Synthesis of azide-alkyne fragments for 'click' chemical applications. formation of chiral 1,4-disubstituted-(β-alkyl) γ- 1,2,3-triazole scaffolds from orthogonally protected chiral β-alkyl-trialkylsilyl γ- Pentynyl azides and chiral β-alkyl γ- Pentynyl-alcohols

Article abstract of DOI:10.1071/CH10306

A library of chiral γ-pentynyl alcohols and γ-pentynyl azides was made using the SuperQuat auxiliary. Coupling of the free alkynes with the azides by Huisgen 1,3-dipolar cycloaddition provided chiral oligomeric 1,4-disubstituted-1,2,3-triazoles as possible peptidomimetic compounds.

Full text of DOI:10.1071/CH10306

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 1541–1549
Synthesis of Azide-alkyne Fragments for ‘Click’ Chemical
Applications. Formation of Chiral 1,4-Disubstituted-(b-
alkyl)-g-1,2,3-triazole Scaffolds from Orthogonally
Protected Chiral b-Alkyl-trialkylsilyl-g-pentynyl Azides
and Chiral b-Alkyl-g-pentynyl-alcohols
A
B
A C
,
Oliver D. Montagnat, Guillaume Lessene, and Andrew B. Hughes
A
Department of Chemistry, La Trobe Institute of Molecular Sciences,
La Trobe University, Melbourne, Vic. 3086, Australia.
B
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
Parkville, Vic. 3052, Australia.
C
Corresponding author. Email: a.hughes@latrobe.edu.au
A library of chiral g-pentynyl alcohols and g-pentynyl azides was made using the SuperQuat auxiliary. Coupling of
the free alkynes with the azides by Huisgen 1,3-dipolar cycloaddition provided chiral oligomeric 1,4-disubstituted-1,2,3-
triazoles as possible peptidomimetic compounds.
Manuscript received: 16 August 2010.
Manuscript accepted: 17 September 2010.
Introduction
peptidomimetics. In particular, it was decided that an additional
carbon within the fragment backbone (chiral b-alkyl-g-pentynyl
azides and alcohols, Fig. 1) would provide greater structural
diversity and flexibility within the triazolamer backbone chain
and thus more conformational control when constructing these
oligomers in a stepwise fashion.
Herein, we report the synthesis of chiral b-alkyl-g-pentynyl-
alcohols 5 and chiral b-alkyl-trialkylsilyl-protected-g-pentynyl
azides 6 using the ‘SuperQuat’ (SQ) group as a chiral auxili-
ary.[13–17] This method provides a novel synthetic strategy to
access chiral b-alkyl-g-pentynyl-alcohols 5 and chiral b-alkyl-
trialkylsilyl-protected-g-pentynyl azides 6 in an enantioselec-
tive manner. We also report the coupling of the two fragments in
a Huisgen, Cu0-catalyzed 1,3-dipolar cycloaddition reaction to
generate chiral 1,4-disubstituted-(b-alkyl)-g-1,2,3-triazole
scaffolds.
Development of strategies to prepare novel peptidomimetic
frameworks is a highly desirable and very active area in med-
icinal chemistry. Many recent developments have shown the
usefulness of unnatural peptide-like frameworks towards many
biological applications,[1] including those such as antimicrobial
polymers (AMP),[2] cell-permeable peptides (CPP),[3] and
anticancer agents.[4]
It has been shown that ‘click’ chemistry[5–7] provides a
reliable pathway for accessing 1,2,3-triazolic scaffolds and
oligomeric foldamers that may act as potential peptidomimetic
compounds with defined secondary structure. Examples of
1,2,3-triazole scaffold development include the works of Arora
et al.[8] and Martinelli et al.,[9] with the most recent applications
in the biological evaluation of a set of chiral a-disubstituted-
(1,4-disubstituted)-1,2,3-triazolamers as active-site inhibitors
of HIV-1 protease.[10]
Recently, we reported the synthesis of chiral b3-
disubstituted-(1,4-disubstituted)-1,2,3-triazole oligomer scaf-
folds from chiral b3-substituted homopropargyl alcohols 1 and
chiral b3-substituted trialkylsilyl-homopropargyl azides 2 as
fragment building blocks, using the Huisgen Cu0-catalyzed
1,3-dipolar cycloaddition as a key coupling step.[11] This work
confirmed earlier observations, which showed that racemic a-
disubstituted-(1,4-disubstituted)-1,2,3-triazole oligomer scaf-
folds could be generated in a stepwise and controlled manner
in excellent yields from racemic a-propargyl alcohols 3 and
racemic a-substituted trialkylsilyl-protected propargyl azides 4,
using the Cu0-catalyzed Huisgen 1,3-dipolar cycloaddition.[12]
We anticipated that an expansion to the set of azide and
alkyne fragments available within our fragment library may
prove to be valuable when designing novel triazolamer
Results and Discussion
The synthetic strategy outlined in Scheme 1 was applied to the
two target molecules: chiral b-alkyl-g-pentynyl-alcohols 5 and
chiral b-alkyl-trialkylsilyl-protected-g-pentynyl azides 6. The
intermediate chiral b-alkyl-trialkylsilyl-protected-g-pentynyl-
alcohol 7 can be generated via LiBH4-mediated reductive SQ-
removal of the alkylated SQ-adduct 8. Alkylation of the SQ
adduct 9 could then be achieved by enolization and introduction
of an appropriate electrophile, and generation of the SQ adduct
could be done via a simple coupling reaction of starting mate-
rials 10 and 11.
Following literature procedures,[13,14] a methyl Grignard
addition to (S)-methyl esters 12 and 13 in THF provided the
(S)-dimethyl alcohols 14 and 15 (Scheme 2). This was followed
by base-induced intramolecular ring closure in the presence of
Ó CSIRO 2010
10.1071/CH10306
0004-9425/10/111541

1542
O. D. Montagnat, G. Lessene, and A. B. Hughes
potassium tert-butoxide and THF to provide (S)-SQ compounds
11a and 11b in 58 and 77% overall yield respectively. The [a]D
values of compounds 11a, 11b, 12–15 correlated well when
compared with literature values of the same compounds.[14,15]
Synthesisoftheotherstartingmaterial, 5-trimethylsilyl-pent-
5-yn-1-oic acid 10, was also performed following literature
procedures.[18,19] Trimethylsilyl-protection of pent-5-yn-1-ol 17
over N-propionyl-5,5-dimethyl-4-phenyloxazolidin-2-one. This
precedent, along with the efficient scale-up procedures for the
synthesis of the N-benzyloxazolidin-2-one 11b,[14] guided the
following alkylation reactions of adducts 9a and 9b.
Asymmetric alkylation was initiated using either the (S)-iPr
or (S)-Bn SQ adduct 9a or 9b, along with a strong base
(LiHMDS, lithium diisopropylamide (LDA), or KHMDS)
and in the presence of an alkyl halide or alkyl triflate as the
electrophile (Scheme 3, Table 1).
In the presence of alkyl halides as the electrophile, all
attempts gave no reaction (entries 1–4, Table 1), with the
exception of the (S)-iPr SQ adduct 8a in the presence of
LiHMDS and MeI (entry 5, Table 1). These conditions provided
a modest amount (22%) of the major product 8d (the (4S,2S)-
diastereoisomer), along with trace amounts (3%) of a minor
product (the (4S,2R)-diastereomer). The corresponding dia-
stereoisomers were assigned based on literature stereoselectiv-
ity for similar model substrates,[17] NOESY analysis and energy
minimization calculations of the major product (see Accessory
Publication). It should be noted that no study or optimization of
the use of the particular bases in Table 1 has been made.
As it has been shown that more strongly activated electro-
philes such as BnBr consistently provide better yields (70–80%)
and excellent levels of stereoselectivity on similar substrates
and under similar conditions,[17] it was decided to attempt the
n
using 3.0 equivalents of BuLi and 6.0 equivalents of TMSCl
in THF was followed by oxidation of 17 in the presence of
pyridinium chlorochromate (PCC) and DMF (Scheme 2) and
gave the desired acid 10 in 70% overall yield.
Coupling of 5-TMS-pent-5-yn-1-oic acid 10 to the (S)-iso-
propyl- and (S)-benzyl-SQ auxiliaries 11a and 11b was per-
formed via addition of 1.1 equivalents of pivaloyl chloride to the
acid 10 in order to the form the mixed anhydride, followed by
addition of the lithium oxazolidin-2-one salt of SQ auxiliaries
11a or 11b at ꢀ408 to ꢀ788C (Scheme 2). Short reaction times
(1 h), lower temperatures (ꢀ788C) and a small excess of base
(1.1 equiv. Et3N and 1.2 equiv. nBuLi) were found to be optimal,
with the (S)-benzyl (Bn) SQ adduct 9b (5,5-dimethyl-(4S)-
benzyloxazolidin-2-one) providing a higher yield (72%)
than the (S)-iPr SQ adduct 9a (5,5-dimethyl-(4S)-iso-
propyloxazolidin-2-one, 56% yield).
The SQ adducts 9a and 9b now required asymmetric alkyla-
tion. There are no records of the asymmetric alkylation of these
compounds; however, there are examples in the literature for
the asymmetric alkylation of other N-acylated SQ adducts. N-
Propionyl-5,5-dimethyl-4-substituted-SQ adducts have been
shown to produce an enolate on treatment with a stoichiometric
base such as lithium hexamethyldisilazide (LiHMDS).[15] Those
enolates are known to react diastereoselectively depending on
the bulkiness of the chiral substituent on the oxazolidin-2-one
ring.[15] A greater level of diastereomeric control was achieved
using N-propionyl-5,5-dimethyl-4-isopropyloxazolidin-2-one
R1
TMS
N3
6
R1
H
R1
TMS
HO
HO
SQ-removal
O
5
7
R3
H
R3
SiR43
HO
N3
R1 ꢀ Me, nPent, iBu
R2 ꢀ Bn, iPr
1
2
Chiral β3-alkyl homopropargyl azides/alcohols
O
R3 ꢀ iPr, iBu, Bn
R4 ꢀ Me
O
N
R1
TMS
R2
R1
R1
8
HO
N3
Alkylation
H
SiR23
3
4
O
O
rac-α-alkyl propargyl azides/alcohols
O
N
R1 ꢀ nPr, iBu, Bn
TMS
R2 ꢀ Me, iPr
R2
9
R5
H
R5
SiR43
SQ-coupling
N3
HO
O
O
HO
5
6
O
NH
R2
؉
TMS
10
Chiral β-alkyl-γ-pentynyl azides/alcohols
R5 ꢀ Me, nPent, iBu
‘SuperQuat’
11
Fig. 1. Click chemistry azides and alkynes.
Scheme 1.

Click Chemical Triazolamers
1543
alkylation of (S)-SQ adducts 8a and 8b using alkyl triflates in
the presence of a strong base in THF at ꢀ788C (entries 6–15,
Table 1). The triflates used in the present work were easily
synthesized from the corresponding alcohols in the presence of
pyridine and triflic anhydride,[20] could be purified by flash
column chromatography and were all stable at 08C for weeks.
Methyl triflate provided the methyl-substituted (4S,2S)-
diastereoisomer 8d as the sole product in 61% yield when used
in conjunction with the (S)-iPr SQ adduct 9a (entry 7, Table 1).
The (S)-Bn SQ adduct 9b showed lower levels of diastereos-
electivity, providing a 4:1 mixture of the methyl-substituted
(4S,2S)- and (4S,2R)-diastereomers 8c, respectively, with an
overall yield of 46% (entry 6, Table 1). The stability of the other
triflate electrophiles seemed to influence the yields of the
R
OMe
BOC
N
H
O
12–R ꢀ iPr
13–R ꢀ Bn
i
reaction. Pentyl triflate, phenyl ethyl triflate, and Bu-triflate
all provided the desired (4S,2S)-diastereoisomers possessing a
pentyl-substituent 8f (entries 9–10, Table 1), phenyl ethyl-
substituent 8g (entry 11, Table 1), and an iso-butyl-substituent
8h (entries 12–15, Table 1) exclusively, in 21–64% yields.
Removal of the SQ chiral auxiliary was performed by LiBH4-
mediated reduction, leading to the formation of the intermediate
(S)-b-alkyl-trialkylsilyl-protected g-pentynyl alcohols 7a, 7b,
and 7c. The reaction proceeded in 60–76% yields using 2.0–3.0
equivalents of LiBH4 in Et2O/H2O, 100:1 (Scheme 4).
(i)
H
HO
R
16
(iii)
BOC
OH
N
H
The desired chiral b-alkyl-trialkylsilyl-g-pentynyl azide
and chiral b-alkyl-g-pentynyl-alcohol fragments were
prepared following the protocol previously described for the
synthesis of rac-a-propargyl alcohols 3, rac-a-substituted
trialkylsilyl-protected propargyl azides 4, chiral b3-substituted
14–R ꢀ iPr
15–R ꢀ Bn
TMS
HO
HO
(ii)
17
(iv)
homopropargyl alcohols
1
trialkylsilyl-homopropargyl azides
and chiral b3-substituted
respectively.[11,12]
2
O
(S)-b-Alkyl-g-pentynyl alcohol 5a was generated quantitatively
via trimethylsilyl-deprotection using 1.5 equivalents of K2CO3
in MeOH (Scheme 5), while trimethylsilyl-protected (R)-b-
alkyl-g-pentynyl azides 6a, 6b, and 6c were synthesized via
mesylation of the corresponding alcohols 7a, 7b, and 7c using
1.5 equivalents of triethylamine and 1.3 equivalents of
methanesulfonyl chloride in dichloromethane in 64–84% yield,
followed by azide ion displacement of mesylates 18a, 18b, and
18c with 3.0 equivalents of sodium azide in DMF (Scheme 4).
The range of yields obtained for the formation of pentynyl
azides 6a–6c (44–77%) was found to be lower than for the
formation of the propargyl azide fragments 4 (70–87%)[11]
but higher than that of homopropargyl azide fragments 2
(43–53%)[12] respectively.
H
O
N
R
O
11a–R ꢀ iPr
11b–R ꢀ Bn
TMS
؉
10
(v)
O
O
9a–R ꢀ iPr
9b–R ꢀ Bn
O
N
R
TMS
This was thought to be due to a combination of the inductive
withdrawing effects of the alkyne and steric hindrance with the
Scheme 2.
O
O
O
O
9a–R1 ꢀ iPr
9b–R1 ꢀ Bn
O
N
O
N
R2
TMS
TMS
R1
R1
8i–R1 ꢀ iPr, R2 ꢀ Me
8j–R1 ꢀ Bn, R2 ꢀ Me
(i)
8a–R1 ꢀ iPr, R2 ꢀ nPr
8b–R1 ꢀ iPr, R2 ꢀ nBu
8c–R1 ꢀ Bn, R2 ꢀ Me
8d–R1 ꢀ iPr, R2 ꢀ Me
8e–R1 ꢀ iPr, R2 ꢀ iPr
8f– R1 ꢀ iPr, R2 ꢀ nPent
O
O
O
N
8g–R1 ꢀ iPr, R2 ꢀ PhCH2CH2
8h–R1 ꢀ iPr, R2 ꢀ iBu
R2
TMS
R1
Scheme 3. Alkylation of 9a and 9b. Reagents and conditions: (i) base, electrophile, THF, ꢀ788C.

1544
O. D. Montagnat, G. Lessene, and A. B. Hughes
side chain of the mesylate substrate. The mesylates 19 are more
deactivated to nucleophilic substitution than the mesylates 20
(Chart 1) owing to the extra carbon between the inductively
withdrawing alkyne and the mesylate displacement site.
Generation of chiral 1,4-disubstituted-(b-alkyl)-g-1,2,3-
triazole scaffolds in a stepwise manner was attempted using
fragments such as alkyne 5a and azide 6c. The Huisgen 1,3-
dipolar cycloaddition of (4S)-iBu-trimethylsilyl-pent-1-yn-5-ol
5a and (4S)-iBu-trimethylsilyl-1-ynyl-5-azide 6c was conducted
using Cu0 in the presence of tBuOH/H2O, 2:1 (Scheme 5).
A good yield was obtained for dimeric triazolamer 21 (73%).
This compared well with the efficiency of the generation
of a-disubstituted-(1,4-disubstituted)-1,2,3-triazole dimer 24
(76%)[11] and chiral b3-disubstituted-(1,4-disubstituted)-1,2,3-
triazole dimer 25 (80%) (Chart 2).[12]
Trimethylsilyl-deprotection of 21 using 1.5 equivalents of
K2CO3 in MeOH provided 22 in 81% yield, which is a lower
yield than was observed in the conversion of silyl alkyne 7c
to acetylene 5a. Cycloaddition of 5a with azide 6c afforded
the pseudo-dimer 21 in 73% yield; however, efficiency of this
cycloaddition step was found to decrease when generating the
1,4-disubstituted-(b-isobutyl)-g-1,2,3-triazole trimer 23 (39%,
Scheme 5). This may be as a result of several factors. Increased
free rotation around the extended backbone chain may be
generating a steric interaction between the copper acetylide
and the azide, leading to lower yields. Alternatively, there is
evidence in the literature suggesting that polytriazole com-
pounds may act as tridentate ligands in the presence of CuI to
form stable tricoordinate CuI complexes.[21] This has been
shown to be true with CuI in the presence of bis(pyrazolyl)-
methane ligands.[22]
SQ substrate to install the chiral alkyl side chain. Furthermore,
it has been shown that the aforementioned fragments may be
sequentially coupled using the Cu0-catalyzed Huisgen 1,3-
dipolar cycloaddition to provide chiral 1,4-disubstituted-(b-
alkyl)-g-1,2,3-triazolamer scaffolds.
O
O
8a–R ꢀ Me
8f– R ꢀ nPent
8h–R ꢀ iBu
O
N
TMS
TMS
R
R
(i)
7a–R ꢀ Me
7b–R ꢀ nPent
7h–R ꢀ iBu
HO
(ii)
18a–R ꢀ Me
18b–R ꢀ nPent
18c–R ꢀ iBu
R
R
TMS
TMS
MsO
(iii)
6a–R ꢀ Me
6b–R ꢀ nPent
6c–R ꢀ iBu
N3
Conclusion
In conclusion, it has been shown that chiral b-alkyl-trialkylsilyl-
protected-g-pentynyl azides and chiral b-alkyl-g-pentynyl-
alcohols may be constructed using asymmetric alkylation of a
Scheme 4. Synthesis of azides 6a–6c. Reagents and conditions: (i) LiBH4,
H2O, Et2O, 08C; (ii) Et3N, methanesulfonyl (Ms)Cl, CH2Cl2, room tem-
perature (rt); (iii) NaN3, DMF, THF, rt.
Table 1. Alkylation of 9a and 9b
N/R, no reaction
Entry
R1
Base [equiv.]A
Electrophile [equiv.]
Time [h]
Yield [%]
1
iPr
iPr
iPr
Bn
iPr
Bn
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
LiHMDS (1.3)B
LDA (1.1)B
nPrBr (3.0)
5
5
5
5
5
4
4
4
4
4
4
4
4
4
4
8a N/R
8a N/R
8b N/R
8c N/R
8d 22 (3)F
8c 36 (10)F
8d 61
2
nPrBr (3.0)
3
KHMDS (1.0)
nBuI (4.0)
4
LiHMDS (2.0)B
LiHMDS (2.0)B
LiHMDS (1.2)B
LiHMDS (1.2)B
LiHMDS (1.2)B
NaHMDS (1.2), DMPU (1.2)
KHMDS (1.2)
MeI (4.0)
5
MeI (4.0)
6
MeOTf (2.0)
MeOTf (2.0)
PentylOTf (2.0)C
PentylOTf (2.0)C
PentylOTf (2.0)C
PhCH2CH2OTf (2.0)D
iBuOTf (2.0)E
iBuOTf (3.8)E
iBuOTf (4.0)E
iBuOTf (5.0)E
7
8
8f 21
9
8f N/R
8f 48
10
11
12
13
14
15
KHMDS (1.2)
8g 30
KHMDS (1.1)
8h 26
KHMDS (1.1)
8h 46
KHMDS (1.1)
8h 64
KHMDS (1.1)
8h 49
AAll reactions were conducted in THF at ꢀ788C.
BPrepared in situ from nBuLi and the corresponding amine at 08C.
CPrepared from PentylOH, C6H6N, and (Tf)2O at 08C. Purified by flash chromatography.
DPrepared from PhCH2CH2OH, C6H6N, and (Tf)2O at 08C. Purified by flash chromatography.
EPrepared from iBuOH, C6H6N, and (Tf)2O at 08C. Solvent was evaporated and the product used directly.
FNumber in brackets gives yield of other diastereomer (compounds 8i and 8j).

Click Chemical Triazolamers
1545
(i)
TMS
OH
OH
7c
5a
(ii)
Chart 2.
TMS
NꢀN
N
allow for the formation of the anion of 11a in situ (Solution B).
After 10 min, Solution A was cooled to ꢀ788C and cannulated
onto Solution B and the mixture was left to stir for 15 min. The
reaction mixture was then warmed to 08C and left to stir for
45 min.Thesolutionwasquenchedwithsat.ammoniumchloride
(10 mL), extracted with Et2O (2 ꢁ 30 mL), washed with H2O
(30 mL), brine (20 mL), dried with sodium sulfate, filtered, and
concentrated under vacuum to leave a slightly pink oil. The
residue was purified by column chromatography on silica gel,
eluting with ethyl acetate/hexane. In the same manner, inter-
mediate 11b generated adduct 9b.
HO
21
(i)
NꢀN
N
HO
22
23
(ii)
4-(S)-iso-Propyl-5,5-dimethyl-3-(5-trimethylsilanyl-
pent-4-ynoyl)-oxazolidin-2-one 9a
The chiral SQ adduct 9a was obtained as a colourless oil
(1.52 g, 72%). Rf ¼ 0.63 (20% ethyl acetate/hexane). [a]D29
þ25.9 (c 1.00 in CHCl3). nmax(NaCl)/cmꢀ1 2965, 2178, 1780,
1704, 1376, 844. dH (300 MHz, CDCl3) 0.0 (s, 9H), 0.86 (d, 3H,
J 6.8), 0.95 (d, 3H, J 7.0), 1.31, 1.44 (2 ꢁ s, 6H), 2.04–2.09 (m,
1H), 2.51 (dd, 1H, J 2.9 and 7.4), 2.53 (dd, 1H, J 2.5 and 7.1),
3.05 (dt, 1H, J 7.1 and 14.2), 3.19 (dt, 1H, J 7.4 and 14.1),
4.08 (d, 1H, J 3.2). dC (75 MHz, CDCl3) ꢀ0.5, 14.8, 16.5, 20.8,
21.1, 28.3, 29.0, 34.3, 65.8, 82.4, 84.6, 104.7, 152.9, 171.6. m/z
310.1835; C16H28NO3Si requires M þ H 310.1833.
TMS
NꢀN
N
HO
2
Scheme 5. Preparation of triazolamers 21–23. Reagents and conditions:
(i) K2CO3, MeOH, room temperature; (ii) 6c, Cu0, tBuOH/H2O 2:1.
R1
R3
SiMe3
MsO
SiR23
MsO
4-(S)-Benzyl-5,5-dimethyl-3-(5-trimethylsilanyl-
pent-4-ynoyl)-oxazolidin-2-one 9b
19
20
R1 ꢀ nPr, iBu, Bn
R2 ꢀ Me, iPr
Compound 9b was prepared by the same procedure as
described for compound 9a, employing (S)-Bn SQ 11b. It was
obtained as a colourless viscous oil (917 mg, 56%). Rf ¼ 0.35
(10% ethyl acetate/hexane). [a]3D0 ꢀ7.4 (c 1.00 in CHCl3).
R3 ꢀ iPr, iBu, Bn
Chart 1.
n
max(NaCl)/cmꢀ1 3030, 2960, 2177, 1780, 1703, 1378, 1356,
Experimental
1277, 1251, 1104, 844. dH (300 MHz, CDCl3) 0.11 (s, 9H), 1.34
(d, 6H, J 6.1), 2.50–2.55 (m, 2H), 2.86 (dd, 1H, J 9.5 and 14.4),
3.11–3.16 (m, 3H), 4.48 (dd, 1H, J 3.9 and 9.5), 7.17–7.31 (m,
5H). dC (75 MHz, CDCl3) ꢀ0.4, 14.6, 21.8, 28.1, 34.5, 34.8,
63.1, 81.9, 84.8, 104.7, 126.4, 128.2, 128.6, 136.4, 152.0, 171.0.
m/z 358.1842; C20H28NO3Si requires M þ H 358.1833.
General experimental details and spectra for key intermediates
can be found in the Accessory Publication.
General Procedure for the Synthesis of Chiral
SQ Adducts 9a and 9b
To a three-necked, argon-flushed 100-mL round-bottom flask
fitted with an argon line, stopper and septum was added the acid
10 (1.16 g, 6.8 mmol) along with dry Et2O (15 mL) and
triethylamine (7.5 mmol, 1045 mL). The flask was cooled to
ꢀ788C and pivaloyl chloride (7.5 mmol, 885 mL) was added
slowly via syringe. The mixture was left to stir at ꢀ788C for
5 min, then warmed to 08C and left to stir for 1 h (Solution A).
Separately, (S)-iPr SQ 11a (7.5 mmol, 1.18 g) was added to a
three-necked, argon-flushed 50-mL round-bottom flask fitted
with an argon line, stopper, and septum along with dry THF
General Procedure for the Alkylation of Chiral
SQ Adducts 9a and 9b
To a flame-dried, argon-filled 5-mL round-bottom flask fitted
with a stopper, argon line and septum was added hexa-
methyldisilazane (2.0 mmol, 452 mL) and dry THF (1 mL). The
flask was cooled to 08C and nBuLi (2.0 mmol, 1.3 mL of a 1.6 M
solution in hexanes) was added via syringe and the mixture was
left to stir at 08C for 30 min (Solution A). Separately, a flame-
dried, argon-filled 25-mL round-bottom flask fitted with a
stopper, argon line, and septum was injected with compound 9a
(1.0 mmol, 300 mg in 1 mL dry THF) via syringe and cooled to
n
(5 mL) and cooled to ꢀ788C. BuLi (8.2 mmol, 5.13 mL of a
1.6 M solution in hexanes) was added via syringe over 5 min, to

1546
O. D. Montagnat, G. Lessene, and A. B. Hughes
ꢀ788C (Solution B). Solution A was cannulated onto solution B
and the reaction mixture was left to stir at ꢀ788C for 1 h. The
appropriate electrophile (methyl iodide, 4.0 mmol, 249 mL) was
added slowly via syringe at ꢀ788C and the mixture was left to
stir at ꢀ788C. After 5 h, the solution was warmed to ꢀ408C and
quenched with sat. NH4Cl (3 mL), then it was left to warm to
room temperature (rt). The reaction mixture was extracted with
Et2O (2 ꢁ 20 mL), washed with H2O (15 mL), brine (15 mL),
dried with sodium sulfate, filtered, and concentrated at reduced
pressure to leave a yellow residue. The residue was purified by
column chromatography on silica gel, eluting with ethyl acetate/
hexane to afford the compound 8d.
was obtained as a clear viscous oil (8 mg, 3%). dH (300 MHz,
CDCl3) 0.10 (s, 9H), 0.95 (d, 3H, J 6.8), 1.03 (d, 3H, J 7.0), 1.20
(d, 3H, J 6.8), 1.35 (s, 3H), 1.49 (s, 3H), 2.11 (doublet of septets,
1H, J 2.9 and 6.8), 2.50 (dd, 1H, J 16.9 and 6.2), 2.64 (dd, 1H,
J 7.1 and 16.9), 3.97 (sextet, J 6.7), 4.17 (d, 1H, J 3.0).
4-(S)-iso-Propyl-5,5-dimethyl-3-(2-(S)-pentyl-5-
trimethylsilanyl-pent-4-ynoyl)-oxazolidin-2-one 8f
Compound 8f was prepared by the same procedure as described
for compound 8d, employing pentyl triflate (prepared as
described in the literature[20]). It was obtained as a colourless
viscous oil (56 mg, 21%). It was also prepared using the same
procedure as described for compound 8d, employing potassium
hexamethyldisilazide as a base, and was obtained then as a
colourless viscous oil (220 mg, 48%). Rf ¼ 0.63 (10% ethyl
acetate/hexane). [a]D30 þ36.4 (c 1.68 in CHCl3). nmax (NaCl)/
cmꢀ1 2961, 2176, 1780, 1698, 1249, 1171. dH (300 MHz,
CDCl3) 0.06 (s, 9H), 0.83 (t, 3H, J 6.2), 0.92 (d, 3H, J 6.8), 0.99
(d, 3H, J 7.0), 1.15–1.33 (m, 6H), 1.37 (s, 3H), 1.47 (s, 3H),
1.48–1.60 (m, 3H), 2.11 (doublet of septets, 1H, J 3.0 and 6.9),
2.38 (dd, 1H, J 5.5 and 16.8), 2.51 (dd, 1H, J 8.9 and 16.8), 3.99–
4.08 (m, 1H), 4.17 (d, 1H, J 2.9). dC (75 MHz, CDCl3) ꢀ0.0,
13.9, 16.9, 21.2, 21.5, 22.2, 22.4, 26.2, 28.8, 29.6, 31.6, 32.6,
42.3, 66.3, 82.3, 85.5, 104.6, 153.2, 175.5.
4-(S)-Benzyl-5,5-dimethyl-3-(2-(S)-methyl-5-
trimethylsilanyl-pent-4-ynoyl)-oxazolidin-2-one 8c
Compound 8c was obtained as a major diastereoisomer using the
same procedure as described for compound 8d. The reaction was
conducted in the presence of (S)-Bn SQ and with methyl triflate
as the electrophile. Compound 8c was obtained as a colourless
viscous oil (111 mg, 36%). Rf ¼ 0.38 (10% ethyl acetate/
hexane). [a]2D9 þ3.5 (c 2.00 in CH2Cl2). dH (300 MHz, CDCl3)
0.09 (s, 9H), 1.18 (d, 3H, J 6.9), 1.35 (s, 3H), 1.36 (s, 3H), 2.34
(dd, 1H, J 7.1 and 16.8), 2.51 (dd, 1H, J 7.0 and 16.9), 2.88 (dd,
1H, J 9.0 and 14.3), 3.03 (dd, 1H, J 4.4 and 14.3), 3.87 (sextet,
1H, J 7.0), 4.49 (dd, 1H, 4.5 and 9.0), 7.18–7.28 (m, 5H). dC
(300 MHz, CDCl3) 0.3, 17.2, 22.0, 23.5, 28.2, 35.3, 37.7, 63.4,
82.1, 85.8, 104.2, 126.7, 128.5, 129.0, 136.6, 152.1, 175.2. m/z
372.2000; C21H30NO3Si requires M þ H 372.1995.
4-(S)-Isopropyl-5,5-dimethyl-3-(2-(S)-phenethyl-5-
trimethylsilanyl-pent-4-ynoyl)-oxazolidin-2-one 8g
Compound 8g was prepared by the same procedure as described
for compound 8d, employing phenylethyl triflate (prepared as
described in the literature[23]). It was obtained as a colourless oil
(715 mg, 30%). Rf ¼ 0.49 (10% ethyl acetate/hexane). [a]D29
þ23.0 (c 1.77 in CHCl3). nmax (NaCl)/cmꢀ1 3027, 2996, 2175,
1777, 1698, 843. dH (300 MHz, CDCl3) 0.10 (s, 9H), 0.96 (d, 3H,
J 6.8), 1.04 (d, 3H, J 7.0), 1.40 (s, 3H), 1.50 (s, 3H), 1.79–2.20
(m, 3H), 2.45–2.71 (m, 4H), 4.09–4.20 (m, 1H), 4.21 (d, 1H,
J 2.9). dC (75 MHz, CDCl3) 0.3, 16.8, 21.1, 21.5, 22.1, 28.6,
29.5, 33.1, 34.4, 42.1, 66.4, 82.6, 85.8, 104.2, 125.9, 128.2,
128.3, 141.4, 153.1, 174.8. m/z 414.2459; C24H36NO3Si
requires M þ H 414.2464.
A
separate fraction was identified as the minor
diastereomer 8j.
4-(S)-Benzyl-5,5-dimethyl-3-(2-(R)-methyl-5-
trimethylsilanyl-pent-4-ynoyl)-oxazolidin-2-one 8j
Compound 8j was obtained as a minor diastereoisomer in the
formation of compound 8c, when conducted in the presence of
(S)-Bn SQ and methyl triflate as the electrophile. Compound 8j
was obtained as a colourless oil (34 mg, 10%). dH (300 MHz,
CDCl3) 0.10 (s, 9H), 1.19 (d, 3H, J 6.9), 1.36 (s, 3H), 1.37 (s,
3H), 2.36 (dd, 1H, J 7.1 and 16.9), 2.54 (dd, 1H, J 6.9 and 16.8),
2.83 (dd, 1H, J 10.0 and 14.5), 3.18 (dd, 1H, J 3.2 and 14.5), 3.90
(sextet, 1H, J 7.0), 4.50 (dd, 1H, 4.2 and 9.2), 7.20–7.26 (m, 5H).
3-(2-(S)-Isobutyl-5-trimethylsilanyl-pent-4-ynoyl)-4-
(S)-isopropyl-5,5-dimethyl-oxazolidin-2-one 8h
4-(S)-iso-Propyl-5,5-dimethyl-3-(2-(S)-methyl-5-
trimethylsilanyl-pent-4-ynoyl)-oxazolidin-2-one 8d
Compound 8h was prepared by the same procedure as described
for compound 8d, employing iso-butyl triflate (prepared as
described in the literature[24]). It was obtained as a colourless
viscous oil (961 mg, 64%). Rf ¼ 0.41 (10% ethyl acetate/
hexane). [a]D25 þ49.2 (c 2.42 in CHCl3). nmax (NaCl)/cmꢀ1 2960,
2176, 1780, 1698, 843. dH (300 MHz, CDCl3) ꢀ0.06 (s, 9H),
0.79–0.82 (m, 9H), 0.84 (d, 3H, J 7.0), 1.16–1.25 (m, 1H), 1.28
(s, 3H), 1.37 (s, 3H), 1.45–1.60 (m, 2H), 2.00–2.08 (m, 1H), 2.23
(dd, 1H, J 5.1 and 16.7), 2.36 (dd, 1H, J 9.1 and 16.7), 4.04–4.14
(m, 2H). dC (75 MHz, CDCl3) ꢀ0.2, 16.6, 21.0, 21.3, 22.3, 22.4,
22.7, 25.6, 28.6, 29.3, 40.1, 41.8, 66.0, 82.1, 85.4, 104.2, 152.8,
175.4. m/z 366.2455; C20H36NO3Si requires M þ H 366.2459.
Compound 8d was obtained as a major diastereoisomer in the
form of a colourless oil (70 mg, 22%). Rf ¼ 0.46 (10% ethyl
acetate/hexane). [a]2D3 þ46.2 (c 1.89 in CHCl3). nmax
(NaCl)/cmꢀ1 2969, 2177, 1779, 1703, 1249. dH (300 MHz,
CDCl3) 0.07 (s, 9H), 0.91 (d, 3H, J 6.8), 0.97 (d, 3H, J 6.9), 1.29
(d, 3H, J 6.9), 1.36 (s, 3H), 1.48 (s, 3H), 2.10 (doublet of septets,
1H, J 3.3 and 6.8), 2.33 (dd, 1H, J 16.8 and 6.9), 2.55 (dd, 1H,
J 7.4 and 16.8), 3.92 (sextet, J 7.0), 4.14 (d, 1H, J 3.3). dC
(75 MHz, CDCl3) 0.00, 16.9, 18.0, 21.3, 21.5, 23.4, 28.6, 29.5,
37.9, 66.2, 82.8, 85.7, 104.5, 153.1, 175.8. m/z 324.1995;
C17H30NO3Si requires M þ H 324.1989.
A
separate fraction was identified as the minor
General Procedure for the Synthesis of Chiral b-Alkyl-
trialkylsilyl-protected g-Pentynyl Alcohols 7a–7c
diastereomer 8i.
4-(S)-iso-Propyl-5,5-dimethyl-3-(2-(R)-methyl-5-
trimethylsilanyl-pent-4-ynoyl)-oxazolidin-2-one 8i
To a 10-mL round-bottomed flask was added compound 8d
(0.56 mmol, 209 mg) along with Et2O (12 mL) and H2O
(1.69 mmol, 30 mL), and the flask was cooled to 08C. Lithium
borohydride (1.69 mmol, 37 mg) was added in small portions
over the course of 15 min, and the heterogeneous mixture was
Compound 8i was obtained as a minor diastereoisomer in the
formation of compound 8d, when conducted in the presence of
(S)-iPr SQ and methyl iodide as the electrophile. Compound 8i

Click Chemical Triazolamers
1547
left to stir vigorously at 08C. The reaction was monitored by
TLC. After 1 h, the reaction mixture was quenched with NH4Cl
solution (4 mL), extracted with Et2O (3 ꢁ 10 mL), and the
organic extracts were pooled. The organic layer was dried with
sodium sulfate, filtered, and concentrated on the rotary eva-
porator to leave a milky residue. The residue was purified by
column chromatography on silica gel, eluting with ethyl acetate/
hexane.
in CHCl3). nmax (NaCl)/cmꢀ1 2961, 2174, 1358, 1250, 1177,
964, 843. dH (300 MHz, CDCl3) 0.1 (s, 9H), 1.02 (d, 3H, J 6.8),
2.07 (octet, 1H, J 6.4), 2.27 (d, 2H, J 6.1), 2.97 (s, 3H), 4.1 (d,
2H, J 6.1). dC (75 MHz, CDCl3) ꢀ0.1, 15.7, 23.2, 32.2, 37.0,
72.8, 87.0, 103.5. m/z 249.0981; C10H21O3SSi requires M þ H
249.0975.
Methanesulfonic Acid 2-(R)-Pentyl-5-trimethylsilanyl-
pent-4-ynyl Ester 18b
2-(R)-Methyl-5-trimethylsilanyl-pent-4-yn-1-ol 7a
Compound 18b was prepared by the same procedure as
described for compound 18a and was obtained as a colourless
oil (70 mg, 64%). Rf ¼ 0.63 (20% ethyl acetate/hexane). [a]D26
þ1.5 (c 1.16 in CHCl3). nmax (NaCl)/cmꢀ1 2957, 2174, 1359,
1250, 1778, 956, 843. dH (300 MHz, CDCl3) 0.11 (s, 9H), 0.85
(t, 3H, J 6.8), 1.20–1.38 (m, 8H), 1.90 (septet, 1H, J 5.8), 2.27
(dd, 1H, J 6.4 and 17.2), 2.36 (dd, 1H, 5.5 and 17.2), 2.98 (s, 3H),
4.14 (dd, 1H, J 6.6 and 9.7), 4.21 (dd, 1H, J 4.9 and 9.7). dC
(75 MHz, CDCl3) ꢀ0.0, 13.9, 21.2, 22.4, 26.1, 29.7, 31.6, 36.9,
37.0, 71.4, 87.0, 103.6. m/z 305.1620; C14H29O3SSi requires
M þ H 305.1601.
Compound 7a was obtained as a colourless oil (66 mg, 69%).
Rf ¼ 0.34 (20% ethyl acetate/hexane). nmax (NaCl)/cmꢀ1 3349,
2960, 2174, 1250, 1037, 842. dH (300 MHz, CDCl3) 0.12 (s, 9H,
Si(CH3)3), 0.97 (d, 3H, J 6.8, CH3), 1.69 (s, 1H, OH), 1.86 (octet,
1H, J 6.4, H2), 2.23 (d, 2H, J 1.0, H3), 3.55 (d, 2H, J 6.1,
CH2OH). dC (75 MHz, CDCl3) ꢀ0.3 (Si(CH3)3), 15.8 (C5), 23.5
(C3), 34.7 (C4), 66.9 (CH2OH), 85.8 (C1), 105.1 (C2). m/z
171.1201; C9H19OSi requires M þ H 171.1200.
2-(R)-Pentyl-5-trimethylsilanyl-pent-4-yn-1-ol 7b
Compound 7b was prepared from compound 8f using the
same procedure as described for compound 7a. It was obtained
as a colourless oil (84 mg, 60%). Rf ¼ 0.63 (20% ethyl acetate/
hexane). [a]D26 þ8.2 (c 1.24 in CHCl3). nmax (NaCl)/cmꢀ1 3335,
2958, 2174, 1249, 988, 842, 760. dH (300 MHz, CDCl3) 0.1
(s, 9H), 0.84 (t, 3H, J 6.4), 1.18–1.32 (m, 8H), 1.62–1.70
(m, 1H), 2.11 (s, 1H), 2.22 (dd, 1H, J 6.6 and 17.1), 2.31 (dd,
1H, J 5.6 and 17.0), 3.55 (dd, 1H, J 7.0 and 10.9), 3.61 (dd, 1H,
J 4.8 and 10.8). dC (75 MHz, CDCl3) 0.0, 14.0, 21.7, 22.5, 26.5,
30.2, 31.9, 39.8, 65.3, 86.1, 105.6. m/z 227.1834; C13H27OSi
requires M þ H 227.1826.
Methanesulfonic Acid 2-(R)-iso-Butyl-5-trimethylsilanyl-
pent-4-ynyl Ester 18c
Compound 18c was prepared by the same procedure as
described for compound 18a and was obtained as a colourless
viscous oil (572 mg, 84%). Rf ¼ 0.63 (20% ethyl acetate/
hexane). [a]D23 ꢀ0.3 (c 5.48 in CHCl3). nmax (NaCl)/cmꢀ1
2958, 2175, 1359, 1250, 1178, 949, 843. dH (300 MHz, CDCl3)
0.89 (s, 9H), 0.85 (d, 3H, J 6.5), 0.87 (d, 3H, J 6.5), 1.18 (ddd,
1H, J 7.2, 6.7, and 13.9), 1.26 (ddd, 1H, J 7.2, 6.7, and 13.9), 1.62
(nonet, 1H, J 6.8), 1.92–2.04 (m, 1H), 2.24 (dd, 1H, J 6.4 and
17.2), 2.34 (dd, 1H, J 5.4 and 17.2), 4.11 (dd, 1H, J 6.7 and 9.7),
4.20 (dd, 1H, J 4.6 and 9.7). dC (75 MHz, CDCl3) ꢀ0.1, 21.3,
22.3, 22.7, 24.9, 34.7, 36.9, 38.9, 71.6, 87.0, 103.6. m/z
291.1449; C13H27O3SSi requires M þ H 291.1445.
2-(R)-iso-Butyl-5-trimethylsilanyl-pent-4-yn-1-ol 7c
Compound 7c was prepared from compound 8h using the
same procedure as described for compound 7a. It was obtained
as a colourless oil (1.12 g, 76%). Rf ¼ 0.66 (20% ethyl acetate/
hexane). [a]D25 þ8.0 (c 1.36 in CHCl3). nmax (NaCl)/cmꢀ1 3347,
2957, 2174, 1250, 1029, 842. dH (300 MHz, CDCl3) 0.1 (s, 9H),
0.84 (d, 3H, J 6.2), 0.86 (d, 3H, J 6.1), 1.05–1.23 (m, 2H), 1.55–
1.68 (m, 1H), 1.70–1.84 (m, 1H), 2.20 (dd, 1H, J 6.5 and 17.1),
2.08 (s, 1H), 2.30 (dd, 1H, J 5.4 and 17.1), 3.52 (dd, 1H, J 6.8
and 10.8), 3.60 (dd, 1H, J 4.5 and 10.8). dC (75 MHz, CDCl3)
0.0, 21.9, 22.5, 23.0, 25.1, 37.5, 39.7, 65.5, 86.1, 105.6. m/z
213.1670; C12H25OSi requires M þ H 213.1669.
General Procedure for the Synthesis of Chiral b-Alkyl-
trialkylsilyl-protected g-Pentynyl Azides 6a–6c
The mesylate 18a (72 mg, 0.29 mmol) was dissolved in dry
DMF (1 mL) and to this solution was added sodium azide
(0.87 mmol, 57 mg) and the mixture was stirred vigorously at rt.
The reaction was monitored by TLC. After 72 h, the reaction
mixture was diluted with Et2O (15 mL), washed with H2O
(15 mL), brine (10 mL), dried with sodium sulfate, filtered, and
concentrated under vacuum to leave a yellow oil. The oil was
purified by column chromatography on silica gel, using ethyl
acetate/hexane as the eluent.
General Procedure for the Synthesis of Chiral b-Alkyl-
trialkylsilyl-protected g-Pentynyl Mesylates 18a–18c
(5-Azido-4-(R)-methyl-pent-1-ynyl)trimethylsilane 6a
The chiral alcohol 7a (65 mg, 0.4 mmol) was dissolved in dry
CH2Cl2 (1 mL) and cooled to 08C. Triethylamine (0.6 mmol,
79 mL) was added in one portion followed by methanesulfonyl
chloride (0.5 mmol, 39 mL). The reaction mixture was left to
stir at 08C. After 20 min, the solution was diluted with CH2Cl2
(30 mL), washed with H2O (20 mL), brine (20 mL), dried with
sodium sulfate, filtered, and concentrated under vacuum. The
residue was purified by column chromatography on silica gel,
using ethyl acetate/hexane as the eluent.
Compound 6a was obtained as a yellow oil (20 mg, 57%).
Rf ¼ 0.49 (5% ethyl acetate/hexane). nmax (NaCl)/cmꢀ1 2959,
2176, 2100, 1733, 1457, 1250, 1037, 843. dH (300 MHz, CDCl3)
0.14 (s, 9H), 1.01 (d, 3H, J 6.7), 1.92 (octet, 1H, J 6.5), 2.25 (d,
2H, J 6.0), 3.20–3.33 (m, 2H). dC (75 MHz, CDCl3) ꢀ0.3, 16.8,
24.1, 32.6, 55.9, 86.3, 103.8.
(4-(R)-Azidomethyl-6-methyl-non-1-ynyl)
trimethylsilane 6b
Methanesulfonic Acid 2-(R)-Methyl-5-trimethylsilanyl-
pent-4-ynyl Ester 18a
Compound 6b was prepared by the same procedure as
described for compound 6a and was obtained as a colourless
oil (24 mg, 44%). Rf ¼ 0.76 (5% ethyl acetate/hexane). nmax
(NaCl)/cmꢀ1 2960, 2176, 2099, 1249, 843. dH (300 MHz,
Compound 18a was obtained as a colourless oil (75 mg,
78%). Rf ¼ 0.66 (20% ethyl acetate/hexane). [a]2D9 ꢀ5.5 (c 1.24

1548
O. D. Montagnat, G. Lessene, and A. B. Hughes
CDCl3) 0.14 (s, 9H), (t, 3H, J 7.0), 1.24–1.35 (m, 8H), 1.73
(septet, 1H, J 6.1), 2.24 (dd, 1H, J 6.5 and 17.1), 2.32 (dd, 1H, J
5.6 and 17.1), 3.31 (dd, 1H, J 2.1 and 12.2), 3.36 (dd, 1H, J 1.4
and 12.2). dC (75 MHz, CDCl3) ꢀ0.3, 14.0, 22.3, 22.5, 26.3,
31.1, 31.8, 37.6, 54.5, 86.6, 104.3. m/z 252.1894; C13H26N3Si
requires M þ H 252.1896.
in CHCl3). nmax (NaCl)/cmꢀ1 3353, 2955, 2174, 1467, 1367,
1249, 1049, 1019, 840, 759. dH (300 MHz, CDCl3) 0.01 (s, 9H),
0.67–0.76 (m, 12H), 0.89–1.22 (m, 4H), 1.44–1.54 (m, 2H),
1.73–1.86 (m, 1H), 1.90–2.13 (m, 3H), 2.63 (d, 2H, J 6.1), 3.26
(dd, 1H, J 6.6 and 11.1), 3.40 (dd, 1H, J 4.1 and 11.1), 3.52 (s,
1H), 4.17 (d, 2H, J 6.2), 7.27 (s, 1H). dC (75 MHz, CDCl3) ꢀ0.2,
21.6, 21.8, 22.5, 22.6, 22.8, 24.6, 24.9 (2), 26.7, 35.5, 38.0, 39.7,
39.8 (2), 52.7, 63.9, 87.3, 103.1, 122.5, 145.5. m/z 378.2935;
C21H40N3OSi requires M þ H 378.2935.
(4-(R)-Azidomethyl-6-methyl-hept-1-ynyl)
trimethylsilane 6c
Compound 6c was prepared by the same procedure as
described for compound 6a and was obtained as a colourless
oil (356 mg, 77%). Rf ¼ 0.39 (100% hexane). [a]2D5 ꢀ1.5 (c 1.57
in CHCl3). nmax (NaCl)/cmꢀ1 2971, 2178, 2101, 1252, 845. dH
(300 MHz, CDCl3) 0.13 (s, 9H), 0.86 (d, 3H, J 4.7), 0.88 (d, 3H,
J 6.5), 1.16 (ddd, 1H, J 6.8, 7.1, and 13.8), 1.25 (ddd, 1H, J 6.5,
7.3, and 13.8), 1.61 (nonet, 1H, J 6.7), 1.75–1.87 (m, 1H), 2.22
(dd, 1H, J 6.4 and 17.1), 2.31 (dd, 1H, J 5.4 and 17.1), 3.30 (dd,
1H, J 6.5 and 12.1), 3.35 (dd, 1H, J 5.4 and 12.1). dC (75 MHz,
CDCl3) 0.1, 22.4, 22.9, 25.1, 35.3, 40.5, 54.7, 86.7, 104.2. m/z
238.1739; C12H24N3Si requires M þ H 238.1739.
2-(1-{2-[1-(2-(R)-iso-Butyl-5-trimethylsilanyl-pent-
4-ynyl)-1H-[1,2,3]triazol-4-ylmethyl]-4-(R)-methyl-
pentyl}-1H-[1,2,3]triazol-4-ylmethyl)-4-(R)-methyl-
pentan-1-ol 23
Compound 23 was prepared by the same procedure as
described for compound 21 and was obtained as a colourless,
viscous oil (96 mg, 39%). Rf ¼ 0.33 (60% ethyl acetate/hexane).
[a]D23 ꢀ19.7 (c 1.55 in CHCl3). nmax (NaCl)/cmꢀ1 3393, 2956,
2176, 1465, 1250, 1052, 843. dH (300 MHz, CDCl3) 0.15 (s, 9H),
0.77–0.85 (m, 18H), 0.95–1.33 (m, 6H), 1.62 (nonet, 3H, J 6.7),
1.82–1.95 (m, 1H), 2.05–2.20 (m, 3H), 2.31–2.43 (m, 1H), 2.55
(d, 2H, J 5.8), 2.68 (dd, 1H, J 6.9 and 14.6), 2.76 (dd, 1H, J 5.4
and 14.9), 3.35 (dd, 1H, J 6.5 and 11.1), 3.48 (dd, 1H, J 3.9 and
11.1), 3.58 (s, 1H), 4.21 (d, 2H, J 6.2), 4.27 (d, 2H, J 6.4), 7.41
(s, 1H), 7.63 (s, 1H). dC (75 MHz, CDCl3) 0.0, 21.8, 22.0, 22.2,
22.8, 22.9, 23.0, 24.8, 24.8, 24.9, 25.1, 26.7, 27.0, 35.8,
36.8, 38.0, 40.0, 40.1, 40.4, 52.7, 52.9, 64.5, 87.7, 103.2,
123.1, 123.2, 144.1, 145.4. m/z 543.4222; C30H55N6OSi
requires M þ H 543.4201.
Procedure for the Synthesis of 2-(R)-iso-Butyl-pent-
4-yn-1-ol 5a
The trimethylsilyl-pentynyl alcohol 7a (300 mg, 1.4 mmol) was
dissolved in dry MeOH (2 mL) and to this was added anhydrous
K2CO3 (2.1 mmol, 292 mg) in one portion. The reaction mixture
was left to stir at rt. After 1.5 h, the reaction mixture was diluted
with Et2O (30 mL), washed with H2O (15 mL), brine (15 mL),
dried with magnesium sulfate, filtered, and evaporated at
reduced pressure to leave a yellow oil. 1H NMR spectroscopy of
the oil showed the desired product was obtained in high purity
and it was used without any further purification.
Procedure for the Trimethylsilyl-deprotection of Chiral 1,4-
Disubstituted-(b-iso-butyl)-g-1,2,3-triazole Oligomer 22
The trialkylsilyl-protected cycloadduct 21 (274 mg, 0.7 mmol)
was added to a 25-mL round-bottom flask along with MeOH
(3 mL) and K2CO3 (0.9 mmol, 120 mg) and the mixture was left
to stir at rt. After 1.5 h, the reaction mixture was diluted with
CH2Cl2 (20 mL) and the organic phase was washed successively
with H2O (15 mL) and brine (15 mL). The organic layer was
dried with sodium sulfate, filtered, and evaporated at reduced
pressure to leave a yellow residue. The residue was purified by
column chromatography on silica gel, eluting with ethyl acetate/
hexane.
2-(R)-iso-Butyl-pent-4-yn-1-ol 5a
Compound 5a was obtained as a yellow oil (198 mg, 100%).
Rf ¼ 0.46 (20% ethyl acetate/hexane). nmax (NaCl)/cmꢀ1 3314,
3311, 2956, 1468, 1024, 629. dH (300 MHz, CDCl3) 0.87 (d, 3H,
J 6.5), 0.89 (d, 3H, J 6.5), 1.12–1.28 (m, 2H), 1.65 (octet, 1H, J
6.8), 1.73–1.87 (m, 1H), 1.95 (t, 1H, J 2.7), 2.22 (ddd, 1H, J 2.7,
6.4, and 16.9), 2.32 (ddd, 1H, J 2.7, 5.3, and 16.9), 3.55–3.68 (m,
2H). dC (75 MHz, CDCl3) 20.3, 22.5, 22.9, 25.1, 37.2, 39.5, 65.2,
69.6, 82.6. m/z 141.1279; C9H16O requires M þ H 141.1274.
2-[1-(2-(R)-iso-Butyl-pent-4-ynyl)-1H-[1,2,3]triazol-
4-ylmethyl]-4-(R)-methyl-pentan-1-ol 22
General Procedure for the Synthesis of Chiral
1,4-Disubstituted-(b-iso-butyl)-g-1,2,3-triazole
Oligomers 21 and 23
Compound 22 was obtained as a yellow oil (180 mg, 81%).
Rf ¼ 0.28 (40% ethyl acetate/hexane). [a]2D2 ꢀ18.2 (c 1.79 in
CHCl3). nmax (NaCl)/cmꢀ1 3315, 3312, 2954, 1467, 1367, 1218,
1051. dH (300 MHz, CDCl3) 0.70–0.82 (m, 12H), 0.90–1.31
(m, 4H), 1.46–1.66 (m, 2H), 1.76–1.89 (m, 1H), 1.90–2.18 (m,
3H), 2.67 (d, 2H, J 5.8), 3.30 (dd, 1H, J 6.4 and 10.2), 3.44 (dd,
1H, J 2.6 and 10.6), 3.89 (s, 1H), 4.22 (d, 2H, J 6.1), 7.32 (s, 1H).
dC (75 MHz, CDCl3) 20.2, 21.8, 22.5, 22.6, 22.8, 24.7, 24.9,
26.8, 35.4, 38.0, 39.7, 39.8, 52.6, 64.0, 70.9, 80.3, 122.6, 145.5.
m/z 306.2536; C18H32N3O requires M þ H 306.2540.
The acetylene 5a (170 mg, 1.21 mmol) was added to a 25-mL
round-bottom flask along with the azide 6c (1.21 mmol,
288 mg), tert-butanol (2.7 mL), H2O (1.3 mL), and excess Cu0
powder (40-mesh, 1.0 g). The mixture was left to stir at rt
overnight. After 24 h, the reaction mixture was diluted with
CH2Cl2 (5 mL) and flushed through a plug of Celite. The filtrate
was washed with H2O (20 mL), brine (20 mL), dried with
magnesium sulfate, filtered, and concentrated at reduced pres-
sure to leave a yellow oil. The oil was purified by column
chromatography on silica gel, eluting with ethyl acetate/hexane.
Accessory Publication
General experimental procedures and spectroscopic data for
selected compounds are available on the Journal’s website.
2-[1-(2-(R)-iso-Butyl-5-trimethylsilanyl-pent-4-ynyl)-1H-
[1,2,3]triazol-4-ylmethyl]-4-(R)-methyl-pentan-1-ol 21
Acknowledgement
Compound 21 was obtained as a colourless oil (334 mg,
73%). Rf ¼ 0.31 (30% ethyl acetate/hexane). [a]2D8 ꢀ21.3 (c 1.96
One of us (O.M.) would like to thank the Australian Government for the
grant of an Australian Postgraduate Award (APA).

Click Chemical Triazolamers
1549
References
[13] S. G. Davies, H. J. Sanganee, Tetrahedron Asymmetry 1995, 6, 671.
doi:10.1016/0957-4166(95)00057-V
[14] S. D. Bull, S. G. Davies, S. Jones, M. E. C. Polywka, R. S. Prasad,
H. J. Sanganee, Synlett 1998, 519. doi:10.1055/S-1998-1700
[15] S. D. Bull, S. G. Davies, S. Jones, H. J. Sanganee, J. Chem. Soc., Perkin
Trans. 1 1999, 387. doi:10.1039/A809715A
[16] S. D. Bull, S. G. Davies, M. Key, R. L. Nicholson, E. D. Savory, Chem.
Commun. 2000, 1721. doi:10.1039/B005419O
[17] S. D. Bull, S. G. Davies, A. C. Garner, D. Kruchinin, M. Key, P. M.
Roberts, E. D. Savory, A. D. Smith, J. E. Thomson, Org. Biomol.
Chem. 2006, 4, 2945. doi:10.1039/B605244D
[18] R. W. Spencer, T. F. Tam, E. Thomas, V. J. Robinson, A. Krantz,
J. Am. Chem. Soc. 1986, 108, 5589. doi:10.1021/JA00278A038
[19] M. Duan, L. A. Paquette, Angew. Chem. Int. Ed. 2001, 40, 3632.
doi:10.1002/1521-3773(20011001)40:19o3632::AID-ANIE36324
3.0.CO;2-5
[1] A. D. Bautista, C. J. Craig, E. A. Harker, A. Schepartz, Curr. Opin.
Chem. Biol. 2007, 11, 685. doi:10.1016/J.CBPA.2007.09.009
[2] G. N. Tew, R. W. Scott, M. L. Klein, W. F. DeGrado, Acc. Chem. Res.
2010, 43, 30. doi:10.1021/AR900036B
[3] M. Okuyama, H. Laman, S. R. Kingsbury, C. Visintin, E. Leo, K. L.
Eward, K. Stoeber, C. Boshoff, G. H. Williams, D. L. Selwood,
Nat. Methods 2007, 4, 153. doi:10.1038/NMETH997
[4] J. D. Sadowsky, J. K. Murray, Y. Tomita, S. H. Gellman,
ChemBioChem 2007, 8, 903. doi:10.1002/CBIC.200600546
[5] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2001,
40, 2004. doi:10.1002/1521-3773(20010601)40:11o2004::AID-
ANIE200443.0.CO;2-5
[6] H. C. Kolb, K. B. Sharpless, Drug Discov. Today 2003, 8, 1128.
doi:10.1016/S1359-6446(03)02933-7
[7] V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem.
[20] C. D. Beard, K. Baum, V. Grakauskas, J. Org. Chem. 1973, 38, 3673.
doi:10.1021/JO00961A003
[21] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004, 6,
2006, 51. doi:10.1002/EJOC.200500483
[8] N. G. Angelo, P. S. Arora, J. Am. Chem. Soc. 2005, 127, 17134.
doi:10.1021/JA056406Z
[9] M. Martinelli, T. Milcent, S. Ongeri, B. Crousse, Beilstein J. Org.
2853. doi:10.1021/OL0493094
[22] K. Fujisawa, Y. Noguchi, Y. Miyashita, K. Okamoto, N. Lehnert,
Inorg. Chem. 2007, 46, 10607. doi:10.1021/IC7011342
[23] C.Aubert,J.P.Begue,Synthesis1985, 759.doi:10.1055/S-1985-31336
[24] R. Ponsinet, G. Chassaing, J. Vaissermann, S. Lavielle, Eur. J. Org.
Chem. 2000, 83. doi:10.1002/(SICI)1099-0690(200001)2000:1o83::
AID-EJOC8343.0.CO;2-2
Chem. 2008, 4, 19. doi:10.3762/BJOC.4.19
[10] A. L. Jochim, S. E. Miller, N. G. Angelo, P. S. Arora, Bioorg. Med.
Chem. Lett. 2009, 19, 6023. doi:10.1016/J.BMCL.2009.09.049
[11] O. D. Montagnat, G. Lessene, A. B. Hughes, Tetrahedron Lett. 2006,
47, 6971. doi:10.1016/J.TETLET.2006.07.131
[12] O. D. Montagnat, G. Lessene, A. B. Hughes, J. Org. Chem. 2010, 75,
390. doi:10.1021/JO9021887