Synthesis of new diverse macrocycles from diol precursors

Article abstract of DOI:10.1016/j.tet.2010.10.071

The formation of a library of diverse macrocycles with different ring sizes from two easily accessible building blocks is presented. Reacting diol precursors with electrophilic reagents lead to 17-membered sulfites and 19-membered malonates in 34-79% yiel

Full text of DOI:10.1016/j.tet.2010.10.071

Tetrahedron 66 (2010) 9849e9859
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new diverse macrocycles from diol precursors
*
Charlotte M. Madsen, Martin Hansen, Marie V. Thrane, Mads H. Clausen
Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 201, DK-2800 Kgs. Lyngby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2010
Received in revised form 6 October 2010
Accepted 25 October 2010
Available online 29 October 2010
The formation of a library of diverse macrocycles with different ring sizes from two easily accessible
building blocks is presented. Reacting diol precursors with electrophilic reagents lead to 17-membered
sulfites and 19-membered malonates in 34e79% yield. Double-reductive amination of dialdehyde ana-
logs of the diol precursors leads to 15-membered amines in yields ranging from 9 to 60%, reflecting large
differences in reactivity based on steric environment.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Macrocyclization
Cyclic esters
Reductive amination
Diversity-oriented synthesis
1. Introduction
naturally occurring substructural motifs, and hence providing rapid
access to synthetic libraries, is providing an increased chance of
Macrocyclic compounds are attractive targets within drug dis-
covery due to the fact that naturally occurring macrocycles often
display diverse and interesting biological activities. This arises from
several structural advantages characteristic for this compound
class. Macrocycles are conformationally preorganized, enabling
them to bind selectively to targets with minimal entropic loss.
However, they have a certain flexibility, which, in combination with
their functionally independent subregions, enables them to bind
non-covalently to each other or to mediate the assembly of other
macromolecules by non-covalent interactions. Furthermore, they
have the ability of burying away polar functionalities, leading to
improved membrane permeability as compared to their linear an-
alogs. Proteolytic and metabolic stability is also improved as
a consequence of the reduced accessible conformational space.1
The substructures of naturally occurring macrocycles provide
valuable inspiration for the design of new synthetic macrocycles,
because of the above mentioned biological activity of this com-
pound class. Substructures frequently present in naturally occur-
ring macrocycles are, for example, polyketides, heterocycles,
peptide, biphenyl, and (bi)aryl ether domains.2 A drawback of tra-
ditional natural product chemistry is the often complex structures
and the synthetic effort thus required. Hence, an approach com-
bining natural product drug discovery, and combinatorial chemis-
try has been suggested.3,4 This strategy, designing synthetic
compounds from easily accessible building blocks containing
finding a potent drug. Despite the challenge in forming large ring
systems, macrocyclic compounds are interesting targets for this
strategy and the generation of libraries of macrocycles has received
significant attention recently.5
Encouraged by our recently reported method on formation of
macrocyclic rings from diol precursors,6 we were interested in
generating a library of diverse macrocycles based on this strategy.
According to the above, we aimed at producing macrocycles in
a few diversity-generating steps starting from two simple building
blocks, one containing a heterocycle (triazole) and one containing
a hydroxy alkene (a fragment inspired by polyketides). Four
structurally isomeric diol precursors are formed through combi-
nations of the two building blocks by esterifications. These are then
cyclized, either in one step by reaction with bis-electrophilic re-
agents, or in two steps by forming the dialdehyde derivatives and
then reacting them with a nucleophilic reagent.
2. Results and discussion
The building blocks for the synthesis of diol precursors were
readily obtained in good yields from simple, commercially available
starting materials (Scheme 1 and 2). Substitution of 4-chlorobutyl
benzoate with sodium azide, followed by a copper(I) catalyzed al-
kyne/azide cycloaddition reaction7 of the resulting azide with
TBDMS protected propargyl alcohol afforded the protected triazole
building block 1 (Scheme 1). Reductive cleavage of the benzoyl
group gave one of the desired alcohol derivatives 2 (ready for es-
terification). The other desired alcohol derivative 4 was obtained by
* Corresponding author. Tel.: þ45 45252131; fax: þ45 45933968; e-mail address:
mhc@kemi.dtu.dk (M.H. Clausen).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.071

9850
C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
TBDPS protection of 2 and subsequent selective monodeprotection
by acidic solvolysis. Preliminary attempts to use a triphenylsilyl
(TPS) ether as a protecting group instead of TBDPS did not give the
desired selectivity, as the TPS group was found to be more prone to
hydrolysis than the TBDMS group.
reductive cleavage of the methyl ester. Deprotection with TBAF
went smoothly, giving the diol 10 in an excellent yield. Most sat-
isfyingly, the allylic hydroxy group could be selectively TBDPS
protected at ꢀ78 ꢁC in dichloromethane. Swern15 and sodium
chlorite16 oxidations yielded the other desired carboxylic acid 12.
Preliminary attempts to selectively cleave the TBDMS group from
the TPS protected analog of 9 proved unsuccessful for the same
reason as specified above for the triazole building block.
The alcohols 2 and 4 were combined with the carboxylic acids 8
and 12 by carbodiimide promoted esterifications17 (Scheme 3)
yielding the four esters 13, 15, 17, and 19, which were deprotected
smoothly with TBAF to give the desired diol precursors.
Scheme 1. Reagents and conditions: (a) (i) NaN3, n-Bu4NI, DMF, 60 ꢁC, (ii) tert-bu-
tyldimethyl(prop-2-ynyloxy)silane, DIPEA, CuI, THF; (b) DIBAL-H, CH2Cl2, ꢀ78 ꢁC; (c)
TBDPSCl, imidazole, DMF; (d) PPTS, MeOH, 55 ꢁC.
Grignard reaction of TBDMS protected hydroxy acetone with
vinyl magnesium chloride (giving 58) followed by a cross-metath-
esis reaction9 with methyl acrylate gave the (E)-enol building block
610 (Scheme 2). The HoveydaeGrubbs second generation catalyst11
was more efficient in this transformation than the Grubbs second
generation catalyst.12 Interestingly, despite the reaction being
somewhat slower with 0.5% catalyst loading as compared to 5%, we
found the overall conversion to be higher with the lower loading.
Scheme 3. Reagents and conditions: (a) EDC$HCl, DMAP, CH2Cl2; (b) TBAF, THF.
The diols 14, 16, 18, and 20 were treated with thionyl chloride,
triethylamine and DMAP under our standard conditions6 to obtain
the 17-membered macrocyclic sulfites 21, 23, 25, and 27, re-
spectively (Scheme 4). The sulfites were obtained in yields ranging
from 43 to 79% reflecting a difference in the steric environment of
the cyclization precursors. This is further emphasized by the fact
that the diastereomeric ratio of 21, formed from the most sterically
hindered diol precursor, differs from the diastereomeric ratios of
the other sulfites in being 2:1 as compared to 1:1 (or 3:2). Not
surprisingly, cyclizations of the two least sterically hindered diol
precursors 18 and 20 result in higher yields than cyclizations of the
more hindered substrates 14 and 16.
Scheme 2. Reagents and conditions: (a) vinyl magnesium chloride, THF, 0 ꢁC; (b)
Hoveyda-Grubbs second gen. cat., methyl acrylate, CH2Cl2, 40 ꢁC; (c) PMBTCA, La(OTf)3,
toluene; (d) LiOH, THF/H2O 3:1; (e) DIBAL-H, CH2Cl2, ꢀ78 ꢁC; (f) TBAF, THF; (g)
TBDPSCl, imidazole, CH2Cl2, ꢀ78 ꢁC; (h) (i) DMSO, (COCl)2, ꢀ78 ꢁC, Et3N, (ii) NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH, THF.
PMB protection of 6 with p-methoxybenzyl trichloroacetimidate
(PMBTCA)13 under mild conditions14 gave 7, which could be hy-
drolyzed under basic conditions to yield one of the desired car-
boxylic acid derivatives 8. The alcohol 9 was obtained from 7 by

C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
9851
(DMBNH2) since it has been reported that removal of the DMB group
from a dialkylated amine can be accomplished under mild condi-
tions by the use of DDQ.20 Unfortunately, double-reductive amina-
tion of 33 by use of our previously reported method6 resulted in only
9% yield of the product 34. The reason for this low yield was likely to
be found in the steric environment of the a,a,a-trisubstituted alde-
hyde group of 33. As several attempts to optimize the yield by al-
tering the reaction conditions (reducing or increasing the
concentration, change of reductive agents and amines, addition of
acid and longer imine formation times) failed, we decided to in-
vestigate the cyclizations of the two less sterically hindered dia-
ldehydes 35 and 39, obtained in excellent yields from 18 and 20. We
werepleased to findthat the products 36 and 40of these cyclizations
were obtained in highly improved yields, 46% and 60%, respectively.
Thus, these results confirm that 33 is too sterically hindered to un-
dergo double-reductive amination in a satisfactory yield.
Scheme 4. Reagents and conditions: (a) SOCl2, Et3N, DMAP, CH2Cl2; (b) DDQ, CH2Cl2/
H2O 18:1.
Subsequent deprotection of the PMB ethers with DDQ to obtain
the sulfites 22a, 24, 26, and 28 resulted in yields ranging from 30 to
67%. The low yield for the deprotection of 21 is caused by lability of
the product to column chromatography. This was proven by the
isolation of a five-membered cyclic sulfite by-product 22b formed
upon nucleophilic attack by the tertiary hydroxy group on the
macrocyclic sulfite. The identification of the product 22a and the
by-product 22b as single diastereomers confirms that only one of
the diastereomers of the deprotected sulfite is susceptible to the
intramolecular transesterification of the sulfite.
Next, we were interested in extending the above cyclization
method to the formation of malonates. Diol precursors 14 and 16
were treated with malonyl chloride under the above conditions,
giving the 19-membered malonates 29 and 31 (Scheme 5) in 37 and
34% yield, respectively. Thus, the yields for formation of malonates
are slightly lower than for the formation of sulfites, possibly related
to the difference in ring sizes formed and/or the relative reactivity
of the reagents.
Scheme 6. Reagents and conditions: (a) IBX, CH3CN, 55 ꢁC; (b) DMBNH2, Na(OAc)3BH,
CH2Cl2; (c) DDQ, CH2Cl2/H2O 5:1; (d) DDQ, CH2Cl2/MeOH 9:1.
The deprotection of the amines turned out to be a very slow
reaction, especially for the removal of the DMB group. Hence, the
PMB group of the amines 36 and 40 could be selectively cleaved by
use of 3 equiv of DDQ, yielding the amines 37 and 41. Several at-
tempts at the full deprotection of 40 to 42 were carried out with
DDQ and CAN; use of the former was found to give little conversion
whereas use of the latter was unsuccessful. It has been reported
that deprotection of DMB protected amines can be inefficient for
some substrates.21 Substituting the usual biphasic CH2Cl2/H2O
solvent to a miscible solvent (CH2Cl2/MeOH 9:1) led to the highest
conversion, although the use of as much as 20 equiv of DDQ over 7
days gave a modest NMR yield of 15%. Attempts at the isolation of
42 (verified by LCMS) from a mixture of the amines 41 and 42 by
flash column chromatography were not successful, presumably due
to the two compounds having the same Rf value. Unfortunately, the
full deprotection of 36e38 was not successful by use of the above
conditions.
Scheme 5. Reagents and conditions: (a) malonyl chloride, Et3N, DMAP, CH2Cl2; (b)
DDQ, CH2Cl2/H2O 18:1.
The malonates were deprotected analogously to the sulfites,
giving 30 and 32. The products were obtained in higher yields than
their sulfite analogs, presumably because the malonates are more
stable than the sulfites.
Our next target was the 15-membered macrocyclic amine 34
(Scheme 6). The dialdehyde cyclization precursor 33 was prepared
by oxidation of 14 in an excellent yield. For this reaction, IBX18 was
found to be superior to the DesseMartin periodinane19 as oxidizing
agent. Our choice of amine was 3,4-dimethoxybenzylamine
3. Conclusion
We have demonstrated that a library of diverse macrocycles
with different ring sizes and functionalities can be formed in a few

9852
C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
steps from simple building blocks containing primary alcohols. The
structural and biological properties of the macrocycles are cur-
rently under investigation.
1.87e1.77 (2H, m, OCH2CH2), 0.91 (9H, s, SiCMe3), 0.10 (6H, s,
Me2Si); 13C NMR (75 MHz, CDCl3)
166.6, 149.0, 133.2, 130.1, 129.6
(2C), 128.5 (2C), 121.5, 64.0, 58.1, 49.9, 27.3, 26.0 (3C), 25.9, 18.4,
ꢀ5.2 (2C); HRMS (ESI): m/z calcd for C20H31N3O3Si [MþH]þ
390.2213, found 390.2231.
d
4. Experimental section
4.1. General
4.1.2. 4-(4-((tert-Butyldimethylsilyloxy)methyl)-1H-1,2,3-triazol-1-
yl)-butan-1-ol (2). A solution of the triazole 1 (1.98 g, 5.08 mmol) in
anhydrous CH2Cl2 (49 mL) was cooled to ꢀ78 ꢁC. DIBAL-H (1.0 M in
hexane,11.2 mL,11.2 mmol) was added, and the mixture was stirred
at ꢀ78 ꢁC for 3 h. The reaction was quenched with MeOH (2.0 mL)
and allowed to reach 20 ꢁC. A satd aq solution of Rochelle’s salt
(60 mL), water (40 mL), and Et2O (250 mL) were added, and the
viscous mixture was stirred vigorously for 15 min. The mixture was
transferred to a separatory funnel and the organic layer was iso-
lated. The aqueous layer was extracted with EtOAc (3ꢂ80 mL) and
the pooled organic phases were dried (MgSO4), filtered, and con-
centrated in vacuo to give a yellow oil. The product was purified by
flash column chromatography (EtOAc/heptane 1:1/EtOAc) to af-
ford the alcohol 2 (1.31 g, 90%) as a colorless oil. Rf 0.10 (EtOAc/
Starting materials, reagents, and solvents were purchased from
SigmaeAldrich Chemical Co. and used without further purification.
Reactions involving air or moisture sensitive reagents were carried
ꢀ
out under N2. CH2Cl2, DMF, and DMSO were dried over 4 A mo-
lecular sieves. THF and toluene were distilled from Na under N2.
Et3N was distilled from CaH2 under N2. TLC was performed on
Merck aluminum sheets precoated with silica gel 60 F254. Com-
pounds were visualized by charring after dipping in a solution of p-
anisaldehyde (10 mL of H2SO4 and 10 mL of p-anisaldehyde in
200 mL of 95% EtOH), or cerium sulfate (6.25 g of (NH4)6Mo7O24
and 1.5 g of Ce(SO4)2 in 250 mL of 10% aq H2SO4). Flash column
chromatography was performed using Merck silica gel 60 (particle
size 0.040e0.063 mm). NMR spectra were recorded using a Varian
Mercury 300 MHz spectrometer or a Varian Unity Inova 500 MHz
spectrometer. Chemical shifts were measured in parts per million
and coupling constants in hertz, and the field is indicated in each
case. The solvent peaks from CDCl3 (7.26 ppm in 1H NMR and
77.16 ppm in 13C NMR) or CD3OD (3.31 ppm in 1H NMR) were used
as standards. In case of diastereomeric mixtures, the following
abbreviations are used; maj: major diastereomer, min: minor di-
astereomer, both: both diastereomers, one: one diastereomer. El-
emental analyses were obtained from H. Kolbe, Mikroanalytisches
heptane 1:1); IR (neat, AgCl)
(w), 1559 (w), 1473 (m), 1257 (m), 1006 (s), 840 (s) cmꢀ1
(300 MHz, CDCl3) 7.50 (1H, s, ]CHN), 4.85 (2H, s, CH2OSi), 4.41
n
3372 (m), 2929 (s), 1734 (w), 1636
;
1H NMR
d
(2H, t, J 7.1 Hz, CH2N), 3.69 (2H, t, J 6.2 Hz, HOCH2), 2.07e1.98 (2H,
m, CH2CH2N), 1.81 (1H, br s, OH), 1.63e1.54 (2H, m, HOCH2CH2),
0.91 (9H, s, SiCMe3), 0.10 (6H, s, Me2Si); 13C NMR (75 MHz, CDCl3)
d
148.8, 121.6, 61.9, 58.0, 50.2, 29.4, 27.1, 26.0 (3C), 18.5, ꢀ5.2 (2C).
Anal. Calcd for C13H27N3O2Si: C, 54.70; H, 9.53; N, 14.72. Found: C,
54.63; H, 9.50; N, 14.81.
€
Laboratorium, Mulheim/Ruhr, Germany. IR analysis was carried out
4.1.3. 4-((tert-Butyldimethylsilyloxy)methyl)-1-(4-(tert-butyldiphe-
on a PerkineElmer 1600 series FTIR spectrometer or on a Bruker
Alpha FTIR spectrometer. Melting points were measured with
a Buch & Holm melting point apparatus and are uncorrected. High-
resolution LC-DAD-MS was performed on an Agilent 1100 system
equipped with a photodiode array detector (DAD) and coupled to
an LCT orthogonal time-of-flight mass spectrometer (Waters-
Micromass) with a Z-spray electrospray ionization (ESI) source and
a LockSpray probe (MþH 556.2771) and controlled by MassLynx 4.0
software.
nylsilyloxy)butyl)-1H-1,2,3-triazole (3). The alcohol 2 (5.95 g,
20.9 mmol) was dissolved in anhydrous DMF (41.7 mL). Imidazole
(2.84 g, 41.7 mmol) and TBDPSCl (8.13 mL, 31.3 mmol) were added.
After stirring for 1 h at 20 ꢁC, the mixture was diluted with EtOAc
(140 mL) and then washed with water (70 mL) and brine (70 mL).
The organic phase was dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography
(EtOAc/heptane 1:1) to give 3 (10.9 g, quantitative yield) as a col-
orless oil. Rf 0.85 (EtOAc/heptane 3:1); IR (neat) 3135 (w), 3071 (w),
3050 (w), 2998 (w), 2953 (m), 2930 (s), 2886 (m), 2857 (s), 1589
(w), 1471 (m), 1463 (m), 1428 (m), 1389 (m), 1361 (w), 1334 (w),
1308 (w), 1255 (m), 1218 (w), 1188 (w), 1134 (m), 1105 (s), 1088 (s),
1045 (m), 1022 (m), 1007 (m), 972 (w), 938 (w), 910 (w), 836 (m),
4.1.1. 4-(4-((tert-Butyldimethylsilyloxy)methyl)-1H-1,2,3-triazol-1-
yl)butyl benzoate (1). 4-Chlorobutyl benzoate (10.0 g, 47.1 mmol)
and n-Bu4NI (1.74 g, 4.71 mmol) were dissolved in anhydrous DMF
(94 mL). NaN3 (3.83 g, 58.9 mmol) was added cautiously. The so-
lution was slowly heated to 60 ꢁC and stirred for 23 h. The mixture
was transferred to a separation funnel and diluted with Et2O
(600 mL). After washing with water (3ꢂ320 mL), the resulting or-
ganic phase was concentrated in vacuo to afford a yellow oil, which
was used without further purification. The crude was dissolved in
THF (422 mL) and DIPEA (12.1 mL, 70.6 mmol) was added followed
by CuI (8.97 g, 47.1 mmol) and tert-butyldimethylsilyl propargyl
ether (9.55 mL, 47.1 mmol). After stirring at 20 ꢁC for 18 h, the
yellow mixture was filtered through a pad of Celite, and the filtrate
was concentrated in vacuo giving a green oil. The residue was
dissolved in EtOAc (500 mL) and washed with water (2ꢂ330 mL)
and brine (330 mL). The organic phase was dried (MgSO4), filtered,
and concentrated in vacuo to afford an oil, which was purified by
flash column chromatography (MeOH/CH2Cl2 3:97) to give the
triazole 1 (18.3 g, quantitative yield) as a yellow oil. Rf 0.60 (EtOAc/
777 (m), 736 (m), 687 (s) cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
7.66e7.63 (4H, m, o-Ph), 7.43e7.35 (7H, m, ]CHN, p-Ph, m-Ph),
4.85 (2H, s, CH2OSi), 4.34 (2H, t, J 7.2 Hz, CH2N), 3.68 (2H, t, J 6.0 Hz,
SiOCH2CH2), 2.06e1.96 (2H, m, CH2CH2N), 1.61e1.52 (2H, m,
OCH2CH2), 1.04 (9H, s, Ph2SiCMe3), 0.91 (9H, s, Me2SiCMe3), 0.10
(6H, s, Me2Si); 13C NMR (75 MHz, CDCl3)
d 147.0, 135.7 (4C), 133.8
(2C), 129.8 (2C), 127.8 (4C), 121.4, 63.1, 58.1, 50.2, 29.4, 27.2, 27.0
(3C), 26.0 (3C), 19.3, 18.5, ꢀ5.1 (2C); HRMS (ESI): m/z calcd for
C29H45N3O2Si2 [MþH]þ 524.3129, found 524.3159.
4.1.4. (1-(4-(tert-Butyldiphenylsilyloxy)butyl)-1H-1,2,3-triazol-4-yl)
methanol (4). The disilylprotected compound 3 (10.9 g, 20.9 mmol)
was dissolved in MeOH (350 mL). PPTS (262 mg, 1.04 mmol) was
added, and the solution was heated to 55 ꢁC. After stirring for 23 h,
the solvent was removed in vacuo. The residue was redissolved in
EtOAc (420 mL) and washed with brine (420 mL) and water
(420 mL). The organic phase was dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAc/heptane 3:7/EtOAc) to give the alcohol 4
(6.54 g, 77%) as white crystals. Rf 0.39 (EtOAc/heptane 3:1); mp
heptane 1:1); IR (neat, AgCl)
(s), 1719 (s), 1602 (m), 1585 (m), 1451 (s), 1389 (m), 1361 (m), 1271
(s), 1219 (m), 1176 (m), 1096 (s) cmꢀ1 1H NMR (300 MHz, CDCl3)
8.04e8.01 (2H, m, o-Ph), 7.60e7.52 (2H, m, p-Ph, ]CCHN),
n 3428 (w), 3138 (m), 3069 (m), 2956
;
d
7.47e7.42 (2H, m, m-Ph), 4.88 (2H, s, CH2OSi), 4.46 (2H, t, J 7.1 Hz,
CH2N), 4.36 (2H, t, J 6.3 Hz, BzOCH2), 2.15e2.05 (2H, m, CH2CH2N),
111e112 ꢁC; IR (neat)
(w), 1427 (m), 1359 (w), 1225 (w), 1145 (w), 1109 (s), 1081 (s), 1020
n 3232 (s), 3126 (m), 2927 (s), 2854 (m), 1472

C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
9853
(m), 980 (m), 817 (w), 708 (s) cmꢀ1
;
1H NMR (300 MHz, CDCl3)
J 10.7 Hz, CHaHbAr), 4.38 (1H, d, J 10.7 Hz, CHaHbAr), 3.81 (3H, s,
BnOMe), 3.77 (3H, s, COOMe), 3.63 (2H, s, CH2OSi), 1.41 (3H, s, Me),
0.89 (9H, s, SiCMe3), 0.05 (3H, s, MeSi), 0.04 (3H, s, MeSi); 13C NMR
d
7.65e7.62 (4H, m, o-Ph), 7.47 (1H, s, ]CHN), 7.43e7.35 (6H, m, p-
Ph, m-Ph), 4.79 (2H, d, J 6.1 Hz, CH2OH), 4.35 (2H, t, J 7.2 Hz, CH2N),
3.68 (2H, t, J 6.0 Hz, SiOCH2), 2.23 (1H, t, J 6.1 Hz, OH), 2.07e1.97
(2H, m, CH2CH2N), 1.63e1.52 (2H, m, OCH2CH2), 1.04 (9H, s,
(75 MHz, CDCl3)
d 167.0, 159.1, 151.2, 131.1, 129.1 (2C), 121.6, 113.9
(2C), 78.3, 69.0, 65.3, 55.4, 51.8, 25.9 (3C), 20.3, 18.3, ꢀ5.3 (2C);
HRMS (ESI): m/z calcd for C21H34O5Si [MþNa]þ 417.2073, found
417.2073.
SiCMe3); 13C NMR (75 MHz, CDCl3)
d 147.8, 135.6 (4C), 133.7 (2C),
129.8 (2C), 127.8 (4C), 121.7, 63.0, 56.3, 50.3, 29.4, 27.0, 27.0 (3C),
19.3. Anal. Calcd for C23H31N3O2Si: C, 67.44; H, 7.63; N, 10.26.
Found: C, 67.52; H, 7.59; N, 10.22.
4.1.8. (ꢃ)-(E)-5-(tert-Butyldimethylsilyloxy)-4-(4-methox-
ybenzyloxy)-4-methylpent-2-enoic acid (8). The methyl ester 7
(3.47 g, 8.79 mmol) was dissolved in THF (132 mL) and cooled to
4.1.5. (ꢃ)-1-(tert-Butyldimethylsilyloxy)-2-methylbut-3-en-2-ol
(5). 1-(tert-Butyldimethylsilyloxy)propan-2-one (12 mL, 62.2 mmol)
was dissolved in anhydrous THF (114 mL). The mixture was stirred at
0 ꢁC, and vinyl magnesium chloride (1.6 M in THF, 47 mL, 74.6 mmol)
was added dropwise over 20 min. The cooling bath was removed and
after 2 h, the reaction mixture was diluted with Et2O (480 mL) and
washed with satd aq NH4Cl (290 mL) and water (290 mL). The
combined aqueous phases were extracted with Et2O (200 mL). The
combined organic phases were dried (MgSO4), filtered, and con-
centrated in vacuo to give 5 as a colorless oil (10.4 g, 78%), which was
used without further purification. Rf 0.63 (EtOAc/heptane 1:1); IR
0
ꢁC. A solution of LiOH (631 mg, 26.4 mmol) in H2O (44 mL) was
added, and the resulting mixture was stirred at 20 ꢁC. After 46 h, the
reaction was quenched with satd aq NaH2PO4 (100 mL), and EtOAc
(100 mL) was added. The organic phase was isolated, and the
aqueous phase was extracted with EtOAc (3ꢂ100 mL). The pooled
organic phases were washed with water (200 mL) and brine
(200 mL). Subsequently, they were dried (MgSO4), filtered and,
concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAc/heptane/AcOH 9:90:1) to afford the car-
boxylic acid 8 (2.97 g, 89%) as a white solid. Rf 0.60 (EtOAc/heptane/
(neat, AgCl)
(m), 1362 (m), 1257 (m), 1100 (s), 1006 (m), 922 (m), 838 (s), 778 (m)
cmꢀ1; 1H NMR (300 MHz, CDCl3)
5.87 (1H, dd, J 17.4, 10.8 Hz, CH]
n
3447 (br), 3088 (w), 2931 (s), 1718 (w), 1653 (w), 1472
AcOH 70:30:1); mp 68e71 ꢁC; IR (neat)
(s), 1652 (m), 1614 (m), 1587 (m), 1515 (s), 1463 (m), 1373 (m), 1254
(s), 939 (m), 845 (s) cmꢀ1; 1H NMR (300 MHz, CDCl3)
7.26 (2H, d, J
n 2927 (br), 1880 (w), 1698
d
d
CHaHb), 5.29 (1H, dd, J 17.4, 1.4 Hz, CH]CHaHb), 5.11 (1H, dd, J 10.8,
1.4 Hz, CH]CHaHb), 3.47 (1H, d, J 9.5 Hz, CHaHb), 3.42 (1H, d, J 9.5 Hz,
CHaHb), 1.23 (3H, s, Me), 0.90 (9H, s, SiCMe3), 0.06 (3H, s, MeSi), 0.06
8.6 Hz, o-Ar), 7.09 (1H, d, J 16.0 Hz, COCH]CH), 6.87 (2H, d, J 8.6 Hz,
m-Ar), 6.06 (1H, d, J 16.0 Hz, COCH]CH), 4.44 (1H, d, J 10.7 Hz,
CHaHbAr), 4.38 (1H, d, J 10.7 Hz, CHaHbAr), 3.80 (3H, s, OMe), 3.63
(2H, s, CH2OSi), 1.42 (3H, s, Me), 0.88 (9H, s, SiCMe3), 0.04 (3H, s,
(3H, s, MeSi); 13C NMR (75 MHz, CDCl3)
(3C), 23.9, 18.5, ꢀ5.2, ꢀ5.3.
d 142.4, 113.6, 73.1, 70.4, 26.0
MeSi), 0.03 (3H, s, MeSi); 13C NMR (75 MHz, CDCl3)
d 171.9, 159.1,
153.8, 131.0, 129.1 (2C), 121.4, 113.9 (2C), 78.3, 68.9, 65.4, 55.4, 25.9
(3C), 20.3, 18.3, ꢀ5.3 (2C). Anal. Calcd for C20H32O5Si: C, 63.12; H,
8.48. Found: C, 63.20; H, 8.36.
4.1.6. (ꢃ)-(E)-Methyl
5-(tert-butyldimethylsilyloxy)-4-hydroxy-4-
methylpent-2-enoate (6). Alcohol 5 (8.40 g, 38.8 mmol) was dis-
solved in anhydrous CH2Cl2 (400 mL) and methyl acrylate (69.5 mL,
776 mmol) was added. HoveydaeGrubbs second generation cata-
lyst (0.12 g, 0.20 mmol) was added, and the mixture was heated to
reflux. After stirring for 48 h, the mixture was concentrated in
vacuo to give a green semisolid, which was recrystallized from
EtOAc/heptane, and a crystalline by-product was filtered off. The
filtrate was concentrated in vacuo to give a green oil. The crude
product was purified by flash column chromatography (EtOAc/
heptane 1:7) to afford the methyl ester 6 (9.31 g, 88%) as a pale
4.1.9. (ꢃ)-(E)-5-(tert-Butyldimethylsilyloxy)-4-(4-methox-
ybenzyloxy)-4-methylpent-2-en-1-ol (9). The methyl ester
7
(703 mg, 1.78 mmol) was dissolved in anhydrous CH2Cl2 (16 mL)
and cooled to ꢀ78 ꢁC. DIBAL-H (1.0 M in hexanes, 3.92 mL,
3.92 mmol) was added, and the mixture was stirred at ꢀ78 ꢁC for
3 h. The reaction was quenched with MeOH (1.0 mL) and the cold
bath was removed. At 20 ꢁC, a satd aq solution of Rochelle’s salt
(20 mL), water (10 mL), and Et2O (100 mL) was added, and the
viscous mixture was stirred vigorously for 15 min. The organic
phase was isolated, and the aqueous phase was extracted with
EtOAc (3ꢂ50 mL). The pooled organic phases were dried (MgSO4),
filtered, and concentrated in vacuo to give a yellow oil. The oil was
purified by flash column chromatography (EtOAc/heptane 1:2) to
afford the alcohol 9 (583 mg, 89%) as a colorless oil. Rf 0.87 (MeOH/
yellow oil. Rf 0.30 (EtOAc/heptane 1:4); IR (neat, AgCl)
2954 (s), 2858 (s), 1728 (s), 1662 (m), 1472 (m), 1437 (m), 1363 (m),
1259 (s), 1100 (s), 981 (m), 838 (s), 778 (m) cmꢀ1 1H NMR
(300 MHz, CDCl3) 6.91 (1H, d, J 15.7 Hz, COCH]CH), 6.10 (1H, d, J
n 3482 (br),
;
d
15.7 Hz, COCH]CH), 3.74 (3H, s, OMe), 3.53 (1H, d, J 9.6 Hz, CHaHb),
3.48 (1H, d, J 9.6 Hz, CHaHb), 1.26 (3H, s, Me), 0.88 (9H, s, SiCMe3),
0.06 (3H, s, MeSi), 0.04 (3H, s, MeSi); 13C NMR (75 MHz, CDCl3)
EtOAc 1:99); IR (neat, AgCl)
1587 (m), 1514 (s), 1464 (m), 1379 (m), 1250 (s), 1172 (m), 1110 (s)
cmꢀ1; 1H NMR (300 MHz, CDCl3)
7.25 (2H, d, J 8.5 Hz, o-Ar), 6.86
n 3418 (br), 2930 (s), 1740 (m), 1613 (m),
d
167.2, 152.1, 119.9, 73.1, 69.8, 51.7, 25.9 (3C), 23.6, 18.4, ꢀ5.3, ꢀ5.4;
HRMS (ESI): m/z calcd for C13H26O4Si [MþH]þ 275.1679, found
d
275.1680.
(2H, d, J 8.5 Hz, m-Ar), 5.88 (1H, dt, J 16.2, 5.3 Hz, CH2CH]CH), 5.74
(1H, d, J 16.2 Hz, CH2CH]CH), 4.39 (2H, s, CH2Ar), 4.19 (2H, dd, J 5.3,
1.0 Hz, CH2CH]CH), 3.79 (3H, s, OMe), 3.59 (1H, d, J 9.9 Hz,
CHaHbOSi), 3.55 (1H, d, J 9.9 Hz, CHaHbOSi), 1.36 (3H, s, Me), 0.89
(9H, s, SiCMe3), 0.04 (3H, s, MeSi), 0.03 (3H, s, MeSi); 13C NMR
4.1.7. (ꢃ)-(E)-Methyl 5-(tert-butyldimethylsilyloxy)-4-(4-methoxybe
nzyloxy)-4-methylpent-2-enoate (7). The methyl ester 6 (4.16 g,
15.2 mmol) and PMBTCA22 (8.14 g, 30.3 mmol) were dissolved in
anhydrous toluene (125 mL), and La(OTf)3 (622 mg, 1.06 mmol) was
added. After stirring at 20 ꢁC for 16 h, the mixture was filtered
through a pad of Celite. The filtrate was concentrated in vacuo to
give a yellowish oil, which was purified by flash column chroma-
tography (EtOAc/toluene/heptane 1:50:50) to give the PMB-pro-
tected methyl ester 7 (5.07 g, 85%) as a colorless oil. Rf 0.73 (toluene/
(75 MHz, CDCl3)
d 158.9, 134.5, 131.8, 130.7, 129.0 (2C), 113.8 (2C),
78.0, 69.6, 64.7, 63.6, 55.4, 26.0 (3C), 20.3, 18.4, ꢀ5.2, ꢀ5.2. Anal.
Calcd for C20H34O4Si: C, 65.53; H, 9.35. Found: C, 65.45; H, 9.31.
4.1.10. (ꢃ)-(E)-4-(4-Methoxybenzyloxy)-4-methylpent-2-en-1,5-diol
(10). The alcohol 9 (8.80 g, 24.0 mmol) was dissolved in anhydrous
THF (59 mL) and TBAF (1.0 M in THF, 36.0 mL, 36.0 mmol) was
added dropwise. After stirring for 19 h, the mixture was diluted
with EtOAc (150 mL) and washed with satd aq NH4Cl (120 mL) and
water (2ꢂ120 mL). The combined aqueous phases were extracted
with EtOAc (2ꢂ120 mL). The combined organic phases were dried
heptane 1:4); IR (neat, AgCl) n 2952 (s), 2856 (s), 2061 (w),1883 (w),
1726 (s), 1658 (m), 1613 (m), 1587 (m), 1515 (s), 1465 (m), 1382 (m),
1250 (s), 1113 (s), 939 (m), 840 (s) cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.26 (2H, d, J 8.6 Hz, o-Ar), 6.99 (1H, d, J 16.0 Hz, COCH]CH), 6.88
(2H, d, J 8.6 Hz, m-Ar), 6.06 (1H, d, J 16.0 Hz, COCH]CH), 4.44 (1H, d,

9854
C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
(MgSO4), filtered, and concentrated in vacuo. The residue was pu-
rified by flash column chromatography (EtOAc/heptane
1:1/MeOH/EtOAc 1:99) giving the diol 10 (6.06 g, quantitative
yield) as a colorless oil, which crystallizes upon storage at 5 ꢁC to
give a white solid. Rf 0.54 (MeOH/EtOAc 1:99); mp 44e45 ꢁC; IR
(m), 971 (m), 939 (m), 909 (m), 821 (m), 735 (m), 700 (s) cmꢀ1; 1H
NMR (300 MHz, CDCl3) 7.68e7.65 (4H, m, o-Ph), 7.42e7.34 (6H, m,
d
p-Ph, m-Ph), 7.25 (2H, d, J 8.7 Hz, o-Ar), 6.89 (2H, d, J 8.7 Hz, m-Ar),
6.01 (1H, dt, J 15.7, 3.4 Hz, CH2CH]CH), 5.92 (1H, m, CH2CH]CH),
4.43 (1H, d, J 10.5 Hz, CHaHbAr), 4.38 (1H, d, J 10.5 Hz, CHaHbAr),
4.29 (2H, dd, J 3.4, 1.1 Hz, CH2CH]CH), 3.82 (3H, s, OMe), 1.65 (3H, s,
(neat, AgCl)
(m), 1381 (m), 1302 (m), 1248 (s), 1173 (m), 1112 (m), 1036 (s), 981
(m), 913 (w), 891 (w), 822 (m), 733 (m) cmꢀ1 1H NMR (300 MHz,
CDCl3) 7.25 (2H, d, J 8.6 Hz, o-Ar), 6.87 (2H, d, J 8.6 Hz, m-Ar), 5.91
n 3379 (br), 2935 (s), 1613 (m), 1586 (m), 1514 (s), 1465
CH3), 1.07 (9H, s, SiCMe3); 13C NMR (75 MHz, CDCl3)
d 175.4, 159.5,
;
135.6 (4C), 133.5, 133.2 (2C), 129.9 (2C), 129.8, 129.6 (2C), 128.1,
127.9 (4C), 114.0 (2C), 80.2, 66.5, 63.6, 55.4, 26.9 (3C), 22.1, 19.4.
Anal. Calcd for C30H36O5Si: C, 71.39; H, 7.19. Found: C, 70.67; H, 7.17.
d
(1H, dt, 16.1, 5.2 Hz, CH2CH]CH), 5.78 (1H, d, J 16.1 Hz, CH2CH]
CH), 4.33 (2H, s, CH2Ar), 4.19 (2H, d, J 5.2 Hz, CH2CH]CH), 3.80 (3H,
s, OMe), 3.50 (2H, s, CH2OSi), 2.08 (2H, br s, 2ꢂOH), 1.38 (3H, s, Me);
4.2. Representative procedure for the preparation of esters
(13, 15, 17, 19)
13C NMR (75 MHz, CDCl3)
d 159.1,132.9, 131.8,131.1, 129.2 (2C), 113.9
(2C), 77.9, 69.7, 64.6, 63.0, 55.4, 19.3; HRMS (ESI): m/z calcd for
C14H20O4 [MþNa]þ 275.1259, found 275.1255.
4.2.1. (ꢃ)-(E)-4-(4-((tert-Butyldimethylsilyloxy)methyl)-1H-1,2,3-
triazol-1-yl)butyl 5-(tert-butyldimethylsilyloxy)-4-(4-methoxybenzyl
oxy)-4-methylpent-2-enoate (13). The carboxylic acid 8 (624 mg,
1.64 mmol) and the alcohol 2 (515 mg,1.80 mmol) were dissolved in
anhydrous CH2Cl2 (25 mL) and DMAP (40 mg, 0.33 mmol) and
EDC$HCl (472 mg, 2.46 mmol) were added. The reaction was stirred
for 18 h at 20 ꢁC and then concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc/heptane 1:2) to
afford the ester 13 (930 mg, 87%) as a colorless oil. Rf 0.31 (MeOH/
4.1.11. (ꢃ)-(E)-5-(tert-Butyldiphenylsilyloxy)-2-(4-methox-
ybenzyloxy)-2-methylpent-3-en-1-ol (11). The diol 10 (1.41 g,
5.60 mmol) was dissolved in anhydrous CH2Cl2 (65 mL) and imid-
azole (539 mg, 8.41 mmol) was added. The mixture was cooled to
ꢀ78 ꢁC, and a solution of TBDPSCl (1.46 mL, 5.60 mmol) in anhy-
drous CH2Cl2 (10 mL) was added over 5 min. After 3 h, the mixture
was diluted with CH2Cl2 (60 mL) and washed with brine (40 mL)
and water (40 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by flash column chromatography (EtOAc/heptane 1:2)
affording the TBDPS-protected alcohol 11 (2.75 g, quantitative
toluene 5:95); IR (neat, AgCl)
(m), 1516 (m), 1472 (m), 1374 (m), 1249 (s), 1104 (s), 939 (w), 839
(m), 779 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3)
7.46 (1H, s, ]CHN),
n 2927 (s), 1734 (s), 1653 (m), 1613
d
7.25 (2H, d, J 8.4 Hz, o-Ar), 6.97 (1H, d, J 16.0 Hz, COCH]CH), 6.86
(2H, d, J 8.4 Hz, m-Ar), 6.02 (1H, d, J 16.0 Hz, COCH]CH), 4.84 (2H, s,
]CCH2OSi), 4.42 (1H, d, J 11.1 Hz, CHaHbAr), 4.38 (2H, t, J 7.4 Hz,
CH2N), 4.37 (1H, d, J 11.1 Hz, CHaHbAr), 4.18 (2H, t, J 6.3 Hz,
OCH2CH2), 3.79 (3H, s, OMe), 3.61 (2H, s, C(OPMB)CH2OSi),
2.05e1.95 (2H, m, CH2CH2N), 1.76e1.65 (2H, m, HOCH2CH2), 1.40
(3H, s, Me), 0.91 (9H, s, SiCMe3), 0.87 (9H, s, SiCMe3), 0.09 (6H, s,
Me2Si), 0.02 (3H, s, MeSi), 0.01 (3H, s, MeSi); 13C NMR (75 MHz,
yield) as a colorless oil. Rf 0.30 (EtOAc/heptane 1:2); IR (neat, AgCl)
n
3457 (br), 2932 (s), 1613 (m), 1588 (m), 1514 (s), 1473 (m), 1428 (m),
1380 (m), 1302 (m), 1249 (s), 1173 (m), 1112 (s), 978 (m), 823 (m),
741 (m), 702 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.70e7.66 (4H,
m, o-Ph), 7.45e7.33 (6H, m, p-Ph, m-Ph), 7.23 (2H, d, J 8.5 Hz, o-Ar),
6.86 (2H, d, J 8.5 Hz, m-Ar), 5.81e5.80 (2H, m, CH]CH), 4.29e4.28
(4H, m, CH2Ar, CH2CH]), 3.80 (3H, s, OMe), 3.52 (1H, d, J 10.9 Hz,
CHaHbOSi), 3.41 (1H, d, J 10.9 Hz, CHaHbOSi), 1.98 (1H, br s, OH), 1.36
CDCl3) d 166.4, 159.1, 151.5, 148.9, 131.1, 129.0 (2C), 121.6, 121.5, 113.9
(2C), 78.3, 68.9, 65.3, 63.5, 58.1, 55.4, 49.9, 27.2, 26.0 (3C), 25.9 (3C),
(3H, s, Me), 1.07 (9H, s, SiCMe3); 13C NMR (75 MHz, CDCl3)
d
159.1,
135.6 (4C), 133.7, 133.7, 131.9, 131.5, 131.2, 129.8 (2C), 129.3 (2C),
127.8 (4C), 113.9 (2C), 77.9, 69.8, 64.7, 64.1, 55.4, 27.0 (3C), 19.4, 19.3.
Anal. Calcd for C30H38O4Si: C, 73.43; H, 7.81. Found: C, 73.27;
H, 7.75.
25.9, 20.2, 18.5, 18.3, ꢀ5.1 (2C), ꢀ5.3 (2C).
4.2.2. (ꢃ)-(E)-(1-(4-(tert-Butyldiphenylsilyloxy)butyl)-1H-1,2,3-tri-
azol-4-yl)methyl 5-(tert-butyldimethylsilyloxy)-4-(4-methoxybenzyl
oxy)-4-methylpent-2-enoate (15). Colorless oil, 87% yield. Rf 0.40
4.1.12. (ꢃ)-(E)-5-(tert-Butyldiphenylsilyloxy)-2-(4-methox-
ybenzyloxy)-2-methylpent-3-enoic acid (12). Anhydrous CH2Cl2
(220 mL) and DMSO (5.79 mL, 81.7 mmol) were mixed and cooled
to ꢀ78 ꢁC. Oxalyl chloride (3.45 mL, 40.8 mmol) was added drop-
wise, followed by dropwise addition of a solution of the alcohol 11
(10.0 g, 20.4 mmol) in anhydrous CH2Cl2 (110 mL). After 30 min,
anhydrous Et3N (28.5 mL, 204 mmol) was added. After further
15 min, the mixture was allowed to reach 20 ꢁC and then diluted
with CH2Cl2 (600 mL) and washed with satd aq NH4Cl (400 mL) and
water (400 mL) The organic phase was dried (MgSO4), filtered, and
concentrated in vacuo to give the crude aldehyde, which was used
without further purification. The crude aldehyde was dissolved in
THF (120 mL). t-BuOH (240 mL) and 2-methyl-2-butene (86 mL,
811 mmol) were added followed by a solution of NaClO2 (23.3 g,
257 mmol) and NaH2PO4 (30.9 g, 257 mmol) in water (160 mL).
After 1½ hours, the mixture was diluted with satd aq NaH2PO4
(500 mL) and stirred for 15 min. Subsequently, the mixture was
extracted with EtOAc (3ꢂ500 mL) and the combined organic pha-
ses were dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography (EtOAc/
heptane/AcOH 66:33:1) to afford the carboxylic acid 12 (9.89 g,
(MeOH/toluene 5:95); IR (neat) n 3139 (w), 3071 (w), 3048 (w),
2998 (w), 2954 (s), 2930 (s), 2894 (m), 2857 (s), 1720 (s), 1656 (w),
1613 (w), 1588 (w), 1514 (m), 1463 (m), 1442 (m), 1428 (m), 1387
(m), 1361 (w), 1301 (m), 1249 (s), 1169 (m), 1105 (s), 1033 (m), 1007
(m), 938 (w), 910 (w), 836 (s), 823 (m), 777 (m), 731 (m), 701 (s)
cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.65e7.62 (4H, m, o-Ph), 7.56
(1H, s, ]CHN), 7.45e7.36 (6H, m, p-Ph, m-Ph), 7.23 (2H, d, J 8.5 Hz,
o-Ar), 7.00 (1H, d, J 16.1 Hz, COCH]CH), 6.85 (2H, d, J 8.5 Hz, m-Ar),
6.05 (1H, d, J 16.1 Hz, COCH]CH), 5.30 (2H, s, CH2OCO), 4.46e4.32
(4H, m, CH2Ar, CH2N), 3.79 (3H, s, OMe), 3.68 (2H, t, J 6.0 Hz,
SiOCH2CH2), 3.60 (2H, s, C(OPMB)CH2OSi), 2.07e1.97 (2H, m,
CH2CH2N), 1.61e1.52 (2H, m, SiOCH2CH2), 1.38 (3H, s, Me), 1.04 (9H,
s, Ph2SiCMe3), 0.86 (9H, s, Me2SiCMe3), 0.01 (3H, s, MeSi), 0.00 (3H,
s, MeSi); 13C NMR (75 MHz, CDCl3)
d 171.6, 164.4, 157.3, 148.2, 141.0
(4C), 139.0 (2C), 136.4, 135.2 (2C), 134.4 (2C), 133.2 (4C), 129.1, 126.7,
119.2 (2C), 83.6, 74.3, 70.6, 68.4, 63.2, 60.7, 55.7, 34.7, 32.4, 32.3 (3C),
31.3 (3C), 25.6, 24.7, 23.7, 0.0, 0.0; HRMS (ESI): m/z calcd for
C43H61N3O6Si2 [MþH]þ 772.4177, found 772.4179.
4.2.3. (ꢃ)-(E)-(1-(4-(tert-Butyldiphenylsilyloxy)butyl)-1H-1,2,3-tri-
azol-4-yl)methyl 5-(tert-butyldiphenylsilyloxy)-2-(4-methoxybenzyl
oxy)-2-methylpent-3-enoate (17). Colorless oil, 58% yield. Rf 0.40
96%) as a colorless oil. Rf 0.25 (MeOH/toluene 5:95); IR (neat) n 3071
(m), 3049 (m), 2997 (m), 2956 (m), 2931 (m), 2893 (m), 2857 (m),
1712 (m), 1613 (m), 1588 (w), 1513 (m), 1462 (m), 1428 (m), 1380
(m), 1302 (m), 1247 (s), 1202 (m), 1174 (m), 1107 (s), 1028 (m), 998
(MeOH/toluene 5:95); IR (neat) n 3136 (w), 3071 (w), 3048 (w),
3013 (w), 2998 (w), 2955 (m), 2931 (m), 2892 (m), 2857 (m), 1736
(m), 1613 (w), 1588 (w), 1514 (m), 1471 (m), 1462 (m), 1427 (m),

C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
9855
1387 (m), 1362 (w), 1302 (w), 1248 (m), 1174 (m), 1105 (s), 1047 (m),
1032 (m), 998 (m), 968 (m), 939 (w), 910 (w), 822 (m), 735 (m), 700
121.8,114.0 (2C), 78.1, 68.9, 65.3, 63.7, 56.7, 55.4, 49.9, 27.1, 25.7,19.3.
Anal. Calcd for C21H29N3O6: C, 60.13; H, 6.97; N, 10.02. Found: C,
60.02; H, 7.06; N, 9.88.
(s) cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.67e7.62 (8H, m, o-Ph), 7.48
(1H, s, ]CHN), 7.44e7.32 (12H, m, p-Ph, m-Ph), 7.26 (2H, d, J 8.7 Hz,
o-Ar), 6.84 (2H, d, J 8.7 Hz, m-Ar), 6.03 (1H, dt, J 15.7, 1.6 Hz,
CH2CH]CH), 5.91 (1H, dt, J 15.7, 4.0 Hz, CH2CH]CH), 5.31 (2H, s,
CH2OCO), 4.42 (1H, d, J 10.6 Hz, CHaHbAr), 4.36 (1H, d, J 10.6 Hz,
CHaHbAr), 4.28 (2H, t, J 7.3 Hz, NCH2), 4.24 (2H, dd, J 4.0, 1.6 Hz,
CH2CH]CH), 3.78 (3H, s, OMe), 3.66 (2H, t, J 6.0 Hz, CH2CH2O),
2.01e1.91 (2H, m, NCH2CH2), 1.56 (3H, s, Me), 1.55e1.48 (2H, m,
CH2CH2O), 1.05 (9H, s, SiCMe3), 1.04 (9H, s, SiCMe3); 13C NMR
4.3.2. (ꢃ)-(E)-(1-(4-Hydroxybutyl)-1H-1,2,3-triazol-4-yl)methyl 5-
hydroxy-4-(4-methoxybenzyloxy)-4-methylpent-2-enoate
(16). White solid, 78% yield. Rf 0.15 (MeOH/EtOAc 1:99); mp
70e71 ꢁC; IR (neat)
n 3332 (br), 3120 (m), 3072 (w), 3034 (w), 2935
(m), 2870 (m), 2838 (m), 1716 (s), 1655 (m), 1612 (m),1586 (w), 1513
(m),1462 (m),1442 (m),1381 (m),1316 (m),1301 (m),1249 (m),1218
(m),1171 (s),1108 (m),1046 (s),1007 (m), 973 (m), 942 (w), 900 (w),
871 (m), 827 (m), 815 (m), 781 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3)
(75 MHz, CDCl3)
d 173.2, 159.2, 142.7, 135.6 (4C), 135.6 (4C), 133.7
(2C), 133.6 (2C), 131.6, 130.7, 129.8 (4C), 129.4, 129.4 (2C), 127.8 (4C),
127.8 (4C), 123.7, 113.8 (2C), 80.1, 66.9, 63.8, 63.0, 58.6, 55.4, 50.3,
29.4, 27.0, 27.0 (3C), 26.9 (3C), 24.2,19.4,19.3; HRMS (ESI): m/z calcd
for C53H65N3O6Si2 [MþH]þ 896.4490, found 896.4462.
d 7.65 (1H, s, ]CHN), 7.24 (2H, d, J 8.7 Hz, o-Ar), 7.00 (1H, d, J 16.1 Hz,
COCH]CH), 6.87 (2H, d, J 8.7 Hz, m-Ar), 6.07 (1H, d, J 16.1 Hz, COCH]
CH), 5.30 (2H, s, CH2OCO), 4.41 (2H, t, J 7.1 Hz, CH2N), 4.37 (1H, d, J
10.4 Hz, CHaHbAr), 4.31 (1H, d, J 10.4 Hz, CHaHbAr), 3.80 (3H, s, OMe),
3.67 (2H, t, J 6.2 Hz, CH2CH2OH), 3.57 (1H, d, J 11.5 Hz, C(OPMB)
CHaHbOH), 3.52 (1H, d, J 11.5 Hz, C(OPMB)CHaHbOH), 2.07e1.97 (2H,
m, NCH2CH2), 1.62e1.53 (2H, m, CH2CH2OH), 1.41 (3H, s, Me); 13C
4.2.4. (ꢃ)-(E)-4-(4-((tert-Butyldimethylsilyloxy)methyl)-1H-1,2,3-
triazol-1-yl)butyl 5-(tert-butyldiphenylsilyloxy)-2-(4-methoxybenzyl
oxy)-2-methylpent-3-enoate (19). Colorless oil, 71% yield. Rf 0.31
NMR (75 MHz, CDCl3)
d 166.0, 159.3, 150.4, 142.7, 130.4, 129.2 (2C),
(MeOH/toluene 5:95); IR (neat)
n
3136 (w), 3071 (w), 3048 (w),
124.1, 122.2, 114.0 (2C), 78.1, 68.8, 65.2, 61.9, 57.8, 55.4, 50.3, 29.3,
27.0, 19.3. Anal. Calcd for C21H29N3O6: C, 60.13; H, 6.97; N, 10.02.
Found: C, 60.04; H, 7.08; N, 9.94.
2997 (w), 2954 (m), 2931 (s), 2893 (m), 2856 (m), 1734 (m), 1613
(m), 1588 (w), 1514 (m), 1462 (m), 1428 (m), 1381 (m), 1362 (m),
1301 (m), 1247 (s), 1174 (m), 1105 (s), 1043 (m), 970 (m), 939 (w),
836 (m), 777 (m), 740 (m), 701 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3)
4.3.3. (ꢃ)-(E)-(1-(4-Hydroxybutyl)-1H-1,2,3-triazol-4-yl)methyl 5-
d
7.68e7.64 (4H, m, o-Ph), 7.42e7.33 (7H, m, ]CHN, p-Ph, m-Ph),
hydroxy-2-(4-methoxybenzyloxy)-2-methylpent-3-enoate
7.28 (2H, d, J 8.6 Hz, o-Ar), 6.85 (2H, d, J 8.6 Hz, m-Ar), 6.04 (1H, dt, J
15.7, 1.5 Hz, CH2CH]CH), 5.92 (1H, dt, J 15.7, 3.8 Hz, CH2CH]CH),
4.83 (2H, s, ]CCH2O), 4.44 (1H, d, J 10.8 Hz, CHaHbAr), 4.38 (1H, d, J
10.8 Hz, CHaHbAr), 4.31 (2H, t, J 7.0 Hz, CH2N), 4.26 (2H, dd, J 3.9,
1.5 Hz, CH2CH]CH), 4.18 (2H, t, J 6.4 Hz, OCH2CH2), 3.79 (3H, s,
OMe), 2.01e1.90 (2H, m, CH2CH2N), 1.73e1.60 (2H, m, OCH2CH2),
1.58 (3H, s, Me), 1.06 (9H, s, Ph2SiCMe3), 0.91 (9H, s, Me2SiCMe3),
(18). Colorless oil, 76% yield. Rf 0.15 (MeOH/EtOAc 1:99); IR (neat) n
3362 (br), 3143 (m), 3042 (w), 2937 (m), 2870 (m), 2839 (m),1732(s),
1612 (m), 1586 (w), 1513 (s), 1456 (m), 1443 (m), 1381 (m), 1302 (m),
1245 (s),1175 (m),1107 (s),1084 (m),1051 (m),1027 (s), 968 (m), 821
(m), 784 (w), 755 (w) cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.60 (1H, s,
]CHN), 7.27 (2H, d, J 8.8 Hz, o-Ar), 6.85 (2H, d, J 8.8 Hz, m-Ar), 5.96
(1H, dt, J 15.8, 4.4 Hz, CH2CH]CH), 5.87 (1H, d, J 15.8 Hz, CH2CH]
CH), 5.35 (1H, d, J 12.7 Hz, CHaHbOCO), 5.29 (1H, d, J 12.7 Hz,
CHaHbOCO), 4.44 (1H, d, J 10.4 Hz, CHaHbAr), 4.39 (2H, t, J 7.0 Hz,
NCH2), 4.37 (1H, d, J 10.4 Hz, CHaHbAr), 4.15 (2H, dd, J 4.4, 0.9 Hz,
CH2CH]CH), 3.79 (3H, s, OMe), 3.63 (2H, t, J 6.2 Hz, CH2CH2OH),
2.08e1.93 (2H, m, NCH2CH2), 1.60 (3H, s, Me), 1.57e1.48 (2H, m,
0.09 (6H, s, Me2Si); 13C NMR (75 MHz, CDCl3)
d 173.2, 159.2, 148.8,
135.6 (4C), 133.6 (2C), 131.5, 130.8, 129.9 (2C), 129.6, 129.2 (2C),
127.8 (4C), 121.5, 113.8 (2C), 80.2, 66.8, 64.3, 63.8, 58.1, 55.4, 49.7,
27.1, 26.9 (3C), 26.0 (3C), 25.7, 24.0, 19.4, 18.5, ꢀ5.1 (2C); HRMS
(ESI): m/z calcd for C43H61N3O6Si2 [MþH]þ 772.4177, found
772.4214.
CH2CH2OH); 13C NMR (75 MHz, CDCl3)
d 173.0, 159.2, 142.5, 131.9,
130.6, 130.5, 129.4 (2C), 123.9, 113.8 (2C), 80.0, 66.8, 62.5, 61.7, 58.4,
55.4, 50.3, 29.3, 26.9, 23.1. Anal. Calcd for C21H29N3O6: C, 60.13; H,
6.97; N, 10.02. Found: C, 60.45; H, 7.06; N, 10.08.
4.3. Representative procedure for the preparation of diols (14,
16, 18, 20)
4.3.1. (ꢃ)-(E)-4-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)butyl 5-
hydroxy-4-(4-methoxybenzyloxy)-4-methylpent-2-enoate (14). The
ester 13 (2.03 g, 3.14 mmol) was dissolved in anhydrous THF
(27.7 mL) and TBAF (1.0 M in THF, 9.42 mL, 9.42 mmol) was added
dropwise. The mixture was stirred for 4½ h and then diluted with
EtOAc (140 mL), washed with satd aq NH4Cl (80 mL) and water
(2ꢂ80 mL). The combined aqueous phases were extracted with
EtOAc (2ꢂ80 mL) and the combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. The residue was pu-
rified by flash column chromatography (MeOH/EtOAc 1:99/5:95)
to afford the diol 14 (1.13 g, 86%) as a colorless oil. Rf 0.10 (MeOH/
4.3.4. (ꢃ)-(E)-4-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)butyl 5-
hydroxy-2-(4-methoxybenzyloxy)-2-methylpent-3-enoate
(20). Colorless oil, 93% yield. Rf 0.10 (MeOH/EtOAc 1:99); IR(neat)
n
3360 (br), 3144 (m), 2961 (m), 2936 (m), 2872 (m), 2839 (m),1730 (s),
1668 (w), 1613 (m), 1586 (w), 1553 (w), 1513 (s), 1457 (m), 1382 (m),
1301 (m),1246 (s),1175 (m),1112 (m),1084 (m),1031 (s), 979 (m), 880
(w), 821 (m), 778 (m), 756 (m)cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.52
(1H, s, ]CHN), 7.28 (2H, d, J 8.7 Hz, o-Ar), 6.85 (2H, d, J 8.7 Hz, m-Ar),
6.00 (1H, dt, J 15.8, 4.5 Hz, CH2CH]CH), 5.90 (1H, d, J 15.8 Hz,
CH2CH]CH), 4.73 (2H, s, ]CCH2OH), 4.45 (1H, d, J 10.6 Hz, CHaHbAr),
4.38 (1H, d, J 10.6 Hz, CHaHbAr), 4.34 (2H, t, J 7.0 Hz, CH2N), 4.20e4.16
(4H, m, CH2CH]CH, OCH2CH2), 3.78 (3H, s, OMe), 3.30 (2H, br s,
2ꢂOH), 1.98 (2H, tt, J 7.3, 7.3 Hz, CH2CH2N), 1.71e1.62 (2H, m,
EtOAc1:99); IR (neat) n 3374 (br), 3142(m), 2938 (m), 2873 (m), 2839
(m), 1712 (s), 1654 (m), 1612 (m), 1513 (m), 1462 (m), 1443 (m), 1383
(m),1301 (m),1247 (s),1171 (m),1110 (m),1031 (s), 895 (w), 821 (m),
OCH2CH2), 1.59 (3H, s, Me); 13C NMR (75 MHz, CDCl3)
d 173.0, 159.1,
778 (w), 754 (w), 726 (w) cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
7.54
147.9,131.9,130.5,130.5,129.2 (2C),122.2,113.8 (2C), 80.0, 66.6, 64.3,
62.3, 56.1, 55.4, 49.8, 27.0, 25.5, 22.9. Anal. Calcd for C21H29N3O6: C,
60.13; H, 6.97; N, 10.02. Found: C, 59.71; H, 7.19; N, 9.94.
(1H, s, ]CHN), 7.25 (2H, d, J 8.8 Hz, o-Ar), 6.97 (1H, d, J 16.1 Hz,
COCH]CH), 6.88 (2H, d, J 8.8 Hz, m-Ar), 6.04 (1H, d, J 16.1 Hz, COCH]
CH), 4.77 (2H, s, ]CCH2OH), 4.40 (2H, t, J 7.1 Hz, CH2N), 4.39 (1H, d, J
10.6 Hz, CHaHbAr), 4.32 (1H, d, J 10.6 Hz, CHaHbAr), 4.17 (2H, t, J
6.3 Hz, OCH2CH2), 3.80 (3H, s, OMe), 3.60 (1H, d, J 11.5 Hz, C(OPMB)
CHaHbOH), 3.55 (1H, d, J 11.5 Hz, C(OPMB)CHaHbOH), 2.07e1.97 (2H,
m, CH2CH2N),1.75e1.66 (2H, m, OCH2CH2),1.42 (3H, s, Me); 13C NMR
4.4. Representative procedure for the preparation of
macrocyclic sulfites (21, 23, 25, 27)
4.4.1. Sulfite (21). The diol 14 (107 mg, 0.26 mmol) was dissolved in
(75 MHz, CDCl3)
d
166.1, 159.3, 150.0, 147.9, 130.4, 129.3 (2C), 122.5,
anhydrous CH2Cl2 (21 mL). Anhydrous Et3N (0.11 mL, 0.77 mmol)

9856
C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
and DMAP (6 mg, 0.05 mmol) were added. A solution of SOCl2 in
anhydrous CH2Cl2 (0.36 M, 1 mL, 0.36 mmol) was added over
10 min at 20 ꢁC, under vigorous stirring. After stirring for 1 h, the
reaction mixture was concentrated in vacuo. The residue was
redissolved in EtOAc, filtered through Celite, and concentrated in
vacuo. Purification by flash column chromatography (MeOH/CH2Cl2
1:99) gave the sulfite 21 (60 mg, 51%) as white crystals. Rf 0.60
(MeOH/EtOAc 1:99); mp 91e93 ꢁC; dr: 2:1, de: 33% (NMR); IR (neat)
732 (m) cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.61 (both, s, ]CHN),
7.33 (both, d, J 8.7 Hz, o-Ar), 6.88 (both, d, J 8.7 Hz, m-Ar), 5.76e5.73
(m, CH]CH), 5.49 (one, d, J 12.5 Hz, CHaHbOCO), 5.46 (one, d, J
12.5 Hz, CHaHbOCO), 5.32 (one, d, J 12.5 Hz, CHaHbOCO), 5.30 (one,
d, J 12.5 Hz, CHaHbOCO), 4.54e4.31 (m, CH2Ar, NCH2, ]CHCHaHb),
4.28e4.26 (m, ]CHCHaHb), 4.12e4.02 (m, OCHaHbCH2), 3.80 (both,
s, OMe), 3.77e3.67 (m, OCHaHbCH2), 2.04e1.92 (m, NCH2CH2), 1.63
(one, s, Me), 1.63 (one, s, Me), 1.59e1.47 (m, OCH2CH2); 13C NMR
n
3133 (w), 2963 (m), 2933 (m), 2879 (m), 2841 (m), 1716 (s), 1657
(75 MHz, CDCl3) d 172.4 (both), 159.3 (both), 143.0 (both), 134.9
(m),1613 (m),1587 (w),1515 (m),1457 (m),1390 (m),1361 (w),1317
(m), 1304 (m), 1286 (m), 1247 (m), 1194 (m), 1168 (s), 1111 (m), 1028
(s), 1001 (m), 939 (m), 899 (m), 828 (m), 777 (m), 729 (m), 706 (m),
(one), 134.4 (one), 130.3 (one), 130.3 (one), 129.4 (2C, both), 125.8
(one), 125.6 (one), 124.3 (one), 124.2 (one), 113.9 (2C, both), 80.0
(one), 79.9 (one), 67.0 (both), 62.3 (one), 62.1 (one), 62.0 (one), 61.7
(one), 58.2 (both), 55.4 (both), 50.0 (both), 27.0 (one), 27.0 (one),
26.4 (one), 26.4 (one), 22.2 (one), 22.1 (one). Anal. Calcd for
C21H27N3O7S: C, 54.18; H, 5.85; N, 9.03. Found: C, 54.28; H, 5.77;
N, 8.95.
690 (m), 669 (m) cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 7.57 (maj, s, ]
CHN), 7.56 (min, s, ]CHN), 7.24 (min, d, J 8.6 Hz, o-Ar), 7.21 (maj, d, J
8.6 Hz, o-Ar), 6.87 (min, d, J 8.7 Hz, m-Ar), 6.86 (maj, d, J 8.7 Hz, m-
Ar), 6.82 (both, d, J 16.1 Hz, COCH]CH), 6.05 (min, d, J 16.1 Hz,
COCH]CH), 6.03 (maj, d, J 16.1 Hz, COCH]CH), 5.55 (maj, d, J
13.3 Hz, ]CCHaHbOSO), 5.49 (min, d, J 13.0 Hz, ]CCHaHbOSO), 4.96
(min, d, J 13.0 Hz, ]CCHaHbOSO), 4.95 (maj, d, J 13.3 Hz, ]
CCHaHbOSO), 4.48e4.33 (m, CH2Ar, CH2N), 4.30e4.24 (m,
OCHaHbCH2), 4.19e4.11 (m, OCHaHbCH2), 4.14 (min, d, J 10.1 Hz, C
(OPMB)CHaHbOSO), 4.13 (maj, J 11.0 Hz, C(OPMB)CHaHbOSO), 3.92
(maj, d, J 11.0 Hz, C(OPMB)CHaHbOSO), 3.87 (min, d, J 10.1 Hz, C
(OPMB)CHaHbOSO), 3.79 (both, s, OMe), 2.09e2.02 (m, NCH2CH2),
1.76e1.66 (m, CH2CH2O), 1.45 (min, s, Me), 1.43 (maj, s, Me); 13C
4.4.4. Sulfite (27). White crystals, 74% yield; Rf 0.60 (MeOH/EtOAc
1:99); mp 92 ꢁC; dr: 1:1 (NMR); IR(neat)
n 3145 (w), 3046 (w), 2994
(m), 2960 (m), 2941 (m), 2922 (m), 2877 (m), 2837 (m), 1735 (s),
1614 (m), 1587 (w), 1512 (m), 1458 (m), 1440 (m), 1387 (m), 1303
(m), 1243 (m), 1201 (m), 1189 (m), 1172 (m), 1145 (m), 1107 (s), 1038
(m), 1006 (m), 981 (m), 941 (m), 924 (m), 904 (s), 839 (m), 813 (m),
804 (m), 786 (m), 757 (m), 739 (m), 717 (m) cmꢀ1
;
1H NMR
(300 MHz, CDCl3)
d 7.65 (one, s, ]CHN), 7.64 (one, s, ]CHN), 7.28
NMR (75 MHz, CDCl3)
d
165.6 (min), 165.5 (maj), 159.3 (min), 159.2
(one, d, J 8.6 Hz, o-Ar), 7.27 (one, d, J 8.6 Hz, o-Ar), 6.86 (both, d, J
8.6 Hz, m-Ar), 5.86e5.84 (m, CH]CH), 5.60 (one, d, J 13.4 Hz, ]
CCHaHbOSO), 5.55 (one, d, J 13.4 Hz, ]CCHaHbOSO), 4.96 (one, d, J
13.4 Hz, ]CCHaHbOSO), 4.93 (one, d, J 13.4 Hz, ]CCHaHbOSO),
4.51e4.22 (m, CH2Ar, NCH2, ]CHCH2, CH2CH2O), 3.79 (both, s,
OMe), 1.99e1.84 (m, NCH2CH2), 1.76e1.64 (m, CH2CH2O), 1.59 (one,
(maj), 149.2 (min), 148.6 (maj), 143.8 (maj), 143.4 (min), 130.2 (maj),
130.2 (min), 129.1 (2C, min), 128.9 (2C, maj), 123.0 (min), 122.9
(maj), 122.8 (maj), 122.5 (min), 114.0 (2C, min), 113.9 (2C, maj), 76.3
(maj), 76.2 (min), 69.3 (maj), 67.7 (min), 65.3 (maj), 65.2 (min), 63.5
(both), 56.6 (min), 56.0 (maj), 55.4 (both), 49.5 (both), 26.8 (both),
25.0 (min), 24.9 (maj), 20.2 (min), 19.6 (maj); HRMS (ESI): m/z calcd
for C21H27N3O7S [MþH]þ 466.1643, found 466.1637.
s, Me), 1.58 (one, s, Me); 13C NMR (75 MHz, CDCl3)
d 172.3 (both),
159.3 (both), 143.4 (one), 143.3 (one), 134.7 (one), 134.7 (one), 130.2
(one), 130.2 (one), 129.3 (2C, both), 125.4 (one), 125.3 (one), 124.1
(one), 124.1 (one), 113.9 (2C, both), 79.9 (one), 79.9 (one), 66.8
(both), 64.1 (one), 64.1 (one), 62.7 (one), 62.6 (one), 55.4 (both),
55.3 (one), 55.1 (one), 49.5 (both), 27.5 (one), 27.5 (one), 25.5 (both),
22.3 (both); HRMS (ESI): m/z calcd for C21H27N3O7S [MþH]þ
466.1643, found 466.1633.
4.4.2. Sulfite (23). White crystals, 43% yield; Rf 0.60 (MeOH/EtOAc
1:99); mp 130e131 ꢁC; dr: 3:2, de: 20% (NMR); IR(neat)
n 3133 (w),
3075 (w), 3034 (w), 2963 (m), 2875 (m), 2841 (w), 1714 (s), 1643
(w), 1612 (m), 1585 (w), 1514 (m), 1462 (m), 1446 (m), 1384 (m),
1304 (m), 1250 (s), 1225 (m), 1203 (m), 1174 (m), 1141 (m), 1115 (m),
1056 (m), 1031 (m), 1001 (m), 977 (m), 897 (m), 884 (m), 854 (m),
824, 806, 773, 733, 711 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
7.63
4.5. Representative procedure for the preparation of
(both, s, ]CHN), 7.22 (both, d, J 8.6 Hz, o-Ar), 6.87 (both, d, J 8.6 Hz,
m-Ar), 6.85 (both, d, J 16.1 Hz, COCH]CH), 6.04 (min, d, J 16.1 Hz,
COCH]CH), 6.03 (maj, d, J 16.1 Hz, COCH]CH), 5.39e5.38 (m,
CH2OCO), 4.53e4.37 (m, NCH2), 4.40 (both, d, J 10.6 Hz, CHaHbAr),
4.34 (both, d, J 10.6 Hz, CHaHbAr), 3.94 (min, d, J 10.3 Hz, C(OPMB)
CHaHbOSO), 3.91 (maj, d, J 9.6 Hz, C(OPMB)CHaHbOSO), 3.79 (both,
s, OMe), 3.78 (min, d, J 10.3 Hz, C(OPMB)CHaHbOSO), 3.74 (maj, d, J
9.6 Hz, C(OPMB)CHaHbOSO), 3.65e3.48 (m, OCH2CH2), 1.97e1.86
(m, NCH2CH2), 1.54e1.46 (m, OCH2CH2), 1.44 (both, s, Me); 13C NMR
deprotected sulfites (22a, 22b, 24, 26, 28)
4.5.1. Sulfite (22a). The sulfite 21 (259 mg, 0.56 mmol) was dis-
solved in CH2Cl2 (52.8 mL) and water (2.9 mL). DDQ (152 mg,
0.67 mmol) was added, and the mixture was stirred at 20 ꢁC for 6 h.
Then the mixture was diluted with EtOAc (260 mL) and washed
with 40% aq NaHSO3 (260 mL) and water (2ꢂ260 mL). The aqueous
phase was extracted with EtOAc (260 mL) and the combined or-
ganic phases were dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified twice by flash column chroma-
tography (EtOAc/toluene 1:1) to give the deprotected sulfite 22a
(58 mg, 30%, one diastereomer) as white crystals and the sulfite 22b
(one diastereomer). Compound 22a: Rf 0.42 (MeOH/EtOAc 1:99);
(75 MHz, CDCl3) d 166.0 (maj), 165.9 (min), 159.3 (maj), 159.3 (min),
150.3 (maj),150.0 (min),144.2 (both),130.2 (min),130.2 (maj),129.1
(2C, maj), 129.0 (2C, min), 123.9 (maj), 123.8 (min), 122.8 (maj),
122.7 (min), 114.0 (2C, maj), 114.0 (2C, min), 76.4 (min), 76.3 (maj),
68.3 (min), 67.4 (maj), 65.3 (maj), 65.2 (min), 62.7 (maj), 62.1 (min),
57.7 (both), 55.4 (both), 50.1 (both), 27.1 (min), 27.0 (maj), 26.3
(min), 26.3 (maj), 19.6 (maj), 19.4 (min); HRMS (ESI): m/z calcd for
C21H27N3O7S [MþH]þ 466.1643, found 466.1639.
mp 121e123 ꢁC; IR(neat)
n 3362 (m), 3134 (m), 2961 (m), 2929 (m),
2876 (m), 1716 (s), 1658 (m), 1467 (m), 1455 (m), 1408 (w), 1392 (w),
1378 (w), 1362 (w), 1304 (m), 1284 (m), 1248 (m), 1194 (m), 1177
(m),1133 (m), 1105 (m),1059 (m), 1049 (m), 1033 (m), 1004 (m), 989
(m), 947 (m), 886 (m), 815 (m), 766 (m), 731 (m) cmꢀ1 1H NMR
;
4.4.3. Sulfite (25). White crystals, 79% yield; Rf 0.60 (MeOH/EtOAc
(300 MHz, CDCl3) d 7.64 (1H, s, ]CHN), 6.78 (1H, d, J 15.8 Hz,
1:99); mp 130e131 ꢁC; dr: 1:1 (NMR); IR (neat)
n
3127 (w), 3071
COCH]CH), 6.05 (1H, d, J 15.8 Hz, COCH]CH), 5.66 (1H, d, J 13.2 Hz,
]CCHaHbOSO), 4.87 (1H, d, J 13.2 Hz, ]CCHaHbOSO), 4.50 (1H, ddd,
J 13.9, 7.0, 5.1 Hz, CHaHbN), 4.38 (1H, ddd, J 13.9, 7.0, 5.1 Hz,
CHaHbN), 4.22 (2H, t, J 5.5 Hz, CH2CH2O), 4.03 (1H, d, J 10.3 Hz, C
(OH)CHaHbOSO), 3.86 (1H, d, J 10.3 Hz, C(OH)CHaHbOSO), 2.99 (1H,
br s, OH), 2.17e2.01 (2H, m, NCH2CH2), 1.77e1.65 (2H, m, CH2CH2O),
(w), 3044 (w), 3001 (w), 2954 (m), 2930 (m), 2877 (w), 2858 (w),
2836 (w), 1730 (s), 1680 (w), 1613 (m), 1586 (w), 1512 (m), 1454 (m),
1390 (m), 1331 (w), 1303 (m), 1274 (w), 1246 (m), 1233 (m), 1199
(m), 1172 (m), 1133 (m), 1106 (m), 1053 (m), 1036 (m), 1011 (m), 994
(m), 971 (m), 951 (m), 919 (m), 898 (m), 820 (m), 780 (m), 754 (m),

C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
9857
1.33 (3H, s, Me); 13C NMR (75 MHz, CDCl3)
d
165.7, 150.8, 143.1,
1278 (m), 1198 (m), 1171 (s), 1134 (m), 1075 (w), 1049 (m), 1027 (m),
978 (m), 940 (m), 925 (m), 889 (m), 854 (m), 835 (m), 788 (m), 767
123.8, 120.9, 71.9, 71.3, 63.3, 55.3, 49.7, 26.6, 25.2, 23.7; HRMS (ESI):
m/z calcd for C13H19N3O6S [MþH]þ 346.1067, found 346.1048. Anal.
Calcd for C13H19N3O6S: C, 45.21; H, 5.55; N, 12.17. Found: C, 45.30;
H, 5.51; N, 12.08. Compound 22b: Rf 0.12 (MeOH/EtOAc 1:99); 1H
(m), 736 (m), 710 (m), 670 (m) cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
7.63 (one, s, ]CHN), 7.61 (one, s, ]CHN), 5.94e5.74 (m, CH]CH),
5.63 (one, dd, J 13.6, 0.4 Hz, ]CCHaHbOSO), 5.54 (one, dd, J 13.6,
0.4 Hz, ]CCHaHbOSO), 4.97 (one, dd, J 13.6, 0.4 Hz, ]CCHaHbOSO),
NMR (300 MHz, CDCl3) d 7.56 (1H, s, ]CHN), 6.81 (1H, d, J 15.5 Hz,
COCH]CH), 6.04 (1H, d, J 15.5 Hz, COCH]CH), 4.81 (2H, s, ]
CCH2OH), 4.56 (1H, d, J 8.9 Hz, CHaHbOSO), 4.42 (1H, d, J 8.9 Hz,
CHaHbOSO), 4.43e4.39 (2H, m, CH2N), 4.18 (2H, t, J 6.3 Hz,
OCH2CH2), 2.05e1.97 (2H, m, CH2CH2N), 1.78 (3H, s, Me), 1.74e1.67
(2H, m, OCH2CH2); HRMS (ESI): m/z calcd for C13H19N3O6S [MþH]þ
346.1067, found 346.1094.
4.91 (one, dd, J 13.6, 0.4 Hz, ]CCHaHbOSO), 4.61e4.18 (m,
CH2CHaHbO, ]CHCH2, CH2N), 4.05e3.98 (m, CH2CHaHbO), 3.36
(both, br s, OH), 1.99e1.62 (m, CH2CH2N, CH2CH2O), 1.46 (one, s,
Me), 1.45 (one, s, Me); 13C NMR (75 MHz, CDCl3)
d 175.1 (one), 175.0
(one), 143.7 (one), 143.7 (one), 135.4 (one), 135.3 (one), 124.1 (one),
124.0 (one), 123.8 (one), 123.6 (one), 74.1 (one), 74.1 (one), 64.6
(one), 64.6 (one), 63.0 (one), 62.2 (one), 55.7 (one), 54.6 (one), 49.5
(one), 49.5 (one), 27.4 (one), 27.3 (one), 26.0 (one), 25.9 (one), 25.8
(one), 25.8 (one); HRMS (ESI): m/z calcd for C13H19N3O6S [MþH]þ
346.1067, found 346,1063. Anal. Calcd for C13H19N3O6S: C, 45.21; H,
5.55; N, 12.17. Found: C, 45.56; H, 5.76; N, 11.85.
4.5.2. Sulfite (24). White crystals, 47% yield; Rf 0.42 (MeOH/EtOAc
1:99); mp 115e118 ꢁC; dr: 3:2, de: 20% (NMR); IR(neat)
n 3152 (w),
3065 (w), 2965 (m), 2944 (m), 2917 (w), 2872 (w), 2842 (w), 1747
(m), 1725 (m), 1711 (s), 1657 (m), 1611 (w), 1514 (m), 1466 (w), 1449
(m), 1413 (w), 1382 (m), 1324 (m), 1300 (m), 1283 (m), 1264 (m),
1249 (m), 1220 (m), 1179 (m), 1149 (m), 1134 (m), 1027 (m), 1003
(m), 975 (m), 928 (m), 892 (m), 846 (w), 821 (m), 802 (w), 787 (m),
4.6. Representative procedure for the preparation of
macrocyclic malonates (29, 31)
757 (m), 741 (m), 700 (m) cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.64
(maj, s, ]CHN), 7.63 (min, s, ]CHN), 6.84 (maj, d, J 15.6 Hz, COCH]
CH), 6.82 (min, d, J 15.6 Hz, COCH]CH), 6.07 (both, d, J 15.6 Hz,
COCH]CH), 5.46 (maj, d, J 12.2 Hz, CHaHbOCO), 5.41 (min, d, J
12.3 Hz, CHaHbOCO), 5.32 (min, d, J 12.3 Hz, CHaHbOCO), 5.27 (maj,
d, J 12.2 Hz, CHaHbOCO), 4.52e4.37 (m, NCH2), 3.91 (min, d, J
10.1 Hz, C(OH)CHaHbOSO), 3.87 (maj, d, J 10.0 Hz, C(OH)CHaHbOSO),
3.77 (maj, d, J 10.0 Hz, C(OH)CHaHbOSO), 3.72 (min, d, J 10.1 Hz, C
(OH)CHaHbOSO), 3.68 (min, dt, J 7.2, 7.2 Hz, OCHaHbCH2), 3.64 (maj,
dt, J 7.1, 7.1 Hz, OCHaHbCH2), 3.51 (maj, dt, J 7.6, 7.6 Hz, OCHaHbCH2),
3.47 (min, dt, J 7.6, 7.6 Hz, OCHaHbCH2), 2.69 (both, br s, OH),
2.02e1.78 (m, NCH2CH2), 1.52e1.41 (m, OCH2CH2), 1.33 (min, s, Me),
4.6.1. Malonate (29). The diol 14 (55 mg, 0.13 mmol) was dissolved
in anhydrous CH2Cl2 (9.74 mL) and anhydrous Et3N (0.05 mL,
0.36 mmol) and DMAP (3 mg, 0.03 mmol) were added. A solution of
malonyl chloride in anhydrous CH2Cl2 (0.18 M, 1 mL, 0.18 mmol)
was added over 10 min at 20 ꢁC, under vigorous stirring. After
stirring for 1½ hours, the reaction mixture was concentrated in
vacuo. The residue was redissolved in EtOAc, filtered through Celite,
and concentrated in vacuo. Purification by flash column chroma-
tography (MeOH/CH2Cl2 1:99) gave the malonate 29 (23 mg, 37%)
as a colorless oil. Rf 0.54 (MeOH/EtOAc 1:99); IR (neat)
n 3146 (w),
2956 (m), 2872 (w), 2838 (w), 1751 (s), 1733 (s), 1715 (s), 1656 (w),
1613 (m), 1586 (w), 1514 (m), 1463 (m), 1443 (m), 1409 (w), 1385
(m), 1364 (m), 1300 (m), 1247 (s), 1172 (m), 1146 (m), 1130 (m), 1030
(m), 993 (m), 911 (m), 822 (m), 727 (m) cmꢀ1; 1H NMR (300 MHz,
1.32 (maj, s, Me); 13C NMR (75 MHz, CDCl3)
d 166.2 (maj), 166.2
(min), 151.8 (maj), 151.8 (min), 144.3 (maj), 144.2 (min), 123.9 (min),
123.8 (maj), 120.8 (both), 72.2 (min), 72.1 (maj), 70.7 (maj), 69.0
(min), 62.6 (min), 62.0 (maj), 57.5 (min), 57.5 (maj), 50.1 (maj), 50.1
(minor), 27.1 (both), 26.2 (both), 23.6 (both); HRMS (ESI): m/z calcd
for C13H19N3O6S [MþH]þ 346.1067, found 346.1068. Anal. Calcd for
C13H19N3O6S: C, 45.21; H, 5.55; N, 12.17. Found: C, 45.06; H, 5.48;
N, 12.07.
CDCl3) d 7.68 (1H, s, ]CHN), 7.24 (2H, d, J 8.7 Hz, o-Ar), 6.91 (1H, d, J
16.0 Hz, COCH]CH), 6.87 (2H, d, J 8.7 Hz, m-Ar), 6.04 (1H, d, J
16.0 Hz, COCH]CH), 5.36 (1H, d, J 12.7 Hz, OCHaHbC]), 5.21 (1H, d,
J 12.7 Hz, OCHaHbC]), 4.46 (2H, t, J 6.4 Hz, NCH2), 4.42 (1H, d, J
10.5 Hz, CHaHbAr), 4.36 (1H, d, J 10.5 Hz, CHaHbAr), 4.29 (1H, d, J
11.1 Hz, C(OPMB)CHaHbO), 4.22 (1H, d, J 11.1 Hz, C(OPMB)CHaHbO),
4.28e4.13 (2H, m, CH2CH2O), 3.80 (3H, s, OMe), 3.48 (1H, d, J
16.3 Hz, COCHaHbCO), 3.42 (1H, d, J 16.3 Hz, COCHaHbCO), 2.05e1.89
4.5.3. Sulfite (26). White crystals, 65% yield; Rf 0.36 (MeOH/EtOAc
1:99); mp 129e130 ꢁC; dr: 1:1 (NMR); IR (neat)
n 3503 (br), 3142
(w), 2970 (m), 2941 (m), 2889 (w), 2871 (w),1713 (s),1470 (w),1447
(m), 1364 (m), 1342 (w), 1264 (m), 1228 (m), 1197 (s) 1150 (m), 1135
(m), 1069 (m), 1053 (m), 983 (m), 970 (m), 946 (m), 920 (m), 871
(m), 839 (w), 821 (w), 805 (w), 777 (m), 731 (m), 678 (m) cmꢀ1; 1H
(2H, m, CH2CH2N), 1.67e1.59 (2H, m, OCH2CH2), 1.45 (3H, s, Me); 13
NMR (75 MHz, CDCl3) 166.7, 165.9, 165.9, 159.3, 149.3, 143.0, 130.3,
C
d
129.0 (2C), 124.0, 122.4, 114.0 (2C), 76.1, 69.5, 65.2, 63.0, 59.1, 55.4,
49.5, 41.2, 27.0, 25.5, 20.6; HRMS (ESI): m/z calcd for C24H29N3O8
[MþH]þ 488.2033, found 488.2036.
NMR (500 MHz, CDCl3)
d 7.55 (both, s, ]CHN), 5.88e5.82 (one, m,
CH]CH), 5.81 (one, d, J 15.4 Hz, CH]CHCH2), 5.75 (one, d, J 15.4 Hz,
CH]CHCH2), 5.70 (both, d, J 12.5 Hz, CHaHbOCO), 5.16 (one, d, J
12.5 Hz, CHaHbOCO), 5.15 (one, d, J 12.5 Hz, CHaHbOCO), 4.58e4.42
(m, NCHaHb, ]CHCHaHb), 4.39e4.23 (m, NCHaHb, ]CHCHaHb),
4.07e4.01 (m, OCHaHbCH2), 3.74e3.65 (m, OCHaHbCH2), 3.28 (both,
br s, OH), 2.07e1.97 (m, NCH2HaHb), 1.96e1.85 (m, NCH2HaHb),
1.66e1.54 (m, OCH2CH2), 1.53 (both, s, Me); 13C NMR (75 MHz,
4.6.2. Malonate (31). White crystals, 34% yield; mp 113e115 ꢁC; Rf
0.54 (MeOH/EtOAc 1:99); IR(neat)
n 3153 (w), 3064 (w), 3039 (w),
2998 (w), 2944 (m), 2916 (w), 2872 (m), 2842 (w), 1747 (s), 1726 (s),
1712 (s), 1657 (m), 1611 (m), 1587 (w), 1514 (m), 1465 (w), 1449 (m),
1413 (w), 1383 (m), 1324 (m), 1300 (m), 1283 (m), 1265 (m), 1249
(m), 1220 (m), 1179 (s), 1149 (m), 1135 (m), 1122 (m), 1059 (m), 1027
(s) 976 (m), 928 (m), 847 (m), 821 (m), 803 (m), 788 (m), 757 (m),
CDCl3)
d 174.9 (one), 174.8 (one), 142.7 (one), 142.7 (one), 136.3
(one), 135.2 (one), 124.1 (both), 124.1 (one), 123.9 (one), 74.3 (both),
62.2 (one), 62.0 (one), 61.9 (one), 61.8 (one), 58.9 (one), 58.8 (one),
50.0 (one), 50.0 (one), 26.9 (one), 26.9 (one), 26.4 (one), 26.3 (one),
25.2 (both); HRMS (ESI): m/z calcd for C13H19N3O6S [MþH]þ
346.1067, found 346.1073. Anal. Calcd for C13H19N3O6S: C, 45.21; H,
5.55; N, 12.17. Found: C, 44.59; H, 5.78; N, 12.07.
742 (w) cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 7.70 (1H, s, ]CHN), 7.24
(2H, d, J 8.5 Hz, o-Ar), 6.94 (1H, d, J 16.0 Hz, COCH]CH), 6.87 (2H, d,
J 8.5 Hz, m-Ar), 6.08 (1H, d, J 16.0 Hz, COCH]CH), 5.38 (1H, d, J
12.8 Hz, OCHaHbC]), 5.35 (1H, d, J 12.8 Hz, OCHaHbC]), 4.48e4.43
(2H, m, NCH2), 4.42 (1H, d, J 10.7 Hz, CHaHbAr), 4.37 (1H, d, J 10.7 Hz,
CHaHbAr), 4.27 (1H, d, J 11.2 Hz, C(OPMB)CHaHbO), 4.15 (1H, d, J
11.2 Hz, C(OPMB)CHaHbO), 4.00e3.90 (2H, m, CH2CH2O), 3.80 (3H,
s, OMe), 3.34 (1H, d, J 15.9 Hz, COCHaHbCO), 3.30 (1H, d, J 15.9 Hz,
COCHaHbCO), 1.96e1.91 (2H, m, NCH2CH2), 1.54e1.47 (2H, m,
4.5.4. Sulfite (28). White crystals, 67% yield; Rf 0.36 (MeOH/EtOAc
1:99); mp 93e95 ꢁC; dr: 1:1 (NMR); IR (neat)
n
3500 (m), 3151 (w),
2966 (m), 2872 (w), 1719 (s), 1676 (w), 1454 (m), 1443 (m), 1373 (m)
CH2CH2O), 1.44 (3H, s, Me); 13C NMR (75 MHz, CDCl3)
d 166.2, 166.1,

9858
C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
165.7, 159.3, 149.4, 148.6, 130.3, 129.0 (2C), 124.2, 122.5, 113.9 (2C),
76.3, 69.5, 65.2, 64.2, 58.1, 55.4, 49.6, 41.3, 26.1, 25.3, 20.2; HRMS
(ESI): m/z calcd for C24H29N3O8 [MþH]þ 488.2033, found 488.2030.
cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 10.13 (1H, s, ]CCHO), 9.62 (1H,
d, J 7.7 Hz, ]CHCHO), 8.02 (1H, s, ]CHN), 7.27 (2H, d, J 8.5 Hz, o-Ar),
6.99 (1H, d, J 15.9 Hz, CH]CHCHO), 6.87 (2H, d, J 8.5 Hz, m-Ar), 6.43
(1H, dd, J 15.9, 7.7 Hz, CH]CHCHO), 4.44 (2H, s, CH2Ar), 4.43 (2H, t, J
7.1 Hz, CH2N), 4.23 (2H, t, J 6.3 Hz, OCH2CH2), 3.80 (3H, s, OMe),
2.07e1.97 (2H, m, CH2CH2N), 1.77e1.70 (2H, m, OCH2CH2), 1.67 (3H,
4.7. Representative procedure for the preparation of
deprotected macrocyclic malonates (30, 32)
s, Me); 13C NMR (75 MHz, CDCl3)
d 193.2, 185.1, 171.3, 159.4, 155.1,
4.7.1. Malonate (30). The malonate 29 (100 mg, 0.21 mmol) was
dissolved in CH2Cl2 (19.5 mL) and water (1.1 mL). DDQ (56 mg,
0.25 mmol) was added, and the mixture was stirred at 20 ꢁC for
5½ h. Then the mixture was diluted with EtOAc (100 mL) and
washed with 40% aq NaHSO3 (120 mL) and water (2ꢂ80 mL). The
aqueous phase was extracted with EtOAc (120 mL) and the com-
bined organic phases were dried (MgSO4), filtered, and concen-
trated in vacuo. The residue was purified twice by flash column
chromatography (EtOAc/toluene 1:1) to give the deprotected mal-
onate 30 (59 mg, 78%) as a colorless oil. Rf 0.38 (MeOH/EtOAc 1:99);
147.9, 132.3, 129.6, 129.1 (2C), 125.3, 113.9 (2C), 80.3, 67.4, 64.9, 55.4,
50.2, 26.9, 25.5, 23.6.
4.8.2. (ꢃ)-(E)-(1-(4-Oxobutyl)-1H-1,2,3-triazol-4-yl)methyl
methoxybenzyloxy)-2-methyl-5-oxopent-3-enoate (35). Colorless
oil, 98% yield; Rf 0.35 (MeOH/CH2Cl2 5:95); IR (neat) 3143 (w),
2-(4-
n
2957 (m), 2938 (m), 2837 (m), 2733 (w), 1723 (s), 1688 (s), 1613 (m),
1514 (s), 1461 (m), 1443 (m), 1386 (m), 1302 (m), 1247 (s), 1175 (m),
1106 (s), 1048 (m), 1028 (m), 979 (m), 913 (m), 821 (m), 729 (m)
cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 9.72 (1H, s, CH2CHO), 9.58 (1H, d,
IR (neat)
(m), 1373 (m), 1328 (m), 1264 (s), 1182 (m), 1136 (s), 1046 (m), 1024
(m), 979 (m) cmꢀ1; 1H NMR (500 MHz, CDCl3)
7.70 (1H, s, ]CHN),
n
3468 (br), 3148 (w), 2958 (m), 1713 (s), 1658 (m), 1444
J 7.8 Hz, ]CHCHO), 7.58 (1H, s, ]CHN), 7.25 (2H, d, J 8.6 Hz, o-Ar),
6.99 (1H, d, J 15.9 Hz, CH]CHCHO), 6.86 (2H, d, J 8.6 Hz, m-Ar), 6.38
(1H, dd, J 15.9, 7.8 Hz, CH]CHCHO), 5.37 (1H, d, J 13.2 Hz, CHaH-
bOCO), 5.32 (1H, d, J 13.2 Hz, CHaHbOCO), 4.44e4.37 (4H, m, CH2Ar,
NCH2), 3.80 (3H, s, OMe), 2.52 (2H, t, J 6.8 Hz, CH2CHO), 2.24e2.15
(2H, m, NCH2CH2), 1.66 (3H, s, Me); 13C NMR (75 MHz, CDCl3)
d
6.92 (1H, d, J 15.7 Hz, COCH]CH), 6.04 (1H, d, J 15.7 Hz, COCH]CH),
5.44 (1H, d, J 12.6 Hz, ]CCHaHbO), 5.17 (1H, d, J 12.6 Hz, ]
CCHaHbO), 4.48 (1H, d, J 10.9 Hz, C(OH)CHaHbO), 4.46 (2H, t, J 6.4 Hz,
NCH2), 4.42 (1H, m, CH2CHaHbO), 4.03 (1H, d, J 10.9 Hz, C(OH)
CHaHbO), 4.02 (1H, m, CH2CHaHbO), 3.48 (1H, d, J 17.5 Hz,
COCHaHbCO), 3.45 (1H, d, J 17.5 Hz, COCHaHbCO), 2.13 (1H, m,
NCH2CHaHb), 2.04 (1H, m, NCH2CHaHb), 1.73 (1H, m, CHaHbCH2O),
1.57 (1H, m, CHaHbCH2O),1.36 (3H, s, Me); 13C NMR (75 MHz, CDCl3)
d
200.3, 193.2, 171.3, 159.4, 155.1, 142.3, 132.2, 129.6, 129.4 (2C),
124.1, 113.9 (2C), 80.2, 67.5, 58.9, 55.4, 49.4, 40.2, 23.8, 22.7.
4.8.3. (ꢃ)-(E)-4-(4-Formyl-1H-1,2,3-triazol-1-yl)butyl 4-(4-methox-
ybenzyloxy)-4-methyl-5-oxopent-2-enoate
(33). Colorless
oil,
d
168.1, 166.1, 165.7, 151.5, 142.5, 124.6, 120.2, 72.2, 71.1, 63.2, 59.1,
quantitative yield; Rf 0.55 (MeOH/EtOAc 1:99); 1H NMR (300 MHz,
CDCl3) 10.15 (1H, s, ]CCHO), 9.51 (1H, s, C(OPMB)CHO), 8.11 (1H,
49.5, 41.1, 26.9, 25.1, 23.6; HRMS (ESI): m/z calcd for C16H21N3O7
[MþH]þ 368.1452, found 368.1449. Anal. Calcd for C16H21N3O7: C,
52.31; H, 5.76; N, 11.44. Found: C, 52.23; H, 5.71; N, 11.40.
d
s, ]CHN), 7.29 (2H, d, J 8.8 Hz, o-Ar), 6.90 (2H, d, J 8.8 Hz, m-Ar),
6.87 (1H, d, J 15.9 Hz, COCH]CH), 6.20 (1H, d, J 15.9 Hz, COCH]CH),
4.51e4.45 (4H, m, CH2Ar, NCH2), 4.20 (2H, t, J 6.3 Hz, OCH2CH2), 3.81
(3H, s, OMe), 2.11e2.01 (2H, m, CH2CH2N), 1.77e1.68 (2H, m,
4.7.2. Malonate (32). White crystals, 69% yield; mp 105e106 ꢁC; Rf
0.38 (MeOH/EtOAc 1:99); IR (neat)
n
3308 (br), 3156 (w), 2986 (w),
OCH2CH2), 1.52 (3H, s, Me); 13C NMR (75 MHz, CDCl3)
d 199.7, 185.3,
2968 (m), 2941 (w), 2873 (w), 1727 (s), 1711 (s), 1650 (w), 1462 (w),
1447 (w), 1422 (w), 1376 (w), 1351 (m), 1324 (m), 1295 (m), 1259
(m), 1239 (m), 1224 (m), 1169 (m), 1075 (m), 1065 (m), 1030 (m),
165.6, 159.6, 148.0, 145.0, 129.6, 129.4 (2C), 125.2, 123.7, 114.1 (2C),
83.3, 66.8, 63.6, 55.4, 50.4, 27.0, 25.7, 19.6.
1007 (m), 981 (m), 841 (m), 782 (m) cmꢀ1
;
1H NMR (500 MHz,
4.9. Representative procedure for the preparation of
macrocyclic amines (34, 36, 40)
CDCl3) d 7.69 (1H, s, ]CHN), 6.96 (1H, d, J 15.7 Hz, COCH]CH), 6.10
(1H, d, J 15.7 Hz, COCH]CH), 5.39 (1H, d, J 12.6 Hz, ]CCHaHbO),
5.33 (1H, d, J 12.6 Hz, ]CCHaHbO), 4.49e4.40 (2H, m, NCH2), 4.24
(1H, d, J 11.2 Hz, C(OH)CHaHbO), 4.17 (1H, d, J 11.2 Hz, C(OH)
CHaHbO), 3.92 (2H, t, J 7.3 Hz, CH2CH2O), 3.35 (1H, d, J 16.4 Hz,
COCHaHbCO), 3.32 (1H, d, J 16.4 Hz, COCHaHbCO), 1.96e1.90 (2H, m,
NCH2CH2), 1.52e1.45 (2H, m, CH2CH2O), 1.35 (3H, s, Me); 13C NMR
4.9.1. Amine (40). The dialdehyde 39 (43 mg, 0.10 mmol) was
dissolved in anhydrous CH2Cl2 (6.9 mL). The mixture was cooled to
0 ꢁC, and a solution of veratrylamine in anhydrous CH2Cl2 (0.11 M,
1 mL, 0.11 mmol) was added. After stirring at 0 ꢁC for 25 min, Na
(OAc)3BH (65 mg, 0.31 mmol) was added. After stirring at 0 ꢁC for
ꢀ
(75 MHz, CDCl3)
d
166.5, 166.1, 165.9, 151.4, 143.8, 124.2, 120.4, 72.3,
further 15 min, powdered 3 A molecular sieves (40 mg) were
71.4, 64.3, 57.8, 49.7, 41.2, 25.9, 25.4, 24.1; HRMS (ESI): m/z calcd for
C16H21N3O7 [MþH]þ 368.1452, found 368,1450. Anal. Calcd for
C16H21N3O7: C, 52.31; H, 5.76; N, 11.44. Found: C, 52.18; H, 5.74;
N, 11.29.
added. The suspension was then stirred at 0 ꢁC for 3 h, whereafter it
was quenched with ether (10 mL) and then water (20 mL). After
filtration, the mixture was transferred to a separatory funnel with
ether (40 mL) and CH2Cl2 (20 mL). The organic phase was isolated
and washed with a mixture of satd aq NaHCO3 (40 mL) and water
(20 mL). The aqueous phase was extracted with CH2Cl2 (2ꢂ30 mL)
and ether (30 mL). The combined organic phases were dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by flash
column chromatography (EtOAc/heptane 3:1) gave the azalide 40
(34 mg, 60%) as an amorphous solid. Rf 0.30 (MeOH/CH2Cl2 5:95); IR
4.8. Representative procedure for the preparation of
dialdehydes (33, 35, 39)
4.8.1. (ꢃ)-(E)-4-(4-Formyl-1H-1,2,3-triazol-1-yl)butyl 2-(4-methox-
ybenzyloxy)-2-methyl-5-oxopent-3-enoate (39). The diol 20 (51 mg,
0.12 mmol) was dissolved in CH3CN (2.1 mL). IBX23 (202 mg,
0.72 mmol) was added, and the suspension was heated to 55 ꢁC.
After stirring at 55 ꢁC for 3½ h, the suspension was concentrated in
vacuo. The residue was redissolved in ether, filtered, and concen-
trated in vacuo giving the dialdehyde 39 (50 mg, quantitative yield)
(neat)
n 3134 (w), 3034 (m), 2996 (m), 2934 (m), 2872 (m), 2834
(m), 1730 (s), 1612 (m), 1589 (m), 1512 (s), 1453 (m), 1418 (m), 1367
(m), 1329 (m), 1301 (m), 1244 (s), 1175 (m), 1108 (s), 1025 (s), 980
(m), 943 (m), 893 (m), 853 (m), 810 (m), 764 (m) cmꢀ1 1H NMR
;
(300 MHz, CDCl3)
d 7.52 (1H, s, ]CHN), 7.27 (2H, d, J 8.8 Hz, o-Ar),
as a colorless oil. Rf 0.46 (MeOH/CH2Cl2 5:95); IR (neat)
n
3133 (w),
6.96 (1H, s, 2-Ar), 6.89 (1H, d, J 8.2 Hz, 6-Ar), 6.85 (2H, d, J 8.8 Hz, m-
Ar), 6.79 (1H, d, J 8.2 Hz, 5-Ar), 5.77 (1H, d, J 15.7 Hz, CH]CHCH2),
5.64 (1H, dt, J 15.7, 4.9 Hz, CH]CHCH2), 4.43 (1H, d, J 10.6 Hz,
OCHaHbAr), 4.41e4.36 (2H, m, CH2CH2N), 4.31 (1H, d, J 10.6 Hz,
2960 (m), 2937 (m), 2872 (m), 2837 (m),1733 (s), 1688 (s), 1612 (m),
1531 (m), 1513 (s), 1463 (m), 1443 (m), 1384 (m), 1301 (m), 1245 (s),
1174 (m), 1110 (s), 1092 (s), 1028 (s), 979 (m), 822 (m), 782 (m)

C.M. Madsen et al. / Tetrahedron 66 (2010) 9849e9859
9859
OCHaHbAr), 4.26e4.11 (2H, m, CH2CH2O), 3.86 (3H, s, OMe), 3.84
(3H, s, OMe), 3.81 (2H, s, ]CCH2NDMB), 3.79 (3H, s, OMe), 3.74 (1H,
d, J 13.3 Hz, NCHaHbAr), 3.68 (1H, d, J 13.3 Hz, NCHaHbAr), 3.21 (2H,
d, J 4.9 Hz, CH]CHCH2), 2.10e2.01 (2H, m, CH2CH2N), 1.68e1.62
(2H, m, CH2CH2O), 1.53 (3H, s, Me); 13C NMR (75 MHz, CDCl3)
1.07 (1H, m, CHaHbCH2NDMB); HRMS (ESI): m/z calcd for
C22H30N4O5 [MþH]þ 431.2289, found 431.2289.
4.10.2. Amine (41). 33% yield; Rf 0.10 (MeOH/CH2Cl2 5:95); 1H NMR
(500 MHz, CD3OD) d 7.87 (1H, s, ]CHN), 7.07 (1H, s, 2-Ar), 6.94 (1H,
d
172.7, 159.2, 149.0, 148.2, 147.4, 131.7, 131.6, 131.0, 130.7, 129.3 (2C),
d, J 8.2 Hz, 6-Ar), 6.91 (1H, d, J 8.2 Hz, 5-Ar), 5.65 (1H, d, J 15.6 Hz,
CH]CHCH2), 5.57 (1H, ddd, J 15.6, 6.2, 4.8 Hz, CH]CHCH2), 4.47
(1H, m, CH2CHaHbN), 4.39 (1H, m, CH2CHaHbN), 4.27 (1H, m,
CH2CHaHbO), 4.03 (1H, m, CH2CHaHbO), 3.85 (3H, s, OMe), 3.82 (3H,
s, OMe), 3.79e3.77 (2H, m, NCH2Ar), 3.74 (2H, s, ]CCH2NDMB),
3.25 (1H, m, CH]CHCHaHb), 3.18 (1H, dd, J 15.5, 6.2 Hz, CH]
CHCHaHb), 2.04 (2H, m, CH2CH2N), 1.66 (1H, m, CHaHbCH2O), 1.57
(1H, m, CHaHbCH2O), 1.36 (3H, s, Me); HRMS (ESI): m/z calcd for
C22H30N4O5 [MþH]þ 431.2289, found 431.2281.
122.0, 121.1, 113.8 (2C), 112.1, 110.9, 80.3, 66.7, 63.4, 60.6, 56.1, 56.0,
56.0, 55.4, 50.1, 49.4, 26.6, 26.5, 22.4; HRMS (ESI): m/z calcd for
C30H38N4O6 [MþH]þ 551.2864, found 551.2859.
4.9.2. Amine (36). White solid, 46% yield; Rf 0.17 (MeOH/CH2Cl2
5:95); mp 141e143 ꢁC; IR(neat)
n 3129 (w), 2994 (w), 2966 (w), 2937
(m), 2915 (w), 2875 (w), 2837 (w), 2797 (m), 1718 (s), 1614 (m), 1589
(w), 1516 (s), 1452 (m), 1420 (w), 1389 (w), 1375 (w), 1328 (w), 1252
(s), 1237 (m), 1184 (m), 1160 (m), 1122 (s), 1058 (w), 1024 (m), 966
(w), 929 (w), 879 (w), 856 (w), 826 (m), 805 (m), 761 (w) cmꢀ1; 1H
Acknowledgements
NMR (300 MHz, CDCl3) d 7.62 (1H, s, ]CHN), 7.32 (2H, d, J 8.7 Hz, o-
Ar), 6.87 (2H, d, J 8.7 Hz, m-Ar), 6.83 (1H, s, 2-Ar), 6.76 (2H, s, 5-Ar, 6-
Ar), 5.66 (1H, dt, J 15.7, 6.0 Hz, CH]CHCH2), 5.49 (1H, d, J 12.1 Hz,
CHaHbOCO), 5.44 (1H, d, J 15.7 Hz, CH]CHCH2), 5.31 (1H, d, J 12.1 Hz,
CHaHbOCO), 4.49 (1H, d, J 10.6 Hz, OCHaHbAr), 4.41 (1H, d, J 10.6 Hz,
OCHaHbAr), 4.39e4.28 (2H, m, ]NNCH2), 3.85 (3H, s, OMe), 3.84 (3H,
s, OMe), 3.80 (3H, s, OMe), 3.47 (1H, d, J 13.9 Hz, NCHaHbAr), 3.42 (1H,
d, J 13.9 Hz, NCHaHbAr), 2.89 (2H, d, J 6.0 Hz, CH]CHCH2), 2.15e2.09
(2H, m, CH2CH2NDMB), 1.90e1.79 (2H, m, ]NNCH2CH2), 1.58 (3H, s,
Me), 1.27e1.15 (2H, m, CH2CH2NDMB); 13C NMR (75 MHz, CDCl3)
We are grateful to the Lundbeck Foundation, the Torkil Holm
Foundation, and the Augustinus Foundation for financial support of
this work.
Supplementary data
Copies of NMR spectra for compounds 1e37, 39e41. Supple-
mentary data associated with this article can be found in online
version at doi:10.1016/j.tet.2010.10.071. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
d
173.0, 159.2, 149.0, 148.1, 142.9, 132.3, 132.3, 131.9, 130.6, 129.3 (2C),
124.7, 120.9, 113.8 (2C), 111.8, 110.8, 80.4, 66.7, 59.3, 58.0, 56.0, 56.0,
55.4, 54.8, 52.7, 50.1, 27.7, 22.7, 20.9; HRMS (ESI): m/z calcd for
C30H38N4O6 [MþH]þ 551.2864, found 551.2862.
References and notes
4.9.3. Amine (34). Yield (9%); Rf 0.30 (MeOH/EtOAc 1:99); 1H NMR
(500 MHz, CD3OD) d 7.57 (1H, s, ]CHN), 7.18 (2H, d, J 8.6 Hz, o-Ar),
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7.05 (1H, m, 2-Ar), 6.90e6.83 (2H, m, 5-Ar, 6-Ar), 6.78 (2H, d, J
8.6 Hz, m-Ar), 6.65 (1H, d, J 16.1 Hz, COCH]CH), 5.85 (1H, d, J
16.1 Hz, COCH]CH), 4.41 (1H, d, J 11.0 Hz, OCHaHbAr), 4.35 (1H, m,
CH2CHaHbN), 4.28 (1H, d, J 11.0 Hz, OCHaHbAr), 4.27 (1H, m,
CH2CHaHbN), 4.23 (1H, m, OCHaHbCH2), 4.16 (1H, d, J 13.6 Hz,
NCHaHbAr), 4.08 (1H, m, OCHaHbCH2), 3.82 (3H, s, OMe), 3.74 (6H, s,
2ꢂOMe), 3.65 (1H, d, J 14.3 Hz, ]CCHaHbNDMB), 3.57 (1H, d, J
13.6 Hz, NCHaHbAr), 3.43 (1H, d, J 14.3 Hz, ]CCHaHbNDMB), 3.05
(1H, d, J 14.2 Hz, C(OPMB)CHaHbN), 2.85 (1H, d, J 14.2 Hz, C(OPMB)
CHaHbN), 2.10e1.97 (2H, m, CH2CH2N), 1.84e1.74 (2H, m, OCH2CH2),
1.35 (3H, s, Me); HRMS (ESI): m/z calcd for C30H38N4O6 [MþH]þ
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5:95); 1H NMR (300 MHz, CD3OD)
d 7.94 (1H, s, ]CHN), 6.95 (1H, d,
J 1.6 Hz, 2-Ar), 6.89 (1H, d, J 8.2 Hz, 6-Ar), 6.83 (1H, dd, J 8.2, 1.6 Hz,
5-Ar), 5.71 (1H, ddd, J 15.4, 8.5, 4.4 Hz, CH]CHCH2), 5.60 (1H, d, J
12.3 Hz, CHaHbOCO), 5.44 (1H, d, J 15.4 Hz, CH]CHCH2), 5.11 (1H, d,
J 12.3 Hz, CHaHbOCO), 4.46e4.41 (2H, m, ]NNCH2), 3.83 (3H, s,
OMe), 3.81 (3H, s, OMe), 3.58 (1H, d, J 13.0 Hz, NCHaHbAr), 3.51 (1H,
d, J 13.0 Hz, NCHaHbAr), 3.07 (1H, ddd, J 14.7, 4.4, 1.6 Hz, CH]
CHCHaHb), 2.85 (1H, dd, J 14.7, 8.5 Hz, CH]CHCHaHb), 2.15 (2H, t, J
8.1 Hz, CH2CH2NDMB), 1.90 (1H, m, ]NNCH2CHaCHb), 1.75 (1H, m,
]NNCH2CHaHb), 1.43 (3H, s, Me), 1.33 (1H, m, CHaHbCH2NDMB),
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