22.8, 18.7, 14.3.
(2R,3R,2’R,3’E)-2-N-(2’-hydroxy-3’-octadecenoyl)-[2-
aminooctadecane-1,3-diol] (38)
Obtained from 36 (38 mg, 0.046 mmol) following the proce-
dure described for compound 1. Purification of the residue
by flash chromatography (cyclohexane/AcOEt: 6/4) afford-
ed 38 as a white solid; yield: 19 mg (70%); [a]2D0: À22.0 (c
0.25, CHCl3). 1H NMR (CDCl3, 400 MHz, 508C): d=6.71
(d, 1H, J=8.0 Hz), 5.91 (dtd, 1H, J=15.4, 6.9 and 0.8 Hz),
5.58 (ddt, 1H, J=15.5, 7.1 and 1.4 Hz), 4.52 (d, 1H, J=
7.1 Hz), 3.95 (td, 1H, J=6.4 and 2.0 Hz), 3.93–3.86 (m, 1H),
3.83 (d like, 2H, J=4.3 Hz), 3.06 (br s, 1H), 2.41 (br s, 1H),
2.36 (br s, 1H), 2.10 (q like, 2H, J=6.8 Hz), 1.54–1.37 (m,
6H), 1.29 (br s, 46H), 0.90 (t, 6H, J=7.0 Hz); 13C NMR
(CDCl3, 100 MHz, 508C): d=173.4, 136.4, 128.2, 73.3, 73.0,
65.2, 54.2, 34.8, 32.4, 32.1, 29.9, 29.5, 29.4, 29.2, 25.7, 22.8,
14.1.
(2R,3R,2’R,3’Z)-2-N-(2’-Hydroxy-3’-octadecenoyl)-[2-
aminooctadecane-1,3-diol] (42)
Obtained from 40 (43 mg, 0.069 mmol) following the proce-
dure described for compound 28. Purification of the residue
by flash chromatography (CHCl3/MeOH: 96/4) afforded 42
as a white solid; yield: 29 mg (72%); [a]2D0: À61.2 (c 0.30,
1
CHCl3). H NMR (CDCl3, 400 MHz, 508C): d=6.72 (d, 1H,
J=8.1 Hz), 5.77 (dt, 1H, J=10.6 and 7.6 Hz), 5.46 (dd, 1H,
J=10.7 and 9.0 Hz), 4.88 (d, 1H, J=8.9 Hz), 3.95 (td, 1H,
J=6.4 and 2.1 Hz), 3.92–3.85 (m, 1H), 3.82 (d, 2H, J=
4.4 Hz), 2.49 (br s, 2H), 2.30–2.16 (m, 2H), 1.54–1.36 (m,
4H), 1.29 (br s, 48H), 0.90 (t, 6H, J=6.8 Hz); 13C NMR
(CDCl3, 100 MHz, 508C): d=173.6, 136.9, 127.6, 72.9, 68.6,
65.2, 54.3, 34.7, 32.1, 29.9, 29.8, 29.5, 28.2, 25.7, 22.8, 14.1.
(2S,3S,2’R,3’E)-2-N-(2’-hydroxy-3’-octadecenoyl)-[2-
aminooctadecane-1,3-diol] (39)
Obtained from 37 (26 mg, 0.032 mmol) following the proce-
dure described for compound 1. Purification of the residue
by flash chromatography (cyclohexane/AcOEt: 45/55) af-
forded 39 as a white solidM; yield: 10 mg (56%); [a]2D0: À3.7
1
(c 0.30, CHCl3). H NMR (CDCl3, 400 MHz, 508C): d=6.76
(d, 1H, J=7.9 Hz), 5.91 (dtd, 1H, J=15.5, 6.9 and 1.0 Hz),
5.59 (ddt, 1H, J=15.3, 7.0 and 1.4 Hz), 4.54 (d, 1H, J=
(2S,3S,2’R,3’Z)-2-N-(2’-Hydroxy-3’-octadecenoyl)-
7.1 Hz), 3.99–3.93 (m, 1H), 3.93–3.87 (m, 1H), 3.84 (d like, [2-aminooctadecane-1,3-diol] (43)
2H, J=4.2 Hz), 2.94 (br s, 1H), 2.35 (br s, 1H), 2.28 (br s,
1H), 2.10 (q like, 2H, J=6.9 Hz), 1.53–1.37 (m, 6H), 1.29
(br s, 46H), 0.90 (t, 6H, J=6.9 Hz). 13C NMR (CDCl3,
100 MHz, 508C): d=173.4, 136.3, 128.1, 73.4, 73.1, 65.3,
54.2, 34.8, 32.4, 32.1, 29.9, 29.5, 29.4, 29.2, 25.8, 22.8, 14.1.
Obtained from 41 (30 mg, 0.048 mmol) following the proce-
dure described for compound 28. Purification of the residue
by flash chromatography (CHCl3/MeOH: 96/4) afforded 43
as a white solid; yield: 21 mg (75%); [a]2D0: À62.2 (c 0.31,
1
CHCl3). H NMR (CDCl3, 400 MHz, 508C): d=6.78 (d, 1H,
J=8.1 Hz), 5.78 (dt, 1H, J=10.2 and 7.4 Hz), 5.46 (dd, 1H,
J=10.6 and 9.0 Hz), 4.89 (d, 1H, J=8.7 Hz), 3.95 (td, 1H,
J=5.2 and 1.7 Hz), 3.91–3.85 (m, 1H), 3.83 (br s, 1H), 3.82
(br s, 1H), 3.06 (br s, 1H), 2.46 (br s, 1H), 2.30–2.16 (m,
2H), 1.54–1.38 (m, 4H), 1.29 (br s, 48H), 0.90 (t, 6H, J=
6.8 Hz). 13C NMR (CDCl3, 100 MHz, 508C): d=173.6, 137.0,
127.5, 72.9, 68.7, 65.2, 54.2, 34.7, 32.1, 29.9, 29.5, 28.2, 25.7,
22.8, 14.1.
(2R,3R,2’R,3’Z)-2-N-(2’-Hydroxy-3’-octadecenoyl)-
1,3-O-isopropylidene-[2-aminooctadecane-1,3-diol]
(40)
Obtained from 33 (40 mg, 0.12 mmol) and 13 (42 mg,
0.10 mmol) following the procedure described for compound
21. Purification of the residue by flash chromatography (cy-
clohexane/AcOEt: 8/2) afforded 40 as a white solid; yield:
52 mg (71%); mp 538C; [a]2D0: À75.9 (c 1.02, CHCl3).
1H NMR (CDCl3, 300 MHz): d=6.66 (d, 1H, J=9.5 Hz), Supporting Information
5.80 (dt, 1H, J=10.7 and 7.6 Hz), 5.45 (dd, 1H, J=10.8 and
1H NMR, 13C NMR and mass spectra for compounds 1, 4, 9–
9.2 Hz), 4.89 (dd, 1H, J=9.1 and 2.4 Hz), 4.07 (dd, 1H, J=
12.0 and 1.7 Hz), 3.99–3.90 (m, 1H), 3.84 (dd, 1H, J=9.5
and 1.7 Hz), 3.71 (dd, 1H, J=12.0 and 1.7 Hz), 3.29 (d, 1H,
J=3.3 Hz), 2.31–2.15 (m, 2H), 1.48–1.34 (m, 4H), 1.46 (s,
3H), 1.38 (s, 3H), 1.25 (br s, 48H), 0.87 (t, 6H, J=6.7 Hz);
13C NMR (CDCl3, 75 MHz): d=172.3, 136.6, 127.6, 99.2,
71.2, 67.9, 65.0, 46.0, 32.1, 31.9, 29.8, 29.7, 29.6, 29.5, 28.1,
24.8, 22.8, 18.7, 14.3.
29 and 31–43 as well as preliminary results for the asymmet-
ric transfer hydrogenation of 4 are available in the Support-
ing Information.
3224
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3213 – 3226

Total Synthesis of Symbioramide: a Flexible Approach for the Efficient Preparation of Structural Isomers
h) M. J. Kim, Y. Ahn, J. Park, Curr. Opin. Biotechnol.
Acknowledgements
2002, 13, 578; i) H. Pellissier, Tetrahedron 2003, 59,
8291; j) E. Vedejs, M. Jure, Angew. Chem. 2005, 117,
4040; Angew. Chem. Int. Ed. 2005, 44, 3974; k) E. Fo-
gassy, M. Nꢅgrꢆdi, D. Kozma, G. Egri, E. Pꢆlovics, V.
Kiss, Org. Biomol. Chem. 2006, 4, 3011; l) B. Martꢇn-
Matute, J. E. Bꢄckvall, Curr. Opin. Chem. Biol. 2007,
11, 226; m) H. Pellissier, Tetrahedron 2008, 64, 1563;
n) H. Pelissier, Adv. Synth. Catal. 2011, 353, 659.
S. P. thanks the Ministꢀre de l’Enseignement Supꢁrieur et de
la Recherche for a grant.
References
[1] a) J. Kobayashi, M. Ishibashi, H. Nakamura, Y. Hirata,
T. Yamasu, T. Sasaki, Y. Ohizumi, Experientia 1988, 44,
800; b) J. Kobayashi, J. Nat. Prod. 1989, 52, 225.
[2] a) M. Nakagawa, J. Yoshida, T. Hino, Chem. Lett. 1990,
1407; b) J. Yoshida, M. Nakagawa, H. Seki, T. Hino, J.
Chem. Soc. Perkin Trans. 1 1992, 343.
[3] K. Mori, K. Uenishi, Liebigs Ann. Chem. 1994, 41.
[4] H. Azuma, R. Takao, H. Niiro, K. Shikata, S. Tamaga-
ki, T. Tachibana, K. Ogino, J. Org. Chem. 2003, 68,
2790.
[5] T. Takanami, H. Tokoro, D. Kato, S. Nishiyama, T.
Sugai, Tetrahedron Lett. 2005, 46, 3291.
[6] L. C. Hess, G. H. Posner, Org. Lett. 2010, 12, 2120.
[7] a) C. Mordant, P. Dꢂnkelmann, V. Ratovelomanana-
Vidal, J.-P. GenÞt, Chem. Commun. 2004, 1296; b) C.
Mordant, P. Dunkelmann, V. Ratovelomanana-Vidal,
J.-P. GenÞt, Eur. J. Org. Chem. 2004, 3017; c) O. La-
beeuw, P. Phansavath, J.-P. GenÞt, Tetrahedron: Asym-
metry 2004, 15, 1899.
[8] a) S. Prꢀvost, S. Gauthier, M. C. CaÇo de Andrade, C.
Mordant, A. R. Touati, P. Lesot, P. Savignac, T. Ayad,
P. Phansavath, V. Ratovelomanana-Vidal, J.-P. GenÞt,
Tetrahedron: Asymmetry 2010, 21, 1436; b) H. Tone, M.
Buchotte, C. Mordant, E. Guittet, T. Ayad, V. Ratove-
lomanana-Vidal, Org. Lett. 2009, 11, 1995; c) C. Roche,
N. Desroy, M. Haddad, P. Phansavath, J.-P. GenÞt, Org.
Lett. 2008, 10, 3911; d) D. Blanc, J. Madec, F. Popo-
wyck, T. Ayad, P. Phansavath, V. Ratovelomanana-
Vidal, J.-P. GenÞt, Adv. Synth. Catal. 2007, 349, 943.
[9] a) T. Ohkuma, M. Kitamura, R. Noyori, in: Catalytic
Asymmetric Synthesis, 2nd edn., (Ed.: I. Ojima), Wiley,
New York, 2000, pp 1–110; b) R. Noyori, Angew.
Chem. 2002, 114, 2108; Angew. Chem. Int. Ed. 2002, 41,
2008; c) H.-U. Blaser, C. Malan, B. Pugin, F. Spindler,
H. Steiner, M. Studer, Adv. Synth. Catal. 2003, 345,
103; d) M. Kitamura, R. Noyori, in: Ruthenium in Or-
ganic Synthesis, (Ed.: S.-I. Murahashi), Wiley-VCH,
Weinheim, 2004, pp 3–41; e) Handbook of Homogene-
ous Hydrogenation, (Eds.: J. G. de Vries, C. J. Elsevier),
Wiley-VCH, Weinheim, 2006; f) J. P. GenÞt, in: Modern
Reduction Methods, (Eds.: P. G. Andersson, I. J. Mun-
slow), Wiley-VCH, Weinheim, 2008, pp 3–38; g) G.
Shang, W. Li, X. Zhang, in: Catalytic Asymmetric Syn-
thesis, 3rd edn., (Ed.: I. Ojima), Wiley, New York,
2010, pp. 343–436.
[11] For the anti-selective ruthenium-mediated asymmetric
hydrogenation of a-amino-b-keto ester derivatives by
DKR, see: a) K. Makino, T. Goto, Y. Hiroki, Y.
Hamada, Angew. Chem. 2004, 116, 900; Angew. Chem.
Int. Ed. 2004, 43, 882; b) K. Makino, T. Goto, Y.
Hiroki, Y. Hamada, Tetrahedron: Asymmetry 2008, 19,
2816; c) A. Lei, S. Wu, M. He, X. Zhang, J. Am. Chem.
Soc. 2004, 126, 1626.
[12] For the syn-selective asymmetric hydrogenation of a-
amido-b-keto esters through DKR, see: a) R. Noyori,
T. Ikeda, T. Ohkuma, M. Widhalm, M. Kitamura, H.
Takaya, S. Akutagawa, N. Sayo, T. Saito, T. Taketomi,
H. Kumobayashi, J. Am. Chem. Soc. 1989, 111, 9134;
b) J.-P. GenÞt, S. Mallart, S. Juge, French Patent
8911159, 1989; c) J.-P. GenÞt, C. Pinel, S. Mallart, S.
Juge, S. Thorimbert, J. A. Laffitte, Tetrahedron: Asym-
metry 1991, 2, 555; d) E. Coulon, M. C. CaÇo de An-
drade, V. Ratovelomanana-Vidal, J.-P. GenÞt, Tetrahe-
dron Lett. 1998, 39, 6467; e) P. Phansavath, S. Duprat
de Paule, V. Ratovelomanana-Vidal, J.-P. GenÞt, Eur. J.
Org. Chem. 2000, 3903; f) K. Makino, N. Okamoto, O.
Hara, Y. Hamada, Tetrahedron: Asymmetry 2001, 12,
1757; g) K. Makino, T. Goto, J. Ohtaka, Y. Hamada,
Heterocycles 2009, 77, 629.
[13] M. C. Bagley, K. Chapaneri, J. W. Dale, X. Xiong, J.
Bower, J. Org. Chem. 2005, 70, 1389.
[14] M. C. Bagley, C. Brace, J. W. Dale, M. Ohnesorge,
N. G. Phillips, X. Xiong, J. Bower, J. Chem. Soc. Perkin
Trans. 1 2002, 1663.
[15] K. Sisido, N. Hirowatari, H. Tamura, H. Kobata, H. Ta-
kagisi, T. Isida, J. Org. Chem. 1970, 35, 350.
[16] For comprehensive reviews on asymmetric transfer hy-
drogenation, see: a) M. J. Palmer, M. Wills, Tetrahe-
dron: Asymmetry 1999, 10, 2045; b) R. Noyori, S. Ha-
shiguchi, Acc. Chem. Res. 1997, 30, 97; c) K. Everaere,
A. Mortreux, J.-F. Carpentier, Adv. Synth. Catal. 2003,
345, 67; d) S. E. Clapham, A. Hadzovic, R. H. Morris,
Coord. Chem. Rev. 2004, 248, 2201; e) S. Gladiali, E.
Alberico, Chem. Soc. Rev. 2006, 35, 226; f) S. M.
Joseph, J. S. Samec, J.-E. Bꢄckvall, P. G. Andersson, P.
Brandt, Chem. Soc. Rev. 2006, 35, 237; g) T. Ikariya,
A. J. Blacker, Acc. Chem. Res. 2007, 40, 1300; h) A. J.
Blacker, in: Handbook of Homogeneous Hydrogena-
tion, (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH,
Weinheim, 2007, pp 1215–1244; i) C. Wang, X. Wu, J.
Xiao, Chem. Asian J. 2008, 3, 1750; j) D. Matharu,
J. E. D. Martins, Chem. Asian J. 2008, 3, 1374.
[10] For reviews on DKR, see: a) R. Noyori, M. Tokunaga,
M. Kitamura, Bull. Chem. Soc. Jpn. 1995, 68, 36;
b) R. S. Ward, Tetrahedron: Asymmetry 1995, 6, 1475;
c) S. Caddick, K. Jenkins, Chem. Soc. Rev. 1996, 25,
447; d) H. Stecher, K. Faber, Synthesis 1997, 1; e) M. T.
El Gihani, J. M. J. Williams, Curr. Opin. Chem. Biol.
1999, 3, 11; f) R. Azerad, D. Buisson, Curr. Opin.
Chem. Biol. 2000, 11, 565; g) F. F. Huerta, A. B. E. Min-
idis, J.-E. Bꢄckvall, Chem. Soc. Rev. 2001, 30, 321;
[17] K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R.
Noyori, Angew. Chem. 1997, 109, 297; Angew. Chem.
Int. Ed. Engl. 1997, 36, 285.
[18] See Supporting Information for further details.
Adv. Synth. Catal. 2011, 353, 3213 – 3226
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3225

Sꢀbastien Prꢀvost et al.
FULL PAPERS
[19] a) E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem.
Soc. 1987, 109, 5551; b) E. J. Corey, R. K. Bakshi, S.
Shibata, J. Am. Chem. Soc. 1987, 109, 7925.
[20] a) M. M. Midland, A. Tramontano, S. A. Zderic, J. Am.
Chem. Soc. 1977, 99, 5211; b) M. M. Midland, D. C.
McDowell, R. L. Hatch; A. Tramontano, J. Am. Chem.
Soc. 1980, 102, 867; c) H. C. Brown, G. G. Pai, J. Org.
Chem. 1982, 47, 1606.
2001 b) S. Duprat de Paule, N. Champion, V. Ratovelo-
manana-Vidal, J.-P. GenÞt, P. Dellis, WO Patent
03029259, 2003; c) S. Duprat de Paule, S. Jeulin, V. Ra-
tovelomanana-Vidal, J.-P. GenÞt, N. Champion, P.
Dellis, Eur. J. Org. Chem. 2003, 1931; d) S. Duprat de
Paule, S. Jeulin, V. Ratovelomanana-Vidal, J.-P. GenÞt,
N. Champion, G. Deschaux, P. Dellis, Org. Process. Res.
Dev. 2003, 7, 399; e) J.-P GenÞt, T. Ayad, V. Ratovelo-
[21] The absolute configurations for compounds 10 and 11
were assigned by comparison of the specific rotation
values of the related enantiomerically pure (E)-allylic
alcohol 14 with those reported in the literature:
(2R,3E)-octadec-3-ene-1,2-diol 14: [a]2D0: À11.0 (c 0.83,
CHCl3), lit.[2b]: [a]15: À8.97 (c 0.858, CHCl3).
manana-Vidal,
047084289X.rn01285.
[24] T. Yamagata, H. Tadaoka, M. Nagata, T. Hirao, Y. Ka-
taoka, V. Ratovelomanana-Vidal, J. P. GenÞt, K. Mashi-
ma, Organometallics 2006, 25, 2505.
e-EROS,
2011,
DOI:10.1002/
[25] S. Jeulin, N. Champion, P. Dellis, V. Ratovelomanana-
[22] a) B. M. Trost, Z.DT. Ball, T. Jçge, J. Am. Chem. Soc.
2002, 124, 7922; b) A. Fꢂrstner, K. Radkowski, Chem.
Commun. 2002, 2182; c) B. M. Trost, Z. T. Ball, J. Am.
Chem. Soc. 2005, 127, 17644.
Vidal, J.-P. GenÞt, Synthesis 2005, 3666.
[26] J. Madec, X. Pfister, P. Phansavath, V. Ratovelomana-
na-Vidal, J.-P. GenÞt, Tetrahedron 2001, 57, 2563.
[27] J.-P. GenÞt, C. Pinel, V. Ratovelomanana-Vidal, S. Mal-
lart, M. C. CaÇo de Andrade, J. A. Laffitte, Tetrahe-
dron: Asymmetry 1994, 5, 665.
[23] a) S. Duprat de Paule, N. Champion, V. Ratovelomana-
na-Vidal, J.-P. GenÞt, P. Dellis, French Patent 2,830,254,
3226
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3213 – 3226