Total Synthesis of the Bis-silyl Ether of (+)-15-epi-Aetheramide A

Article abstract of DOI:10.1021/acs.joc.6b02535

Synthesis of the macrolactone depsipeptide aetheramide A was attempted by three different approaches. The first approach to form the macrolactone involving macrolactonization to form the C1-C21 bond and the second approach using a ring-closing metathesis (RCM) strategy to form the C10-C11 olefinic bond failed. The third approach starting from R-mandelic acid, involving the RCM reaction to install the C18-C19 ring junction, was successful in assembling the macrolactone.

Full text of DOI:10.1021/acs.joc.6b02535

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Article
Total Synthesis of the bis-Silyl Ether of (+)-15-epi-Aetheramide A
Omkar Revu, and Kavirayani R. Prasad
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02535 • Publication Date (Web): 29 Nov 2016
Downloaded from http://pubs.acs.org on November 30, 2016
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Total Synthesis of the bisꢀSilyl Ether of (+)ꢀ15ꢀepiꢀ
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Aetheramide A
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Omkar Revu and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Eꢀmail: prasad@orgchem.iisc.ernet.in
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FAX: +918023600529
OMe
TIPSO
Aldol Reaction
O
O
O
Amidation
N
NH
O
11
1
O
19
15
Ph
OMe
OTBS 18
RCM
Abstract: Synthesis of the macrolactone depsipeptide aetheramide A was attempted by three different
approaches. First approach to form the macrolactone involving macrolactonization to form the C1ꢀC21
bond and the second approach using RCM strategy to form the C10ꢀC11 olefinic bond failed. Third
approach starting from ꢀmandelic acid, involving the ring closing metathesis reaction to install the C18ꢀ
R
C19 ring junction was successful in assembling the macrolactone.
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Introduction
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Aetheramide A 1 and B 2 (fig. 1) are two novel depsipeptides isolated from the myxobacterial genus
Aetherobacter by Müller’s group.1 The structures of aetheramides were established with the aid of
extensive 1D, 2D NMR quantum mechanical calculations and the αꢀmethoxyꢀαꢀ
trifluoromethylphenylacetic acid (MTPA) esters. Structurally aetheramide A 1 and B 2 are 22 and 21ꢀ
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membered macrolactones containing a polyketide moiety and a dipeptide residue which contain ꢀvaline
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and an abnormal 3ꢀ(4ꢀhydroxyꢀ3ꢀmethoxyphenyl)ꢀ2ꢀ(methylamino) propanoic acid. Aetheramides
contain six stereogenic centers in which the absolute configuration of the two stereogenic centers at C8
and C15 was not established. Another interesting observation about aethreamides is that aetheramide A
1 rearranges to aetheramide B 2 with a halfꢀlife of 24 hours in MeOH. Aetheramides were shown to
exhibit potent inhibitory activity against HIVꢀ1, with IC50 values of 0.015 ꢁM, and good cytotoxic
activity against HCTꢀ116 cells (IC50 0.11 ꢁM). During the course of our investigations concerning the
synthesis of aetheramides, Ghosh et. al. reported the synthesis of the macrolactone core of 3
aeteheramide A involving an intramolecular lactamization as the key step. For the synthesis of the
polyketide unit, they relied on asymmetric dihydroxylation, Wittig olefination, asymmetric allylation
and aldol reactions.2 However, they faced difficulty in deprotection of the 2ꢀmethoxyethoxymethyl
(MEM) group in the macrolactone 3 to aetheramide A 1. At the same time, we reported an expeditious
approach for the polyketide unit 4 present in aetheramides starting from a chiral furyl carbinol.3 Our
work was based on the oxidative opening of furan to the corresponding E-butꢀ2ꢀeneꢀ1,4ꢀdione and
further elaboration using Wittig olefination and Nagao aldol reactions. While this manuscript was under
preparation, Gerstmann and Kalesse reported the total synthesis of aethereamide A 1 using an
intramolecular lactamization of an acylketene.4 They have confirmed the stereochemistry at the C15
carbon bearing the methoxy group as R by comparison of the 1H NMR data, while they were not able to
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record a conclusive C NMR spectrum of the natural product.5 Very recently, while this manuscript
was being submitted, a report by Qi et. al. surfaced which described the total synthesis and
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stereochemical assignment of aetheramides A and B.6 They affirmed the stereochemistry of the C8 and
the C15 centers as S and R respectively and assigned the structure 1A for aetheramide A. Herein we
report in detail our efforts towards the synthesis of aetheramide A 1 involving the macrolactonization
strategy and two approaches involving the ring closing metathesis strategy one of which led to the
successful synthesis of the bisꢀsilyl ether of aetheramide A.
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Figure 1: Reported approaches for the synthesis of aetheramide A 1 and B 2.
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Results and Discussion
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i) Macrolactonization approach: Our initial approach for the synthesis of aetheramide A 1 is outlined in
schemeꢀ1. It was anticipated to assemble the macrolactone by macrolactonization of the hydroxy acid 6,
the synthesis of which was envisaged by coupling of the polyketide fragment 7 with the dipeptide unit 8.
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While synthesis of the dipeptide unit 8 was planned from
D
ꢀtyrosine and ꢀvaline, synthesis of the
L
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polyketide fragment 7 was envisioned by elaboration of the diene ester 9 obtained from the phenyl furyl
carbinol 10 involving an oxidative ring opening of the furan moiety to the corresponding keto aldehyde
and further elaboration (Schemeꢀ1).
Scheme 1: Retrosynthesis for synthesis of aetheramide A 1 involving macrolactonization strategy
Accordingly, the synthetic sequence commenced with the oxidation of the silyloxy furyl carbinol 10
(prepared from the corresponding known phenyl furyl carbinol) with NBS leading to the keto aldehyde
which on Wittig olefination with the phosphonate (EtO)2(O)PCH(CH3)CO2Et in presence of LiHMDS
as base afforded exclusively the E-unsaturated ester 9 in 91% yield. Performing the Witting reaction
with the ylide Ph3P=C(CH3)ꢀCO2Et in refluxing toluene produced the diene ester 9 as a mixture of E:Z
isomers in 78:22 ratio while the use of NaH as base furnished the product as 84:16 mixture of E:Z
isomers. Reduction of the keto group in 9 with NaBH4/ CeCl3 afforded the alcohol 11 (>95:5 dr) in 87%
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yield. Conversion of the alcohol in 11 to the MOM ether (93% yield) followed by transformation of the
ester to the Weinreb amide 12 was accomplished in 85% yield. Addition of (4ꢀ((tetrahydroꢀ2Hꢀpyranꢀ2ꢀ
yl) oxy) butyl)magnesium bromide to the Weinreb amide 12 gave the ketone 13 in 83% yield. CBS
reduction of the keto group present in 13 with BH3.SMe2 using (S)ꢀCBS oxazaborolidine7 as catalyst at
−25 °C furnished the alcohol 14 (dr >99:1) in 82% yield. Conversion of the free alcohol in 14 to the
methyl ether (82% yield) followed by selective deprotection of the THP group under mild conditions
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using pyridinium ꢀtoluene sulfonate (PPTS) in MeOH provided the primary alcohol 15 in 84% yield.
p
IBX mediated oxidation of the alcohol 15 produced the aldehyde which on Wittig olefination with the
ylide Ph3P=C(CH3)CO2Et in toluene under reflux conditions afforded the α,βꢀunsaturated ester 16 in
95% yield for two steps. DIBALꢀH reduction of the α,βꢀunsaturated ester 16 at −78 °C furnished the
primary allyl alcohol 17 in 87% yield. The primary alcohol in 17 was oxidized with MnO2 to yield the
aldehyde which was subjected to Nagao aldol reaction8 with the thiazolidine thione 18 to furnish the
aldol adduct 19 in 90% yield for two steps after column chromatography. The secondary alcohol in 19
was protected as its TES ether (92% yield) which on reaction with LiOH and H2O2 in THF furnished the
acid 7 in 60% yield. Using the same procedure, the diastereomeric alcohol dia-19 as well as the acid
dia-7 were prepared from the allylic alcohol 17 using the thiazolidine thione entꢀ18 derived from ꢀ
D
valine. Alcohol in dia-19 was protected as its TIPS ether dia-19a and was further converted to the acid
dia-7 in 68% yield (Schemeꢀ2).
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i) NBS, NaHCO3, Furan, Pyridine
OTBS
O
O
1
2
3
4
5
6
7
8
Acetone: H2O, 2 h, 80%
ii) (EtO)2POCH(CH3)CO2Et, LiHMDS
THF, 78 °C, 2 h, 91%
NaBH4, CeCl3. 7H2O
MeOH, rt to 78 °C
1.5 h, 87%
Ph
O
Ph
OEt
OTBS
10
9
i) MOMCl, iPr2NEt
O
OTBS
OTBS
O
DMAP, CH2Cl2,
BrMg
THF, 0 °C, 1 h, 83%
OTHP
OMe
2
Ph
OEt
Ph
N
0 °C to rt, 8 h, 93%
OH
OMOM
THPO
ii) NHMe(OMe).HCl
iPrMgCl, THF, 0 °C
1 h, 85%
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12
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THPO
OTBS
i) NaH, MeI, DMF, 0 °C to rt, 80%
ii) PPTS, MeOH, rt, 6 h, 84%
OTBS
(S) ꢀ CBS, BH3—SMe2
THF, 25 °C, 10 h
82%
Ph
OH
Ph
O
OMOM
OMOM
13
14
O
EtO
HO
DIBALꢀH, CH2Cl2
i) IBX, EtOAc, , 3 h
OTBS
78 °C, 30 min, 87%
ii) Ph3P=C(CH3)CO2Et, toluene
, 1 h, 95% for 2 steps
OTBS
Ph
OMe
Ph
S
OMe
OMOM
OMOM
15
16
O
OH
HO
N
i) MnO2, CH2Cl2, , 2 h
ii) 18, TiCl4, iPr2NEt, CH2Cl2
25 °C, 30 min
S
i) TESOTf, Pyridine
CH2Cl2, 50 °C to rt
2 h, 92%
OTBS
OTBS
then aldehyde, 20 °C, 10 min
90% for 2 steps
OMe
ii) LiOH, H2O2, THF
H2O, rt, 2 h, 60%
OMe
Ph
Ph
OMOM
OMOM
17
19
O
OTES
O
OH
O
OTIPS
S
HO
N
HO
S
O
S
S
N
OTBS
OTBS
OTBS
18
Ph
OMe
Ph
OMe
OMe
Ph
OMOM
OMOM
diaꢀ19
OMOM
7
diaꢀ7
Scheme 2: Synthesis of the polyketide chain present in aetheramides
Synthesis of the dipeptide fragment 8 was accomplished as described below. Utilizing a procedure
that was described earlier,9
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ꢀtyrosine was elaborated to the amino ester 20 using FriedelꢀCrafts
acylation followed by esterification of the carboxylic acid and protection of the free amine as the Cbz
carbamate. Protection of the free phenolic hydroxy group in 20 as the MOM ether 21 was accomplished
in 82% yield. BaeyerꢀVilliger oxidation of 21 cleanly furnished the corresponding phenylacetate which
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on reaction with K2CO3 in MeOH afforded the free phenol 22 in 80% yield for two steps. Conversion of
the phenol to the methyl ether (90% yield) with concomitant Nꢀ methylation of the carbamate was
achieved using NaH/ MeI to furnish the NꢀMe amino ester 22a which on reaction with LiOH produced
the Cbz protected NꢀMe aminoacid 23 in 93% yield. Coupling of the free acid present in 23 with methyl
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Lꢀvalinate using EDCl, HOBT in Et3N produced the dipeptide 24 in 80% yield. Removal of the Cbz
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group using H2/Pd in MeOH furnished the amino ester 8 in 92% yield (Schemeꢀ3).
O
O
COOMe MOMCl, iPr2EtN
COOH
COOMe
NHCbz
DMAP, CH2Cl2
0 °C to rt, 12 h
82%
Ref. 7
NHCbz
NH2
DꢀTyrosine
HO
HO
MOMO
20
21
i) mꢀCPBA, CH2Cl2
40 °C, 12 h
ii) K2CO3, MeOH
0 °C to rt, 2 h
80%
i) NaH, MeI, THF/DMF
0 °C to 80 °C, 12 h, 90%
b) LiOH, THF:H2O, rt, 7 h
93%
MeO
MOMO
COOH
HO
COOMe
NHCbz
NMeCbz
MOMO
23
22
OMe
OMe
MOMO
MOMO
H2, Pd/C, MeOH, rt, 1 h
92%
methyl Lꢀvalinate.HCl
EDC, HOBT, Et3N, CH2Cl2
0 °C to rt, 1.5 h, 80%
O
O
NMeCbz
NHMe
NH
NH
CO2Me
CO2Me
24
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Scheme 3: Synthesis of the dipeptide unit present in aetheramides from ꢀtyrosine
D
i
Coupling of the acid 7 (polyketide fragment) and the dipeptide unit 8 using HATU, Pr2EtN in DMF
afforded the coupled product 25 in a moderate yield in 68% yield. Deprotection of the TES group in 25
was performed under mild conditions using PPTS in MeOH and CH2Cl2 mixture to furnish the
compound 26 possessing the free alcohol in 75% yield. DessꢀMartin periodinane oxidation10 of the
alcohol in 26 afforded the βꢀketo amide 27 in excellent yield. Reaction of 27 with LiOH did not furnish
the free acid, instead cleavage of the βꢀketo amide to form the acid 4 was observed in very low yields11
(Scheme 4).
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OMe
O
OMe
O
1
2
3
4
5
6
7
8
MOMO
MOMO
O
OTES
O
OTES
NH
N
HO
NH Me
NH Me Me
HATU, iPr2EtN
+
MeO
O
DMF, rt, 8 h, 68%
MeO2C
Ph
OTBS
OTBS
8
9
OMe
Ph
OMe
10
11
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OMOM
OMOM
7
25
OMe
O
MOMO
O
OH
N
NH
Dessꢀ Martin Periodinane
NaHCO3, CH2Cl2, 2 h
94%
PPTS, MeOH:CH2Cl2
rt, 1 h, 75%
MeO2C
OTBS
Ph
OMe
OMOM
26
OMe
OMe
MOMO
MOMO
O
O
O
O
O
N
O
N
NH
NH
aq. LiOH
X
THF, rt, 5 h
MeO2C
Ph
OTBS
HO2C
Ph
OTBS
OMe
OMe
OMOM
27
OMOM
Scheme 4: Attempted synthesis of the hydroxy acid precursor for macrolactonization
To avoid the unanticipated cleavage of the βꢀketo amide in 27 instead of the methyl ester hydrolysis
in the reaction with LiOH, the βꢀtriisopropyl silyloxy acid dia-7 (prepared in an analogous way to the
TBS ether 25) was coupled with the dipeptide 8 to yield the amide 28 in 68% yield. Reaction of 28 with
TBAF afforded the TIPS as well as TBS deprotected compound 29 in 75% yield. Hydrolysis of the ester
in 29 using 1M aq. LiOH furnished the hydroxy acid 30 in excellent yield. Attempts at
macrolactonization of the seco acid 30 to form the macrolactone core of aetheramide using normal
esterification as well as Yamaguchi and Shiina macrolactonization methods were futile (Scheme 5).
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OMe
1
MOMO
2
3
4
O
OTIPS
O
OTIPS
HO
O
N
5
6
7
8
i
8
, HATU, Pr2EtN
NH
DMF, rt, 8 h, 68%
OTBS
MeO2C
Ph
OTBS
Ph
OMe
9
OMe
OMOM
diaꢀ7
10
11
12
13
14
15
16
17
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19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
OMOM
28
OMe
O
MOMO
O
OH
N
NH
TBAF, THF, 0 °C to rt
4 h, 75%
aq. LiOH, THF, rt, 4 h
95%
MeO2C
Ph
OH
OMe
OMOM
29
OMe
MOMO
O
OH
O
N
NH
OH
macrolactonization
HO2C
Ph
OMe
OMOM
30
Scheme 5: Attempted Synthesis of the macrolactone core of aetheramide A
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ii) Ring-closing metathesis approach failing to produce the macrolactone
With the macrolactonization of the seco acid 30 failed to produce the required macrolactone, we
envisaged the synthesis of aetheramide A 1, using ring closing metathesis as the key reaction with the
strategic RCM disconnection to form the C10ꢀC11 olefin of the macrolactone. It was anticipated that
RCM of the ester 31 should lead to the macrolactone, the synthesis of which was planned by combining
the acid fragment derived from functionalized tyrosine 32 and the polyketide chain 33. Synthesis of 33
was planned by elaboration of the Weinreb amide 12 possessing the orthogonally protected diol
functionality. Synthesis of the unsaturated amide 12 was reported by us from furylphenyl carbinol 10,
while synthesis of the functionalized tyrosine fragment 32 was envisaged from the coupling of the βꢀ
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silyloxy acid 34 and the amino acid 35 (Scheme 6).
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Scheme 6: Retrosynthesis for aetheramide A 1 with key RCM disconnection
Accordingly, addition of pentꢀ4ꢀenꢀ1ꢀylmagnesium bromide to the Weinreb amide 12 afforded the
ketone 36 in 70% yield. Reduction of the ketone in 36 under Luche reduction conditions using
NaBH4/CeCl3·7H2O at −78 °C furnished the alcohol 37 in excellent yield as a nonꢀseparable mixture of
diastereomers. The alcohol 37 was converted to corresponding methyl ether 37a in 57% yield, which on
treatment with TBAF in THF afforded the required alcohol fragment 33 as a 1:1 mixture of
diastereomers (as estimated by 1H NMR) in 95% yield. Coupling of the acid 3412 with the free amine in
i
the dipeptide 8 using HATU and Pr2EtN afforded the product 38 in 58% yield. Saponification of the
methyl ester in 38 using LiOH produced the free acid 39 in 77% yield. However, all our efforts to form
the ester 31 from the alcohol and acid fragments 33 and 39 were futile under various conditions with a
variety of coupling reagents and was also futile under Yamaguchi esterification and Shiina esterification
conditions (Scheme 7).
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Scheme 7: Attempted synthesis of the RCM precursor 31
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To circumvent this unforeseen difficulty, we detoured from the esterification reaction of the alcohol
33 and acid 39 fragments and envisaged the synthesis of 31 by amide formation between the acid
fragment 32 and the valine ester 44 derived from the functionalized phenethanol 33. Accordingly,
tyrosine derived amino ester 40 was coupled to the βꢀsilyloxy acid 34 to yield the amide 41 which on
saponification produced the free acid 32 in 81% yield. The amine fragment was synthesized by
esterification of Nꢀphthalimide protected ꢀvaline 42 with alcohol 33 under Yamaguchi esterification
L
conditions to yield the ester 43 in 60% yield. Deprotection of pthalimide in 43 using hydrazine hydrate
in MeOH afforded the free amine 44 in 65% yield. Gratifyingly, coupling of the amine 44 with the acid
32 using EDCl, HOBT in CH2Cl2 formed the amide bond and furnished the RCM precursor 31 in 93%
yield. Deprotection of the TIPS group was accomplished using TBAF to yield the free alcohol 31a in
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73% yield (Scheme 8).
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59
60
Scheme 8: Synthesis of the RCM precursors 31 & 31a
Ring closing metathesis (RCM) reaction of diene 31 and 31a was explored under various conditions.
None of them afforded the desired macrolactone core of aetheramide A. In most cases starting material
was recovered and no appreciable reaction was observed. However, reaction of 31 in toluene under
refluxing conditions resulted in the formation of the dimer 45 and the truncated aetheramide analogue
46 as evident from the HRMS analysis of the crude reaction mixture (Scheme 9). Reaction of 31a with
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HoveydaꢀGrubbs’ second generation catalyst furnished a trace amount of the macrolactone, evident
from HRMS analysis. However, the yield could not be improved either by increased catalyst loading or
by performing the reaction at higher dilution.
1
2
3
4
5
6
7
MeO
8
9
TIPSO
O
MOMO
10
11
12
13
14
15
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17
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OMe
N
O
MOMO
NH
MOMO
Ph
O
H
N
O
O
O
O
O
N
RCM
Me
31
Ph
O
O
OMOM
O
Ph
OTIPS
HN
N
OMOM
O
46
TIPSO
OMOM
OMe
45
Indiacative of the formation of these from HRMS
Scheme 9: Products obtained in the RCM reaction of 31.
iii) Successful ring-closing metathesis approach for the formation of 15-epi-aetharamide A
Although RCM reaction of 31 and 31a failed to produce the required product, formation of the dimer
45 and the truncated analogue 46 has provided the pivotal information that the less substituted alkene in
the diene (C18ꢀC19 alkene of the aethreamide) was forming the active ruthenium carbene. This positive
outcome gave us the impetus to reorganize our approach towards aetheramides. Accordingly, we revised
our plan with the anticipation that the macrolactone could be assembled via ring closing metathesis of
an appropriately substituted alkene 47 to form the ring junction at the C18ꢀC19 position. Assembly of the
tetraene 47 was planned by the coupling of the acid fragment 48 and the amine fragment 49. Synthesis
of the acid fragment 48 was planned by aldol reaction of the aldehyde 50 the synthesis of which was
planned from allyl trityl ether 51. Synthesis of the amine fragment 49 was envisaged from
acid 53 (scheme 10).
R
ꢀmandelic
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48
49
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52
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59
60
Scheme 10: Retrosynthesis for aetheramide A with strategic C18ꢀ19 disconnetction using RCM
Accordingly synthesis of the acid fragment 48 commenced with the conversion of allyl trityl ether 51
to the α,βꢀunsaturated ester 54 involving oxidative cleavage of the olefin to aldehyde and further Wittig
olefination reaction. Formation of the Weinreb amide 55 from the ester 54 was accomplished by
reaction of 54 with Weinreb amine and isopropylmagnesium chloride in 70% yield. Addition of (4ꢀ
((tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)oxy)butyl)magnesium bromide to the Weinreb amide 55 afforded the ketone
56 in 74% yield, which on CBS reduction afforded the allyl alcohol 57 in 81% yield. Reaction of 57
with NaH and MeI in DMF at 0 °C furnished the methyl ether 58 in 92% yield. Deprotection of the THP
as well as the trityl groups in 58 was accomplished by reaction with PPTS in MeOH to afford the diol
59 in 75% yield. Selective oxidation of the allyl alcohol in 59 was accomplished by treating with MnO2
which on Wittig olefination with CH2=PPh3 afforded the diene 60 in 70% yield. IBX mediated oxidation
of the primary alcohol in 60 followed by Wittig olefination using phosphorane Ph3P=C(Me)CO2Et
furnished the α,βꢀunsaturated ester 61 in 81% for the two steps. DIBALꢀH reduction of ester in 61
furnished the alcohol 62 in 92% yield. Oxidation of the alcohol 62 to the aldehyde 50 using DessꢀMartin
periodinane and further Nagao aldol reaction with titanium enolate derived from thiazolidine thione 18
furnished the required aldol adduct 63 in 85% for the two steps. Alcohol in 63 was protected as the
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corresponding TES ether 64 using TESOTf and pyridine in CH2Cl2 in good yield. Thiazolidine thione in
1
2
3
64 was cleaved using LiOH and H2O2 to afford the acid 65 in 75% yield. Coupling of the acid 65 with
4
5
6
i
Nꢀmethyl
D
ꢀtyrosine ester 40 in the presence of HATU and Pr2EtN in DMF afforded the amide 66 in
7
8
52% yield. The methyl ester in 67 was hydrolyzed using LiOH to give the acid 48 in 89% yield (Scheme
9
11).
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Scheme 11: Synthesis of the acid fragment 48
Synthesis of the amine 49 fragment commenced with the addition of vinylmagnesium bromide to the
silyloxy Weinreb amide 6713 at 0 °C to furnish the ketone 68 in 82% yield, which on reduction under
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Luche reduction conditions afforded the allyl alcohol 69 in good yield with 96:4 diastereomeric ratio.
Secondary allyl alcohol in 69 was protected as the TBS ether 70 and the selective deprotection of the
TES group was accomplished with PPTS to furnish the benzylic alcohol 52 in 80% yield. Esterification
of the benzylic alcohol 52 with NꢀFmoc protected Lꢀvaline gave the ester 71 in good yield. Deprotection
of the Fmoc group by treating with 20% piperidine in DMF afforded the free amine 49 in 93% yield
(Scheme 12).
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3
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OTES
OTES
OH Me
N
Me
MgBr
TESCl, Imidazole, DMAP
CH2Cl2, 0 °C to rt, 5 h
95%
N
Ph
THF, 0°C, 1 h
82%
Ph
Ph
OMe
OMe
O
O
68
O
67a
67
OTES
OTES
CeCl3—7H2O, NaBH4
MeOH, 0 °C to 78 °C
1 h, 91% (96:4 dr)
TBSCl, Imidazole
DMAP, CH2Cl2
0 °C to rt, 8 h
94%
PPTS (50 mol%)
MeOH:CH2Cl2 (1:1)
5 °C, 4 h, 80%
Ph
Ph
OTBS
OH
69
70
NHFmoc
NH2
NHFmoc
OH
O
OH
20% piperidine in DMF
rt, 0.5 h, 93%
O
O
O
O
Ph
2,4,6ꢀtrichlorobenzoyl chloride
Et3N, DMAP, CH2Cl2, rt, 2 h
81%
Ph
Ph
OTBS
52
OTBS
49
OTBS
71
Scheme 12: Synthesis of the amine fragment 49.
After synthesizing both the acid 48 and the amine 49 fragments, the peptide coupling was achieved
using EDCl to furnish the tetraene 47 in 50% yield. Ring closing metathesis reaction of the tetraene 47
using HoveydaꢀGrubbs second generation catalyst in refluxing toluene afforded the vital macrolactone
72 in 45% yield. Though formation of the macrolactone 72 was observed, its purification was
cumbersome and the structure was determined by NMR spectral data. Efforts to deprotect the phenolic
MOM groups under acidic conditions resulted in nonꢀcharacterizable mixture of products (Scheme 13).
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OMe
O
OMe
1
2
3
4
5
6
7
8
MOMO
MOMO
O
OTES
O
OTES
O
N
N
HGꢀII (10 mol%)
toluene, , 8 h
45%
NH
NH
O
EDCl.HCl, HOBT
48 + 49
CH2Cl2, rt, 2 h
50%
O
O
O
9
Ph
OMe
OMe
Ph
10
11
12
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48
49
50
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58
59
60
OTBS
OTBS
47
72
attempted deprotection of MOM and TBS groups
under acidic conditions led to non-characterizable
mixture of products
Scheme 13: Formation of the macrolactone core of aetheramide 72.
From the above findings and from the difficulties reported by Ghosh et. al. in the deprotection of
MEM group in their synthesis of aetheramide, it was inferred that the acid sensitive MOM protecting
group for the phenolic hydroxy should be avoided in the synthesis of aetheramide. Hence it was planned
to change the phenolic OH protection from MOM ether to the silyl ether. Accordingly methylation of
the phenol as well as the carbamate NHCbz in 73 (obtained from tyrosine using the procedure described
earlier) using NaH and MeI furnished the O,Nꢀdimethylated product 74 in good yield. Deprotection of
the benzyl as well as the Cbz groups in 74 using Pd/C furnished the free amino phenol 75 in 92% yield,
which was protected as its TIPS ether 76 in 82% yield. Coupling of 76 with the acid 65 afforded the
amide 77 in 60% yield. Hydrolysis of the ester in 77 was accomplished using potassium
trimethylsilonate in THF to give the acid 78 in 83% yield. Coupling of the acid 77 with the valine ester
49 afforded 79 in 80% yield. Ring closing metathesis of 79 with HoveydaꢀGrubbs’ second generation
catalyst afforded the macrolactone, the purification of which turned out to be cumbersome. Hence the
product obtained was reacted with PPTS which selectively deprotected the TES ether to furnish the βꢀ
hydroxy amide 80 in 34% yield for two steps. DessꢀMartin periodinane oxidation of the alcohol in 80
afforded the βꢀketo amide 81 in 84% yield. The crucial deprotection of the silyl groups in 81 with
TBAF was clean and did provide 15ꢀepiꢀaetheramide A 1 as evidenced from HRMS (Scheme 14).
However, we were not able to record pure 1H and 13C NMR spectra and our efforts to purify and isolate
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The Journal of Organic Chemistry
by column chromatography were futile. 14
1
2
3
4
5
6
7
8
NaH, MeI
COOH
HO
COOMe
MeO
BnO
COOMe
NMeCbz
THF:DMF
0 °C to 80 °C
12 h, 90%
Ref. 7
NH2
DꢀTyrosine
NHCbz
HO
BnO
9
74
73
10
11
12
13
14
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60
MeO
COOMe
NMeH
MeO
HO
COOMe
H2, Pd/C, MeOH, rt
1 h, 92%
TIPSCl, Imidazole, DMAP
CH2Cl2, 3 h, 82%
NMeH
TIPSO
75
76
OMe
OMe
TIPSO
TIPSO
O
OTES
O
OTES
O
OTES
HO
O
O
N
N
76
HATU, iPr2EtN
DMF, rt, 8 h
60%
OMe
OH
TMSOK, THF
rt, 2 h, 83%
OMe
OMe
OMe
65
78
77
OMe
O
OMe
O
TIPSO
TIPSO
NH2
O
O
OH
O
N
OTES
O
N
i) HGꢀII (10 mol%)
toluene, , 8 h
ii) PPTS
Ph
NH
NH
49
OTBS
EDCl.HCl, HOBT
O
O
O
O
CH2Cl2: MeOH (1:1)
rt, 2 h
CH2Cl2, rt, 2 h, 80%
Ph
OMe
Ph
OMe
34% (for 2 steps)
OTBS
OTBS
80
79
OMe
OMe
O
TIPSO
HO
O
O
O
O
O
N
N
NH
O
NH
DessꢀMartin Periodinane
NaHCO3, CH2Cl2, rt, 3 h
84%
TBAF, THF
rt, 2 h
O
O
O
Ph
OMe
Ph
OMe
OTBS
OH
15ꢀepiꢀaetheramide A1
81
Scheme 14: Total synthesis of 15ꢀepiꢀaetheramide A 1
In conclusion, a systematic investigation for the target oriented total synthesis of macrolactone natural
product aetheramide A by three different approaches is presented. The first approach involved
macrolactonization; however, it did not form the macrolactone while the second approach involved the
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ringꢀclosing metathesis for the C10ꢀC11 bond formation which afforded a truncated analogue. The
successful approach for the macrolactone was accomplished with formation of the strategic C18ꢀC19
bond by ring closing metathesis. Synthesis of the precursor for the successful RCM reaction was
achieved using chiral pool mandelic acid to install the chiral centers at the C20, C21 positions while
CBS reduction and Nagao aldol reactions were utilized to install the chiral centers at the C15 and C8
positions respectively.
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Experimental:
General Procedures: Column chromatography was performed on silica gel, Acme grade 100ꢀ200
mesh. TLC plates were visualized either with UV, in an iodine chamber, or with phosphomolybdic acid
spray. All reagents were purchased from commercial sources and used without additional purification.
1
THF was freshly distilled over Naꢀbenzophenone ketyl. Melting points were uncorrected. H NMR and
13C NMR spectra were recorded on a 400 MHz machine in CDCl3 as solvent with TMS as reference.
HRMS was obtained using a QꢀTOF spectrometer using electrospray ionization (ESI).
Preparation of (2S,3S,4E,9R,10E,12E,14R,15R)-15-((tert-butyldimethylsilyl)oxy)-3-hydroxy-1-((R)-
4-isopropyl-2-thioxothiazolidin-3-yl)-9-methoxy-14-(methoxymethoxy)-2,4,10-trimethyl-15-
phenylpentadeca-4,10,12-trien-1-one (dia-19): To a stirred solution of the alcohol 17 (0.14 g, 0.27
mmol) in CH2Cl2 was added MnO2 (0.241 g, 2.7 mmol) at room temperature and the resulting
suspension was refluxed for 2 h. The reaction mixture was filtered through a celite pad and
concentrated to afford the crude aldehyde, which was used as such in the next step without further
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The Journal of Organic Chemistry
purification.
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9
To a stirred solution of thiazolidine thione ent-18 (0.114 g, 0.54 mmol) in freshly distilled CH2Cl2 (15
mL) was added, TiCl4 (0.06 mL, 0.54 mmol) dropwise at −25 ºC under inert atmosphere and was stirred
for 5 min. Diisopropylethylamine (0.14 mL, 0.81 mmol) was introduced into the reaction mixture and
the resulting dark brown reaction mixture was stirred for 30 min at −25 °C. The solution of crude
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aldehyde (obtained above) in CH2Cl2 (4 mL) was added dropwise at −25 °C and stirred at the same
temperature. After completion of the reaction (15 min), it was quenched by addition of saturated NH4Cl
solution (10 mL). The reaction mixture was extracted with EtOAc (2 × 10 mL). The organic layer was
washed with brine, and then dried over anhyd. Na2SO4. It was concentrated in vacuo to provide the
crude residue which was purified by Silica gel column chromatography using petroleum ether: EtOAc
(5:1) as eluent to afford the pure alcohol dia-19 (0.17 g, 92% for 2 steps) as a yellow oil. [α]D: −147.1 (c
1.06, CHCl3); IR (Neat): νmax 3355, 2931, 2887, 1604, 1466 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 7.35ꢀ
7.20 (m, 5H), 6.35 (dd, J = 15.2, 10.8 Hz, 1H), 5.87 (d, J = 10.8 Hz, 1H), 5.54 (t, J = 6.8 Hz, 1H), 5.40
(dd, J = 15.4, 7.2 Hz, 1H), 5.24ꢀ5.18 (m, 1H), 5.00 (dd, J = 7.0, 3.6 Hz, 1H), 4.39, 4.06 (ABq, J = 6.4
Hz, 1H), 4.58 (d, J = 6.8 Hz, 1H), 4.47 (s, 1H), 4.21(t, J = 6.2 Hz, 1H), 3.55ꢀ3.45 (m, 1H), 3.41 (t, J =
6.4 Hz, 1H), 3.15 (s, 3H), 3.13 (s, 3H), 3.01 (d, J = 11.6 Hz, 1H), 2.86 (bs, 1H), 2.40ꢀ2.28 (m, 1H),
2.10ꢀ1.92 (m, 2H), 1.59 (bs, 3H), 1.58 (bs, 3H), 1.47ꢀ1.32 (m, 2H), 1.10ꢀ1.00 (m, 8H), 0.97 (d, J = 6.8
Hz, 3H), 0.87 (s, 9H), 0.04 (s, 3H), −0.10 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 202.9 , 178.0, 141.5,
137.4, 133.5, 129.9, 128.8, 127.5 (2 × C), 127.1 (3 × C), 126.9, 126.1, 94.5, 87.0, 80.7, 77.8, 74.8, 71.8,
55.8, 55.2, 40.7, 33.2, 30.7, 29.6, 27.4, 25.73 (3 × C), 25.67, 19.0, 18.2, 17.4, 13.5, 11.0, 10.6, –4.9, –
5.0; HRMS: m/z calcd for C39H63NO6S2Si+Na 756.3764; found 756.3763.
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Preparation
of
(2S,3S,4E,9S,10E,12E,14R,15R)-15-((tert-butyldimethylsilyl)oxy)-1-((R)-4-
isopropyl-2-thioxothiazolidin-3-yl)-9-methoxy-14-(methoxymethoxy)-2,4,10-trimethyl-15-phenyl-
3-((triisopropylsilyl)oxy)pentadeca-4,10,12-trien-1-one (dia-19a): To a solution of diaꢀ19 (0.17 g,
0.24 mmol) and pyridine (0.04 mL, 0.48 mmol) in CH2Cl2 (2 mL) was added TIPSOTf (0.064 mL,
0.36 mmol) at −50 °C. The mixture was allowed to warm up to room temperature and was stirred at
room temperature for 2 h. After the reaction was complete (TLC), it was washed with saturated aq.
NaHCO3 solution (5 mL) and was extracted with EtOAc (3×10 mL). The combined organic layers were
washed with brine (5 mL), dried over anhyd. Na2SO4, and the solvent was evaporated off to give crude
residue which was purified by silica gel column chromatography using petroleum ether: EtOAc (10:1)
as eluent to afford desired product dia-19a (0.15 g, 75%) as yellow oil. [α]D: −110.9 (c 1.28, CHCl3); IR
(Neat): νmax 2931, 2862, 1694, 1602, 1462 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 7.37ꢀ7.17 (m, 5H), 6.35
(dd, J = 15.2, 11.0 Hz, 1H), 5.87 (d, J = 11.0 Hz, 1H), 5.40 (dd, J = 15.4, 7.2 Hz, 1H), 5.33 (t, J = 6.4
Hz, 1H), 5.21(dd, J = 7.6, 6.0 Hz, 1H), 5.17ꢀ5.07 (m, 1H), 4.70 (d, J = 5.2 Hz, 1H), 4.66 (d, J = 6.8 Hz,
1H), 4.58 (d, J = 6.8 Hz, 1H), 4.48 (d, J = 9.2 Hz, 1H), 4.21 (t, J = 6.0 Hz, 1H), 3.45ꢀ3.33 (m, 2H), 3.15
(s, 3H), 3.13 (s, 3H), 2.89 (d, J = 11.6 Hz, 1H), 2.14 (dq, J = 13.0, 6.4 Hz, 1H), 1.97 (td, J = 14.8, 7.6
Hz, 1H), 1.87ꢀ1.75 (m, 1H), 1.61 (s, 3H), 1.58 (s, 3H), 1.48ꢀ1.29 (m, 2H), 1.26 (d, J = 6.8 Hz, 3H),
1.30ꢀ1.15 (m, 2H), 1.10ꢀ1.00 (m, 21H), 0.98 (d, J = 6.8, 3H), 0.90 (s, 9H), 0.89ꢀ0.84 (m, 3H), 0.05 (s,
3H), −0.10 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 202.3, 176.0, 141.6, 137.6, 135.8, 129.9, 128.8 (2 ×
C), 127.6 (2 × C), 127.1 (3 × C), 126.8, 94.5, 87.1, 80.8, 80.4, 77.8, 71.3, 55.8, 55.2, 43.1, 33.6, 30.8,
28.5, 27.6, 25.8 (3 × C), 25.4, 19.0, 18.3, 18.2 (3 × C), 18.1 (3 × C), 17.0, 15.5, 12.6 (3 × C), 11.7, 11.0,
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–4.8, –4.9; HRMS: m/z calcd for C48H83NO6S2Si2+Na 912.5098; found 912.5096.
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Preparation of (2S,3S,4E,9S,10E,12E,14R,15R)-15-((tert-butyldimethylsilyl)oxy)-9-methoxy-14-
(methoxymethoxy)-2,4,10-trimethyl-15-phenyl-3-((triisopropylsilyl)
oxy)
pentadeca-4,10,12-
trienoic acidd (dia-7): To a stirred solution of thione dia-19a (0.150 g, 0.21 mmol) in THF (3 mL)
were added LiOH (0.63 mL of 1.0 M aq.solution, 0.63 mmol) followed by H2O2 (1.0 mL of 30% w/v
solution in water). The reaction mixture was stirred for 2 h at room temperature and was acidified to pH
= 7 carefully with 2N HCl. The reaction mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layer was washed with brine (5 mL), dried over anhyd. Na2SO4 and concentrated. The crude
residue thus obtained was purified by silica gel column chromatography using EtOAc as eluent to afford
dia-7 (0.106 g, 68%) as a colorless oil. [α]D: −28.4 (c 1.9, CHCl3); IR (Neat): νmax 3400, 2919, 1710,
1
1655, 1086 cmꢀ1; H NMR (400 MHz, CDCl3):
δ 7.40ꢀ7.20 (m, 5H), 6.34 (dd, J = 15.2, 11.0 Hz, 1H),
5.87 (d, J = 11.0 Hz, 1H), 5.41 (dd, J = 15.2, 7.2 Hz, 1H), 5.33 (t, J = 7.2 Hz, 1H), 4.70, 4.66 (ABq, J =
6.8 Hz, 2H), 4.58 (d, J = 6.8 Hz, 1H), 4.31 (d, J = 6.8 Hz, 1H), 4.27ꢀ4.16 (m, 1H), 3.41 (t, J = 6.4 Hz,
1H), 3.15 (s, 3H), 3.14 (s, 3H), 2.74ꢀ2.61 (m, 1H), 2.08ꢀ1.95 (m, 2H), 1.59 (s, 3H), 1.58 (s, 3H), 1.50ꢀ
13
1.20 (m, 4H), 1.15ꢀ1.00 (m, 24H), 0.87 (s, 9H), 0.04 (s, 3H), −0.10 (s, 3H); C NMR (100 MHz,
CDCl3):
δ 176.5 (Cq), 141.6 (Cq), 137.3 (Cq), 134.3 (Cq), 130.1 (CH), 129.5 (CH), 128.8 (CH), 127.6
(2 × CH), 127.2 (3 × CH), 127.0 (CH), 94.5 (CH2), 87.2 (CH), 81.0 (CH), 80.8 (CH), 77.8 (CH), 55.8
(CH3), 55.2 (CH3), 44.2 (CH), 33.0 (CH2), 27.2 (CH2), 25.8 (3 × CH3), 25.4 (CH2), 18.3 (Cq), 18.0 (3 ×
CH3), 17.9 (3 × CH3), 13.0 (CH3), 12.3 (3 × CH), 11.3 (CH3), 11.0 (CH3), –4.8 (CH3), –4.9 (CH3);
HRMS: m/z calcd for C42H74O7Si2+Na 769.4871; found 769.4873.
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Preparation
of
methyl
(R)-3-(3-acetyl-4-(methoxymethoxy)phenyl)-2-
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(((benzyloxy)carbonyl)amino) propanoate (21): To a precooled (0 °C) solution of 209 (4.17 g, 11.25
i
mmol) in dichloromethane (20 mL) were added DMAP (0.274 g, 2.25 mmol) and Pr2NEt (11.7 mL,
67.48 mmol) dropwise followed by MOMCl (2.60 mL, 33.74 mmol). The reaction mixture was slowly
allowed to warm to room temperature and stirred at room temperature for 6 h. After completion of the
reaction (TLC), it was poured into water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined
organic layers were washed with brine (5 mL) and dried over Na2SO4. Evaporation of solvent gave the
crude residue which was purified by silica gel column chromatography using petroleum ether: EtOAc
(3:1) as an eluent to furnish 21 (3.71 g, 82%) as a colorless oil. [α]D24: −45.0 (c 0.5, CHCl3); IR (Neat):
ν
max 3341, 2953, 1725, 1608, 1494 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 7.48 (d, J = 2.4 Hz, 1H), 7.40ꢀ
7.26 (m, 5H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.41 (d, J = 7.2 Hz, 1H), 5.24 (s,
2H), 5.08 (s, 2H), 4.62 (dd, J = 13.6, 6.0 Hz, 1H), 3.73 (s, 3H), 3.49 (s, 3H), 3.11 (dd, J = 14.0, 5.4 Hz,
1H), 3.03 (dd, J = 14.0, 6.2 Hz, 1H), 2.61 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 199.3, 171.7, 155.6,
136.1, 134.3, 130.9, 129.0, 128.7, 128.5 (3 × C), 128.2, 128.0 (2 × C), 115.0, 94.4, 67.0, 56.4, 54.7,
52.4, 37.1, 31.8; HRMS: m/z calcd for C22H25NO7+Na 438.1529; found 438.1526.
Preparation of methyl (R)-2-(((benzyloxy)carbonyl)amino)-3-(3-hydroxy-4-(methoxymethoxy)
phenyl) propanoate (22): A solution of 21 (0.91 g, 2.26 mmol) in 10 mL of dry CH2Cl2 was treated
with mCPBA (57ꢀ85%, 1.20 g) and warmed at 40 °C overnight. The solution was diluted with ether and
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washed with saturated sodium thiosulfate (15 mL), sat. sodium bicarbonate (15 mL), and brine (20 mL),
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3
dried over anhyd. Na2SO4 and concentrated in vacuo to afford crude residue.
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7
8
To a stirred solution of the crude residue (obtained above) in MeOH (10 mL) was added potassium
carbonate (0.468 g, 3.39 mmol) at room temperature. The stirring was continued until completion (TLC)
of the reaction. Then MeOH was evaporated in vacuo to give crude, which was washed with water (10
mL) followed by brine (5 mL) and was extracted with ethyl acetate. The organic layer was dried over
Na2SO4, concentrated and purified by silica gel column chromatography using petroleum ether: EtOAc
(3:1) as eluent to furnish 22 (0.70 g, 80%) as a colorless oil. [α]D24: −47.4 (c 2.1, CHCl3); IR (Neat):
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ν
max 3368, 2955, 1744, 1512, 1221 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 7.43ꢀ7.24 (m, 5H), 6.95 (d, J =
8.2 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.53 (dd, J = 8.2, 2.0 Hz, 1H), 6.21 (bs, 1H), 5.38 (d, J = 7.4 Hz,
1H), 5.12 (s, 2H), 5.08 (s, 2H), 4.61 (dd, J = 13.8, 5.8 Hz, 1H), 3.70 (s, 3H), 3.47 (s, 3H), 3.08ꢀ2.93 (m,
13
2H); C NMR (100 MHz, CDCl3):
δ 171.9, 156.6, 146.3, 143.6, 136.1, 130.5, 128.3 (3 × C), 128.0,
127.9, 120.8, 116.2, 115.6, 95.8, 66.8, 56.2, 54.7, 52.2, 37.3; HRMS: m/z calcd for C20H23NO7+Na
412.1372; found 412.1374.
Preparation
of
methyl
(R)-2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-
(methoxymethoxy) phenyl) propanoate (22a): To a preꢀcooled solution of alcohol 22 (1.863 g, 4.62
mmol) in THF:DMF (15 mL:1.5 mL) was added NaH (0.407 g of 60% dispersed in mineral oil, 10.17
mmol) portion wise at 0 °C and stirred at the same temperature for 0.5 h. Then methyl iodide (1.5 mL,
23.11 mmol) was introduced into the reaction mixture at 0 °C and slowly warmed to room temperature,
raised to 80 °C and the stirring was continued for an additional 8 h. After completion of the reaction
(TLC), it was cooled to room temperature and was cautiously quenched by addition of sat. NH4Cl
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solution (20 mL). The reaction mixture was extracted with EtOAc (2 × 20 mL). The combined organic
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3
layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent
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6
gave the crude residue which was purified by silica gel column chromatography using petroleum ether:
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8
24
EtOAc (5:1) as eluent to furnish 22a (1.74 g, 90%) as a colorless oil as a mixture of rotamers. [α]D
:
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1
+11.6 (c 1.25, CHCl3); IR (Neat): νmax 2948, 1742, 1697, 1512, 1450 cmꢀ1; H NMR (400 MHz,
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CDCl3):
δ 7.37ꢀ7.15 (m, 5Hmaj+min), 7.07ꢀ6.98 (m, 1Hmaj+min), 6.80ꢀ6.68 (m, 0.7Hmaj), 6.67ꢀ6.56 (m,
1Hmaj+min, 0.3Hmin), 5.19 (s, 2Hmaj+min), 5.15ꢀ4.95 (m, 2Hmaj+min), 4.78 (dd, J = 10.4, 4.4 Hz, 0.3Hmin),
4.35ꢀ4.05 (m, 0.7Hmaj), 3.79 (s, 2Hmaj), 3.74 (s, 1Hmin), 3.73 (s, 2Hmaj), 3.68 (s, 1Hmin), 3.50 (s,
3Hmaj+min), 3.35ꢀ3.20 (m, 0.7Hmaj), 3.10ꢀ2.90 (m, 0.3Hmin, 1Hmaj+min), 2.88 (s, 1Hmin), 2.81 (s, 2Hmaj); 13C
NMR (100 MHz, CDCl3):
δ 173.8 (maj), 171.4(min), 156.5 (maj+min), 149.5 (maj+min), 145.1
(maj+min), 136.5 (maj), 136.2 (min), 131.1 (maj+min), 128.3 (3 × C maj+min), 127.7 (min+min), 127.4
(maj+min), 120.9 (min+maj), 116.2 (maj+min), 112.2 (min), 112.0 (maj), 95.4 (maj+min), 67.3 (min),
67.1 (maj), 60.6 (min), 59.8 (maj), 56.0 (maj+min), 55.6 (maj+min), 52.2 (maj+min), 34.7 (min), 34.3
(maj), 32.0 (min), 31.5 (maj); HRMS: m/z calcd for C22H27NO7+Na 440.1788; found 440.1784.
Preparation of (R)-2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-(methoxymethoxy)
phenyl) propanoic acid (23): To a stirred solution of 22a (1.404 g, 3.26 mmol) in THF (16 mL) was
added 2M aq. solution of LiOH (8.14 mL, 16.29 mmol) and was stirred at room temperature for 4 h.
Progress of the reaction was monitored by TLC and after completion of the reaction, it was diluted with
water (5 mL), neutralized with dil. HCl (pH = 4) and extracted with EtOAc (2 × 10 mL). The combined
organic layer was washed with brine (5 mL), dried (anhyd. Na2SO4). The solvent was removed under
reduced pressure and silica gel column chromatography of the resulting crude residue using EtOAc as
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eluent afforded 23 (1.22 g, 93%) as a colorless oil as a mixture of rotamers. [α]D: +13.2 (c 2.5, CHCl3);
IR (Neat): νmax 3377, 2835, 1802, 1705, 1514cmꢀ1; 1H NMR (400 MHz, CDCl3):
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2
3
4
δ
8.45 (bs, 1Hmaj+min),
5
6
7.40ꢀ7.15 (m, 5Hmaj+min), 7.04 (d, J = 8.0 Hz, 1Hmaj+min), 6.83ꢀ6.56 (m, 2Hmaj+min), 5.20 (s, 2Hmaj+min),
7
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5.17ꢀ5.02 (m, 2Hmaj+min), 5.04ꢀ4.94 (m, 0.7Hmaj), 4.87ꢀ4.77 (m, 0.3Hmin), 3.77 (s, 2Hmaj), 3.72 (s, 1Hmin),
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3.50 (s, 3Hmaj+min), 3.44ꢀ3.22 (m, 0.7Hmaj), 3.20ꢀ3.10 (m, 0.3Hmin), 3.10ꢀ2.95 (m, 1Hmaj+min), 2.88 (s,
13
1Hmin), 2.81 (s, 2Hmaj); C NMR (100 MHz, CDCl3):
δ 175.6 (maj), 175.5 (min), 156.8 (maj), 155.8
(min), 149.6 (maj+min), 145.5 (min), 145.1 (maj), 136.3 (maj), 136.0 (min), 131.0 (maj), 129.7 (min),
128.5 (maj+min), 128.4 (maj+min), 128.2 (maj), 128.0 (min), 127.9 (maj), 127.8 (min), 127.5
(maj+min), 121.5 (min), 120.9 (maj), 116.2 (maj+min), 112.7 (maj), 112.0 (min), 95.4 (min), 95.3
(maj), 67.6 (min), 67.4 (maj), 60.5 (maj), 60.3 (min), 56.1 (maj), 55.7 (maj), 34.6 (maj), 34.1 (CHmin),
32.0 (maj+min), 21.0 (min), 20.7 (maj); HRMS: m/z calcd for C21H25NO7+Na 426.1529; found
426.1529.
Preparation
of
methyl
((R)-2-(((benzyloxy)carbonyl)(methyl)amino)-3-(3-methoxy-4-
(methoxymethoxy) phenyl) propanoyl)-L-valinate (24): To a stirred solution of acid 23 (1.175 g, 2.91
mmol) in CH2Cl2 (15 mL) were added EDCl·HCl (1.673 g, 8.73 mmol), HOBT (1.10 g, 8.15 mmol) and
Et3N (0.81 mL, 5.83) in sequence at room temperature and it was cooled to 0 °C and methyl Lꢀvalinate
(0.974 g, 5.83 mmol) was introduced into the reaction mixture at the same temperature. Then it was
slowly warmed to room temperature and stirred. After completion of the reaction (TLC) it was washed
with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with
brine (5 mL), dried over anhyd. Na2SO4. The solvent was removed in vacuo and silica gel column
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chromatography of the resulting crude residue using petroleum ether: EtOAc (2:1) as eluent afforded 24
(1.21 g, 80%) as a colorless oil as a mixture of rotamers [α]D: +65.6 (c 0.8, CHCl3); IR (Neat): νmax
1
2
3
4
5
6
3382, 2927, 2370, 1741, 1265 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 7.45ꢀ7.15 (m, 5Hrot1+rot2), 7.03 (d, J
7
8
9
= 8.0 Hz, 1Hrot1+rot2), 6.80ꢀ6.55 (m, 3Hrot1+rot2), 5.25ꢀ4.90 (m, 3Hrot1+rot2), 5.19 (s, 1Hrot1), 5.14 (s, 1Hrot2),
4.47 (bd, J = 4.8 Hz, 1Hrot1+rot2), 3.81 (s, 1.5Hrot1+rot2), 3.80 (s, 1.5Hrot1+rot2), 3.69 (s, 1.5Hrot1+rot2), 3.50 (s,
1.5Hrot1+rot2), 3.75ꢀ3.60 (m, 1Hrot1+rot2), 3.50 (s, 2Hrot1+rot2), 3.40ꢀ3.25 (m, 1Hrot1+rot2), 3.00ꢀ2.80 (m,
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1Hrot1+rot2), 2.87 (s, 3Hrot1+rot2), 2.12 (td, J = 12.4, 6.0 Hz, 1Hrot1+rot2), 0.86 (d, J = 6.8 Hz, 3Hrot1+rot2), 0.81
13
(d, J = 6.8 Hz, 3Hrot1+rot2); C NMR (100 MHz, CDCl3):
δ 171.9 (rot1+rot2), 171.0 (rot1+rot2), 155.8
(rot1+rot2), 149.5 (rot1+rot2), 145.2 (rot1+rot2), 135.9 (rot1+rot2), 130.4 (rot1+rot2), 128.3 (2 × C
rot1+rot2), 127.9 (rot1+rot2), 127.7 (rot1+rot2), 127.3 (rot1+rot2), 121.2 (rot1+rot2), 116.2 (rot1+rot2),
112.4 (rot1+rot2), 95.0 (rot1+rot2), 77.3 (rot1+rot2), 66.7 (rot1+rot2), 57.0 (rot1+rot2), 55.8
(rot1+rot2), 55.5 (rot1+rot2), 51.9 (rot1+rot2), 38.1 (rot1+rot2), 30.8 (rot1+rot2), 18.7 (rot1+rot2), 18.5
(rot1+rot2), 17.5 (rot1+rot2); HRMS: m/z calcd for C27H36N2O8+Na 539.2369; found 539.2364.
Preparation
of
methyl
((R)-3-(3-methoxy-4-(methoxymethoxy)phenyl)-2-(methylamino)
propanoyl)-L-valinate (8): To a solution of 24 (1.136 g, 2.06 mmol) in MeOH (20 mL) was added 10%
palladium on activated charcoal (0.114 g) under argon atmosphere. The reaction mixture was stirred for
1 h under hydrogen atmosphere. After completion of the reaction (TLC), it was filtered through a short
pad of celite® and the celite pad was washed with EtOAc (20 mL). Evaporation of solvent followed by
silica gel column chromatography of the resulting crude residue using EtOAc as eluent yielded 8 (0.722
g, 92%) as a colorless oil. [α]D: +52.0 (c 0.39, CHCl3); IR (Neat): νmax 3382, 2923, 1659, 1512, 1463
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1
cmꢀ1; H NMR (400 MHz, CDCl3):
δ 7.61 (d, J = 9.2 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H),
1
2
3
4
5
6
7
8
6.64 (d, J = 8.0 Hz, 1H), 5.11 (s, 2H), 4.45 (dd, J = 9.2, 4.8 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 3.42 (s,
3H), 3.13 (dd, J = 9.8, 4.0 Hz, 1H), 3.05 (dd, J = 13.8, 3.8 Hz, 1H), 2.55 (dd, J = 13.8, 10.0 Hz, 1H),
2.23 (s, 3H), 2.12 (td, J = 13.0, 6.4 Hz, 1H), 1.49 (bs, 1H), 0.87 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.8 Hz,
9
3H); 13C NMR (100 MHz, CDCl3):
δ 173.4, 172.0, 149.7, 145.1, 131.6, 120.9, 116.3, 112.1, 96.2, 66.1,
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56.3, 55.9, 55.6, 51.8, 38.7, 35.4, 30.8, 18.9, 17.5; HRMS: m/z calcd for C19H30N2O6+H 383.2182;
found 383.2184.
Preparation of methyl ((R)-2-((2R,3R,4E,9S,10E,12E,14R,15R)-15-((tert butyldimethylsilyl)oxy)-9-
methoxy-14-(methoxymethoxy)-N,2,4,10-tetramethyl-15-phenyl-3-((triethylsilyl)oxy) pentadeca-
4,10,12-trienamido)-3-(3-methoxy-4-(methoxymethoxy) phenyl) propanoyl)-L-valinate (25): To a
stirred solution of the acid 7 (0.072 g, 0.10 mmol) in DMF (1 mL) was added HATU (0.057 g, 0.15
mmol) at rt and stirring was continued for 5 minutes, iPr2EtN (0.04 mL, 0.3 mmol) was introduced into
the reaction flask and stirred for 15 minutes at rt. Then amine 8 (0.059 g, 0.15 mmol) in DMF (2 mL)
was added to the reaction and stirred. After the reaction was complete (as indicated by TLC), the
contents were poured into ice cold water and extracted with EtOAc (2 × 10 mL). The combined organic
layers were washed with brine (10 mL) and dried over anhyd. Na2SO4. The crude residue obtained after
removal of solvent in vacuo was purified by silica gel column chromatography using petroleum ether:
EtOAc (4:1) as eluent to afford the required product 25 (0.065 g, 68%) as a colorless oil. [α]D: −1.5 (c
0.20, CHCl3); IR (neat): νmax 2955, 2935, 1746, 1651, 1512 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ
7.40ꢀ
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