Toward an Asymmetric Synthesis of Bistramide K

Article abstract of DOI:10.1002/ejoc.201800875

The bistramides family has shown antitumoral activity. More specifically bistramide K exhibits lower toxicity than its congeners. In this work, we describe a highly stereoselective and convergent synthesis of two building blocks of the marine metabolite b

Full text of DOI:10.1002/ejoc.201800875

DOI: 10.1002/ejoc.201800875
Full Paper
Natural Products
Toward an Asymmetric Synthesis of Bistramide K
Claude Bauder*[a]
This work is dedicated to the memory of Dr. Dominique Mandon
Abstract: The bistramides family has shown antitumoral activ- ments C1–C18 (89) and C19–C40 (81) of bistramide K. As a
ity. More specifically bistramide K exhibits lower toxicity than
its congeners. In this work, we describe a highly stereoselective
and convergent synthesis of two building blocks of the marine
metabolite bistramide K. Thus, we report the synthesis of frag-
challenge, we have used nonracemic methyl p-tolyl sulfoxide as
unique source of chirality for the elaboration of all stereogenic
centers of the natural compound.
Introduction
was first isolated in 1988[1a] by Gouiffès and co-authors, while
the other congeners (bistramides B, C, D, and K) were isolated
Bistramide K (Figure 1) is one of the marine metabolites of a later in 1994[1b] or in 2009 for the 39-oxo bistramide K.[1c] Bis-
unique bistramide family, isolated from the ascidian Lissoclinum tramides are attractive molecules due to diverse bioactivities
bistratum collected in New Caledonia (Nouméa). Bistramide A like cytotoxicity, neurotoxicity, immunomodulating and likely
Figure 1. Bistramide A and retrosynthetic approach for bistramide K.
antimalarial activity, but particularly because of their antiprolif-
erative properties which make them potential candidates for
anticancer therapy. It was reported by Statsuk and coll., that
actin, a protein essential for cellular motility and division, is a
specific cellular receptor of bistramide A.[2a] An X-ray structure
was obtained of the actin-natural bistramide A complex show-
ing binding interactions with the monomeric G-actin counter-
[a] Laboratoire de Synthèse Organométallique et Catalyse (SOCAT), Institut de
Chimie, UMR 7177 CNRS, Université de Strasbourg,
4 rue Blaise Pascal, 67070 Strasbourg, France
E-mail: cbauder@unistra.fr
http://lcimc.u-strasbg.fr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800875.
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part.[2b] Consequently, a severing of actin filaments, which in- is the result of a controlled cyclisation because of the previously
hibits growth of cancer cells occurs, leading to their death. created centers. Its absolute configuration was determined by
However, this compound was deemed too toxic to observe a ROESY experiment.
significant antitumor effect.
Bistramides D and K have similar activity to bistramide A but
exhibit lower toxicity in vivo and are thereby more effective as
antitumor inhibitors in the case of slowly evolving tumors, such
Results and Discussion
as non-small cell pulmonary carcinoma.[1b] Several total synthe-
ses were achieved for bistramide A[3a–3e] or bistramide C[3f–3g]
alongside of numerous fragments of bistramides A, B and D.[4]
Surprisingly, no total synthesis was reported in the literature for
bistramide D and K. However, we have reported previously the
hemi synthesis of bistramide D by stereoselective reduction of
natural bistramide A whose hydroxy functions were previously
acetylated.[5a] During this work, we were able to determine the
absolute configuration of C4 as well as the relative configura-
tion of stereogenic centers in the pyran part and four in the
spiro moiety of the bistramide skeleton. We have also described
a protected derivative of bistramide D, which allowed us to
get a X-ray crystal structure.[5b] Hence, we have determined the
absolute configuration of all stereogenic centers of a chemical
derivative of bistramide D by radiocrystallographic analysis
starting from the natural material. We assumed that the same
absolute configuration could be extended to the other related
bistramides. In another publication, we have also reported the
synthesis of the C1–C13 fragment of bistramide K using an
oxazolidinone as chiral auxiliary.[6] We have earlier reported a
methodology, using chiral sulfoxide chemistry, for the prepara-
tion of enantiopure propionate-derived motifs.[7] Hence, our re-
sults focused us toward the synthesis of bistramide K were the
different stereogenic centers were induced by a chiral sulfoxide.
The retrosynthetic approach of bistramide K is depicted in Fig-
ure 1. We have envisaged a convergent enantioselective synthe-
sis from three highly functionalized fragments which could be
assembled by two peptidic couplings. Thus, we have first devel-
oped the synthesis of fragment C1–C13 having a terminal acid
function, the intermediate amino-acid fragment C14–C18 and
finally the spiro fragment C19–C40, which includes a terminal
amine function.
As shown in Figure 1, the fragment 32 (C1–C13) which con-
tains two olefins with a trans configuration was synthesized by
a Julia coupling of aldehyde 28 and benzothiazole 22. The syn-
thetic approach for the spiro unit (C19–C40) 81 is based on
the connection between iodide 78 and the sulfone 59. Finally,
preparation of the amino-acid fragment C14–C18 will be also
discussed.
Preparation of the Fragment C1–C13
As outlined in Scheme 1, we have used, as starting material,
the known nonracemic sulfoxide 1[7] developed by us, where
the methyl and the OAc groups are in an anti-conformation.
For the continuation of our synthesis we had to inverse the
configuration at C-11. Sulfoxide 1 was transformed by a one-pot
Chiral sulfoxides are widely used in the field of the asymmet- Pummerer rearrangement using trifluoroacetic acid anhydride
ric synthesis of optically pure compounds. Their applications (TFAA) as activating reagent and sodium borohydride (NaBH4)
like chiral auxiliaries leading to high asymmetric inductions, reduction,[10] to give a regioisomeric mixture of 2 and 3. During
were presented in several articles as a powerful strategy in the the reaction the acetyl group at position C-11 have moved par-
synthesis of numerous natural products.[8] Recently, new advan- tially toward the primary alcohol at C-12. The isomeric mixture
ces of efficient methods leading to the expansion in the use 2 and 3 was transformed by saponification (K2CO3 in MeOH) to
of chiral sulfoxides have been developed for the synthesis of the vicinal diol 4 which was then exposed to oxidative cleavage
enantiopure molecules.[7,9] As a challenge in this paper, we per- using sodium periodate to give the known aldehyde unit 5.[11]
formed a synthesis of C1–C18 and C19–C40 fragments of bis- This aldehyde was oxidized into the corresponding acid 6,[13a]
tramide K, whose all stereogenic centers were generated using with the mild Pinnick's conditions,[12] which in turn was esteri-
methyl p-tolyl sulfoxide as unique chiral inductor, excepted for fied according Steglich procedure[13b] to yield the known ester
the stereochemistry at the spiroketal at C27. This stereocenter 7.[13c]
Scheme 1. Reagents and conditions: a) TFAA (trifluoroacetic acid anhydride), Et3N, aq. NaHCO3, CH2Cl2 then NaBH4, (2 and 3; 90 %); b) MeOH, K2CO3, (4; 77 %);
c) NaIO4, THF/H2O, (5; 84 %); d) NaClO2, NaH2PO4, tBuOH/amylene, (6; 78 %); e) DCC (N,N′-dicyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine), CH2Cl2,
MeOH, (7; 76 %).
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Ester 7 was then condensed with the lithium anion of iodide 20 was added to the anion of 2-methyl benzothiazole in
(–)-(S)-methyl p-tolyl sulfoxide 8 (Scheme 2) and the resulting the presence of HMPA to provide homologated benzothiazole
ꢀ-ketosulfoxide 9 was diastereoselectively reduced with DiBAL- 21 in very good yield.
H[14] in a very good yield to give cleanly the vicinal syn hydroxy-
Next, we needed the sulfone 22 in view to a Julia olefination
methyl compound 10. The absolute configuration at C11 was
confirmed by NMR spectroscopic analysis of 12. In this view, we
desilylated 10 with TBAF (tetrabutylammonium fluoride) and
the resulting diol 11 was transformed to the acetonide com-
pound 12. The syn relationship was determined by nOe experi-
ment on the basis of the absolute configuration of carbon C-9
(see Supporting Information).
with aldehyde 28 (Scheme 3). Initially, we tried the oxidation of
the sulfide 21 with H2O2-ammonium molybdate (NH4)6Mo7O24).
However, these conditions gave sulfone 23 in 59 % yield with
concomitant deprotection of the benzylidene group. Thus, fur-
ther benzylidene protection of the diol 23 was necessary to
isolate 22 in 74 % yield. On the other hand, smoothly oxidation
of sulfide 21 with mCPBA (meta-Chloroperoxybenzoic acid)[16a]
gave the required sulfone 22 in very good yield (92 %) avoiding
any deprotection.
Scheme 3. Reagents and conditions: a) mCPBA (meta-Chloroperoxybenzoic
acid), CH2Cl2, NaHCO3, (22; 92 %); b) (NH4)6Mo7O24, EtOH, H2O2, (23; 59 %);
c) MeOC6H4CH(OMe)2, CH2Cl2, CSA, (22; 74 %); d) Al/Hg, THF/H2O, (25; 85 %);
e) TBSCl (tert-butyldimethylchlorosilane), imidazole, DMF, (26; 80 %); f) DiBAL-
H, THF, (27; 84 %); g) Py·SO3 (Sulfur trioxide pyridine complex), Et3N, DMSO,
CH2Cl2, (28; 82 %).
Scheme 2. Reagents and conditions: a) LDA (lithium diisopropylamide), THF,
– 65 °C then 7, (9; 91 %); b) DiBAL-H (diisobutylaluminum hydride), THF,
– 78 °C, (10; 94 %); c) TBAF (tetrabutylammonium fluoride), THF, 0 °C, (11;
26 %); d) acetone, DMP (2,2-dimethoxypropane), pTosOH, (12; 83 %); e) from
10, Ac2O, Et3N, DMAP, CH2Cl2, (13; 99 %); f) TFAA, Et3N, CH2Cl2 then NaHCO3,
(14; 90 %); g) Ph3PMeBr, THF, KHMDS (potassium hexamethyldisilazide), 0 °C,
(15; 95 %); h) MeOH, K2CO3, (16; 92 %); i) 9-BBN (9-borabicyclo[3.3.1]-nonane),
THF, NaOH/H2O2, (17; 75 %); j) MeOC6H4CH(OMe)2, CH2Cl2, CSA (camphor-
sulfonic acid), (18; 96 %); k) TBAF, THF, 0 °C, (19; 96 %); l) I2, imidazole, PPh3,
THF, (20; 92 %); m) LDA, HMPA (hexamethylphosphoramide), THF, Bzt-SMe
(Bzt = benzothiazolyl), (21; 97 %).
Aldehyde 28 was prepared from the known sulfoxide 24 that
we had earlier developed.[17] To this aim, we proceeded to an
aldolization reaction between tert-butyl p-tolyl sulfinyl acetate
and crotonaldehyde[17] to give 24. After desulfurization of 24,
with aluminum amalgam in aqueous THF,[18] the resulting
hydroxy-ester 25[19] was silylated to generate compound 26.
The following reactions, DIBAL-H reduction of ester 26 and
Parikh–Doering oxidation on the corresponding primary alcohol
27,[20] lead to the aldehyde 28. The analytical data, for 27 and
28, are in accordance with those of our previous work in which
we applied the Evans aldolization protocol using oxazolidinone
as chiral auxiliary to perform the synthesis of C1-C6 synthon of
bistramide K.[6]
Thereafter, the hydroxyl function in derivative 10 was acetyl-
ated under classical conditions (Ac2O, Et3N, CH2Cl2) leading
compound 13. This later was then converted into the corre-
sponding aldehyde 14 by a Pummerer rearrangement using
TFAA followed by aqueous hydrogencarbonate in a one pot
reaction. Olefin 15 was obtained from aldehyde 14 by a
Wittig reaction (Ph3PMeBr, THF, KHMDS, 0 °C). At that stage, a
deacetylation (MeOH, K2CO3) of 15 was necessary prior an oxid-
This aldehyde 28 can now be used in a Wittig reaction as
ative hydroboration to isolate the diol 17 in good yield. Attempt outlined in Scheme 4 for the synthesis of the C1-C13 unit. The
an oxidative hydroboration on the acetylated allylic alcohol 15 deprotonated sulfone 22 using LHMDS in THF at – 78 °C, was
gave a lower yield. In order to access to the benzothiazole 21, coupled with the unsaturated aldehyde 28 to led the olefin 29
the diol 17 has been transformed to its benzylidene 18 in 66 % yield as a mixture (1:1) of E and Z stereoisomers. These
[MeOC6H4CH(OMe)2, CSA, CH2Cl2] which was desilylated allow- two isomers were properly isolated by TLC (Thin Layer Chroma-
ing the iodination of the terminal alcohol of 19.[15] The resulting tography) impregnated with AgNO3.[21]
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sulfurized by a Pummerer reaction in a one pot procedure with
NaBH4 to provide alcohol 38.[26] Azidation was performed on
38 by a Mitsunobu reaction with DPPA to give 39 in very good
yield (96 %). However, the attempt of reductive cleavage
(DiBAL-H) to obtain the alcohol 40 was unsuccessful. Conse-
quently, we decided to remove the benzylidene group of 39 in
a THF solution with 4
N
HCl according to the literature.[29] We
obtained the corresponding diol 41[27] but with an unaccepta-
ble yield of 25 %. In another way, we have cleaved the benzyl-
idene group of 39 in MeOH/pTosOH (para-toluenesulfonic acid)
in 49 % to obtain 41 which in turn was regioselectively monosil-
ylated at the terminal hydroxy function with a large excess of
silylating agent to afford the known azide 42.[28] Unfortunately,
this product 42 had caused problems in the following steps
during the synthesis of the C1–C18 moiety.
Scheme 4. Reagents and conditions: a) aldehyde 28, LHMDS (lithium hexa-
methyldisilazide), THF, (29; 66 %) mixture of E/Z (1:1) separated on TLC im-
pregnated with AgNO3; b) from 29 (E), DiBAL-H, CH2Cl2, 0 °C, (30; 81 %);
c) TEMPO (2,2,6,6-tetramethylpiperidinyloxy), BAIB [(diacetoxyiodo)benzene],
CH2Cl2/H2O, (31; 96 %); d) NaClO2, NaH2PO4, tBuOH/amylene, (32; 86 %); from
30, TEMPO, BAIB, MeCN/H2O, (32; 22 %).
The above olefin (E)-29 was transformed to the carboxylic
acid 32 in a three steps procedure with an overall yield of
74.4 %. Thus, this olefin (E)-29 was subjected to a regioselective
cleavage with DiBAL-H in CH2Cl2,[22] followed by oxidation of
the terminal alcohol of 30 with a TEMPO (2,2,6,6-tetramethyl-
piperidinyloxy)/BAIB [(diacetoxyiodo)benzene] system in
CH2Cl2[23] to give the aldehyde 31 instead of the corresponding
expected acid 32 despite of the presence of water. Neverthe-
less, we have observed an overoxidation of the alcohol 30 to-
wards the carboxylic acid 32 when we used the TEMPO/BAIB
conditions in MeCN/H2O but with low yield (22 %). Conse-
quently, the carboxylic acid 32 was obtained in 86 % by oxid-
ation of the aldehyde 31 under Pinnick conditions.[12]
Scheme 6. Reagents and conditions: a) PMB-CH(OMe)2, CH2Cl2, pTsOH cat.,
(37; 96 %); b) TFAA, NEt3, aq. NaHCO3, CH2Cl2 then NaBH4, (38; 96 %); c) PPh3,
THF, DIAD, DPPA, (39; 96 %); d) MeOH/pTsOH (para-toluenesulfonic acid), (41;
49 %); e) TBSCl, imidazole, DMAP, CH2Cl2, (42; 87 %).
Preparation of the C14–C18 Fragment
We have summarized in Scheme 7 a more gratifying way for
the synthesis of C14–C18 fragment starting from the sulfoxide
ent-1 that we have previously described.[7] The synthesis began
still with a one pot Pummerer reaction with NaBH4 which gave
rise to a regioisomeric mixture of ent-2 and ent-3 arising once
more from partial migration of the acetyl group. Then, saponifi-
cation (MeOH, K2CO3) of this mixture to give the diol ent-4[28]
was followed by benzylidene acetal protection providing com-
pound 43, which can be readily cleaved to generate the pri-
mary alcohol 44. Substitution of the terminal hydroxy group
by an azide function was performed according to Mitsunobu
conditions with DPPA and then TBAF-assisted desilylation al-
lowed the synthesis of 46. The resulting alcohol 46 was trans-
formed to its appropriate carboxylic acid 48 in a two steps oxid-
ation. Thus, alcohol 46 was submitted to the Dess Martin rea-
gent[30] to give the aldehyde 47 which in turn was subjected
by means of the Pinnick oxidation protocol.[12] The carboxylic
function of 48 was then protected by a TIPS group to afford
the C14–C18 moiety 49. This protection was necessary to con-
Subsequently, we focused our attention in the preparation of
the C14–C18 fragment 35 (Scheme 5) starting from chiral sulf-
oxide 33.[7]
Scheme 5. Reagents and conditions: a) TFAA, Et3N, aq. NaHCO3 then NaBH4,
(34; 56 %); b) DIAD (diisopropyl azodicarboxylate), THF, DPPA (diphenylphos-
phoryl azide), 35 which could not be purified properly.
Thus, compound 33 was converted into alcohol 34[24] in a
one pot reaction according the Pummerer protocol with NaBH4
in 55 % yield. Azidation of compound 34 was carried out under
Mitsunobu conditions with DPPA (Diphenylphosphoryl azide) as
azide transfer reagent[25] to give 35 in a disappointed low yield
likely due to a very tedious purification. Therefore, an alterna-
tive strategy was attempted.
Thus, we focused our efforts in the preparation of azide 42 trol the formation of the amide during the peptidic coupling
(Scheme 6). This synthesis began with a benzylidene acetal pro- between the carboxylic function of C1-C13 and the amine func-
tection of sulfoxide 36[7] to afford 37 which has been de- tion of C14–C18.
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Scheme 7. Reagents and conditions: a) TFAA, NEt3, aq. NaHCO3, CH2Cl2, then NaBH4, (ent-2 and ent-3; 85 %); b) MeOH, K2CO3, (ent-4; 75 %); c) PMB-CH(OMe)2,
CH2Cl2, CSA, (43; 83 %); d) DiBAL-H, CH2Cl2, 0 °C, (44; 78 %); e) PPh3, THF, DIAD, DPPA, (45; 78 %); f) TBAF, THF, 0 °C, (46; 92 %); g) Dess Martin reagent, CH2Cl2,
NaHCO3, (47; 78 %); h) NaClO2, NaH2PO4, tBuOH/amylene, (48; 80 %); i) TiPSCl, NEt3, DMF, (49; 93 %).
Preparation of the C19–C40 Fragment
Desulfurization of 52[32] followed by classical acetylation and
then TBAF-assisted desilylation afforded alcohol 55. Applying
the Hata procedure[33] to the alcohol 55 afforded sulfide 56
which was oxidized to obtain sulfone 57. However, the anion
of sulfone 57 gave unsuccessful results in the coupling reaction
with iodide 78, while with sulfone 59, readily prepared from 57
in a two steps reaction (deacylation then silylation), the reaction
was more effective.
Next, we turned our attention towards the synthesis of the spi-
ranic fragment C19–C40. It was mentioned in Figure 1 that the
construction of this spiranic portion was planned from the
anion of sulfone 59 and the iodide 78. As shown in Scheme 8,
the synthesis of sulfone 59 started with the ester 50, which was
obtained by a Wittig reaction[31] with aldehyde 5, already used
for the preparation of the unit C1-C13, and Methyl 2-(triphenyl-
The construction of the spiranic unit 78 was planned from
phosphoranylidene)propanoate. Treatment of 50 with the anion the iodide 66 (Scheme 9) and the hydrazone 73 (Scheme 10).
of the chiral (–)-(S)-methyl-p-tolyl sulfoxide 8 gave ꢀ-ketosulf- All stereogenic centers for both fragments, 66 and 73, were
oxide 51 which was subjected to diastereoselective reduction created from (+)-methyl p-tolyl sulfoxide as chiral auxiliary.
of the ꢀ-ketone function using DiBAL-H[14] to provide the opti-
cally pure alcohol 52. The absolute configuration of the new
formed stereogenic center in compound 52 was confirmed by
X-ray analysis (see Supporting Information).
Thus, we first prepared the iodide 66 starting from the non-
racemic sulfoxide 1 (Scheme 9), which was converted into the
aldehyde 60 as we have earlier reported.[7]
Scheme 8. Reagents and conditions: a) CH2Cl2, Ph3P=C(Me)CO2Me, room temp., (50; 94 %); b) methyl sulfoxide 8, LDA, THF, – 60 °C, (51; 91 %); c) DiBAL-H,
THF, – 70 °C, (52; 86 %); d) EtNH2, Li°, THF, – 65 °C, (53; 72 %); e) Ac2O, DMAP, NEt3, CH2Cl2, (54; 83 %); f) TBAF, THF, 0 °C, (55; 99 %); g) PhSSPh, nBu3P, CH2Cl2,
room temp., (56; 65 %); h) (NH4)6Mo7O24, EtOH, H2O2, (57; 83 %); i) MeOH, K2CO3, room temp., (58; 84 %); j) TBSCl, Imd, DMAP, CH2Cl2, (59; 96 %).
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Scheme 9. Reagents and conditions: a) TFAA, NEt3, CH2Cl2, aq. NaHCO3, (60; 99 %); b) BnOCH2CH2PPh3-Br, KHMDS, THF, –65 to – 10 °C, (61; 80 %); c) TBAF,
THF, 0 °C, (62; 89 %); d) CoCl2·6H2O, MeOH, NaBH4, (63; 58 %); e) MeOH, K2CO3, (64; 75 %); f) PPh3, imidazole, I2, THF, (65; 79 %); g) TBSCl, imidazole, DMAP,
CH2Cl2, (66; 65 %).
Scheme 10. Reagents and conditions: a) Ac2O, NEt3, DMAP, CH2Cl2, (68; 85 %); b) TFAA, NEt3, CH2Cl2, aq. NaHCO3, then NaBH4, (69; 46 %); c) DMP, pTsOH,
MeOH, (70; 57 %); d) LAH (lithium aluminium hydride), THF, (71; 88 %); e) diethylether/MeCN, PPh3, imidazole, I2, (72; 91 %); f) Me2C=NNMe2, nBuLi, THF, (73;
95 %); g) from 73, NH4Cl, HCl 10 %, (74; 61 %).
We obtained the olefin 62 by a Wittig reaction in good yield ture (Z,E) of hydrazone 73.[36e,37] This product is very sensitive
(80 %) followed by a desilylation (TBAF, 89 %). The next crucial and was readily transformed to the ketone 74 after treatment
step was a selective hydrogenation of the olefin while preserv- with a diluted aqueous HCl solution. Attempts of condensation
ing benzylic alcohol. This was achieved with sodium boro- of the dianion of ketone 74 with iodide 66 were unsuccessful,
hydride in the presence of CoCl2·6H2O[34] to give 63 with ac- while condensation with lithiated hydrazone 73 gave better re-
ceptable yield (58 %).
sults likely because of the possible chelation of the lithium with
the amine of the hydrazone function. Consequently, the purifi-
cation of 73 by chromatography column necessitated neutral
alumina or silica gel treated with Et3N (2 %) to prevent partial
hydrolysis of the hydrazone function leading to the ketone 74.
The precursors 66 and 73 can now be assembled for the con-
struction of the spiranic unit (Scheme 11).
Iodide 66 was added to the lithiated hydrazone 73 to give
ketone 75 after purification on silica gel column. Then, acid-
catalyzed spiroketalization (TFA, trifluoroacetic acid) of 75 in
CH2Cl2 gave a mixture of alcohol 76 and trifluoroacetate ester
77 which could not be avoided. A saponification of this mixture
The presence of the acetyl group on C-22 was not compati-
ble in the condensation step with the lithiated hydrazone 73
(Scheme 10). Consequently, we have envisaged a TBS protect-
ing group at position C-22. An earlier introduction of TBS pro-
tection or another protecting group than acetyl at the stage of
the formation of 1, was unsuccessful. The acetate 63 was sa-
ponified with K2CO3 in MeOH resulting to the formation of diol
64 which was submitted to iodination of the primary alcohol
to give 65. Compound 66 was obtained by silylation of alcohol
65. With the iodide 66 in hand, our efforts were directed to the
construction of the hydrazone 73 as outlined in Scheme 10.
After acetylation of the sulfoxide 67[35] followed by Pum- (K2CO3 in THF/MeOH) afforded properly alcohol 76. The abso-
merer rearrangement and a one pot treatment with NaBH4, we lute stereochemistry at the spiroketal carbon C27 was unambig-
isolated a regioisomeric mixture of 69. This mixture was sub- uously assigned by ROESY experiment by observing strong cor-
jected to the conditions of acetonide formation (pTsOH, MeOH, relations between the hydrogens H-22 and H-31 (see Support-
2,2-dimethoxypropane) to generate 70. The ester function of ing Information). After iodination of alcohol 76, the resulting
70 was reduced with LAH[36a,36c–36e] and the resulting alcohol compound 78 was added to the lithiated sulfone 59 leading to
71 was substituted to the well-known iodide 72[36d,36e] which a diastereoisomeric mixture of sulfone 79 which in turn was
was homologated with N,N-dimethylhydrazone to afford a mix- subjected to reductive cleavage conditions (Li°, EtNH2, THF) to
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furnish the known spiro-alcohol 80.[3c–d,38] Preparation of azide
81, corresponding to the C19–C40 fragment of bistramide K,
was performed according Mitsunobu conditions with DPPA as
reported in the literature.[3c–d,38] For the next step, we have to
couple the amine derivative of 81 with C1–C18 fragment.
Preparation of the C1–C18 Fragment
A peptidic coupling between acid 32 (C1-C13) and amine C14–
C18 has been achieved, using pyBOP (benzotriazol-1-yl-oxytri-
pyrrolidinophosphonium hexafluorophosphate), to produce the
C1–C18 fragment (Scheme 12). The three azide units, 42, 45
and 49 (Figure 2) can be involved as amine precursor for C14–
C18 after an in situ reduction of the azide function. In the case
of azides 42 and 45, the reduction was carried out with PPh3
in wet THF, while catalytic hydrogenation on Pd–C was required
for the reduction of azide 49.
The coupling between the corresponding amine of com-
pound 42 and acid 32 gave 82 in good yield (77 %) which was
then regioselectively desilylated (MeOH, CSA) to obtain diol 83.
However, all attempts to oxidize the primary alcohol of 83 to
the corresponding acid 84 led only to degradation products.
Then, we have assembled the corresponding amine of com-
pound 45 with acid 32 (93 %) to give 85 and then alcohol 86
after a regioselective desilylation (MeOH, CSA). Alcohol 86 dif-
fers from the previous diol 83 by a PMB-protection of the
hydroxyl function at C-15. But again, attempts to oxidize the
Scheme 11. Reagents and conditions: a) LDA, THF, then iodide 66, room
temp., 14h, (75; 66 %); b and c) TFA, CH2Cl2, room temp., giving a mixture of
76 and 77 which was treated with THF, MeOH, K2CO3 (76; 84 %); d) PPh3,
imidazole, I2, THF, room temp., (78; 92 %); e) sulfone 59, nBuLi, HMPA, THF,
(79; 54 %); f) Li°, EtNH2, THF, (80; 37 %); g) THF, PPh3, DIAD, DPPA, (81; 58 %).
Scheme 12. Reagents and conditions: a) azide 42, PPh3, THF/H2O then acid 32, CH2Cl2, pyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexa-
fluorophosphate), Et3N, (82; 77 %); b) MeOH, CSA, 0 °C, (83; 78 %); c) azide 45, PPh3, THF/H2O then acid 32, CH2Cl2, pyBOP, Et3N, (85; 93 %); d) MeOH, CSA,
0 °C, (86; 46 %); e) azide 49, Pd-C/H2, THF then acid 32, CH2Cl2, pyBOP, Et3N, (88; 92 %); f) TBAF, THF, 0 °C, (89; 94 %); g) (see ref. 3c–d, 38 for a similar
coupling).
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Figure 2. Potential amine precursors (42, 45, 49) for coupling with acid 32.
q = quartet, m = multiplet, br. = broad, and ABX = ABX system.
Chemical shifts are given in ppm, and coupling constants are pre-
sented in Hz. 13C NMR spectra were calibrated from the central
triplet peak (δ = 77.0 ppm) of CDCl3. For NMR assignments, please
refer to the atom numbering in the schemes Optical rotations [α]D
were recorded with a Polarimeter Model 341 (Perkin–Elmer) at a
wavelength of 589 nm in a 10 cm quartz cuvette and are reported
as follows: [α]2D0, concentration (c in g/100 mL) and solvent. Mass
spectra (ESI-MS) and were obtained with a microTOF instrument
(Bruker Daltonics, Bremen, Germany). Elemental analyses were
measured at the Service de Microanalyse of the University Louis
Pasteur of Strasbourg (France).
terminal alcohol of 86 failed. Clearly, oxidation of terminal
hydroxyl group for alcohols 83 and 86 is not the best way to
prepare the corresponding carboxylic acid.
Subsequently, we adopted a strategy developed in the litera-
ture[3c–d,38] for the synthesis of bistramide A. Consequently, we
used the azide 49, which contains a protected alcohol at C-15
and a terminal TIPS-protected carboxyl function. This azide 49
was transformed to its amine (H2, Pd-C) and coupled to the
acid 32 in good yield (92 %) prior a specific deprotection of
triisopropylsilyl acid function to provide acid 89 (94 %). Finally,
to obtain the bistramide K, the acid 89 (C1–C18) could be
bonded to the corresponding amine of azide 81 (C19–C40) as
described by two other groups[3c–d,38] for the synthesis of bis-
tramide A (Figure 1).
(2S,3S)-4-(tert-Butyldimethylsilyloxy)-2-hydroxy-3-methylbutyl
Acetate (2) and (2S,3S)-4-(tert-Butyldimethylsilyloxy)-1-
hydroxy-3-methylbutan-2-yl Acetate (3): Triethylamine (250 μL,
3.16 equiv.) and trifluoroacetic anhydride (250 μL, 3.11 equiv.) were
successively added to a solution at 0 °C of the sulfoxide 1 (226.8 mg,
0.568 mmol) in CH2Cl2 (6 mL). After stirring for 30 min at 0 °C, an
Conclusions
aqueous solution of NaHCO3 (0.5 M, 4.4 mL, 3.86 equiv.) was added.
In summary, we realized a study toward a convergent and enan-
tioselective synthesis of the potent antitumor inhibitor bistram-
ide K. We performed the elaboration of the acid C1–C18 (89)
and azide C19–C40 (81) fragments whose final peptidic cou-
pling was not accomplished in our work. On the other hand, a
similar coupling was described in the literature[3c–d,38] for the
synthesis of bistramide A including the same C19–C40 fragment
and a C1–C18 portion containing a pyrane unit. In this project,
we have shown that a stereoselective synthesis of complex nat-
ural product can carried out by using nonracemic p-tolyl sulfox-
ide as unique chiral source to generate many stereogenic cen-
ters.
Stirring was continue vigorously at room temperature for 1 h. Then
solid NaBH4 (88 mg, 4.1 equiv.) was added to the mixture at 0 °C
which was vigorously stirred for 30 min before to be quenched with
water (10 mL) and diluted with CH2Cl2 (10 mL). After 15 min at
ambient temperature, the organic layer was washed with water (2 ×
6 mL), brine (6 mL), dried with MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by chroma-
tography on silica gel (AcOEt/cyclohexane, 1:2) to give a mixture of
two isomers of 2 and 3 (colorless oil, 140.7 mg, 89.6 %). A sample
was purified on TLC to separate the two isomers 2 and 3 (Rf = 0.6
for 2 and Rf = 0.4 for 3 AcOEt/CH2Cl2, 1:7). NMR analysis for 2: 1H
NMR (400 MHz, CDCl3): δ = 4.14 (AB part of an ABX system,
J12a-12b = 11.4 Hz, J12a–11 = 6.6 Hz, J12b–11 = 3.2 Hz, Δν = 42 Hz, 2
H, H-12), 3.78–3.74 (X part of an ABX system, 1 H, H-11), 3.70 (AB
part of an ABX system, J8a-8b = 10.0 Hz, J8a-9 = 7.2 Hz, J8b-9 = 4.0 Hz,
Δν = 54.4 Hz, 2 H, H-8), 2.09 (s, 3 H, AcO), 1.85 (m, 1 H, H-9), 0.90
(d, J = 7.0 Hz, 3 H, Me-10), 0.89 (s, 9 H, tBu-Si), 0.08 (s, 6 H, 2 × Me-
Si). 13C NMR (75 MHz, CDCl3): δ = 171.2 (CO), 74.3 (CH-11), 67.6
(CH2-8), 67.2 (CH2-12), 36.9 (CH-9), 25.8 [C(CH3)3Si], 20.9 (MeCO),
18.1 [C(Me)3Si], 13.4 (Me-10), –5.6 (MeSi), –5.7 (MeSi). NMR analysis
for 2B: 1H NMR (400 MHz, CDCl3): δ = 4.92 (dt, J = 5.3 Hz, J = 4.9 Hz,
1 H, H-11), 3.73 (AB part of an ABX system, J12a-12b = 12.2 Hz,
J12a-11 = 5.4 Hz, J12b-11 = 4.6 Hz, Δν = 32.5 Hz, 2 H, H-12), 3.58 (AB
part of an ABX system, J8a-8b = 10.2 Hz, J8a-9 = 6.4 Hz, J8b-9 = 4.0 Hz,
Δν = 30.5 Hz, 2 H, H-8), 2.10 (s, 3 H, AcO), 2.04 (m, 1 H, H-9), 0.94
(d, J = 7.0 Hz, 3 H, Me-10), 0.89 (s, 9 H, tBu-Si), 0.063 (s, 3 H, Me-
Si),0.059 (s, 3 H, Me-Si). 13C NMR (75 MHz, CDCl3): δ = 171.1 (CO),
76.6 (CH-11), 64.3 (CH2-8), 62.7 (CH2-12), 37.1 (CH-9), 25.8 [C(CH3)3Si],
21.0 (MeCO), 18.2 [C(Me)3Si], 13.4 (Me-10), –5.6 (2 × MeSi). HR Mass
spectrum (ESI), m/z 299.1614 [M + Na]+ (C13H28O4SiNa+ requires
299.1649).
Experimental Section
General Information: All the starting materials and reagents were
obtained from commercial suppliers and used as received. All sol-
vents were purified according to standard methods. THF and diethyl
ether (Na-benzophenone ketyl), toluene (Na), CH2Cl2, Et3N and
DMSO (calcium hydride). Anhydrous MeCN and DMF were used as
obtained from commercial suppliers. Air and moisture sensitive re-
actions were carried out in heatgun-dried glassware under argon,
and were monitored by thin-layer chromatography (TLC) with
0.25 mm Merck pre-coated silica gel plates (60F-254). Spots were
detected under UV irradiation (254 nm) and/or by staining with
acidic ceric ammonium molybdate, unless otherwise noted. Flash
chromatographic purifications were performed with silica gel 60
(particle size 0.040–0.063 mm), packed in glass column, supplied by
Merck, Geduran. Yields refer to chromatographically and spectro-
scopically pure compounds, unless otherwise stated. All the NMR
spectra (1H, 13C, COSY, NOESY, HMQC as well as HSQC) were re- (2S,3S)-4-(tert-Butyldimethylsilyloxy)-3-methylbutane-1,2-diol
corded on Bruker AV300, AV400 or AV500 spectrometers using an
internal deuterium lock at ambient temperature. If not otherwise
noted, CDCl3 (δ = 7.26 ppm relative to residual CHCl3) was used as
(4): A mixture of the monoacetate 2 and 3 (113.9 mg, 0.412 mmol)
and K2CO3 (250 mg, 4.39 equiv.) was stirred at room temperature
in MeOH (5 mL) for 1.5 h. The mixture was then filtered through a
solvent for all NMR experiments. Multiplicities are described by us- pad of silica, rinsed with diethylether (10 mL) and the volatiles were
ing the following abbreviations: s = singlet, d = doublet, t = triplet,
removed in vacuo. The crude yellow oil was purified by chromatog-
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raphy on silica gel (AcOEt/cyclohexane, 1:1) to give the diol 4 reduced pressure. The crude was purified by chromatography on
(74.9 mg, 77.6 %) as a colorless oil. [α]2D0 = +19.7 (c = 1.6, CHCl3). 1H silica gel (AcOEt/cyclohexane, 1:2) to give the corresponding ester
NMR (500 MHz, CDCl3): δ = 3.73 (dd, J = 10.1 Hz, J = 3.9 Hz, 1 H, H-
12a), 3.62–3.58 (m, 3 H, H-12b, H-13 and OH), 3.62 (AB part of an an ABX system, JAB = 9.7 Hz, JAX = 6.9 Hz, JBX = 6.0 Hz, Δν = 43 Hz,
7 (33.2 mg, 76.4 %). 1H NMR (300 MHz, CDCl3): δ = 3.70 (AB part of
ABX system, J8a-8b = 11.0 Hz, J8a –14 = 4.0 Hz, J8b-14 = 2.7 Hz, Δν =
42.4 Hz, 2 H, H-8), 3.05–2.50 (broad s, 1 H, OH), 1.86 (m, 1 H, H-14),
0.90 (s, 9 H, tBu-Si), 0.84 (d, J = 7.0 Hz, 3 H, Me-10), 0.08 (s, 6 H,
2 × Me-Si). 13C NMR (125 MHz, CDCl3): δ = 76.7 (CH-13), 68.0 (CH2-
2 H, H-8), 3.66 (s, 3 H, COOCH3), 2.64 (ddq, J9-10 = J9-8a = 6.9 Hz,
J9-8b = 6.0 Hz, 1 H, H-9), 1.13 (d, J10-9 = 7.0 Hz, 3 H, Me-10), 0.86 (s,
9 H, tBu-Si), 0.029 (s, 3 H, Me-Si), 0.026 (s, 3 H, Me-Si). 13C NMR
(75 MHz, CDCl3): δ = 175.5 (CO), 65.2 (CH2), 51.5 (MeO), 42.5 (CH),
12), 64.8 (CH2-8), 36.9 (CH-14), 25.7 [C(CH3)3Si], 18.0 [C(Me)3Si], 13.2 25.8 [C(CH3)3Si], 18.2 [C(Me)3Si], 13.4 (Me-35), –5.5 (2 × MeSi). Spec-
(Me-10), –5.6 (MeSi), –5.7 (MeSi). HR Mass spectrum (ESI), m/z
troscopic data matched that reported in the literature.[13c]
257.1514 [M + Na]+ (C11H26O3SiNa+ requires 257.1543).
(S)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-[(S)-p-tolyl-
sulfinyl]butan-2-one (9): A solution of (–) (S)-methyl-p-tolyl sulfox-
ide 8 (1.387 g, 0.00899 mol) in THF (6 mL) was added via cannula
at – 65 °C to a stirred solution of LDA (1.05 equiv.), freshly prepared
from diisopropylamine (1.65 mL, 1.3 equiv.) and nBuLi (1.05 equiv.)
in THF (10 mL). After 1 h at the same temperature, a solution of
ester 7 (1.046 g, 4.5 mmol) in THF (6 mL) was added to the previous
anion. The yellow solution was stirred for 2 h allowing the tempera-
ture to rise – 50 °C before to be quenched with a saturated aqueous
NH4Cl solution (5 mL) and a 10 % aqueous HCl solution (18 mL)
until pH = 2. After addition of AcOEt (30 mL) the aqueous layer was
extracted with AcOEt (10 mL) and the combined organic layers were
washed with water (2 × 10 mL), brine (10 mL), filtered and concen-
trated under reduced pressure. The crude product was purified by
chromatography on silica gel column (AcOEt/cyclohexane, 1:1 as
eluent) to give a colorless oil of 9 (1.459 g, 91.5 %). [α]2D0 = –20.1
(c = 1.59, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.54 and 7.32
(AA′BB′, J = 8.5 Hz, Δν = 88.9 Hz, 4 H, pTol), 4.00 and 3.97 (AB
system, JAB = 14.5 Hz, Δν = 3.8 Hz, 2 H, H-12), 3.66 (AB part of an
ABX system, JAB = 10.0 Hz, JAX = 7.5 Hz, JBX = 5.5 Hz, Δν = 18.9 Hz,
2 H, H-8), 2.78 (m, 1 H, H-9), 2.41 (s, 3 H, Me of pTol), 0.93 (d,
JMe-9 = 7.0 Hz, 3 H, Me-10), 0.84 (s, 9 H, tBu-Si), 0.02 (s, 3 H, Me-Si),
0.01 (s, 3 H, Me-Si). 13C NMR (125 MHz, CDCl3): δ = 204.9 (CO), 142.0
(Cq arom), 140.0 (Cq arom), 130.0 (CH arom), 124.2 (CH arom), 68.3
(CH2-12), 65.3 (CH2-8), 49.7 (CH-9), 25.8[C(CH3)3Si], 21.4 (Me of pTol),
18.1 [C(Me)3Si], 12.0 (Me-10), –5.61 (MeSi), –5.63 (MeSi). Mass spec-
trum (ESI), m/z 377.1555[M + Na]+ (C18H30O3SSiNa+ requires
377.1577).
(S)-3-(tert-Butyldimethylsilyloxy)-2-methylpropanal (5): Solid
NaIO4 (136.8 mg, 2.11 equiv.) was added to a solution of diol 4
(70.9 mg, 0.302 mmol) in THF/H2O (6 mL, 1:1). The mixture was
stirred at room temperature for 2.5 h before to be diluted with
water (10 mL) and diethylether (15 mL). Brine (5 mL) was added to
the aqueous layer which was extracted with diethylether (5 mL).
The combined organic layers were washed with water (2 × 5 mL),
brine (5 mL), dried with MgSO4, and carefully concentrated under
reduced pressure. The crude product was purified by chromatogra-
phy on silica gel (diethylether: pentane 1:4) to afford the desired
aldehyde 5 (51.5 mg, 84.3 %). The analytic characteristics are identi-
cal as in the literature: [α]2D0 = +30.8 (c = 0.78, CHCl3), [lit.[11] [α]D20
=
+32.5 (c = 1.0, CHCl3)]. 1H NMR (500 MHz, CDCl3): δ = 9.73 (d, J =
1.7 Hz, 1 H, CHO), 3.82 (AB part of an ABX system, JAB = 10.5 Hz,
JAX = 6.3 Hz, JBX = 5.3 Hz, Δν = 20.2 Hz, 2 H, H-33), 2.52 (m, X part
of an ABX system, 1 H, H-34), 1.08 (d, J = 6.9 Hz, 1 H, Me-35), 0.87
(s, 9 H, tBu-Si), 0.04 (s, 6 H, 2 × Me-Si). 13C NMR (125 MHz, CDCl3):
δ = 204.6 (CO), 63.4 (CH2-33), 48.8 (CH-34), 25.8 [C(CH3)3Si], 18.2
[C(Me)3Si], 10.3 (Me-35), –5.5 (MeSi), –5.6 (MeSi).
(S)-3-(tert-Butyldimethylsilyloxy)-2-methylpropanoic Acid (6): A
premixed solution of NaClO2 (231 mg, 10 equiv.) and NaH2PO4·H2O
(182 mg, 5.1 equiv.) in distilled water (1.5 mL) was added to a vigor-
ous stirred solution of tBuOH (3 mL) and amylene (1.2 mL). The
mixture was stirred for 15 min at ambient temperature before to
be added to a solution of aldehyde 5 (51.5 mg, 0.254 mmol) in
tBuOH (0.5 mL). The reaction was run for 2 h at room temperature
until the disappearance of the aldehyde before to be diluted with
water (5 mL), AcOEt (10 mL) and carefully with an aqueous solution
(2R,3S)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-[(S)-p-tolyl-
of Na2S2O3·5H2O (1
M, 0.9 mL). The aqueous phase was extracted
sulfinyl]butan-2-ol (10): A solution of DiBAL-H (1
M in toluene,
with AcOEt (5 mL) and the combined organic layers were concen-
trated. The residue was diluted with AcOEt (10 mL) and washed
with water (2 × 5 mL), brine (5 mL), dried (MgSO4), filtered and
concentrated under reduced pressure. The crude was purified by
chromatography on silica gel (AcOEt/cyclohexane, 1:1) to give the
acid 6 (43.1 mg, 77.7 %). The analytic characteristics are identical as
in the literature: [α]D20 = +15.4 (c = 1.04, CHCl3), [lit.[13a] [α]2D0 = +17.2
6 mL, 1.45 equiv.) was added dropwise at – 78 °C to a solution of
keto-sulfoxide 9 (1.459 g, 4.11 mmol) in THF (25 mL). After 1 h, the
reaction was quenched carefully with an aqueous saturated solu-
tion of K-Na tartrate [La Rochelle's salt, 10 mL and AcOEt (10 mL)].
Stirring was continued at room temperature for 1.5 h and the mix-
ture was diluted with water (6 mL) and a 10 % aqueous HCl solution
(5 mL) until pH = 6. The aqueous phase was extracted with AcOEt
(10 mL) and the combined organic layers were washed with water
(2 × 10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated
under reduced pressure. The crude was purified by chromatography
on silica gel column (AcOEt/cyclohexane, 1:1 as eluent) to afford a
white solid of 10 (1.376 g, 93.9 %). [α]2D0 = –180.2 (c = 1.16, CHCl3).
M.p. 80 °C. 1H NMR (500 MHz, CDCl3): δ = 7.53 and 7.33 (AA′BB′, J =
8.0 Hz, Δν = 99.7 Hz, 4 H, pTol), 4.42 (m, 1 H, H-11), 3.67 (AB part
of an ABX system, JAB = 10.0 Hz, JAX = 6.0 Hz, JBX = 4.0 Hz, Δν =
62.2 Hz, 2 H, H-8), 2.84 (AB part of an ABX system, JAB = 13.2 Hz,
1
(c = 3.08, CHCl3)]. H NMR (500 MHz, CDCl3): δ = 10.9 (large s, 1 H,
COOH), 3.72 (m, 2 H, H-8), 2.64 (m, 1 H, H-9), 1.15 (d, J = 7.2 Hz, 1
H, Me-10), 0.86 (s, 9 H, tBu-Si), 0.046 (s, 3 H, Me-Si), 0.045 (s, 3 H,
Me-Si). 13C NMR (125 MHz, CDCl3): δ = 179.6 (CO2 H), 64.8 (CH2-8),
41.9 (CH-9), 25.7 [C(CH3)3Si], 18.2 [C(Me)3Si], 13.1 (Me-10), –5.54
(MeSi), –5.55 (MeSi).
(S)-Methyl 3-(tert-Butyldimethylsilyloxy)-2-methylpropanoate
(7): A solution of DCC (43.9 mg, 1.1 equiv.) in CH2Cl2 (0.7 mL) was
added dropwise to a mixture of acid 6 (40.9 mg, 0.187 mmol),
DMAP (8 mg, 0.3 equiv.), and MeOH (50 μL, 6.6 equiv.) in CH2Cl2 JAX = 10.5 Hz, JBX = 1.7 Hz, Δν = 120.8 Hz, 2 H, H-12), 2.41 (s, 3 H,
(0.8 mL). The heterogeneous mixture was stirred for 2.5 h and the
white precipitate was filtered off. The filtrate was concentrated and
the residue was taken up in CH2Cl2 (8 mL), washed with aq. HCl
solution (0.1N, 5 mL) and then with a sat. NaHCO3 aqueous solution
(4 mL) and then dried with MgSO4, filtered and concentrated under
Me of pTol), 1.69 (m, 1 H, H-9), 0.91 (d, JMe-9 = 7.0 Hz, 3 H, Me-10),
0.86 (s, 9 H, tBu-Si), 0.04 (s, 3 H, Me-Si), 0.03 (s, 3 H, Me-Si). 13C NMR
(125 MHz, CDCl3): δ = 141.4 (Cq arom), 140.4 (Cq arom), 130.0 (CH
arom), 123.9 (CH arom), 68.6 (CH-11), 67.1 (CH2-8), 61.7 (CH2-12),
39.5 (CH-9), 25.8 [C(CH3)3Si], 21.4 (Me of pTol), 18.1 [C(Me)3Si], 10.6
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(Me-10), –5.6 (MeSi), –5.7 (MeSi). Mass spectrum (ESI), m/z 379.1708 6.0 Hz, J8b-9 = 5.7 Hz, Δν = 18.9 Hz, H-8), 3.02 (AB part of an ABX
[M + Na]+ (C18H32O3SSiNa+ requires 379.1734).
system, J12a-12b = 13.5 Hz, J12a-11 = 6.0 Hz, J12b–11 = 5.7 Hz, Δν =
14.9 Hz, H-12), 2.40 (s, 3 H, Me of pTol), 2.04 (overlap of s and m, 4
H, Ac and H-9), 0.92 (d, JMe–9 = 7.0 Hz, 3 H, Me-10), 0.80 (s, 9 H, tBu-
Si), –0.018 (s, 3 H, Me-Si), –0.024 (s, 3 H, Me-Si). 13C NMR (125 MHz,
CDCl3): δ = 169.9 (CO), 141.5 (Cq arom), 141.0 (Cq arom), 129.9 (CH
arom), 124.0 (CH arom), 69.6 (CH-11), 64.0 (CH2-8), 60.7 (CH2-12),
39.0 (CH-9), 25.7 [C(CH3)3Si], 21.4 (Me of pTol), 20.9 (Ac), 18.0
[C(Me)3Si], 11.8 (Me-10), –5.6 (MeSi), –5.7 (MeSi). Mass spectrum
(ESI), m/z 399.2058 [M + H]+ (C20H35O4SSi+ requires 399.2020).
(2S,3R)-2-Methyl-4-[(S)-p-tolylsulfinyl]butane-1,3-diol (11): To a
chilled (0 °C) solution of sulfoxide 10 (106.1, 0.297 mmol) was
added dropwise a solution of TBAF (1
M in THF, 0.4 mL, 1.3 equiv.).
The resulting yellow solution was stirred for 2 h allowing the tem-
perature to reach ambient temperature. Water (5 mL), AcOEt (3 mL)
and a saturated aqueous NaHCO3 solution (1 mL) were successively
added. The aqueous layer was extracted with AcOEt (5 mL) and the
combined organic layers were washed with water (3 × 5 mL), brine,
dried with MgSO4, filtered and concentrated under reduced pres- (2R,3S)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-oxobutan-2-yl
sure. The crude product was purified by chromatography on silica Acetate (14): Triethylamine (0.52 mL, 3.31 equiv.) and trifluoroacetic
gel column (AcOEt as eluent) to furnish 11 as a white solid (18.8 mg,
anhydride (0.50 mL, 3.13 equiv.) were successively added to a
26.1 %). [α]2D0 = –261 (c = 0.95, CHCl3). M.p. 131 °C. 1H NMR chilled (0 °C) solution of sulfoxide 13 (450.1 mg, 1.12 mmol) in
(400 MHz, CDCl3): δ = 7.53 and 7.34 (AA′BB′, J = 8.0 Hz, Δν =
76.4 Hz, 4 H, pTol), 4.43 (m, X part of ABX system, 1 H, H-11), 3.70
(br. s, 2 H, OH × 2), 3.64 (m, 2 H, H-8), 2.90 (AB part of an ABX
system, J12a-12b = 13.2 Hz, J12a-11 = 11.2 Hz, J12b-11 = 1.6 Hz, Δν =
CH2Cl2 (10 mL). An aqueous solution of NaHCO3 (0.5 M, 13 mL,
5.7 equiv.) was added after 25 min at 0 °C and the mixture was
stirred for an additional 2 h at room temperature. The aqueous layer
was extracted with CH2Cl2 (10 mL) and the combined organic layers
106.6 Hz, H-12), 2.42 (s, 3 H, Me of pTol), 1.77 (m, 1 H, H-9), 0.83 (d, were washed with water (6 mL × 4), brine (6 mL), dried (MgSO4),
JMe-9 = 7.0 Hz, 3 H, Me-10). 13C NMR (100 MHz, CDCl3): δ = 141.8
filtered and concentrated under reduced pressure. The residue was
(Cq arom), 139.3 (Cq arom), 130.2 (CH arom), 124.1 (CH arom), 66.5 purified by column chromatography with silica gel (CH2Cl2 as elu-
(CH-11), 65.3 (CH2-8), 61.1 (CH2-12), 39.9 (CH2-9), 21.4 (Me of pTol),
10.2 (Me-10). Mass spectrum (ESI), m/z 265.0861[M + Na]+
(C12H18O3SNa+ requires 265.0869).
ent) to afford the aldehyde 14 (276.9 mg, 90.1 %) as a light yellow
liquid. [α]2D0 = +13.2 (c = 1.11, CHCl3). 1H NMR (500 MHz, CDCl3): δ =
9.54 (d, J12-11 = 0.5 Hz, 1 H, CHO), 5.19 (d, J11-9 = 3.8 Hz, 1 H, H-11),
3.55 (AB part of an ABX system, J8a-8b = 10.0 Hz, J8a-9 = 8.0 Hz,
J8b-9 = 4.5 Hz, Δν = 63.2 Hz, H-8), 2.31 (m, 1 H, H-9), 2.17 (s, 3 H,
Ac), 0.94 (d, JMe-9 = 7.0 Hz, 3 H, Me-10), 0.88 (s, 9 H, tBu-Si), 0.04 (s,
3 H, Me-Si), 0.03 (s, 3 H, Me-Si). 13C NMR (125 MHz, CDCl3): δ =
198.2 (CO), 170.3 (COOMe), 78.4 (CH-11), 63.5 (CH2-8), 36.5 (CH-9),
25.8 [C(CH3)3Si], 20.5 (Ac), 18.2 [C(Me)3Si], 11.3 (Me-10), –5.56 (MeSi),
–5.65 (MeSi). Mass spectrum (ESI), m/z 275.1677 [M + H]+
(C13H27O4S+ requires 275.1673).
(4R,5S)-2,2,5-Trimethyl-4-[(S)-p-tolylsulfinylmethyl]-1,3-dioxane
(12): The diol 11 (17.3 mg, 0.0713 mmol) was dissolved with acet-
one (0.3 mL) and 2,2-dimethoxypropane (1 mL) before the addition
of a catalytic amount of pTsOH. The reaction was stirred for 3 h at
room temperature until no starting material was detected on TLC.
The solvents were removed under reduced pressure and the result-
ing oil was dissolved with AcOEt (5 mL). The organic layer was
washed with water (2 × 5 mL), brine (5 mL), dried with MgSO4,
filtered and concentrated under reduced pressure leaving a color-
(3S,4S)-5-(tert-Butyldimethylsilyloxy)-4-methylpent-1-en-3-yl
less oil of 12 (16.7, 82.9 %). [α]2D0 = –179.4 (c = 1.83, CHCl3) 1H NMR Acetate (15): A solution of KHMDS (0.5M in toluene, 8.0 mL,
(500 MHz, CDCl3): δ = 7.54 and 7.32 (AA′BB′, J = 8.2 Hz, Δν =
108.6 Hz, 4 H, pTol), 4.63 (ddd, J = 10.6 Hz, J = 2.6 Hz, J = 2.2 Hz, 1
1.52 equiv.) was added slowly to a heterogeneous solution of meth-
yltriphenylphosphonium bromide (1.652 g, 1.75 equiv.) in THF
H, H-11), 4.18 (dd, J = 11.6 Hz, J = 2.8 Hz, 1 H, H8ax), 3.60 (dd, J = (15 mL) at 0 °C. After 40 min, the aldehyde 14 (723.6 mg, 0.00263
11.6 Hz, J = 1.6 Hz, 1 H, H8eq), 2.70 (AB part of an ABX system, mol) in THF (5 mL) was added dropwise at 0 °C to the resulting
J12a-12b = 13.0 Hz, J12a-11 = 10.5 Hz, J12b-11 = 2.5 Hz, Δν = 44.6 Hz,
yellow solution. Stirring was continued for 2 h at ambient tempera-
H-12), 2.41 (s, 3 H, Me of pTol), 1.54 (s, 3 H, Meax acetonide), 1.49 ture before quenching the reaction with a saturated aqueous solu-
(m, 1 H, H-9), 1.44 (s, 3 H, Meeq acetonide), 1.04 (d, JMe-9 = 7.0 Hz,
3 H, Me-10). 13C NMR (125 MHz, CDCl3): δ = 141.5 (Cq arom), 141.41
(Cq arom), 130.0 (CH arom), 123.8 (CH arom), 99.4 (Cq acetonide),
66.5 (CH2-8), 65.5 (CH-11), 62.9 (CH2-12), 31.9 (CH-9), 29.5 (Meeq
tion of NH4Cl (5 mL). Water (10 mL) and a 10 % aq. HCl solution
(3.7 mL) were added until pH 6. cyclohexane (30 mL) was added
and the organic layer was washed with water (12 mL × 3), brine
(10 mL), dried (MgSO4), filtered and concentrated under reduced
acetonide), 21.4 (Me of pTol), 19.1 (Meax acetonide), 10.9 (Me-10). pressure. The residue was purified on silica gel column chromatog-
Mass spectrum (ESI), m/z 283.1366 [M + H]+ (C15H23O3S+ requires raphy (CH2Cl2 as eluent) to give the olefin 15 (677.9 mg, 94.6 %) as
283.1362).
a light yellow liquid. [α]2D0 = +3.4 (c = 1.09, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 5.77 (m, 1 H, H-12), 5.33 (m, 1 H, H-11), 5.18
(m, 2 H, H-13), 3.49 (AB part of an ABX system, J8a-8b = 10.0 Hz,
J8a-9 = 6.5 Hz, J8b-9 = 6.0 Hz, Δν = 26.6 Hz, H-8), 2.06 (s, 3 H, Ac),
1.86 (m, 1 H, H-9), 0.91 (d, JMe-9 = 6.9 Hz, 3 H, Me-10), 0.88 (s, 9 H,
tBu-Si), 0.02 (s, 6 H, 2 × Me-Si). 13C NMR (125 MHz, CDCl3): δ = 170.2
(CO), 135.3 (CH-12), 116.6 (CH2-13), 75.1 (CH-11), 64.4 (CH2-8), 39.6
(CH-9), 25.8 [C(CH3)3Si], 21.1 (Ac), 18.2 [C(Me)3Si], 11.7 (Me-10), –5.5
(MeSi). Mass spectrum (ESI), m/z 295.1648 [M + Na]+ (C14H28O3SiNa+
requires 295.1700).
(2R,3S)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-[(S)-p-tolyl-
sulfinyl]butan-2-yl Acetate (13): Acetic anhydride (0.9 mL,
2.14 equiv.) and triethylamine (1.8 mL, 2.9 equiv.) were successively
added to a solution of the alcohol 10 (1.588 g, 4.45 mmol) and
DMAP (114 mg, 0.21 equiv.) in CH2Cl2 (30 mL). The mixture was
stirred for 2 h at room temperature before to be quenched with
water (12 mL) and diluted with CH2Cl2 (10 mL). Stirring was contin-
ued for 0.5 h and the organic layer was washed with water (4 ×
12 mL), brine (10 mL), dried (MgSO4), filtered and concentrated un-
der reduced pressure. The resulting yellow liquid was purified on a
silica gel chromatographic column (AcOEt/cyclohexane, 1:1) to af-
(3S,4S)-5-(tert-Butyldimethylsilyloxy)-4-methylpent-1-en-3-ol
(16):[15] A solution of the acetate 15 (132.2 mg, 0.485 mmol) in dry
MeOH (4 mL) was treated with anhydrous K2CO3 (272.6 mg,
ford 13 a colorless viscous oil (1.754 g, 98.9 %). [α]2D0 = –100.1 (c =
1.05, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.52 and 7.30 (AA′BB′, 4 equiv.). The heterogeneous solution was stirred at room tempera-
1
J = 8.0 Hz, Δν = 108.2 Hz, 4 H, pTol), 5.35 (dt, J = 8.2 Hz, J = 4.5 Hz,
1 H, H-11), 3.49 (AB part of an ABX system, J8a-8b = 10.0 Hz, J8a-9
ture for 1.5 h (monitored by TLC). After decantation, the superna-
tant solution was quickly filtered through a little pad of silica gel
=
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rinsed with diethylether. The resulting solution was conceentrated
under reduced pressure. The crude was purified on a silica gel by
column chromatography (CH2Cl2 as eluent) to afford the allylic alco-
hol 16 (102.4 mg, 91.6 %) as a colorless liquid. [α]2D0 = –10.7 (c =
1.25, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.86 (m, 1 H, H-12), 5.27
(dt, J = 17.1 Hz, J = 1.7 Hz, 1 H, H-13 trans), 5.16 (dt, J = 10.5 Hz,
J = 1.7 Hz, 1 H, H-13 cis), 4.26 (m, 1 H, H-11), 3.65 (AB part of an
ABX system, J8a-8b = 9.7 Hz, J8a-9 = 7.2 Hz, J8b-9 = 4.2 Hz, Δν =
23.1 Hz, H-8), 3.31 (large s, 1 H, OH), 1.92 (m, 1 H, H-9), 0.88 (s, 9 H,
tBu-Si), 0.84 (d, JMe-9 = 7.2 Hz, 3 H, Me-10), 0.050 (Me-Si), 0.048 (Me-
Si). 13C NMR (125 MHz, CDCl3): δ = 138.5 (CH-12), 115.0 (CH2-13),
75.8 (CH-11), 67.2 (CH2-8), 39.4 (CH-9), 25.8 [C(CH3)3Si], 18.1
[C(Me)3Si], 11.1 (Me-10), –5.6 (MeSi), –5.7 (MeSi). Mass spectrum
(ESI), m/z 231.1724 [M + H]+ (C12H27O2Si+ requires 231.1775).
[C(CH3)3Si], 18.3 [C(Me)3Si], 11.9 (Me-10), –5.4 (2 × MeSi). Mass spec-
trum (ESI), m/z 307.2233 [M + H]+ (C20H35O4Si+ requires 307.2299).
(S)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]propan-1-ol
(19): To a cold solution (0 °C) of benzylidene 18 (659.5 mg,
1.79 mmol) in THF (16 mL) was added dropwise a solution of TBAF
(1M in THF, 2.4 mL, 1.34 equiv.). The mixture was stirred at 0 °C
during 0.5 h and then for 1.5 h at room temperature. The reaction
was quenched with water (10 mL) and a saturated aqueous solution
of NaHCO3 (2 mL) and diluted with AcOEt (30 mL). The organic
layer was washed with water (6 mL × 6), dried (MgSO4), filtered and
concentrated under reduced pressure. The crude product was puri-
fied on silica gel column chromatography (AcOEt/cyclohexane, 7:3)
to afford the alcohol 19 (431.7 mg, 95.6 %) as a viscous colorless
oil. [α]2D0 = +17.1 (c = 1.62, CHCl3). [Lit.[15] [α]2D0 = +13.9 (c = 1;
1
CH2Cl2)]. H NMR (500 MHz, CDCl3): δ = 7.38 and 6.89 (AA′BB′, J =
(3S,4S)-5-(tert-Butyldimethylsilyloxy)-4-methylpentane-1,3-diol
8.5 Hz, Δν = 252.3 Hz, 4 H, PMP), 5.46 (s, 1 H, H acetal), 4.29 (ddd,
J = 11.4 Hz, J = 5.0 Hz, J = 1.4 Hz, 1 H, H-13a), 4.03 (ddd, J = 11.6 Hz,
J = 4.1 Hz, J = 2.3 Hz, 1 H, H-11), 3.96 (ddd, J = 12.2 Hz, J = 11.3 Hz,
J = 2.6 Hz, 1 H, H-13b), 3.80 (s, 3 H, MeO), 3.69 (AB part of an ABX
system, J8a-8b = 11.0 Hz, J8a-9 = 7.3 Hz, J8b-9 = 4.5 Hz, Δν = 48.5 Hz,
2 H, H-8), 2.01 (m, 1 H, H-12a), 1.98 (m, 1 H, H-9), 1.44 (m, 1 H, H-
12b), 1.00 (d, J = 7.2 Hz, 3 H, Me-10). 13C NMR (125 MHz, CDCl3):
δ = 159.9 (Cq arom), 131.1 (Cq arom), 127.2 (CH arom), 113.6 (CH
arom), 101.3 (CH acetal), 79.7 (CH-11), 67.1 (CH2-13), 65.5 (CH2-8),
55.3 (MeO), 39.4 (CH-9), 27.1 (CH2-12), 11.7 (Me-10). Spectroscopic
data matched that reported in the literature.[15] Mass spectrum (ESI),
m/z 275.1231 [M + Na]+ (C14H20O4SiNa+ requires 275.1254).
(17): A solution of 9-BBN (16 mL, 3.1 equiv., 0.5
M in THF) was added
dropwise to a cold (0 °C) solution of the allylic alcohol 16 (593.0 mg,
2.57 mmol) in anhydrous THF (35 mL). After 10 min, the reaction
was stirred at room temperature for 3 h. Then an aqueous solution
of NaOH (3M, 12 mL) and a 30 % aq. H2O2 (12 mL) were successively
added at 0 °C. The mixture was stirred for 1.5 h at room temperature
before to be diluted with a saturated aqueous solution of NaCl
(30 mL) and AcOEt (40 mL). The aqueous phase was carefully
treated with an aqueous solution of Na2S2O3·5H2O (1M, 8 mL) and
then extracted with AcOEt (40 mL). The combined organic phases
were washed with Na2S2O3·5H2O (1M, 2 mL) diluted in brine (20 mL)
dried (MgSO4), filtered and concentrated under reduced pressure.
The crude was purified by column chromatography on silica gel
(AcOEt/cyclohexane, 2:8 to 1:1) to yield the diol 17 (481.1 mg,
75.3 %) as a colorless oil. [α]2D0 = –2.8 (c = 1.04, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 4.04 (dt, J = 10.6 Hz, J = 2.5 Hz, 1 H, H-11),
3.85 (m, 2 H, H-13), 3.72 (AB part of an ABX system, J8a –8b = 10.0 Hz,
J8a-9 = 6.0 Hz, J8b-9 = 3.5 Hz, Δν = 38.9 Hz, H-8), 2.87 (large s, 2 H,
2 × OH), 1.83 (m, 1 H, H-12a), 1.79 (m, 1 H, H-9), 1.55 (m, 1 H, H-
12b), 0.92 (d, JMe-9 = 7.2 Hz, 3 H, Me-10), 0.90 (s, 9 H, tBu-Si), 0.07
(s, 6 H, Me-Si). 13C NMR (125 MHz, CDCl3): δ = 75.8 (CH-11), 68.1
(CH2-8), 62.3 (CH2-13), 39.1 (CH-9), 35.0 (CH2-12), 25.8 [C(CH3)3Si],
18.1 [C(Me)3Si], 10.9 (Me-10), –5.6 (MeSi), –5.7 (MeSi). Mass spec-
trum (ESI), m/z 249.1872 [M + H]+ (C12H29O3Si+ requires 249.1880).
(2S,4S)-4-[(R)-1-Iodopropan-2-yl]-2-(4-methoxyphenyl)-1,3-di-
oxane (20): Imidazole (479.4 mg, 4.3 equiv.) and triphenylphos-
phine (758.5 mg, 1.77 equiv.) were successively added to a solution
of alcohol 19 (419.5 mg, 1.63 mmol) in dry THF (18 mL) at 0 °C. A
solution of iodine (708.7 mg, 1.71 equiv.) in dry THF (7.0 mL) was
added dropwise and the mixture was stirred for 2 h at room tem-
perature. A solution of Na2S2O3·5H2O (1
M, 2 mL) followed by a
saturated solution of NaHCO3 (2 mL), water (10 mL) and AcOEt
(30 mL) were added. The organic layer was washed with water (4 ×
6 mL), brine (6 mL), dried (MgSO4), filtered and concentrated under
reduced pressure. The crude material was purified by chromatogra-
phy on silica gel column (AcOEt/cyclohexane, 1:1) to afford 20 as a
colorless liquid (544.2 mg, 92.1 %). [α]2D0 = +45.8 (c = 0.95, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.40 and 6.89 (AA′BB′, J = 8.7 Hz,
Δν = 255.8 Hz, 4 H, PMP), 5.48 (s, 1 H, H acetal), 4.28 (ddd, J =
11.4 Hz, J = 5.0 Hz, J = 1.4 Hz, 1 H, H-13a), 3.97 (td, J = 11.8 Hz, J =
2.6 Hz, 1 H, H-13b), 4.03 (ddd, J = 11.5 Hz, J = 5.1 Hz, J = 2.3 Hz, 1
tert-Butyl{(S)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-
yl]propoxy}dimethylsilane (18): To a solution of diol 17 (466.6 mg,
1.87 mmol) in CH2Cl2 (20 mL) containing anhydrous Na2SO4
(824 mg) were added successively p-methoxybenzaldehyde di-
methyl acetal (410 μL, 1.28 equiv.) and a catalytic amount of
camphorsulfonic acid (9 mg, 0.02 equiv.). The mixture was stirred
at room temperature for 1.5 h before the addition of water (10 mL),
and saturated aqueous solution of NaHCO3 (3 mL). The organic layer
was washed with water (12 mL × 2), brine (8 mL), filtered and con-
centrated under reduced pressure. After purification of the crude by
chromatography on silica gel (AcOEt/cyclohexane, 2:8) the desired
benzylidene 18 (659.5 mg, 96.2 %) was obtained as colorless oil.
H, H-11), 3.80 (s, 3 H, MeO), 3.28 (AB part of an ABX system, J8a-8b
=
10.0 Hz, J8a-9 = 6.5 Hz, J8b-9 = 5.7 Hz, Δν = 79.2 Hz, 2 H, H-8), 1.87
(dddd, 1 H, J = 12.9 Hz, J = 12.7 Hz, J = 11.5 Hz, J = 5.2 Hz, H-12a),
1.76 (m, 1 H, H-9), 1.48 (m, 1 H, H-12b), 1.13 (d, J = 6.7 Hz, 3 H, Me-
10). 13C NMR (125 MHz, CDCl3): δ = 159.8 (Cq arom), 131.2 (Cq
arom), 127.2 (CH arom), 113.5 (CH arom), 101.1 (CH acetal), 79.3
(CH-11), 66.8 (CH2-13), 55.3 (MeO), 39.8 (CH-9), 28.0 (CH2-12), 15.9
(Me-10), 11.9 (CH2-8). Mass spectrum (ESI), m/z 363.0489[M + H]+
1
[α]2D0 = +31.2 (c = 0.84, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.40
+
(C14H20IO3 requires 363.0452).
and 6.88 (AA′BB′, J = 8.5 Hz, Δν = 261.8 Hz, 4 H, PMP), 5.45 (s, 1 H,
H acetal), 4.26 (ddd, J = 11.3 Hz, J = 4.9 Hz, J = 1.4 Hz, 1 H, H-13eq),
3.94 (m, 1 H, H-13ax), 3.90 (m, 1 H, H-11), 3.80 (s, 3 H, OMe), 3.59
2-{(S)-3-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-
butylthio}benzo[d]thiazole (21): A solution of 2-(methyl-
thio)benzo[d]thiazole [427.8 mg, 3.8 equiv. in dry THF (6 mL)] was
added to a precooled (– 65 °C) solution of LDA (3.7 equiv.), prepared
from diisopropylamine (0.35 mL) and nBuLi (1.07M in hexane,
2.15 mL) in 10 mL dry THF. The solution was stirred for 1 h during
(AB part of an ABX system, J8a-8b = 9.7 Hz, J8a-9 = 7.0 Hz, J8b-9
=
5.2 Hz, Δν = 36.8 Hz, 2 H, H-8), 1.94 (m, 1 H, H-12ax), 1.77 (m, 1 H,
H-9), 1.44 (m, 1 H, H-12eq), 0.99 (d, J = 6.9 Hz, 3 H, Me-10), 0.90 (s,
9 H, tBu-Si), 0.04 (s, 3 H, Me-Si), 0.03 (s, 3 H, Me-Si). 13C NMR
(125 MHz, CDCl3): δ = 159.7 (Cq arom), 131.7 (Cq arom), 127.2 (CH which time the temperature was allowed to reach – 50 °C. Then a
arom), 113.4 (CH arom), 101.0 (CH acetal), 77.3 (CH-11), 67.2 (CH2- mixture of iodide 20 (223.4 mg, 0.616 mmol) and HMPA (0.37 mL,
13), 64.5 (CH2-8), 55.2 (OMe), 40.6 (CH-9), 28.6 (CH2-12), 25.9 3.2 equiv.) in dry THF (6 mL) was added at – 65 °C. Stirring was
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Full Paper
continued for 2 h allowing the temperature to rise – 40 °C. The
reaction was quenched with an aqueous saturated ammonium
chloride solution (8 mL), water (20 mL) and a 10 % aqueous solution
of HCl (4.5 mL) until pH 4. After dilution of the mixture with AcOEt
(40 mL), the organic phase was washed with water (4 × 10 mL),
matography on silica gel column (AcOEt/cyclohexane, 3:7 and
AcOEt) to yield a viscous pale yellow oil of the diol 23 (15.7 mg,
1
59.1 %). H NMR (500 MHz, CDCl3): δ = 8.19 (d, J = 7.9 Hz, 1 H, H-
arom), 8.00 (d, J = 8.2 Hz, 1 H, H-arom), 7.62 (dd, J = 8.2 Hz, J =
7.0 Hz, 1 H, H-arom), 7.58 (dd, J = 8.2 Hz, J = 6.9 Hz, 1 H, H-arom),
brine (10 mL), dried (MgSO4), filtered and concentrated under re- 3.88 (m, 1 H, H-7a), 3.81 (m, 1 H, H-11), 3.78 (m, 1 H, H-7b), 3.59 (m,
duced pressure. The residue was purified by chromatography on
1 H, H-13), 2.65 (br. s, 2 H, OH × 2), 2.08 (m, 1 H, H-12a), 1.74 (m, 1
H, H-12b), 1.70 (m, 1 H, H-9), 1.69 (m, 1 H, H-8a), 1.53 (m, 1 H, H-
silica gel column (AcOEt/cyclohexane, 1:9) to afford the sulfide 21
(249.5 mg, 97.4 %) as a thick yellow oil. [α]2D0 = +8.89 (c = 1.18, 8b), 0.90 (d, J = 6.7 Hz, 3 H, Me-10). 13C NMR (125 MHz, CDCl3): δ =
CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.85 (d, J = 8.1 Hz, 1 H, H
arom of Bzt), 7.75 (d, J = 7.9 Hz, 1 H, H arom of Bzt), 7.41 (t, J =
165.7 (Cq arom), 152.6 (Cq arom), 136.7 (Cq arom), 128.0 (CH arom),
127.7 (CH arom), 125.4 (CH arom), 122.3 (CH arom), 74.4 (CH-11),
8.4 Hz, 1 H, H arom of Bzt), 7.40 and 6.86 (AA′BB′, J = 8.7 Hz, Δν = 62.0 (CH2-7), 53.0 (CH2-13), 37.6 (CH-9), 34.6 (CH2-8), 25.2 (CH2-25),
269.8 Hz, 4 H, PMP), 7.29 (t, J = 8.4 Hz, 1 H, H arom of Bzt), 5.47 (s,
1 H, acetal), 4.27 (dd, J = 11.4 Hz, J = 4.9 Hz, 1 H, H-7a), 3.94 (td,
J = 11.8 Hz, J = 2.6 Hz, 1 H, H-7b), 3.79 (s, 3 H, MeO), 3.77 (m, 1 H,
H-11), 3.49 (m, 1 H, H-13a), 3.37 (m, 1 H, H-13b), 2.11 (m, 1 H, H-
12a), 1.91 (m, 1 H, H-9), 1.90 (m, 1 H, H-8a), 1.75 (m, 1 H, H-12b),
1.46 (m, 1 H, H-8b), 1.08 (d, J = 6.9 Hz, 3 H, Me-10). 13C NMR
(125 MHz, CDCl3): δ = 167.1 (Cq arom), 159.7 (Cq arom), 153.3 (Cq
arom), 135.1 (Cq arom), 131.4 (Cq arom), 127.3 (CH arom), 126.0 (CH
arom), 124.1 (CH arom), 121.4 (CH arom), 120.9 (CH arom), 113.5
(CH arom), 101.1 (CH acetal), 80.1 (CH-11), 67.0 (CH2-7), 55.2 (MeO),
37.0 (CH-9), 31.9 (CH2-12), 31.6 (CH2-13), 27.6 (CH2-8), 14.7 (Me-10).
Mass spectrum (ESI), m/z 416.1330 [M + H]+ (C22H26NO3S2+ requires
416.1349).
14.0 (Me-10).
2-{(S)-3-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-
butylsulfonyl}benzo[d]thiazole (22) from the Diol (23): To a solu-
tion of diol 23 (15.7 mg, 0.0476 mmol) in CH2Cl2 (1 mL) containing
anhydrous Na2SO4 (83.7 mg) were added successively p-methoxy-
benzaldehyde dimethyl acetal (15 μL, 1.8 equiv.) and a catalytic
amount of camphorsulfonic acid. The mixture was stirred at room
temperature for 4 h before the addition of water (4 mL), a saturated
aqueous solution of NaHCO3 (0.5 mL) and CH2Cl2 (5 mL). The or-
ganic layer was washed with water (5 mL × 2), brine (4 mL), filtered
and concentrated under reduced pressure. After purification of the
crude by chromatography on silica gel (AcOEt/cyclohexane, 3:7) the
desired benzylidene 22 (15.8 mg, 74.1 %) was obtained as yellow
oil.
2-{(S)-3-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-
butylsulfonyl}benzo[d]thiazole (22): A solution of anhydrous m-
CPBA (70 %, 130.6 mg, 2.9 equiv.) in CH2Cl2 (3 mL) was added drop-
wise to a cooled solution (0 °C) of CH2Cl2 (4 mL) containing solid
NaHCO3 (108 mg, 6.2 equiv.) and the sulfide 21 (85.3 mg,
0.205 mmol). The orange mixture was stirred for 3.5 h from 0 °C to
ambient temperature. The light yellow solution was quenched with
aq. Na2S2O3 (1M, 2 mL), water (3 mL) and diluted with CH2Cl2 (5 mL).
The organic layer was washed with water (3 × 5 mL), brine (5 mL),
dried (MgSO4), filtered and concentrated under reduced pressure.
The crude was chromatographed for purification on silica gel col-
umn (AcOEt/cyclohexane, 3:7) to give sulfone 22 (84.7 mg, 92.3 %)
as a thick yellow oil. [α]2D0 = +11.17 (c = 1.19, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 8.21 (d, J = 8.1 Hz, 1 H, arom of bzt), 8.02 (d,
J = 7.9 Hz, 1 H, arom of bzt), 7.62 (m, 2 H, arom of bzt), 7.31 and
6.81 (AA′BB′, J = 8.7 Hz, Δν = 252.8 Hz, 4 H, PMP), 5.40 (s, 1 H, H-
acetal), 4.24 (ddd, J = 11.4 Hz, J = 4.9 Hz, J = 1.4 Hz, 1 H, H-13a),
3.90 (td, J = 11.7 Hz, J = 2.5 Hz, 1 H, H-13b), 3.78 (s, 3 H, OMe), 3.74
(m, 1 H, H-11), 3.62 (m, 2 H, H-7), 2.14 (m, 1 H, H-8a), 1.87 (m, 1 H,
H-9), 1.86 (m, 1 H, H-8b), 1.85 (m, 1 H, H-12a), 1.39 (m, 1 H, H-12b),
1.01 (d, J = 6.6 Hz, 3 H, Me-10). 13C NMR (125 MHz, CDCl3): δ =
165.7 (Cq arom), 159.7 (Cq arom), 152.6 (Cq arom), 136.7 (Cq arom),
131.1 (Cq arom), 128.0 (CH arom), 127.6 (CH arom), 127.2 (CH arom),
125.4 (CH arom), 122.3 (CH arom), 113.5 (CH arom), 101.1 (CH
acetal), 79.7 (CH-11), 66.9 (CH2-13), 55.2 (OMe), 53.0 (CH2-7), 36.5
(CH-9), 27.1 (CH2-12), 24.9 (CH2-8), 14.6 (Me-10). Mass spectrum
(ESI), m/z 470.1069 [M + Na]+ (C22H25NO5S2Na+ requires 470.1066).
(R,E)-tert-Butyl 3-Hydroxyhex-4-enoate (25): The sulfoxide (–)-
24[17] (0.4 g; 0.00123 mol) was dissolved in a mixture of THF/H2O
(95 mL/9.5 mL) and then freshly prepared aluminium amalgam
(from Al, 1.6 g and HgCl2, 1 g in 100 mL of H2O) was added slowly.
The reaction becomes lightly exothermic and it is necessary to cold
it from time to time. This black solution was stirred at room temper-
ature during 15 h. The thick mixture was then filtered through Celite
with AcOEt. After evaporation of the solvents we obtained essen-
tially a white solid and further purification on silica gel chromatog-
raphy (AcOEt/cyclohexane, 3:7) afforded (+)-25 (194 mg) in 84.6 %
as a light yellow liquid. [α]2D0 = +18.8 (c = 1.59, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 5.72 [dqd, 1 H, J2,3(trans) = 15.3 Hz, J2,1
=
6.8 Hz, J2.4 = 1.1 Hz, H-2], 5.49 [ddq, 1 H, 3-H, J3,2(trans) = 15.3 Hz,
J3,4 = 6.6 Hz, J3,1 = 1.7 Hz, H-3], 4.42 (m, X part of a degenerated
ABX, 1 H, H-4), 2.43 (AB part of a degenerated ABX, 2 H, CH2-2),
2.65 (broad s, 1 H, OH), 1.69 (ddd, 3 H, J1,2 = 6.5 Hz, J1,3 = 1.7 Hz,
J
1,4 = 0.8 Hz, Me-1), 1.45 [s, 9 H, C(CH3)3]. 13C NMR (125 MHz, CDCl3):
δ = 171.9 (CO), 131.8 (CH-3 vinyl), 127.2 (CH-2 vinyl), 81.3 [C(CH3)3],
69.0 (CH-4), 42.4 (CH2-5), 28.1 [C(CH3)3], 17.6 (Me-1). C10H18O3
(186.248): calcd. C 64.49, H 9.74; found C 64.72, H 9.71.
(R,E)-tert-Butyl 3-(tert-Butyldimethylsilyloxy)hex-4-enoate (26):
The hydroxyester (+)-25 (613.4 mg; 0.0033 mol) was dissolved un-
der argon in DMF (46 mL). Imidazole (681 mg; 3.4 equiv.) and tert-
butyldimethylsilyl chloride (0.94 g; 1.8 equiv.) were successively
added at 0 °C. The reaction was then stirred 13 h at room tempera-
ture. The solution was quenched with water (100 mL) and diluted
with diethylether (80 mL) and stirring was continue during 2 h. The
(3S,4S)-6-(Benzo[d]thiazol-2-ylsulfonyl)-4-methylhexane-1,3-
diol (23): To a cold (0 °C) solution of the sulfide benzothiazole 21
(35.5 mg, 0.0806 mmol) in EtOH (1.4 mL) was added dropwise a aqueous layer was extracted with diethyl ether (2 × 30 mL) and the
premixed (0 °C) solution of ammonium molybdate (6.2 mg; 6.2 mol-
% equiv.) in water (0.13 mL) and hydrogen peroxide 30 % in water
(0.13 mL). yellow mixture, in which a white precipitate appears, was
combined organic layers were washed with water (4 × 40 mL), brine
(30 mL), dried (MgSO4), filtered and concentrated to furnish (+)-26
(792.6 mg; 80.2 %) as a colorless liquid after purification on silica
stirred during 17 h allowing the temperature to rise room tempera- gel chromatography column (AcOEt/cyclohexane, 3:7). [α]2D0 = +6.9
ture. The solvent was evaporated under reduced pressure and the
residue was dissolved with AcOEt (8 mL). The organic phase was
washed with water (4 mL), brine (2 × 4 mL), dried with MgSO4,
filtered and concentrated. The crude product was purified by chro-
(c = 1.06, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.72 [dqd, 1 H,
J2,3(trans) = 15.3 Hz, J2,1 = 6.6 Hz, J2,4 = 0.9 Hz, H-2], 5.43 [ddq, 1 H,
J3,2(trans) = 15.3 Hz, J3,4 = 7.1 Hz, J3,1 = 1.7 Hz, H-3], 4.48 (X part of
an ABX system, 1 H, H-4), 2.37 (AB part of an ABX system, J5a-5b
=
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14.5 Hz, J5a-4 =.5 Hz, J5b-4 = 6.0 Hz, Δν = 51.7 Hz, H-5), 1.66 (d, J =
6.6 Hz, 3 H, Me-1), 1.43 (s, 9 H, OtBu),0.86 (s, 9 H, SitBu), 0.02 (s, 3
(CH vinyl), 128.3 (CH vinyl), 127.2 (CH arom), 124.9 (CH-2 vinyl),
113.5 (CH arom), 100.9 (CH acetal), 80.3 (CH-11), 73.7 (CH-4), 67.1
H, SiMe), 0.05 (s, 3 H, SiMe). 13C NMR (125 MHz, CDCl3): δ = 170.5 (CH2-13), 55.3 (OMe), 41.9 (CH2-5), 38.0 (CH-9), 35.6 (CH2-8), 28.2
(CO), 133.5 (CH-3 vinyl), 125.9 (CH-2 vinyl), 80.2 [C(CH3)3], 70.8 (CH- (CH2-12), 25.9 [C(CH3)3], 18.3 [SiC(CH3)3], 17.6 (Me-1), 14.8 (Me-10),
4), 45.1 (CH2-5), 28.1 [SiC(CH3)3], 25.8 [C(CH3)3], 18.1 [SiC(CH3)3], 17.5
(Me-1), –4.2 (SiMe), –4.9 (SiMe). C16H32O3Si (300.509): calcd. C 63.95,
H 10.73; found C 64.10, H 10.91.
–4.3 (SiMe), –4.7 (SiMe). Olefin 29 (Z): [α]2D0 = +15.0 (c = 0.63,
CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.41 and 6.88 (AA′BB′, J =
8.5 Hz, Δν = 266.9 Hz, 4 H, PMP), 5.51 (dq, J2,3 = 15.3 Hz, J2,1
=
6.5 Hz, 1 H, H-2), 5.45 (m, 2 H, H-6 and H-7), 5.44 (s, 1 H, H-acetal),
5.41 (ddq, J3,2 = 15.4 Hz, J3,4 = 6.6 Hz, J3,1 = 1.6 Hz, 1 H, H-3), 4.26
(ddd, J = 11.1 Hz, J = 4.8 Hz, J = 1.1 Hz, 1 H, H-13a), 4.03 (app q,
J = 6.6 Hz, 1 H, H-4), 3.92 (td, J = 11.9 Hz, J = 2.6 Hz, 1 H, H-13b),
3.80 (s, 3 H, OMe), 3.67 (m, 1 H, H-11), 2.25 (m, 1 H, H-8a), 2.18 (m,
2 H, H-5), 1.93 (m, 1 H, H-8b), 1.88 (m, 1 H, H-12a), 1.68 (m, 1 H, H-
9), 1.65 (dq, J = 6.4 Hz, J = 0.7 Hz, 3 H, Me-1), 1.44 (m, 1 H, H-12b),
0.98 (d, J = 6.9 Hz, 3 H, Me-10), 0.87 (s, 9 H, SitBu), 0.03 (s, 3 H,
SiMe), 0.01 (s, 3 H, SiMe). 13C NMR (125 MHz, CDCl3): δ = 159.7 (Cq
arom), 134.4 (CH-3vinyl), 131.6 (Cq arom), 129.3 (CH vinyl), 127.3
(CH arom), 127.2 (CH vinyl), 125.0 (CH-2 vinyl), 113.5 (CH arom),
101.0 (CH acetal), 80.0 (CH-11), 73.5 (CH-4), 67.1 (CH2-13), 55.3
(OMe), 38.2 (CH-9), 36.5 (CH2-5), 30.2 (CH2-8), 28.3 (CH2-12), 25.9
[C(CH3)3], 18.3 [SiC(CH3)3], 17.6 (Me-1), 14.9 (Me-10), –4.3 (SiMe),
–4.7 (SiMe). Mass spectrum (ESI), m/z 499.2631 [M + K]+
(C27H44O4SiK+ requires 499.2640).
(R,E)-3-(tert-Butyldimethylsilyloxy)hex-4-en-1-ol (27): To a solu-
tion of the ester (+)-26 (758 mg; 0.00252 mol) in THF (24 mL) was
added slowly at – 78 °C the Dibal-H (1M in hexane; 7.6 mL; 3 equiv.).
After 3 h the reaction was quenched at –78 °C with a saturated
solution of ammonium chloride (3 mL) and put to room tempera-
ture. The mixture was then dilute with water (20 mL) and acidified
with H2SO4 20 % (3 mL) to pH = 2. The aqueous layer was extracted
with AcOEt (3 × 25 mL) and the combined organic layers were
washed with brine (10 mL), dried with MgSO4, filtered and concen-
trated. The residue was purified on silica gel chromatography
(AcOEt/cyclohexane, 1:1) to get (+)-27 (487.5 mg; 83.9 %) as a yel-
low liquid. [α]D20 = +23.3 (c = 0.70, CHCl3), Lit.[6] [α]2D0 = +23.8 (c =
1.02, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 5.61 [dq, 1 H, J2,3(trans)
15.3 Hz, J2,1 = 5.6 Hz, H-2], 5.45 [ddq, 1 H, J3,2(trans) = 15.3 Hz, J3,4
=
=
6.2 Hz, J3,1 = 1 Hz, H-3], 4.35 (q, 1 H, J = 6.2 Hz, H-4), 3.8–3.7 (m, 2
H, H-6), 2.61 (s broad, 1 H, OH), 1.8–1.6 (m, 2 H, H-5), 1.68 (d, 3 H,
J = 5.6 Hz, H-1), 0.88 [s, 9 H, SiC(CH3)3], 0.07 [s, 3 H, Si(CH3)2], 0.03
[s, 3 H, Si(CH3)2]. 13C NMR (50 MHz, CDCl3): δ = 134.3 (CH vinyl),
126.4 (CH vinyl), 74.2 (CH-OTBS), 61.2 (CH2), 40.2 (CH2), 26.5
[SiC(CH3)3], 18.8 [SiC(CH3)3], 18.2 (CH3 vinyl), –3.5 (SiCH3), –4.3
(SiCH3). For the next oxidation step, we have used the Parikh–Doer-
ing conditions. The analytical data is in accordance with those in
the literature.[6] C12H26O2Si (230.419): calcd. C 62.55, H 11.37; found
C 63.37, H 11.55.
(3S,4S,6E,9R,10E)-9-(tert-Butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-4-methyldodeca-6,10-dien-1-ol (30E) and
(3S,4S,6Z,9R,10E)-9-(tert-Butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-4-methyldodeca-6,10-dien-1-ol (30Z): A solution of
DiBAL-H (1M in toluene, 0.25 mL, 4.6 equiv.) was added dropwise
to a chilled (0 °C) solution of acetal 29 (E-olefin) (25.1 mg,
0.054 mmol) in CH2Cl2 (2.5 mL). The reaction was stirred for 1.5 h
at 0 °C before to be quenched carefully with MeOH (0.1 mL) and
then an aqueous saturated solution of K-Na tartrate (La Rochelle's
salt, 2.5 mL). The mixture was diluted with water (3 mL), CH2Cl2
(10 mL) and acidified to pH 6 with a 10 % aqueous solution of HCl
(0.3 mL) and stirred 1h at room temperature. The aqueous layer was
extracted with AcOEt (2 × 4 mL) and the combined organic layers
were concentrated and diluted again with AcOEt (5 mL) to be
washed with water (2 × 5 mL), brine (5 mL), dried (MgSO4), filtered
and concentrated under reduced pressure. The crude was purified
by chromatography on silica gel (AcOEt/cyclohexane, 3:7) to afford
the alcohol 30 (20.5 mg, 81.4 %) as a yellow oil. For comparison,
these conditions were also applied on acetal 29 (Z-olefin) (10.6 mg,
tert-Butyl{(2E,4R,6E,9S)-9-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-di-
oxan-4-yl]deca-2,6-dien-4-yloxy}dimethylsilane (29): A solution
of lithium hexamethyldisilazide (LHMDS 1M in THF, 0.45 mL,
2. equiv.) was added slowly to a mixture of sulfone 22 (114.5 mg,
0.255 mmol, 1.15 equiv.) in dry THF (4 mL) and aldehyde 28
(50.8 mg, 0.222 mmol, 1 equiv.) in dry THF (2 mL) at – 78 °C. The
reaction was stirred 2 h, leaving the temperature to reach – 20 °C
before to be quenched with an aqueous saturated NH4Cl solution
(2 mL). After dilution with water (5 mL) and AcOEt (10 mL) the
aqueous phase was acidified with a 10 % aqueous HCl solution
(0.6 mL) till pH 3. The aqueous layer was extracted with AcOEt
(5 mL) and the combined organic layers were washed with water
(3 × 5 mL), brine (5 mL), dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by chromatography col-
umn on silica gel (CH2Cl2) to yield a mixture of conformers (E/Z, 1:1)
of olefin 29 (67.5 mg, 66.0 %) as a light yellow oil. The separation
of the two isomers was obtained on preparative thin layer plate
impregnated with AgNO3 in MeCN (1 g/6 mL). Elution (AcOEt/cyclo-
hexane, 1:9) afforded the E-olefin (Rf = 0.25) and Z-olefin (Rf = 0.15).
Each olefin was correctly characterized by 2D NMR spectroscopy at
0.023 mmol) to give 30(Z) (7.7 mg, 72.3 %). Olefin 30 (E): [α]D20
–14.12 (c = 0.92, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.26 and
6.88 (AA'BB′, J = 8.7 Hz, Δν = 191.3 Hz, 4 H, PMB), 5.54 (dq, J2,3
=
=
15.3 Hz, J2,1 = 6.5 Hz, 1 H, H-2), 5.43 (m, 1 H, H-3), 5.40 (m, 2 H, H-
6 and H-7), 4.55 and 4.40 (AB system, JAB = 11.0 Hz, Δν = 74.7 Hz,
2 H, CH2-Ar), 4.03 (ddd, J = 7.1 Hz, J = 6.3 Hz, J = 5.7 Hz, 1 H, H-4),
3.80 (s, 3 H, OMe), 3.72 (m, 2 H, H-13), 3.52 (m, 1 H, H-11), 2.36
(broad s, 1 H, OH), 2.31 (m, 1 H, H-8a), 2.18 (m, 2 H, H-5), 1.88 (m,
1 H, H-9), 1.75 (m, 1 H, H-8b), 1.71 (m, 2 H, H-12), 1.66 (dq, J =
high field. Olefin 29 (E): [α]2D0 = +25.8 (c = 1.28, CH2Cl2). 1H NMR 6.4 Hz, J = 0.7 Hz, 3 H, Me-1), 0.89 (s, 9 H, SitBu), 0.88 (d, J = 6.9 Hz,
(500 MHz, CDCl3): δ = 7.41 and 6.88 (AA′BB′, J = 8.3 Hz, Δν =
265.4 Hz, 4 H, PMP), 5.53 (dq, J2,3 = 15.1 Hz, J2,1 = 6.3 Hz, 1 H, H-2),
5.44 (s, 1 H, H-acetal), 5.42 (m, 1 H, H-3), 5.39 (m, 2 H, H-6 and H-
7), 4.24 (ddd, J = 11.3 Hz, J = 4.9 Hz, J = 1.4 Hz, 1 H, H-13a), 4.03
(app q, J = 6.4 Hz, 1 H, H-4), 3.92 (ddd, J = 12.2 Hz, J = 11.5 Hz, J =
2.6 Hz, 1 H, H-13b), 3.80 (s, 3 H, OMe), 3.66 (m, 1 H, H-11), 2.25 (m,
1 H, H-8a), 2.19 (m, 2 H, H-5), 1.88 (m, 1 H, H-8b), 1.85 (m, 1 H, H-
12a), 1.67 (m, 1 H, H-9), 1.66 (dq, J = 6.5 Hz, J = 0.8 Hz, 3 H, Me-1),
1.46 (m, 1 H, H-12b), 0.97 (d, J = 6.9 Hz, 3 H, Me-10), 0.88 (s, 9 H,
SitBu), 0.03 (s, 3 H, SiMe), 0.01 (s, 3 H, SiMe). 13C NMR (125 MHz,
3 H, Me-10), 0.03 (s, 3 H, SiMe), 0.02 (s, 3 H, SiMe). 13C NMR
(125 MHz, CDCl3): δ = 159.2 (Cq arom), 134.4 (CH-3 vinyl), 131.0
(CH-6 or CH-7 vinyl), 130.5 (Cq arom), 129.4 (CH arom), 128.2 (CH-6
or CH-7 vinyl), 124.9 (CH-2 vinyl), 113.8 (CH arom), 82.3 (CH-11), 73.7
(CH-4), 71.1 (CH2-Ar), 61.4 (CH2-13), 55.2 (OMe), 42.0 (CH2-5), 35.4
(CH-9), 34.6 (CH2-8), 32.0 (CH2-12), 25.9 [C(CH3)3], 18.3 [SiC(CH3)3],
17.6 (Me-1), 15.4 (Me-10), –4.3 (SiMe), –4.7 (SiMe). Olefin 30 (Z):
[α]2D0 = –27.97 (c = 0.84, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.26
and 6.88 (AA′BB′, J = 8.5 Hz, Δν = 193.8 Hz, 4 H, PMB), 5.54 (dq,
J2,3 = 15.4 Hz, J2,1 = 6.4 Hz, 1 H, H-2), 5.45 (m, 2 H, H-6 and H-7),
CDCl3): δ = 159.7 (Cq arom), 134.4 (CH vinyl), 131.6 (Cq arom), 130.5 5.41 (m, 1 H, H-3), 4.56 and 4.39 (AB system, JAB = 11.0 Hz, Δν =
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80.7 Hz, 2 H, CH2-Ar), 4.05 (app q, J = 6.5 Hz, 1 H, H-4), 3.80 (s, 3 H,
stirring was continued for 1.5 h at room temperature. After water
OMe), 3.73 (m, 2 H, H-13), 3.53 (m, 1 H, H-11), 2.35 (broad s, 1 H,
(3 mL), Na2S2O3·5H2O (1 M, 0.5 mL) and AcOEt (8 mL) were added,
OH),2.26 (m, 1 H, H-8a), 2.22 (m, 2 H, H-5), 1.88 (m, 1 H, H-9), 1.85 the aqueous layer was extracted with AcOEt (5 mL). The combined
(m, 1 H, H-8b), 1.71 (m, 2 H, H-12), 1.66 (dq, J = 6.4 Hz, J = 0.7 Hz, organic layers were concentrated (to remove tBuOH) and diluted
3 H, Me-1), 0.89 (d, J = 6.7 Hz, 3 H, Me-10), 0.88 (s, 9 H, SitBu), 0.04
with AcOEt (10 mL) before to be washed with water (2 × 5 mL),
brine (5 mL), dried (MgSO4) filtered and concentrated under re-
(s, 3 H, SiMe), 0.02 (s, 3 H, SiMe). 13C NMR (125 MHz, CDCl3): δ =
159.2 (Cq arom), 134.3 (CH-3 vinyl), 130.4 (Cq arom), 129.7 (CH-6 or duced pressure. The residue was purified by chromatography on
CH-7 vinyl), 129.5 (CH arom), 127.0 (CH-6 or CH-7 vinyl), 125.0 (CH-
2 vinyl), 113.8 (CH arom), 82.3 (CH-11), 73.5 (CH-4), 71.2 (CH2-Ar),
61.4 (CH2-13), 55.2 (OMe), 36.5 (CH2-5), 35.6(CH-9), 32.0 (CH2-12),
29.1 (CH2-8), 25.9 [C(CH3)3], 18.3 [SiC(CH3)3], 17.6 (Me-1), 15.6 (Me-
10), –4.3 (SiMe), –4.7 (SiMe). Mass spectrum (ESI), m/z 485.3041 [M
+ Na]+ (C27H46O4SiNa+ requires 485.3058).
silica gel column (AcOEt–cyclohexane, 2:8 then 1:1 as eluent) to
furnish the desired acid 32 (10.6 mg, 86.2 %) as a yellow oil. [α]D20
–5.55 (c = 1.18, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.25 and
6.87 (AA′BB′, J = 8.5 Hz, Δν = 189.8 Hz, 4 H, PMB), 5.53 (dq, J2,3
15.1 Hz, J2,1 = 6.4 Hz, 1 H, H-2), 5.41 (m, 1 H, H-3), 5.38 (m, 2 H, H-
6 and H-7), 4.52 and 4.49 (AB system, JAB = 11.0 Hz, Δν = 10.2 Hz,
2 H, CH2-Ar), 4.03 (dt, J = 6.8 Hz, J = 5.7 Hz, 1 H, H-4), 3.81 (m, 1 H,
=
=
(3S,4S,6E,9R,10E)-9-(tert-Butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-4-methyldodeca-6,10-dienal (31): To a solution of al-
cohol 30 (12.5 mg, 0.0218 mmol) in CH2Cl2 (3 mL) were added
successively BAIB (68.0 mg, 7.8 equiv.), TEMPO (7.1 mg, 1.7 equiv.)
and water (1 mL). The reaction was stirred for 21 h at room temper-
ature and then quenched with an aqueous Na2S2O3·5H2O solution
H-11), 3.80 (s, 3 H, OMe), 2.55 (AB part of an ABX system, J12a-12b
=
15.5 Hz, J12a-11 = 7.7 Hz, J12b-11 = 4.5 Hz, Δν = 19.7 Hz, 2 H, H-12),
2.26 (m, 1 H, H-8a), 2.18 (m, 2 H, H-5), 1.83 (m, 1 H, H-9), 1.78 (m, 1
H, H-8b), 1.66 (d, J = 6.4 Hz, 3 H, Me-1), 0.91 (d, J = 6.6 Hz, 3 H, Me-
10), 0.88 (s, 9 H, SitBu), 0.03 (s, 3 H, SiMe), 0.01 (s, 3 H, SiMe). 13C
NMR (125 MHz, CDCl3): δ = 174.8 (COOH), 159.3 (Cq arom), 134.3
(CH-3 vinyl), 130.4 (CH-6 or CH-7 vinyl), 130.0 (Cq arom), 129.4 (CH
arom), 128.6 (CH-6 or CH-7 vinyl), 125.0 (CH-2 vinyl), 113.8 (CH
arom), 78.9 (CH-11), 73.6 (CH-4), 71.8 (CH2-PMB), 55.3 (OMe), 41.9
(CH2-5), 36.3 (CH-9), 36.0 (CH2-12), 35.2 (CH2-8), 25.9 [C(CH3)3], 18.3
[SiC(CH3)3], 17.6 (Me-1), 14.8 (Me-10), –4.3 (SiMe), –4.7 (SiMe). Mass
spectrum (ESI), m/z 515.2603 [M + K]+ (C27H44O5SiK+ requires
515.2590).
[(4R,5R)-2,2,5-Trimethyl-1,3-dioxan-4-yl]methanol (34):[24] Tri-
ethylamine (0.3 mL, 2.43 equiv.) and trifluoroacetic anhydride (TFAA,
0.3 mL, 2.39 equiv.) were successively added to a chilled (0 °C) solu-
tion of sulfoxide 33 (250.5 mg, 00.887 mmol) in CH2Cl2 (6 mL). The
solution was stirred at 0 °C for 30 min before the addition of an
(1
M, 0.5 mL). The mixture was diluted with water (3 mL), AcOEt
(10 mL) and the organic layer was washed with water (2 × 4 mL),
brine (5 mL), dried (MgSO4), filtered and concentrated under re-
duced pressure. The residue was purified by chromatography on
silica gel column (AcOEt/cyclohexane, 2:8 as eluent) to give alde-
hyde 31 (11.9 mg, 95.6 %) as a yellow oil. 1H NMR (500 MHz, CDCl3):
δ = 9.77 (dd, J = 2.3 Hz, J = 2.0 Hz, 1 H, CHO), 7.23 and 6.87 (AA′
BB′, J = 8.7 Hz, Δν = 181.8 Hz, 4 H, PMB), 5.53 (dqd, J2.3 = 15.3 Hz,
J2.1 = 6.4 Hz, J2.4 = 0.9 Hz, 1 H, H-2), 5.41 (m, 1 H, H-3), 5.39 (m, 2
H, H-6 and H-7), 4.49 and 4.43 (AB system, JAB = 11.0 Hz, Δν =
26.8 Hz, 2 H, CH2-Ar), 4.03 (dt, J = 6.8 Hz, J = 5.7 Hz, 1 H, H-4), 3.89
(dt, J = 8.4 Hz, J = 4.0 Hz, 1 H, H-11), 3.80 (s, 3 H, OMe), 2.64 (ddd,
J = 16.3 Hz, J = 8.4 Hz, J = 2.6 Hz, 1 H, H-12a), 2.48 (ddd, J = 16.3 Hz,
J = 4.0 Hz, J = 1.9 Hz, 1 H, H-12b), 2.28 (m, 1 H, H-8a), 2.18 (m, 2 H,
H-5), 1.82 (m, 1 H, H-9), 1.78 (m, 1 H, H-8b), 1.66 (dq, J = 6.4 Hz, J =
0.8 Hz, 3 H, Me-1), 0.89 (d, J = 6.7 Hz, 3 H, Me-10), 0.88 (s, 9 H,
SitBu), 0.03 (s, 3 H, SiMe), 0.01 (s, 3 H, SiMe). 13C NMR (125 MHz,
CDCl3): δ = 202.0 (CHO), 159.2 (Cq arom), 134.3 (CH-3 vinyl), 130.5
(CH-6 or CH-7 vinyl), 130.4 (Cq arom), 129.3 (CH arom), 128.5 (CH-6
or CH-7 vinyl), 125.0 (CH-2 vinyl), 113.8 (CH arom), 77.3 (CH-11), 73.6
(CH-4), 71.4 (CH2-PMB), 55.3 (OMe), 45.4 (CH2-12), 41.9 (CH2-5), 36.4
(CH-9), 35.2 (CH2-8), 25.9 [C(CH3)3], 18.3 [SiC(CH3)3], 17.6 (Me-1), 15.0
(Me-10), –4.3 (SiMe), –4.7 (SiMe).
aqueous solution of NaHCO3 (0.5
M, 5 mL, 2.8 equiv.). Stirring was
continued for 1 h at room temperature. Then solid NaBH4 (258 mg,
7.68 equiv.) was added carefully at 0 °C. The mixture was stirred for
20 min at the same temperature then water (10 mL) and CH2Cl2
(10 mL) were added. The organic layer was washed with a saturated
aqueous NH4Cl solution (4 × 5 mL), water (5 mL), dried with MgSO4,
filtered and concentrated under reduced pressure. The residue was
purified on silica gel chromatography column (AcOEt/cyclohexane,
1:1) to give 34 (79 mg, 55.6 %) as a colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 3.74–3.69 (m, 2 H, H-14a and H-18a), 3.59 (m,
1 H, H-15), 3.58–3.49 (m, 2 H, H-14b and H-18b), 2.07 (dd, J = 6.8 Hz,
J = 5.2 Hz, OH),1.84 (m, 1 H, H-16), 1.45 (s, 3 H, Me of acetonide),
1.40 (s, 3 H, Me of acetonide), 0.77 (d, J = 6.6 Hz, 3 H, Me-17). 13C
NMR (100 MHz, CDCl3): δ = 98.4 (Cq, acetonide), 75.6 (CH-15), 65.5
(CH2-14), 63.5 (CH2-18), 29.7 (CH-16), 29.6 (Me of acetonide), 19.2
(Me of acetonide), 12.4 (Me-17). Spectroscopic data matched that
reported in the literature.[24]
(3S,4S,6E,9R,10E)-9-(tert-butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-4-methyldodeca-6,10-dienoic Acid (32)
Method A, Oxidation from Alcohol 30 to Carboxylic Acid 32: To
a solution of alcohol 30 (9.2 mg, 0.0198 mmol) in MeCN (1 mL)
were added successively BAIB (52.9 mg, 8.3 equiv.), TEMPO (5.2 mg,
1.6 equiv.) and water (0.5 mL). The reaction was stirred for 9.5 h at
room temperature and then quenched with an aqueous
(2R,4R,5R)-2-(4-Methoxyphenyl)-5-methyl-4-[(S)-p-tolylsulfinyl-
methyl]-1,3-dioxane (37): To a solution of diol sulfoxide 36
(118 mg, 0.486 mmol) in CH2Cl2 (3 mL) at room temperature were
added successively p-methoxybenzaldehyde dimethyl acetal
(0.1 mL, 1.2 equiv.) and a catalytic amount of pyridinium p-toluenes-
ulfonate. The reaction mixture was stirred for 1.5 h until no more
starting material was detected on TLC before dilution with water
(5 mL) and CH2Cl2 (10 mL). The organic phase was washed with
water (5 mL), dried (Na2SO4), filtered and then concentrated to
leave a colorless liquid. The crude product was purified on silica gel
column chromatography (AcOEt/cyclohexane, 1:1 as eluent) to af-
Na2S2O3·5H2O solution (1 M, 0.5 mL) and diluted with water (4 mL)
and AcOEt (6 mL). The aqueous layer was extracted with AcOEt
(4 mL) and the combined organic layers were washed with water
(5 mL), brine (4 mL), dried (MgSO4), filtered and concentrated under
reduced pressure. The residue was purified by chromatography on
silica gel column (AcOEt/cyclohexane, 2:8 as eluent) to give acid 32
(2.1 mg, 22.2 %) as a yellow oil.
Method A, Oxidation from Aldehyde 31 to Carboxylic Acid 32:
A premixed solution of NaClO2 (67.7 mg) and NaH2PO4.H2O
(45.6 mg) in water (1.3 mL) was added to a solution of tBuOH (2 mL)
and amylene (1.2 mL). The mixture was stirred at ambient tempera- ford after concentration a white gummy foam of the desired prod-
ture for 10 min. Then a portion (1.5 mL) from the previous mixture
was transferred to the aldehyde 31 (11.9 mg, 0.0258 mmol) and
uct 37 (169 mg, 96.4 % yield). [α]2D0 = –153.9 (c = 2.32, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.54 and 7.31 (AA′BB′, J = 8.4 Hz, Δν =
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68.8 Hz, 4 H, pTol), 7.46 and 6.90 (AA′BB′, J = 8.8 Hz, Δν = 168.3 Hz,
4 H, PMP), 5.60 (s, 1 H, H acetal), 4.16–4.09 (m, 2 H, H-18ax + H-15),
3.80 (s, 3 H, OMe), 3.57 (dd, J18eq-18ax = J18eq-16 = 11.2 Hz, 1 H, H-
(2R,3R)-4-Azido-2-methylbutane-1,3-diol (41): The acetal 39
(42.9 mg, 0.162 mmol) was dissolved in dry MeOH (1.5 mL) and p-
toluenesulfonic acid (9 mg, 0.3 equiv.) was added. The reaction was
stirred for 6.5 h and quenched with a saturated aqueous NaHCO3
solution (0.8 mL). Prolongation of the reaction, resulted in degrada-
tion. The solvent was evaporated and the residue was dissolved in
18eq), 2.92 (AB part of an ABX system, J14a-14b = 13.8 Hz, J14a-15
=
11.0 Hz, J14b-15 = 2.0 Hz, Δν = 71.3 Hz, 2 H, H-14), 2.40 (s, 3 H, Me
of pTol), 1.89 (m, 1 H, H-3), 0.79 (d, J = 6.7 Hz, 3 H, Me-17). 13C NMR
(75 MHz, CDCl3): δ = 159.8 (Cq arom), 141.4 (Cq arom), 141.2 (Cq AcOEt (8 mL) and brine (5 mL). The organic layer was dried (MgSO4),
arom), 130.4 (Cq arom), 129.9 (CH arom), 127.3 (CH arom), 123.8 (CH
arom), 113.5 (CH arom), 100.8 (CH acetal), 76.5 (CH-15), 72.6 (CH2-
filtered and concentrated under reduced pressure to give a colorless
liquid. Purification by chromatography on silica gel (AcOEt as elu-
18), 62.5 (CH2-14), 55.2 (OMe), 33.8 (CH-15), 21.3 (Me of pTol), 12.0 ent) afforded the diol 41 (11.5 mg, 48.9 %) as a colorless oil. [α]D20
=
(Me-17). HR Mass spectrum (ESI), m/z 383.1276 [M + Na]+
–37.9 (c = 0.81; CHCl3), lit[27] for its enantiomer [α]2D0 = +35.6 (c =
(C20H24O4SNa+ requires 383.1288).
1.73, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 3.73 (AB part of an ABX
system, J18a-18b = 10.6 Hz, J18a-16 = 7.5 Hz, J18b-16 = 3.6 Hz, Δν =
37.2 Hz, 2 H, H-18), 3.72 (m, 1 H, H-15), 3.42 (AB part of an ABX
system, J14a-14b = 12.4 Hz, J14a-15 = 6.9 Hz, J14b-15 = 3.2 Hz, Δν =
37.2 Hz, 2 H, H-14), 3.20 (broad s, 1 H, OH), 2.34 (broad s, 1 H, OH),
1.88 (m, 1 H, H-16), 0.90 (d, J = 7.0 Hz, 3 H, Me-17). 13C NMR
(75 MHz, CDCl3): δ = 75.9 (CH-15), 67.4 (CH2-18), 55.4 (CH2-14), 37.6
(CH-16), 13.5 (Me-17).
[(2R,4R,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]meth-
anol (38): Triethylamine (370 μL, 3.2 equiv.) and trifluoroacetic an-
hydride (360 μL, 3.1 equiv.) were added successively to a chilled
(0 °C) solution of the sulfoxide 37 (299.1 mg, 0.829 mmol) in CH2Cl2
(7 mL). The reaction was stirred at 0 °C for 30 min before the addi-
tion an aqueous solution of NaHCO3 (0.5
M, 6 mL, 3.6 equiv.). The
mixture was stirred at ambient temperature for 1 h and then solid
NaBH4 (306 mg, 9.7 equiv.) was added at 0 °C. Stirring was contin-
ued for 20 min and then water (10 mL) and CH2Cl2 (10 mL) were
added. The organic layer was washed with water (2 × 5 mL), a satu-
rated aqueous NH4Cl solution (3 × 5 mL) until neutral pH, brine
(5 mL), dried (MgSO4) and concentrated under reduced pressure.
The yellow oil was purified by chromatographic column on silica
gel (AcOEt/cyclohexane, 1:1) to yield 38 as an colorless oil
(2R,3R)-1-Azido-4-(tert-butyldimethylsilyloxy)-3-methylbutan-
2-ol (42): To a solution of diol 41 (10 mg, 0.0688 mmol), DMAP
(cat.), imidazole (84.4 mg, 18 equiv.) and Na2SO4 (115 mg,
11.7 equiv.) in CH2Cl2 (1 mL) were added a solution of tert-butyldi-
methylsilyl chloride (62.4 mg, 6 equiv.) in CH2Cl2 (0.7 mL). After
stirring for 2.5 h at room temperature the reaction was quenched
with water (4 mL) and diluted with CH2Cl2 (5 mL). The organic phase
was washed by water (2 × 4 mL), brine (4 mL), dried with MgSO4,
filtered and concentrated under reduced pressure. The crude was
purified by chromatography on silica gel column (AcOEt/cyclohex-
ane, 1:9) to give monosilylated diol 42 (15.5 mg, 86.8 %) as a color-
less liquid. No trace of disilylated product was observed in spite of
excess of tert-butyldimethylsilyl chloride. 1H NMR (500 MHz, CDCl3):
δ = 4.14 (d, J = 2.9 Hz, 1 H, OH), 3.71 (m, 1 H, H-15), 3.69 (AB part
of an ABX system, J18a-18b = 10.0 Hz, J18a-16 = 8.0 Hz, J18b-16 = 4.0 Hz,
(189.7 mg, 96.0 %). [α]2D0 = –13.58 (c = 4.3, CHCl3), lit[26]: [α]2D0
=
–14.5 (c = 1.01; benzene). C13H18O4 (238.279): calcd. C 65.53, H 7.61;
1
found C 64.80, H 7.54. H NMR (400 MHz, CDCl3): δ = 7.42 and 6.90
(AA′BB′, J = 8.8 Hz, Δν = 209.1 Hz, 4 H, PMP), 5.49 (s, 1 H, acetal),
4.12 (dd, JH18eq-H18ax = 11.3 Hz, JH18eq-H16 = 4.9 Hz, 1 H, H-18eq),
3.83 (m, 1 H, H-14a), 3.80 (s, 3 H, OMe), 3.68 (m, 1 H, H-14b), 3.57
(m, 1 H, H-15), 3.50 (t apparent, JH18ax-H16 = JH18ax-H18eq = 11.3 Hz,
1 H, H-18ax), 2.15 (dd, JOH-14a = 7.3, JOH-14b = 5.8 Hz, 1 H, OH), 2.03
(m, 1 H, H-16), 0.81 (d, J = 6.7 Hz, 3 H, Me-17). 13C NMR (100 MHz,
CDCl3): δ = 160.0 (Cq arom), 130.7 (Cq arom), 127.4 (CH arom), 113.6
(CH arom), 101.1 (CH acetal), 83.3 (CH-15), 72.6 (CH2-18), 63.2 (CH2-
14), 55.3 (OMe), 29.7 (CH-15), 12.1 (Me-17). Spectroscopic data
matched that reported in the literature.[26] HR Mass spectrum (ESI),
m/z 261.1097 [M + Na]+ (C13H18O4Na+ requires 261.1097).
Δν = 78.5 Hz, 2 H, H-18), 3.35 (AB part of an ABX system, J14a-14b
=
12.7 Hz, J14a-15 = 6.0 Hz, J14b-15 = 3.0 Hz, Δν = 54.1 Hz, 2 H, H-14),
1.90 (m, 1 H, H-16), 0.90 (s, 9 H, tBuSi), 0.85 (d, J = 7.0 Hz, 3 H, Me-
17), 0.090 (s, 3 H, MeSi), 0.089 (s, 3 H, MeSi). 13C NMR (125 MHz,
CDCl3): δ = 76.2 (CH-15), 68.2 (CH2-18), 54.9 (CH2-14), 37.1 (CH-16),
25.8 [C(CH3)3Si], 18.1 [C(Me)3Si], 13.2 (Me-17), –5.6 (MeSi), –5.7
(MeSi). Spectroscopic data matched that reported in the litera-
ture.[28] Mass spectrum (ESI), m/z 260.1761 [M + H]+ (C11H26N3O2Si+
requires 260.1789).
(2R,4R,5R)-4-(Azidomethyl)-2-(4-methoxyphenyl)-5-methyl-1,3-
dioxane (39): To a cooled (0 °C) solution of the alcohol 38
(152.3 mg, 0.639 mmol) in dry THF (8 mL) were added triphenyl- (2R,3R)-4-(tert-Butyldimethylsilyloxy)-1-hydroxy-3-methyl-
phosphine (336 7 g, 2 equiv.) and DIAD (diisopropylazodicarboxyl-
ate, 252 μL, 2 equiv.). The reaction was stirred for 20 min before
the dropwise addition of DPPA (diphenylphosphoryl azide, 280 μL,
2 equiv.). Stirring was continued for 3 h 45 at room temperature
and the mixture was concentrated. The crude product was purified
by chromatographic column on silica gel (AcOEt/cyclohexane, 3:7)
butan-2-yl Acetate (ent-2): Triethylamine (1.4 mL, 3.4 equiv.) and
trifluoroacetic anhydride (1.2 mL, 3.0 equiv.) were added succes-
sively to a chilled (0 °C) solution of sulfoxide ent-1[7] (1.109·g,
2.78 mmol) in CH2Cl2 (20 mL). After 20 min, an aqueous solution of
NaHCO3 (0.5 M, 20 mL, 3.6 equiv.) was added. Stirring was continued
for 45 min at room temperature and solid NaBH4 (496 mg,
4.7 equiv.) was slowly added. After 20 min at 0 °C, water (10 mL)
to give the desired product 39 as a colorless liquid (161.6 mg,
1
96.0 %). [α]2D0 = –26.34 (c = 2.65, CHCl3). H NMR (500 MHz, CDCl3): was added and the aqueous layer was extracted with CH2Cl2 (5 mL).
δ = 7.44 and 6.90 (AA′BB′, J = 8.7 Hz, Δν = 163.6 Hz, 4 H, PMP),
5.50 (s, 1 H, acetal), 3.82 (AB part of an ABX system, J18a-18b
The combined organic layers were washed with water (2 × 10 mL),
saturated aqueous NH4Cl solution (5 × 12 mL), water (10 mL), brine
(10 mL), dried (Na2SO4), filtered and concentrated under reduced
pressure. The crude mixture was purified on silica gel by chromato-
graphic column (diethylether/cyclohexane, 1:1) to give the desired
diastereomer mixture ent-2 and ent-3 as a colorless liquid
=
11.2 Hz, J18a-16 = 11.3 Hz, J18b-16 = 4.9 Hz, Δν = 181 Hz, 2 H, H-18),
3.80 (s, 3 H, OMe), 3.66 (m, 1 H, H-15), 3.42 (AB part of an ABX
system, J14a-14b = 13.2 Hz, J14a-15 = 6.3 Hz, J14b-15 = 2.7 Hz, Δν =
18.1 Hz, 2 H, H-14), 2.06 (m, 1 H, H-16), 0.81 (d, J = 6.8 Hz, 3 H, Me-
17). 13C NMR (125 MHz, CDCl3): δ = 160.0 (Cq arom), 130.5 (Cq
(655.6 mg, 85.3 %). A fraction was purified to isolate the major prod-
1
arom), 127.3 (CH arom), 113.6 (CH arom), 101.1 (CH acetal), 82.4 uct ent-2. [α]2D0 = +3.6 (c = 0.87, CHCl3). H NMR (400 MHz, CDCl3):
(CH-15), 72.5 (CH2-18), 55.2 (OMe), 52.4 (CH2-14), 31.0 (CH-16), 12.1 δ = 4.92 (ddd, J = 5.3 Hz, J = 5.1 Hz, J = 4.8 Hz, 1 H, H-15), 3.82–
(Me-17). HR Mass spectrum (ESI), m/z 286.1160 [M + Na]+
3.62 (m, 2 H, H-14), 3.58 (AB part of an ABX system, J4a-4b = 10.0 Hz,
J4a-3 = 6.2 Hz, J4b-3 = 4.3 Hz, Δν = 24.4 Hz, 2 H, H-18), 2.89 (t, J =
(C13H17N3O3Na+ requires 286.1162).
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6.4 Hz, 1 H, OH), 2.12–1.99 (m, 1 H, H-16), 2.08 (s, 3 H, OAc), 0.93
reaction was quenched with AcOEt (2 mL), a saturated solution of
K-Na tartrate (La Rochelle's salt, 7 mL), water (10 mL) and diluted
(d, J = 7.1 Hz, 3 H, Me-17), 0.89 (s, 9 H, tBu-Si), – 0.06 (s, 3 H, Me-
Si), – 0.05 (s, 3 H, Me-Si). 13C NMR (100 MHz, CDCl3): δ = 171.1 with CH2Cl2 (10 mL). Stirring was continued for 15 min and a 10 %
(CO), 76.6 (CH-15), 64.2 (CH2-18), 62.6 (CH2-14), 37.1 (CH-16), 25.8 HCl solution was added (2 mL) until pH 7. The aqueous phase was
[C(CH3)3Si], 21.1 (OAc), 18.2 [C(Me)3Si], 13.4 (Me-17), –5.6 (MeSi).
13H28O4Si (276.444): calcd. C 56.48, H 10.21; found C 58.31, H 10.13.
extracted with CH2Cl2 (15 mL) and the combined organic layers
were washed with water (2 × 12 mL), brine (8 mL), dried (Na2SO4),
filtered and concentrated under reduced pressure. The crude was
purified by column chromatography on silica gel (AcOEt/cyclohex-
ane, 1:1) to afford the alcohol 44 as a light yellow liquid (263.8 mg,
78.0 %). [α]2D0 = +4.8 (c = 1.04, CH2Cl2). 1H NMR (500 MHz, CDCl3):
δ = 7.27 and 6.88 (AA'BB′, J = 8.4 Hz, Δν = 193.6 Hz, 4 H, PMB), 4.53
and 4.50 (AB system, JAB = 11.0 Hz, Δν = 5.9 Hz, 2 H, PhCH2O), 3.80
(s, 3 H, MeO), 3.73 (m, 1 H, H-14a), 3.63 (d, J = 5.0 Hz, 2 H, H-18),
3.57 (m, 1 H, H-14b), 3.50 (m, 1 H, H-15), 2. 47 (t, J = 6.4 Hz, 1 H,
OH), 1.99 (m, 1 H, H-16), 0.93 (d, J = 7.2 Hz, 3 H, Me-17), 0.90 (s, 9
H, tBu-Si), –0.06 (s, 6 H, 2 × SiMe). 13C NMR (125 MHz, CDCl3): δ =
159.2 (Cq arom), 130.7 (Cq arom), 129.4 (CH arom), 113.8 (CH arom),
80.6 (CH-15), 71.8 (OCH2Ph), 64.7 (CH2-18), 61.7 (CH2-14), 55.3
(MeO), 37.3 (CH-16), 25.9 [C(CH3)3Si], 18.2 [C(Me)3Si], 13.1 (Me-17),
–5.4 (SiMe), –5.5 (SiMe). Mass spectrum (ESI), m/z 377.2162 [M +
Na]+ (C19H34O4SiNa+ requires 377.2119).
C
(2R,3R)-4-(tert-Butyldimethylsilyloxy)-3-methylbutane-1,2-diol
(ent-4): Anhydrous K2CO3 (140 mg, 3.89 equiv.) was added to an
isomeric mixture of the acetate ent-2 and ent-3 (653 mg,
2.36 mmol) dissolved in dry MeOH (17 mL). The reaction was stirred
at room temperature for 1 h until total consumption of the starting
material. The supernatant was then filtered through a short pad of
silica gel and rinsed with diethylether before to be concentrated
under vacuum. The residue was purified on silica gel chromatogra-
phy (AcOEt/cyclohexane, 1:1) to yield the diol ent-4 as a colorless
liquid (386.3 mg, 69.8 %). [α]2D0 = –18.3 (c = 1.82, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 3.74 (dd, J = 10.1 Hz, J = 3.9 Hz, 1 H, H-14a),
3.68 (dd, J = 10.8 Hz, J = 3.0 Hz, 1 H, H-18a), 3.62–3.55 (m, 3 H, H-
14b, H-15 and H-18b), 3.0 (broad s, 2 H, 2 × OH), 1.86 (m, 1 H, H-
16), 0.90 (s, 9 H, tBu-Si), 0.85 (d, J = 6.9 Hz, 3 H, Me-17), 0.09 (s, 3
H, Me-Si), 0.08 (s, 3 H, Me-Si). 13C NMR (125 MHz, CDCl3): δ = 76.7
(CH-15), 68.0 (CH2-14), 64.9 (CH2-18), 36.9 (CH-16), 25.8 [C(CH3)3Si],
18.1 [C(Me)3Si], 13.2 (Me-17), –5.6 (MeSi), –5.7 (MeSi). In the litera-
ture[28] the authors described a diastereomeric mixture (9:1) of the
diol.
[(2R,3R)-4-Azido-3-(4-methoxybenzyloxy)-2-methyl-
butoxy](tert-butyl)dimethylsilane (45): Triphenylphosphine
(438 mg, 2.06 equiv.) was added to a cooled solution (0 °C) of alco-
hol 44 (286.7, 0.808 mmol) in dry THF (15 mL) followed by diiso-
propylazodicarboxylate (DIAD, 0.36 mL, 2.24 equiv.). The homoge-
neous yellow solution was stirred for 25 min before the addition of
diphenylphosphoryl azide (DPPA, 0.37 mL, 2.12 equiv.). The hetero-
geneous mixture was stirred for 4 h at room temperature and the
solvent was evaporated under vacuum to leave an orange liquid.
This crude material was directly purified by chromatography on sil-
ica gel column (AcOEt/cyclohexane, 1:15 as eluent) to afford the
azide compound 45 (240.2 mg, 78.3 %) as a yellow-orange liquid.
tert-Butyl{(2R)-2-[(4R)-2-(4-Methoxyphenyl)-1,3-dioxolan-4-
yl]propoxy}dimethylsilane (43): Camphor sulfonic acid (40 mg,
0.1 equiv.) and p-methoxybenzaldehyde dimethyl acetal (0.3 mL,
1.1 equiv.) were successively added to a solution of diol ent-4
(386.3 mg, 0.00164 mol) in CH2Cl2 (20 mL) at 0 °C. After 1.5 h, the
reaction was quenched with a saturated aqueous NaHCO3 solution
(1 mL) and water (10 mL). The organic layer was washed with water
(4 × 6 mL), brine (8 mL), dried with Na2SO4, filtered and concen-
trated under reduced pressure. The crude was purified by chroma-
tography on silica gel (AcOEt/cyclohexane, 2:8) to afford 43 (as a
mixture of two diastereomers: 43:57) as a colorless liquid (478.3 mg,
82.7 %). 1H NMR (500 MHz, CDCl3): δ = 7.41 and 6.90 (AA′BB′,
J = 8.7 Hz, Δν = 254.3 Hz, 4 H, PMP for diaB), 7.39 and 6.89 (AA′BB′,
J = 8.5 Hz, Δν = 247.3 Hz, 4 H, PMP for diaA), 5.85 (s, 1 H, acetal for
diaA), 5.73 (s, 1 H, acetal for diaB), 4.22 (m, 1 H, H-14 for diaA), 4.12
(m, 1 H, H-15 for diaB), 4.08 (m, 1 H, H-15 for diaA), 4.02 (app t, J =
7.4 Hz, 1 H, H-14 for diaB), 3.83 (app t, J = 7.4 Hz, 1 H, H-14 for
diaB), 3.81 (s, 3 H, MeO for diaB), 3.80 (s, 3 H, MeO for diaA), 3.75
(m, 1 H, H-18 for diaA), 3.74 (m, 1 H, H-14 for diaA), 3.67 (AB part
of an ABX system, J18a-18b = 9.7 Hz, J18a-16 = 5.5 Hz, J18b-16 = 4.5 Hz,
Δν = 20.8 Hz, 2 H, H-18 for diaB), 3.62 (m, 1 H, H-18 for diaB), 1.98
(m, 1 H, H16 for diaB), 1.93 (m, 1 H, H16 for diaA), 0.96 (d, J = 6.9 Hz,
3 H, Me-17 for diaB), 0.93 (d, J = 6.9 Hz, 3 H, Me-17 for diaA), 0.90
(s, 9 H, tBu-Si for diaB), 0.89 (s, 9 H, tBu-Si for diaA), 0.045 (s, 3 H,
Me-Si for diaA), 0.041 (s, 3 H, Me-Si for diaB). 13C NMR (125 MHz,
CDCl3): δ = 160.3 (Cq arom), 160.2 (Cq arom), 130.7 (Cq arom), 130.0
(Cq arom), 128.0 (CH arom), 127.8 (CH arom), 113.7 (CH arom), 103.6
(CHAr-B) 103.3 (CHAr-A), 78.5 (CH-15B), 77.6 (CH-15A), 69.1 (CH2-
14A), 67.9 (CH2-14B), 65.0 (CH2-18 for diaA or diaB), 64.9 (CH2-18 for
diaA or diaB), 55.3 (OMe), 39.1 (CH-16A), 38.9 (CH-16B), 25.9
[C(CH3)3Si], 18.3 [C(Me)3Si], 12.4 (Me-17 for diaA or diaB), 12.3 (Me-
17 for diaA or diaB), –5.5 (MeSi). Mass spectrum (ESI), m/z 375.1939
[M + Na]+ (C19H32O4SiNa+ requires 375.1962).
1
[α]2D0 = +34.2 (c = 1.03, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 7.30
and 6.88 (AA′BB′, J = 8.5 Hz, Δν = 206.8 Hz, 4 H, PMB), 4.60 and
4.51 (AB system, JAB = 10.7 Hz, Δν = 42.1 Hz, 2 H, PhCH2O), 3.80 (s,
3 H, MeO), 3.61 (AB part of an ABX system, J18a-18b = 10.0 Hz,
J18a-16 = J18b-16 = 5.0 Hz, Δν = 49.0 Hz, 2 H, H-18), 3.59 (td, J =
6.7 Hz, J = 2.9 Hz, 1 H, H-15), 3.34 (AB part of an ABX system,
J14a-14b = 13.0 Hz, J14a-15 = 7.0 Hz, J14b-15 = 2.5 Hz, Δν = 44.7 Hz, 2
H, H-14), 1.96 (m, 1 H, H-16), 0.90 (d, J = 6.7 Hz, 3 H, Me-17), 0.89
(s, 9 H, tBu-Si), 0.05 (s, 3 H, SiMe), 0.04 (s, 3 H, SiMe). 13C NMR
(125 MHz, CDCl3): δ = 159.2 (Cq arom), 130.4 (Cq arom), 129.5 (CH
arom), 113.8 (CH arom), 79.4 (CH-15), 72.3 (OCH2Ph), 64.5 (CH2-18),
55.3 (MeO), 52.2 (CH2-14), 37.8 (CH-16), 25.9 [C(CH3)3Si], 18.2
[C(Me)3Si], 12.9 (Me-17), –5.4 (SiMe), –5.5 (SiMe). Mass spectrum
(ESI), m/z 402.2210 [M + Na]+ (C19H33N3O3SiNa+ requires 402.2183).
(2R,3R)-4-Azido-3-(4-methoxybenzyloxy)-2-methylbutan-1-ol
(46): A solution of tetrabutylammonium fluoride (TBAF, 1
M in THF,
0.8 mL, 2.1 equiv.) was added to a solution of azide 45 (140.2 mg,
0.369 mmol) in THF (5 mL) at 0 °C. After 15 min at 0 °C, stirring was
continued for 1 h at room temperature. The reaction was quenched
with a saturated aqueous solution of NaHCO3 (0.5 mL), water (5 mL)
and diluted with AcOEt (8 mL). The organic layer was washed with
water (2 × 5 mL), brine (5 mL), dried (Na2SO4), filtered and concen-
trated under reduced pressure. The crude was purified by chroma-
tography on silica gel column (AcOEt/cyclohexane, 1:1 as eluent) to
give the alcohol 46 (90.3 mg, 92.2 %) as a colorless liquid. [α]D20
=
+43.6 (c = 1.14, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.29 and
6.89 (AA′BB′, J = 8.5 Hz, Δν = 199.8 Hz, 4 H, PMB), 4.69 and 4.48
(AB system, JAB = 10.7 Hz, Δν = 104.4 Hz, 2 H, PhCH2O), 3.81 (s, 3
H, MeO), 3.64 (m, 1 H, H-18a), 3.57 (m, 1 H, H-18b), 3.54 (m, 1 H, H-
14a), 3.51 (m, 1 H, H-15), 3.31 (dd, J = 12.6 Hz, J = 4.8 Hz, 1 H, H-
(2R,3R)-4-(tert-Butyldimethylsilyloxy)-2-(4-methoxybenzyloxy)-
3-methylbutan-1-ol (44): A mixture of the diastereomeric com-
pound 43 (336.6 mg, 0.954 mmol) in CH2Cl2 (15 mL) was treated at
0 °C with DiBAL-H (1
M
in toluene, 3.6 mL, 3.8 equiv.). After 1 h the
Eur. J. Org. Chem. 0000, 0–0
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Full Paper
14b), 2.27 (br. t, J = 5.1 Hz, 1 H, OH), 1.98 (m, 1 H, H-16), 0.92 (d,
J = 7.2 Hz, 3 H, Me-17). 13C NMR (125 MHz, CDCl3): δ = 159.5 (Cq
(3 mL), water (2 × 5 mL), dried (Na2SO4), filtered and concentrated
under reduced pressure. The residue was purified by chromatogra-
arom), 129.8 (CH arom), 129.5 (Cq arom), 114.0 (CH arom), 81.7 (CH- phy on silica gel (AcOEt/cyclohexane, 1:1 as eluent) to leave the
15), 72.4 (OCH2Ph), 65.8 (CH2-18), 55.3 (MeO), 51.9 (CH2-14), 37.3 silyl ester 49 (50.9 mg, 93.5 %) as an amber-colored liquid. [α]D20
=
(CH-16), 13.8 (Me-17). Mass spectrum (ESI), m/z 288.1288 [M + Na]+
+12.6 (c = 1.31, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.28 and
(C13H19N3O3Na+ requires 288.1319).
6.86 (AA′BB′, J = 8.5 Hz, Δν = 206.8 Hz, 4 H, PMB), 4.57 (s, 2 H,
PhCH2O), 3.87 (m, 1 H, H-15), 3.80 (s, 3 H, MeO), 3.34 (AB part of an
ABX system, J14a-14b = 13.5 Hz, J14a-15 = 6.0 Hz, J14b-15 = 3.2 Hz, Δν =
2 6 . 3 H z , 2 H , H - 1 4 ) , 2 . 8 7 ( m , 1 H , H -1 6) , 1 . 3 0 { m, 3 H,
Si[CH(Me)2]3},1.16 (d, J = 7.3 Hz, 3 H, Me-17), 1.06 {d, J = 7.5 Hz, 18
H, Si[CH(Me)2]3}. 13C NMR (125 MHz, CDCl3): δ = 174.0 (CO), 159.3
(Cq arom), 129.9 (Cq arom), 129.6 (CH arom), 113.7 (CH arom), 79.2
(CH-15), 72.3 (OCH2Ph), 55.2 (MeO), 51.3 (CH2-14), 43.3 (CH-16), 17.8
{Si[CH(Me)2]3}, 12.7 (Me-17), 11.9 {Si[CH(Me)2]3}.. Mass spectrum
(ESI), m/z 474.2177 [M + K]+ (C22H37N3O4SiK+ requires 474.2185).
(2S,3R)-4-Azido-3-(4-methoxybenzyloxy)-2-methylbutanal (47):
Solid NaHCO3 (35.5 mg, 2 equiv.) followed by Dess–Martin reagent
(94.6 mg, 1.1 equiv.) were successively added to a solution of alco-
hol 46 (53.5 mg, 0.201 mmol) in dry CH2Cl2 (3 mL) at 0 °C. After
1 h at the same temperature the reaction mixture was quenched
with an aqueous solution of Na2S3O3·5H2O (1
M, 0.5 mL) and an
aqueous saturated solution of NaHCO3 (1 mL). Water (4 mL) and
AcOEt (10 mL) were added, and the organic layer was washed with
water (2 × 5 mL), brine (5 mL), dried (Na2SO4), filtered and concen-
trated under reduced pressure. The crude was purified by chroma-
tography on silica gel column (AcOEt/cyclohexane, 1:1 as eluent) to
afford the desired aldehyde 47 (41.5 mg, 78.4 %) as a yellow-orange
oil. 1H NMR (500 MHz, CDCl3): δ = 9.72 (d, J = 1.9 Hz, 1 H, CHO),
7.26 and 6.89 (AA′BB′, J = 8.7 Hz, Δν = 186.8 Hz, 4 H, PMB), 4.63
and 4.50 (AB system, JAB = 11.0 Hz, Δν = 65.1 Hz, 2 H, PhCH2O),
3.81 (s, 3 H, MeO), 3.80 (m, 1 H, H-15), 3.39 (AB part of an ABX
system, J14a-14b = 13.2 Hz, J14a-15 = 5.0 Hz, J14b-15 = 4.0 Hz, Δν =
70.1 Hz, 2 H, H-14), 2.76 (m, 1 H, H-16), 1.08 (d, J = 7.2 Hz, 3 H, Me-
17). 13C NMR (125 MHz, CDCl3): δ = 203.0 (CHO), 159.5 (Cq arom),
129.7 (CH arom), 129.3 (Cq arom), 113.9 (CH arom), 78.1 (CH-15),
72.2 (OCH2Ph), 55.3 (MeO), 51.2 (CH2-14), 48.2 (CH-16), 10.1 (Me-17).
(R,E)-Methyl 5-(tert-Butyldimethylsilyloxy)-2,4-dimethylpent-2-
enoate (50): The aldehyde 5 (360 mg) dissolved in CH2Cl2 (8 mL)
was added at ambient temperature to a solution of ylide [methyl(tri-
phenylphosphoranylidene) propionate] (824 mg; 1.3 equiv.). After
stirring for 10 h at room temperature, the solvent was evaporated
to give a yellow oil which solidified on standing. This crude product
was purified by chromatography on silica gel (AcOEt/cyclohexane,
3:7) to give the desired ester 50 as a colorless liquid (453.1 mg;
93.9 %). Only the (E)-conformation was observed on the 1H NMR
1
spectrum. [α]2D0 = +1.1 (c = 0.94, CHCl3). H NMR (300 MHz, CDCl3):
δ = 6.55 (dq, J36-34 = 9.9 Hz, J36-38 = 1.5 Hz, 1 H, H-36), 3.72 (s, 3 H,
OMe), 3.48 (d, J33-34 = 6.5 Hz, 2 H, H-33), 2.68 (m, 1 H, H-34), 1.85
(d, J38-36 = 1.5 Hz, 3 H, H-38), 1.01 (d, J35-34 = 6.7 Hz, 3 H, H-35), 0.87
(s, 9 H, tBu-Si), 0.025 (s, 3 H, Me-Si), 0.018 (s, 3 H, Me-Si). 13C NMR
(75 MHz, CDCl3): δ = 168.7 (CO2Me), 144.9 (CH-36), 127.7 (C-37),
67.1 (CH2-33), 51.7 (OMe), 36.3 (CH-34), 25.9 [C(CH3)3Si], 18.3
[C(Me)3Si], 16.2 (Me-35), 12.7 (Me-38), –5.3 (MeSi), –5.4 (MeSi).
C14H28O3S (272.456): calcd. C 61.72, H 10.36; found C 62.45, H 11.14.
(2S,3R)-4-Azido-3-(4-methoxybenzyloxy)-2-methylbutanoic
Acid (48): A premixed solution of NaClO2 (134.3 mg, 9.4 equiv.) and
NaH2PO4.H2O (95.5 mg, 4.4 equiv.) in distilled water (2 mL) was
added to a well stirred solution of aldehyde 47 (41.5 mg,
0.157 mmol) in tert-butyl alcohol (2 mL) and amylene (1.5 mL). Stir-
ring was continued for 2 h (disappearance of the starting material
monitored by TLC) and the reaction was then quenched with an
(R,E)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethyl-1-[(S)-p-tolyl-
sulfinyl]hex-3-en-2-one (51): (–) (S) Methyl p-toluene sulfoxide 8
(4.078 g, 2.0 equiv.) in dry THF (25 mL) was added at – 60 °C to a
solution of LDA (2.15 equiv., freshly prepared from diisopropylamine
and nBuLi) in dry THF (50 mL). After stirring for 1 h at the same
temperature, the ester 50 (3.61 g, 0.0132 mol) in dry THF (15 mL)
was then added to the clear yellow solution containing the anion
of methyl p-toluene sulfoxide. The mixture was stirred for 2 h allow-
ing the temperature to reach 0 °C. The reaction was quenched with
an aqueous saturated NH4Cl solution (10 mL), diluted with water
(10 mL), EtOAc (50 mL), and acidified with a 10 % HCl aqueous
solution (50 mL) till pH = 4. The layers were separated and the
organic phase was washed with water (4 × 15 mL), brine (10 mL),
dried (MgSO4), filtered and concentrated under reduced pressure.
The crude yellow product was then purified by column chromatog-
raphy on silica gel eluting with ethyl acetate/cyclohexane (7:3) to
aqueous solution of Na2S3O3·5H2O (1
diluted with water (4 mL), AcOEt (10 mL) and the organic phase
was separated and washed with water (2 mL). The combined aque-
ous layer was treated with an aqueous 3
M, 2 mL). The mixture was
N HCl solution until pH 3
and then extracted with AcOEt (2 × 5 mL). These combined organic
layers were washed with water (2 × 5 mL), brine (5 mL), dried
(Na2SO4), filtered and concentrated under reduced pressure. The
crude was pure enough for the next step but can be purified by
chromatography on silica gel (AcOEt/cyclohexane, 1:1 then AcOEt
as eluents) to afford the acid 48 (35.1 mg, 80.0 %) as colorless oil.
1
[α]2D0 = +39.4 (c = 0.61, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 7.26
and 6.87 (AA′BB′, J = 8.7 Hz, Δν = 196.8 Hz, 4 H, PMB), 4.61 and
4.54 (AB system, JAB = 11.2 Hz, Δν = 34.1 Hz, 2 H, PhCH2O), 3.81
(m, 1 H, H-15), 3.79 (s, 3 H, MeO), 3.37 (AB part of an ABX system,
J14a-14b = 13.0 Hz, J14a-15 = 5.5 Hz, J14b-15 = 3.2 Hz, Δν = 51.9 Hz, 2
H, H-14), 2.88 (m, 1 H, H-16), 1.17 (d, J = 7.2 Hz, 3 H, Me-17). 13C
NMR (125 MHz, CDCl3): δ = 179.1 (COOH), 159.4 (Cq arom), 129.7
(CH arom), 129.4 (Cq arom), 113.9 (CH arom), 79.0 (CH-15), 72.6
(OCH2Ph), 55.2 (MeO), 51.1 (CH2-14), 41.9 (CH-16), 12.7 (Me-17).
Mass spectrum (ESI), m/z 318.0825 [M + K]+ (C13H17N3O4K+ requires
318.0851).
provide ketosulfoxide 51 (4.729 g, 90.6 %) as a colorless oil. [α]D20
=
–113.8 (c = 1.31, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.55 and
7.31 (AA′BB′, J = 8.1 Hz, Δν = 73 Hz, 4 H, pTol), 6.40 (dq, J36-34
9.5 Hz, J36-38 = 1.3 Hz, 1 H, H-36), 4.34 and 3.93 (AB system, JAB
=
=
13.9 Hz, Δν = 123 Hz, 2 H, H-40), 3.48 (m, 2 H, H-33), 2.74 (m, 1 H,
H-34), 2.40 (s, 3 H, MePh), 1.77 (d, J38-36 = 1.3 Hz, 3 H, H-38), 1.02
(d, J35-34 = 6.8 Hz, 3 H, H-35), 0.84 (s, 9 H, tBu-Si), 0.006 (s, 3 H,
Me-Si), 0.002 (s, 3 H, Me-Si). 13C NMR (125 MHz, CDCl3): δ = 192.5
(2S,3R)-Triisopropylsilyl 4-Azido-3-(4-methoxybenzyloxy)-2-
methylbutanoate (49): Triethylamine (30 μL, 1.7 equiv.) and triiso-
propylsilyl chloride (TIPSCl, 30 μL, 1.1 equiv.) were added succes- (CO), 149.6 (CH-36 vinyl), 141.9 (Cq), 140.4 (Cq), 137.4 (Cq), 129.9
sively to the acid 48 (34.9 mg, 0.124 mmol) in DMF (0.5 mL). The
heterogeneous solution was stirred for 25 min and then quenched
with water (5 mL) and diluted with diethylether (6 mL). The organic
layer was washed with a saturated aqueous solution of NaHCO3
(CH arom), 124.3 (CH arom), 66.7 (CH2-33), 65.5 (CH2-40), 36.9 (CH-
34), 25.8 [C(CH3)3Si], 21.4 (Me arom), 18.2 [C(Me)3Si], 16.0 (Me-35),
11.4 (Me-38), –5.4 (MeSi). C21H34O3SSi (394.643): calcd. C 63.91, H
8.68; found C 65.43, H 9.06.
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Full Paper
(2R,5R,E)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethyl-1-[(S)-p-tol- (CH2-33), 34.9 (CH-34), 25.9 [C(CH3)3Si], 21.6 (Me-40), 18.3 [C(Me)3Si],
ylsulfinyl]hex-3-en-2-ol (52): A solution of DiBAL-H (1M in toluene, 17.1 (Me-35), 11.7 (Me-38), –5.3 (MeSi), –5.4 (MeSi). HR Mass
2.1 mL, 1.75 equiv.) was added dropwise to a solution of the previ- spectrum (ESI), m/z 281.1907 [M + Na]+ (C14H30O2SiNa+ requires
ous ketosulfoxide 51 (473 mg, 1.19 mmol) in dry THF (15 mL)
at – 70 °C. Stirring was continued for 1 h allowing the temperature
to reach – 45 °C until complete consumption of the starting mate-
rial was observed by TLC analysis (EtOAc/cyclohexanes, 1:1). The
reaction was then quenched slowly with AcOEt (5 mL) and an aque-
281.1900).
(2S,5R,E)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethylhex-3-en-
2-yl Acetate (54): Anhydride acetic (0.70 μL, 1.5 equiv.), triethyl-
amine (1.15 μL, 1.7 equiv.) and catalytic amount of DMAP (20 mg)
were successively added to a solution of the alcohol 53 (1.279 g,
4.94 mmol) in CH2Cl2 (30 mL). The reaction was stirred at room
temperature for 4 h and then quenched with water (20 mL) and
diluted with CH2Cl2 (10 mL). The organic layer was washed with
water (3 × 15 mL), brine (10 mL) dried (MgSO4), filtered and concen-
trated under reduced pressure. The crude product was purified by
chromatographic column on silica gel (CH2Cl2/cyclohexane, 1:1) to
afford the acetylated product 54 as a colorless liquid (1.236 g,
83.3 %). [α]2D0 = –18.9 (c = 3.15, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 5.24 (q, J = 6.8 Hz, 1 H, H-39), 5.21 (d, J = 9.0 Hz, 1 H, H-36),
3.38 (AB part of an ABX system, JAB = 9.7 Hz, JAX = 5.9 Hz, JBX
5.7 Hz, Δν = 13.4 Hz, 2 H, H-33), 2.54 (m, X part of ABX system, 1
H, H-34), 2.03 (s, 3 H, AcO), 1.64 (d, JMe-36 = 1.3 Hz, 3 H, Me-38),
1.28 (d, JMe-39 = 6.5 Hz, 3 H, Me-40), 0.94 (d, JMe-34 = 6.8 Hz, 3 H,
Me-35), 0.87 (s, 9 H, tBu-Si), 0.02 (s, 3 H, Me-Si), 0.01 (s, 3 H, Me-Si).
13C NMR (75 MHz, CDCl3): δ = 170.3 (CO), 134.5 (Cq vinyl, C-37),
130.1 (CH vinyl, C-36), 75.3 (CH-39), 67.7 (CH2-33), 35.0 (CH-34), 25.9
[C(CH3)3Si], 21.4 (AcO), 19.1 (Me-40), 18.3 [C(Me)3Si], 16.9 (Me-35),
12.3 (Me-38), –5.3 (MeSi), –5.4 (MeSi). HR Mass spectrum (ESI), m/z
323.1997 [M + Na]+ (C16H32O3SiNa+ requires 323.2013).
ous disodium tartaric acid salt solution (1
M, 5 mL) before to be
diluted with EtOAc (30 mL). The mixture was vigorously stirred at
ambient temperature for 1.5 h until the aqueous layer became
cloudy. At that time an aqueous 10 % HCl solution (4 mL, aqueous
phase pH = 4) was added to get two limpid layers which were
stirred for an additional 0.5 h. The aqueous phase was extracted
with EtOAc (10 mL) and the combined organic extracts were
washed with water (3 × 10 mL), brine (5 mL), dried with Na2SO4,
filtered and concentrated under reduced pressure to afford a white
solid. This crude solid was chromatographed on silica gel column
for purification (elution solvent: EtOAc/cyclohexane, 1:1) to yield the
desired alcohol 52 (407.5 mg, 86.3 %) as a white crystalline solid.
=
4
1
M.p. 114–115 °C. [α]2D0 = –172.2 (c = 0.8, CHCl3). H NMR (300 MHz,
CDCl3): δ = 7.53 and 7.35 (AA′BB′, J = 8.1 Hz, Δν = 54.6 Hz, 4 H,
pTol), 5.24 (d, J = 9.6 Hz, 1 H, H-36), 3.41 (d, J = 2.9 Hz, 1 H, OH),
4.52 (d apparent, X part of ABX system, J = 10.1 Hz, 1 H, H-39), 3.35
(AB part of an ABX system, JAB = 9.8 Hz, JAX = 6.9 Hz, JBX = 6.3 Hz,
Δν = 14.5 Hz, 2 H, H-33), 2.77 (AB part of an ABX system, JAB
=
13.5 Hz, JAX = 10.2 Hz, JBX = 2.1 Hz, Δν = 97.5 Hz, 2 H, H-40), 2.52
(m, X part of ABX system, 1 H, H-34), 2.43 (s, 3 H, MePh), 1.60 (d,
4JMe-36 = 1.3 Hz, 3 H, Me-38), 0.92 (d, JMe-34 = 6.8 Hz, 3 H, Me-35),
0.85 (s, 9 H, tBu-Si), –0.005 (s, 3 H, Me-Si), –0.01 (s, 3 H, Me-Si). 13C
NMR (75 MHz, CDCl3): δ = 141.5 (Cq), 139.7 (Cq), 135.0 (Cq), 130.3
(CH-36 vinyl), 130.0 (CH arom), 124.0 (CH arom), 71.7 (CH-39), 67.6
(CH2-33), 60.5 (CH2-40), 35.1 (CH-34), 25.9 [C(CH3)3Si], 21.4 (Me
arom), 18.3 [C(Me)3Si], 17.0 (Me-35), 12.3 (Me-38), –5.3 (MeSi), –5.4
(MeSi). C21H36O3SSi (396.659): calcd. C 63.59, H 9.15; found C 63.42,
H 9.38.
(2S,5R,E)-6-Hydroxy-3,5-dimethylhex-3-en-2-yl Acetate (55): A
solution of TBAF (in THF 1M, 6 mL, 1.4 equiv.) was added dropwise
at 0 °C to the silylated alcohol 54 (1.236 mg, 4.11 mmol) in dry THF
(30 mL). After being stirred at room temperature for 2 h, the reac-
tion mixture was quenched with water (20 mL) and after 35 min
diluted with diethylether (30 mL). The aqueous layer was extracted
with diethylether (20 mL) and the combined organic layers were
washed with water (3 × 10 mL), brine (10 mL), dried (MgSO4) and
concentrated under reduced pressure. The crude product was puri-
fied on silica gel chromatography (diethylether as eluent) to give a
colorless liquid of 55 (0.760 g, 99.3 %). [α]2D0 = –21.9 (c = 1.1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 5.24–5.16 (m, 2 H, H-39 and H-36),
CCDC 1540885 (for 52) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
(2S,5R,E)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethylhex-3-en-
2-ol (53): Small pieces of lithium wire (314 mg, 10.8 mmol,
10.7 equiv.) was added to dry ethylamine (ca 35 mL) at – 65 °C.
The deep blue-colored solution was stirred for 1 h at the same
temperature before the addition of the ꢀ-hydroxy sulfoxide 52
(1.666 g, 4.20 mmol) in dry THF (10 mL). Stirring was continued for
30 min allowing the temperature to reach – 55 °C. Solid NH4Cl (7 g)
was slowly added to destroy the excess of lithium. The solvent was
then evaporated and the residue was diluted with diethylether
(50 mL), water (40 mL) and a 20 % aqueous HCl solution until pH =
2. The organic layer was washed with an aqueous saturated solution
of NH4Cl (2 × 10 mL), water (3 × 12 mL), brine (10 mL), dried
(MgSO4) and filtered. The crude product was purified on silica gel
by chromatographic column (AcOEt/cyclohexane, 1:9) to give the
3.40 (AB part of an ABX system, JAB = 10.5 Hz, JAX = 7.5 Hz, JBX
=
6.0 Hz, Δν = 30.9 Hz, 2 H, H-33), 2.62 (m, X part of ABX system, 1
4
H, H-34), 2.04 (s, 3 H, AcO), 1.68 (d, JMe-36 = 1.3 Hz, 3 H, Me-38),
1.65 (br. s, 1 H, OH), 1.30 (d, JMe-39 = 6.5 Hz, 3 H, Me-40), 0.95 (d,
JMe-34 = 6.6 Hz, 3 H, Me-35). 13C NMR (75 MHz, CDCl3): δ = 170.4
(CO), 136.7 (Cq vinyl, C-37), 128.8 (CH vinyl, C-36), 75.0 (CH-39), 67.6
(CH2-33), 35.0 (CH-34), 21.4 (AcO), 19.2 (Me-40), 16.6 (Me-35), 12.7
(Me-38). HR Mass spectrum (ESI), m/z 209.1142 [M + Na]+
(C10H18O3Na+ requires 209.1148).
(2S,5R,E)-3,5-Dimethyl-6-(phenylthio)hex-3-en-2-yl Acetate (56):
Tri-n-butylphosphine (0.26 μL, 1.53 equiv.) was added dropwise to
a solution containing diphenyl disulfide (227.6 mg, 1.51 equiv.) and
alcohol 55 (128.4 mg, 0.689 mmol) in CH2Cl2 (5 mL). The mixture
was stirred for 31 h at ambient temperature before being diluted
allylic alcohol 53 (782.3 mg, 72.1 %) as a colorless liquid. [α]D20
=
–40.5 (c = 2.05, CHCl3). A byproduct was isolated identified as an
epoxide (10.6 mg). 1H NMR (300 MHz, CDCl3): δ = 5.17 (d, J = 9.2 Hz,
1 H, H-36), 4.19 (qd, J39-40 = 6.4 Hz, J39-HO = 0.7 Hz, 1 H, H-39), 3.39
(AB part of an ABX system, JAB = 9.6 Hz, JAX = 7.2 Hz, JBX = 6.3 Hz,
Δν = 17.8 Hz, 2 H, H-33), 2.56 (m, X part of ABX system, 1 H, H-34),
with CH2Cl2 (5 mL) and quenched with NaOH (1
was continued for 0.5 h and an additional solution of NaOH (1
M, 9 mL). Stirring
M,
10 mL) was added. The aqueous layer was extracted with CH2Cl2
(10 mL) and the combined organic extracts were washed with water
(2 × 10 mL), brine (5 mL), dried with MgSO4, filtered and concen-
trated under reduced pressure. Purification of the residue on silica
gel (cyclohexane) provided the expected sulfide 56 as a colorless
4
1.65 (d, JMe-36 = 1.3 Hz, 3 H, Me-38), 1.24 (d, JMe-39 = 6.6 Hz, 3 H,
Me-40), 0.94 (d, JMe-34 = 6.8 Hz, 3 H, Me-35), 0.88 (s, 9 H, tBu-Si),
0.03 (s, 3 H, Me-Si), 0.02 (s, 3 H, Me-Si). 13C NMR (75 MHz, CDCl3): liquid (123.9 mg, 64.6 %). [α]D20 = –6.28 (c = 0.78, CHCl3). 1H NMR
δ = 138.8 (Cq vinyl, C-37), 128.0 (CH vinyl, C-36), 73.4 (CH-39), 67.8 (300 MHz, CDCl3): δ = 7.4–7.2 (m, 4 H, Ph), 7.2–7.1 (m, 1 H, Ph), 5.27
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(d, J36-34 = 9.0 Hz, 1 H, H-36), 5.22 (q, J39-40 = 6.6 Hz, 1 H, H-39),
crude product by chromatography on silica gel column (AcOEt/cy-
clohexane, 1:5), the desired silyl ether 59 was obtained as a color-
less oil (208.6 mg, 95.8 %). [α]2D0 = –1.4 (c = 1.04, CHCl3). 1H NMR
2.84 (m, 2 H, H-33), 2.7–2.6 (m, 1 H, H-34), 2.03 (s, 3 H, AcO), 1.56
4
(d, JMe-36 = 1.5 Hz, 3 H, Me-38), 1.27 (d, JMe-39 = 6.5 Hz, 3 H, Me-
40), 1.08 (d, JMe-34 = 6.6 Hz, 3 H, Me-35). 13C NMR (75 MHz, CDCl3): (500 MHz, CDCl3): δ = 7.89–7.88 (m, 2 H, Ph), 7.65–7.63 (m, 1 H, Ph),
δ = 170.2 (CO), 137.0 (Cq), 134.7 (Cq), 131.0 (CH vinyl, C-36), 129.2 7.57–7.54 (m, 2 H, Ph), 5.07 (d, J = 9.3 Hz, 1 H, H-36), 4.05 (d, J =
(CH arom), 128.8 (CH arom), 125.8 (CH arom), 75.2 (CH-39), 41.0 6.3 Hz, 1 H, H-39), 3.04 (degenerated ABX, 2 H, H-33), 2.94 (m, 1 H,
(CH2-33), 32.0 (Me-34), 21.4 (AcO), 20.0 (CH-35), 19.1 (Me-40), 12.1
(Me-38). HR Mass spectrum (ESI), m/z 301.1204 [M + Na]+
(C16H22O2SNa+ requires 301.1233).
H-34), 1.47 (d, 4JMe-36 = 1.4 Hz, 3 H, Me-38), 1.10 (d, JMe-39 = 6.9 Hz,
3 H, Me-35 or Me-40), 1.09 (d, JMe-34 = 6.3 Hz, 3 H, Me-35 or Me-
40), 0.85 (s, 9 H, tBu-Si), 0.030 (s, 3 H, Me-Si), 0.034 (s, 3 H, Me-Si).
13C NMR (125 MHz, CDCl3): δ = 139.9 (Cq), 139.6 (Cq), 133.5 (CH
arom), 129.2 (CH arom), 127.9 (CH arom), 126.4 (CH-36), 73.6 (CH-
39), 62.4 (CH2-33), 27.7 (CH-34), 25.8 [C(CH3)3Si], 22.9 (Me-35 or Me-
40), 20.7 (Me-35 or Me-40), 18.2 [C(Me)3Si], 11.2 (Me-38), –4.79
(MeSi), –4.98 (MeSi). Mass spectrum (ESI), m/z 405.1895 [M + Na]+
(C20H34O3SSiNa+ requires 405.1890).
(2S,5R,E)-3,5-Dimethyl-6-(phenylsulfonyl)hex-3-en-2-yl Acetate
(57): A solution of ammonium molybdate tetrahydrate (261 mg,
0.1 equiv.) prepared at 0 °C in water (3.5 mL) and hydrogen peroxide
[30 % (w/w), 3.5 mL] was added dropwise to a precooled (0 °C)
solution of sulfide 56 (546.5 mg, 1.96 mmol) in EtOH (15 mL). The
reaction was stirred for 9 h allowing the mixture to reach room
temperature. Then AcOEt (30 mL) and sat. NaCl (15 mL) were added
and stirring was continued for a further 20 min before the elimina-
tion of the volatile solvents. The residue was diluted with AcOEt
(20 mL) and the aqueous layer was extracted with AcOEt (3 ×
10 mL). The combined organic layers were washed with sat. NaCl
(10 mL) dried (MgSO4), filtered and concentrated under reduced
pressure. Chromatographic purification on silica gel (AcOEt/cyclo-
hexane, 3:7) afforded pure sulfone 57 as a colorless viscous oil
(507.8 mg, 83.5 %). [α]D20 = –28.36 (c = 1.16, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.9–7.5 (m, 5 H, Ph), 5.16 (d, J36-34 = 9.0 Hz,
1 H, H-36), 5.10 (q, J39-40 = 6.6 Hz, 1 H, H-39), 3.06 (m, 2 H, H-33),
(2S,3S)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-oxobutan-2-yl
Acetate (60): Triethylamine (450 μL, 3.36 equiv.) and trifluoroacetic
anhydride (420 μL, 3.1 equiv.) were successively added at 0 °C to a
solution of the sulfoxide 1 (383.2 mg, 0.961 mmol) in CH2Cl2
(8.5 mL). After stirring at the same temperature for 25 min, the
reaction was treated with an aqueous solution of NaHCO3 (0.5
M,
11 mL, 5.72 equiv.). The mixture was left at ambient temperature
for 2 h and then diluted with water (10 mL) and CH2Cl2 (10 mL).
The organic layer was washed with water (3 × 15 mL), brine (5 mL),
dried (Na2SO4), filtered and concentrated under reduced pressure.
The crude yellow oil was purified by chromatography column on
silica gel (CH2Cl2) to leave the aldehyde 60 (263.0 mg, 99.7 %) as a
colorless oil. [α]2D0 = +7.8 (c = 0.81, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 9.49 (s, 1 H, CHO), 4.97 (d, J = 2.9 Hz, 1 H, H-22), 3.56 (AB of a
degenerated ABX system, 2 H, H-25), 2.49 (m, 1 H, H-23), 2.19 (s, 3
H, AcO), 0.97 (d, J = 7.0 Hz, 3 H, Me-24), 0.87 (s, 9 H, tBu-Si), 0.03 (s,
6 H, 2 × Me-Si). 13C NMR (75 MHz, CDCl3): δ = 197.7 (CHO), 170.7
(COOMe), 79.9 (CH-22), 63.6 (CH2-25), 38.2 (CH-23), 25.8 [C(CH3)3Si],
20.6 (MeCO), 18.3 [C(Me)3Si], 13.2 (Me-24), –5.7 (2 × MeSi). HR Mass
spectrum (ESI), m/z 297.1482 [M + Na]+ (C13H26O4SiNa+ requires
297.1493).
4
2.99 (m, 1 H, H-34), 2.03 (s, 3 H, AcO), 1.54 (d, JMe-36 = 1.5 Hz, 3 H,
Me-38), 1.20 (d, JMe-39 = 6.5 Hz, 3 H, Me-40), 1.10 (d, JMe-34 = 6.6 Hz,
3 H, Me-35). 13C NMR (125 MHz, CDCl3): δ = 170.1 (CO), 140.0 (Cq),
135.2 (Cq), 133.5 (CH arom), 129.2 (CH arom), 129.1 (CH vinyl, C-36),
127.9 (CH arom), 74.5 (CH-39), 62.3 (CH2-33), 27.9 (CH-34), 21.3
(AcO), 20.7 (Me-35), 18.9 (Me-40), 12.1 (Me-38). HR Mass spectrum
(ESI), m/z 333.1122 [M + Na]+ (C16H22O4SNa+ requires 333.1131).
(2S,5R,E)-3,5-Dimethyl-6-(phenylsulfonyl)hex-3-en-2-ol (58): The
sulfone acetate 57 (218.6 mg, 0.704 mmol) was treated in dry meth-
anol (5 mL) with anhydrous potassium carbonate (356.0 mg,
3.6 equiv.). The heterogeneous solution was stirred at room temper-
ature for 4 h until no starting material was detected (TLC). After
filtration of the mixture over a pad of Celite surmounted by silica
gel to remove the carbonate, the filtrate was concentrated. The resi-
due was purified by chromatography on a silica gel column AcOEt/
cyclohexane, 1:1 to give the alcohol 58 (158.1 mg, 83.7 %) as a
colorless oil. [α]2D0 = –3.5 (c = 1.11, CHCl3). 1H NMR (500 MHz, CDCl3):
δ = 7.88–7.86 (m, 2 H, Ph), 7.66–7.63 (m, 1 H, Ph), 7.57–7.54 (m, 2
H, Ph), 5.2 (d, J = 9.3 Hz, 1 H, H-36), 4.01 (q, J39-40 = 6.8 Hz, 1 H, H-
39), 3.08 (degenerated ABX, 2 H, H-33), 3.02 (m, 1 H, H-34), 1.54 (d,
4JMe-36 = 1.4 Hz, 3 H, Me-38), 1.16 (d, JMe-39 = 6.4 Hz, 3 H, Me-40),
1.09 (d, JMe-34 = 6.7 Hz, 3 H, Me-35). 13C NMR (125 MHz, CDCl3): δ =
140.0 (Cq), 139.5 (Cq), 133.5 (CH arom), 129.0 (CH arom), 127.9 (CH
arom), 126.5 (CH vinyl, C-36), 72.4 (CH-39), 62.4 (CH2-33), 27.8 (CH-
34), 21.4 (Me-35), 20.9 (Me-40), 12.2 (Me-38). Mass spectrum (ESI),
m/z 291.1054 [M + Na]+ (C14H20O3SNa+ requires 291.1025).
(2S,3R,E)-6-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)-2-methyl-
hex-4-en-3-yl Acetate (61): A solution of KHMDS (0.5
M in toluene,
0.42 mL, 1.1 equiv.) was added into a suspension of [2-(benzyl-
oxy)ethyl]triphenylphosphonium bromide (102 mg, 1.1 equiv.) in
dry THF (2 mL) at – 65 °C. The homogeneous yellow mixture was
stirred 15 min before the addition of the aldehyde 60[7] (53.2 mg,
0.193 mmol) in dry THF (1.5 mL). Stirring was continued for 1.5 h
allowing the temperature to rise – 10 °C and during which time
total consumption of the aldehyde was observed (TLC). The reac-
tion was quenched with a saturated solution NH4Cl (2 mL) and
water (5 mL), diluted with AcOEt (5 mL). The aqueous layer was
acidified with a 10 % aqueous solution of HCl (0.3 mL) to pH = 3.
The organic phase was washed with water (2 × 5 mL), brine (5 mL),
dried with MgSO4, filtered and concentrated under reduced pres-
sure. The crude product was purified on silica gel chromatography
(CH2Cl2 as eluent) to yield the olefin 61 (60.8 mg, 80.2 %) as a yel-
low liquid. [α]2D0 = +33.9 (c = 2.81, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.4–7.3 (m, 5 H, Ph), 5.81 (m, 1 H, H-20), 5.45 (m, 2 H, H-22 and
H-21), 4.55 and 4.49 (AB system, JAB = 11.7 Hz, Δν = 12.5 Hz, 2 H,
PhCH2O), 4.25 (m, 2 H, H-19), 3.49 (d, J = 5.5 Hz, 2 H, H-25), 2.02 (s,
3 H, AcO), 1.90 (m, 1 H, H-23), 0.89 (s, 9 H, tBu-Si), 0.88 (d, J = 7.0 Hz,
3 H, Me-24), 0.02 (s, 6 H, 2 × Me-Si). 13C NMR (125 MHz, CDCl3): δ =
tert-Butyl[(2S,5R,E)-3,5-Dimethyl-6-(phenylsulfonyl)hex-3-en-2-
yloxy]dimethylsilane (59): A catalytic amount of dimethylamino-
pyridine (DMAP, 12.5 mg, 0. 17 equiv.), imidazole (281.7 mg,
7.2 equiv.) and tert-butyldimethylsilyl chloride (447.0 mg, 5.2 equiv.)
were successively added to a solution of alcohol 58 (152.9 mg,
0.569 mmol) in CH2Cl2 (10 mL). The resulting heterogeneous solu-
tion was stirred for 3.5 h at ambient temperature before to be di- 170.0 (CO), 138.3 (Cq arom), 131.7 (vinyl CH-20), 128.3 (CH arom),
luted with CH2Cl2 (5 mL) and water (10 mL). The organic phase was
washed with water (3 × 5 mL), brine (5 mL), dried (MgSO4), filtered
and concentrated under reduced pressure. After purification of the
128.2 (vinyl CH-21), 127.8 (CH arom), 127.5 (CH arom), 72.5
(OCH2Ph), 71.1 (CH-22), 66.5 (CH2-19), 64.1 (CH2-25), 39.5 (CH-23),
25.8 [C(CH3)3Si], 21.1 (MeCO), 18.2 [C(Me)3Si], 12.4 (Me-24), –5.4
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(MeSi), –5.5 (MeSi). Mass spectrum (ESI), m/z 415.2261 [M + Na]+
20), 1.75 (m, 1 H, H-21a), 1.68 (m, 1 H, H-23), 1.50 (m, 1 H, H-21b),
0.86 (d, J = 6.9 Hz, 3 H, Me-24). 13C NMR (125 MHz, CDCl3): δ =
137.7 (Cq arom), 128.4 (CH arom), 127.8 (CH arom), 77.3 (CH-22),
73.2 (OCH2Ph), 70.6 (CH2-19), 68.0 (CH2-25), 40.0 (CH-23), 33.2 (CH2-
21), 26.0 (CH2-20), 14.0 (Me-24). Mass spectrum (ESI), m/z 319.1340
[M + K]+ (C16H24O4K+ requires 319.1306).
(C22H36O4SiNa+ requires 415.2275).
(2S,3R,E)-6-(Benzyloxy)-1-hydroxy-2-methylhex-4-en-3-yl Acet-
ate (62): A solution of TBAF (1
M in THF, 0.15 mL) was added drop-
wise to a chilled (0 °C) solution of compound 61 (38.4 mg,
0.0978 mmol) in dry THF (2 mL). The temperature rises slowly the
ambient during 2.5 h. After complete conversion of the starting
material (TLC) the reaction was quenched with water (5 mL), an
aqueous saturated solution of NaHCO3 (0.1 mL) and diluted with
AcOEt (8 mL). The organic layer was washed with water (5 mL),
(2R,3R)-6-(Benzyloxy)-1-iodo-2-methylhexan-3-ol (65): Imidaz-
ole (35.5 mg, 3.14 equiv.), triphenylphosphonium (49.8 mg,
1.14 equiv.) and iodine (49.2 mg, 1.16 equiv.) dissolved in dry THF
(1 mL) were successively added to a solution of 64 (39.5 mg,
brine (5 mL), dried with Na2SO4, filtered and concentrated under 0.165 mmol) in dry THF (2 mL). The mixture was stirred for 1.5 h at
reduced pressure. The crude was purified by chromatography on room temperature before to be quenched with an aqueous solution
silica gel (diethylether/cyclohexane, 6:1) to give the alcohol 62 as a
of Na2S2O3·5H2O (1 M, 0.5 mL), water (4 mL) and diluted with AcOEt
colorless oil (24.3 mg, 89.3 %). [α]2D0 = +3.60 (c = 0.79, CH2Cl2). 1H (8 mL). The organic layer was washed with water (2 × 5 mL), brine
NMR (500 MHz, CDCl3): δ = 7.37–7.29 (m, 5 H, Ph), 5.79 (m, 1 H, H-
20), 5.62 (m, 1 H, H-21), 4.55 and 4.52 (AB system, JAB = 11.7 Hz,
Δν = 10.1 Hz, 2 H, OBn), 4.25 (m, 1 H, H-22), 4.16 (m, 2 H, H-19a
and H-25a), 4.05 (m, 2 H, H-19b and H-25b), 2.28 (d, J = 3.2 Hz, 1
H, OH), 2.04 (s, 3 H, AcO), 1.92 (m, 1 H, H-23), 0.89 (d, J = 7.0 Hz, 3
H, Me-24). 13C NMR (125 MHz, CDCl3): δ = 171.3 (CO), 137.8 (Cq
(5 mL), dried with Na2SO4, filtered and concentrated under reduced
pressure. The crude was purified over silica gel chromatography
column (AcOEt/cyclohexane, 1:3) to yield the iodide 65 as a color-
less liquid (45.3 mg, 78.8 %). [α]2D0 = –2.25 (c = 1.13, CH2Cl2). 1H
NMR (500 MHz, CDCl3): δ = 7.37–7.27 (m, 5 H, Ph), 4.53 (s, 2 H, OBn),
3.53 (t, J = 5.7 Hz, 2 H, H-19), 3.43 (m, 1 H, H-22), 3.39 (AB part of
arom), 133.7 (CH-21 vinyl), 129.3 (CH-20 vinyl), 128.4 (CH arom), an ABX system, J25a-25b = 9.5 Hz, J25a-23 = 6.5 Hz, J25b-23 = 3.7 Hz,
127.8 (CH arom), 72.5 (OCH2Ph), 68.9 (CH-22), 66.1 (CH2-19 or CH2- Δν = 18.9 Hz, 2 H, H-25), 2.75 (d, J = 4.9 Hz, 1 H, OH), 1.76 (m, 2 H,
25), 65.8 (CH2-19 or CH2-25), 38.7 (CH-23), 20.9 (OAc), 13.0 (Me-24). H-20), 1.75 (m, 1 H, H-21a), 1.49 (m, 1 H, H-21b), 1.44 (m, 1 H, H-
Mass spectrum (ESI), m/z 301.1367 [M + Na]+ (C16H22O4Na+ requires
301.1410).
23), 0.98 (d, J = 6.6 Hz, 3 H, Me-24). 13C NMR (125 MHz, CDCl3): δ =
137.9 (Cq arom), 128.4 (CH arom), 127.8 (CH arom), 127.7 (CH arom),
74.3 (CH-22), 73.2 (OCH2Ph), 70.4 (CH2-19), 40.3 (CH-23), 31.7 (CH2-
21), 26.1 (CH2-20), 17.5 (Me-24), 15.3 (CH2-25). Mass spectrum (ESI),
(2S,3R)-6-(Benzyloxy)-1-hydroxy-2-methylhexan-3-yl Acetate
(63): Solid CoCl2·6H2O (31.2 mg, 1.37 equiv.) was added to a solu-
tion of the olefin 62 (26.6 mg, 0.0955 mmol) in methanol (1.4 mL)
m/z 349.0625 [M + H]+ (C14H22IO2 requires 349.0659).
+
at 0 °C. Solid NaBH4 (9.3 mg, 2.57 equiv.) was added carefully by [(2R,3R)-6-(Benzyloxy)-1-iodo-2-methylhexan-3-yloxy](tert-
portions and the resulting dark solution was stirred for 3 h at room
temperature. The reaction was quenched with an aqueous solution
of HCl (3 N, 0.1 mL), brine (2 mL) and diluted with AcOEt (5 mL).
The aqueous solution extracted with AcOEt (5 mL) and the com-
bined organic layers were concentrated to remove the MeOH. The
residue was diluted with AcOEt (5 mL), washed with water (2 ×
butyl)dimethylsilane (66): To a chilled (0 °C) solution of alcohol
65 (24.6 mg, 0.0706 mmol) in dry DMF (1.8 mL) were successively
added imidazole (47.4 mg, 9.8 equiv.), DMAP (15 mg, 1.7 equiv.)
and a solution of tert-butyldimethylsilyl chloride (52 mg, 4.9 equiv.)
in dry DMF (0.6 mL). The reaction was stirred at room temperature
for 15 h and then diluted with diethylether (15 mL) and quenched
4 mL), brine (4 mL), dried with Na2SO4, filtered and concentrated with water (10 mL). The organic layer was washed with water (2 ×
under reduced pressure. The crude was purified by chromatography
on silica gel (diethylether/cyclohexane, 1:3) to give the unsaturated
product 63 as a colorless liquid (15.6 mg, 58.3 %). [α]D = +7.86 (c =
5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated under
reduced pressure. The crude was purified by silica gel chromatogra-
phy column (AcOEt/cyclohexane, 1:2) to afford the silylated product
66 (21.2 mg, 64.9 %) as a colorless liquid. [α] = –3.46 (c = 1.04,
1
0.89, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H, Ph),
1
4.52 (s, 2 H, OBn), 4.15 (AB part of an ABX system, J25a-25b = 11.0 Hz,
J25a-23 = 6.0 Hz, J25b-23 = 5.0 Hz, Δν = 21.6 Hz, 2 H, H-25), 3.52 (t,
J = 5.8 Hz, 2 H, H-19), 3.47 (m, 1 H, H-22), 2.79 (d, J = 4.6 Hz, 1 H,
OH), 2.06 (s, 3 H, AcO), 1.83 (m, 1 H, H-23), 1.76 (m, 2 H, H-20), 1.72
CHCl3). H NMR (300 MHz, CDCl3): δ = 7.35–7.28 (m, 5 H, Ph), 4.51
(s, 2 H, OBn), 3.73 (m, 1 H, H-22), 3.47 (m, 2 H, H-19), 3.17 (AB part
of an ABX system, J25a-25b = 9.4 Hz, J25a-23 = 7.5 Hz, J25b-23 = 6.1 Hz,
Δν = 65.9 Hz, 2 H, H-25), 1.85 (m, 1 H, H-23), 1.60 (m, 1 H, H-20a),
(m, 1 H, H-21a), 1.47 (m, 1 H, H-21b), 0.95 (d, J = 7.0 Hz, 3 H, Me- 1.54 (m, 1 H, H-20b), 1.51 (m, 2 H, H-21), 0.98 (d, J = 6.8 Hz, 3 H,
24). 13C NMR (125 MHz, CDCl3): δ = 171.4 (CO), 138.1 (Cq arom),
128.4 (CH arom), 127.7 (CH arom), 73.0 (OCH2Ph), 72.9 (CH-22), 70.4
Me-24),0.89 (s, 9 H, tBu-Si), 0.08 (Me-Si), 0.06 (Me-Si). 13C NMR
(75 MHz, CDCl3): δ = 138.5 (Cq arom), 128.3 (CH arom), 127.6 (CH
(CH2-19), 66.7 (CH2-25), 38.7 (CH-23), 31.6 (CH2-21), 26.2 (CH2-20), arom), 127.5 (CH arom), 74.0 (CH-22), 72.9 (OCH2Ph), 70.2 (CH2-19),
21.0 (OAc), 13.8 (Me-24).
41.0 (CH-23), 30.3 (CH2-21), 25.9 [C(CH3)3Si], 25.8 (CH2-20), 18.1
[C(Me)3Si], 14.7 (Me-24), 12.6 (CH2-25), –4.2 (SiMe), –4.4 (SiMe).
C20H35IO2Si (462.480 ): calcd. C 51.94, H 7.63; found C 52.35, H 7.86.
(2S,3R)-6-(Benzyloxy)-2-methylhexane-1,3-diol (64): The acetate
63 (77 mg) dissolved in dry MeOH (8 mL) was treated with solid
K2CO3 (140.3 mg, 3.8 equiv.). The reaction mixture was stirred for
3 h and then the solvent was removed by evaporation. The residue
was diluted with diethylether and filtered through a pad of silica.
After evaporation of the solvent the crude was purified chromatog-
raphy on silica gel (AcOEt/cyclohexane, 1:1) to give the diol 64 as
a colorless liquid (49 mg, 74.8 %). [α]D = +19.6 (c = 0.8, CHCl3).
C14H22O3 (238.329): calcd. C 70.56, H 9.3; found C 68.89, H 8.93. H
NMR (500 MHz, CDCl3): δ = 7.37–7.28 (m, 5 H, Ph), 4.53 (s, 2 H, OBn),
3.80 (br. s, 1 H, OH), 3.66 (AB part of an ABX system, J25a-25b
10.7 Hz, J25a-23 = 7.2 Hz, J25b-23 = 3.7 Hz, Δν = 36.0 Hz, 2 H, H-25),
(S)-Methyl 3-Acetoxy-4-[(R)-p-tolylsulfinyl]butanoate (68): Tri-
ethylamine (0.40 mL, 3.0 equiv.) and anhydride acetic (0.22 mL,
2.45 equiv.) were successively added to a solution of sulfoxide 67
(243.3 mg, 1.086 mmol) and DMAP (14.7 mg, 0.12 equiv.) in CH2Cl2
(6 mL). The solution was stirred at room temperature during 45 min
(reaction monitored by TLC) and then quenched with water (10 mL)
and diluted with CH2Cl2 (5 mL). Stirring was continue for 1.5 h and
the organic layer was washed with water (3 × 10 mL), brine (5 mL),
dried with MgSO4, filtered and concentrated under reduced pres-
sure. The crude material was purified on silica gel chromatography
(AcOEt/cyclohexane, 1:1) to afford a colorless oil of the acetate 68
1
=
3.51 (m, 3 H, H-19 and H-22), 3.28 (br. s, 1 H, OH), 1.76 (m, 1 H, H-
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(241.1 mg, 85.1 %). [α]D20 = +142.3 (c = 0.94, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.53 and 7.33 (AA′BB′, J = 8.3 Hz, Δν =
of 71 (1.784; 87.8 %). [α]2D0 = +0.89 (c = 1.12, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 4.23 (dddd, X part of an ABX system, J31-32a
=
101.6 Hz, 4 H, pTol), 5.59 (m, 1 H, H-31), 3.67 (s, 3 H, MeO), 3.09 (AB J31-32b = J31-30a = J31-30b = 5.6 Hz, 1 H, H-31), 3.80 (AB part of an
part of an ABX system, J30a-30b = 13.5 Hz, J30a-31 = 6.2 Hz, J30b-31
=
ABX system, JAB = 5.3 Hz, JAX = 4.9 Hz, JBX = 4.0 Hz, Δν = 109 Hz,
2 H, H-32), 3.75 (m, 2 H, H-29), 2.56 (br. s, 1 H, OH), 1.80 (m, 2 H, H-
30),1.39 (s, 3 H, Me), 1.33 (s, 3 H, Me). 13C NMR (75 MHz, CDCl3): δ =
4.0 Hz, Δν = 14.0 Hz, 2 H, H-30), 2.80 (AB part of an ABX system,
J32a-32b = 15.3 Hz, J32a-31 = 6.5 Hz, J32b-31 = 5.8 Hz, Δν = 59.8 Hz, 2
H, H-32), 2.41 (s, 3 H, Me of pTs), 2.05 (s, 3 H, Me of Ac). 13C NMR 109.0 (Cq acetonide), 74.9 (CH-O), 69.4 (CH2-O), 60.3 (CH2-O), 35.7
(125 MHz, CDCl3): δ = 169.8 (CO), 141.9 (Cq arom), 140.4 (Cq arom),
130.1 (CH arom), 123.9 (CH arom), 65.7 (CH-31), 61.3 (CH2-30),
52.0 (OMe), 38.4 (CH2-32), 21.4 (Me of pTs), 20.8 (Me of Ac). Mass
spectrum (ESI), m/z 321.0745 [M + Na]+ (C14H18O5SNa+ requires
321.0767).
(CH2), 26.9 (Me), 25.7 (Me).
(S)-4-(2-Iodoethyl)-2,2-dimethyl-1,3-dioxolane (72):[36d,36e] Imid-
azole (0.69 g, 2.26 equiv.) and triphenylphosphine (1.34g,
1.14 equiv.) were added successively to a solution of alcohol 71
(0.78 g, 0.00447 mol) in diethylether/acetonitrile (20 mL/5 mL). Iod-
ine (1.31 g, 1.15 equiv.) was added at 0 °C to this colorless solution
which turned to an orange mixture with a white precipitate. After
a few minutes, the reaction was then stirred at room temperature
for 7 h before to be quenched with water (25 mL) and aq.
(S)-Methyl 3-Acetoxy-4-hydroxybutanoate (69a) and (S)-Methyl
4-Acetoxy-3-hydroxybutanoate (69b): Triethylamine (0.2 mL,
3.2 equiv.) and trifluoroacetic anhydride (0.2 mL, 3.2 equiv.) were
added successively to a chilled (0 °C) solution of sulfoxide 68
(132.5 mg, 0.444 mmol) in CH2Cl2 (5 mL). After 10 min, an aqueous
Na2S2O3·5H2O (2
M, 1 mL) and diluted with diethylether (30 mL).
Stirring was continue for 30 min and the aqueous layer was ex-
tracted with diethylether (10 mL). The combined organic layers
were washed with water (2 × 25 mL), brine (5 mL), dried (MgSO4)
filtered and concentrated under reduced pressure. The crude resi-
due was purified on a silica gel column (diethylether/pentane, 5:1)
to afford 72 as a colorless liquid (1.04 g; 90.8 %). [α]2D0 = –23.0 (c =
solution of NaHCO3 (0.5
M, 3.4 mL, 3.8 equiv.) was added. Stirring
was continued for 20 min at 0 °C and solid NaBH4 (64.5 mg,
3.8 equiv.) was slowly added. After 25 min at 0 °C, water (10 mL)
and CH2Cl2 (5 mL). The aqueous layer was extracted with CH2Cl2
(5 mL) and the combined organic layers were washed with water
(3 × 6 mL), brine (5 mL), dried (MgSO4), filtered and concentrated
under reduced pressure. The crude was purified on silica gel by
chromatographic column (AcOEt/cyclohexane, 1:1) to give an iso-
meric mixture of 69 (35.7 mg, 45.6 %). NMR analysis for the major
1.22, CHCl3), [lit[36d]: [α]D20 = –22.3 (c = 2.12, CHCl3), lit[36e]: [α]2D0
=
1
–23.8 (c = 2.1, CHCl3)]. H NMR (300 MHz, CDCl3): δ = 4.16 (m, 1 H,
H-31), 3.81 (AB part of an ABX system, JAB = 7.8 Hz, JAX = 6.5 Hz,
JBX = 6.0 Hz, Δν = 159 Hz, 2 H, H-32), 3.23 (m, 2 H, H-29), 2.06 (m,
2 H, H-30), 1.39 (s, 3 H, Me), 1.34 (s, 3 H, Me). 13C NMR (75 MHz,
CDCl3): δ = 109.1 (Cq acetonide), 75.6 (CH-31), 68.6 (CH2-32), 37.9
(CH2-30), 26.9 (Me), 25.7 (Me), 1.21 (CH2-29).
1
isomer: H NMR (500 MHz, CDCl3): δ = 4.25 (m, 1 H, H-31), 4.08 (AB
part of an ABX system, J30a-30b = 11.7 Hz, J30a-31 = 4.2 Hz,
J30b-31 = 6.0 Hz, Δν = 21.9 Hz, 2 H, H-30), 3.70 (s, 3 H, OMe), 2.55–
2.48 (degenerated ABX, 2 H, H-32), 2.07 (s, 3 H, Me of Ac). 13C NMR
(125 MHz, CDCl3): δ = 172.4 (CO), 171.0 (CO), 67.0 (CH2-30), 66.2
(CH-31), 52.0 (OMe), 37.6 (CH2-32), 20.8 (Me of Ac).
(S)-2-[5-(2,2-Dimethyl-1,3-dioxolan-4-yl)pentan-2-ylidene]-1,1-
dimethylhydrazine (73):[36e,37] Butyllithium (1.65 mL of a 1.6
M
cyclohexane solution, 1.97 equiv.) was added dropwise to a solution
of acetone N,N-dimethyl hydrazone (283 mg, 2.1 equiv.) in dry THF
(5 mL) at – 55 °C. Rapidly a white precipitate was formed and this
heterogeneous solution was stirred for 40 min. leaving the tempera-
ture to reach –30 °C. The reaction mixture was cooled back to
– 55 °C and treated with a solution of iodide 72 (343.1 mg, 1 equiv.)
The heterogeneous solution was warmed to room temperature dur-
ing 1.5 h and became a yellow homogeneous solution after 20 min.
The reaction was diluted with diethylether (10 mL) and quenched
with distilled water (5 mL). The aqueous layer was extracted with
diethylether (5 mL) and the combined organic layers were dried
(MgSO4), filtered and concentrated under reduced pressure. The
crude material was purified by filtration through a pad of neutral
alumina with diethylether as eluant to afford a mixture of (E) and
(Z) of 73 as a lemon liquid (290.8 mg, 95.1 %) which can be stored
at – 20 °C. Neutral alumina was preferred to silica gel to prevent
partial hydrolysis of the hydrazone function to yield the by-product
ketone 74. However silica gel (treated with 2 % of NEt3) can be
used to give 73 with the same range of yield. 1H NMR (500 MHz,
CDCl3): δ = 4.06 (m, 1 H, H-31), 4.01 (m, 1 H, H-32a), 3.48 (app t, J =
7.3 Hz, 1 H, H-32b), 2.40 (s, 3 H, NMe2), 2.20 (t, J = 7.4 Hz, 2 H, H-
28), 1.92 (s, 3 H, Me-26),1.63 (m, 1 H, H-30a),1.59 (m, 1 H, H-29a),
1.51 (m, 1 H, H-30b),1.50 (m, 1 H, H-29b), 1.37 (s, 3 H, Me acetonide),
1.32 (s, 3 H, Me acetonide). 13C NMR (125 MHz, CDCl3): δ = 167.2
(C=N), 108.6 (Cq acetonide), 75.7 (CH-31), 69.3 (CH2-32), 47.0 (Me of
NMe2), 38.8 (CH2-28), 33.2 (CH2-30), 26.9 (Me of acetonide), 25.6 (Me
of acetonide), 23.1 (CH2-29), 16.5 (Me-26). 1H NMR (500 MHz, C6D6):
δ = 3.87 (m, 1 H, H-31), 3.76 (m, 1 H, H-32a), 3.31 (app t, J = 7.7 Hz,
1 H, H-32b), 2.40 (s, 3 H, NMe2), 2.05 (t, J = 7.3 Hz, 2 H, H-28), 1.73
(s, 3 H, Me-26), 1.63 (m, 1 H, H-29a), 1.48 (m, 1 H, H-30a), 1.47 (m,
1 H, H-29b), 1.42 (s, 3 H, Me acetonide), 1.33 (s, 3 H, Me acetonide),
(S)-Methyl 2-(2,2-Dimethyl-1,3-dioxolan-4-yl)acetate (70):[36a–
36c]
The isomeric mixture of ester 69 (67.2 mg, 0.381 mmol) was
diluted in MeOH (1 mL) and dimethoxypropane (1 mL) with a cata-
lytic amount of pTsOH. The clear solution was stirred at room tem-
perature for 3 days before the evaporation of all the solvents. The
residue was diluted in AcOEt (5 mL) and washed with water (2 ×
5 mL), brine (3 mL), dried (MgSO4) and concentrated under reduced
pressure to give the acetonide 70 (37.8 mg, 56.9 %) which is pure
enough according NMR analysis and optical rotation. [α]2D0 = +12.4
(c = 0.88, CHCl3), [lit[36a]: [α]D20 = +9.0 (c = 0.2, CHCl3), lit[36b]: [α]2D0
=
+17.0 (c = 2.00, CHCl3)]. 1H NMR (500 MHz, CDCl3): δ = 4.47 (m, 1
H, H-31), 3.90 (AB part of an ABX system, JAB = 8.3 Hz, JAX = 6.3 Hz,
JBX = 6.1 Hz, Δν = 183.7 Hz, 2 H, H-32), 3.70 (s, 3 H, OMe), 2.62 (AB
part of an ABX system, JAB = 16.0 Hz, JAX = 7.0 Hz, JBX = 6.5 Hz,
Δν = 70.9 Hz, 2 H, H-30), 1.41 (s, 3 H, Me), 1.35 (s, 3 H, Me). 13C
NMR (125 MHz, CDCl3): δ = 171.1 (CO), 109.2 (Cq acetonide), 72.0
(CH-31), 69.1 (CH2-32), 51.8 (MeO), 38.8 (CH2-30), 26.9 (Me aceton-
ide), 25.5 (Me acetonide).
(S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol (71):[36a,36c–36e]
A
solution of the ester 70 (2.437 g; 0.0139 mol, 1 equiv.) in dry THF
(30 mL) was added dropwise to a suspension of LiAlH4 (0.630 g,
1.19 equiv.) in dry THF (50 mL) at 0 °C. The reaction was stirred at
ambient temperature during 3 h and then carefully quenched by
slow addition of a solution of THF/H2O (14 mL:14 mL). A white
precipitate occurred and stirring was continue for 0.5 h. The precipi-
tate was filtered off and rinsed with AcOEt. The filtrate was passed
on Celite and rinsed again with AcOEt before to be dried on Na2SO4,
filtered and concentrated under reduced pressure. The light yellow
residue was purified by distillation with a Kugelrohr apparatus
(108 °C; 2.2 mbar) to give the title compound as a colorless liquid
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1.29 (m, 1 H, H-30b). 13C NMR (125 MHz, C6D6): δ = 166.2 (C=N), (Benzyloxy)propyl]-9-methyl-1,7-dioxaspiro[5.5]undecan-2-
109.1 (Cq acetonide), 76.4 (CH-31), 70.0 (CH2-32), 47.5 (Me of NMe2),
39.1 (CH2-28), 33.8 (CH2-30), 27.7 (Me of acetonide), 26.4 (Me of
acetonide), 23.5 (CH2-29), 16.8 (Me-26).
yl}methyl 2,2,2-Trifluoroacetate (77): Trifluoroacetic acid (60 μL)
was added dropwise to a solution of ketone 75 (18.1 mg,
0.0347 mmol) in dichloromethane (2 mL). The solution was stirred
at ambient temperature for 2.5 h during which time a mixture of
the desired alcohol and its trifluoroacetate ester were formed. The
reaction was quenched with a saturated aqueous solution of NaH-
CO3 (1 mL) and diluted with water (2 mL) and AcOEt (5 mL). The
organic phase was washed with water (2 × 4 mL), brine (4 mL),
dried (MgSO4), filtered and concentrated under reduced pressure.
The residue, containing a mixture of 76 and 77, was dissolved in
THF (1 mL) and MeOH (0.2 mL). Solid K2CO3 (9.8 mg) was added
and the mixture was stirred at room temperature for 1 h. The solu-
tion was filtered through Celite, washed with diethyl ether (5 mL),
and then concentrated to dryness. The crude material was purified
on silica gel chromatography column (AcOEt/cyclohexane, 1:5 as
eluent) to give 76 as a colorless oil (10.2 mg, 84.3 %). [α]2D0 = +52.4
(c = 1.04, CHCl3). NMR analysis for 76: 1H NMR (500 MHz, CDCl3):
δ = 7.35–7.27 (m, 5 H, Ph), 4.51 (s, 2 H, CH2Ph), 3.67 (m, 1 H, H-31),
3.56 (dd, J = 11.2 Hz, J = 3.4 Hz, A part of an ABX system, 1 H, H-
32a), 3.50 (m, 2 H, H-19), 3.48 (m, B part of an ABX system, 1 H, H-
32b), 3.20 (td, J = 9.9 Hz, J = 2.5 Hz, 1 H, H-22), 1.96 (m, 1 H, H-20a),
1.89 (m, 1 H, H-29a), 1.74 (m, 1 H, H-21a), 1.64 (m, 1 H, H-20b), 1.62
(m, 1 H, H-26a), 1.57 (m, 1 H, H-29b), 1.50 (m, 1 H, H-25), 1.49 (m, 1
H, H-26b), 1.46 (m, 1 H, H-30a), 1.39 (m, 1 H, H-28), 1.33 (m, 1 H, H-
21b), 1.26 (m, 1 H, H-30b), 0.83 (d, J = 6.4 Hz, 3 H, Me-24). 13C NMR
(125 MHz, CDCl3): δ = 138.6 (Cq arom), 128.3 (CH arom), 127.6 (CH
arom), 127.5 (CH arom), 95.5 (Cq acetonide), 74.5 (CH-22), 72.9 (CH2-
Ph), 70.7 (CH2-19), 69.6 (CH-31), 66.2 (CH2-32), 35.8 (CH2-26), 35.5
(CH2-28), 35.0 (CH-23), 29.7 (CH2-21), 28.0 (CH2-25), 26.5 (CH2-30),
26.1 (CH2-20), 18.4 (CH2-29), 17.9 (Me-24). NMR analysis for 68: 1H
NMR (500 MHz, CDCl3): δ = 7.34–7.25 (m, 5 H, Ph), 4.52 (s, 2 H,
(S)-5-(2,2-Dimethyl-1,3-dioxolan-4-yl)pentan-2-one (74): The
hydrazone 73 was prepared as described above, from iodide 72
(128.2 mg, 0.500 mmol), acetone N,N-dimethyl hydrazone
(104.9 mg, 2 equiv.) and nBuLi (0.65 mL of a 1.6M solution in hex-
anes, 2 equiv.). The mixture was diluted with water and quenched
by a saturated NH4Cl aqueous solution (2 mL). An aqueous 10 %
HCl solution (0.9 mL) was slowly added until pH 6–7. Stirring was
continued at room temperature for 2 h and AcOEt (4 mL) was
added. The organic layer was washed with water (5 mL × 2), brine
(4 mL), dried (MgSO4), filtered and concentrated under reduced
pressure. The crude material was purified by chromatography on
silica gel column (AcOEt/cyclohexane, 2:3 as eluant) to afford the
ketone 74 as a pale yellow liquid (56.5 mg, 60.7 %). [α]2D0 = +18.7
1
(c = 1.2, CHCl3). H NMR (500 MHz, CDCl3): δ = 4.05 (m, 1 H, H-31),
4.01 (m, 1 H, H-32a), 3.48 (app t, 1 H, J = 7.2 Hz, H-32b), 2.47 (t, J =
6.9 Hz, 2 H, H-28), 2.12 (s, 3 H, Me-26), 1.66 (m, 1 H, H-29a), 1.57
(m, 1 H, H-29b), 1.56 (m, 1 H, H-30a), 1.52 (m, 1 H, H-30b), 1.37 (s,
3 H, Me acetonide), 1.32 (s, 3 H, Me acetonide). 13C NMR (125 MHz,
CDCl3): δ = 208.5 (CO), 108.7 (Cq acetonide), 75.7 (CH-31), 69.3 (CH2-
32), 43.3 (CH2-28), 32.8 (CH2-30), 29.9 (Me-CO), 26.9 (Me-acetonide),
25.6 (Me-acetonide), 19.9 (CH2-29). Mass spectrum (ESI), m/z
209.1142 [M + Na]+ (C10H18NaO5 requires 209.1148).
+
(7S,8R)-11-(Benzyloxy)-8-(tert-butyldimethylsilyloxy)-1-[(S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-7-methylundecan-4-one (75): The
hydrazone 73 (337.3 mg, 1.47 mmol) in THF (3 mL) was added
dropwise to a cooled solution (–78 °C) of LDA (prepared from nBuLi,
1.4M in hexanes, 2.4 mL and diisopropylamine, 0.5 mL) in THF
(3 mL). The resulting orange-red mixture was stirred for 1h at –78 °C
to –30 °C and at ambient temperature for 0.5 h and cooled again
to –78 °C. Then a solution of iodide 66 (319.8 mg, 0.691 mmol,
0.47 equiv.) in THF (4 mL) was added dropwise to the dianion solu-
tion. After 30 min the reaction was stirred at room temperature for
14 h before to be quenched with a saturated NH4Cl solution (2 mL).
Water (5 mL) and AcOEt (10 mL) were added followed by a 10 %
HCl aqueous solution (5 mL) until pH 5. The organic layer was
washed with water (6 mL), brine (5 mL), dried (MgSO4) and filtered
and concentrated under reduced pressure. The crude product was
purified by silica gel chromatography (AcOEt/cyclohexane, 1:5 as
CH2Ph), 4.27 (AB part of an ABX system, J32a-3b = 11.2 Hz, J32a-31
=
8.4 Hz, J32b-31 = 3.2 Hz, Δν = 60.5 Hz, 2 H, H-32), 3.88 (dddd, J =
11.9 Hz, J = 8.4 Hz, J = 3.0 Hz, J = 2.3 Hz, 1 H, H-31), 3.50 (t, J =
6.7 Hz, 2 H, H-19), 3.14 (td, J = 10.0 Hz, J = 2.6 Hz, 1 H, H-22), 1.94
(m, 1 H, H-20a), 1.91 (m, 1 H, H-29a), 1.73 (m, 1 H, H-21a), 1.61 (m,
3 H, H-20b, H-26a, H-29b), 1.53 (m, 1 H, H-30a), 1.46 (m, 2 H, H-25,
H-26b), 1.41 (m, 1 H, H-28), 1.33 (m, 1 H, H-21b), 1.28 (m, 1 H, H-
23), 1.25 (m, 1 H, H-30b), 0.83 (d, J = 6.6 Hz, 3 H, Me-24). 13C NMR
(125 MHz, CDCl3): δ = 157.3 (q, JCF = 42 Hz, CO-CF3), 138.6 (Cq
arom), 128.3 (CH arom), 127.6 (CH arom), 127.5 (CH arom), 154.3 (q,
JCF = 285.7 Hz, CO-CF3), 95.6 (Cq acetonide), 74.6 (CH-22), 72.9 (CH2-
eluent) to yield 75 as a light yellow oil (278.2 mg, 77.2 %). [α]D20
=
Ph), 70.7 (CH2-19), 70.1 (CH2-32), 66.7 (CH-31), 35.6 (CH2-26), 35.0
(CH2-28), 34.9 (CH-23), 29.7 (CH2-21), 27.6 (CH2-25), 26.4 (CH2-30),
26.2 (CH2-20), 18.4 (CH2-29), 17.6 (Me-24). Mass spectrum (ESI), m/z
1
+7.5 (c = 1, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.3–7.2 (m, 5 H,
Ph), 4.49 (s, 2 H, OCH2Ph), 4.07 (m, 1 H, H-31), 4.03 (m, 1 H, H-32a),
3.53 (m, 1 H, H-22), 3.51 (m, 1 H, H-32b), 3.46 (t, J = 6.5 Hz, 2 H, H-
19), 2.49–2.41 (m, 2 H, H-26a),2.44 (m, 2 H, H-28), 2.37–2.29 (m, 2 H,
H-26b),1.72–1.56 (m, 2 H, H-29), 1.69 (m, 1 H, H-20a), 1.61–1.47 (m,
2 H, H-30), 1.56 (m, 1 H, H-20b), 1.54 (m, 1 H, H-23), 1.45 (m, 2 H,
H-21), 1.39 (s, 3 H, Me acetonide), 1.34 (s, 3 H, Me acetonide), 1.31
(m, 2 H, H-25), 0.88 (s, 9 H, tBu-Si),0.85 (d, J = 6.9 Hz, 3 H, Me-24),
0.03 (s, 3 H, Me-Si),0.02 (s, 3 H, Me-Si). 13C NMR (100 MHz, CDCl3):
δ = 210.7 (CO), 138.6 (Cq arom), 128.3 (CH arom), 127.6 (CH arom),
127.4 (CH arom), 108.7 (Cq acetonide), 75.8 (CH-31 or CH-22), 75.7
(CH-31 or CH-22), 72.8 (CH2-Ph), 70.5 (CH2-19), 69.3 (CH2-32), 42.3
(CH2-28), 41.0 (CH2-26), 37.9 (CH-23), 32.9 (CH2-30), 28.8 (CH2-21),
26.9 (Me acetonide), 26.3 (CH2-25), 26.0 (CH2-20), 25.9 [C(CH3)3Si],
25.7 (Me acetonide), 20.0 (CH2-29), 18.1 [C(Me)3Si], 14.4 (Me-24),
–4.4 (MeSi), –4.5 (MeSi). Mass spectrum (ESI), m/z 543.3444 [M +
Na]+ (C30H52NaO5Si+ requires 543.3476).
371.2165 [M + Na]+ (C21H32NaO4 requires 371.2193).
+
(2R,3S,6R,8S)-2-[3-(Benzyloxy)propyl]-8-(iodomethyl)-3-methyl-
1,7-dioxaspiro[5.5]undecane (78): The alcohol 76 (52.3 mg,
0.150mmol) and imidazole (34.4 mg, 3.36 equiv.) were dissolved in
dry THF (5 mL) and triphenylphosphine (80.7 mg, 2.05 equiv.) was
added followed by a solution of iodine (76.9 mg, 2.01 equiv.) in dry
THF (2 mL). The heterogeneous orange solution was stirred for 17
h at ambient temperature. To the resulting colorless solution were
added an aqueous of Na2S2O3·5H2O (1 M, 1 mL), water (6 mL) and
AcOEt (10 mL). The organic layer was washed with water (3 × 5 mL),
brine (5 mL), dried (MgSO4), filtered and then concentrated to dry-
ness to leave a white solid which was triturated twice with diethyl-
ether. After filtration the combined ethereal solution was concen-
trated and the residue was purified on silica gel chromatography
column (AcOEt/cyclohexane, 1:5 as eluent) to give 78 as a colorless
oil (63.1 mg, 91.8 %). [α]2D0 = +56.6 (c = 1.31, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.35–7.27 (m, 5 H, Ph), 4.52 (s, 2 H, CH2Ph),
{(2S,6R,8R,9S)-8-[3-(Benzyloxy)propyl]-9-methyl-1,7-dioxa-
spiro[5.5]undecan-2-yl}methanol (76) and {(2S,6R,8R,9S)-8-[3-
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3.62 (m, 1 H, H-31), 3.51 (m, 2 H, H-19), 3.47 (td, J = 10.0 Hz, J = diethylether (15 mL) and water (10 mL). The aqueous layer was
2.4 Hz, 1 H, H-22), 3.12 (AB part of an ABX system, J32a-32b = 10.1 Hz,
J32a-31 = 9.1 Hz, J32b-31 = 3.6 Hz, Δν = 32.5 Hz, 2 H, H-32), 1.94 (m,
1 H, H-20a), 1.87 (m, 1 H, H-29a), 1.78 (m, 1 H, H-21a), 1.72 (m, 1 H,
H-30a), 1.66 (m, 1 H, H-20b), 1.65 (m, 1 H, H-25a), 1.55 (m, 2 H, H-
acidified with a 10 % HCl solution till pH = 2 and then extracted
with diethylether (5 mL). The combined organic layers were washed
with a saturated aqueous NH4Cl solution (10 mL), water (2 × 5 mL),
brine (5 mL), dried (MgSO4), filtered and concentrated under re-
28a and H-29b), 1.47 (m, 3 H, H-25b and H-26), 1.38 (m, 1 H, H-28), duced pressure. The residue was purified on silica gel chromato-
1.31 (m, 2 H, H-21b and H-23), 1.14 (m, 1 H, H-30b), 0.86 (d, J =
graphic column (AcOEt/cyclohexane, 1:9) to afford the alcohol 80
6.6 Hz, 3 H, Me-24). 13C NMR (125 MHz, CDCl3): δ = 138.6 (Cq arom),
(20 mg, 37.3 %) as a colorless oil. [α]2D0 = +30.1 (c = 0.81, CH2Cl2).
128.3 (CH arom), 127.7 (CH arom), 127.5 (CH arom), 96.2 (Cq aceton- 1H NMR (500 MHz, CDCl3): δ = 5.09 (d, J = 9.6 Hz, 1 H, H-36), 4.13
ide), 74.2 (CH-22), 72.9 (CH2-Ph), 70.7 (CH2-19), 69.1 (CH-31), 66.3 (q, J = 6.3 Hz, 1 H, H-39), 3.66 (m, 2 H, H-19), 3.46 (m, 1 H, H-31 or
(CH2-32), 35.8 (CH2-25), 35.1 (CH-23), 35.0 (CH2-28), 31.1 (CH2-30), 22), 3.22 (apt t, J = 10.5 Hz, 1 H, H-22 or 31), 2.32 (m, 1 H, H-34),
29.6 (CH2-21), 27.6 (CH2-26), 26.1 (CH2-20), 18.9 (CH2-29), 18.0 (Me-
1.83 (m, 1 H), 1.79 (m, 1 H), 1.76 (m, 1 H), 1.64 (m, 1 H), 1.62 (m, 1
24), 10.2 (CH2-32). Mass spectrum (ESI), m/z 481.1214 [M + Na]+ H), 1.58 (m, 1 H), 1.57 (m, 1 H), 1.56 (d, J = 1.2 Hz, 3 H, Me-38), 1.54
+
(C21H31INaO3 requires 481.1210).
(m, 1 H), 1.53 (m, 1 H), 1.48 (m, 1 H), 1.47 (m, 1 H), 1.46 (m, 1 H),
1.38 (m, 1 H), 1.37 (m, 1 H), 1.30 (m, 1 H), 1.25 (m, 2 H), 1.13 (m, 1
H), 1.17 (d, J = 6.3 Hz, 3 H, Me-40), 0.93 (d, J = 6.6 Hz, 3 H, Me-35),
0.87 (s, 9 H, tBu-Si), 0.83 (d, J = 6.6 Hz, 3 H, Me-24), 0.03 (s, 3 H, Me-
Si), 0.01 (s, 3 H, Me-Si). 13C NMR (125 MHz, CDCl3): δ = 137.4 (Cq,
C-37), 130.2 (CH vinyl, C-36), 95.8 (Cq, C-27), 74.5 (CH-22 or CH-31),
74.0 (CH-39), 69.1 (CH-22 or CH-31), 63.3 (CH2-19), 36.1 (CH2), 35.2
(CH2), 34.3 (CH-23), 34.2 (CH2), 33.6 (CH2), 31.7 (CH-34), 31.2 (CH2),
29.6 (CH2), 28.5 (CH2), 27.8 (CH2), 25.9 [C(CH3)3Si], 23.4 (Me-40), 20.9
(Me-35), 19.1 (CH2-29), 18.3 [C(Me)3Si], 17.9 (Me-24), 11.6 (Me-38),
–4.7 (MeSi), –5.0 (MeSi). Spectroscopic data matched that reported
in the literature.[3c–d,38] Mass spectrum (ESI), m/z 505.3609 [M + Na]+
(C28H54O4SiNa+ requires 505.3684).
((2S,5R,E)-7-{(2S,6S,8R,9S)-8-[3-(Benzyloxy)propyl]-9-methyl-
1,7-dioxaspiro[5.5]undecan-2-yl}-3,5-dimethyl-6-(phenylsulf-
onyl)hept-3-en-2-yloxy)(tert-butyl)dimethylsilane (79): A solu-
tion of butyllithium (1.41
M in cyclohexane, 0.36 mL, 4 equiv.) was
added dropwise to a solution of sulfone 59 (192.8 mg, 0.503 mmol,
4 equiv.) in THF (4 mL) at – 70 °C. After 55 min at – 70 °C, HMPA
(0.130 mL, 5.9 equiv.) and a solution of iodide 78 (57.8 mg,
0.126 mmol) in THF (2 mL) were successively added. Stirring was
continued for 3.5 h leaving the temperature to reach 0 °C. The
reaction was quenched with a saturated aqueous NH4Cl solution
(1 mL) and a 10 % aqueous HCl solution (0.3 mL) until pH 5. The
mixture was diluted with water (3 mL) and AcOEt (10 mL). The
organic layer was washed with water (2 × 5 mL), brine (5 mL), dried
(MgSO4), filtered and concentrated under reduced pressure. The
crude was purified by chromatography on silica gel column (CH2Cl2
as eluent) to afford the coupling product 79 (48.7 mg, 54.1 %) as a
yellow oil. NMR analysis for one of the major diastereomer: 1H NMR
(500 MHz, CDCl3): δ = 7.81–7.80 (m, 2 H, arom), 7.61–7.58 (m, 1 H,
{(2S,5S,E)-7-[(2S,6S,8R,9S)-8-(3-Azidopropyl)-9-methyl-1,7-diox-
aspiro[5.5]undecan-2-yl]-3,5-dimethylhept-3-en-2-yloxy}(tert-
butyl)dimethylsilane (81): Diisopropylazodicarboxylate (DIAD,
16 μL, 2 equiv.) was added to a chilled (0 °C) solution containing
alcohol 80 (19.6 mg, 0.0405 mmol) and triphenylphosphine
(21.6 mg, 2 equiv.) in dry THF (0.6 mL). After 20 min at 0 °C, diphen-
arom), 7.51–7.48 (m, 2 H, arom), 7.34–7.24 (m, 5 H, arom), 5.23 (d, ylphosphoryl azide (DPPA, 18 μL, 2 equiv.) was added and the re-
J = 9.5 Hz, 1 H, H-36), 4.51 (s, 2 H, OBn), 4.13 (q, J = 6.4 Hz, 1 H, H-
39), 3.75 (m, 1 H, H-31), 3.53 (m, 2 H, H-19), 3.33 (ddd, J = 7.6 Hz,
J = 3.0 Hz, J = 1.8 Hz, 1 H, H-33), 3.27 (td, J = 9.6 Hz, J = 2.5 Hz, 1
H, H-22), 2.81 (m, 2 H, H-34), 2.12 (m, 1 H, H-32a), 1.93 (m, 1 H, H-
20a), 1.81 (m, 2 H, H-21a and H-29a), 1.79 (m, 1 H, H-20b), 1.75 (m,
1 H, H-32b), 1.58 (m, 1 H, H-28a), 1.56 (m, 2 H, H-25a and H-30a),
1.52 (m, 1 H, H-29b), 1.48 (d, J = 1.1 Hz, 3 H, Me-38), 1.47 (m, 1 H,
sulting heterogeneous mixture was stirred for 7 h leaving the tem-
perature to reach the ambient. The solvent was evaporated under
vacuum and the residue was directly purified by chromatography
on silica gel column (CH2Cl2/cyclohexane, 1:1) to give the azide 81
(12 mg, 58.3 %). The final product is identical to that reported in
the literature according the NMR spectroscopic data.[3c,3d] 1H NMR
(300 MHz, CDCl3): δ = 5.10 (d, J = 9.4 Hz, 1 H, H-36), 4.14 (q, J =
H-28b), 1.46 (m, 2 H, H-26), 1.43 (m, 1 H, H-25b), 1.40 (m, 1 H, H- 6.3 Hz, 1 H, H-39), 3.41 (m, 1 H, H-31), 3.32 (m, 2 H, H-19), 3.16 (td,
21b), 1.32 (m, 1 H, H-23), 1.17 (d, J = 6.3 Hz, 3 H, Me-40), 1.07 (m,
1 H, H-30b), 0.99 (d, J = 7.0 Hz, 3 H, Me-35), 0.87 (s, 9 H, tBu-Si),
0.86 (d, J = 7.3 Hz, 3 H, Me-24), 0.02 (s, 3 H, Me-Si), – 0.005 (s, 3 H,
J = 9.7 Hz, J = 2.4 Hz, 1 H, H-22), 2.32 (m, 1 H, H-34), 1.95 (m, 1 H),
1.86–1.57 (m, 8 H), 1.56 (d, J = 1.3 Hz, 3 H, Me-38), 1.53–1.27 (m, 10
H), 1.18 (d, J = 6.5 Hz, 3 H, Me-40), 0.93 (d, J = 6.6 Hz, 3 H, Me-35),
Me-Si). 13C NMR (125 MHz, CDCl3): δ = 139.5 (Cq), 138.8 (Cq), 138.7 0.88 (s, 9 H, tBu-Si), 0.83 (d, J = 6.6 Hz, 3 H, Me-24), 0.03 (s, 3 H, Me-
(Cq), 133.4 (CH arom), 129.0 (CH arom), 128.7 (CH arom), 128.2 (CH Si), 0.01 (s, 3 H, Me-Si).
arom), 127.6 (CH arom), 127.3 (CH arom), 123.3 (CH vinyl, C-36), 95.3
(Cq of spiro, C-27), 74.7 (CH-22), 74.1 (CH-39), 72.6 (CH2-Bn), 70.8
(CH2-19), 67.6 (CH-31), 65.4 (CH-33), 35.9 (CH2-25), 35.4 (CH2-28),
34.8 (CH-23), 31.8 (CH-34), 31.7 (CH2-30), 31.3 (CH2-32), 30.1 (CH2-
29), 28.1 (CH2-26), 25.8 [C(CH3)3Si], 25.4 (CH2-20), 22.9 (Me-40), 19.7
(Me-35), 18.7 (CH2-29), 18.2 [C(Me)3Si], 18.1 (Me-24), 11.1 (Me-38),
(3S,4S,6E,9R,10E)-9-(tert-Butyldimethylsilyloxy)-N-[(2R,3R)-4-
(tert-butyldimethylsilyloxy)-2-hydroxy-3-methylbutyl]-3-(4-
methoxybenzyloxy)-4-methyldodeca-6,10-dienamide (82):
Azide 42 (16 mg, 0.0617 mmol) and triphenylphosphine (33.5 mg,
2.1 equiv.) were dissolved in dry THF (2.5 mL) at 0 °C, then water
(0.25 mL) was added. The solution was stirred 30 min at 0 °C and
23 h at room temperature. The solvents were evaporated and the
residue was azeotropically dried in benzene (3 × 1 mL) to afford
–4.7 (MeSi), –5.0 (MeSi). Mass spectrum (ESI), m/z 735.4096 [M +
Na]+ (C41H64O6SSiNa+ requires 735.4085).
3-{(2R,3S,6S,8S)-8-[(3S,6S,E)-6-(tert-Butyldimethylsilyloxy)-3,5-
dimethylhept-4-enyl]-3-methyl-1,7-dioxaspiro[5.5]undecan-2-
yl}propan-1-ol (80): Small pieces of lithium wire (26 mg, 3.7 mmol,
crude amine which was used without further purification in the
next step. A solution of acid 32 (13.9 mg, 0.0291 mmol) in dry
CH2Cl2 (3.5 mL) was added to the previous amine followed by a
34 equiv.) was added to dry ethylamine (ca 10 mL) at – 60 °C. The solution of pyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium
deep blue colored solution was stirred for 1 h at the same tempera-
ture before the addition of the sulfone 79 (79.3 mg, 0.111 mmol)
in dry THF (3 mL). Stirring was continued for 1 h before the careful
addition of solid NH4Cl (325 mg) to destroy the excess of lithium.
The solvent was then evaporated and the residue was diluted with
hexafluoro phosphate, 21.5 mg, 0.0413 mmol, 1.4 equiv. in CH2Cl2
(2.5 mL) and Et3N (7 μL, 0.0503 mmol, 1.7 equiv.). The mixture was
stirred at room temperature for 20 h and then diluted with AcOEt
(8 mL). The organic layer was washed with a saturated aqueous
NaHCO3 solution (5 mL), water (2 × 5 mL), brine (5 mL), dried
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(MgSO4), filtered and concentrated under reduced pressure. The
crude was purified by chromatography on silica gel (AcOEt/cyclo-
hexane, 2:8 then AcOEt/cyclohexane, 1:2) to afford the coupling
product 82 (15.5 mg, 76.6 %) as a colorless oil. [α]2D0 = –10.3 (c =
0.7, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 7.25 and 6.85 (AA′BB′,
J = 8.7 Hz, Δν = 201.8 Hz, 4 H, PMB), 6.45 (br. t, J = 5.7 Hz, 1 H,
butyl]-3-(4-methoxybenzyloxy)-4-methyldodeca-6,10-dien-
amide (85): Azide 45 (17.7 mg, 0.0466 mmol) and triphenylphos-
phine (25.0 mg, 2 equiv.) were dissolved in dry THF (1 mL) at 0 °C,
then water (0.1 mL) was added. The solution was stirred 30 min at
0 °C and 22 h at room temperature. The solvents were evaporated
and the residue was azeotropically dried in benzene (3 × 1 mL) to
1
NH), 5.53 (dqd, J2,3 = 15.3 Hz, J2,1 = 6.4 Hz, J2,4 = 0.9 Hz, 1 H, H-2), afford crude amine which was used without further purification in
5.42 (m, 1 H, H-3), 5.38 (m, 2 H, H-6 and H-7), 4.47 (degenerated AB
the next step. A solution of acid 32 (10.2 mg, 0.0213 mmol) in dry
system, 2 H, CH2-Ar), 4.38 (br. s, 1 H, OH), 4.02 (app q, J = 6.5 Hz, 1
CH2Cl2 (2.5 mL) was added to the previous amine followed by a
H, H-4), 3.80 (m, 1 H, H-11), 3.79 (s, 3 H, MeO), 3.74 (dd, 1 H, J = solution of pyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium
10.1 Hz, J = 4.1 Hz, H-18a), 3.60–3.51 (m, 3 H, H-15, H-18b and H-
14a), 3.20 (m, 1 H, H-14b), 2.35 (m, 2 H, H-12), 2.27 (m, 1 H, H-8a),
2.16 (m, 2 H, H-5), 1.81 (m, 1 H, H-9), 1.74 (m, 2 H, H-8b and H-16),
1.66 (d, J = 6.6 Hz, 3 H, Me-1), 0.89 (s, 9 H, SitBu), 0.88 (d, J = 6.7 Hz,
3 H, Me-10), 0.87 (s, 9 H, SitBu), 0.83 (d, J = 6.9 Hz, 3 H, Me-17), 0.08
(s, 3 H, SiMe), 0.07 (s, 3 H, SiMe), 0.03 (s, 3 H, SiMe), 0.01 (s, 3 H,
hexafluoro phosphate, 19.0 mg, 0.0365 mmol, 1.7 equiv. in CH2Cl2
(2.5 mL) and Et3N (8 μL, 0.0575 mmol, 2.7 equiv.). The mixture was
stirred at room temperature for 17 h and then diluted with AcOEt
(10 mL). The organic layer was washed with a saturated aqueous
NaHCO3 solution (3 mL), water (2 × 5 mL), brine (5 mL), dried
(MgSO4), filtered and concentrated under reduced pressure. The
SiMe). 13C NMR (125 MHz, CDCl3): δ = 172.0 (CONH), 159.1 (Cq), crude was purified by chromatography on silica gel (AcOEt/cyclo-
134.4 (CH vinyl, C-3), 130.8 (CH vinyl, C-6 or C-7), 130.7 (Cq), 129.3
(CH-Ar), 128.3 (CH vinyl, C-6 or C-7), 124.9 (CH vinyl, C-2), 113.7 (CH-
hexane, 2:8 then AcOEt/cyclohexane, 1:2) to afford the coupling
product 85 (16.1 mg, 92.9 %) as a light yellow oil. [α]2D0 = –2.42 (c =
Ar), 80.0 (CH-11), 75.9 (CH-15), 73.7 (CH-4), 71.8 (CH2-Ar), 68.6 (CH2- 1.61, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.21 (m, 4 H, PMB),
18), 55.2 (MeO), 43.5 (CH2-14), 41.9 (CH2-5), 38.7 (CH2-12), 37.6 (CH2- 6.86–6.80 (m, 4 H, PMB), 6.14 (br. t, J = 5.5 Hz, 1 H, NH), 5.53 (dqd,
16), 36.4 (CH-9), 35.2 (CH2-8), 25.9 [C(CH3)3], 25.8 [C(CH3)3], 18.3 J2,3 = 12.9 Hz, J2,1 = 6.4 Hz, J2,4 = 0.9 Hz, 1 H, H-2), 5.40 (m, 1 H, H-
[SiC(CH3)3], 18.0 [SiC(CH3)3], 17.6 (Me-1), 15.0 (Me-10), 13.1 (Me-17),
3), 5.37 (m, 2 H, H-6 and H-7), 4.47 and 4.41 (AB system, JAB
11.5 Hz, Δν = 27.7 Hz, 2 H, CH2-Ar), 4.44 and 4.41 (AB system, JAB
=
=
–4.3 (SiMe), –4.7 (SiMe), –5.6 (SiMe), –5.7 (SiMe). Mass spectrum
(ESI), m/z 692.4684 [M + H]+ (C38H70NO6Si2 requires 692.4736).
11.3 Hz, Δν = 11.4 Hz, 2 H, CH2-Ar), 4.03 (ddd, J = 7.1 Hz, J = 6.4 Hz,
J = 5.7 Hz, 1 H, H-4), 3.78 (s, 3 H, MeO), 3.77 (s, 3 H, MeO), 3.76 (m,
1 H, H-11), 3.57 (AB part of an ABX system, J18a-18b = 10.0 Hz,
J18a-16 = J18b-16 = 5.0 Hz, Δν = 32.8 Hz, 2 H, H-18), 3.54 (m, 1 H, H-
14a), 3.46 (m, 1 H, H-15), 3.22 (m, 1 H, H-14b), 2.26 (m, 1 H, H-12a),
2.25 (m, 1 H, H-8a), 2.19 (m, 1 H, H-5a), 2.17 (m, 1 H, H-12b), 2.14
(m, 1 H, H-5b), 1.84 (m, 1 H, H-16), 1.79 (m, 1 H, H-9), 1.72 (m, 1 H,
H-8b), 1.66 (d, J = 6.5 Hz, 3 H, Me-1), 0.89 (s, 9 H, SitBu), 0.88 (s, 9
H, SitBu), 0.88 (d, J = 6.9 Hz, 3 H, Me-10 or Me-17), 0.87 (d, J =
7.4 Hz, 3 H, Me-10 or Me-17), 0.05 (s, 3 H, SiMe), 0.04 (s, 3 H, SiMe),
0.03 (s, 3 H, SiMe), 0. 01 (s, 3 H, SiMe). 13C NMR (125 MHz, CDCl3):
δ = 171.6 (CONH), 159.2 (Cq arom), 159.0 (Cq arom), 134.4 (CH vinyl,
C-3), 130.73 (CH vinyl, C-6 or C-7), 130.71 (Cq arom), 130.6 (Cq
arom), 129.5 (CH arom), 129.2 (CH arom), 128.3 (CH vinyl, C-6 or C-
7), 124.9 (CH vinyl, C-2), 113.9 (CH arom), 113.6 (CH arom), 79.9 (CH-
11), 78.3 (CH-15), 73.7 (CH-4), 71.8 (CH2-Ar), 71.5 (CH2-Ar), 64.5 (CH2-
18), 55.2 (MeO), 42.0 (CH2-5), 39.4 (CH2-14), 38.7 (CH2-12), 37.6 (CH-
16), 36.4 (CH-9), 35.3 (CH2-8), 26.0 [C(CH3)3], 25.9 [C(CH3)3], 18.3
[SiC(CH3)3], 17.6 (Me-1), 15.0 (Me-10 or M-17), 13.0 (Me-10 or M-17),
–4.3 (SiMe), –4.7 (SiMe), –5.4 (SiMe), –5.5 (SiMe). Mass spectrum
+
(3S,4S,6E,9R,10E)-9-(tert-Butyldimethylsilyloxy)-N-[(2R,3R)-2,4-
dihydroxy-3-methylbutyl]-3-(4-methoxybenzyloxy)-4-methyl-
dodeca-6,10-dienamide (83): Solid (DL)-camphorsulfonic acid
(CSA, 0.5 mg, 0.15 equiv.) was added to a solution of 82 (10 mg,
0.0144 mmol) in CH2Cl2/MeOH (0.7 mL: 0.1 mL) at 0 °C. The reaction
was stirred for 7.5 h at this temperature. Monitoring by TLC indi-
cates the presence of starting but also the beginning of degrada-
tion. The reaction was quenched with saturated aqueous NaHCO3
(0.1 mL), water (4 mL), and diluted with AcOEt (5 mL). The aqueous
layer was extracted with AcOEt (3 mL) and the combined organic
layers were washed with brine (3 mL), dried (MgSO4), filtered, and
concentrated under vacuum. The crude was purified on preparative
TLC to afford the diol 83 in 77.6 % yield (3.5 mg, based upon 4.6 mg
recovery of starting material and 3.5 mg of targeted product).
[α]2D0 = –12.85 (c = 0.14, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.25
and 6.88 (AA′BB′, J = 8.7 Hz, Δν = 187.3 Hz, 4 H, PMB), 6.55 (br. t,
J = 5.6 Hz, 1 H, NH), 5.53 (dqd, J2,3 = 15.3 Hz, J2,1 = 6.4 Hz, J2,4
=
1.0 Hz, 1 H, H-2), 5.41 (m, 1 H, H-3), 5.39 (m, 2 H, H-6 and H-7), 4.55
and 4.40 (AB system, JAB = 11.7 Hz, Δν = 74.7 Hz, 2 H, CH2-Ar), 4.42
(br. s, 1 H, OH), 4.03 (app q, J = 6.5 Hz, 1 H, H-4), 3.80 (s, 3 H, MeO),
3.77 (m, 1 H, H-11), 3.63 (m, 2 H, H-18), 3.54 (m, 1 H, H-15), 3.38 (m,
1 H, H-14b), 3.26 (m, 1 H, H-14b), 2.94 (br. s, 1 H, OH), 2.36 (AB part
of an ABX system, J12a-12b = 14.5 Hz, J12a-11 = 8.7 Hz, J12b-11 = 3.7 Hz,
Δν = 22.2 Hz, 2 H, H-12), 2.29 (m, 1 H, H-8a), 2.17 (m, 2 H, H-5), 1.87
(m, 1 H, H-9), 1.74 (m, 1 H, H-8b), 1.70 (m, 1 H, H-16), 1.66 (d, J =
6.4 Hz, 3 H, Me-1), 0.91 (d, J = 6.9 Hz, 3 H, Me-10), 0.88 (s, 9 H,
SitBu), 0.79 (d, J = 6.9 Hz, 3 H, Me-17), 0.03 (s, 3 H, SiMe), 0.01 (s, 3
H, SiMe). 13C NMR (125 MHz, CDCl3): δ = 173.8 (CONH), 159.3 (Cq),
134.4 (CH vinyl, C-3), 130.4 (CH-Ar), 130.3 (Cq), 129.4 (CH vinyl, C-6
or C-7), 128.6 (CH vinyl, C-6 or C-7), 125.0 (CH vinyl, C-2), 113.8 (CH-
Ar), 80.2 (CH-11), 77.6 (CH-15), 73.6 (CH-4), 71.7 (CH2-Ar), 67.9 (CH2-
18), 55.3 (MeO), 44.6 (CH2-14), 41.9 (CH2-5), 38.1 (CH2-12), 37.8 (CH-
16), 36.0 (CH-9), 34.8 (CH2-8), 25.9 [C(CH3)3], 18.3 [SiC(CH3)3], 17.6
(Me-1), 15.3 (Me-10), 13.6 (Me-17), –4.3 (SiMe), –4.7 (SiMe). Mass
spectrum (ESI), m/z 578.3872 [M + H]+ (C32H56NO6Si+ requires
578.3871).
(ESI), m/z 812.5351 [M + H]+ (C46H78NO7Si2 requires 812.5311).
+
(3S,4S,6E,9R,10E)-9-(tert-Butyldimethylsilyloxy)-N-[(2R,3R)-4-
hydroxy-2-(4-methoxybenzyloxy)-3-methylbutyl]-3-(4-
methoxybenzyloxy)-4-methyldodeca-6,10-dienamide (86): A so-
lution of the bis-silyl 85 (15.3 mg, 0.0188 mmol) in CH2Cl2 (2 mL)
and MeOH (0.35 mL) was treated with solid (DL)-camphorsulfonic
acid (CSA, 2.5 mg, 0.57 equiv.) at 0 °C for 7.5 h. Monitoring by
TLC indicates the presence of starting but also the beginning of
desilylation on the secondary alcohol at C-4. The reaction was so
quenched with an saturated aqueous NaHCO3 (0.3 mL), water
(5 mL) and diluted with CH2Cl2 (10 mL). The aqueous layer was
washed with water (2 × 5 mL), dried (Na2SO4), filtered, and concen-
trated under vacuum. The crude was purified on preparative TLC to
afford the diol 86 in 46.4 % yield (4.7 mg, based upon 3.5 mg recov-
ery of starting material and 2.8 mg of diol). [α]2D0 = –10.2 (c = 0.47,
CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.22–7.20 (m, 4 H, PMB),
6.86–6.82 (m, 4 H, PMB), 6.39 (br. t, J = 5.9 Hz, 1 H, NH), 5.53 (dqd,
J2,3 = 15.2 Hz, J2,1 = 6.4 Hz, J2,4 = 0.9 Hz, 1 H, H-2), 5.38 (m, 2 H, H-
6 and H-7), 5.42 (m, 1 H, H-3), 4.50–4.40 (m, 4 H, 2 × CH2-Ar), 4.03
(3S,4S,6E,9R,10E)-9-(tert-Butyldimethylsilyloxy)-N-[(2R,3R)-4-
(tert-butyldimethylsilyloxy)-2-(4-methoxybenzyloxy)-3-methyl-
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(app q, J = 6.5 Hz, 1 H, H-4), 3.79 (s, 3 H, MeO), 3.77 (s, 3 H, MeO),
3.73 (m, 1 H, H-11), 3.56 (m, 2 H, H-18), 3.54 (m, 1 H, H-14a), 3.45
(m, 1 H, H-15), 3.29 (m, 1 H, H-14b), 2.31 (AB part of an ABX system,
J12a-12b = 14.7 Hz, J12a-11 = 8.7 Hz, J12b-11 = 3.7 Hz, Δν = 37.1 Hz, 2
H, H-12), 2.25 (m, 1 H, H-8a), 2.17 (m, 2 H, H-5), 2.07 (br. s, 1 H, OH),
1.86 (m, 1 H, H-9), 1.84 (m, 1 H, H-16), 1.73 (m, 1 H, H-8b), 1.66 (d,
J = 6.3 Hz, 3 H, Me-1), 0.90 (d, J = 6.7 Hz, 3 H, Me-10), 0.88 (s, 9 H,
SitBu), 0.85 (d, J = 7.0 Hz, 3 H, Me-17), 0.03 (s, 3 H, SiMe), 0.01 (s, 3
H, SiMe). 13C NMR (125 MHz, CDCl3): δ = 172.13 (CONH), 159.4 (Cq),
159.2 (Cq), 134.4 (CH vinyl, C-3), 130.5 (CH vinyl, C-6 or C-7), 130.4
88 (20.6 mg, 0.0237 mmol) in solution in dry THF (2 mL) was treated
at 0 °C by a solution of TBAF (tetrabutylammonium fluoride, 1
THF solution, 1.14 equiv.). Stirring was continued for 25 min and
diethylether (10 mL), water (5 mL) and an aqueous 0.01 HCl solu-
M
M
tion (1.5 mL) were added. The organic layer was washed with water
(5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated under
reduced pressure. The residue was purified on silica gel chromato-
graphic column (AcOEt) to afford 89 as a colorless oil (16 mg,
1
94.5 %). [α]2D0 = –2.29 (c = 0.83, CH2Cl2). H NMR (500 MHz, CDCl3):
δ = 7.21–7.19 (m, 4 H, PMB), 6.85–6.82 (m, 4 H, PMB), 6.31 (br. t, J =
(Cq), 129.8 (Cq), 129.7 (CH-Ar), 129.2 (CH-Ar), 128.5 (CH vinyl, C-6 or 5.8 Hz, 1 H, NH), 5.52 (dqd, J2,3 = 15.3 Hz, J2,1 = 6.4 Hz, J2,4 = 1.1 Hz,
C-7), 125.0 (CH vinyl, C-2), 114.0 (CH-Ar), 113.8 (CH-Ar), 81.2 (CH-15), 1 H, H-2), 5.42 (m, 1 H, H-3), 5.36 (m, 2 H, H-6 and H-7), 4.50 and
80.1 (CH-11), 73.7 (CH-4), 71.7 (CH2-Ar), 71.5 (CH2-Ar), 66.2 (CH2-18), 4.40 (AB system, JAB = 11.0 Hz, Δν = 40.5 Hz, 2 H, CH2-Ar), 4.49 (s,
55.24 (MeO), 55.23 (MeO), 42.0 (CH2-5), 39.2 (CH2-14), 38.2 (CH2-12),
2 H, CH2-Ar), 4.03 (app q, J = 6.5 Hz, 1 H, H-4), 3.78 (s, 3 H, MeO),
36.9 (CH-9), 36.2 (CH-16), 35.1 (CH2-8), 25.9 [C(CH3)3], 18.3 3.77 (s, 3 H, MeO), 3.73 (m, 1 H, H-11), 3.66 (m, 1 H, H-15), 3.41 (m,
[SiC(CH3)3], 17.6 (Me-1), 15.2 (Me-10), 13.4 (Me-17), –4.3 (SiMe), –4.7
(SiMe). Mass spectrum (ESI), m/z 736.4006 [M + K]+ (C46H78NO7Si2K+
requires 736.4005).
2 H, H-14), 2.67 (m, 1 H, H-16), 2.33 (m, 1 H, H-12a), 2.26 (m, 1 H,
H-8a), 2.25 (m, 1 H, H-12b), 2.18 (m, 2 H, H-5), 1.84 (m, 1 H, H-9),
1.75 (m, 1 H, H-8b), 1.66 (d, J = 6.3 Hz, 3 H, Me-1), 1.15 (d, J = 7.2 Hz,
3 H, Me-17), 0.89 (d, J = 7.3 Hz, 3 H, Me-10), 0.88 (s, 9 H, SitBu), 0.03
(SiMe), 0.01 (SiMe). 13C NMR (125 MHz, CDCl3): δ = 175.5 (COOH),
172.2 (CONH), 159.4 (Cq), 159.2 (Cq), 134.4 (CH vinyl, C-3), 130.5
(Cq), 129.7 (CH vinyl, C-6 or C-7), 129.4 (Cq), 128.5 (CH vinyl, C-6 or
C-7), 125.0 (CH vinyl, C-2), 113.9 (CH-Ar), 113.8 (CH-Ar), 80.0 (CH-11),
78.8 (CH-15), 73.7 (CH-4), 72.2 (CH2-Ar), 71.7 (CH2-Ar), 55.3 (MeO),
55.2 (MeO), 41.9 (CH2-5), 41.5 (CH-16), 39.1 (CH2-14), 38.1 (CH2-12),
36.1 (CH-9), 35.0 (CH2-8), 25.9 [C(CH3)3], 18.3 [SiC(CH3)3], 17.6
(Me-1), 15.2 (Me-10), 13.3 (Me-17), –4.3 (SiMe), –4.7 (SiMe). Mass
spectrum (ESI), m/z 750.3753 [M + K]+ (C40H61KNO8Si+ requires
750.3798).
(2S,3R)-Triisopropylsilyl 4-[(3S,4S,6E,9R,10E)-9-(tert-Butyldi-
methylsilyloxy)-3-(4-methoxybenzyloxy)-4-methyldodeca-6,10-
dienamido]-3-(4-methoxybenzyloxy)-2-methylbutanoate (88):
Palladium on carbon (10 wt.-%, 4.6 mg) was added to a solution of
the silyl ester 49 (25.3 mg, 0.058 mmol, 1.53 equiv.) in dry THF
(3 mL). The mixture was stirred under an atmosphere of hydrogen
for 2 h at room temperature. The heterogeneous solution was fil-
tered through a short plug of Celite® and concentrated under re-
duced pressure. A solution of acid 32 (18 mg, 0.038 mmol) in CH2Cl2
(3 mL) was immediately added to the above crude amine followed
by a solution of pyBOP (32.2 mg, 1.64 equiv.) in CH2Cl2 (2.9 mL) and
NEt3 (20 μL, 3.8 equiv.). The reaction was stirred at room tempera-
ture for 17 h, and then diluted with AcOEt (20 mL), water (5 mL)
and a saturated aqueous solution of NaHCO3 (2 mL). The organic
layer was washed with water (2 × 5 mL), brine (5 mL), dried
(Na2SO4), filtered and concentrated under reduced pressure. The
resulting residue was purified by chromatography over silica gel
column (AcOEt/cyclohexane, 1:4) to afford the amide 88 (30.0 mg,
91.6 %) as a colorless oil. [α]2D0 = +9.5 (c = 1.48, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 7.21–7.17 (m, 4 H, PMB), 6.82–6.79 (m, 4 H,
Acknowledgments
C. B. is grateful to Dr. Dominique Matt for his constant support
and encouragement. Thanks also to Prof. Rémy Louis for helpful
discussions and assistance with X-ray crystallographic analysis.
Keywords: Bistramide K · Chirality · Asymmetric synthesis ·
Marine metabolites · Enantioselectivity
PMB), 6.20 (br. t, J = 5.6 Hz, 1 H, NH), 5.53 (dqd, J2,3 = 15.3 Hz, J2,1
=
6.4 Hz, J2,4 = 0.9 Hz, 1 H, H-2), 5.40 (ddq, J3,2 = 15.3 Hz, J3,4 = 6.4 Hz,
J3,1 = 1.5 Hz, 1 H, H-3), 5.36 (m, 2 H, H-6 and H-7), 4.50 and 4.43
(AB system, JAB = 11.5 Hz, Δν = 36.2 Hz, 2 H, CH2-Ar), 4.44 (s, 2 H,
CH2-Ar), 4.02 (app q, J = 6.4 Hz, 1 H, H-4), 3.78 (s, 3 H, MeO), 3.77
(s, 3 H, MeO), 3.73 (m, 2 H, H-11 and H-15), 3.42 (m, 2 H, H-14), 2.71
(m, 1 H, H-16), 2.25 (AB part of an ABX system, J12a-12b = 14.7 Hz,
J12a-11 = 8.2 Hz, J12b-11 = 3.5 Hz, Δν = 27.5 Hz, 2 H, H-12), 2.24 (m,
1 H, H-8a), 2.15 (m, 2 H, H-5), 1.79 (m, 1 H, H-9), 1.72 (m, 1 H, H-8b),
1.66 (d, J = 6.4 Hz, 3 H, Me-1), 1.30 {m, 3 H, Si[CH(Me)2]3},1.15 (d,
J = 7.2 Hz, 3 H, Me-17), 1.07 {d, J = 7.5 Hz, 18 H, Si[CH(Me)2]3}, 0.88
(s, 9 H, SitBu), 0.87 (d, J = 6.9 Hz, 3 H, Me-10), –0.03 (SiMe), –0.01
(SiMe). 13C NMR (125 MHz, CDCl3): δ = 174.4 (COOTIPS), 171.7
(CONH), 159.2 (Cq), 159.1 (Cq), 134.4 (CH vinyl, C-3), 130.6 (CH vinyl,
C-6 or C-7), 130.5 (Cq), 130.2 (Cq), 129.5 (CH-Ar), 129.3 (CH-Ar), 128.4
(CH vinyl, C-6 or C-7), 124.9(CH vinyl, C-2), 113.75 (CH-Ar), 113.71
(CH-Ar), 80.0 (CH-11 or CH-15), 79.1 (CH-11 or CH-15), 73.7 (CH-4),
71.9 (CH2-Ar), 71.7 (CH2-Ar), 55.2 (MeO), 43.8 (CH-16), 42.0 (CH2-5),
38.7 (CH2-12), 38.4 (CH2-14), 36.3 (CH-9), 35.2 (CH2-8), 25.9 [C(CH3)3],
18.3 [SiC(CH3)3], 17.8 {Si[CH(Me)2]3}, 17.6 (Me-1), 15.1 (Me-10), 13.7
(Me-17), 11.9 {Si[CH(Me)2]3}, –4.3 (SiMe), –4.7 (SiMe). Mass spectrum
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+
(2S,3R)-4-[(3S,4S,6E,9R,10E)-9-(tert-Butyldimethylsilyloxy)-3-(4-
methoxybenzyloxy)-4-methyldodeca-6,10-dienamido]-3-(4-
methoxybenzyloxy)-2-methylbutanoic Acid (89): The Tips-ester
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Received: June 5, 2018
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Natural Products
Studies toward stereoselective synthe-
sis of the marine metabolite bistram-
ide K was described using nonracemic
methyl p-tolyl sulfoxide as unique
source of chirality.
C. Bauder* ......................................... 1–27
Toward an Asymmetric Synthesis of
Bistramide K
DOI: 10.1002/ejoc.201800875
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